Androgenetic Alopecia From A To Z - Vol. 2 Drugs, Herbs, Nutrition and Supplements

Konstantinos Anastassakis
Androgenetic
Alopecia From A to Z
Vol. 2 Drugs, Herbs, Nutrition and
Supplements
123
Androgenetic Alopecia From A to Z
Androgenetic Alopecia From

A to Z
Vol. 2 Drugs, Herbs, Nutrition
and Supplements
Athens, Attiki, Greece
Original Greek edition published by G. Zevelekakis and Co., Athens, 2014.
ISBN 978-3-031-08056-2 ISBN 978-3-031-08057-9 (eBook)

https://doi.org/10.1007/978-3-031-08057-9
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2014,
2022
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Dedicated to my parents
–Konstantinos Anastassakis
Foreword
I first met Dr. Konstantinos Anastassakis in Chicago, at an ISHRS meeting where hair trans-
plant surgeons from around the globe assembled under one roof. These meetings facilitate the
sharing of innovative techniques and exciting new discoveries. The man before me was a char-
ismatic surgeon with piercing eyes, a generous smile, and an obvious exuberance for life.
Dr. Anastassakis clearly loved what he did. As we spoke, he shared with me his dream, to
create a hair restoration textbook, possibly the first one ever created in Greece. He had planned
to create a three-volume textbook, encompassing the entire scope of hair restoration surgery
from its infancy to the present day and beyond. This was a monumental undertaking, yet he
was clearly driven to write this reference textbook. He has succeeded, and I have been
impressed with the details and the step-by-step process he used to define many of the
processes.
I recommend that newcomers to the field focus on the essentials defined in this book with
particular attention to the sections regarding diagnostics (including scalp diseases), how to
build a personalized master plan for your patients’ hair loss over time, and how to calculate the
recipient-site needs and balance that against the original donor-site capacity. It is vital to learn
how to draw down on the donor area with a critical focus on leaving enough donor supply to
address future hair loss, which your patients will, almost certainly, encounter.
These three volumes comprising “Androgenetic Alopecia From A to Z” are an excellent and
invaluable resource for a hair transplant surgeon. New surgeons entering this specialty will find
the detailed narratives invaluable. This book will allow a new surgeon an easier transition into
this field and provide a valuable reference source that ultimately benefits a new doctor’s
patients.
NHI Medical William R. Rassman

Los Angeles, CA, USA
vii
Foreword
Androgenetic alopecia is a very common skin condition that clearly influences the quality of
life and mental equilibrium of affected patients. A book entirely devoted to the treatment of
this very common disorder is highly needed not only by dermatologists but also by all
doctors. This is a reason to welcome this volume titled Androgenetic Alopecia From A to Z:
Drugs and Medical Treatment of AGA/FPH. The book counts approx. 350,000 words and 61
dedicated chapters including chapters on emergent treatments and alternative, nonmedical
options. I am sure that all readers will learn and enjoy.
Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery Antonella Tosti
University of Miami Miller School of Medicine
Miami, FL, USA
ix
Preface
Androgenetic Alopecia and Female Pattern Hair Loss (AGA/FPHL) account for >98% of hair
loss cases in males and >70% cases in females, making these conditions probably the most
common adult (18–50 years) health disorders besides dental caries!
Surprisingly, AGA/FPHL have been somehow neglected in scientific literature, and no book
approaches these all-too-common conditions “holistically,” comprehensively explaining the
causative and aggravating factors, dangerous comorbidities, and, most importantly, all treat-
ment options, pharmaceutical, surgical, and adjuvant.
This book is purposefully designed as a complete reference tool for understanding, manag-
ing, and efficiently treating AGA/FPHL according to all the latest research and clinical find-
ings. It has been published in three related volumes, each with a specific focus (with intertwined
contents), due to the huge amount of relevant, useful information, and the vast number of fig-
ures, tables, graphs, and clinical photos.
Every aspect of the condition is evaluated, including biology, diagnosis, etiology, and
related disorders (Vol 1), drug treatment, the intricate effects of nutrition, lifestyle, and food
supplements on hair loss (Vol 2), surgical hair restoration, hair care, as well as adjuvant and
upcoming treatment options (Vol 3).
Each subject is addressed according to learning and clinical needs, and the presented infor-
mation is sourced from several thousands of peer-reviewed papers so that readers can rest
assured that they will not have to look anywhere else.
The idea for this book occurred to me out of personal interest (as in most major projects in
life!) when I started losing my own hair due to AGA at an early age. I tried to find answers on
how to save my mane in countless scientific papers and numerous Dermatology/Plastic surgery
textbooks. Soon, I realized that a book dedicated to AGA/FPHL that included all the essential
information I was constantly discovering in multiple sources was painfully missing. Therefore,
out of youthful zeal and with herculean dedication, I decided to review and collect all the rel-
evant and valuable literature findings under one cover. And while this book could be described
as “too specialized,” one should consider that it actually offers answers to more than 90% of
all hair loss cases in humans.
The initial 891-pages-long Greek edition of this book was published in 2015, included an
excess of 7000 citations, and took me more than 8 years of daily hard work, often 16-h work-
days, to complete. Numerous readers approached me and suggested that this work must be
translated into English. Even though I could immediately see the logic in their argument, the
amount of work required was overwhelming, and it took me more than 2 years to finally jump
in the project.
The English edition was extensively updated (more than 9500 citations) and enriched with
thousands of pictures from my clinical practice as a certified Hair Restoration Surgeon. Another
4 painstaking years were required, and priceless sacrifices in every domain of my life, fortu-
nately, most not irreparable.
The goal was to bring together all the valuable, up-to-date information on every possible
AGA/FPHL-related question and offer it to the interested reader for immediate reference and
application.
xi
xii Preface
Collecting all the relevant literature was an extremely laborious task, mainly since many
papers date back to the 1960s and only hard copies were available, most of which were person-
ally traced and photocopied by myself. All the material included in the text was selected based
on professional/scientific responsibility, ethics, transparency, and, above all, considering the
validity of the information provided. Every possible effort has been made to include substanti-
ated, specific, objective, honest, responsible, accurate, balanced, fair, and complete informa-
tion that the reader can rely on.
The full text of every published, peer-reviewed (or not) paper that can be traced in the litera-
ture was individually assessed, and results were evaluated not according to the personal experi-
ence or beliefs of the author but according to the established evidence-based evaluation process.
Misrepresentation, exaggeration, unjustified emphasis, or oversight of information that could
mislead the reader was diligently avoided, focusing on preventing any type of known biases
when reviewing the literature (such as selectively collecting citations that support some previ-
ous idea or belief of the author).
One would argue: why go into so much trouble?
Seen from a strictly medical perspective, AGA/FPHL are mild and biologically benign
dermatological conditions. However, hair and its appearance have always been associated with
youth, virility, strength, and sensuality. Both sexes and affected individuals experience great
psycho-emotional stress due to balding, often leading to a severe reduction of quality of life
and secondary morbidity.
AGA/FPHL progress unpredictably, their etiology remains uncertain, and the therapeutic
options are limited, making it very difficult for patients to accept or adapt.
Accordingly, the “hair loss industry” is worth billions of dollars annually, and a significant
proportion of this money funds a section of the industry that preys on the desperate balding
individual, who hopes to halt hair loss and regrow hair, advertising untested and mostly inef-
fective hair loss treatments.
Most balding patients will be initially “fatally” attracted to the fake promises of Internet
advertisers, irresponsible and inaccurate advice from friends or casual acquaintances, and
charming, yet shameless, charlatans. Unfortunately, most of the patients who suffer from
AGA/FPHL will first fall victims to one or more of the above, and only a few will seek profes-
sional, credible, and responsible diagnosis and direction by the specialist physician.
The overall goal of this three-volume series is to offer the physician a complete “toolbox”
to deal with any question on every possible aspect of AGA/FPHL using evidence-based data
and according to ethical standards. This book offers every plausible scientific “ammunition” to
the physician to treat successfully and safely balding patients, debunk myths and lies concern-
ing hair loss, and keep patients safe, happy, and … hairy.
Hopefully, the professional readers will use this massive amount of fully updated, peer-
reviewed, and relevant information to educate their patients, to keep them sailing in safe,
evidence-based waters, and away from commercially advertised “snake oils,” and even manu-
factured “pay-per-page” popular literature that supports several world-famous hair loss
products.
The material in this book can indeed be a “beacon of knowledge” for physicians and help
them debunk the pseudo-myth of the “incurable” nature of AGA/FPHL that dooms patients to
unnecessary progressive hair loss (and distress).
It can also help physicians keep patients away from the perilous waters of pseudo-scientific
“online discussions” and the catastrophic decisions often made by the desperate balding
patients after getting “self-educated” on hair loss forums and social media.
My ambition is that the physician, and their patients, will realize that with the right strategy
more than 90% of patients with AGA/FPHL can safely maintain their hair for even decades
after being diagnosed with AGA/FPHL.
A final comment on choosing to adopt a distinctly idiosyncratic style: the text contains
expressions that might surprise the reader on several occasions. This more genuine approach
might include imperfections but, in the writer's idea, will make reading the text a livelier
Preface xiii
e xperience, without diminishing its clarity or negatively impacting contents or methodology.

Indeed, one might argue, endeavoring to hide one's inevitable flaws is as pointless as trying to
borrow someone else's more elegant nose in having one's portrait taken. Fortunately, editors
did not object too much to this stylistic choice, and I hope the readers will not, either.
Athens, Greece Konstantinos Anastassakis

Acknowledgments
Words of acknowledgment are far from sufficient to express my gratitude to my parents. This
task would not have been possible without their unabated support, unconditional love, under-
standing, faith, and patience. They have always been there for me through every endeavor, in
ways I cannot even fathom. I aspire to match their strength, ethos, integrity, kindness, caring,
and love for my future family. I hope they are as proud of me as I am of them.
The guidance of my brother, Ioannis Anastassakis, has also been decisive. As an interna-
tional author himself, he inspired me with the proper mindset for this huge work. In his own
words, “If you don’t think big, no one else will do it for you.” Thank you, my brother.
With great respect and thankfulness, I would like to acknowledge my deepest gratitude to
Prof. Christos Zouboulis, Prof. Antonella Tosti, and Dr. William Rassman for sacrificing their
valuable time to review the text of the individual volume they foreworded and for honoring me
with their warm words.
Furthermore, I would like to acknowledge Panagiotis Itsios for his creativity, patience, and
professionalism in designing all the unique figures and charts in this work. His elegant, clear,
and comprehensive illustrations animate the text and aid the reader to apprehend concepts
better.
The names of the dozens of contributors who supported me in numerous ways during the
creation of the earlier (2014) single-volume version of this book are extensively addressed in
the relevant section of that book.
I would like to express my sincere thanks and deep appreciation to my editor, Juliette Ruth
Kleemann, for her patience, assistance, support, and guidance to make this project a reality.
She generously offered me her valuable time and know-how on every occasion, and she went
above and beyond to make my “dream project” an actual book. Any author benefiting from her
work is fortunate beyond belief.
Finally, I would like to recognize all my hair loss patients over the years, especially the dif-
ficult ones, who have challenged me and herewith taught me the most about hair loss and its
successful management than any academic authority. All this work is for you, actually! I hope
it will make a difference in your life.
xv
Contents
Part V Drugs
23 Minoxidil�� 11
23.1 Initial Studies and FDA Approval�� 12
23.2 Mechanism of Action�� 12
23.3 Minoxidil Effects and Clinical Results �� 14
23.4 Minoxidil Topical Solution and Early Research �� 15
23.5 Minoxidil and FPHL �� 17
23.6 Ideal Candidates for Minoxidil �� 18
23.6.1 Is Minoxidil Effective Only on the Vertex?�� 18
23.7 Efficacy of Minoxidil�� 19
23.7.1 How Soon Will Minoxidil Grow Hair?�� 20
23.7.2 Minoxidil Discontinuation and Effects�� 21
23.8 How to Use MTS/MTF Properly�� 22
23.9 Adverse Effects �� 23
23.9.1 Systemic Adverse Effects�� 23
23.9.2 Local Adverse Effects �� 25
23.9.3 Ectopic Hypertrichosis�� 26
23.10 Minoxidil and Daily Practice�� 27
23.11 Minoxidil Topical Foam�� 27
23.12 Novel Minoxidil Formulations�� 29
23.13 Oral Minoxidil�� 29
23.14 A Final Note by the Author�� 32
References�� 34
24 Finasteride�� 41
24.1 Finasteride in BPH�� 42
24.2 Finasteride in AGA �� 42
24.3 Mechanism of Action of Finasteride�� 43
24.3.1 Does Finasteride Act in Any Other Way? �� 43
24.4 Clinical Studies on Finasteride �� 44
24.5 Clinical Efficacy of Finasteride 1 mg �� 47
24.6 Metabolism of Finasteride�� 50
24.7 Adverse Effects of Finasteride�� 51
24.7.1 Finasteride 5 mg and Sexual Adverse Experiences (SAEs)�� 51
24.7.2 Finasteride 1 mg and SAEs�� 52
24.7.3 The Nocebo Effect!�� 54
24.7.4 Are SAEs Reversible?�� 54
24.7.5 Post-Finasteride Syndrome (PFS)�� 55
24.7.6 Can Persistent SAEs Be Explained? �� 56
24.7.7 Finasteride Effects on Fertility�� 56
24.7.8 Finasteride Effects on PSA �� 57
xvii
xviii Contents
24.7.9 Finasteride and Prostate Cancer (PCa) �� 58

24.7.10 Finasteride, Gynecomastia and Breast Cancer�� 59
24.7.11 Finasteride, Depression and CNS Effects �� 60
24.8 Topical Use of Finasteride�� 62
24.9 Finasteride Vs. Minoxidil�� 64
24.10 How to Best Combine Finasteride and MTS�� 65
24.11 Finasteride and FPHL �� 65
24.12 Final Notes�� 68
References�� 70
25 Dutasteride�� 77
25.1 Mechanism of Action and Pharmacodynamics�� 77
25.2 Pharmacokinetics of Dutasteride�� 78
25.3 Dutasteride in BPH �� 78
25.4 Dutasteride and ΑGΑ�� 79
25.5 Dutasteride and FPHL�� 83
25.5.1 Dutasteride and Prostate Cancer (PCa)�� 84
25.5.2 Dutasteride, Gynecomastia and Breast Cancer�� 85
25.5.3 Dutasteride and Sexual Adverse Experiences (SAEs)�� 85
25.5.4 Dutasteride and Fertility �� 87
25.5.5 Dutasteride, Depression and CNS Effects�� 87
25.6 Topical Use of Dutasteride�� 87
25.6.1 Intralesional Dutasteride and Mesotherapy�� 88
25.7 Dutasteride + Finasteride, Dutasteride + Minoxidil �� 90
25.8 Concerns Over the Use of Dutasteride in AGA�� 90
25.9 Conclusion�� 91
References�� 92
26 Spironolactone�� 97
26.2 Spironolactone as an Antiandrogen�� 98
26.3 Spironolactone and FPHL�� 98
26.4 Topical Spironolactone �� 99
References�� 101
27 Cimetidine�� 105
27.2 Use of Cimetidine �� 105
27.3 Cimetidine and ΑGΑ/FPHL �� 106
28 Cyclosporin�� 109
28.1 Mechanism of Action on the Hair Follicle�� 109
28.2 Cyclosporin A in Alopecia Areata�� 110
28.3 Cyclosporin A in AGA/FPHL �� 111
29 Cyproterone Acetate (CPA)�� 115
29.2 Uses of CPA�� 116
29.3 CPA and FPHL�� 116
29.4 Topical CPA Solution�� 118
Contents xix

29.6 CPA in Men�� 119
30 Topical Corticosteroids�� 121
30.1 The Chemical Structure of Corticosteroids�� 121
30.2 Topical Corticosteroids (TCs)�� 122
30.3 Actions of Corticosteroids�� 122
30.4 Adverse Effects of TCs �� 123
30.5 Systemic Adverse Effects of TCs�� 123
30.6 Topical Adverse Effects of TCs�� 124
30.7 TCs and Alopecia Areata�� 125
30.8 TCs and AGA/FPHL�� 126
31 Ketoconazole�� 133
31.1 Pharmacology of Ketoconazole�� 133
31.2 Oral Ketoconazole�� 134
31.3 Ketoconazole Shampoo�� 134
31.4 Ketoconazole and ΑGΑ/FPHL �� 135
31.5 How to Use the Ketoconazole Shampoo�� 137
32 Retinoic Acid�� 141
32.1 Mechanism of Action of Retinoids and ATRA �� 141
32.2 ATRA and the Hair Follicle�� 142
32.3 ATRA and AGA/FPHL �� 144
32.3.1 Use of ATRA in AGA/FPHL�� 145
32.5 Combining ATRA and Minoxidil�� 145
32.6 New Pharmaceutical Formulations of ATRA and Newer Retinoids�� 146
33 Azelaic Acid�� 151
33.2 Azelaic Acid and AGA/FPHL�� 152
34 Bimatoprost�� 155
34.2 Bimatoprost and Hair Follicles �� 155
34.3 Bimatoprost Mechanism of Action on Hair Follicles �� 156
34.4 Effect of Bimatoprost in Healthy Eyelashes �� 157
34.5 Bimatoprost Vs. Latanoprost�� 157
34.6 Bimatoprost and AGA/FPHL�� 157
35 Latanoprost�� 161
35.1 Latanoprost and Hair Follicles�� 161
35.1.1 Latanoprost Mechanism of Action on Hair Follicles�� 162
35.2 Effects of Latanoprost in Eyelashes�� 163
35.2.1 Latanoprost and Healthy Eyelashes�� 163
35.2.2 Latanoprost and Eyelash Alopecia�� 163
xx Contents
35.3 Effects of Latanoprost on The Scalp�� 163

36 Estrogens�� 167
36.1 Mechanism of Action of Estrogens�� 167
36.2 Estrogens and Hair Follicles in Lab Animals �� 168
36.3 Estrogens and Hair Follicles in Humans�� 169
36.4 Estrogens, AGA and FPHL�� 170
36.4.1 Oral Estrogens�� 170
36.4.2 Topical Estrogens�� 171
37 Progestins�� 179
37.1 Categories of Progestins �� 179
37.3 Actions in the Skin and Hair Follicles�� 181
37.4 Topical Progestin Solutions�� 182
37.5 Progestins and AGA/FPHL�� 182
38 Hormonal Contraceptives �� 187
38.1 General Hormonal Effects of OCs�� 188
38.2 Hormonal Effects of OCs in Hair Follicles�� 188
38.3 Clinical Image�� 189
38.4 How to Avoid OCs-Mediated Hair Loss? �� 190
38.5 COCs as a Treatment for FPHL�� 190
39 Flutamide�� 193
39.2 Flutamide and Hair Follicles�� 194
39.3 Topical Use of Flutamide�� 195
40 Recently
Reported Hair Growth Drugs �� 199
40.1 Adenosine �� 199
40.2 Cetirizine�� 200
40.3 Roxithromycin�� 200
40.4 Botulinum Toxin �� 201
40.5 Crescina�� 202
41 Caffeine �� 205
41.1 Caffeine in Dermatology�� 205
41.2 Caffeine and the Hair Follicles �� 206
41.3 Caffeine and AGA/FPHL�� 207
41.4 Conclusion�� 209
42 Cysteine and Cystine�� 211
42.1 Sources of Cysteine�� 212
42.2 Cystine/Cysteine Dietary Supplements�� 212
42.3 Cystine and the Hair Follicle�� 213
Contents xxi
43 Free Fatty Acids �� 219

43.1 Free Fatty Acids (FFAs)�� 219
43.2 FFAs, Hair Follicles, AGA and FPHL�� 221
44 Copper Tripeptides�� 225
44.1 Mechanism of Action and Properties of GHK-Cu�� 225
44.2 GHK-Cu and Hair Follicles�� 227
44.3 Clinical Studies �� 227
44.4 GHK-Cu and in Hair Restoration Surgery�� 228
45 Melatonin�� 231
45.1 The Effects of Melatonin in the Hair Follicles of Animals�� 232
45.2 The Effects of Melatonin in Human Hair Follicles�� 232
46 Marine Extract Compounds �� 239
46.1 Nourkrin®�� 239
46.2 Hairgain® �� 241
46.3 Viviscal®�� 241
46.3.1 Viviscal® in the Twenty-First Century�� 243
47 The Helsinki Formula®: Polysorbate 60 and Polysorbate 80 �� 247
47.1 Polysorbate 60 and Hair Follicles �� 248
47.2 Polysorbate 60 and the Hair Growth Craze�� 248
47.3 Was Polysorbate 60 Effective Against Hair Loss?�� 249
47.4 What Happened with Polysorbate 60 Products?�� 250
Part VI Nutrition, Lifestyle Factors and AGA/FPHL
48 Diet, Lifestyle, and AGA/FPHL�� 255

48.1 Are Systemic Androgens Increased in AGA/FPHL?�� 255
48.2 Adrenal Hormones and Androgens�� 256
48.2.1 What Can Cause Chronically Increased Cortisol Secretion
in Otherwise Healthy Adults? �� 256
48.2.2 Other Factors that Increase Androgens in the Serum�� 257
48.2.3 High-Fat Diets and Androgens�� 257
48.2.4 Deprivation (Crash) Diets and Androgens�� 258
48.2.5 Alcohol Abuse and Androgens�� 259
48.2.6 Smoking�� 260
48.3 Tips That Could Reduce Further Hair Loss in AGA/FPHL�� 262
Part VII Dietary Supplements and Androgenetic Alopecia
49
The Inconvenient Truth About Food Supplements (or “Hope in a Capsule”) �� 281
49.1 Why Are These Products So Popular?�� 282
49.2 Regulatory Issues�� 284
49.3 Who Is Using Food Supplements?�� 285
49.4 Who Really Needs Food Supplements?�� 286
49.5 Group …Therapy�� 287
xxii Contents
49.6 Can Food Supplements Be Dangerous?�� 288

49.7 Supplements That Can Eventually Kill�� 289
49.8 Questions Nobody Seems to Ask�� 290
50 Vitamins: Definition and Types�� 295
50.1 Vitamins in General�� 295
51 Vit A�� 297
51.1 Actions of Vit A�� 297
51.2 Vit A and the Hair Follicle�� 298
51.3 Food Sources�� 298
51.4 Dietary Recommendations�� 298
51.5 Deficiency- Excess of Vit A�� 298
51.6 Topical Use of Vit A�� 300
52 Vit Β3 (Niacin)�� 303
52.1 Actions of Vit B3�� 303
52.2 Vit B3 and the Hair Follicle�� 304
52.5 Deficiency- Excess of Vit B3�� 305
53 Vit B5 (Pantothenic Acid)�� 309
53.5 Deficiency- Excess of Vit B5�� 311
54 Vit B6 (Pyridoxine)�� 315
54.3.1 Dietary Recommendations�� 316
54.3.2 Deficiency- Excess of Vit B6�� 317
55 Vit
B7 (Vit H, Biotin, Coenzyme R)�� 321
55.1 Actions of Biotin�� 321
55.2 Biotin and the Hair Follicle�� 322
55.5 Deficiency- Excess of Biotin�� 324
56 Vit C (L-Ascorbic Acid)�� 329
56.1 Actions of Vit C�� 329
56.4 Vit C Deficiency�� 331
56.5 Vit C Excess�� 331
Contents xxiii
56.6 Vit C and Hair Follicles In Vitro �� 332

56.7 Topical Action of Vit C �� 333
57 Vit E (α-Tocopherol)�� 337
57.1 Actions of Vit Ε�� 337
57.2 Topical Action of Vit E�� 338
57.3 Vit E and the Hair Follicle�� 338
57.6 Deficiency- Excess of Vit E�� 340
58 Inositol (Vitamin B8) �� 343
58.1 Actions of Inositol�� 343
58.2 Inositol and the Hair Follicle�� 344
58.5 Deficiency- Excess of Inositol�� 344
59 Minerals, Trace Elements, and Hair Follicles�� 347
60 Calcium (Ca+2)�� 349
60.1 Actions of Ca+2�� 349
60.2 Ca+2 and the Hair Follicle�� 349
60.5 Deficiency- Excess of Ca+2�� 350
60.5.1 Hypocalcemia �� 350
60.5.2 Hypercalcemia�� 351
61 Boron (B)�� 353
61.1 Actions of Boron�� 353
61.2 Boron and the Hair Follicle�� 354
61.5 Deficiency- Excess of Boron�� 355
62 Sulfur (S)�� 357
62.1 Actions of Sulfur�� 357
62.2 Sulfur, the Skin, and the Hair Follicle�� 358
62.5 Deficiency- Excess of Sulfur�� 359
63 Iodine (I) �� 363
63.1 Actions of Iodine�� 363
63.2 Thyroid Hormones and the Hair Follicle�� 364
63.5 Deficiency- Excess of Iodine�� 364
xxiv Contents
64 Magnesium (Mg+2)�� 367

64.1 Actions of Magnesium�� 367
64.2 Mg+2 and the Hair Follicle�� 367
64.5 Deficiency- Excess of Magnesium�� 368
65 Silicon (Si) �� 373
65.1 Actions of Silicon �� 373
65.2 Silicon, the Skin and the Hair Follicle�� 374
65.5 Deficiency- Excess of Silicon �� 375
66 Selenium (Se)�� 379
66.1 Actions of Selenium�� 379
66.2 Selenium and the Hair Follicle �� 380
66.5 Deficiency- Excess of Selenium �� 382
67 Iron (Fe+2)�� 385
67.1 Actions of Iron�� 385
67.2 Iron Distribution�� 386
67.3 Iron Deficiency (ID)�� 386
67.4 How Can Iron Deficiency Affect Hair Follicles?�� 387
67.5 Iron and Hair loss in General�� 387
67.6 Association Between Iron Deficiency, Ferritin and Hair Loss�� 389
67.7 Iron and AGA/FPHL�� 389
67.8 Topical Iron �� 391
67.11 Deficiency- Excess of Iron�� 392
67.12 Future Challenges �� 394
67.13 Conclusions So Far �� 395
67.14 Author’s Notes�� 395
68 Copper (Cu)�� 399
68.1 Actions of Copper �� 399
68.2 Copper and the Hair Follicle�� 400
68.5 Deficiency- Excess of Copper�� 402
69 Zinc (Zn) �� 405
69.1 Actions of Zinc �� 405
69.2 Zinc and the Hair Follicle �� 406
69.3 Zinc and Alopecias�� 408
69.4 Zinc and AGA/FPHL�� 409
69.4.1 Topical Use of Zinc�� 410
Contents xxv

69.7 Deficiency- Excess of Zinc �� 411
70
“Alternative Medicine”, Herbs, and Hair Loss �� 417
70.1 Herbals and Botanicals in General�� 417
70.2 Medicine and “Alternative Medicine”�� 418
70.3 Medicine and Herbal …“Medicine” �� 419
70.4 Why Do Patients Prefer Herbs Over Drugs?�� 419
70.5 Just How Effective Are Herbs Actually?�� 420
70.6 Challenges in Studying the Efficacy of Herbs�� 420
70.7 Are Herbal Supplements Actually Safe?�� 420
70.8 The Legal Status of Herbals and Botanicals �� 421
70.9 Standardization of Herbs�� 422
70.10 Why is Herbal Standardization Impossible?�� 422
70.11 Herbs and Benign Prostate Hypertrophy (BPH)�� 423
70.12 Herbs for BPH = Herbs for AGA?�� 423
70.13 Herbal Products and ΑGΑ/FPHL �� 424
70.14 “Instructions for Use” of the Following Chapters�� 424
70.15 Final Note�� 425
71
Saw Palmetto (Serenoa repens Sabal serrulatum)�� 429
71.1 Saw Palmetto Mechanism of Action�� 429
71.2 Saw Palmetto and Lower Urinary Tract Symptoms�� 430
71.3 The Saw Palmetto Controversy�� 431
71.4 Saw Palmetto and ΑGΑ�� 432
71.4.1 Is SPE a True 5α-R Inhibitor?�� 432
71.4.2 Can Saw Palmetto Be Useful in AGA/FPHL?�� 434
71.5 Dosage- Adverse Effects—Safety�� 436
72 Pygeum Africanum (Prunus Africana)�� 441
72.1 Pygeum Africanum’s Mechanism of Action �� 441
72.2 Pygeum Africanum, BPH, and Prostate Cancer�� 442
72.3 Pygeum Africanum and AGA �� 442
73 Proanthocyanidins �� 445
73.1 Proanthocyanidins and the Hair Follicle.�� 445
73.2 Mechanism of Action of Proanthocyanidins on the Hair Follicle�� 446
73.3 Proanthocyanidins and AGA�� 446
74 Green Tea (Camellia sinensis) �� 451
74.1 General Properties of Green Tea�� 451
74.2 Green Tea and the Skin �� 452
74.3 Green Tea as an Antiandrogen�� 452
74.4 Green Tea and the Hair Follicle�� 453
xxvi Contents
75 Ginkgo Biloba (Maidenhair Tree)�� 459

75.1 General Properties of Ginkgo Biloba�� 459
75.2 Ginkgo Biloba, Scientific Research and Applications�� 460
75.3 Ginkgo Biloba, the Skin, and the Hair Follicle�� 460
76 Allium
Cepa (Red Onion)�� 465
76.1 General Properties of Allium Cepa �� 465
76.2 Allium Cepa, Hair Follicles and AGA/ FPHL�� 466
77 Sophora Flavescens�� 471
77.1 General Properties of Sophora Flavescens�� 471
77.2 Sophora Flavescens and ΑGΑ�� 472
78 Oryza
Sativa Bran (Rice Bran)�� 475
78.1 General Properties of Oryza Sativa Bran�� 475
78.2 Oryza Sativa Bran and Hair Follicles�� 476
78.3 Oryza Sativa Bran and AGA �� 476
79 Polygonum Multiflorum (Ho-Shou-Wu)�� 479
79.1 General Properties of Polygonum Multiflorum�� 479
79.2 Polygonum Multiflorum and the Hair Follicle�� 479
80 Panax
Ginseng (Korean or Asian Ginseng) �� 485
80.1 General Properties of Ginseng�� 486
80.2 Ginseng and the Hair Follicle �� 486
80.2.1 PG Effects In Vitro and Ex Vivo �� 486
80.2.2 PG Effects in Clinical Trials �� 489
81 Rosemary (Rosmarinus Officinalis) �� 495
81.1 General Properties of Rosmarinus Officinalis�� 495
81.2 The Action of Rosmarinus Officinalis on the Hair Follicle�� 496
81.3 Rosmarinus Officinalis and AGA/FPHL�� 496
82 Capsicum (Red Pepper)�� 501
82.1 General Properties of Capsaicin�� 502
82.2 Mechanism of Action of Capsaicin�� 502
82.3 Action of Capsaicin on the Hair Follicle�� 502
83 A
Few More and Recently Reported Herbs�� 507
83.1 Acanthopanax Koreanum�� 507
83.2 Asiasari Radix (Asiasarum Root) �� 507
Contents xxvii
83.3 Chaemacyparis Obtuse (Japanese Cypress, Hinoki)�� 508

83.4 Citrullus Colocynthis (Bitter Cucumber) (9-�� 508
83.5 Curcuma Aeruginosa�� 508
83.6 Cuscuta Reflexa�� 509
83.7 Ecklonia Cava �� 510
83.8 Eclipta Alba (False Daisy)�� 511
83.9 Erica Multiflora�� 511
83.10 Equisetum Arvense (Horsetail) �� 512
83.11 Hibiscus Rosa-Sinensis (China Rose)�� 512
83.12 Illicium Anisatum (Japanese Star Anise)�� 512
83.13 Lygodii Spora�� 512
83.14 Piper Nigrum (Black Pepper)�� 513
83.15 Puerariae Flos�� 513
83.16 Salvia Officinalis (Sage) �� 513
83.17 Sanguisorba Officinalis�� 513
83.18 Schisandra Nigra�� 514
83.19 T-Flavanone�� 514
83.20 Tectona Grandis (Teak Tree)�� 515
83.21 Trigonella Foenum-Graecum (Fenugreek) �� 515
83.22 Urtica Dioica (Stinging Nettle)�� 516
83.23 Zizyphus Jujube (Chinese Date) �� 516
Index�� 521
Part V
Drugs
Androgenetic alopecia (AGA) and Female Pattern Hair Loss (FPHL) extend beyond the mere
physical aspects of hair loss or growth and are strongly associated with negative psychosocial
effects. Few dermatologic problems carry as much emotional overtones as the complaint of
hair loss.
Not surprisingly, patients with AGA/FPHL frequently embark on a motivated search for
ways to halt, reverse, or conceal their condition in an attempt to restore a sense of personal and
physical acceptability [1]. During their search for a “cure,” patients will encounter a plethora
of products claiming they can help them grow their hair back. These include local to oral treat-
ments and range from pharmaceuticals, cosmeceuticals, cosmetics, “natural” products, dietary
supplements, herbs, Laser, “do-it-yourself” lotions, and microneedling. Overall, the “hair loss
industry” is a multi-billion-dollar business [2], and a significant part of revenues is “re-
invested” in promoting mostly ineffective hair-growth treatments, targeting at the despair and
panic of those who see their hair falling [3].
A Patient’s “Odyssey”
Patients with hair loss typically do not start their search wisely -by consulting an expert physi-
cian-, but by searching in all the “wrong” places. The patient is first attracted by claims and
promises in ads, TV commercials, late-night telemarketing, online shops, social media and
Internet rumors, even folk advice from friends and relatives [3].
Some investigators have speculated that especially men fail to seek professional hair-loss
advice and treatment for various reasons. Reluctance to consult a physician or to be seen as
vain, or to acknowledge that their hair loss bothers them, or being skeptical about the efficacy
of available treatments, are a few [1, 4]. This is consistent with men’s general avoidance of
health-related, help-seeking behavior [5, 6] due to perceived fear, vulnerability, and denial.
Other reasons are personal barriers related to traditional masculine role characteristics such as
a sense of immunity and immortality, difficulty relinquishing control, a belief that seeking help
reflects weakness, and the notion that men are not prevention-oriented [1, 5]. Things are not
much different for women with hair loss, who typically suffer from low self-esteem and poor
body image. It is not uncommon for these women to try different shampoos, supplements, and
treatments promising hair regrowth -albeit in vain- before seeking a hair specialist. This could
explain the reported average gap of 4 years between the onset of hair loss and the first consulta-
tion visit to a hair clinic [7].
So, until the moment most hair loss patients enter the door of a physician, they have already
fallen victims to their own despair to save their hair by taking advice from seemingly “honest,”
“expert” sources, such as hairdressers, friends, and the Internet [8]. Most have experimented
with cosmetic or cosmeceutical treatments, which were costly and totally ineffective, often
resulting in a cynical and distrustful attitude towards any future treatment [9].
2 Drugs
Some patients have tried over-the-counter FDA-approved treatments in the past. Studies
have shown that before attending a tertiary clinic or expert, approx. 40% of patients have
already used Minoxidil Topical Solution or Foam (MTS, MTF), 20% have used oral Finasteride
1 mg, and 5–10% have used a combination of both [10]. However, most have not used these
treatments correctly or consistently and therefore had diminished treatment results.
There is also a large percentage of patients with AGA/FPHL who are utterly unaware of the
proven efficacy of FDA-approved treatments. Others have never tried any type of treatment,
either because they have heard (or have read online) stories of “ineffectiveness” from other
patients, or because they hope that Hair Restoration Surgery will fully restore their “teenage
hair” [7] so, there is no point in taking drugs. In the “hair loss field,” misinformation is the rule.
This is where the physician must come in rescue!
What Hair Loss Patients Expect from a Physician
Several factors will motivate patients with hair loss to consult a physician, the most important
of which is their body-image distress and concern that their hair loss would worsen. Other fac-
tors include dissatisfaction with the results of non-prescription products and a desire to benefit
from a doctor’s expertise and products only available through physicians [1].
What do men with AGA want as a treatment outcome? According to Cash, on a 5-point
disagree/agree scale, 84% of respondents agreed that prevention of additional hair loss was
important to them, and 81% agreed that while they would like to re-grow their hair they would
be happy to prevent further loss. Approximately 78% reported that they were likely, very likely,
or extremely likely to consider a treatment that stops their hair loss. Finally, 71% expected that
a physician-prescribed treatment would surpass other treatments ineffectiveness [1].
It was also revealed that a failure of physicians to meet the expectations of a patient trans-
lated into patient dissatisfaction (25%). This was particularly related to:
• a lack of a specific treatment recommendation (66%),

• having unanswered questions (54%),
• a perception that the practitioner appeared uninterested in discussing their hair loss,
• a feeling that they had not conveyed to the doctor how much their hair loss bothered them
(52%),
• getting a recommendation for a treatment that they had already tried or could have obtained
on their own (44%) [1].
Thus, as recommended for any successful office visit, practitioners should ensure that patients’
key expectations and concerns about AGA/FPHL have been directly and adequately addressed
in a clear, open, and non-judgmental manner. This can be achieved by increasing physicians’
awareness of possible emotional, psychological, and logistical barriers that patients may need
to overcome or suppress to initiate a hair-loss discussion [11]. The results from the survey by
Cash suggest that patients’ satisfaction improve by outlining the expected time frame of treat-
ment benefits, prescribing patients’ requested brand of treatment, reviewing the costs of vari-
ous treatments, and emphasizing the treatable nature of AGA/FPHL and the consequences of
doing nothing. Moreover, physicians should reinforce realistic outcome expectations that
regard stabilization of hair loss as a valued goal [1].
Classification of Hair-Growth Medications
Until the serendipitous discovery of Minoxidil’s hair growth potential in the late 1970s, treat-
ment options for hair loss did not technically differ from those literary available during the
Stone Age. Hair loss sufferers had to use unsubstantiated mixtures -often disgusting- and
“snake-oils” with no evidence of efficacy, other than the “faith” of the seller or “inventor” [12].
Medical Treatments and Online Advice 3
Minoxidil surprisingly grew hair on patients treated for high blood pressure and MTS, and
later MTF soon became a boon for millions of patients AGA/FPHL. Similar to Minoxidil, it
was discovered by accident that Finasteride could grow hair on the bald scalp in men treated
for an enlarged prostate. Ever since, both compounds have been studied in multiple, extensive
randomized clinical studies and have been approved by the FDA (Food and Drug Administration)
for AGA treatment in men, while only MTS/MTF has been approved for the treatment of
FPHL in women.
Of course, there are other compounds that possess hair growth potential. However, Minoxidil
and Finasteride are the only FDA-approved ones with this specific indication, which is quite
reassuring concerning a positive efficacy/side effects ratio and long-term safety. Interestingly,
both are considered “lifestyle drugs,” since they do not reduce morbidity or mortality.
Pharmaceutical substances that have a hair growth potential and will be reviewed in the fol-
lowing chapters can be divided into the following categories:
1. FDA-approved compounds with specific indication against ΑGΑ/FPHL (on-label):

Minoxidil, Finasteride.
2. Pharmaceutical compounds under clinical investigation for FDA-approval with specific
indication against ΑGΑ/FPHL (off-label at the moment): Dutasteride, Bimatoprost.
3. Pharmaceutical compounds that happen to possess hair growth potential (will remain off-
label), such as cyclosporine, spironolactone, etc.
4. Non-pharmaceuticals compounds with reported hair growth potential.
What to Expect from Medical Treatment?
Both the number and distribution of hair follicles are embryologically determined and remain
constant throughout life [13] Although there is no way to increase the number of hair follicles
in post-fetal life, changes in the hair follicle cycle caused either naturally or following a medical
intervention can significantly impact the number and quality of hair present on the scalp [14].
For a treatment to be considered effective in treating AGA/FPHL, it should be able to
reverse the effects of AGA/FPHL on affected hair follicles. More specifically, it should be able
to achieve one or more of the following:
1. Delay the onset of catagen,

2. Stimulate the transition from telogen to anagen (initiation of anagen),
3. Prolong anagen,
4. Reverse miniaturization.
In the following chapters, all compounds that achieve any of these and whether they are safe to
be used in the treatment of AGA/FPHL, will be presented. But before that, it is crucial to
understand the “hair loss landscape” the hair loss patient is facing when searching for medical
treatment. This will help physicians understand why it is often impossible to “talk some sense”
to desperate hair loss patients, mostly young men.
Medical Treatments and Online Advice
Until the 1990s, a man losing his hair would ask for advice from his barber, pharmacist, friends,
or relatives, and very few would start their search by paying a visit to a specialist [15].
Nowadays, hair loss patients will begin by seeking information online, and only after will they
try to confirm in one of the previous sources.
The Internet is easily accessible, free, anonymous, and “rich” in information, nevertheless
often low-quality information, since very few sites contain credible health material. Concerning
hair loss issues, there are numerous Internet Forums dedicated to hair loss. These forums are
supposedly supportive communities that educate and help people with hair loss. Unfortunately,
4 Drugs
these online communities have a dark face as well. In these Forums, one can find the so-called
“expert patients,” the most influential and dangerous “species” of this “habitat.”
The “Hair Loss Forum Habitat”
An Internet forum, or message board, is an online discussion site/tool where people can hold
conversations in the form of posted messages on one or more subjects. Registered members or
just visitors with common interests can start up discussions, express and exchange views, ideas
and share information for various issues acting as an online community. However, despite
efforts from administrators and moderators, “Hair Loss Forums” are often sources of misinfor-
mation, deception, conspiracy theories, and extreme aggression.
• People with no scientific background will cite, comment, or even “judge,” published scien-
tific papers, suggest treatments and combinations of compounds to other members. Most
often, they will “review,” endorse, or “flame” medical doctors or hair restoration surgeons.
• In these forums, strong oral or topical anti-androgens are presented as effective hair growth
treatments, a choice that no medical doctor would make for a hair loss patient. In these low-
quality information sources, the “negative” aspects of approved and effective treatments are
highlighted. At the same time, pseudo-scientific advantages of “natural,” alternative, and
“do-it-yourself” treatments are strongly promoted, accompanied by personal success sto-
ries, many of which can be fake.
• Forum members with a large number of posts, hence “high status” (but still with no scien-
tific background), take up the role of an “expert,” who “initiate” new members to “the best
treatments” and/or “the best surgeons.”
• Occasionally, “experienced” members suggest to new members to try “a new treatment”
(potentially harmful), claiming (deceptively) that they are using it themselves. In other
instances, they will manipulate desperate new members, who think they have found an oasis
of knowledge and support, into becoming a “test subject” for a new “miraculous formula-
tion,” which is on experimental stage and the production company (with unknown address)
is recruiting volunteers online.
• Several lawsuits have been brought against the forums and moderators claiming libel and
damage. For the most part, though, forum owners and moderators in the United States are
protected by Section 230 of the Communications Decency Act, which states that “[no] pro-
vider or user of an interactive computer service shall be treated as the publisher or speaker
of any information provided by another information content provider.”
It is the duty of the physician to guide patients towards effective and safe, “on-label,”
FDA approved treatments and keep them away from “pseudo-miraculous,” “promising”
treatments that will waste their money and time and increase their disappointment.
Moreover, the physician should help patients realize the requirements and limitations of
each proposed treatment, help them decide based on their expectations, wishes and pref-
erences but also based on their lifestyle and affordability.
Hair loss patients visiting doctors are often members of these Forums, and their heads are filled
with useless, harmful, and misleading information on their condition. They know dozens of sub-
stances with hair growth potential and often test the doctor’s knowledge (and patience) with
myriads of questions. Unfortunately, necessary parameters concerning “online do-it-yourself”
treatments, such as eligibility, interactions with other compounds, frequency and severity of side
effects, long-term safety, whether the damage is reversible or not, as well as efficacy and oppor-
tunity cost (compared to using and FDA-approved compound during the same period of time) are
entirely neglected by these patients.
The physician will face questions regarding the efficacy of all sorts of products that claim
hair recovery, from drugs to cosmetics. Thus, the physician must have fully updated informa-
Basic Principles of Pharmaceutical Treatment in AGA/FPHL 5
tion to know their properties, hair growth potential, as well as their side-effects and possible
interactions. The doctor should remember that providing information and solutions are essen-
tial strategies that improve a patient’s psychology, help him/her trust the doctor, come to terms
with his/her condition and increase compliance with treatment [1].
In the following chapters, all molecules that have been reported to have a hair growth poten-
tial will be discussed in detail so that the physician will have all the necessary information in
order to make an evidence-based decision on the treatment he/she will suggest.
Basic Principles of Pharmaceutical Treatment in AGA/FPHL
Before proceeding on to the dedicated chapters for each pharmaceutical compound that has
been reported as useful in treating AGA/FPHL, the following points should be stressed:
• It is important to manage AGA/FPHL strategically with the variety of current therapeutic

options.
• Left untreated, AGA/FPHL are progressive conditions, and the rate of progression is indi-
vidualized. It is undeniable that the earlier an effective treatment is started, the better are the
odds for the patient to have a fuller look for more years.
• The doctor should not wait until thinning has become visible to the naked eye to prescribe
a hair growth treatment. The human eye cannot detect the loss in total hair mass (due to
thinning, shedding, or both), unless >50% hair mass is lost [16]. The correct use of diagnos-
tic tools allows early diagnosis, before thinning becomes macroscopically visible and
before it is “too late.”
• There is no cure for AGA/FPHL. Any compound used is an ongoing treatment, and patients
will enjoy potential benefits for as long as they continue using it. The physician must make sure
that the patient understands this prerequisite but without making him/her feeling “trapped.”
• Patients should constantly and continuously take medication to maintain hair density and must
understand the limitations of pharmacologic interventions. The main purpose is to prevent
further progression of hair loss, although in some patients regrowth of hair can be achieved.
Usually, hair density does not completely return to the level before hair loss began [17].
• The response to treatment is individualized. Some patients respond well, others poorly or
not at all. Even for FDA-approved treatments, one cannot predict response and efficacy.
Compliance with treatment for at least 6 months will answer these questions.
• Even while on treatment, hair loss will often progress, but at a much slower rate compared
to being left untreated, since genetic predisposition will prevail over any medical interven-
tion in the long-run.
• Doctors should avoid prescribing “off-label” compounds as the first-choice treatment for
AGA/FPHL. This strategy has both ethical and medico-legal liabilities.
• Published articles often report hair growth numbers, but the cosmetic value of this hair is what
matters. Vellus hair growth is cosmetically insignificant, and this is what most off-label com-
pounds will grow on the scalp. Additionally, in vitro or even in vivo hair growth in lab animals,
as reported in the literature, does not always translate in patients actually growing hair.
• The benefit/side effects ratio should always be the first criterion of a hair growth treatment.
There are pharmaceutical substances that can grow hair, but their side-effects and the long-
term consequences of their use are so severe that no sane physician will prescribe (e.g.,
cyclosporin).
• The concept of “opportunity cost” is essential when treating AGA/FPHL. Before prescrib-
ing any treatment, one should first compare the expected results with the ones the patient
would have while using an FDA-approved treatment for the same period. Even a placebo
lotion can grow some hair. The correct question to ask is how much hair the patient would
have grown has he/she used an FDA-approved treatment [18].
• Losing time with a non-optimal treatment for 12 or more months will come with a price
even if the patient is later switched to an FDA-approved treatment. It has been shown that
follicles that miniaturize beyond a certain point will never recover [19].
6 Drugs
• Compliance with treatment is reversely proportional to the dosing regimen and practicality
of use. Patients soon get tired of b.i.d. (bis in die, 2 times/day.) or t.i.d. (ter in die, 3 times/
day.) dosing regimens. Lifestyle issues, such as using formulations with intense odor, oily
composition, or expensive, will also reduce compliance. The physician must consider all
these when aiming to keep a patient as long as possible to long-term, effective treatment.
• FDA-approved treatments have a clear indication in AGA/FPHL and may be used indefinitely
with safety. Treatment discontinuation for more than a week will reverse positive effects and
cause unnecessary hair loss, distress, and loss of hope for the future of his/her hair.
• An FDA-approved treatment that works well for the patient should be discontinued only if
side-effects occur. It is considered malpractice to suggest “breaks” of weeks or months in
order for the skin or body to “rest” from the continuous use of a treatment. All these may
lead a distressed patient who will seek “safer/natural” treatments that will only empty his/
her wallet. Moreover, it is doubtful that hair “lost” in every such treatment interruption will
recover with re-starting treatment.
• No treatment will show any significant results earlier than 3–4 months. Hair follicle minia-
turization occurs between two life cycles of the hair follicle. Accordingly, the results of any
given treatment will be visible on the follicle of the next life cycle [20]. As already described
in the relevant section (Chap. 5, Vol. 1), the duration of catagen is ≥2 weeks and of telogen
≥3 months. Terminal hair follicles of the scalp grow at a rate of 0.3 mm/day. Thus, the first
clinical signs of new hair growth -increased scalp coverage- will not be visible before the
new anagen VII and before “new” hair reaches a length of 1–2 cm, which will practically
need approx. 6 months and ideally, 12 months (Figs. 1 and 2).
Mild / Moderate Moderate / Severe Severe
III vertex IV V VI VII
II III IV Medical treatment

IVa Va
(only for younger patients)
and hair restoration surgery
or full-head SMP*
IIa IIIa Improvement or satisfied

Medical treatment
for 12 months
Yes No
Improvement or satisfied
Medical treatment Continue

for 12 months Medical hairpiece
Treatment
Yes No
5% Minoxidil Topical Solution or Foam

and/or oral 1mg Finasteride
Continue Change or add medical
Consider off-label treatments: Medical treatment and consider
• Oral low-dose Minoxidil Treatment hair restoration
• Topical Finasteride surgery or SMP
• Oral or topical Dutasteride (scalp micropigmentation)
Fig. 1 Algorithmic guideline for the management of AGA

Basic Principles of Pharmaceutical Treatment in AGA/FPHL 7
Pre-menopausal women
no sign of sign of
hyperandrogenism hyperandrogenism
Exclude PCOS*
(FSH, LH, testosterone assess endocrine
ovarian ultrasound) status (exclude ovarian and
adrenal diseases)
normal PCOS*
+ topical Minoxidil Cyproterone acetate normal hyperandrogenism

or LDO* Minoxidil + topical Minoxidil
or LDO* Minoxidil
1 year + OCP* topical Minoxidil
anti-androgen
assess outcome or LDO* Minoxidil
+ topical or LDO* Minoxidil
and OCP*
1 year and OCP*
assess outcome
1 year 1 year
improved/ assess outcome assess outcome
stable worse
improved/ worse
stable
continue options: improved/ worse improved/
• add anti-androgen stable stable worse
Minoxidil
• add OCP* continue
• hair concealer • Spironolactone
treatment • hair concealer
• SMP*
• HRS* • SMP* continue options: continue options:
• hairpiece • HRS* treatment • add anti-androgen treatment • add anti-androgen
• hairpiece • hair concealer • change OCP*
• SMP* • hair concealer
• HRS* • SMP*
• hairpiece • HRS*
• hairpiece
options:
• SMP*
worse
1 year • HRS*
assess outcome • hairpiece
Post-menopausal • topical Minoxidil or LDO* Minoxidil
women • consider hormone replacement therapy
and/or Finasteride 2,5 - 5mg
improved/ continue
*LDO: Low-Dose Oral stable treatment
*OCP: Oral contraceptive pill
*PCOS: Polycystic ovary syndrome
*SMP: Scalp micropigmentation
*HRS: Hair Restoration Surgery
Fig. 2 Algorithmic guideline for the management of FPHL
• Moreover, this explains why hair loss occurs upon the onset of any effective treatment
against AGA/FPHL. Hair follicles will prematurely interrupt their life cycle, enter an
early catagen and telogen in order to re-grow, this time larger, under the effects of the
active compound. The patient who sees this as shedding might panic and thus must be
reassured.
• The doctor should keep photographic data of the patient’s condition. Scalp photos upon the
initiation of treatment and at re-evaluation at 6 and 12 months will offer a clear perspective
and will compensate for any natural, seasonal variations in scalp coverage that may “hide”
or “magnify” the actual efficacy of treatment.
• More than one treatment options may be combined, aiming for a faster and higher efficacy.
However, it is best to avoid starting more than one treatment at once because it will be
impossible to evaluate the efficacy of each separately (see Chap. 24).
• Mixing active compounds in one bottle carries two significant risks: the potential interac-
tion between molecules and the overall dilution. Galenic formulations containing 2 or 3
lotions in one larger bottle makes it easier to use but changes the concentration of all com-
pounds down to sub-therapeutic level. When you add Betamethasone lotion 60 mL × 0.1%
to a Minoxidil solution 60 mL × 5%, you end up with a 120 mL solution that contains
Betamethasone 0.05% and Minoxidil 2.5%.
8 Drugs
• Hair loss patients, especially younger ones, are over-educated by Google and are almost
always misinformed. Many become preoccupied with side effects when they are reluctant
to undergo treatment with oral Finasteride and consider that topicals are safer and “more
targeted.” Indeed, patients will often question the knowledge of the doctor concerning
potential sexual adverse effects of Finasteride, whether short or long-term.
• The doctor must educate patients on how to use their treatment efficiently, since most
patients will use it incorrectly if they do not receive detailed instructions and will there-
fore have diminished or no results at all.
• Non-medical approaches can provide cosmetic relief to both men and women with thinning
hair, if medical treatments are not indicated, ineffective or not desired by the patient. They
can also be used as adjuvant tools to medical or surgical treatments. These approaches
include hair loss concealers, scalp micropigmentation and wigs. The reader will find dedi-
cated chapters for each approach on Vol. 3 of this textbook.
Beyond Evidence-Based Medicine
Good medical practice means integrating individual clinical expertise with the best available
external evidence from evidence-based medicine, EBM.
In times of EBM and patient choice, it is of up-most importance to inform patients on the
appropriate management of AGA/FPHL, primarily with FDA-approved treatments, and on
potential adverse effects and their frequency. Patients should be guided away from inefficient
and pseudo-scientific dietary supplements, lotions, and shampoos that will exhaust them finan-
cially and psychologically while losing their faith in real science.
Yet, the real concern is often the fear of the treatment itself, and confusingly, even the fear
of further hair loss (and “disfigurement”) due to no treatment! Is some occasions, the hair loss
patient seems to “deer freeze” for years -without choosing to go under treatment or not- as
baldness is “closing up,” until it is too late to do anything to save his hair.
This is why many experts believe that effective hair loss treatment starts during the first
office encounter, even before physical examination and diagnosis; this is the time when com-
munication skills matter the most. Communication skills require a genuine interest in hair loss
on the technical level and a genuine interest in the patient on the psychological and human
level. For a successful initial encounter, one needs to be sure that the patient’s key concerns
have been directly and specifically solicited and addressed. To be effective, the physician must
gain an understanding of the patient’s perspective on his condition. Patient concerns can be
wide-ranging, including fear of hair loss and disfigurement; apprehension of scalp symptoms;
distrust of the medical profession or pharmacologic agents; concern about loss of wholeness,
role, status, or independence; denial of reality of medical conditions; grief; and other uniquely
personal issues.
Most AGA patients are young males who can even be suspicious of physicians and treat-
ments, obsessed with their hair loss, impulsive in their decisions, often overly dramatic and
emotional, even socially withdrawn due to their hair loss (see Chap. 20, Vol. 1). Adding to
some patient’s worry and distrust may be prior frustrating experiences with physicians, who
tend to trivialize hair loss complaints or dismiss them altogether. This attitude on the part of
physicians is related either to lack of comprehension of the impact of hair loss on quality of life
or lack of confidence in treating alopecia [21].
However, it is paramount for the physician to support the hair loss patient psychologically,
to help him adopt a broader perspective and not a vision narrowed by fear and skepticism. The
influence of the prescribing physician should be kept in mind since inspiring confidence versus
doubt and fear clearly impacts the outcome of treatment [21].
References 9
The physician’s role is to help the patient figure out what he/she really wants and then to use
the power of persuasion to show the patient the way there. The way a physician phrases his/her
recommendations can powerfully sway a patient’s choice and even have an impact on the treat-
ment outcome [22, 23]. Success depends not only on comprehension of the underlying pathol-
ogy but also on unpatronizing sympathy from the part of the physician.
An appropriate management strategy for AGA/FPHL and psychological support to increase
compliance will allow most patients to maintain a satisfactory image of their hair for years,
even for decades, despite popular beliefs that AGA/FPHL is a losing battle.
Because it is not!
References
1. Cash TF. Attitudes, behaviors, and expectations of men seeking medical treatment for
male pattern hair loss: results of a multinational survey. Curr Med Res Opin
2009;25(7):1811–20.
2. Haber RS. Pharmacologic management of pattern hair loss. Facial Plast Surg Clin North
Am 2004;12(2):181–9.
3. Bandaranayake I, Mirmirani P. Hair loss remedies-separating fact from fiction. Cutis
2004;73(2):107–14.
4. Harth W, Linse R. Body dysmorphic disorder and life-style drugs. Overview and case
report with finasteride. Int J Clin Pharmacol Ther 2001;39(7):284–7.
5. Tudiver F, Talbot Y. Why don’t men seek help? Family physicians’ perspectives on help-
seeking behavior in men. J Fam Pract 1999;48(1):47–52.
6. Galdas PM, Cheater F, Marshall P. Men and health help-seeking behaviour: literature
review. J Adv Nurs 2005;49(6):616–23.
7. Siah TW, Muir-Green L, Shapiro J. Female pattern hair loss: a retrospective study in a tertiary
referral center. Int J Trichology 2016;8(2):57–61.
8. Alfonso M, Richter-Appelt H, Tosti A, Viera MS, Garc a M. The psychosocial impact of
hair loss among men: a multinational European study. Curr Med Res Opin
2005;21(11):1829–36.
9. Οlsen EA, Messenger AG, Shapiro J, Bergfeld WF, Hordinsky MK, Roberts JL, Stough D,
Washenik K, Whiting DA. Evaluation and treatment of male and female pattern hair loss.
J Am Acad Dermatol 2005;52(2):301–11.
10. Khandpur S, Suman M, Reddy BS. Comparative efficacy of various treatment regimens
for androgenetic alopecia in men. J Dermatol 2002;29(8):489–98.
11. Budd D, Himmelberger D, Rhodes T, Cash TE, Girman CJ. The effects of hair loss in
European men: a survey in four countries. Eur J Dermatol 2000;10(2):122–7.
12. Giacometti L. Facts, legends, and myths about the scalp throughout history. Arch Dermatol
1967;95(6):629–31.
13. Habif TP. Hair diseases. In: Habif TP. Clinical dermatology: a color guide to diagnosis and
treatment. 4th ed. St. Louis, MO: Mosby Inc.; 2003.
14. Paus R, Cotsarelis G. The biology of hair follicles. N Engl J Med 1999;341(7):491–7.
15. Girman CJ, Rhodes T, Lilly FR, Guo SS, Siervogel RM, Patrick DL, Chumlea WC. Effects
of self- perceived hair loss in a community sample of men. Dermatology
1998;197(3):223–9.
16. Marritt E. The death of the density debate. Dermatol Surg 1999;25(8):654–60.
17. Trüeb RM, Lee WS. Diagnosis and treatment. In: Male alopecia. Springer, Cham; 2014.
p. 90.
10 Drugs
18. Gupta AK, Mays RR, Versteeg SG, Shear NH, Piguet V, Piraccini BM. Efficacy of off-
label topical treatments for the management of androgenetic alopecia: a review. Clin Drug
Investig 2019;39(3):233–39.
19. Rushton DH, Gilkes JJ. Delaying treatment in male-pattern hair loss affects the therapeu-
tic response. Clin Exp Dermatol 2011;36(2):204–5.
20. Sinclair R. Male pattern androgenetic alopecia. BMJ 1998;317(7162):865–9.
21. Trüeb RM, Lee WS. Patient expectation management. In: Male alopecia. Cham: Springer;
2014. pp. 233.
22. Groopman J. How doctors think. Boston/New York: Houghton Mifflin Company; 2007.
23. Rezende HD, Dias MFRG, Trüeb RM. A comment on the post-finasteride syndrome. Int J
Trichol 2018;10(6):255–61.
Minoxidil
23
Basic Concepts however, with the introduction of Minoxidil Topical

• Minoxidil was initially developed as a potent anti- Foam 5%, these became exceedingly rare.
hypertensive, but due to the adverse hypertrichotic • Minoxidil is the most widely used drug for the
effect it had on most patients, it soon became the treatment of AGA and FPHL worldwide. The major
first compound prescribed to grow hair, used as disadvantages are the cumulative cost and the need
Minoxidil Topical Solution, MTS. for continuous open-ended use. Strict compliance is
• Minoxidil is a KATP channel-opener, however, the necessary to achieve a positive cosmetic response,
exact hair growth stimulating mechanisms remain and this is the hardest part for the vast majority of
not fully clarified, yet, it is not related to local vaso- patients.
dilation and is more likely associated with the
increase in prostaglandin PGE-2 production in the
dermal papilla. In the 1970s, the American pharmaceutical company Upjohn
• Minoxidil increases the size and diameter of AGA- & Pharmacia developed the antihypertensive drug Minoxidil
miniaturized hair follicles, gradually converts them and launched it under the brand name Loniten®, in the form
into terminal ones, stimulates telogen follicles to of 2.5 mg and 10 mg tablets. Minoxidil is a pyrimidine deriv-
enter into anagen, increases the duration of anagen, ative (2,4 diamino-6-piperidinopyrimidine-3-oxide), has a
and decreases the duration of kenogen but does not molecular weight of 209.25, and its action is focused on vas-
shorten telogen. cular adenosine triphosphate-sensitive potassium channels
• The efficacy of 5% MTS is concentration-dependent (KATP). Intravenous and oral Minoxidil will potently reduce
and consistently superior to 2% MTS. It stabilizes both systolic and diastolic pressure, as well as the peripheral
hair loss in 85% of patients, 65% of which report resistance of arteries, but not veins [1]. Minoxidil is very
new hair growth, and 30% experience significant potent, and its antihypertensive use seemed, in the begin-
hair growth, starting at 8 weeks and reaching a pla- ning, particularly promising for the management of severe,
teau at approximately 12 months. refractory hypertension [2].
• In order to retain results, Minoxidil use must con- However, during Phase III clinical trials, C.A. Chidsey
tinue uninterrupted, twice daily, and it should not be observed one surprising adverse effect was reported: more
mixed with other solutions. Unlike popular beliefs, than 80% of patients in the active drug group experienced
there is no Minoxidil tolerance nor Minoxidil hirsutism and hypertrichosis on areas of the body, namely the
rebound effect, and increased shedding at the begin- cheeks, forehead, and back of the hands, while most AGA
ning of the treatment is temporary and indicates a patients noticed scalp hair regrowth [3]. In later postmarket-
synchronized shifting of intermediate hairs from a ing studies, hypertrichosis due to Minoxidil occurred in
late anagen or early telogen to a new anagen. nearly all adult patients [4–6]. In pediatric patients, 5 out of
• Systemic adverse effects of MTS are very rare, 6 children with resistant hypertension treated with Minoxidil
while local dermatological adverse effects are com- also exhibited hypertrichosis [7]. Concerning other adverse
mon, transient, reversible, and correlated to the high effects, a few patients developed skin pigmentation and a
concentration of propylene glycol in 5% MTS; peculiar coarsening of the facial features, whereas no endo-
crine disorders were reported [2].
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 11

K. Anastassakis, Androgenetic Alopecia From A to Z, https://doi.org/10.1007/978-3-031-08057-9_1
12 23 Minoxidil
These adverse effects posed severe limitations on the Table 23.1 Timeline for FDA approval of Rogaine® solutions and
extensive use of Minoxidil as an antihypertensive agent. foam. (From Rogers et al. [12])
Nevertheless, since Minoxidil could clearly induce hair FDA approvals of Rogaine® (minoxidil) solution
growth, the Research & Development department of Upjohn 1979—Oral formulation approved by the FDA for severe
hypertension
& Pharmacia decided to determine whether Minoxidil could
1988—FDA approval for the 2% solution, for hair loss in men with
be used to address different forms of alopecia. AGA, with prescription
1992—FDA approval for the 2% solution for hair loss in women
1996—FDA approval for the 2% solution for OTC use in men and
23.1 Initial Studies and FDA Approval women with AGA
1997—FDA approval for the 5% solution for OTC use in men,
labeled as “extra strength for men”
Minoxidil-induced hypertrichosis was first reported in the
2006—FDA approval for the 5% foam for OTC use in men
literature in 1978 by Burton et al. [3], while Zappacosta first
reported the oral administration of Minoxidil on an AGA
patient for hair growth stimulation in 1980 [8]. Weiss et al.
(1981) were the first to report the use of a Minoxidil Topical MTS is the only FDA approved and clinically proven
Solution (MTS) for the treatment of alopecia areata [9]. topical solution with a proven hair growth potential,
However, since Minoxidil was not yet approved for the treat- and it is considered the “Gold Standard” against which
ment of hair loss by the FDA, there was no “official” MTS any potential topical treatment for AGA is compared
available in the US. Several years of delay in granting to.
Minoxidil approval for treating AGA resulted in illicit
importing, off-label prescribing, and instances of faulty
extemporaneous compounding. The authors and researchers Unlike any other pharmaceutical formulation, MTS is
had to either import it from other countries, where MTS was not essential for human health or well-being. It is the first
freely accessible (Canada), or prepare it from Loniten® tab- prescription drug available for a purely cosmetic indica-
lets dissolved in an alcohol-water solution [10]. tion. For this reason, it is the final consumer and the extent
In August 1988, MTS, as Rogaine® 2% (Regaine® inter- of his/her expectation fulfillment that determines the effi-
nationally), was finally approved by the FDA as the first and cacy of MTS.
only (at the time) clinically proven pharmaceutical formula-
tion, which could halt hair loss and lead to new hair growth,
with first noticeable results appearing after 4–6 months [11]. 23.2 Mechanism of Action
The 2% MTS was enthusiastically welcomed by both doc-
tors and patients since it allowed, for the first time in history, Despite extensive research spanning over almost 40 years,
justified hopes for the treatment of AGA, based on scientific the exact mechanism by which Minoxidil stimulates hair
evidence and away from worthless “snake oils.” 2% MTS growth remains inconclusive. However, the continuously
contained Μinoxidil 20 mg/mL, dissolved in 60% ethyl alco- growing knowledge of follicular physiology allows some
hol, 20% propylene glycol, and 20% water since Minoxidil justified speculations based on reliable scientific data.
is poorly soluble to water alone. In 1991, FDA approved Little is known about its pharmacological activity and the
Regaine 2% for women with FPHL. Until 1996, Regaine® specific target cells in hair follicles. Notably, Minoxidil’s
was a prescription-only medication in the USA, but in mechanisms of action, identified in cultures of isolated hair
February 1996, it was licensed as an “over-the-counter” follicle cell populations, might not be equally significant
product” (OTC). in vivo or for the hair follicle as an organ. The relationship
However, results from 2% MTS were not as impressive as between the complexities of hair growth and the behavior of
expected. This urged the company to launch an “upgraded” a single cell type cultured in a Petri dish is uncertain.
MTS containing a higher concentration of Minoxidil, this Therefore, the following mechanisms of action of Minoxidil
time 5%, aiming at a higher efficacy and patient satisfaction. are all verified potential, but it is still elusive, which is the
The 5% MTS was initially approved in 1993 as a prescription- major one in vivo since we are yet to discover the Minoxidil
only medication, under the brand name Rogaine® Extra target cell population or the signaling mechanisms for the
Strength 5% and FDA licensed 5% MTS as an OTC in 1997, effects of Minoxidil on the different follicular cell
for male AGA only. The 5% MTS contains Minoxidil 50 mg/ populations.
mL, 50% propylene glycol, 30% ethyl alcohol and 20% The recognized general mechanism of action attributed to
water. In 2006, the FDA approved the Rogaine® 5% Minoxidil focuses on KATP channels. KATP channels control
Μinoxidil Topical Foam (MTF) for AGA treatment in men the flow of Κ+ cations through cellular membranes in many
and in 2014 to treat FPHL in women (Table 23.1). tissues, including heart, pancreatic β-cells, brain, skeletal
23.2 Mechanism of Action 13
and smooth muscle, kidneys, and vessels [13–15]. KATP chan- 3. According to Sato et al. (1999), another possible mecha-
nels are regulated by ATP and ADP’s intracellular levels, nism of action is through the induction of a 40% increase
thus providing a unique link between cellular energetics and in the activity of the enzyme 17β-hydroxysteroid dehy-
electrical excitability. Numerous other chemical molecules drogenase in the dermal papilla cells (DPCs) of balding
can also attach to KATP channels, inducing them to open or scalp [27]. This results in a higher conversion of
close. KATP channels consist of 8 subunits, forming 4:4 Testosterone (T) into weaker androgens, instead of
hetero-octamers, arranged in two rings. The correlation Dihydrotestosterone (DHT). However, a high concentra-
between KATP and Μinoxidil is not yet clear because of the tion of Minoxidil (0.5 mmol/L) was used in this study,
contradicting in vitro results. In vitro studies assessing the and the relevance of the results to hair growth in vivo is
effects of Μinoxidil on cultured follicles and cells from sev- dubious.
eral species have produced variable, confusing, and often 4. Minoxidil is implicated in collagen metabolism by
contradictory results [16, 17]. More recently, Shorter et al. reducing the expression and action of the enzyme lysyl
(2008) demonstrated that there are two types of KATP chan- hydroxylase gene in fibroblasts [28, 29]. Through this
nels in the human hair follicle, and only one of them is sensi- mechanism, Minoxidil is reducing the production and
tive in Minoxidil [18]. deposition of collagen fibers in the perifollicular space
Overall, it seems that Minoxidil is a non-specific agent of and subsequent perifollicular fibrosis occurring in AGA,
hair growth stimulation, which acts directly on the special- which might facilitate the reversal of miniaturization of
ized mesenchymal cells of the follicular dermal papilla or hair follicles.
hair matrix cells or possibly both [19]. Up until 2020, the 5. The active metabolite of Minoxidil is considered to be
following mechanisms of action have been proposed accord- its sulfated metabolite, Minoxidil sulfate, which has
ing to in vitro results: been demonstrated to stimulate cysteine incorporation in
cultured follicles and hair follicle growth [30]. Minoxidil
1. The “vasodilation theory” or “increased cutaneous is converted to Minoxidil sulfate through at least four
blood flow theory” of hair growth stimulation after cytosolic sulfotransferases found in the skin, the human
topical application of Minoxidil, even though it reso- scalp [31], smooth muscle, liver, and fibroblasts [32, 33].
nates quite well with “conventional wisdom”, has been The latter are the most important ones for hair growth,
rejected. A Laser Doppler velocimetry study by Wester according to Dooley et al. (1999), since Minoxidil is
et al. (1984) in 16 males applying 1%, 2%, and 5% catalyzed locally into Minoxidil sulfate [34]. Minoxidil
MTS showed blood flow stimulation only by the 5% sulfate is 15 times more potent than Minoxidil [30], and
MTS [20]. However, subsequent studies by Bunker its primary mechanism of action is through the reduction
et al. (1987) did not replicate these results [21], and of Ca+2 influx into cells. However, evidence that its effect
neither did a Laser Doppler Flowmetry study on nine on hair growth is due to the opening of KATP channels is
males by de Boer et al., reporting no reaction in the circumstantial, direct proof is lacking, and it is unclear
cutaneous blood flow after the application of 2% MTS, how this action modulates hair growth. One theory sug-
5% MTS or placebo lotion [22]. Additionally, other gests that Ca+2 influx decreases hair growth by increas-
compounds with similar vasodilating properties to ing EGF action (Εndothelial Growth Factor) [35].
Minoxidil do not elicit hair growth nor stabilize hair Minoxidil sulfate induces entry of Κ+ into cells and
loss [23], rendering the “vasodilation theory” even decreases the permeability of Ca+2, thus reducing EGF
less plausible. action in hair follicles [36]. In a clinical setting study by
2. The principal mechanism of action of Minoxidil is most Buhl et al. (1994), inter-individual variations in levels of
likely the activation of prostaglandin endoperoxidase scalp sulfotransferase were evident, and patients with
synthase-1 (PGHS-1) enzyme and the consequent higher activity had a more favorable response to MTS
increased production of prostaglandin PGE2. PGE2 has [37]. Interestingly, according to Whiting et al. (1993),
cytoprotective effects and induces stem cell activation, only 55% of AGA patients with microinflammation had
follicular cell proliferation, and hair growth [24]. hair regrowth in response to Minoxidil treatment com-
According to findings by Garza et al. (2012), another pared to 77% of patients with no signs of inflammation
prostaglandin, PGD2 is the major biochemical factor in [38].
AGA pathophysiology [25] (see Chap. 11, Vol. 1). The 6. Minoxidil exhibits direct mitogenic actions on keratino-
fact that PDΕ2 exhibits opposing, “yin and yang” func- cytes, stimulating their differentiation and proliferation
tions to PGD2 makes this mechanism of Minoxidil action [39]. It has also been reported to increase DNA synthesis
most relevant [26]. Minoxidil treatment increases PGE2 in DPCs, and follicular germ cells [40] since the KATP
levels, but whether it influences PGD2-related pathways channel activity is required for G1 progression of the
is unknown. cell cycle [41]. Immunocytochemistry and autoradio-
14 23 Minoxidil
graphic analysis of scalp biopsies of primates have indi- mals were used, and Testosterone, which can be con-
cated that Minoxidil increased the number of DNA verted to estradiol in hair follicles rather than DHT, was
synthesizing cells in DPCs, in the matrix, and the outer investigated [52]. Hsu et al. (2014) hypothesized that
root sheath. These changes result in the prolongation of Minoxidil might influence the androgen receptor (AR)
anagen and the conversion of pseudo-vellus hairs into or its downstream signaling and tested Minoxidil in an
terminal ones [42]. Interestingly, at concentrations AR transcription reporter assay using LNCaP prostate
higher than 5%, Minoxidil has been reported to suppress cancer cells. They published their results in 2014, show-
DNA synthesis. ing that Minoxidil interferes with AR-related functions,
7. Minoxidil activates the expression of vascular endothe- decreasing AR transcriptional activity, reducing expres-
lial growth factor (VEGF) in hair follicles, resulting in sion of targets at the protein level, and suppressing AR-
the advancement of dermal papilla micro-vascularization positive LNCaP cell growth. Furthermore, they
and improved perfusion [43], though a mechanism of demonstrated that the suppressive effect of Minoxidil on
adenosine secretion [44]. This mechanism supports the AR-related functions reflected its ability to bind to the
hypothesis that Minoxidil has a physiological role in AR directly; interfere with AR-peptide, AR-co-regulator,
maintaining an adequate vascularization of hair follicles and AR N-C interactions; and reduce AR protein stabil-
in AGA. ity [53].
8. Minoxidil increases production and secretion of hepato- 13. In 2017, Stamatas et al. [54] analyzed the results obtained
cyte growth factor (HGF) and Matrix Metalloproteinase-2 from an analysis of gene expression data from a Minoxidil
by hair follicles in vitro [45], which both have a stimula- study conducted by Mirmirani et al. (2015) in which both
tory effect on hair growth, in vitro and in vivo. frontal and vertex areas of the scalp were treated [55].
9. Minoxidil has been reported to inhibit enzymes lysyl Both scalp regions showed upregulation of genes that
hydroxylase [46] and prostacyclin synthase [47] encode keratin-associated proteins, PTEN, cellular apop-
enzymes, as well as keratinocyte growth altogether tosis pathways, protein digestion and absorption (KEGG),
[48]. However, these actions were achieved in concen- Ras, mTOR, and Wingless-related integration site (Wnt)
trations between 25–1000 μΜ, which are several times pathways. Downregulated pathways included Akt, PTEN,
higher than those achieved in vivo by topical (0.02 μΜ) MAPK, ILK, mechanistic target of rapamycin (mTOR),
or oral (0.7 μΜ) Minoxidil administration [49]. JAK/STAT, and Ras pathways. These findings suggested,
Therefore, Minoxidil has a concentration-dependent for the first time, that control of inflammation in conjunc-
biphasic effect on the proliferation and differentiation tion with keratin stimulation may contribute to the
of normal human keratinocytes. Minoxidil stimulates improvement of hair growth disorders with the use of
keratinocytes to proliferate in micromolar concentra- Minoxidil Topical Foam [54].
tions, while in millimolar concentrations, it has anti-
proliferative, pro-differentiative, and partially cytotoxic
effects [39]. 23.3 Minoxidil Effects and Clinical Results
10. Minoxidil has purely anti-apoptotic properties in vitro
and at concentrations similar to those achieved with 5% Even though Minoxidil’s exact mechanism of action as a hair
MTS in vivo since it promotes the survival of human growth stimulant remains unclear, the positive clinical effects
DPCs by activating both ERK and Akt genes. It also pre- are known and adequately substantiated. These will be sum-
vents cellular death by increasing the ratio of Bcl-2/Bax marized below for the reader to evaluate better the studies
in a dose-dependent manner [50]. presented.
11. Minoxidil activates the transcriptional activity of pTop- Minoxidil treatment will:
flash (TCF reporter plasmid) and increases phosphoryla-
tion of GSK3β, PKA, and PKB. Additionally, it triggers • increases the size and diameter [56] of AGA-miniaturized
the expression of Axin2, Lef-1, and EP2, prolonging hair follicles,
anagen through the activation of β-catenin activity in • gradually converts intermediate and pseudo-vellus, min-
DPCs [51]. iaturized hair follicles into terminal ones,
12. Minoxidil has been thought of not having any hormonal, • stimulates telogen hair follicles to re-enter into anagen
immunosuppressive, or direct anti-androgen effect [16]. (anagen initiation),
These results originate from earlier studies using the • increases the duration of anagen,
golden Syrian hamster model, in which no anti- • inhibits entry into catagen [57],
androgenic effect of Minoxidil on androgen-dependent • restores the duration of telogen to normal levels [58],
cutaneous structures was noticed. However, female ani- • decreases the duration of kenogen.
23.4 Minoxidil Topical Solution and Early Research 15
hair growth agents became more precise and sophisticated,

Overall, Minoxidil will stimulate AGA-affected hair providing more objective results and allowing more useful
follicles to produce longer, thicker, more pigmented conclusions. Researchers realized that the effectiveness of
hairs that will remain longer on the scalp surface, agents that promote hair growth could be reliably established
resulting in an overall improved cosmetic coverage. only by evaluating many parameters and setting comparable
protocols, including the following: global photos before and
after the completion of the study, long and standardized
duration of studies, counting the number of hairs over a
23.4 Minoxidil Topical Solution and Early small, predetermined target area of the scalp (target area hair
Research counts, TAHC), measuring total unit area density (TUAD)
and by measuring the changes in hair weight, according to a
Research on Minoxidil’s efficacy in AGA and other hair loss standard protocol developed by Price [68].
conditions was intense for more than 15 years after its The efficacy of 2% MTS was officially demonstrated in
launch, and dozens of studies were continuously published. Phase II trials sponsored by Upjohn & Pharmacia, and Olsen
Minoxidil being such a “hot” topic was not a surprise. For published the results in 1989. This large, multicenter, double-
the first time in history, researchers and clinicians had an blind, 12 months-long study included 27 independent centers
actual hair-growth drug with a very favorable adverse effect/ and tested the efficacy of 2% MTS. From 1983 to mid-1984,
benefit ratio, and consequently, everybody was eager to 2326 men, aged 18–50, were selected, and 1833 completed
study it. Actually, Minoxidil initiated and inspired current the study. During the first 4 months, patients were divided
scientific inquiry into hair biology and led to the realization into three groups: one group used 2% MTS, the second group
that hair loss is potentially treatable [59]. used MTS 3%, and the third group used a placebo solution.
The first official research study on Minoxidil’s efficacy After 4 months, the placebo group was crossed-over with the
and safety was conducted by Uno et al. (1985) on the stump- other two groups, and it was demonstrated that 2% MTS
tailed macaque [60], which is considered an ideal experi- b.i.d. (bis in die, twice daily) resulted in moderate to signifi-
mental model for AGA research [61]. Both male and female cant hair growth in 30–35% of patients, while the results of
macaques, upon entering puberty, develop non-pathological 3% MTS were not statistically superior [69].
hair loss, which is similar to AGA in humans. Uno et al. Clinical experience, data from clinical trials, pharmacoki-
were the first to report that Minoxidil increased the size of netic studies, postmarketing surveillance, and worldwide
miniaturized hair follicles in macaques and that the enlarged drug surveillance suggested that applying higher concentra-
follicles regressed after Minoxidil withdrawal. They noticed tions of topical Minoxidil may enhance its therapeutic effi-
that follicular growth was re-stimulated when treatment cacy without increased safety risk. Therefore, researchers
with Minoxidil was reinstituted and that Minoxidil was quite early [70] (1987) experimented with higher MTS con-
more effective when used in higher concentrations, 5% vs. centrations, mostly with 5% MTS [71, 72]. Positive results
2% [62, 63]. led to the FDA approval and launch of 5% MTS in 1996. The
In humans, it was first necessary to evaluate Minoxidil’s 5% MTS set a new standard since studies have repeatedly
concentration in the topical solution that would have the proven that Minoxidil efficacy is purely concentration-
optimal adverse effects/benefit ratio. Olsen et al. (1986) con- dependent. For this reason, mixing any other solution with
ducted a dose-response, 6-month-long, double-blind, MTS decreases the Minoxidil concentration in sub-
placebo-controlled study using topical solutions of 0.01%, therapeutic levels by dilution.
0.1%, 1%, and 2% Minoxidil concentration on 89 healthy The most seminal paper was the double-blind study con-
men with AGA and reported that 2% topical Minoxidil was ducted by Price et al. (1999) investigating the efficacy of the
the minimum standard treatment for AGA [64]. Later, stud- new product by comparing 2% MTS and 5% MTS during
ies by Olsen et al. [65] and Rietschel et al. [66] (both 1987) 120 weeks of the study [71]. Four groups of AGA-affected
reported a considerable, statistically significant increase in men (total n = 33) were randomly divided. The interval hair
the absolute number of hairs in treated subjects. However, weight from baseline was measured in predetermined scalp
these results were later questioned because of the inaccurate areas to test whether Minoxidil changes other hair charac-
hair-growth assessment method used, i.e., the simple visual teristics besides hair counts and to what extent the concen-
measurement of all hair within a circle of 1inch diameter tration Minoxidil affects these changes. The first two groups
(2.53 cm) [67]. The reason was that even though there was a were treated with 5% MTS and 2% MTS, the third group
statistically significant increase in the number of hairs in the received a placebo vehicle, and the fourth group used no
areas where MTS was applied, most hairs were cosmetically product. The result was that in 96 weeks, the 5% MTS had a
insignificant, did not increase the meaningful hair density, 35% superior result compared to the 2% MTS group, while
and, therefore, unable to improve the cosmetic appearance of no hair growth was observed in the other two groups. Peak
patients. Since then, evaluation methods on the efficacy of hair growth for the MTS groups occurred within 20 weeks
16 23 Minoxidil
Fig. 23.1 Comparison of the 60

mean percentage change in
interval weight per square
centimeter for 4 treatment
Mean percent change in interval weight per sq cm

groups: 5% MTS, 2% MTS,
40
placebo, and untreated. Vertical
line at 96 weeks marks the
cessation of treatment. (From
Price et al. [71]) One can
notice a sudden decline after 20
the initial 12 months of growth,
followed by a rate of decline
that seems similar to the
untreated group 0
-20
-40
0 12 24 36 48 60 72 84 96 108 120
Week
5% minoxidil 2% minoxidil Placebo Untreated

number per square centimeter
for 4 treatment groups: 5%
Mean percent change in number per sq cm
MTS, 2% MTS, placebo, and

30
untreated. Vertical line at
96 weeks marks the cessation
of treatment. (From Price et at
[71])
20
10
-10
0 12 24 36 48 60 72 84 96 108 120
Week
after treatment initiation, and 5% MTS induced and main- hair loss in the subject of both MTS groups. Hair weight and
tained an increase in interval weight over baseline of approx. hair counts for the Minoxidil groups returned to levels simi-
30%. In contrast, the placebo and control groups showed a lar to those of placebo at 24 weeks. This demonstrated that
mean 6% reduction in hair weight per year, while shedding the hair growth effect of Minoxidil is tangible yet fully
continued unabated. During the last 24 weeks of the study, reversible upon treatment discontinuation (Figs. 23.1, 23.2,
all treatments were discontinued, which resulted in rapid and 23.3).
23.5 Minoxidil and FPHL 17

excess cumulative weight for
30
Mean percent change in excess cumulative weight

4 treatment groups: 5% MTS,
2% MTS, placebo, and
untreated. Vertical line at 25
96 weeks marks the cessation
of treatment. (From Price et at
[71]) 20
15
10
-5
-10
0 12 24 36 48 60 72 84 96 108 120
Week
studies, which included 735 females. Since the publication

Based on these studies, Upjohn [57] reported that 5% of these studies, there is a clear and specific clinical indica-
MTS would induce moderate to significant hair growth tion for only 5% MTS in men with AGA.
in 26% of the patients, while another 33% will have
minimal to moderate growth, starting at 4 months.
Interestingly, 11% of patients in the placebo group also 23.5 Minoxidil and FPHL
exhibited moderate to significant hair growth, while
31% had minimal growth during the first 4 months. In clinical practice, Minoxidil appears to be more effective
Notably, these results refer to the vertex, where in FPHL than AGA. Studies on the efficacy of MTS in
Minoxidil is most effective. women with FPHL have also consistently shown better
results than those in men with AGA. DeVillez et al. pub-
lished in 1993 the results of a 32-week, double-blind, pla-
A subsequent 48-week, double-blind, placebo-con- cebo-controlled multicenter trial conducted in 11 US
trolled, randomized, multicenter trial by Olsen et al. centers evaluating 2% MTS for the treatment of
(2002) compared 2% MTS, 5% MTS, and placebo [72]. A FPHL. Three hundred eight women with FPHL aged 18–45
total of 393 males with AGA applied 5% MTS (n = 157), were enrolled, and 256 of these women completed the
2% MTS (n = 158), or placebo (n = 78) twice daily, and trial. A refined photographic technique was used to deter-
efficacy was evaluated by scalp TAHC and patient and mine the number of nonvellus hairs regrown objectively.
investigator assessments of changes in scalp coverage. It They reported that 50% of the active group subjects had
was demonstrated that within 48 weeks, 5% MTS was minimal hair growth, 13% had moderate hair growth,
clearly superior to 2% MTS in 4 out of 6 efficacy mea- while respective placebo rates were 33% and 6% [73].
sures; 5% MTS resulted in 45% higher hair growth than Jacobs et al. (1993) published the results of a similar,
2% MTS (18.6 vs. 12.7 nonvellus hairs respectively), ear- 32-week study conducted in 10 European centers and
lier growth response (8th week vs. 16th week respec- showed that 44% of the females in the 2% MTS group
tively) and higher patient satisfaction regarding the course achieved new hair growth compared to 29% in the placebo
of hair loss. group, while an average of 33 new hairs were counted in
Altogether, the efficacy of 5% MTS in the treatment of the control area in the 2% MTS group which was signifi-
AGA and FPHL has been demonstrated in 4 extensive clini- cantly higher than that of 19 hairs in the placebo group
cal studies, which included 827 males, and three clinical [74] (Protocol M/7415/0009).
18 23 Minoxidil
As expected, 5% MTS was tested in women with FPHL, appears probably because the depth into which the
as well. The first randomized, double-blind, placebo- Minoxidil “reservoir” is formed in vellus hair follicles is
controlled study was conducted by Trancik et al. (1994) but just 100 μm, while, in terminal hair follicles, it exceeds
remained unpublished (M/7415/0009) [75]. It included 297 300 μm [81]. Minoxidil may have a positive effect in all
women with FPHL who were evaluated at the 8th, 16th, and terminal and intermediate hair follicles in a given area but
32nd week, according to terminal hair counts in a predeter- only rarely in vellus hairs, and it will not “resurrect” hair
mined 1cm2 of scalp area. The 5% MTS increased hair counts follicles in areas that have been bald for years [82],
from baseline by 35, 49, and 26 terminal hairs, respectively. • Although significant hair growth can occur in patients of
The 2% MTS resulted in 30, 36, and 26 hairs, respectively, all ages, response to Minoxidil correlates with the patient’s
while the placebo increased the number of hairs by 14, 11, age, and AGA patients in their 20s and 30s are more likely
and 6, respectively. After the end of the study, a small meth- to respond favorably to Minoxidil. In general, the younger
odology trial followed (M/7410/0286) [76] on 44 patients the patient is when treatment is initiated, the more the
who continued using 5% MTS for an additional 12 weeks. chances that he will have a positive response. Rundegren
The result was a slightly diminished benefit, with hair counts studied 636 men with ΑGΑ and 630 women with FPHL
returning to 16th-week levels. Another study by Price et al. and reported that the efficacy of 2% MTS and 5% MTS
(1990) confirmed the positive results of 2% MTS in women was strongly dependent on the age of patients, and that age
with FPHL for 32 weeks. The study demonstrated that the may be the main denominator for predicting treatment
average total hair weight of Minoxidil-treated subjects success in both sexes. One additional parameter was to
increased over the 32-week test period by 42.5%, compared start treatment in less than a year from the onset of notice-
to 1.9% for the placebo-treated subjects, indicating MTS able hair loss [79]. However, in females with FPHL, there
increase hair mass is more than absolute hair numbers [68]. was no correlation of efficacy and duration of balding,
In contrast, Whiting et al. (1992) conducted a 32-week
double-blind placebo-controlled trial, enrolling 28 females Patients with AGA or FPHL who fulfill all or most of these
with FPHL, 15 patients in the 2% MTS group, and 13 con- “criteria” are better candidates for MTS, and most will have
trols. They reported that 2% MTS had a mean nonvellus hair very positive results. More particularly, male patients in
count of 195 hairs versus a mean hair count of 177 for stages II, III, and III vertex of the Norwood-Hamilton scale
patients in the placebo group; 60% (n = 9) of patients in the and female patients in Ludwig I or II stages may expect
2% MTS group showed minimal to moderate hair growth higher efficacy compared to more advanced AGA/FPHL
compared to 46% [6] of the patients in the placebo group, patients [80]. In these patients, according to data derived
results being of borderline significance [77]. Lucky et al. from multiple, double-blind placebo-controlled trials, twice
(2004) studied 381 women to compare the efficacy of 2% daily application of MTS would result in [83]:
MTS vs. 5% MTS vs. placebo and proved that 5% MTS was
clearly more effective, although it was correlated to more • 15–20% of the AGA patients will experience moderate to
adverse effects [78]. significant hair growth,
Overall, 5% MTS seems to be more effective than 2% • 50% of patients will experience mild hair growth or stabi-
MTS in FPHL, but FDA has not cleared it for women with lization of hair loss,
FPHL, and its use is off-label. • 30% of the patients will experience retardation of hair
loss but will continue losing hair at a slower pace [84].
23.6 Ideal Candidates for Minoxidil

23.6.1 Is Minoxidil Effective Only
Response to Minoxidil is individualized and non-predictable. on the Vertex?
Some patients respond very well; others not so much. Certain
clinical features have been demonstrated to correlate with The clinical trials of MTS [72] and MTF [85] initially evalu-
favorable response to Minoxidil [79, 80]: ated only hair growth properties on men’s vertex with
AGA. However, it remained unclear whether topical Minoxidil
• Individuals with mild or moderate thinning on the crown could be useful in other scalp regions also susceptible to hair
due to AGA (and not to other pathological causes), miniaturization, namely the frontotemporal region and the
• Individuals with a small thinning surface on the crown hairline. This issue has not been answered or was actually
(diameter < 10 cm), “avoided”, probably because results in the frontal areas were
• Individuals who have developed noticeable AGA in the not as favorable as in the midscalp and vertex areas, and
last 5 years and still have terminal hair follicles in the researchers did not want to diminish the “crown success” of
thinning areas, MTS. Experienced clinicians already knew that MTS grows
• MTS will be more effective in areas where there are at hair all over the scalp, but less experienced physicians and
least 17 terminal hairs/cm2, length > 2 cm. This effect patients believed that MTS worked only on the crown.
23.7 Efficacy of Minoxidil 19
The first results on frontal areas were not published until few reviews of its efficacy have been published. Kanti et al.
the Minoxidil Topical Foam 5% was available and tested in [87], in their systematic review (Evidence-based (S3) guide-
frontal areas. Mirmirani et al. (2015) conducted a placebo- line for the treatment of androgenetic alopecia in women and
controlled, double-blind, prospective, pilot study on 16 healthy in men, 2018), included 48 studies assessing the efficacy of
males with AGA. They investigated whether scalp biopsies Minoxidil in male patients with AGA and 19 studies that
from men with AGA show variable expression of genes before investigated the efficacy of Minoxidil in female patients with
and after 8 weeks of treatment with 5% MTF vs. placebo (9 FPHL. Overall, five studies treated both male and female
used 5% MTF, and 4 used placebo). They also determined patients, seven studies obtained grade A2 evidence, nine
whether microarray gene expression profiles in the frontal studies grade B evidence, and three studies grade C evidence,
scalp would be the same as that seen in the vertex scalp. Global altogether resulting in Evidence Level 1.
stereotactic photographs showed that 5% MTF induced hair In males, average increase from baseline total hair count
growth in both the frontal and vertex scalp, and genes encod- ranged between 5.4–29.9 hair/cm2 (range 11.0–54.8%) at
ing hair keratin-associated proteins were significantly upregu- 6 months, 15.5–83.3 hair/cm2 (range 14.8–248.5%) at
lated after treatment in both the vertex and frontal scalp. Also, 12 months, all statistically significant compared to placebo (p
the expression of epidermal differentiation complex (EDC) between = 0.074 and < 0.0001). Comparable to the results in
and inflammatory genes in both scalp regions decreased, even total hair count was the mean changes in nonvellus hair counts
though regional differences in gene expression profiles were vs. placebo (p between <0.05 and < 0.001), with a mean change
observed before treatment. Both scalp regions showed upregu- between 4.7–37.3 hairs/cm2 (17.2–59.4%) at 6 months and 9.4
lation of genes that encode keratin-associated proteins and hairs/cm2 to 41.8 hairs/cm2 vs. baseline hair counts (p
downregulation of ILK, Akt, and MAPK signaling pathways between < 0.01 and p < 0.0001). Respectively, outcomes of
after 5% MTF treatment. Results suggested that control of MTS applied twice daily in females patients were the following
inflammation in conjunction with keratin stimulation may at 6 months: 1% MTS led to mean changes from baseline total
contribute to the improvement of hair growth disorders [55]. hair count of 15.2 hairs/cm2 (8.0%), 2% MTS showed a mean
Stamatas et al. (2017) further analyzed the results obtained change between 21.0–50.1 hairs/cm2 (12.4–31.3%), 3% MTS
from this study, as presented earlier [54]. showed a mean change of 11.9 hairs/cm2 (12.4%) and 5%
Kanti et al. (2016) conducted an 80-week, open-label Minoxidil Topical Foam, applied once daily led to mean
study, followed by a 24-week randomized, double-blind, changes between 13.4–31.9 hairs/cm2 (16.2%). (all p < 0.0001).
placebo-controlled extension [86]. The enrolled 22 men with Gupta et al. (2015) performed a systematic review of the
AGA who received ongoing 5% MTF treatment for literature and conducted random-effects pairwise meta-
104 weeks and 23 controls who applied placebo. The treat- analyses for the outcomes percent increase in hair count
ment effectively stabilized hair density, hair diameter, and from baseline, investigator assessment, and patient self-
scalp coverage in both frontotemporal and vertex areas over assessment. Results showed that Minoxidil is more effective
the whole 104 weeks-period, while having an excellent than placebo in promoting total and nonvellus hair growth
safety and tolerability profile, with a low rate of irritant con- (Mean Difference [MD], 16.68; 95% Confidence Interval
tact dermatitis. Frontotemporal and vertex target area non- [CI]: 9.34–24.03 and MD: 20.90; 95% CI: 9.07–32.74). A
vellus hair counts (f-TAHC, v-TAHC) and cumulative hair significantly higher proportion of participants in the
width (f-TAHW, v-TAHW) were assessed and results dem- Minoxidil group had more significant hair growth than par-
onstrated that 5% MTF was equally effective in both areas in ticipants in the placebo group as judged by both investigators
terms of hair counts and cumulative hair width. and self-reports (Relative Risk [RR]: 2.28; 95% CI: 1.58–
3.31 and RR: 1.56; 95% CI: 1.34–1.80) [88].
Adil et al. (2017) conducted a systematic review, including
According to these results and clinical experience, only randomized controlled trials of good or fair quality based
Minoxidil, in both MTS and MTF formulation, should on the US Preventive Services Task Force quality assessment
be considered as useful in all scalp areas, even though process. They meta-analyzed results of 5% MTS and 2% MTS
not equivocally, and that it is safe for humans even for in men, and 2% MTS in women. The meta-analysis of these
long-term exposure. studies showed a significant mean difference in hair count for
5% MTS in men (14.94 hairs/cm2), 2% MTS in men (8.11
hairs/cm2), and 2% MTS in women (12.41 hairs/cm2), with all
treatments being superior to placebo (p < 0.00001) [89].
23.7 Efficacy of Minoxidil Gupta et al. (2018) published a network meta-analysis of
the available literature of the six most common non-surgical
Dozens of clinical studies have investigated Minoxidil’s effi- treatment options for treating AGA/FPHL. Overall, 78 stud-
cacy, either as 2% MTS, as 5% MTS or 5% MTF. However, ies met the inclusion criteria, and 22 studies had the data
despite being a longstanding treatment for AGA, relatively necessary for a network meta-analysis. Relative effects
20 23 Minoxidil
showed that PRP, Finasteride 1 mg (male & female), 5%

MTS, 2% MTS, and Dutasteride (male) are approximately mature, massive, and almost synchronized telogen
equivalent in mean change hair count following treatment. before entering into a new anagen. Another explana-
However, the quality of evidence of 2% MTS vs. 5% MTS tion is due to the early release of telogen hairs. In sim-
was high; 5% MTS vs. placebo was moderate; Dutasteride ple terms, old hairs fall out as new hairs grow in their
(male) vs. placebo, Finasteride (female) vs. placebo, 2% place, which should be explained to patients. This phe-
MTS vs. placebo, and 5% MTS vs. LLLT were low; and nomenon, which occurs 2–6 weeks into treatment and
Finasteride (male) vs. placebo, LLLT vs. sham, PRP vs. pla- alarms most patients, is temporary and subsides within
cebo and Finasteride vs. 2% MTS was very low [90]. 2–3 weeks, given that treatment is continued.
23.7.1 How Soon Will Minoxidil Grow Hair? MTS. If unaware of this side effect, patients may discontinue
use prematurely.
During the unofficial preliminary trials, De-Villez [91] Since Minoxidil helps hair follicles to remain longer
reported that hypertrichosis first became observable into anagen and produce thicker, longer, and darker hair, it
3–4 months into treatment with 2% MTS. Price noted that results in better scalp coverage, evident in 3–4 months.
with 5% MTS there was an even earlier response, with the However, several cycles will be required before the hair
first positive results being evident within just 8 weeks [92]. In regrowth peak is reached for all AGA-affected hair folli-
both MTS concentrations, fine, colorless pseudo-vellus and cles. According to Olsen et al. (1990), who followed up 31
intermediate hairs found in the balding or thinning areas will men with AGA using 2% MTS for 5 years, hair regrowth
thicken and grow longer. Since it is improbable that such a peaked at 1 year, slowly declined over subsequent years,
rapid response can be accounted for by reversal of follicular indicating that the overall efficacy of MTS should not be
miniaturization in AGA, a more likely explanation is that evaluated before 12 months of treatment [93] (Fig. 23.4). If
Minoxidil triggers follicles in a prolonged telogen to enter it shows favorable effect, treatment needs to be continued.
anagen [16]. Since hair cycles in AGA are shorter, treatment
with MTS forces hairs to enter telogen and fall out sooner, to
a 500
be replaced by another wave of hairs with a longer anagen
duration, while hairs thicken and become more pigmented. 400
This process is continuous, and most researchers concluded
Nonvellus Hairs
that the maximal growth response is attained after 12 months 300

of MTS use. Long-term treatment is generally characterized
by a slow decline in regrowth over the following years since 200
the long-term hair number counts eventually decrease [62], as
100
will be explained later, but remain higher than at baseline.
Overall, Minoxidil promotes the growth of new terminal 0
hairs of larger diameter and increases the duration of anagen, 0 1 2 3 4 5 6
Years
hence the increased length of hairs in treated areas. However,
Minoxidil will not decrease the duration of telogen below the b 600
minimum physiological telogen duration of approx. 100 days
for scalp hairs. Minoxidil first accelerates transit through a 500
premature exogen phase without otherwise affecting the
Nonvellus Hairs
400
duration of telogen (approx. 100 days for scalp hairs), and
this early effect comes along with initiation of anagen. 300
All patients must be informed of this temporary shedding
period following the initiation of topical application of 200
100 Bid application throughout treatment course

Bid application to 2 years, qd 2 yr to 3 years, bit thereafter
This is the reason why patients frequently experience a 0
transitory increase in hair shedding during the first 0 1 2 3 4 5 6
weeks of treatment. However, this is a positive sign of Years
efficacy and is most likely due to Minoxidil’s shifting
Fig. 23.4 (a) Longitudinal nonvellus target area hair counts in patients
pseudo-vellus and intermediate hair follicles from with AGA treated with 2% MTS, (b) Longitudinal analysis of target
being in a late anagen or early catagen to enter a pre- area hair counts in patients using 2% MTS for AGA: comparison of fre-
quency of application. (Adapted with permission from Olsen et al. [93])
23.7 Efficacy of Minoxidil 21
a b
c d
Fig. 23.5 A 23-year-old male at stage III AGA before (a–d) and after 6 months of 5% MTF treatment. The difference in coverage is significant,
and this type of result is more frequent in younger males with thinning instead of shedding
Most studies agree that a patient can expect regrowth of After MTS discontinuation, 95% of Minoxidil in the skin
lost hair during the previous 2 years. In areas where there are reservoir will be eliminated in 4 days. During the first
still intermediate hairs, larger and thicker, cosmetically sig- 2 weeks, there is no change in hair appearance. Starting at
nificant hairs will emerge, while completely bald areas will 3rd week, severe telogen effluvium-like shedding begins and
only rarely show any improvement (Fig. 23.5). At the begin- lasts until all previously-grown hair during treatment, shed,
ning of treatment, thin, hypopigmented intermediate hairs while not even Finasteride administration can prevent this
will shed and eventually will be replaced by progressively phenomenon [94].
thicker, pigmented, terminal hairs, similar to normal scalp
hair. Nevertheless, MTS treatment should be continued
indefinitely to retain the therapeutic effect. In approximately 3–4 months, the patient will return
not only to his pre-therapeutic hair loss state but will
progress to the AGA stage he would have reached if he
23.7.2 Minoxidil Discontinuation and Effects had never used MTS at all [63, 95–97].
This point is crucial: MTS is not a cure for AGA but a hair
growth-treatment, i.e., the effects will only last as long as MTS The fact that after MTS discontinuation, patients often
is continuously used. Olsen et al. [65], Price et al. [71], and end up with less hair compared to baseline has led to the
several other authors [94–97] have consistently demonstrated erroneous impression of a “rebound effect“ [96, 97]. What
in their studies that upon MTS discontinuation, results will be actually happens is that Minoxidil causes a short-lived telo-
soon and reversed in a predictable mane, with dramatic conse- gen shedding by triggering an immediate telogen release of
quences on the appearance and psychology of the patient. all the hair that has grown due to its effects [96].
22 23 Minoxidil
Fig. 23.6 Schematic timeline No treatment

of MTS efficacy and effect of 100%
MTS
discontinuation, leading to the
reversal of positive results and
Start of treatment Discontinuation of treatment
transition to the stage of AGA
the patient would have
reached if he had never used
the drug
50%
0%
Start 1 Year 2 Years 3 Years 4 Years 5 Years 10 Years
Another “myth” about the long-term efficacy of with discontinuation of treatment for some weeks per year.
Minoxidil is the “tolerance effect” or tachyphylaxis theory This is entirely wrong and is considered malpractice. Also,
(Fig. 23.6). According to the study of Kanti et al. [86], there suggesting a decreased dosage regimen, from the required
was a statistically significant increase in frontotemporal and b.i.d. to o.d. (omne in die, once daily) the scheme is also
vertex target area non-vellus hair counts from baseline to wrong unless there are adverse effects that this practice can
week 52 and week 76, respectively, returning to values com- control. It is also entirely unsubstantiated and wrong that
parable to baseline at week 104. Given that hair growth the frequency of application may be reduced to less than
peaks in approximately 12 months and then regrowth slowly twice daily or to “every other day” after some months of
declines over subsequent years, it has led to another wrong treatment.
assumption that Minoxidil loses its efficacy. However, this MTS is generally very safe and tolerable. It will not affect
is entirely false and does not consider the amount of hair hair color, does not delay or expedite hair greying, and does
that would have been lost had Minoxidil not been used dur- not aggravate dandruff. There are no reported interactions
ing this long period. with any known pharmaceutical substances, while the use of
Finally, there are anecdotal reports on patients under MTS cosmetic products in the scalp does not reduce Minoxidil’s
treatment, who report periods of excessive shedding fol- efficacy. There are some details one should know in order to
lowed by a full “recovery.” This one may be a real phenom- maintain optimum efficacy, which has derived from decades
enon, unlike the two previous unsubstantiated theories. It can of clinical experience:
be explained by the “synchronization” of hair cycles that the
compound induces, which results in hair follicles entering 1. The application of MTS/MTF should be daily and unin-
massively into catagen and then in a synchronized exogen/ terrupted. The recommended dose is 1 mL; the dosage
shedding, thus giving the image of a pseudo-telogen efflu- regimen is b.i.d., the dose is the same regardless of the
vium. This phenomenon is most likely self-limited and extent of the bald surface. The solution or foam is applied
reversible but has not been extensively studied [98]. evenly to the affected area of the scalp and gently rubbed
in. Each application should be spaced at least 8-h apart;
missing a dose cannot be compensated by a following
23.8 How to Use MTS/MTF Properly double dose, neither does a double dose have a double
effect. If a dose is missed, the missed dose is to be
Clinical experience and the findings of controlled clinical skipped, and the usual dosing schedule resumed.
studies have demonstrated that successful treatment with Overdosing should be avoided.
MTS requires proper use of the formulation. 2. Lower frequency of application will reduce results as
In general, standard 12-month treatment should be the Olsen et al. demonstrated [93] and higher frequency than
starting treatment goal. If the patient does not have satisfac- the recommended b.i.d. will only increase the probability
tory results, i.e., hair regrowth or at least halting of further of adverse effects (Fig. 23.4). According to Eller et al.
hair loss, treatment discontinuation should be considered. (1989), who studied the impact of frequency and site of
If results are satisfactory, treatment is continued indefi- MTS application, it paradoxically reduces Minoxidil
nitely, and the dosage regimen remains twice daily (b.i.d.). absorption and reduces efficacy [99]. Their results indi-
Some physicians might suggest an intermittent scheme, cate that every MTS dose provides enough Minoxidil to
23.9 Adverse Effects 23
maintain saturation within the stratum corneum for of the active compound to hair follicles. This reservoir
approximately 10–12 h [99]. Shin et al. (2007), in a small keeps Minoxidil concentration high in the stratum cor-
randomized, double-blind, comparative, clinical trial, neum for optimal delivery of Minoxidil but also acts as
demonstrated that the efficacy and safety of combined an indirect mechanism of prolonged release of the com-
5% MTS and 0.01% Tretinoin o.d. therapy was equiva- pound [108]. Consequently, after the application of
lent to those of conventional 5% MTS b.i.d. for the treat- MTS, hair should be allowed to dry completely before
ment of AGA [100]. This agrees with the results reported using other styling products, e.g., gels or mousse, or
by Ferry et al. [101] back in 1990, who conducted a before going to bed.
smaller scale, randomized study on 19 males and demon- 7. Scalp massage of the after MTS application increases the
strated a threefold increase in the percutaneous absorp- depth of substance absorption through the follicular chan-
tion of 2% MTS by mixing it with 0.05% Tretinoin. They nels [109–112]. Lademann et al. (2006), who has con-
also noticed an increase in the urinary excretion of ducted a large amount of research on skin and follicular
Minoxidil when combined with Tretinoin when applied absorption, speculated that during scalp massage, each
o.d. compared to b.i.d. (see Chap. 32) rigid hair shaft acts as a geared pump, moving the mole-
3. The scalp should be preferably clean since increased, and cules deeper into the hair follicle [113].
persisting greasiness reduces the active substance’s 8. After the application of MTS, hands should be thoroughly
absorption [102]. Lademann et al. (2008) demonstrated washed. Additionally, since facial hypertrichosis may
with the use of laser scanning microscopy and cyanoacry- occur due to “pillow contamination,” it is recommended
late skin surface biopsies that not all hair follicles are to apply MTS at least 2 h before bedtime.
available to absorb substances at any given moment and 9. Using after-market formulas with higher than 5% con-
that some follicular ducts are “open”, while some others centration does not improve growth response. In contrast,
are “closed” [103]. “Closed” follicles are due to plugs of 5% MTS has been found superior to 10% MTS in terms
shed corneocytes pushed out of the follicular orifices by of change from baseline in total vertex, and mean frontal
growing hair or emerging sebum that blocks the duct. hair count, whereas 10% MTS caused significantly more
Washing can actually “open” more follicles since follicu- irritation, shedding, and psychosocial stress [114].
lar penetration is the principal route of Minoxidil absorp-
tion in the scalp [104].
4. Minoxidil in MTS is dissolved in ethyl alcohol and pro- 23.9 Adverse Effects
pylene glycol, and absorption is achieved mostly by dif-
fusion from propylene glycol. Scalp stratum corneum is 23.9.1 Systemic Adverse Effects
saturated by MTS and acts as a reservoir, resulting in a
continuous flow of Minoxidil into the deeper layers of the Some skepticism is reasonable when a potent anti-
scalp, which is completed in approx. 11.5 h [83, 105, hypertensive drug is used to treat AGA. The likelihood of
106]. After topical application, Minoxidil accumulates in adverse effects associated with the absorption of Minoxidil
the stratum corneum and is only gradually distributed in into the circulation worries many candidates. If we consider
the body. The half-life after topical application averages that the scalp is a body area with 3–4 times higher than aver-
22 h [63]. age absorbability [115], this concern is justified. The higher
5. Application of MTS on wet scalp significantly increases absorbability was not sufficiently clear until recently. A
absorption; therefore, it is recommended to leave the study by Blume-Peytavi et al. (2010) addressed the follicular
scalp to dry prior to application to avoid possible sys- and transcellular absorption rate of Minoxidil in vivo, incor-
temic adverse effects. In contrast, Angelo et al. (2016) porating a technique of selective blockade of hair follicle
recently suggested that MTS might be more efficient if ducts. They demonstrated that follicular channels represent a
applied on a damp scalp since drug penetration is highly relevant and efficient penetration pathway and reser-
increased [107]. Shampooing should be avoided for at voir for topically applied substances, especially when on the
least 4 h post-application since absorption of Minoxidil scalp [116]. It has also been reported that Minoxidil’s absorp-
continues several hours after application (75% of tion from the intact scalp skin ranges between 0.3–4.5%
Minoxidil is absorbed in 4 h) and reaches a maximum in (average 1.7%) for 2% MTS [117] and 1.6–3.9% for 5%
approx. 11.5 h [83, 105, 106]. MTS [118]. Therefore, a dose of 1 mL 2% MTS containing
6. Hair dryers should not be used to facilitate the drying of 20 mg Minoxidil will result in absorption of ≈0.3 mg, while
the solution. The solvent vaporizes, and the required a dose of 1 mL 5% MTS containing 50 mg Minoxidil results
reservoir of Minoxidil is not attained in the scalp skin, in absorption of ≈0.85 mg. The serum Minoxidil
which has been observed to maintain a continuous flow concentration-time profile observed for both 2% MTS and
24 23 Minoxidil
5% MTS is characteristically flat, reflecting a long-term Table 23.2 Adverse reactions to 2 or 5% MTS. (Adapted with permis-
zero-order percutaneous absorption process following topi- sion from Trüeb [120])
cal application. Rare (treatment should be withheld
Notably, the minimum effective clinical dose of Minoxidil Common immediately)
for the treatment of hypertension is 25 mg. The standard Hair shedding (during Severe allergic reactions (most often to
initial 4–6 weeks of propylene glycol): rash, hives, itching,
dose of 1 mL 5% MTS allows for a wide margin of dose treatment) difficulty in breathing, tightness in the
safety no less than 37 times higher before the average patient chest, swelling of the mouth, face, lips,
experiences hypotensive symptoms. Topically applied or tongue
Minoxidil is not subject to first-pass metabolism, unlike oral Ectopic hypertrichosis Cardiovascular effects: hypotension,
(usually chest pain, tachycardia, palpitations,
administration, during which Minoxidil is metabolized facial in women, within sudden, fluid retention, unexplained
extensively and rapidly by the liver and excreted almost 3–6 weeks of treatment) weight gain, swollen hands or feet
exclusively (>97%) in the urine [118]. Cardiological symp- Dryness, desquamation, Neurologic effects: headache, dizziness,
toms occur when serum Minoxidil concentration exceeds eczematous lesions light-headedness, weakness, taste
disturbances, and distaste for smoking
20 ng/mL [119]. Therefore, concentrations of 0.60 ng/mL
Itching, redness, burning Unexplained: breast tenderness, changes
and 1.6 ng/mL, which are observed after long-term use of prickling or irritation at in vision or hearing
2% MTS and 5% MTS, respectively, allow for a wide safety the treated area (usually
margin. Also, there are no apparent trends for serum due to propylene glycol)
Minoxidil levels to increase with time according to available Changes in hair color or Thrombocytopenia and leukopenia
texture (WBC < 3000/mL) have very rarely
clinical trials on 5% MTS, involving 1885 subjects. The been reported with oral Minoxidil
absorption of Minoxidil by the inflamed or non-intact skin Burning or irritation of the
has not been studied, and MTS should be avoided under eyes
these conditions [118, 119].
Nevertheless, when idiosyncratic fluctuations in skin were there any effects on blood pressure in normotensive
absorption (up to 300% of the average value) are taken into subjects by oral doses of up to 10 mg/day [123]. However,
consideration, combined with the possibility that a patient Leenen et al. (1988), in a double-blind, randomized, parallel
applies a much higher amount of Minoxidil, there is a remote groups study (n = 20 for Minoxidil, n = 15 for placebo),
chance that this “rare” patient will experience MTS-related reported that healthy subjects who used MTS for 6 months
systemic adverse effects. These include hypotension, fluid exhibited significant increases in left ventricular end-
retention with associated edema, hypotension, tachycardia, diastolic volume, in cardiac output, and in left ventricular
pericarditis, palpitations, and even chest pain. Consequently, mass [124]. The largest, 12-month, prospective observa-
individuals with a diagnosed cardiovascular disorder need to tional, safety study on Minoxidil was conducted by Shapiro
be informed on the likelihood of exacerbation of their condi- et al. (2003) following 10,085 men and 1037 women (control
tion in case of overly increased Minoxidil absorption [118, group 9731 men, 1442 women). They demonstrated that
119] (Table 23.2). Minoxidil did not add any risk factor in any system (circula-
The potential risk of patients with hypertension, both tory, reproductive, respiratory) of the study subjects [125].
treated and untreated, experiencing hemodynamic evens Neurologic events have been reported only rarely and
when using MTS was studied in structured clinical trials by include headache, dizziness and light-headedness [126],
Friedman et al. (1988) They who conducted a 16-week, con- weakness and dizziness [127], taste disturbances, and dis-
trolled, placebo study, using MTS 3% b.i.d., in 98 patients taste for smoking [72]. There is only one report of ectopic
with AGA, who received concomitant anti-hypertensive depigmentation in the neck and lumbar spine in a 57-year-
treatment, including vasodilators. There were no indications old man who used Minoxidil for 14 days [128].
of interaction with any other treatment or any reports of Accidental or purposeful oral ingestion of MTS can be
arrhythmia, weight gain, hypotension, or pericardial effusion hazardous. The severity of symptoms and the prognosis will
[121]. According to the post-marketing surveillance study, depend on the amount used [129]. Only a few reports of
participants in the MTS cohort who entered with known car- Minoxidil intoxication have been described in the literature.
diovascular risk factors or a history of cardiovascular dis- There is only one pediatric case, probably because MTS’s
ease, were not at increased risk of hospitalization compared unpleasant taste reduces accidental or intentional ingestion
to non-treated subjects with similar conditions. by children. Most serious cases have been described in
Overall, 5% MTS has demonstrated impressive safety, adults, causing severe prolonged hypotension, acute coro-
with less than 40 reports of hypotension reported to nary syndrome, and compensatory tachycardia, which can be
Pharmacia & Upjohn since 1996. The 5% MTS did not affect successfully managed with norepinephrine bolus and infu-
arterial hypertension in normotensive subjects [122], nor sion [130].
23.9.2 Local Adverse Effects cosmetic acceptability and clinical efficacy of a novel pro-
pylene glycol (PG)-free 5% MTS on 30 subjects of both
While systemic adverse effects are rare, the same does not sexes with a diagnosis of AGA/FPHL. The authors reported
apply to dermatologic adverse events induced by the topical an excellent cosmetic acceptability/tolerability profile that
action of MTS formulations. The most common adverse no subjects reported burning, itching, or redness sensations
effects reported in clinical studies were generally mild appli- and that the PG-free MTS showed similar skin penetration
cation site reactions. Incidence of irritation accounts for 7% levels and amount of absorbed dose compared with regular
of cases with 2% MTS, inducing local irritation, dryness, MTS [136].
desquamation, erythema, and in-use skin intolerance (itch-
ing, burning, and prickling). 23.9.2.1 Propylene Glycol
A comparative study of 2% MTS, 5% MTS and placebo, Propylene glycol is a very potent synthetic organic solvent,
demonstrated that skin-related events were more frequent in primarily used in the production of polymers, but also sees
the 5% MTS group, while severity was similar between 2% use in food processing and as a process fluid in low-
MTS and 5% MTS groups. The higher content of propylene temperature heat exchange applications, i.e., brake fluid and
glycol in the 5% MTS formulation is probably responsible antifreeze. When applied to human skin, it increases the con-
for the increased local adverse effects since 8% of the popu- tent of stratum corneum in water, so it is widely used in sev-
lation are allergic to it and a much higher percentage are irri- eral cosmetic products. Prolonged contact with propylene
tated by its local effects [131]. glycol is essentially non-irritating to the skin, and it is very
extensively used in the cosmetic industry, found in every
form of cosmetic products (deodorants, lipsticks, toothpaste,
While irritant dermatitis usually develops early in the etc.). However, Goldsmith reported that propylene glycol
course of treatment, allergic reactions are usually produces both reversible and irreversible changes in protein
acquired later. Thus, in most cases, individuals experi- moieties, enhances the solubility of some proteins in water,
encing an early local reaction to MTS are reactive to including keratin proteins, and alters the cross-link density
propylene glycol or the formulated topical solution of keratin within the stratum corneum. He also reported that
and not allergic to the active substance per se [72]. propylene glycol at concentrations higher than 60% causes
protein denaturation, causing proteins to lose their quater-
nary, tertiary, and even secondary structural features [137].
Minoxidil has a very favorable safety profile but can occa- The absorption of propylene glycol by the skin is rapid, and
sionally cause irritant and allergic contact dermatitis (ACD). in high doses, it is related to significant cellular damage, both
ACD due to MTS can present as pustular dermatosis of the in vitro and in vivo in lab animals [138]. It is also hypothe-
scalp, eczematous lesions, erythema, pruritis, or scaling of sized to remain as an endocellular residue even after discon-
the scalp. These individuals should be subjected to patch tinuation [137–139]. In vitro experiments have shown that
tests to verify whether the reaction is due to the solvent or to propylene glycol is approximately 2.5 times more toxic for
Minoxidil [59]. In the case of propylene glycol or formulation keratinocytes and skin fibroblasts than ethanol [138].
allergy, the pharmacist may prepare a solution with an alter- Damages potentially related to its chronic use have not been
native vehicle [132, 133] (glycerine, butylene glycol, poly- officially reported, and there is no evidence of being a car-
sorbate), tolerable by the patient. In those rare cases of true cinogen or being genotoxic.
Minoxidil allergy [134], topical treatment should be immedi-
ately discontinued [59]. 23.9.2.2 Ethanol
These rare and challenging cases of ACD to MTS might Chronic application of ethanol on the skin has not been
safely tolerate oral Minoxidil since systemic skin reactions related to clinically significant damage. It is generally milder
to topical or oral minoxidil have never been described. than propylene glycol, according to in vitro and ex vivo stud-
Actually, Therianou et al. (2020) has presented 9 cases of ies [140], but it is known to cause skin dehydration and irre-
female patients who became allergic to MTS and could tol- versible local skin atrophy. Neuman et al. (2002)
erate low-dose oral Minoxidil (0.5 mg o.d.) without side demonstrated that ethanol, even at low concentrations (3%),
effects [135]. is a potent inducer of epidermal cellular apoptosis since it
It is noteworthy that the use of ethyl alcohol and propyl- enhances the effect of TNF-α activity by more than 400%.
ene glycol as Minoxidil solvents, as well as their chronic use The concentration of ethyl alcohol in 2% MTS is higher than
in human skin, are likely to carry negative health conse- 50%, and the increase of TNF-α activity depends directly on
quences. Recently, Barbareschi et al. (2020) investigated the the concentration of alcohol in the solution [141].
26 23 Minoxidil
23.9.3 Ectopic Hypertrichosis concentration is more frequently related to ectopic hypertri-

chosis in women than in men. The incidence correlated with
One of the most frequently reported adverse effect is extra- MTS concentration (5% > 2% > placebo), and a dose-related
neous hair growth in areas where MTS is not applied, such as pattern of response was evident. Interestingly, post-marketing
the chest, legs, forearms, and in areas of the face that were data showed a lower occurrence (0.5%) of hypertrichosis/
previously hairless, such as cheeks in females and forehead facial hair than clinical trials [144]. According to other
in both sexes, while several patients report increased scalp authors, some women are prone to develop facial hair, hav-
greasiness. The etiology of hypertrichosis is not known, but ing hair follicles that are very sensitive to MTS, and should
the most likely cause is the inadvertent transfer of topical use the lowest strength of MTS (2%) to help avoid unwanted
Minoxidil residue to other skin sites, either manually or on hair growth [145].
pillows, towels, and linens [131]. Ectopic hair growth from
Minoxidil is a cosmetic liability but poses no immediate
short-term or long-term threat to the patient’s health. It can Hypertrichosis is typically reversible within
be usually controlled by careful MTS application, and it is 3–5 months and does not always require discontinua-
fully reversible in 1–3 months upon discontinuation of treat- tion of therapy [142, 144].
ment [142] or even while treatment continues.
Hypertrichosis is reported more frequently in women
[143] (up to 17.5%) than in men, but it is unclear whether According to early results by Carson et al. (1977),
this occurs because it is genuinely more common or just Minoxidil is not teratogenic in animals, even in doses five
more noticeable (Fig. 23.7). Dawber et al. (2003) analyzed times higher than human therapeutic doses [146]. However,
the data from placebo-controlled clinical trials in 1333 there are contradicting results reporting fetal defects and
females and studied spontaneous reports of hypertrichosis increased mortality in embryos in lab animals, but at expo-
and/or increased facial hair. They indicated that higher MTS sure levels that in comparison to levels obtained in humans
b
a
c d
Fig. 23.7 Minoxidil-induced hypertrichosis due to over-treatment the excessive concentration and amount of drug applied daily resulted
with 5% MTS. This 24-years-old medical student decided to triple the in hypertrichosis in many areas of her body. Notably, the patient was
dose of 5% MTS b.i.d. hoping for better and faster results. Naturally, reluctant to reduce her scheme in fear of losing her scalp hair
23.11 Minoxidil Topical Foam 27
are extremely high (up to 2100 times the human dose). A fascinating study was conducted by Mapar et al. (2007)
Details on the teratogenesis incidence in humans under and offered valuable insights into the phenomenon of poor
Minoxidil treatment are insufficient [117]. There are rare compliance with MTS. The researchers conducted a pro-
case reports of severe fetal malformations that could be spective, non-randomized study to evaluate the ratio of
linked to maternal Minoxidil use [147–149] well as sporadic patients satisfied with MTS and continued to use it compared
case reports of hypertrichosis in infants due to transdermic to those who were displeased and discontinued treatment,
exposure to Minoxidil [150]. Even though Minoxidil has not and what were the reasons for MTS discontinuation. The
been proven to be mutagenic, teratogenic, or carcinogenic, it 5-year long study included 1480 patients of a private
should not be administered to pregnant and nursing women Dermatology clinic. None of the subjects participated in any
since it is secreted in human milk [119]. Given that Minoxidil official research protocol, and results on compliance were
easily crosses biological barriers and accumulates into lipids, markedly different than in official trials. Between
brain and fetal concentrations may be significantly higher 2–4 months, already 29% of patients had discontinued treat-
than the concentrations detected in plasma. Since there are ment, and by 6 months, that percentage climbed to 55%.
no adequate and well-controlled studies in humans, but
potential benefits may warrant using the drug in pregnant
women despite potential risks. Therefore, Minoxidil is clas- Approximately 13% of patients discontinued treat-
sified as a class C drug during pregnancy [151]. ment due to adverse effects; by month 12, 95% of
Wu et al. (2016) who examined the clinical reports sub- patients had dropped out, and the rest gradually
mitted to the FDA Adverse Event Reporting System avoided continuing the treatment. By the end of year 5,
(FAERS) from 2004 to 2014 and published an excellent one single patient (0.07%) out of 1480 patients
review, reported that Minoxidil was extremely rarely remained on treatment [155].
accused of reproductive or CNS adverse effects, unlike
Finasteride [152].
Differences in compliance in this study compared to clini-
cal trials may be due to different behavior of patients under
23.10 Minoxidil and Daily Practice “everyday” conditions compared to scientific studies. When
participating in a study, no charges on the product or medical
The correlation between medication adherence, compli- monitoring are imposed on patients, their curiosity on the
ance, and the required frequency of drug administration final results is stimulated, and therefore, they are motivated
(dosage regimen) is inversely proportional [153, 154]. A to comply with treatment. On the contrary, in real-life clini-
large number of individuals starting MTS treatment will cal practice, only very few patients follow MTS treatment
discontinue it soon afterward since they cannot comply persistently, especially when the cosmetic result does not
with the required twice-daily dosage regimen for an encourage them to use the product daily with due interest
extended period. Additional reasons for poor compliance and enthusiasm. The doctor should keep this in mind and fol-
include undesirable hair texture and scalp irritation. This low patients using MTS and be ready to change or modify
has been reported first by Koperski et al. in one of the first treatment if results are unsatisfactory.
(1987) long-term studies (30-months long) in which
patient compliance to treatment was less than 70% after
30 months [106]. Shapiro reported in 2004, that, in a total 23.11 Minoxidil Topical Foam
of 3 million subject-days in a large-scale, 12-month, obser-
vational study, compliance to the approved b.i.d. dosage Since MTS is the “Gold Standard” topical treatment for
regimen was 89% at month 1 and dropped to 70% month AGA, there have been significant efforts to further increase
12, while daily use dropped from 95% at month 1–82% at its efficacy. These efforts focus on the pharmaceutical form
month 12. Interestingly, 56% of patients reported multiple of MTS to increase absorption by the scalp and reduce the
discontinuation episodes for more than four consecutive adverse events of organic solvents. Upjohn presented in 2006
days at some point. The same study reported that out of an innovative foam product [156], Minoxidil Topical Foam
8075 patients who completed the study, 92% described 5% (5% MTF), which has been proven to deliver a higher
MTS’s efficacy in slowing or stopping hair loss as excel- amount of the active compound at an increased rate com-
lent, good, or fair, while 32% reported excellent hair pared to other vehicles and has higher efficacy compared to
growth [125]. So, poor compliance in MTS is not corre- any other pharmaceutical form [157]. Even before the mar-
lated to poor results [125]. ket launch, Upjohn had conducted consumer use studies,
28 23 Minoxidil
which indicated that MTF 5% rated significantly higher on daily for 24 weeks in frontotemporal and vertex regions and
several aesthetic attributes compared to 5% MTS, including measured the target area non-vellus TAHC and target area
ease of application, lack of dripping, quick absorption, dry- cumulative non-vellus hair width (TAHW). They demon-
ing, and fitting easily into a daily routine. strated that at 24 weeks, frontotemporal TAHW increased
The formula of 5% MTF is propylene glycol-free, it is a significantly in the 5% MTF group compared to the placebo
liquid pressurized in an aluminum canister with a hydrocarbon group (p = 0.017), while 5% MTF users rated a significant
propellant, which forms a foam lattice on valve actuation. This improvement in scalp coverage for both the frontotemporal
matrix is thermolabile and breaks down rapidly as soon as it (p = 0.016) and the vertex areas (p = 0.027) [161].
comes in contact with the skin. The volatile constituents evap-
orate and, within 20–30 s, little or no residue remains on the
skin. The active ingredient concentrates on the vehicle-skin
interface and facilitates penetration [156]. In the hamster ear Overall, 5% MTF is easier to use, does not drip, dries
model, 5% MTF showed a fivefold increase in Minoxidil’s quickly, and is absorbed with a low residue, resulting in
uptake over 5% MTS at 2 h of application [158]. A human an easy adaptation in the daily routine of patients. Patients
pharmacokinetic study showed that systemic absorption of demonstrate increased compliance and report increased
Minoxidil with 5% MTF (1 mL twice daily) was half of 5% satisfaction on ease of use and enhanced results.
MTS (1 mL twice daily) and that application of 3gr of MTF
b.i.d. resulted in systemic levels that were significantly lower
than the 21 μgm/mL threshold for cardiac- related events Since the twice-daily dosage regimen is always an issue,
[155]. These results demonstrated that the locally increased a 24-week study of Blume-Peytavi et al. (2011) compared
absorption of 5% MTF is related to decreased systemic bio- the efficacy, safety, and acceptability of 5% MTF vs. 2%
availability, besides increased efficacy. MTS. The authors hypothesized that once-daily 5% MTF
A direct comparison of 5% MTF and 5% MTS efficacy was (50 mg Minoxidil/day) was not inferior in results to twice-
first conducted in 6 macaques [159] and later confirmed in daily 2% MTS (40 mg Minoxidil/day), analyzing 113 women
AGA patients [85]. In the macaque study, Rundegren et al. with FPHL (100 completed the study) in a 24-weeks long
(2005) reported that animals under treatment with 5% MTF at study. They concluded that o.d. 5% MTF was as effective in
the end of 4 months exhibited increased hair weight by 12.4 mg stimulating hair growth as b.i.d. 2% MTS in women FPHL
(range 8.23–26.00 mg), compared to just 9.27 mg (range 4.96– and associated with several aesthetic and practical advan-
11.53 mg) of the MTS 5% group [159]. Olsen et al. (2007) tages, namely increased convenience of use, less adverse
assessed the new 5% MTF formulation’s efficacy and safety in effects, better compliance, and increased product acceptabil-
a double-blind, placebo-controlled, randomized, multicenter ity by patients [143].
study, enrolling 352 men with AGA, aged 18–49. At 16 weeks, Blume-Peytavi et al. published in 2016 the results of a
the mean increase in hair counts relative to baseline between similar, more extended (1-year), randomized, single-blind,
5% MTF and placebo (20.9 vs. 4.7 nonvellus hairs and 13.4% phase III clinical trial of o.d. 5% MTF vs. b.i.d. 2% MTS in
vs. 3% total nonvellus hairs, respectively) was statistically sig- women with FPHL, conducted at 12 sites in the United
nificant, while subjects on 5% MTF reported a mean 70.6% States, Canada, France, Germany, and the United Kingdom
increase in hair growth vs. 42.4% of control subjects [85]. (ClinicalTrials.gov identifier NCT01145625). Even though
Researchers commented that the novel foam vehicle offered the treatment difference in hair counts between o.d. 5% MTF
certain advantages over MTS, including the absence of propyl- (23.9 ± 2.1 hairs/cm2) and b.i.d. 2% MTS (24.2 ± 2.1 hairs/
ene glycol, the ability to limit spread beyond the intended cm2) was just −0.3 hairs/cm2, the authors considered that the
application site, and less time to dry after application. Its pre-specified, non-inferiority goal was not met [162]. Similar
enhanced cosmetic acceptability increases compliance with results were reported by Bergfeld et al. (2016) in their Phase
treatment and enhances the results of treatment, combined with III, randomized, double-blind, vehicle-controlled, parallel-
the fact that itching with 5% MTF was 1.1% vs. 6% seen in the group, international multicenter trial (17 sites) in 404 women
previous trial of 5% MTS [72]. Another smaller study, con- with FPHL. Subjects were treated o.d. with 5% MTF or vehi-
ducted by Hasanzabeh et al. (2016) in Iran, on 12 young males cle foam for 24 weeks, and target area hair count (TAHC),
with AGA, confirmed the superior efficacy of 5% MTF. The total unit area density (TUAD) were measured, and subject
average hair count at week 0 (162.85 ± 45.93) was significantly assessment of scalp coverage was evaluated. At 24 weeks,
increased at week 24 (194.58 ± 62.82, p < 0.019), and satisfac- 5% MTF treatment resulted in regrowth of 9.1hairs/cm2
tion on ease of use increased between week 16 (85.7%) and more than the vehicle foam, and an improved scalp coverage
week 24 (91.6%) [160]. was observed by both subject self-assessment and expert
Hillman et al. (2015) conducted a study on 70 males with panel review. TUAD increased by 644 μm/cm2 more with 5%
moderate AGA who applied 5% MTF or placebo foam twice MTF than with vehicle foam (all p < 0.0001) [163].
23.13 Oral Minoxidil 29
23.12 Novel Minoxidil Formulations 2018. Mean age was 48.44 years (range 18–80), mean hair
loss stage at baseline was 2.79 in the Sinclair scale (range
Aiming to increase the efficacy, various researchers and 1–5), and the mean hair shedding score at baseline was 4.82
commercial companies have tried to incorporate Minoxidil (range 1–6). The authors reported that the mean reduction
into ethosomes [164], liposomes [165], cyclodextrins [108, in hair loss severity score was 0.1 at 3 months, 0.85 at
166], nanoparticles [167], alternative foam vehicles [168], 6 months, 1.1 at 9 months, and 1.3 at 12 months. Mean
as well as to penetration enhancer-containing vesicles reduction in hair shedding score was 1.1 at 3 months, 2.3 at
[169], nanostructured lipid carriers [170], effervescent for- 6 months, 2.7 at 9 months, and 2.6 at 12 months. Side
mulation [171], alginate-based hydrogel [172], and effects were seen in 8 women but were generally mild. The
nanovesicles [173]. full-text article contains good-quality, before-and-after
A study by Jain et al. (2010) using liposomes in vitro and photos of 5 patients with significant hair growth at
ex-vivo showed absorption threefold higher than MTS [174]. 12 months [180].
All the efforts mentioned above have been reported as suc- Beach et al. (2018) published the results of a case series
cessful, but it remains to be seen whether innovative methods of 18 patients (17 females, 1 male) with FPHL/AGA who
of Minoxidil application will actually be available, at what were prescribed 1.25 mg LDOM nightly. Six of 18 patients
cost, and with what actual efficacy. (33%) reported decreased hair shedding, while five of
those (28%) reported increased scalp hair (5/18).
Hypertrichosis was reported in 39% (7/18) on the face
23.13 Oral Minoxidil (most commonly the skin lip) and arms, yet all affected
patients continued therapy due to its perceived benefit for
Until recently, oral Minoxidil (OM) has rarely been used to their scalp hair [181].
treat hair loss due to the drug’s potential side effects when
used at maintenance doses between 10–40 mg daily.
Therefore, the “off-label” use of OM for hair loss has been The authors argued that aside from tolerability, there
sporadically reported. Those rare literature reports con- are five practical advantages of this therapy, the “5 C’s
cerned the successful treatment of chemotherapy-induced of OM”:
alopecia [175], alopecia areata [176], and chronic telogen
effluvium [177]. • convenience to swallow Minoxidil than to apply it
Interestingly, the use of low dose OM (LDOM) over- topically,
comes many of these therapeutic limitations and is • enhanced cosmesis because oral prescription ther-
recently becoming an increasingly common practice. apy does not generate product residue or distort hair
LDOM has been used with significant improvement in color or luster,
both AGA/FPHL patients in doses varying from 0.25 to • cost-savings relative to the topical “over-the-coun-
5 mg/day, alone and in combination with other therapies. ter” product,
Since 2015, but mostly since 2019, there is an increasing • co-therapy such as the application of commercial
amount of papers published on the off-label” use of keratin fibers to visually enhance fullness was sim-
LDOM in AGA. pler without the use of competing topical Minoxidil
Lueangarun et al. (2015) reported improvement in all 30 on the scalp,
men (100%) with AGA who were administered 5 mg LDOM • enhanced compliance since 78% of patients contin-
o.d. However, 93% of patients showed ectopic hypertricho- ued oral therapy.
sis, 10% had lower limbs edema, and 10% mild electrocar-
diogram alterations were reported [178]. One explanation for
the hypertrichosis is probably the higher dose of LDOM Jimenez-Cauhe et al. (2019) evaluated the effectiveness
compared to most other studies. and safety of LDOM in a cohort of 41 male patients (mean
Sinclair reported using LDOM in men and women with age of 33.3 years, range 20–55) at a daily dose of 2.5 mg
AGA/FPHL, respectively, who were either intolerant to (10 patients) or 5 mg (31 patients). Clinical improvement
MTS either because of scalp irritation or altered hair tex- was observed in 37 patients (90.2%), with 11 of those
ture. Sinclair initially reported his results in a scientific (26.8%) presenting a marked improvement. Interestingly,
congress poster concerning the safety and efficacy of the initial clinical response was shown after 3 months of treat-
combined regimen of 0.25 mg LDOM and Spironolactone ment, being faster than MTS or Finasteride, whose response
25 mg. He used the treatment on 100 women with FPHL, at assessment is usually recommended at 6–12 months. Four
a Sinclair stage 2–5, for 12 months [179]. The detailed patients (9.8%) showed stabilization, and none worsened.
results of this study were published in an article in late Adverse effects were detected in 12 patients (29.3%):
30 23 Minoxidil
hypertrichosis in 10 patients (24.3%), lower limb edema in was 121.85 mmHg, and DBP was 77.46 mmHg, respectively.
2 patients (4.8%) and shedding in 1 patient (2.4%). All There were no serious adverse effects recorded, and the most
adverse effects were mild and well-tolerated. Only one common adverse effect was mild hypertrichosis, recorded in
patient discontinued treatment because of pedal edema. 12.5% (eight females) of patients. Mild postural dizziness
These adverse effects appeared with the dose of 5 mg, occurred in 7.8% (three males, two females) of patients, and
except in 2 patients with slight hypertrichosis and one mild peripheral edema in 3.1% (two females) [185].
patient with shedding (2.5 mg daily) [182]. Beach et al. (2020) retrospectively examined 51 patients
Pirmez et al. (2019) performed a retrospective review of who received at least one three-month prescription for
medical records from 25 male patients with AGA (mean age 1.25 mg Minoxidil over a 3-year period. Results indicated
36.7 years, range 23–53 years) AGA using formulated cap- increased scalp hair growth (33/51; 65%) and decreased hair
sules of very-low-dose OM (0.25 mg/day). The authors shedding (14/51; 27%). In this article, the authors proposed
reported that statistical analysis did not show a significant a sixth “C” of LDOM as an addition to their previous paper
variation in the group as a whole, probably due to the small [181], namely “crown efficacy“, due to the increased hair
sample size and the high percentage of patients with advanced growth at this scalp region [186]. Ortega-Quijano et al.
AGA in the study. Therefore, the lack of statistical signifi- (2021) commented on the article by providing Minoxidil-
cance can be attributed to a type II error (false negative find- related information from the FDA Adverse Event Reporting
ing) [183]. System (FAERS) Database, from inception (1969) to Nov
Ramos et al. (2019) conducted a 24-week, randomized, 11, 2020. From a total of 57,129 minoxidil-associated
open, comparative study of LDOM 1 mg vs. 5% MTS for the adverse events reported to the FAERS, only eight [2] were
treatment of FPHL on 50 female patients. After 24 weeks of related to LDOM used for alopecia, and only 5 were related
treatment, the total hair density increased by 12% (95% CI: to Minoxidil established adverse effects [187].
8.0–16.1%) in women taking LDOM vs. 7.2% (95% CI: Panchaprateep et al. (2020) conducted an open-label, pro-
1.5–12.9%) in women applying 5% MTS, with no difference spective, single-arm clinical trial on 30 males aged
between groups (p = 0.10). Scalp pruritus affected 19% of 24–59 years with AGA types III vertex to V who were treated
the MTS group participants, and pretibial edema occurred in with LDOM 5 mg o.d. for 24 weeks. This is the first study
4% of the LDOM group participants. Also, hypertrichosis that efficacy was evaluated by hair counts, hair diameter
was more common in the LDOM group (27%) vs. the MTS measurements, photographic assessment, and self-
group (4%), although it was mild and well-tolerated. There administered questionnaire. There was a significant increase
was no difference between groups regarding the variation of in total and non-vellus hair counts. Non-vellus hair counts
mean blood pressure over time. The mean heart rate at rest significantly increased from baseline (152.3 ± 33.0) at
increased by 6.5% in the LDOM group, while no tachycardia 12 weeks (+ 26 ± 18.4 hairs/cm2; p = 0.006) and 24 weeks
and no hypotension-related events occurred. The authors (+ 35.9 ± 15.6 hairs/cm2; p = 0.001), respectively. Hair diam-
concluded that LDOM improves FPHL that does not differ eter significantly increased from baseline by 10.6% (from
from 5% MTS solution, with a safe profile and well-tolerated 58.5 μm ± 11.8 to 64.7 ± 15.2 μm) at 12 weeks (p = 0.002)
adverse effects. LDOM can be considered an option for and by 15.21% (from 58.5 μm ± 11.8 to 67.4 ± 14.5 μm) at
FPHL patients with poor compliance and/or intolerability to 24 weeks (p < 0.001). Photographic assessment of the vertex
MTS [184]. area by an expert panel revealed 100% improvement
Sinclair et al. (2020) retrospectively reviewed all patients (score > + 1), with 43% of patients showing excellent
seen in their specialist hair clinic with AGA and FPHL improvement (score + 3, 71–100% increase). The frontal
treated with sublingual minoxidil monotherapy for area also showed a significant response but less than that of
>6 months. Sixty-four patients (33 males and 31 females) the vertex area. Common side effects were hypertrichosis
were included. The mean age was 50.92 years (range (93% of patients) and pedal edema (10%). No serious cardio-
17–76 years). The starting dose of LDOM was 0.45 mg daily. vascular adverse events and abnormal laboratory findings
In 19 patients, the dose was increased to 0.9 mg daily at were observed. These results suggest that LDOM 5 mg is
3 months. Patients were reviewed at 3-monthly intervals, and superior to a 2–5% MTS, 5% MTF, Finasteride 1 mg, and
clinical photographs were scored using the Sinclair stage for Dutasteride 0.5 mg daily in all measurements [188].
each time period. The mean Sinclair stage at baseline was Jha et al. (2020) published the results of a case-series of
2.77. The mean reduction in Sinclair stage for all patients LDOM monotherapy at 1.25 mg/day for 24 weeks in 32
was 0.33 at 3 months, 0.53 at 6 months, 0.81 at 9 months, and patients with AGA, aged 18–45 years (mean age
1.07 at 12 months. At baseline, the mean systolic blood pres- 28.83 ± 7.12 years). Of the included patients (n = 32), 18
sure (SBP) and diastolic blood pressure (DBP) were 126.27 (56.2%) were treatment-naive, whereas 14 (43.8%) had
and 76.69 mmHg, respectively. At 12 months, the mean SBP failed previous monotherapy with either 5% MTS or oral
23.13 Oral Minoxidil 31
Finasteride received for at least 1.5–2 years. Efficacy out- dence (less than 10% of patients). Cardiovascular adverse
come measures included global clinical photography and effects were rare and relatively minor. Blood pressure was
quantitative digital video trichoscopic assessment. At monitored in some of the studies with only minor changes;
24 weeks, marked and mild improvement was observed in 14 however, the pulse rate increased by 6.5%. Postural hypo-
patients (14/32, 43.8%) and 13 patients (13/32, 40.6%), tension/dizziness was reported in 2% of patients. Lower
respectively. Overall, a 48.4% improvement in hair density limb edema was only seen in 3% of patients, most of whom
and increment of average hair caliber per unit area or average were on 5 mg LDOM. EKG changes were reported in
hair shaft diameter from 5011.7 μm to 68.1611.6 μm approximately 1% of cases; however, it is unclear if patients
(p < 0.01) were noticed at the vertex [189]. were regularly examined with EKG as this was only
Rodrigues-Barata et al. (2020) retrospectively studied the reported in one study [192].
most extensive series of patients with FPHL treated with Jimenez-Cauhe et al. (2020) conducted a systematic
LDOM to date; 148 FPHL women with a mean age of review of 14 studies, including 442 patients in LDOM for
47.2 years (range 17–85) were analyzed. LDOM of 0.25 mg treating hair loss. They also reported that all doses had an
and 2 mg were used daily (median 1 mg daily), for a mean increased odds ratio of hypertrichosis, compared to 0.25 mg
time of 9 months (range 6–27). A total of 23 patients (15.5%) to 0.5 mg (p < 0.001). Pedal edema was observed in 2% and
received LDOM as monotherapy, while 125 patients (84.5%) was also associated with higher doses of LDOM (p = 0.009).
received other concomitant therapies. Regarding effective- Postural hypotension and heart rate alterations occurred
ness, 30 patients (20.3%) presented stabilization of their alo- only in 1.1% and 1.3% of the patients, respectively. Four
pecia, and 118 patients (79.7%) presented clinical studies using LDOM for AGA reported a clinical response
improvement. Of these, 95 patients (64.2%) presented a in 70% to 100% of patients. Overall, LDOM has a good
slight improvement, and 23 patients (15.5%) a marked safety profile, which is particularly important for off-label
improvement. The clinical improvement was higher in more medications [193].
advanced stages of FPHL (p = 0.026). Of the subgroup of Overall, LDOM remains an off-label treatment for AGA,
patients receiving LDOM in monotherapy (n = 23), 12 (52%) and treatment should be individualized. It may be considered
presented a slight improvement, and 3 (13%) a marked in patients with AGA to whom standard treatment options
improvement. The rate of improvement of patients receiving failed or were contraindicated; lower dosages may be prefer-
LDOM in monotherapy was comparable to patients receiv- able in female patients with FPHL. Hypertrichosis is the
ing combined therapies (65 vs. 79%, respectively) [190]. only constant adverse effect in all studies, but it is considered
Vastarella et al. (2020) published similar results in a mild by patients of both sexes. Hypertrichosis is dose-
small, retrospective analysis of 12 FPHL patients aged dependent, ranging from 4% of the patients treated with
18–66 years (mean age 36.66 ± 18.79 years) who started 0.25 mg [180], to 93% with 5 mg [178] and represents the
with an LDOM dose of 0.5 mg o.d. and at 3 months, the dose main limiting factor to the efficacy and compliance.
was increased to 1.5–2 mg. An overall improvement of 38% Jimenez-Cauhe et al. (2020) conducted a prospective study
and 23% in hair density in the frontal and vertex area, respec- to describe the characteristics and management of LDOM-
tively, was observed after 24 weeks. Both the total average induced hypertrichosis in 105 patients (98 females and 7
hair density (131.47 ± 36.11 vs. 181.40 ± 57.38; p = 0.025) males) with a mean age of 39.4 years (range 15–78 years).
and the total number of hairs per unit area (118.72 ± 32.61 The mean dose of LDOM was 1.07 mg daily overall (range
vs. 163.81 ± 51.82; p = 0.025) increased at 24 weeks. LDOM 0.25–5 mg), 0.88 mg (0.25–5 mg) in females, and 3.71 mg
was generally well tolerated by patients even at doses of (0.5–5 mg) in males. The mean time between the start of
2.5 mg/day without any severe adverse effects [191]. LDOM and the appearance of hypertrichosis was 2.05 months
Randolph and Tosti reviewed a total of 16 studies with (range 0.5–6), occurring in the first 3 months in 92.4% of
622 patients discussing the use of LDOM as the primary patients. Most affected areas were sideburns in 85 patients
treatment modality for eight different types of alopecia. (81%), and temples in 77 patients (73%), followed by arms,
They reported that LDOM is well tolerated with only minor upper lip, and chin. Overall, 90% of the patients had a total
adverse effects described in the literature. The most hypertrichosis score < 10/48, supporting that hypertrichosis
reported side effect was hypertrichosis, apparent in 20% of degree was generally mild. In this respect, 41 patients (39%)
patients. Interestingly, hypertrichosis was rarely a cause for were not concerned about it and did not have their hair
discontinuation of the medication as many patients consid- removed. In the remaining 64 patients (61%), the unwanted
ered it only a mild side effect and easily manageable. hair was removed by laser, waxing, shaving, depilatory
Overall, hypertrichosis was more common among patients cream, or plucking. Twenty-four patients (23%) required
who used 5 mg daily and was seen in a little over half of decreasing the dose of LDOM due to hypertrichosis, improv-
them. A dose of 0.25 mg had the lowest hypertrichosis inci- ing in 20 of them (83%) with the lower dose. Only 4 females
32 23 Minoxidil
(4%) discontinued the treatment due to hypertrichosis. The severe hepatic impairment. Also, the use of LDOM is contra-
authors proposed to start LDOM in female patients at a dose indicated in individuals with severe pulmonary hypertension
of 0.5 mg daily and consider up-titrating the dose every with mitral stenosis, and risk of cardiovascular events should
3 months according to response and degree of hypertrichosis be carefully planned [199].
[194]. On a final note, similar to MTS/MTF use, LDOM is asso-
do Nascimento et al. (2020) conducted a systematic ciated with a temporary period of increased hair shedding
review to examine the evidence of an association of LDOM that can last 3–6 weeks, and the patient should be made
with hair growth. Of 1960 studies retrieved in several elec- aware. This adverse effect was reported by 32% of 435
tronic databases and three additional records identified patients who were prescribed LDOM for AGA from
through reference list from potentially eligible studies, nine January-2017 to May-2020 at three hair clinics in Brasil
studies (one randomized controlled trial and eight nonran- [200]. Comparably, temporary hair shedding at the begin-
domized controlled trials) met the requirements and were ning of treatment occurs in up to 17.5% of patients using
used in their analysis. All 9 studies yielded a pooled sample MTS [143].
size of 19,270 patients. The authors identified studies evalu- In conclusion, LDOM at a dose of 1.25 mg/day can be
ating the effect of LDOM in four different types of alopecia used in AGA/FPHL, although a higher dose (2.5–5 mg/day)
(alopecia areata, AGA, traction alopecia, and telogen efflu- may be required if, despite 6 months of treatment, the
vium). Overall, all included studies were associated with a response is suboptimal. Further controlled studies are
high risk of bias, ranging from lack of blinding of partici- required to determine better the efficacy and safety as well as
pants and personnel (open study design), conflict of interest, the most suitable posology in men with AGA and females
selection bias, and other biases due to confounding factors with FPHL [201].
(e.g., use of concomitant active drugs for alopecia). Based on
their results, the authors considered that there is insufficient
evidence to support the use of LDOM for alopecia in human The prescribing physician should always be aware that
populations [195]. the off-label prescription of drugs occurs at the discre-
tion of the prescribing physician and that even though
the off-label use of drugs is legal, but the promotion of
However, clinical experience and anecdotal reports
drugs toward unapproved indications can be illegal.
show high efficacy, with an acceptable adverse effects
profile, consisting mostly of peripheral edema and
hypertrichosis.
23.14 A Final Note by the Author

Fortunately, as with MTS/MTF, LDOM-induced hypertri-
chosis is typically reversible within 3–5 months same and In some countries, it is common practice to mix MTS with
does not always require therapy discontinuation [142, 144]. other solutions to allegedly “increase” efficacy or give the
However, for patients with marked hypertrichosis or psycho- impression that the patient is getting a “customized
social disturbances, laser hair removal is an option to get rid treatment.”
of unwanted hairs [196]. In patients who cannot accept the Obviously, physicians resorting to this practice speculate
hypertrichosis, it usually resolves within 2–3 weeks after that by mixing of MTS with any kind of topical pharmaceuti-
stopping the medication [197]. cal lotion (i.e., tretinoin or corticosteroid) or cosmetic lotion
Hemodynamic effects and serious cardiovascular (polysorbate), the patient is granted a more effective formu-
adverse effects may discourage LDOM prescription for lation, which is easier to apply (since he will only have to
hair loss by physicians. However, changes in BP or pulse apply one solution instead of three or more). Simplifying
rate are minimal, and other cardiovascular complications treatment regimens may have the potential to enhance com-
such as ischemic heart disease, pericarditis, pericardial pliance, and this practice, called galenic formulation, deals
effusion and tamponade, pulmonary hypertension, and high with the principles of preparing and compounding medicines
output cardiac failure have only been reported in very early in order to optimize their absorption or efficacy [202].
studies when therapeutic Minoxidil doses were used for More than that, both the doctor suggesting a galenic for-
hypertension management of 10–40 mg daily maintenance mulation and the pharmacist who is ordered how to prepare
doses [198]. it attain an increased status in the eyes of the patient as
Relative contraindications for LDOM include hypoten- “authorities”: the doctor is not just prescribing an OTC
sion, cardiac comorbidities, and pregnancy; LDOM is strictly lotion, and the pharmacist is not just selling a lotion but is
contraindicated in patients with pheochromocytoma and actively engaged in its preparation.
23.14 A Final Note by the Author 33
However, this practice has severe repercussions. The hair- In support of these, Gajjar et al. [203] conducted a random-
growth effects of Minoxidil are concentration-dependent. It ized, active-controlled trial, enrolling 49 clinically diag-
does not matter how much active substance is in the solution; nosed males of AGA and randomly allotted them into two
only the end concentration matters. Mixing and adding any groups -mesotherapy (A) (n = 25) and Minoxidil (B) (n = 24).
other solution in the MTS vial will result in the dilution of Males in Group A were given a total of 8 sessions of intral-
MTS, decreasing Minoxidil’s concentration. esional resolution with a micro-needling procedure, while
Group B males were prescribed 5% MTS twice daily for
4 months. As expected, dermoscopic, trichoscan, and subjec-
Therefore, under no circumstances should any other tive measurement tools failed to show a significant differ-
solution be added in MTS because it decreases ence between the two groups [202].
Minoxidil’s concentration to below-therapeutic levels. Uzl et al. [204] published the results of an older single-
It is certain that the minimal hair growth potential –if blind, randomized, placebo-controlled trial conducted on 54
any- of the other solution (polysorbate, corticosteroid women with FPHL (18–65 years old) seen at a private der-
lotion, biotin solution, etc.) cannot compensate for the matology clinic from March 2012 to February 2013. They
MTS dilution-induced therapeutic loss. were divided into two groups: one group received intrader-
mal injections of 0.5% minoxidil, and the other received
0.9% saline. Biopsy, trichogram, Trichoscan, and self-
The galenic formulation may be a popular practice, it may assessment findings were used to evaluate the outcomes of
be attractive for the doctor’s reputation in the layman treatment with Minoxidil. The intradermal injections were
patient’s eyes, but it is wrong and unsubstantiated. Mixing administered to the affected area of the scalp weekly for 10
MTS with any other solution on the pretext of “increased consecutive weeks, and the treatment response was assessed
efficacy” or “ease of use” results in lower efficacy and is 6 weeks after the last session of intradermal injections.
considered malpractice. According to the authors, in the treated group, there was a
Finally, in meetings and congresses, one can often find significant increase in the terminal-to-vellus hair ratio
posters, presentations, and lectures on the efficacy of meso- (p < 0.001) and in the percentage of anagen hairs (p = 0.048)
therapy in hair loss. and an improvement in hair loss and volume (p = 0.021 and
In mesotherapy (from Greek word meso = in between, p = 0.028, respectively). The author commented that
therapeia = treat), active substances are injected intrader- Minoxidil intradermal injections were more effective than
mally into a depth of approx. 3–4 mm using 30–32G needles. placebo (p < 0.001) in the treatment of FPHL with a good
The procedure involves using multiple intradermal or subcu- safety profile. However, the full-text article contains medium-
taneous injections of a mixture of compounds in minute quality, before-and-after photos of 3 patients with minimal
doses, using very fine needles, directly over/near the affected hair growth. Also, one must consider the nuisance, cost, and
sites. Mesotherapy in the treatment of AGA/FPHL has risks of weekly injections on the scalp to just get these mini-
received much publicity in the media and the Internet but the mal results [204].
subject remains controversial in view of the lack of docu-
mented evidence. Synopsis
Since the severe potential complications (infection, Minoxidil is the only clinically proven (evidence level 1)
abscesses, hypotension, etc.) of this pseudo-scientific prac- topical pharmaceutical for the treatment of AGA and
tice are beyond the scope of this chapter, the only things that FPHL. Even though it was initially developed as an antihy-
the reader should bear in mind concerning injectable pertensive compound, the fact that Minoxidil can stimulate
Minoxidil mesotherapy are the following: hair growth was a serendipitous discovery and remains the
«gold standard» hair growth treatment many decades later.
• Minoxidil does not need to be injected into the scalp to According to evidence-based guidelines, it should be pre-
reach the dermal papilla; it reaches efficiently through the scribed to all patients with ΑGΑ/FPHL as soon as they are
follicular canals. diagnosed. Despite significant clinical efficacy, cosmeti-
• No matter how deep and at what concentration one injects cally acceptable results are present in only a subset of
Minoxidil, its half-life after extended topical application patients. It is safe, effective, and the physician has to
is just 22 h [63]. Furthermore, this long duration is attrib- explain how MTS (Minoxidil Topical Solution) or MTF
uted only to the skin’s reservoir effect after repeated (Minoxidil Topical Foam) is used appropriately to maxi-
application. The half-life of Minoxidil in the serum is 3h, mize efficacy and debunk perpetuating myths on Minoxidil
and this is how long it is expected to act if injected topi- use and misuse. Compliance is a major limiting factor and
cally [130]. is being addressed by novel formulations and combina-
34 23 Minoxidil
tions. The newer formulation of 5% MTF has significant 20. Wester RC, Maibach HI, Guy RH, Novak E. Minoxidil stimulates
advantages over 5% MTS and should be preferred. Patients cutaneous blood flow in human balding scalps: pharmacodynamics
measured by laser Doppler velocimetry and photopulse plethys-
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than the approved ones. Low dose oral Minoxidil is an cal minoxidil increase skin blood flow? A laser Doppler flowmetry
exciting novel off-label modality, but further controlled study. Acta Derm Venereol. 1988;68(3):271–4.
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178. Lueangarun S, Panchaprateep R, Tempark T, et al. Efficacy MS. Effect of oral minoxidil for alopecia: systematic review. Int J
and safety of oral minoxidil 5 mg daily during 24-week treat- Trichol. 2020;12(4):147–55.
ment in male androgenetic alopecia. J Am Acad Dermatol. 196. Benmously Mlika R, Ben Hamida M, Hammami H, Dorbani Ben
2015;72(5):AB113. Thabet I, Rouatbi M, Mokhtar I. Long-pulsed Nd:YAG laser in
179. Sinclair R. Treatment of female pattern hair loss with oral minoxi- the treatment of facial hypertrichosis during topical minoxidil
dil. Austral J Dermatol. 2016;57(Suppl 1):27. therapy. J Cosmet Laser Ther. 2013;15(4):217–8.
180. Sinclair RD. Female pattern hair loss: a pilot study investigating 197. Keusch GW, Weidmann P, Campese V, Lee DB, Upham AT,
combination therapy with low-dose oral minoxidil and spironolac- Massry SG. Minoxidil therapy in refractory hypertension analysis
tone. Int J Dermatol. 2018;57(1):104–9. of 155 patients. Nephron. 1978;21(1):1–15.
References 39
198. Hagstam KE, Lundgren R, Wieslander J. Clinical experience of 202. Zoellner Y, Balp MM, Marco AG. The role of galenic innovation
long-term treatment with minoxidil in severe arterial hyperten- in improving treatment compliance and persistence: three case
sion. Scand J Urol Nephrol. 1982;16(1):57–63. studies. Clinicoecon Outcomes Res. 2011;3:109–16.
199. Pfizer Canada I. LONITEN (minoxidil tablets USP) Product 203. Gajjar PC, Mehta HH, Barvaliya M, Sonagra B. Comparative
Monograph. Quebec: Kirland; 2013. study between mesotherapy and topical 5% minoxidil by dermo-
200. Sanabria B, de Nardo VT, Miot HA, Ramos PM. Adverse effects scopic evaluation for androgenic alopecia in male: a randomized
of low-dose oral minoxidil for androgenetic alopecia in 435 controlled trial. Int J Trichol. 2019;11(2):58–67.
patients. J Am Acad Dermatol. 2020;S0190-9622(20):33074–7. 204. Uzel BPC, Takano GHS, Chartuni JCN, Cesetti MV, Gavioli CFB,
201. Jimenez-Cauhe J, et al. Reply to “Very low dose oral min- Lemes AM, Costa IMC. Intradermal injections with 0.5% min-
oxidil in male androgenetic alopecia: a study with quantitative oxidil for the treatment of female androgenetic alopecia: a ran-
trichoscopic documentation”. J Am Acad Dermatol. 2019. pii: domized, placebo-controlled trial. Dermatol Ther. 2020;34(1):
S0190–9622(19)32738–0 e14622.
Finasteride
24
Basic Concepts and rarely being the reason for discontinuation.

• Finasteride is a selective, potent, irreversible inhibitor However, recent clinical studies, case studies, and
of the 5α-Reductase isotype ΙΙ. It decreases the sys- meta-analyses report an increased incidence of
temic levels of DHT produced by the liver and gonads SAEs and CNS adverse effects (depression, mood
by 65–70% without having any direct hormonal, disorders, etc.) and criticize the inadequacy of
estrogenic, progesteronic, or antiandrogenic actions. adverse effect reporting in early clinical trials.
• The reduced systemic DHT results in an increase in • There have been low-quality reports with strong
the size and the diameter of AGA-miniaturized hair selection bias reporting non-reversible SAEs and
follicles, in an increased number of anagen terminal CNS-related adverse effects that have received a
hair follicles, in prolonged anagen duration, and in great deal of media and internet attention but have
the decreased duration of kenogen and shortened not been confirmed yet in well designed, more
time from shedding to regrowing of hairs. extensive studies. Meanwhile, the overall safety of
• Long-term use of Finasteride results in progressive Finasteride in doses up to 5 mg and the low adverse
clinical improvement, scalp density stabilizes after event profile has been demonstrated in 20.5 million
12 months, but coverage continues to increase for men and 6.7 million patient-years of exposure using
2 years, suggesting that Finasteride improves the Proscar® and Propecia® till 2012.
quality of hair in terms of hair caliber, length, growth • Probably there is a vulnerable cohort of patients
rate, growth duration, and pigmentation. Continuous into whom Finasteride 1 mg can result in persistent
use is recommended to sustain benefit, which should SAEs, which remains poorly understood and con-
be re-evaluated periodically. Discontinuation leads to troversial, and further, properly designed studies
a reversal of effect within 12 months. are required for confirmation of this hypothesis.
• The FDA has approved Finasteride 1 mg for the treat- • Topical Finasteride is an exciting and effective
ment of male AGA since in long-term studies (5 years treatment option since it minimizes systemic
long), >90% of the patients on Finasteride exhibited adverse effects. The safety of topical Finasteride
halting of hair loss and >66% grew new hair, attribut- seems to be excellent, but despite its proven effi-
ing Finasteride with an Evidence Level 1 score as a cacy, it is limited due to a small number of studies.
treatment against AGA. It can also work synergisti- Further studies are warranted to determine the most
cally with 5% MTS for added benefits. The off-label efficacious formulations, ideal topical concentra-
use of Finasteride in women with FPHL is effective tion, and application frequency.
mostly when there is an excess androgen background • Before commencing an eligible patient on
and at higher doses, at least 2.5 mg. Finasteride, it is wise to order a PSA test, a careful
• Adverse effects reported in initial clinical trials andrological screening, and have him answer an
were comparable in frequency to placebo, and the erectile-function questionnaire to use as reference
most common ones (1–2%) were sexual adverse points for subsequent measurements or complaints.
effects (SAEs), such as erectile dysfunction, libido In case of adverse events, lowering the dosage to
decrease, and ejaculatory disorders. SAEs are usu- 0.5 mg/daily or lower can be considered since anec-
ally self-limited even upon treatment maintenance dotal efficacy is comparable to 1 mg/daily.

42 24 Finasteride
Finasteride is the result of a long-term research program by 24.2 Finasteride in AGA

Merck & Co., dating back to 1950 when their R&D depart-
ment got engaged in the study of androgen effects in Benign According to the findings by Imperato-McGinley et al. back
Prostatic Hyperplasia (BPH). BPH is defined as an increase in 1974, DHT is implicated in the pathogenesis of AGA (see
in the prostate’s size caused by the growth of the prostatic Chap. 11, Vol. 1). Men with inherited 5α-R type IΙ deficiency
periurethral transition zone, is due to androgen action, and do not experience BPH or AGA, despite the presence of
occurs in 50% of men who are >50 years old [1]. BPH 5α-R type I, suggesting that AGA is a DHT and -mostly- a
causes a partial obstruction of the endoprostatic part of the 5α-R type IΙ-dependent process. It was hypothesized that
urethra and consequently increases urethral resistance, using Finasteride to suppress DHT at the 5α-R type IΙ level
whereas BPH patients exhibit typical, progressive symp- would lead to a significant cosmetic improvement of patients
toms: difficulty initiating urination, decreased urinary flow with AGA [5], maybe even to a complete cure. However,
pressure, intermittent urination, incomplete emptying of these hopes for complete AGA reversal or cure were soon
the bladder, faster bladder filling, urinary frequency, uri- dashed.
nary urgency, and nocturia [2]. This group of clinical symp- A single oral dose of 5 mg Finasteride decreases DHT
toms is referred to as “Lower Urinary Tract Symptoms concentration by 65–70% in the serum [6], and 80% in the
(LUTS)” in the literature. prostate [7]. Finasteride potently inhibits isotype II 5α-R but
It has been known since the 1960’s that the enzyme much less efficiently isotype I [8]. Isotype I and II contribute
5α-Reductase (5α-R) is necessary for the conversion of to approximately 30% and 70% of the total DHT production,
Testosterone (T) to Dihydrotestosterone (DHT). Merck & respectively [9]. The concentration of Finasteride that would
Co. developed Finasteride specifically to inhibit this par- inhibit 50% of enzyme 5α-R Ι (IC50S) is 670 nM for and just
ticular enzymic system. Finasteride was to be the first 4.2 nM for isotype 5α-R ΙΙ. In order to achieve a DHT
selective, irreversible, potent -yet not complete- inhibitor decrease in the serum >85%, one would need a daily dose of
of the 5α-R isotype ΙΙ and a weak inhibitor of 5α-R isotype Finasteride >50 mg [10]. Therefore, with the standard dose
Ι. Although Finasteride’s favorable action in hair growth of Finasteride 5 mg, a modest amount of DHT remains in the
was immediately evident during Phase III & III trials on circulation. Since scalp perfusion is extensive, and the serum
BPH, Merck & Co. decided to focus on BPH management concentration of DHT determines DHT concentration in the
and postpone the research on Finasteride’s hair growth scalp, scalp DHT reduction with Finasteride 5 mg is approxi-
effects for later. mately 64%.
Nevertheless, results from early studies (funded by Merck
& Co.) were extremely encouraging regarding inhibition of
24.1 Finasteride in BPH the AGA-induced hair loss. In these studies, it was demon-
strated that 1 mg/day Finasteride was adequately effective in
In 1992, Finasteride 5 mg was approved by the FDA for the men with AGA [11–13]. Roberts et al. also conducted two
treatment of BPH, which Merck & Co. marketed under the separate clinical dose-ranging studies to establish the opti-
brand name Proscar®, longing to be the first efficient, non- mal dose of Finasteride in men 18–36 years of age, testing
surgical approach to BPH management. Notably, until that doses of Finasteride 5 mg, 1 mg, 0.2 mg, 0.01 mg/day and
time, BPH could only be treated by surgical resection of the placebo, based on random assignment. Efficacy was demon-
prostate’s enlarged periurethral part. Phase trials and clinical strated for all endpoints for Finasteride at doses of 0.2 mg/
experience proved that Proscar® was indeed effective as day or higher, with 1 mg and 5 mg demonstrating similar
monotherapy for the treatment and control of BPH. However, efficacy, superior to lower doses [14]. Interestingly, the dif-
it was not as potent as urologists and patients hoped for, even ferences in mean change from baseline total hair count
though long-term Finasteride treatment was safe and well- between the Finasteride groups (0.2–5 mg) did not reach
tolerated. Proscar® could reduce the prostate size by a mean significance.
28% from baseline, but patient satisfaction was not as
expected since only 30% of the patients reported remarkable
improvement. The onset of Finasteride action on the prostate Finasteride 1 mg, i.e., 1/5 of Proscar® dosage, was
occurred between 3–6 months of treatment, with peak action reported to be the optimal dose for AGA treatment,
at 12–18 months [3]. Nevertheless, Proscar® reduced urgent combining high efficacy and low adverse effects [14,
catheterizations for acute urinary retention by 50%, decreased 15]. More particularly, finasteride 1 mg was able to
obstructive symptoms in most patients, increased urinary reduce scalp DHT levels by 64.1% (vs. 69.4% with
flow, and decreased the prostatic volume, making Finasteride 5 mg) and serum DHT levels 71.4% (vs. 72.2% with
the «Gold Standard» of BPH pharmaceutical treatment until 5 mg) [16, 17].
today [4].
24.3 Mechanism of Action of Finasteride 43
5a-R 5a-R
Merck & Co. applied for FDA approval (New Drug Type I Type II
Application, NDA), submitting the Phase III clinical trial
results on Finasteride 1 mg for AGA treatment. A year later, Scalp
Beard
on December 19th 1997, Propecia® (Finasteride 1 mg) was Sebaceous glands
approved as the first-ever oral drug indicated for male AGA
treatment. Torso Chest skin
Experience with Finasteride 5 mg for BPH treatment is Liver
vast, and significant knowledge has been acquired con-
Liver
cerning AGA treatment with Finasteride 1 mg. According Seminal vesicles
to Mella et al. (2010), since the FDA approval of Finasteride Suprarenal glands
(1992 and 1997), 20.5 million men and 6.7 million patient- Prostate
Kidneys
years of exposure using Proscar® and Propecia® respec- Testicles
tively have been documented with a very low profile of Epididymis
adverse effects and very high safety and tolerance [18]. Prepuce
Since 1988, more than 3400 articles have been published Scrotum
on Finasteride, 325 of which are randomized, controlled
trials.
24.3 Mechanism of Action of Finasteride
Androgen-dependent hair growth and AGA are both depen-

dent on the effects of DHT in the hair follicle. DHT produc-
tion from Testosterone (T) is regulated by the enzyme 5α-R,
which exists in two isoforms, 5α-R isotype Ι and II. As men- Fig. 24.1 Spatial tissue distribution of Type I and type II 5α-R enzyme
activity. (Adapted with permission from Steers [214])
tioned, Finasteride is a selective, potent, and irreversible
inhibitor of 5α-R isotype ΙΙ and a very weak inhibitor of iso-
type Ι. The selective affinity of Finasteride for type 5α-R ΙΙ is may affect androgen-dependent growth of hair follicles and,
100 times higher than that of isotype 5α-R Ι [19]. Finasteride most probably, the overall effect involves a combination of
exerts no hormonal, estrogenic, progesteronic or true antian- all three [25]:
drogen action [20].
In humans, 5α-R type I is nearly ubiquitous, being present 1. The inhibition of 5α-R ΙΙ activity in the liver and gonads.
in tissues such as the liver, adipose tissue, muscles, and CNS This systemic inhibition reduces the production and cir-
[21], and it is also the dominant skin isotype (besides genital culating levels of DHT, and, consequently, a reduced
skin) (see Chap. 11, Vol. 1). amount of DHT reaching the hair follicles (primary
action). In this case, DHT would principally act as an
• Isotype I 5α-R is primarily located in the sebaceous endocrine factor,
glands, epidermal and follicular keratinocytes, dermal 2. The inhibition of 5α-R ΙΙ activity in situ at the level of the
papilla cells (DPCs), and sweat glands; it is responsible dermal papilla and the reduction in the local production
for 25–30% of the total production of DHT in the body of DHT (secondary to minimal action). In this case, DHT
[22]. would act as a paracrine-autocrine factor.
• Isotype II 5α-R is the dominant urogenital isotype, includ- 3. The weak/partial inhibition of enzyme 5α-R I activity and
ing genital skin (scrotum, foreskin, etc.) and is mainly reduction of DHT production in the sebaceous gland
found in the prostate, epididymis, vas deferens, seminal (probably negligible action).
vesicles, and in low concentrations in the inner and outer
root sheath of scalp hair follicles [23]. Isotype II 5α-R is
responsible for the remaining 70–75% of DHT produc-
tion in the human body [24] (Fig. 24.1). 24.3.1 Does Finasteride Act in Any Other
Way?
Unlike Minoxidil, the exact mechanism of action of
Finasteride in the management of AGA is known. There are Yes, it does. Ryu et al. analyzed the concentration of DHT
three possible -yet interconnected- ways whereby Finasteride and Τ in hair follicles from the vertex and occipital regions
44 24 Finasteride
of balding men using gas chromatography-mass spectrome- The two replicate, pivotal, Phase III, 1-year long, double-
try (GC-MS). The ratios of DHT/T in the vertex scalp hair blind, placebo-controlled, randomized, multicenter trials
and in the plasma were remarkably decreased after treatment testing the efficacy of Finasteride on the crown included
with Finasteride for 5 months. In contrast, no significant dif- 1553 men, aged 18–41 with mild to moderate AGA [31].
ference in DHT/T ratio in the occipital scalp hair was found Both continued as extended trials for one more year to deter-
before and after Finasteride treatment [26]. On a molecular mine the effect of treatment at 2 years and the impact of the
level, Sawaya et al. reported that after 6 months of Finasteride withdrawal of treatment after 1 year. Evaluation procedures
treatment, DHT reduction resulted in changes in gene pro- included Target Area Hair Counts (TAHC) in a 1-inch diam-
gramming of hair follicles. Finasteride reduced caspases −1 eter circular area (5.1cm2) and global photographs evaluated
and −3 and increased XIAP levels (X-linked inhibitor of by researchers and by blinded, independent investigators, as
apoptosis protein) in males with AGA to levels exhibited in well as patient self-assessment. Subjects were divided into
normal subjects. These effects resulted in the prolongation of two groups; 779 patients received Finasteride 1 mg, and the
anagen and the inhibition of shedding [27], proving that cas- remaining 774 received placebo. During the extension
pase-1 is a key element in triggering an innate immune period, there was a crossover of 50% of subjects taking pla-
response in the hair follicle’s life cycle and physiology AGA, cebo, switching to Finasteride and vice versa. During the
resulting in miniaturization and apoptosis. 24-months long study, four groups were devised, Fin-Fin
In 2012, de Rivero Vaccari et al. published their immuno- (12 months Finasteride +12 months Finasteride), Pbo-Fin
histochemical staining study on scalp tissue sections. (12 months placebo +12 months Finasteride), Fin-Pbo
Caspase-1 and protein lysates were analyzed from 18 indi- (12 months Finasteride +12 months placebo), and Pbo-Pbo
viduals with AGA, separated into a Finasteride and a control (12 months placebo +12 months placebo). Finasteride was
group. Using anti-caspase-1 antibodies, they demonstrated superior to placebo at all time points, even as early as
that caspase-1 expression is higher in hormone-sensitive 3 months, halted hair loss, improved density and coverage in
areas of the scalp of men with AGA, that Finasteride reduces 66% of patients during the first year and in 81% during the
the expression of caspase-1 in vivo and that keratinocytes second year (Fin-Fin group). After the crossover, patients
treated with Finasteride in combination with T or DHT show receiving Finasteride, who were switched to placebo (Fin-
reduced caspase-1 levels in vitro [28]. Tang et al., in an ear- Pbo), lost all the hair they had acquired during the previous
lier study, focused on identifying and quantifying changes in 12 months. When subjects in the placebo group were crossed
expression of specific molecular hair growth regulators in to Finasteride (Pbo-Fin), they showed significant hair growth,
DPCs of men with AGA treated with Finasteride. They cor- mostly on the crown, but did not reach the same degree of
related these findings to clinical efficacy, and an increase of improvement as seen in patients in the Fin-Fin group.
IGF-1 was observed, allowing researchers to report that the Regarding the absolute number of terminal hairs, Finasteride
response of patients to Finasteride was dependent on the treatment produced progressive increases in hair counts at
level of the IGF-1 rise in the hair follicle [29]. Yoo et al. months 6 and 12 (+86 ± 3.6 hairs at month 12), whereas treat-
found that concomitant administration of Finasteride and Τ ment with placebo resulted in significant hair loss (−21 ± 3.4
in a culture of human scalp dermal fibroblasts significantly hairs at month 12). At month 24, the Fin-Fin group maintained
decreased the expression of TGF-β1, which is considered a the hair count of month 12, whereas the Pbo-Pbo demonstrated
key mediator in AGA pathophysiology [30]. further hair loss (−37 ± 13 hairs vs. month 12), resulting in an
overall difference of +138 ± 16 hairs for the Fin-Fin group,
accounting for 16% of more hair than the Pbo-Pbo group. Only
24.4 Clinical Studies on Finasteride 17% of patients under Finasteride treatment lost hair in abso-
lute numbers during the 2 years of the study, compared to 72%
The serendipitous discovery that a compound initially of the placebo patients. By month 24, 66% of patients were
designed to treat BPH could stop hair loss and regrow hair by rated as improved by the expert panel (30% slightly improved,
altering systemic DHT production triggered skepticism con- 36% moderately or significantly improved) in the Fin-Fin
cerning efficacy and safety. group vs. 7% in the Pbo-Pbo group.
Three double-blind, randomized, placebo-controlled,
Phase III trials were conducted, including 1879 men, aged
18–41, with mild to moderate AGA (Norwood-Hamilton In summary, finasteride efficacy was evident within
stage ΙΙ-V). These extensive trials were conducted by the 3 months of treatment; hair counts progressively
Finasteride Male Pattern Hair Loss Study Group, comprised increased over 12 months and were maintained through
of prominent Dermatologists and researchers of hair follicle the second year, resulting in a net improvement of
physiology (Kaufman, Olsen, Whiting, Price, Van Neste, approx. 138 hairs in the predetermined 5cm2 area in
Shapiro, et al.). Two of the studies were intended to verify 2 years compared to placebo.
Finasteride’s efficacy on the crown [31], while the third one
would determine the efficacy on frontal areas [32].
24.4 Clinical Studies on Finasteride 45
The third study monitored Finasteride’s efficacy in the fron- The study’s extension to 4 years (192 weeks) demonstrated
tal area, which is the most important cosmetically [32]. This that the results continued being overly satisfying. After the
24-month, double-blind study was conducted by Leyden et al., fourth study extension (week 144 to 192), a 21.6% mean
and 326 men with AGA were included 166 in the Finasteride increase in hair weight from baseline was measured in the
group and 160 in the placebo group. During the second year, Finasteride group, a 24.5% decrease from baseline in the pla-
133 subjects were switched to the Finasteride group and 123 to cebo group, and an overall 46% net gain in hair weight
the placebo group. The study was conducted in 15 investiga- between the two groups [34]. At the same time, there was
tional sites in the USA, simultaneously with the vertex trials a + 20.35 net increase in hair count in the Finasteride group
[31]. Overall, in the first 12 months of the trial, the Finasteride compared to the placebo group (Fig. 24.2). These results
group had an increased hair count by +9.6 ± 1.5 in the frontal confirmed previous reports that Finasteride produces more
1cm2 predetermined circular area, while the placebo group had significant gains in hair weight than in hair count. Hair
a hair count reduction of −11.6 ± 2.0 hairs. Notably, 70% of weight increase, attributed mostly to increased hair diameter,
Finasteride-treated patients demonstrated no further frontal hair is significantly more important cosmetically since hair
loss by hair count (hair count was either increased or remained caliber has a much more substantial effect on scalp coverage
unchanged), whereas 56% of placebo-treated patients continued than just hair counts (see Chap. 99, Vol. 3).
to lose hair [32]. Compared to the vertex trials results, this might The efficacy of Finasteride was also tested (and con-
seem less of an improvement (9.6 ± 1.5 cm2), considering that firmed) on monozygotic twins. It is recognized from the
the 12-month hair count increase in the vertex trial was 107 studies of Christian and Kang (1972) that identical twins are
hairs in 12 months in an area of 5.1cm2, which equates to 20.9 ideal candidates to examine the efficacy of pharmaceutical
hairs/cm2. Nevertheless, considering the lower baseline hair treatments, mostly when the underlying condition is primar-
density in the frontal vs. vertex areas (the lower the baseline hair ily attributed to genetic causes, as is the case with AGA [35].
density, the lower the increase in hair counts with treatment), In 2002, Stough et al. published a 12-months-long, random-
Finasteride’s hair growth efficacy in the frontal areas was ized, double-blind, placebo-controlled, single-center study
deemed comparable to that of the vertex. Results were further on the efficacy of Finasteride 1 mg in 9 pairs of identical
substantiated by the high level of patient satisfaction, matching twins; one brother received Finasteride 1 mg, and the other
the high scores of the vertex trials; 50% of patients noted received placebo. After 12 months, the total hair count in the
improvement in their hair’s appearance, and 70% reported slow- predetermined 1cm2 surface showed an increase of +16 ± 4
ing of hair loss in the frontal areas. hair from baseline for the Finasteride group and a decrease
Price et al. conducted a 96-week-long, double-blind, ran- of −4 ± 5 hair for the placebo group, resulting in a net
domized, placebo-controlled study on 66 males with AGA, improvement of +20 ± 5 hairs/cm2 for the twins in the
intending to determine the efficacy of Finasteride on scalp Finasteride 1 mg group vs. placebo [36].
hair count and hair weight. Thirty-three men received As the results of long-term studies on Finasteride 1 mg
Finasteride for 48 weeks, and 26 of them remained on progressively piled up, they were becoming increasingly
Finasteride during the 48 weeks-long extension, while 33 promising [37]. Kaufman et al. extended the initial Phase III
men with AGA received a placebo for 48 weeks, and 23 of trials [31] to 5 years, providing a unique opportunity to eval-
them entered the extension 48 weeks-long study, still on pla- uate the effects of Finasteride 1 mg on the likelihood of fur-
cebo. At 48 weeks, the Finasteride group showed a hair ther hair loss in men with AGA over a 5-year-long period.
weight increase of 20.4 ± 3.1% (p < 0.01), and the placebo This analysis initially included 713 patients (n = 645
group showed a hair weight decrease of −5.2 ± 1.9% Finasteride, n = 68 placebo), but only 295 individuals con-
(p < 0.05). The net increase in percent change in hair weight cluded the 5 years of the observation trial (n = 279 Finasteride,
for the Finasteride group vs. the placebo group at week 48 n = 16 placebo). Based on the global photographic assess-
was 25.6 ± 3.6% (p < 0.001). At 96 weeks, the Finasteride ment data, Finasteride 1 mg led to a nine-fold decrease
group maintained a mean increase in hair weight from base- (−93%) in the cumulative incidence rate to develop further
line of 21.5 ± 3.3% (p < 0.001), while subjects treated with visible hair loss. Meanwhile, the likelihood of developing
placebo showed a mean decrease in hair weight from base- further visible hair loss in the placebo group progressively
line of −14.2 ± 2.4% (p < 0.001). The Finasteride group’s net increased over 5 years.
gain at week 96 was 35.8 ± 4.6% vs. placebo (p < 0.001). At After 5 years of treatment, the hair count remained similar
all points, hair weight increased to a greater extent than hair to the 1-year level, but a significant improvement in the gross
count, which remained stabilized after year one. This finding hair appearance was noticed in global photography. It was
indicated that Finasteride will reach a plateau in hair counts suggested that the peak number of hairs is obtained by the
after approximately 12 months but will continue increasing end of 12–18 months on treatment, and further improvement
the size, the growth rate, and the diameter of previously min- results from increase in hair length, diameter, and
iaturized hairs even during the second year of treatment [33]. pigmentation.
46 24 Finasteride
Fig. 24.2 (a) Mean percent a Initial First Second Third

change from baseline in hair study extension extension extension
weight across the study, and 35
(b) Mean percent change
30
from baseline in hair count
across the study. (From Price 25
et al. [34]) 20
Percent Change from Baseline ±SE

15
10
Hair Weight Mean

5
0
-5
-10
-15
Finasteride
-20
1 mg
-25
-30 Placebo
-35
0 6 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192
Week
Finasteride N: 31 32 31 29 28 25 25 24 22 17 16 15 15 15 15 15 15
Placebo N: 32 31 30 29 28 20 16 15 15 10 10 9 9 8 8 7 7
b Initial First Second Third

study extension extension extension
20
15
Percent Change from Baseline ±SE
10
Hair Count Mean
-5
-10 Finasteride
1 mg
-15
Placebo
-20
0 24 48 72 96 120 144 168 192
Week
Finasteride N: 31 28 25 22 16 15 15 15
Placebo N: 30 28 16 15 10 9 8 7
24.5 Clinical Efficacy of Finasteride 1 mg 47
of 12–18 months on treatment, and further improvement

Overall, finasteride led to durable improvements in results from increase in hair length, diameter, and
scalp hair compared to treatment with placebo in men pigmentation.
with AGA. More than 90% of patients who shall con-
tinue treatment with finasteride 1 mg for 5 years or
more will witness halting of further hair loss. More 24.5 Clinical Efficacy of Finasteride 1 mg
than 2/3 of them will grow new hair of normal caliber
and length, both over the crown and the frontal area. These and numerous other studies on Propecia® demonstrated
Of these patients who have actual hair growth, half will that the efficacy of Finasteride 1 mg in AGA management is
report minimal hair growth, and the rest will report substantial. The initial positive results of Propecia® appear at
moderate or significant hair growth [38–40]. 3 months on treatment, with patients initially reporting halting
of hair loss. Soon after, hair growth starts progressively, and at
6 months, increased hair growth rate and thickness are notice-
After 5 years of treatment, the hair count remained similar able. After 12 months on treatment, previously thin or bald
to the 1-year level, but a significant improvement in the gross areas are more covered; by 18–24 months, treatment will reach
hair appearance was noticed in global photography. It was its peak effect, with results being stabilized and preserved ever
suggested that the peak number of hairs is obtained by the end after, with an almost flat rate of decline [31–40] (Fig. 24.3).
Mean change in hair count over

5 years, including crossover data
120
100 PROPECIA®
(n=679)
80
60
40 ∆=107 +38
+30
20 ∆=138
+4
0
Mean change in hairs from baseline
-20 ∆=146
-40 Placebo
∆=216
(n=672)
-60
-80
-100
-120 ∆=277
-140
-160
-180
-200
PROPECIA® for 5 years
-220
Placebo for 1 year, PROPECIA® for 4 years
-240 -239
PROPECIA® for 1 year, Placebo for 1 year, PROPECIA®
-260 for 3 years
-280 Placebo for 5 years
-300
Baseline Month 6 Year 1 Year 1 Year 2 Year 3 Year 4 Year 5
n= 539 n= 433 n= 351 n= 291 n= 219
n= 534 n= 425 n= 329 n= 250 n= 176
n= 64 n= 48 n= 38 n= 31 n= 26
n= 60 n= 47 n= 32 n= 20 n= 15
n= number of patients
Fig. 24.3 Mean hair count change from baseline. The group which Finasteride. When these males were re-introduced to Finasteride on the
stayed on Finasteride during the complete study duration (5 years) had third year, the response was positive, but they never grew all the hair of
the best results. The worst results were evident in subjects who remained the first year’s treatment. The numbers on the right end of the graph
in the placebo group for the whole study. The group that started in the show the number of hairs at 5 years compared to baseline, and the Δ is
first year with placebo and then switched to Finasteride on the second the difference in hair counts of the placebo group vs. the Finasteride
year had the second-best results, while the group that started with group at each year point. (Adapted with permission from [40])
Finasteride and then turned to placebo lost all the hair grown with
48 24 Finasteride
MGPA hairs in the predefined area was significantly increased com-

7 pared to the group receiving placebo [42].
N-H: I
N-H: II Overall, Finasteride will have the following effects [31–
N-H: III 40, 43]: (Figs. 24.4, 24.5, and 24.6).
6
total
• Will increase the size, the diameter, and weight of AGA-
N-H: IV miniaturized hair follicles,
N-H: V • Will increase the number of terminal hair follicles and
5
N-H: VI will gradually convert pseudo-vellus and intermediate
N-H: VII AGA-affected hair follicles into terminal ones,
4 • Will increase the amount and percentage of anagen hair
(increased anagen to telogen ratio) and increase anagen
duration allowing more hairs to grow on the scalp at any
3 given moment,
0 1 2 3 4 5 6 7 8 9 10 Year
• Will stimulate telogen hair follicles to re-enter anagen and
Fig. 24.4 Changes in modified global photographic assessment scores will restore standard telogen duration, which, in AGA,
(MGPA) from before treatment through year 10 of treatment on each usually rises from the typical 3 months to >12 months,
Norwood-Hamilton scale (N-H) group at first visit. (From Yanagisawa • Will decrease the duration of kenogen and shorten the
et al. [215])
time from hair shaft shedding to new anagen,
• Will result in hair loss halting in 91% of users and in hair
Yanagisawa et al. (2019) evaluated the efficacy and safety
growth in 66% of patients when used long-term (≥5 years)
of 1 mg/day Finasteride in 532 Japanese men with AGA for
• Will result in a progressive clinical improvement well
10 years. The age at first visit was 37.8 ± 10.0 years; age
beyond 12 months, suggesting that Finasteride improves the
range, 20–69 years; and values of each Norwood-Hamilton
quality of hair (thickness, length, growth rate, growth dura-
stage at the first visit were: I:6, II:116, III:204, IV:124, V:61,
tion, and/or pigmentation) in long-term use. The minimal
VI:18, and VII:3. The proportions of patients with improve-
period of use to assess Finasteride’s efficacy for reducing
ment modified global photographic assessment scores
hair loss is 6 months and 12 months for regrowth of hair.
(MGPA) (≥5) or prevention of disease progression
• Discontinuation of Finasteride results in total regression
(MGPA ≥ 4) at treatment year 10 were 91.5% (487/532) and
of results. Even worse, the patient will return, not only to
99.1% (527/532), respectively (Fig. 24.4).
his pre-therapeutic hair loss image but will progress to the
AGA stage he would have reached if he had never used
This is the most extended study of its kind, and nota- Finasteride at all [44] (Fig. 24.7).
bly, the positive and durable changes due to finasteride
use were visible to all stages of AGA and age groups. Interestingly, recent evidence by Dominique van Neste
(2019) seriously challenges the “reversal hypothesis.”
He recruited 13 AGA volunteers who completed a
However, as is the case with Minoxidil, not all patients
24-month phototrichogram study. In this extensive and
respond equally to Finasteride. Camacho et al. conducted a
very elaborate study, van Neste could not recover any
12-month long study on 166 male patients of 26 years of age
terminal hair from scalp hair follicles found initially to
and younger and 104 patients over 26 years old. They
produce a miniaturized hair accounted by several hun-
reported that patients <26 years old respond better to
dreds of thinning hair follicles monitored for 2 years.
Finasteride. The level of response in that study was reported
According to the author, moderate hair improvement
to be directly proportional to pre-therapeutic DHT serum
resulted from the increased productivity of deficient
levels, i.e., the higher the DHT levels, the better the response
terminal follicles, but not yet irreversibly affected at
to treatment. In these patients, the response was dramatic in
baseline without the implication of miniaturized hair
the first 6 months and slowed down afterward. Interestingly,
follicles. The latter further regressed even with oral
serum T levels increased by approx. 8%, with no change in
intake of Finasteride [209, 210].
sebum production [41].
Finasteride has been found to improve the image of AGA
in older men as well. Brenner et al. conducted a small-scale, Dominique van Neste presented the first evidence that
double-blind, placebo-controlled, multicenter study on 28 the initiation of anagen while “on-drug” may have an effect
men aged 35–76 with moderate symptoms of BPH. The sub- that lasts at least until the completion of the hair cycle’s
jects received Finasteride 5 mg for BPH, and the number of launched growth phase. The transformation of terminal hair
24.5 Clinical Efficacy of Finasteride 1 mg 49
Fig. 24.5 Clinical result of Finasteride 1 mg treatment for 9 months on a 28-year-old male at stage III AGA. The difference in coverage of both
midscalp and frontal areas is significant
into miniaturized hair occurred only after 12 months with- 25 studies investigating the efficacy of Finasteride in male
out treatment; that is the time necessary to complete a clini- patients with AGA that met the inclusion criteria of the
cally significant full hair cycle initiated during the drug guideline. Twenty four of these 25 studies assessed the effi-
intake [210]. cacy of Finasteride monotherapy in male patients with AGA,
Overall, there have been several extensive, well-designed and one included both male and female patients. Thirteen
clinical studies on the efficacy of Finasteride in AGA, too studies obtained grade A2 evidence, 9 grade B, and 3 grade
many to include them all. Kanti et al. [45], in their systematic C, whereas 14 studies were placebo-controlled. Summarizing
review (Evidence-based (S3) guideline for the treatment of these results, Evidence Level 1 was attributed to Finasteride
androgenetic alopecia in women and in men, 2018) included by the authors.
50 24 Finasteride
Fig. 24.6 Clinical result of Finasteride 1 mg treatment for 6 months on a 24-year-old male with DPA (Diffuse Patterned Alopecia). Finasteride is
exceptionally useful in this type of AGA
24.6 Metabolism of Finasteride saturation of 5α-R isotype II binding of Finasteride50. This

finding was clinically already apparent in the early clinical
Regardless of dose, Finasteride’s terminal serum half-life is dose-ranging studies of Roberts et al. [14] This was clini-
4.7–7.1h [46] in men aged 18–60 and ≥8 h in men >60 years cally verified by Kawashima et al. [51], who undertook a
old [47]. The duration of action is 25h [48], and the washout 48-week long, double-blind, randomized, placebo-controlled
period is approximately 7 days [49]. The pharmacokinetics study on 414 Japanese men with AGA. The subjects were
of Finasteride are not linear. Daily administration of doses as separated into a Finasteride 1 mg group (n = 139), a
low as 0.2 mg will lead to steady serum levels and complete Finasteride 0.2 mg group (n = 137), and a placebo group
24.7 Adverse Effects of Finasteride 51
Fig. 24.7 Schematic No treatment

representation of the 100% Finasteride
hair-growth effects of
Finasteride and the
consequence of Start of treatment Discontinuation of treatment
discontinuation
50%
0%
(n = 38), to identify the optimal dosage of Finasteride and to efforts focused on the potential short- and long-term adverse
evaluate its efficacy and safety. The researchers reported effects of Finasteride.
58% and 54% improvement in global expert panel assess- Since the adverse effects of Finasteride, especially those
ment for Finasteride 1 mg and 0.2 mg, respectively. of the male reproductive system, have remained a “hot sub-
Nevertheless, the efficacy of doses <1 mg o.d. has not been ject” for decades, in order to have a more global understand-
officially tested in other extensive trials. ing of the matter, studies on both Finasteride 1 mg and the
Finasteride is quickly absorbed after oral intake, with five-fold higher dose of Finasteride 5 mg will be presented.
peak plasma levels occurring 1–2 h after intake. The bio-
availability averages at 65% (range 26–170%), the peak
serum concentration is 9.2 ng/mL, and 90% of the drug is 24.7.1 Finasteride 5 mg and Sexual Adverse
bound to plasma proteins. Finasteride is metabolized in the Experiences (SAEs)
liver by hydroxylation and oxidation through the P450 3A4
pathway, but no interactions with other drugs known to be During Phase II & III trials on the safety and efficacy of
metabolized by this cytochrome, such as warfarin, theophyl- Finasteride 5 mg in patients with BPH, three sexual adverse
line, digoxin, and propranolol have been reported. Final experiences (SAEs), were most commonly reported during
metabolites are excreted in the urine and feces [52], and cau- trials:
tion should be exerted in patients with known hepatic dis-
ease. Finasteride must be taken once daily, at regular hours, 1. Erectile dysfunction,
but taking the double dosage the next day is not recom- 2. Decrease of libido,
mended if a dose is missed. Finasteride administration is not 3. Ejaculatory disorders.
affected by simultaneous food intake [52], but its bioavail-
ability increases with concomitant consumption of grapefruit However, one should consider the urological and sexual func-
juice. Serum DHT levels return to normal within 2 weeks tion background of these elderly patients and the increased
after Finasteride discontinuation, while there are no reports frequency of SAE that occurs anyway in this age- group
of tolerance and tachyphylaxis with long-term administra- already suffering from BPH. Thus, it was challenging for the
tion [53]. researchers to conclude whether Finasteride was actually
increasing the frequency of SAEs (causality) or the findings
were circumstantial (simple correlation). Results were insuf-
24.7 Adverse Effects of Finasteride ficient to draw a reliable conclusion because the mechanism
likely relating 5α-R II inhibition, DHT reduction, and SAEs
The indirect antiandrogenic effects of Finasteride cause is elusive.
intense and justified skepticism in AGA patients. The pri- DHT is less relevant than T concerning erectile function,
mary concern is that oral Finasteride’s systemic action might and conversion of T to DHT is not required for penile erec-
affect the hormonal balance of the male reproductive system. tion [5, 54]. Another problem was that randomized, con-
All AGA-affected patients want to regain their lost hair, but trolled clinical trials in SAEs in patients under treatment
how many among them would sacrifice their fertility or with Finasteride or other 5α-R inhibitors (5ARIs) report
“maleness” for a thicker mane? Therefore, intense research hugely varying rates of SAEs, ranging between 2.1% to
38%. The most common SAE was erectile dysfunction, fol-
52 24 Finasteride
lowed by ejaculatory disorders and decreased libido, with Only ejaculatory disorders were more common in the
usually these effects occurring early in therapy and attenuat- Proscar® group (1.5%) than the placebo group (0.5%). Most
ing over time [55]. of the patients who experienced SAEs reported mild or mod-
Grover et al. (2006) surveyed a cross-sectional sample of erate severity, and only 6% reported high severity of
3921 Canadian men aged 40–88 years who did not receive symptoms (Finasteride 3.6% vs. placebo 2.4%), resulting in
Finasteride and were seen by primary care physicians. They treatment discontinuation.
reported an overall prevalence of erectile dysfunction of
49.4%, indicating that many men in Finasteride studies
Interestingly, in men who discontinued treatment due
might have enrolled with established SAEs before even tak-
to one or more SAEs, 50% and 41% experienced reso-
ing Finasteride [56].
lution of their SAEs after discontinuing finasteride or
placebo therapy, respectively. This finding indicated
Another difficulty lies in the fact that early clinical stud- that 50% of patients who discontinued finasteride and
ies, which reported increased frequency of SAEs in 59% of patients who discontinued placebo reported
patients treated with finasteride (5 mg/day or 1 mg/day), that SAEs persisted even after discontinuation [60].
used protocols that did not include baseline assessment
of sexual function by validated questionnaires [57, 58].
Therefore, persistent SAEs were reported by more sub-
jects treated with placebo than by patients treated with
Lack of these data raises the need to conduct extensive,
Finasteride. These results have been confirmed by other
long-term clinical studies, controlled with placebo groups,
studies in middle-aged and older men, who experienced
including objective methods of evaluation of sexual function
SAEs mostly during the first year, and 50% of these men
and reliable questionnaires, to prove or exclude the causality
reported attenuation and full resolution after 3–7 years of
between Finasteride and SAEs.
treatment continuation [61, 62]. Overall, the occurrence of
The most extensive observational cohort study was con-
SAEs was marginally higher in the Finasteride groups
ducted by Wilton et al. (1996), using prescription-event
compared to placebo.
monitoring (PME) on Proscar® data (Finasteride 5 mg).
Probably the most informative trial explicitly analyzing
PME is a well-established, post-marketing surveillance
the effect of Finasteride on sexual function was the Prostate
technique designed to monitor the overall safety of newly
Cancer Prevention Trial (PCPT) [63, 64], which included
marketed medicines as used in real-life clinical practice.
18,882 men, >55 years old, observed over 7 years; the proto-
They included 14,772 male patients, and during the
col will be analyzed in more detail later. The authors utilized
12-months of the study [59], the following adverse effects
a sexual activity scale (range 0 to 100), with higher numbers
were reported:
demonstrating greater sexual dysfunction. They noted a sta-
• Impotence/ejaculatory disorders: 313 patients (2.1%), tistically significant increase in the sexual activity scale of
• Decreased libido: 153 patients (1.0%), 3.21/100 in the Finasteride group at 6 months, which
• Gynecomastia/breast tenderness: 42 patients (0.4%). decreased to 2.11/100 at 7 years, constituting a small differ-
ence on a scale of 100, with minimal impact. The authors
The incidence of these adverse effects was almost identi- concluded that Finasteride’s effect on sexual functioning was
cal to placebo, and the authors concluded that the results minimal and that it should not interfere with prescribing
strongly suggested that Finasteride is safe. Wessells et al. practices.
(2003) conducted a 4-year-long, randomized, double-blind,
placebo-controlled trial assessing the efficacy and safety of
Finasteride 5 mg in 3040 men, aged 45–78 years, with symp- 24.7.2 Finasteride 1 mg and SAEs
tomatic BPH, enlarged prostate, and no evidence of Prostate
Cancer (PCa). The study was named PLESS Study Group However, since the incidences of SAEs mentioned in the
(Proscar Long-term Efficacy and Safety) [60]. Overall, 46% PCPT refer to Finasteride 5 mg and to patients with an
of patients in each treatment group reported some history of average age of 69 ± 9.2 years (sample range: 45–99 years
SAE. During the first year, 15% of patients in the Proscar® old), one should contemplate that these patients are already
group and 7% of the placebo group experienced SAEs con- vulnerable to urological and hormonal disorders. In con-
sidered drug-related by the investigators. During the next trast -according to post-marketing surveys- the typical
3 years, the incidence of new SAEs in both groups dropped male who will receive Finasteride 1 mg for AGA is
to 7%. SAEs spontaneously resolved in 12% of Finasteride 33 ± 1.2 years old (range: 18–41), healthy, and in a good
patients and 19% of placebo patients while on treatment. urological and reproductive condition.
Table 24.1 Adverse events occurring in 1% of patients or more. (From Kaufman et al. [31])
Original studies (first year) Extension studies (second year)
Finasteride Placebo Fin ➝ Fin Pbo ➝ Fin Fin ➝ Pho Pbo ➝ Pbo
(n = 779) (n = 774) (n = 547) (n = 543) (n = 65) (n = 60)
Genitourinary system
Urinary frequency 0 0 0 0 0 1 (1.7)
Sexual function
Libido decreased 15 (1.9) 10 (1.3) 6 (1.1) 7 (1.3) 0 1 (1.7)
Erectile dysfunction 11 (1.4) 7 (0.9) 4 (0.7) 6 (1.1) 0 0
Decreased ejaculate volume 8 (1.0) 3 (0.4) 1 (0.2) 0 0 0
Skin and skin appendages
Body hair growth increased 7 (0.9) 7 (0.9) 1 (0.2) 4 (0.7) 0 3 (5.0)
Kaufman et al. [31] (Finasteride Male Pattern Hair Loss Index of Erectile Function-5, IIEF-5). Statistical analysis
Study Group, 1998) monitored 1553 subjects in this age group showed no difference between scores obtained with the IIEF
and investigated the incidence of reported SAEs after 2 years in subjects taking Finasteride 1 mg and age-matched con-
of Finasteride 1 mg treatment compared to placebo trols. This finding coincides with the everyday clinical expe-
(Table 24.1). During the study, treatment discontinuation due rience of countless physicians, who daily prescribe
to adverse effects occurred in 1.7% of cases in the Finasteride Finasteride in balding patients and observe SAEs in a much
group and 2.1% in the placebo group. These results raise ques- more limited percentage (0.5%) than the one reported in the
tions on the objectivity and validity of reported symptoms as literature. Tosti et al. (2004) conducted another multicenter
the reason for treatment discontinuation. In all other studies by study on 186 males to evaluate variations in both sexual and
Kaufman et al., SAEs in the Finasteride 1 mg groups were erectile functions in subjects before and 4–6 months after
indistinguishable in frequency from the placebo group. All Finasteride 1 mg initiation. Results confirmed that SAEs
SAEs resolved after discontinuation of Finasteride and even were actually much less common than reported in clinical
resolved in most men while remaining on therapy [38–40]. trials and that the sexual function of all patients remained
In the 5-year long extension of the original Phase II study, stable during treatment with Finasteride 1 mg [67].
each major SAE incidence decreased to 0.3% by the fifth In the so-far largest and most recent population study,
year of treatment with Finasteride 1 mg [39]. In the Leyden Sato et al. (2012) enrolled 3177 Japanese men with AGA
et al. [32] study (326 men, 1-year long trial, 1999), there was (age at first visit, 37.5 ± 11.9 years;) treated with Finasteride
only one patient in the placebo arm complaining of an ejacu- 1 mg from January 2006 to June 2009 (3.5 years) at the
latory disorder and one patient in the Finasteride arm who Tokyo Memorial Clinic Hirayama Department of Plastic and
reported impotence. In the Van Neste et al. [43] study (212 Aesthetic Surgery, School of Medicine, Kitasato University,
men, 48-week long trial, 2000), only two men in the Tokyo, Japan. The efficacy was evaluated in 2561 men by a
Finasteride group reported SAEs vs. one in the placebo modified global photographic assessment; the photographs
group. Notably, both Finasteride cases were reversible upon were assessed using the standardized 7-point rating scale.
discontinuation [38]. In the Whiting et al. [65] study (424 The safety data were assessed by interviews and laboratory
men, 2-year long trial, 2003), 8.7% of patients in the tests. The overall effect of hair growth was seen in 2230 of
Finasteride group reported drug-related SAEs compared to 2561 men (87.1%), in whom hair greatly (11.1%), moder-
5.1% in the placebo group, but the difference was not statisti- ately (36.5%), and slightly (39.5%) increased. The response
cally significant. Kaufman et al. (2008) reported that the fre- rate improved with the increasing duration of treatment.
quency of the major, known SAEs due to Finasteride 1 mg is Adverse reactions occurred in 0.7% of men (23/3177) during
significantly reduced with treatment continuation and wane the entire period of the study. The reactions included
into <0.3% after 5 years [39]. decreased libido (n = 8), hepatic functional disorder (n = 3)
However, incidence and correlation do not prove causal- and unilateral mammary hypertrophy (n = 2). Seven men dis-
ity. To determine the validity of reports relating Finasteride continued treatment based on risk-benefit considerations,
with the occurrence of SAEs, one should know the baseline and no specific safety problems associated with long-term
level of sexual function of patients. Tosti et al. (2001) con- use were observed. Notably, there was no increase in the
ducted a preliminary study, including 236 patients under incidence of adverse reactions due to longer treatment, and
treatment with Finasteride 1 mg and 236 age-matched con- actually, the reverse effect was noted [211].
trols, addressing the sexual function of patients prior to Many experts believe that even though SAEs are rare in
Finasteride 1 mg treatment [66]. Subjects of both groups clinical practice (<0.5%), there are specific causes, which
answered a detailed 15-questions questionnaire (International raise the frequency of SAEs to levels >2% in published,
54 24 Finasteride
extensive studies, both in Finasteride and control groups, Notably, since 2012 there has been an increased aware-
including: ness on an issue brought up by a couple of low-quality, meth-
odologically flawed, uncontrolled studies. These claimed
• Inaccurate pre-treatment testing of urological and sexual- that, in specific patients, SAEs might be permanent and
function of patients, remain even after Finasteride discontinuation [70, 71].
• Patients in official trials have “incentives” to easily report Before proceeding to the analysis of the results and the
even the slightest adverse effect, hoping to receive better severe limitations of these publications, which, nevertheless,
treatment or monitoring, made both authors quite famous and overly cited in the lit-
• Informing patients in advance of the potential occurrence erature and in media, one should bear in mind the
of SAEs resulted in attributing pre-existing problems to following:
Finasteride, a phenomenon coined “nocebo effect.”
• From 1992 till 2012, more than 2000 articles have been
published on Finasteride, and more than 200 randomized,
24.7.3 The Nocebo Effect! controlled trials have been conducted. There has been no
single report of SAEs in patients on Finasteride persisting
The “nocebo effect” was proposed to explain the increased after discontinuation of the drug.
occurrence of SAEs in Finasteride trials. • In these studies that never reported persistent SAEs are
included: the Phase II and Phase III studies on Finasteride
1 mg and Phase II and Phase III studies on Finasteride
A “nocebo effect” is an adverse side effect that is not a
5 mg, the Wilton et al. [59] study (Finasteride 5 mg,
direct result of the drug’s specific pharmacological
14,772 men), the Wessells et al. [60] PLESS Study Group
action but due to patient awareness of the possibility of
(Finasteride 5 mg, 3040 men, 4-years long), the PCPT,
this adverse effect [68].
(Finasteride 5 mg, 18,882 men, 7-years long) [63, 64] and
all other smaller, randomized studies on Finasteride 1 mg.
Whether a nocebo effect can explain the psychological • Until 2012, only in one high-quality, randomized trial, the
exacerbation of SAEs in Finasteride users was controlled by Wessells et al. [60] PLESS Study Group (Finasteride
Mondaini et al. (2007), who tried to explain the dichotomy 5 mg, 3040 men, 4-years long) study were persistent
between literature’s data and clinical practice data. They SAEs reported. Surprisingly, in those subjects who with-
conducted a study on 120 sexually-active patients with BPH drew from the study due to SAEs, more subjects in the
and with an IIEF-EF score >/=25, who were randomly placebo groups noted persistent SAEs after discontinua-
divided into two groups: group 1 received Finasteride 5 mg tion than in the Finasteride group (59% vs. 50%).
concealed as an “…X compound of proven efficacy for the
treatment of BPH” for 1 year while group 2 was counseled The first report on persistent SAEs was published by Traish
on the drug sexual side effect with the phrase “...it may cause et al. (2011), and it was a case-study of a 24-year-old male
erectile dysfunction, decreased libido, problems of ejacula- with AGA who self-reported having a normal sex drive and
tion, but these are uncommon.” One hundred seven patients normal erectile capacity. Upon starting treatment in 1999
completed the study. The incidence of erectile dysfunction, with Finasteride for just 1 month, he developed permanent
decreased libido and ejaculatory disorders were 9.6%, 7.7%, loss of libido, erectile dysfunction, and depression [70]. The
and 5.7% in group 1, and 30.9%, 23.6%, and 16.3% in group authors presented a very extensive review of hypothetical
2, respectively (p = 0.02, p = 0.04, and p = 0.06). Overall, mechanisms that could explain this unique case of a young
patients in group 2 (n = 55) reported a significantly higher man who developed permanent erectile and loss of libido and
proportion of one or more SAEs as compared to group 1 still suffered from these that 11 years later, even though his T
(n = 52) (43.6% vs. 15.3%), resulting in an unexplained levels and all other tests were normal. Since 2011,
increase of 300% in the report of SAEs for the informed Abdulmaged M. Traish has published no less than 9 reviews
group [69]. about permanents SAEs and 5ARIs, making him probably
the most prolific author on the subject, even though he seems
to fight a very lonely battle.
24.7.4 Are SAEs Reversible? The “status quo” shifted permanently when Irwig et al.
(2012) published an uncontrolled study in the Journal of
Certain SAEs seem to appear in almost all Finasteride stud- Sexual Medicine titled “Persistent Sexual Side Effects of
ies, for both BPH and AGA, even if their incidence is limited Finasteride for Male Pattern Hair Loss.” They presented the
and comparable to placebo. interviews of 71 men who reported persistent SAEs due to
Finasteride treatment for AGA. Patients were recruited 24.7.5 Post-Finasteride Syndrome (PFS)
from a website targeting men who wanted to report the
inefficacy of Finasteride treatment of AGA or problems Post-Finasteride Syndrome (PFS) is a term coined to charac-
related to Finasteride, named www.propeciahelp.com, and terize a constellation of reported undesirable side effects that
cases from the author’s clinical practice and physician developed during or after stopping Finasteride treatment and
referrals. The patients were aged 21–46, had received persisted even after drug discontinuation. These effects were
Finasteride 1 mg for at least 28 months, had discontinued initially described only in post-marketing reports and small,
for more than 40 months, but SAEs persisted. Irwig et al. poor-quality, uncontrolled studies. The most frequent symp-
conducted the study via telephone or Skype interview, ret- toms are SAEs and depression. Other symptoms include sui-
rospectively inquiring about symptoms before and after cidal ideation, impaired cognition, fatigue, and decreased
Finasteride use. No less than 94% of these men reported penile sensitivity [45].
low libido, 92% reported erectile dysfunction, 92% devel- In 2012, a health advocacy group called the “Post-
oped decreased arousal, and 69% reported problems with Finasteride Syndrome Foundation” claiming to have (quot-
orgasm [71]. ing) “…the primary goal of finding a cure for the reported
syndrome and a secondary goal of raising awareness” was
The study had obvious and crucial limitations that the started by two physicians. The son of one of these physicians
authors themselves admitted. These included: No hor- developed severe depression during a period in his life when
mone levels measurement, post hoc analysis, selection he was also using Finasteride. In 2016 the Post-Finasteride
bias, recall bias for before finasteride data, and psycho- Syndrome Foundation sent an email to Dermatologists prac-
logical or other benefits that emerged from patients ticing in the United States to inform them about the syn-
upon their voluntary entry to the study. Nevertheless, drome and its inclusion into the National Institute of Health’s
the study provoked intense scientific debate and, unfor- Genetic and Rare Diseases Information Center (GARD).
tunately, received a great deal of media and internet However, they failed to explain that inclusion in the GARD
attention, as did the following two publications of does not constitute official recognition of PFS by the NIH as
Irwig, all suffering from the same severe methodologi- described in the website disclaimer (quoting) “The addition
cal flaws and biases [72, 73]. of PFS to the NIH’s GARD database does not officially
recognize PFS by the NIH but instead serves as a resource to
find more information regarding reported adverse events.”
Despite the low quality of evidence, on April 11, 2012, The NIH is currently funding a study on the epidemiology of
the U.S. Food and Drug Administration (FDA) ordered adverse events of 5ARIs specifically focused on persistent
changes in the package labeling for Propecia® and Proscar® side effects [75].
to include persistent side effects, admitting though that may Since 2012, the “field” of PFS has attracted excessive
or may not have a causal relationship to the drug. The list attention, and a significant number of publications have
included libido disorders, ejaculation disorders, and orgasm appeared in the literature, mostly cohort studies and meta-
disorders that continued after discontinuation of the drug, analyses. These are trying to locate previously unreported or
even though clear causal links between Finasteride and SAEs neglected adverse effects in large-scale, randomized studies.
have not been established. Interestingly, according to Google Trends, Google searches
The assessment of any relationship of SAEs with for “PFS” started steadily rising around 2012 [75].
Finasteride is extremely complicated because these symp- A recent review by Fertig et al. (2017) in collaboration
toms also occur in the general population and might be exac- with three prominent Dermatologists (Shapiro J, Bergfeld W,
erbated psychologically through a nocebo effect. Even Tosti A.) who have been working in the Finasteride studies
though a definitive causal relationship had yet to be estab- since “day-one” (even before 1998), concluded that none of
lished, the labeling change captured immediate media atten- these effects is documented in high-quality studies. They
tion. Shortly thereafter, many pharmacovigilance databases also commented that unless the PFS Foundation starts to
saw an increase in Finasteride’s adverse event reports, include Dermatologists in its advisory board to generate data
including controversial adverse events such as suicidality from prospective rather than retrospective studies, results
and mental health concerns. These subsequent reports of sui- cannot be considered relevant [76].
cidality and adverse psychological events, together with the Even though the causal relationship is very uncertain,
well-publicized SAEs, resulted in the coining of the term some men who have taken Finasteride for AGA seem to
“Post-Finasteride Syndrome” and the establishment of the experience long-term disability, and patients should be
Post-Finasteride Syndrome Foundation in 2012. informed about the issue. Unfortunately, as the study of
56 24 Finasteride
Basaria et al. (2016) showed, there are no predictable risk nal surgery. However, the authors had not measured levels
factors for the development of persistent SAEs that can be prior to Finasteride treatment [81]. In a small controlled
identified before treatment. The authors analyzed study by Di Loreto et al. (2014), an increased number of ARs
Finasteride users who reported persistent SAEs after dis- were found in the foreskin stromal and epithelial cells of
continuing Finasteride (group 1); age-matched Finasteride patients with PFS but not in vascular smooth muscle cells.
users who did not report SAEs (group 2); and healthy men The ratio of AR to T or free T levels was two-fold higher than
who had never used Finasteride (group 3). Symptomatic in controls. Those patients with more severe sexual side
Finasteride users were similar in body composition, effects had relatively more ARs. The reason for these changes
strength, and nucleotide sequences of androgen receptors and the actual activity of these ARs is still unknown. The
(AR), SRD5A1, and SRD5A2 genes to asymptomatic authors hypothesized that the modulation of local AR levels
Finasteride users and nonusers. Testosterone, DHT, might be implicated in the long-term side effects of
5α-androstane-3α,17β-diol-glucuronide, T/DHT and Finasteride use. Possible reasons are a regulatory feedback-
androsterone glucuronide/etiocholanolone glucuronide effect, a direct effect of low androgens, or inhibition of the
ratios and markers of peripheral androgen action and AR by Finasteride. However, no pre-treatment data are avail-
expression levels of AR-dependent genes in skin did not able [82].
differ among groups [77]. Khera et al. (2020) conducted a prospective case-control
Interestingly, Borgo et al. (2020) analyzed the fecal study with 25 subjects with a history of Finasteride use for
microbiota of 23 PFS patients and conducted 16S rRNA AGA and 28 controls to evaluate potential penile vascular
gene sequencing, and reported that gut microbiota popula- changes that could explain persistent SAEs. The subjects in
tion was altered in PFS patients, suggesting that it might rep- the Finasteride group (mean age 38, range 33–42 years) had
resent a diagnostic marker and a possible therapeutic target a median drug exposure of 18 months with an interquartile
for this syndrome [78]. range of 4–96 months. Penile duplex Doppler ultrasound
According to Wikipedia, as of 2016, Merck is a defendant (PDDU) was performed by administering intracavernosal
in 1385 product liability lawsuits that have been filed by cus- injections to induce erection and recording peak systolic and
tomers alleging they have experienced persistent sexual side end-diastolic velocities after a baseline evaluation of the
effects following cessation of treatment with Finasteride penis in the flaccid state. In total, 17 of 25 (68%) of subjects
[79]. in the Finasteride group had some vascular abnormality on
PDDU. Eight of twenty-four (32%) patients had arterial
insufficiency (defined as peak systolic velocity < 25 cm/s),
24.7.6 Can Persistent SAEs Be Explained? while 5 of 25 (20%) patients fell into the “gray zone” of pos-
sible erectile dysfunction, defined as a peak systolic velocity
Kanti et al. [45] (2018), in their systematic review, eloquently between 25–35 cm/s. Four of twenty-four (16%) patients had
summarized the available data on this question. a venous leak, defined as an end-diastolic velocity >5 cm/s.
However, the study suffered from severe limitations, includ-
ing selection bias, lack of baseline questionnaire data before
They stated that a possible explanation for symptoms Finasteride use, and, above all, lack of PDDU results in the
occurring for the first time shortly after discontinua- control arm. This is the first PDDU study, and results have
tion of the drug is a withdrawal effect comparable to not been replicated by any other group [83].
steroid withdrawal. It has been hypothesized that alter-
ations of androgen receptors (AR), androgen resis-
tance, or changes in androgen production levels during 24.7.7 Finasteride Effects on Fertility
the time the drug was taken have led to irreversible
androgen-deprivation changes, for example, in erectile Effects of Finasteride on ejaculate volume and on other
tissue physiology and function. semen parameters have not been reported in detail in the lit-
erature even though these SAEs occur in 2.1–7.7% of patients
[84]. Since it remains unclear which one of the two 5α-R
Another explanation is a sustained change of neuroactive isotypes is responsible for spermatogenesis or what is the
steroids and androgen receptors in the brain tissue [80]. One minimal serum DHT level required for spermatogenesis,
moderate-quality study by Caruso et al. (2015) found signifi- data on the issue remain incomplete.
cantly lower levels of 5α-reduced neuroactive steroids (allo- Regarding the effects of Finasteride on the reproductive
pregnanolone, 3α-androstanediol) in plasma and in CSF of function and spermatogenesis in patients treated for AGA,
men with neuropsychiatric symptoms post-Finasteride com- data is sporadic. Overstreet et al. (1999) conducted a double-
pared to otherwise healthy control subjects undergoing spi- blind, placebo-controlled multicenter study in 181 men,
19–41 years old. Subjects were randomized to receive Pallotti et al. (2020) retrospectively evaluated 55 male
Finasteride 1 mg or placebo for 48 weeks, followed by a subjects aged 18–45 years with AGA who underwent sys-
60-week “off-drug” period, and the researchers studied sper- temic therapy with Finasteride 1 mg/day at 6 months (T6)
matogenesis and sperm production. They reported that and 12 (T12) months after the beginning of therapy and
Finasteride does not affect spermatogenesis or semen pro- 1 year after treatment discontinuation (TD). At T6, they
duction in young men. There were no significant effects of detected a statistically significant worsening of total
Finasteride 1 mg on sperm concentration, total ejaculate vol- sperm number (232.4 ± 160.3 vs. 133.2 ± 82.0; p = 0.01
ume, sperm motility or morphology, and only ejaculate vol- vs. T0) and abnormal forms (79.8 ± 6.0 vs. 82.7 ± 5.7;
ume in the Finasteride group decreased by 0.3 mL (−11%) p < 0.05 vs. T0). No difference was found for all sperm
compared to baseline vs. a decrease of 0.2 mL (−8%) in the parameters at T12 and T24, except for the percentage of
placebo group [85]. The authors concluded that T is respon- abnormal forms (79.8 ± 6.0 vs. 82.6 ± 4.8; p < 0.05 T24
sible for all physiological processes resulting in sperm pro- vs. T0). Testosterone levels were increased at T0 vs. T6
duction, and consequently, Finasteride does not affect them (22.1 ± 7.1 vs. 28.0 ± 8.0 ng/mL; p < 0.03) and remained
negatively. These findings had been already reported by the higher at TD [90].
study of Schwartz et al. [86] (1997). They monitored 100
men during a 2-week period of Finasteride 5 mg administra-
Since there are very few reports in the literature, this
tion, reporting a reduction of DHT in the sperm by 88% with
effect can be considered rare and is possibly explained
negligible effects in sperm parameters.
by an idiosyncratic response to 5α-R inhibition.
A later, randomized, double-blind, placebo-controlled
study of Amory et al. [87] (2007) compared the effects of
Finasteride and Dutasteride in 99 healthy men (n = 34 on According to Elzanaty et al. (2006), it might be explained
Finasteride, n = 33 on Dutasteride, n = 32 on placebo). At by the polymorphism of the SRD5A2 gene, expressed in a
52 weeks, the semen volume was decreased (−14.5%), as very limited percentage of the population [91]. Probably, a
was sperm concentration (−7.4%), and there was a signifi- few men have increased sensitivity to Finasteride that may
cant reduction of −6 to −12% in sperm motility during treat- lead to a significant reduction of sperm quality and infertility,
ment and at follow-up, whereas Finasteride did not affect rendering Finasteride a potential causative factor of infertil-
sperm morphology. It is noteworthy that 5% of patients had ity that should be taken into account [92]. Sub-fertile and
a 90% reduction in sperm counts. Nevertheless, after infertile men, as well as men with severe oligospermia or
52 weeks of treatment and during the subsequent 24 weeks azoospermia, who are treated for AGA with Finasteride,
of follow-up, reduction in all three parameters was no longer should discontinue treatment before resorting to more
statistically significant and did not affect fertility. The dra- interventional fertility treatments, according to Price [93]. It
matic decrease in sperm counts in that 5% of the patients was is also wise to subject men of reproductive age to a sperm
restored to normal levels in the 24-week follow-up period of count before initiation of Finasteride treatment to have a ref-
Finasteride discontinuation. erence, baseline measurement.
Collodel et al. [88] (2007) reported three cases of young
infertile men who had used Finasteride for 5 years, one of
them being azoospermic. The other two showed a normal 24.7.8 Finasteride Effects on PSA
sperm count test had severely reduced motility. Semen
quality investigated by light microscopy analysis revealed The use of Finasteride 5 mg for BPH is known to affect PSA
altered sperm morphology. The examination was repeated serum concentration. In men taking Finasteride 5 mg who
1 year after Finasteride discontinuation, and recovery of the are screened for PCa, a compensatory adjustment of the PSA
spermatogenetic process was observed. Liu et al. (2008) concentration is recommended by merely doubling the PSA
presented two case-studies of infertile patients with severe value. Whether this recommendation should apply to men
oligospermia or even azoospermia, reduction of ejaculation taking Finasteride 1 mg for AGA treatment was still unknown
volume, and sperm mobility while on Finasteride 1 mg, but when the FDA approved Finasteride 1 mg for AGA.
upon treatment discontinuation, significant improvements Camacho et al. (2008) investigated the matter and reported
were seen within 6 months [89]. Since patients were not a 20% reduction in PSA values in patients between
subjected to a sperm count prior to Finasteride administra- 27–58 years old after 12 months of treatment with Finasteride
tion, results cannot be attributed to Finasteride, even if the 1 mg [41]. According to a study by D′ Amico et al. (2007) in
condition of both patients improved upon treatment 355 men, after 48 weeks of Finasteride 1 mg, men aged
discontinuation. 40–49 years and 50–60 years had a median decrease in serum
58 24 Finasteride
PSA concentration of 40% (95% CI: 34–46%) and 50% effect, the PCPT was designed. PCPT was a 9-year long trial,
(95% CI: 44–57), respectively. They suggested that the cur- including 18,882 men aged 55 years or older. The trial was
rent recommendation for the adjustment of serum PSA con- terminated 15 months before the anticipated completion for
centration in PCa screening in men taking Finasteride 5 mg ethical reasons since the trial objective had been met, evi-
should also apply to men taking the 1 mg/day preparation for dence was overwhelming, and the conclusions were
AGA [94]. Gormley et al. evaluated the effect of both doses extremely unlikely to change. Of the 9060 men who were
of Finasteride (1 mg and 5 mg) and placebo for 12 months, included in the final analysis, PCa was detected in 803 of the
in 895 men with BPH and reported a 48% decrease in PSA 4368 in the Finasteride group (18.4%) and 1147 of the
values among those who received Finasteride 1 mg and an 4692 in the placebo group (24.4%), a relative risk reduction
18% decrease in prostatic volume [6]. of 24.8% (p < 0.001). Unexpectedly, in the Finasteride group
Therefore, in men >40 years old, on treatment with there was a higher proportion of tumors with Gleason scores
Finasteride 1 mg, PSA value should be doubled and only of 7–10 (280 of 757 graded tumors [37.0%], or 6.4% of the
then compared to the normal range of values. This adaptation 4368 men included in the analysis) than in the placebo group
preserves PSA testing’s sensitivity and specificity and main- (237 of 1068 graded tumors [22.2%], or 5.1% of the 4692
tains its ability to detect PCa in those men in the future. men included in the analysis). The significance of the com-
Levels of PSA should be measured prior to treatment initia- parison between groups in terms of the percentage of graded
tion with Finasteride 1 mg and repeated yearly afterward. tumors was strong (p < 0.001) [63]. So, even though
Any increase of PSA, even if it remains within the normal Finasteride lowered the overall incidence of PCa when PCa
range, should be carefully evaluated, and the patient should was diagnosed in a Finasteride patient, chances were that it
be clinically examined, especially those with a positive fam- would be more aggressive [64]. These results raised many
ily history of PCa [95]. questions and controversies within the scientific community,
and even the conclusion of an initial Cochrane Database
meta-analysis by Wilt et al. (2008) was ambiguous [101].
24.7.9 Finasteride and Prostate Cancer (PCa) Nevertheless, later meta-analyses of the findings of the
PCPT proved that this result was an artifact and was not due
Finasteride’s long-term use and its indirect effects on androgen to morphological changes of the prostatic tissue induced by
and estrogen balance as well as in the immune surveillance of Finasteride. In contrast, these results were due to the selec-
cancer cells raised suspicions for a potential negative effect of tive inhibition of low aggression PCa and the reduction of
Finasteride on PCa. PCa is the second most common malig- the prostate’s size, which ultimately enhanced the identifi-
nancy in males after superficial skin cancer, and it is the second cation of the remaining aggressive cells through biopsy
leading cause of cancer-related death in American men [96, [102]. PCPT modeling studies suggest that biases, including
97]. The lifetime risk of PCa in the United States is 16%. changes in prostate volume, increase PSA’s sensitivity for
However, most men have minimal risk of dying from a PCa- detecting high-grade PCa, and a reduced ability of
related condition, having only 3% lifetime-chance of actually Finasteride to preferably shrink high-grade (vs. low-grade)
dying from this malignancy [98] (see Chap. 22, Vol. 1). cancers could adequately explain the increase in high-grade
Many studies have demonstrated that BPH and PCa often PCa on biopsy with Finasteride [103]. Serfling et al. (2007)
emerge in an estrogens-rich environment. This hormonal proved that the standard Finasteride-induced reduction of
imbalance is expected in the elderly but can also occur iatro- the prostate volume by 25% enhanced PCa biopsy-detection
genically in Finasteride users. More particularly, 5α-R inhi- by 23% [104].
bition initially leads to increased serum T levels, with the
highest increases occurring in men with low baseline T lev-
Therefore, one of the reasons for the increased number
els. In these men, the peripheral aromatization of T results in
of cases of aggressive PCa in the finasteride group was
high estrogen levels [99]. Immune competent cells bear
that finasteride rendered prostatic biopsy and PSA
androgen receptors, and androgens are known to affect the
more sensitive for the diagnosis of PC [105].
Th1/Th2 balance. Thus, Finasteride could indirectly alter the
immune surveillance of cancer cells in aging males, and it
was initially speculated there could be an increased risk for Moreover, more aggressive PCas (Gleason scale >6) have
PCa in Finasteride users [100]. The exact reverse opinion has been demonstrated to be related to isotype 5α-R I and are
also been expressed initially, that long-term Finasteride use therefore not affected by Finasteride [106]. Overall, other
would likely exhibit a cancer-protective effect on the prostate meta-analyses concluded that Finasteride ultimately reduces
through reduction of DHT. the risk of high-grade PCa by 27% and of low-grade PCa by
In order to answer this crucial question, whether 34% [107, 108]. Most importantly, Lacy and Kyprianou
Finasteride has a cancer-protective or a cancer-inducing (2014), found that the PCPT trial and the REDUCE trial on
Dutasteride (see Chap. 25) both had inherent biases that of T to estradiol. Estrogen exposure is a major determinant
potentially led to elevated Gleason scores. When computer of breast cancer (BC) risk, and estrogen metabolites are
models attempted to correct for these biases, there was no known to be genotoxic and mutagenic, whereas stimulation
significant difference found in high-grade PCa between the of tissue growth by the hormone is involved in the pathogen-
Finasteride group and controls [95]. esis of BC [115].
Wang et al. (2020) performed a systematic literature Gynecomastia, an enlargement of breast tissue, is a com-
review and meta-analysis to assess the association between mon adverse effect of numerous conditions related to hor-
Finasteride and PCa. Eight studies were identified, including monal disorders [116, 117]. It was not initially reported as an
54,335 cases of patients that used Finasteride and 9197 adverse effect of Finasteride in Phase II & III studies, and the
patients who served as placebo controls. Their results illus- actual incidence was unknown. In the literature, unilateral
trate a significant correlation between Finasteride use and gynecomastia seems more frequent, especially in the low
PCa with combined ORs: 0.70. As expected, a substantial doses of Finasteride 1 mg [118–121]; Finasteride 5 mg has
correlation between Finasteride use and high-grade PCa was been correlated with bilateral gynecomastia [122]. Typically,
also observed with combined ORs: 2.10. Overall, this study this adverse effect has a delayed onset compared to other
confirmed that Finasteride significantly reduced the risk of adverse effects or SAEs, and it is reported after 4–6 months
PCa even though the malignant degree of PCa was increased of treatment. The PCPT study showed that gynecomastia
[109]. was among the most common side effects of Finasteride
Using Finasteride in PCa chemoprevention would be a therapy along with SAEs since gynecomastia was observed
fascinating off-label indication, but the use of Finasteride in in 4.5% (426/9423) of Finasteride and 2.8% (261/9457) of
the general male population remains controversial, and there placebo subjects.
is no consensus on the prophylactic administration of Male BC occurs in the general population at a frequency
Finasteride [110]. A subsequent study of economic parame- of 1.24/100,000 man-years, and it is an exceptionally rare
ters indicated that Finasteride is not a cost-effective, prophy- adverse effect of Finasteride use. According to the results of
lactic treatment for the general male population but only for “Medicines and Health care products Regulatory Agency”
a sub-group of men at high risk for PCa [111]. For these (MHRA), there is an increased frequency of BC in men
reasons, Vickers et al. (2010) proposed that the ideal strategy under Finasteride treatment [123]. According to other
would be the preventive treatment or Finasteride chemopre- reports, the incidence might be even 100 times higher in
vention only of this subgroup of men at high risk [112]. patients in treatment with Finasteride vs. the general popula-
However, the vital metric is to consider the PCa mortality tion [124]. MHRA reported 50 cases of BC worldwide in
in Finasteride users vs. controls. Bonde Miranda et al. (2020) men taking Finasteride 5 mg daily and 3 cases in men taking
analyzed the data from the Prostate Cancer data Base 1 mg daily, as of November 2009. However, inadequate
Sweden; 89,227 men diagnosed with PCa between July 2007 information and relatively short times to onset make the
and December 2016, 5816 had been on 5ARIs for more than causal relationship unlikely [123].
180 days before the date of diagnosis. In men with high-risk McConnell et al. (2003) published the results of the
cancer, the risk of PCa death was similar among 5α-R inhibi- Medical Therapy of Prostatic Symptoms Study (MTOPS), a
tor users and nonusers, and there was no difference in mor- large-scale, long-term study with the recruitment of 3047
tality was observed among 5α-R inhibitor users and nonusers men with BPH and a mean follow-up period of 4.5 years.
in each Gleason group [113]. They reported that Finasteride increased BC’s rate by even
Overall, data on Finasteride use at 5 mg/day (1) confers 200 times from that observed in the general population [125].
reduced lifetime PCa risk, (2) might actually lower the risk In contrast to the MTOPS study results, results from 2 other
for high-grade PCa, and (3) does not change the prognosis large trials, PLESS [60] and PCPT [63], do not support the
for overall survival nor prostate-cancer mortality. For physi- association of Finasteride with male BC. In the PLESS study,
cians prescribing Finasteride 1 mg for AGA, it is safe to no cases of male BC were reported in the Finasteride-treated
assume that the prostate effects are similar, although a head- subjects. However, two cases of BC were reported in the pla-
to-head study would be needed to prove parity with respect cebo group. In the PCPT study (18,882 men >55 years old),
to the different doses [114]. receiving Finasteride 5 mg (n = 9423) and placebo (n = 9459)
for 7 years, one case of BC was reported in the Finasteride
arm and one in the placebo arm.
24.7.10 Finasteride, Gynecomastia In 2017, Hagberg et al. published a cohort study con-
and Breast Cancer ducted with nested, case-control analyses using the UK
Clinical Practice Research Datalink (CPRD). CPRD is an
As explained earlier, inhibiting DHT synthesis may alter the extensive, longitudinal, population-based electronic medical
estrogen to androgen ratio by shifting peripheral metabolism record database containing data on ~10 million people. They
60 24 Finasteride
identified all men in the CPRD from 1992 through 2014 who plained sadness. Depression developed even though most
had a BPH diagnosis and who received a prescription for patients were satisfied with the effects that Finasteride had
either Finasteride or Dutasteride. The risk for BC was higher on their hair. Upon treatment discontinuation, depressive
for Dutasteride (adjusted Odds Ratio, OR = 5.40, 95% CI: symptoms resolved promptly in all patients within 3 days to
3.64–8.00) than for Finasteride (adjusted OR = 2.92, 95% 3 weeks. Two out of 17 patients who were re-challenged with
CI: 2.31–3.68). Users of either drug did not have an increased Finasteride -after discontinuing therapy due to depressive
risk of BC compared to unexposed men (OR = 1.52, 95% CI: symptoms- quickly relapsed within 2 weeks, and the mood
0.61–3.80). The authors concluded that despite the massive was restored only after re-discontinuation of the treatment.
size of the database, there were too few cases to estimate the Irwig [73] studied 61 men who previously used Finasteride
risk of BC for users of 5ARIs alone or to assess differences 1 mg for AGA and 29 control subjects. According to a self-
in risk by type of 5α-R inhibitor prescribed [126]. administered questionnaire (Beck Depression Inventory
The Propecia Summary of Product Characteristics (SPC) (BDI), 75% of former Finasteride 1 mg users had depressive
mentions BC as a possible risk, but current data suggest BC’s symptoms (BDI-II > 14), and 64% had severe depressive
occurrence in men taking Finasteride is coincidental. symptoms (BDI-II > 20). The respective rates in the control
groups were 10% and 0%.
Rahimi-Ardabili et al. enrolled 128 men with AGA (mean
24.7.11 Finasteride, Depression and CNS age 25.8 ± 4.4) years) who were prescribed Finasteride 1 mg/
Effects day. Information on depressed mood and anxiety was obtained
by BDI, and Hospital Anxiety and Depression Scale (HADS).
Lately, the emphasis has been placed on Finasteride’s potential Participants completed BDI and HADS questionnaires before
adverse effects in the central nervous system (CNS) since beginning the treatment and 2 months after it. Finasteride
androgens are extensively metabolized in the human brain [127] treatment increased both BDI (p < 0.001) and HADS depres-
and affect non-reproductive functions as well [128, 129]. sion scores significantly (p = 0.005). HADS anxiety scores
Depression as an adverse effect of Finasteride has received were raised, but the difference was not significant (p = 0.061)
plenty of media attention, although the evidence is very limited. [137].
The physiological basis of mood disorders caused by Finasteride Ganzer et al. [138] (2015) investigated the extent to which
has been associated with androgen deficiency and neurosteroids healthy men with a recent history of taking Finasteride for
dysregulation [130]. It has been postulated that neurosteroids AGA experienced persistent psychological, physical, and
have anxiolytic, antidepressant, and memory enhancement cognitive adverse effects for periods ≥3 months after discon-
properties and are involved in neuroprotection [131]. tinuing Finasteride. The authors used an online questionnaire,
Studies on lab animals have demonstrated that Finasteride and patients were recruited from www.propeciahelp.com. In
can impact behavioral activity [132]. Some researchers spec- total, 131 patients were recruited, and results showed a high
ulate a similar effect in humans since Finasteride efficiently prevalence of adverse psychological effects in former
crosses the blood-brain barrier [133]. Recent studies report Finasteride users, with more than 70% of study subjects
that Finasteride reduces allopregnanolone levels in animal reporting anxiety, depression, attention difficulties, slowed
models. Changes in allopregnanolone levels in the human thought process, and anhedonia once they discontinued
brain have been correlated with depression, anxiety [130, Finasteride therapy. In the same study, 50–60% of subjects
134], and other behavioral disorders [135]. It has been experienced emotional sensitivity, suicidal ideations, memory
hypothesized initially by Traish et al. that the inhibition of problems, and mental cloudiness or “brain fog”; the latter was
5α-R by Finasteride results in alterations in neurosteroid bio- reported by 95 of 131 patients. A subsequent study by Ganzer
synthesis and contributes to CNS adverse events [70]. At the and Jacobs (2016) investigated the psychological health of 97
moment there are no data on whether Finasteride reduces Finasteride users and whether having a preexisting personal
allopregnanolone levels in humans. or family history of psychiatric diagnosis and certain person-
Psychiatric side effects of Finasteride have not been docu- ality traits influenced anxiety and depression. Once again,
mented in high-quality randomized trials and were only patients were recruited from a link to the questionnaire posted
reported in 2 moderate-quality studies [81, 136], 3 low- to www.propeciahelp.com and the author’s clinical practice.
quality studies [66, 137, 138], and one very low-quality According to the BDI results, 38 subjects scored within the
study [133]. These included depression, anxiety, and suicidal moderate to severe depression range, and five subjects scored
ideation [76]. within the extreme depression range [139].
Starting with the lowest-quality study, Altomare et al. Unger et al. (2016) analyzed Medicare claims from the
[133] (2002) published a case report, according to which 17 PCPT participants; 13,935 of 18,880 participants, 73.8%, in
patients (5 women, 12 men) out of 25 who received the PCPT were linked to Medicare claims. They found no
Finasteride reported mood disorders, anxiety, and unex- increase in sexual dysfunction and only a marginal increase
in depression with long-term use of Finasteride (HR: 1.10, Deng et al. (2020) conducted a meta-analysis to explore
95% CI: 1.01–1.19, p = 0.04) [140]. the association between Finasteride/Dutasteride (5ARIs) use
and risk of depression. They included 6 clinical studies with
265,672 participants and concluded that 5ARIs could
According to the excellent, detailed review by Fertig
increase the risk of depression based on both pooled unad-
et al. [76], the studies of Irwig [71–73] and Ganzer
justed (95% CI: 1.28–2.78, Relative Risk, RR = 1.89,
[138, 139] suffer from several serious methodological
p = 0.001) and multivariable-adjusted RRs (95% CI: 1.01–
flaws and biases, just two of which are selection bias
1.17, RR = 1.09, p = 0.03). In subgroup analyses, Dutasteride
and recall bias, while lack of control group in all but
was associated with depression significantly (95% CI: 1.37–
one of these studies is another limitation.
1.70, RR = 1.53, p < 0.001), while Finasteride was not.
Regarding the degree of depression, 5ARIs mainly caused
Selection bias is particularly a factor in studies where patients mild depression (95% CI: 1.91–2.33, RR = 2.11, p < 0.001)
were recruited from the website www.propeciahelp.com and instead of moderate or severe depression [145].
sought treatment of reported symptoms after taking Finasteride. Dyson et al. (2020) used the administrative data from the
These patients may have experienced more severe symptoms National Veterans Health Administration to identify 53,848
and have been more likely to seek out the study. Additionally, it male patients initiating 5ARIs therapy during the fiscal year
is unclear whether the drug itself caused depressive symptoms 2014. Incident antidepressant prescribing was observed in
or whether SAEs contributed to the depression. Studies that 2563 patients following 5ARIs initiation and 3051 patients
have related mood disorders with Finasteride have been reported preceding 5ARIs initiation (OR = 0.84; 95% CI: 0.80–0.89).
in BPH patients, although in that case, it was considered that Similar findings were observed for incident depression
depression was due to the underlying disease (BPH) problems diagnosis (OR = 0.83; 95% CI: 0.79–0.86). Stratification by
and less to Finasteride [141]. age group, 5ARIs agent, antidepressant class, and depres-
These low-quality studies suggest that Finasteride may be sion diagnosis type failed to demonstrate any positive asso-
correlated with adverse psychological effects in a very limited ciation between 5ARIs and depression. The authors
number of susceptible patients, but no definitive conclusions considered that their findings support the hypothesis that
have been reached. Moreover, before accusing Finasteride of depression is more likely attributable to underlying BPH
causing psychiatric disorders, one should bear in mind that and associated lower urinary tract symptoms than
studies have reported personality disorders in 75% of patients 5α-reductase inhibitor exposure [146].
with early AGA, while the corresponding rate in the general However, the results of Nguyen et al. (2021) challenge
population is 10.3% [142, 143]. Also, 5ARIs may have thera- these findings. Nguyen et al. conducted a pharmacovigilance
peutic effects in several disorders related to dopaminergic case-noncase using data from VigiBase, the World Health
hyperactivity, including psychotic disorders [144]. Organization’s global database of individual case safety
Welk et al. (2017) conducted a population-based, retro- reports. They investigated the association of suicidality (ide-
spective, matched cohort study using linked administrative ation, attempt, and completed suicide) and adverse psycho-
data for 93,197 men ages 66 years or older (median age, 75 logical events (depression and anxiety) with Finasteride use.
(70–80) years ) in Ontario, Canada, who initiated a new pre- A significant disproportionality signal for suicidality
scription for a 5ARI during the study period (2003 through (OR = 1.63; 95% Confidence Interval, CI: 1.47–1.81) and
2013) to treat BPH. The authors matched these men with psychological adverse events (OR = 4.33; 95% CI: 4.17–
those without any 5ARI prescriptions, and assessed 96 dif- 4.49) in Finasteride was identified. In sensitivity analyses,
ferent covariates, representing medical and psychiatric younger patients (OR = 3.47; 95% CI: 2.90–4.15) and those
comorbidities, medication usage, and health care utilization. with AGA (OR = 2.06; 95% CI: 1.81–2.34) had significant
The incident depression risk was elevated during the initial disproportionality signals for increased suicidality; such sig-
18 months after 5ARI initiation (HR: 1.94; 95% CI, 1.73– nals were not detected in older patients with BPH. As men-
2.16), and continued to be elevated, but to a lesser degree, for tioned earlier, in 2012 the first clinical study reporting an
the remainder of the follow-up period (HR: 1.22; 95% CI, association between suicidality and Finasteride was pub-
1.08–1.37). Men who used 5ARIs were not at a significantly lished and highly publicized [73].
increased risk of suicide (HR: 0.88; 95% CI, 0.53–1.45).
Risk of self-harm was significantly increased during the ini-
Interestingly, the sensitivity analyses showed that the
tial 18 months after 5ARIs initiation (HR: 1.88; 95% CI,
reports of these adverse events doubled after 2012
1.34–2.64), but not thereafter. However, one should consider
(OR = 2.13; 95% CI: 1.91–2.39), suggesting that these
that the study population is not representative of the typical
disproportional signals of adverse events may be due
5ARI user for AGA and that these patients received
to reporting bias or stimulated reporting [147].
Finasteride 5 mg does [216].
62 24 Finasteride
Other authors, such as Dr. Ho (2021), advised caution Medicines Agency, studies on topical Finasteride in hair loss
when interpreting the results, as there are many limitations to treatment remain sparse.
this kind of pharmacovigilance study prohibiting the estab- Initial results of topical Finasteride in balding men were
lishment of causality [74]. Without a plausible biological disappointing because even though it decreased DHT pro-
hypothesis pharmacodynamically linking the drug and the duction locally in the hair follicles, it did not inhibit the pro-
reported adverse event, this kind of analysis may lead to false gressive course of AGA [154]. Rushton et al. as early as 1996
findings [148]. Most importantly, reporting bias can simi- conducted a study on men with AGA, using a topical solu-
larly occur in these adverse event databases due to reporting tion of 0.05% Finasteride. Even though skin absorption was
behavior, such as false reports submitted by patients who are adequate, there was no hair growth, possibly because serum
dissatisfied or involved in litigation or stimulated reporting DHT concentration was reduced by just 40% [155]. This
affected by mass media. In fact, the sensitivity analyses by result led to the conclusion that Finasteride’s main action is
Nguyen et al. did reveal such reporting bias. The lack of sui- to lower circulating DHT by inhibiting systemic production,
cidality signal observed for Dutasteride, a drug similar to rather than affecting the metabolism of androgens in the hair
Finasteride in the mechanism of action but has not attracted follicle per se. The question of whether Finasteride could
media attention, hints at a potential reporting bias unique to have a substantial local effect in hair follicles remained,
Finasteride. Definitive causal inferences cannot be drawn though.
from this kind of pharmacovigilance study, and indeed, the Mazzarella et al. (1997) conducted a single-blind,
signals for suicidality and adverse psychological events that placebo-controlled, 16-month trial on 28 males with AGA
Nguyen et al. identified for Finasteride should not be mis- and 24 females with FPHL. Subjects were randomly allo-
taken for proof that there is a causal association between the cated to receive 0.005% Finasteride solution or vehicles
two due to the inherent biases described [74]. (50% ethyl alcohol, 25% propylene glycol, and 25% dis-
Notably, it is confirmed that low levels of neuroactive ste- tilled water) b.i.d. for 16 months. Hair regrowth was
roids have been associated with depression (in the absence of observed among patients treated with topical Finasteride in
Finasteride therapy), post-natal depression, and post- the fourth month and were sustained throughout the study.
traumatic stress disorder, providing some support for the Increased hair density at the periphery of balding patches
idea [149]. Since depression and mood disturbances in men and progressive thickening of hair texture were reported as
taking Finasteride were not reported in the pivotal clinical the treatment responses. By 6 months, the rate of hair loss
trials, they are probably very uncommon. More studies are evaluated by hair counts from the wash tests showed a sig-
required to evaluate the potential of adverse neuropsychiatric nificant decrease compared to those applying vehicles,
effects of Finasteride on humans. Therefore, it is possible whereas no change in the serum DHT levels was observed
that Finasteride does have a negative impact on those who [156].
have a constitutive predisposition to psychological disorders. In 2000, Price et al. [25] studied nine women with hirsut-
Basaria et al. reported that symptomatic Finasteride users ism and demonstrated that the skin absorption of Finasteride
revealed depressed mood and fMRI findings consistent with was negligible, as was the decrease in serum DHT, which
those observed in depression [77]. resulted in a non-efficient, topical action against female hir-
Therefore, patients with a history or predisposition of sutism. Hajheydari et al. (2009) conducted a double-blind,
psychiatric disease should be closely monitored when randomized clinical trial on 45 males with AGA randomly
administered Finasteride [150, 151]. In patients with active divided into a topical Finasteride and an oral Finasteride
depression or active sexual dysfunction, Finasteride is group. Patients in the topical Finasteride group received a
contraindicated. topical gel of 1% Finasteride and placebo tablets, while the
oral Finasteride group received Finasteride tablets (1 mg)
and a placebo gel base for 6 months. Results demonstrated
24.8 Topical Use of Finasteride that the use of Finasteride gel 1% and oral Finasteride 1 mg
had a relatively similar therapeutic response (p = 0.643)
Finasteride is absorbed by the skin and is soluble in ethyl [157].
alcohol and other organic solvents (ethanol, methanol, and
chloroform). Therefore, a topical Finasteride solution could
These initial studies showed promising results, and
be quite a reasonable approach, but its low aqueous solubil-
since the topical use of finasteride would have signifi-
ity limits its therapeutic possibilities.
cant advantages compared to the oral route, several
The efficacy of topical Finasteride has been demonstrated
researchers have tried to incorporate finasteride into
to locally inhibit the sebaceous gland growth in the hamster
various vesicles that allegedly increase skin absorption
flank organ [152] and in the stump-tail macaque [153]. As it
and thus the efficacy of the topical formulation.
has not yet been approved by the FDA or the European
24.8 Topical Use of Finasteride 63
A topical formulation with high skin penetration and (FMX) vs. 3% MTS solution. At week 24, FMX was signifi-
deposition but low systemic absorption is preferable. Several cantly superior to MTS in hair density improvement, hair
compounds have been explored to provide appropriate drug diameter, and global photographic assessment (all p < 0.05).
delivery and biomedical applications, including topical solu- The mean change from baseline in total hair density at week
tions, gels, liposomes, vesicular nanocarriers, polymer- 24 was 61.84 ± 15.65hairs/cm2 in the FMX group and
somes, vesicular ethosomal carriers, niosomes, polymeric 34.88 ± 10.24hairs/cm2 in the MTS group, with an amount of
nanoparticles, and liquid crystalline nanoparticles. Among superiority of 27 hairs/cm2. The mean change from baseline
these, a Finasteride liposomal gel system containing 2% in hair diameter at week 24 was 17 ± 5.24 μm in the FMX
methylcellulose and agel system containing poloxamer P407 group and 13 ± 4.15 μm in the MTS group, with an amount
exhibited the highest skin penetration at the site of applica- of superiority at 4 μm. The FMX combined solution also had
tion. These may be the ideal future delivery systems for topi- minimal effect on plasma DHT levels, approximately 5%
cal Finasteride [158]. reduction. There were also no systemic adverse events
Recent in vivo results of Finasteride topical formulations reported by patients in both groups [162].
in balding men have been quite impressive, especially those Lee et al. (2018) conducted a systematic review to identify
reporting the synergistic effect of topical Finasteride and studies regarding human in vivo topical Finasteride treatment
Minoxidil topical solution (MTS) in treating male efficacy, including clinically relevant case reports, randomized
AGA. Tanglertsampan (2012) compared the efficacy and controlled trials, and prospective studies. They included seven
safety of 24-weeks application of 3% MTS vs. combined 3% articles in their review, and in all studies, there was a signifi-
MTS and 0.1% Finasteride lotion (FMX) in forty men with cant decrease in the rate of hair loss, an increase in total and
AGA, randomized into two groups of 20 patients each. At terminal hair counts, and positive hair growth assessment with
week 24, hair counts were increased from baseline in both topical Finasteride. Both scalp and plasma DHT were signifi-
groups, and unpaired t-test revealed no statistical difference cantly decreased with topical Finasteride application, but no
between the two groups with respect to the change of hair changes in serum T were noted [163].
counts (p = 0.503). However, FMX showed significantly For the interested reader, Khan et al. (2018) published a
higher efficacy than MTS by global photographic assess- comprehensive review of all the available literature on
ment (p = 0.003) [159] Finasteride’s topical delivery, aiming to help elaborate the
Caserini et al. (2014) conducted a randomized, single- best dosage form, i.e., a formulation having a maximum per-
center, open-label, parallel-group, exploratory study on 24 meation rate [158]. Suchonwanit et al. (2020) reviewed 28
healthy men with AGA who received either Finasteride studies and summarized the pharmacology, therapeutic effi-
0.25% topical solution b.i.d. or oral Finasteride 1 mg o.d. for cacy, and safety of topical Finasteride in the treatment of
7 days. Plasma DHT was reduced by 68–75% with the topi- AGA and FPHL. The reported that topical Finasteride is an
cal solution and by 62–72% with the tablet, albeit Finasteride upcoming and promising modality in the treatment of AGA/
plasma exposure was 11-fold lower with the topical solution FPHL with excellent therapeutic outcomes according to clin-
than with the oral product (p < 0.0001). The reduction in the ical studies. Furthermore, combination therapy with topical
scalp DHT levels from baseline was similar for 0.25% topi- Finasteride exhibited an additional effect over topical
cal solution twice daily (47%) and oral Finasteride 1 mg Minoxidil as a monotherapy [164]
daily (51%), and significantly lower for daily application Overall, current data support the therapeutic potential of
once (71%) [160]. topical Finasteride in increasing hair density and hair diam-
Chandrashekar et al. (2015) conducted a retrospective eter while decreasing the systemic adverse effects associated
assessment in 45 AGA patients aged 20–40 years to assess with oral administration.
the efficacy of maintaining hair growth with 5% MTS forti-
fied with 0.1% Finasteride after initial treatment with 5%
Topical finasteride is an exciting alternative treatment
MTS and oral Finasteride for 2 years. Of the 45 patients who
option for individuals who would like to avoid possible
were switched from oral to topical Finasteride, 25 patients
complications of oral finasteride since it minimizes
initially experienced some hair loss and then reached a pla-
systemic adverse effects. Topical Finasteride’s safety
teau phase; thus, hair density was moderately maintained,
seems to be excellent, and no severe side effects or
without further hair loss. Seven patients had a mild decline in
SAEs have been reported in clinical studies.
hair density, and 13 patients did not experience a decline or
even showed a density improvement [161].
Suchonwanit et al. (2018) conducted a randomized, Although alterations in the serum DHT levels were
double-blind controlled trial in 40 men aged 18–60 years observed, no patient developed SAEs caused by the changes
with AGA to assess the efficacy and safety of a topical solu- in DHT levels, and no significant difference in serum T lev-
tion of 0.25% Finasteride admixed with 3% Minoxidil els with the topical application was observed [164].
64 24 Finasteride
The tolerability of various topical Finasteride formula- Hu et al. (2015) conducted a 12-month, randomized,
tions is excellent. Side effects are local and insignificant, open-label, comparative trial, and the efficacy was evaluated
such as scalp pruritus, irritation, burning sensation, contact through global photographic evaluation. The subjects were
dermatitis, dryness, flaky scalp, and erythema. The combina- assigned into three groups; 154 males with moderate AGA
tion of topical Finasteride and MTS provides an additional received oral Finasteride 1 mg, 122 received MTS 5%, and
benefit over MTS monotherapy and may be a promising 152 received both treatments. At 12 months, 80.5%, 59%,
treatment option in the future. However, as several different and 94.1% of men treated with Finasteride, 5% MTS and the
concentrations and vehicles for topical Finasteride have been combination therapy showed an improvement, respectively.
used, further studies are required in the future to establish the The authors concluded that Finasteride was superior to 5%
most effective drug-delivery system, compositions, formula- MTS, while the combined medication showed the highest
tions, regimens, and concentrations of topical finasteride as efficacy [168].
monotherapy and as a combination therapy with MTS [164]. Chen et al. (2020) conducted a meta-analysis to deter-
Despite its proven efficacy, the use of topical Finasteride mine the efficacy and safety of combined treatment of
is limited due to a smaller number of studies. Further studies Finasteride and MTS. Five RCTs composed of 640 patients
are warranted to determine the most efficacious formulations were used in the meta-analysis. All studies compared com-
and investigate the consequences of topical Finasteride’s bined therapy with MTS, but only 2 RCTs compared com-
long-term use. Continued research into drug-delivery, ideal bined therapy with Finasteride. Compared with MTS or
topical concentration and application frequency, side effects, Finasteride alone, the combined group had a significantly
and use for other alopecias will help to elucidate the full higher global photographic evaluation score (p < 0.00001),
extent of topical Finasteride use. more patients with marked hair increase (p < 0.001), and
fewer patients with deterioration or no change (p < 0.001)
and similar incidences of adverse events, indicating that
24.9 Finasteride Vs. Minoxidil combined therapy is a better choice for AGA patients
[169].
The efficacy of oral Finasteride 1 mg compared to MTS’s Van Neste (2020) conducted a fascinating study employing
efficacy has been a “hot” scientific subject. No more than an analytical and exhaustive study protocol to demonstrate
four studies have been published comparing Finasteride how these two compounds work in clinical practice. Volunteers
1 mg and MTS. All three demonstrated the superiority of with AGA (n = 22) took oral Finasteride 1 mg daily with ran-
Finasteride 1 mg against both MTS 2% and MTS 5%. domly either 5% MTS or control lotion (1 mL/day). He
In the study of Saraswat et al. (2003), at 12 months, the employed a patented variant of contrast enhancement photo-
mean change from baseline total hair count was 36.1 hair/ trichogram (CE-PTG) hair extraction procedure where the
cm2 (29.1%) for Finasteride 1 mg and 19.6 hair/cm2 (14.8%) loosely attached elements would be specifically removed,
for MTS 2% (p = 0.003) [165]. named exogen collection CE-PTG-EC. After 12 months on
Khandpur et al. (2002) tested the comparative efficacy of the oral drug, 14 subjects were randomized for a dose-effect
various treatment regimens for AGA in an open, randomized, study of topical 2% or 5% MTS. Each 3-month “on-lotion”
parallel-group study on 100 males, separated into 4 groups: was followed by a 3-month “off-lotion.” There were a series of
Group I (n = 30 patients) was administered Finasteride, statistically significant variations indicating a positive effect of
Group II (n = 36 patients) was given a combination of the combination treatment as compared to the oral drug with
Finasteride, and 2% MTS, Group III (n = 24 patients) applied control lotions where no change from baseline was observed.
2% MTS alone, and Group IV (n = 10 patients) was admin- MTS effect was mainly due to accelerated re-launching minia-
istered Finasteride with Ketoconazole shampoo. At the end turized and terminal anagen from non-productive, that is telo-
of 12 months, hair growth was observed in all the groups, gen, exogen, or empty scalp follicles.
with best results recorded with a combination of Finasteride The author noted that after 12 months on oral Finasteride,
and MTS (Group II) followed by groups IV, I, and III, while all possible units were not optimized in terms of production
87% of patients taking Finasteride vs. 42% of the MTS 2% unless MTS was added. Finasteride appeared to have a “sta-
patients were rated as improved (p < 0.001) [166]. bilizing effect” and MTS a “boosting” effect.
Arca et al. (2004) randomly assigned 40 patients
(61.53%) to receive 1 mg/day oral Finasteride for 12 months,
and 25 patients (38.47%) to apply 5% MTS twice daily for Therefore, if clinicians and/or patients are not satisfied
12 months. Results indicated that both drugs were effective after 1 year on oral finasteride, improvement can still
and safe in the treatment of mild to severe AGA, although be obtained by adding a 1 per day course of topical 5%
oral Finasteride treatment was more effective than MTS 5% MTS, but a warning should be provided that both drugs
(80% vs. 52% improvement, respectively) in scalp coverage need to be maintained for efficacy [170].
at 12 months [167].
24.11 Finasteride and FPHL 65
24.10 How to Best Combine Finasteride preferably for six- before discontinuing MTS 5% in order
and MTS to avoid significant hair loss, while Finasteride action can
take over. However, Tosti et al. have demonstrated that
The mechanism of action of Finasteride on the miniaturized Finasteride treatment may not prevent telogen effluvium
AGA hair follicles differs from that of Minoxidil. Minoxidil after Minoxidil withdrawal [174], and these results were
is considered to act by stimulating the cellular proliferation confirmed by Van Neste [170].
of DPCs, while Finasteride acts on the hormonal level, inhib-
iting the harmful effects of DHT on hair follicles. Their com- Regarding the action of Finasteride in hair restoration sur-
bined action and clinical benefit qualify as synergistic and gery, it has been found to correlate with faster graft regrowth,
result in enhanced hair regrowth than either compound alone, higher graft survival and higher patient satisfaction [175] and
both in the stump-tail macaque [171] and in men with AGA will be analyzed in Chap. 115, Vol. 3.
[172–174] (Fig. 24.8).
However, it is wiser not to administer both drugs on the
first visit since it will be impossible to measure each drug’s Since regular finasteride administration results in steady
effect on the patient. A strategic protocol is the following: serum levels in weeks, a useful practice for patients
experiencing side effects is reducing the dose to 0.5 mg
• It is better to start with MTS 5% and evaluate the effect and eventually down to 0.2 mg o.d. this dose will result
after 6–8 months. If the results are significant, there is no in comparable serum finasteride levels (and efficacy) to
need to add Finasteride just yet; if they are mild to moder- the 1 mg o.d. in a matter of days [50], but it will proba-
ate, one can add topical or oral Finasteride, bly be associated with fewer adverse effects.
• If the patient notices an impressive improvement only upon
Finasteride addition, he might consider discontinuing MTS
5% altogether. Finasteride treatment is more patient-
friendly, thus increasing compliance, and these cases seem 24.11 Finasteride and FPHL
to have a better long-term result. However, the results of
Van Neste strongly disagree with this view [170], DHT is necessary for the normal development of male geni-
• If the addition of Finasteride offers an added slight or talia in utero. In animal studies, Finasteride has caused
moderate improvement in coverage, it is wise for the abnormal development of external genitalia in male embryos,
patient to continue both drugs since both are needed to undervirilization or feminization, and therefore, it is classi-
have a fuller result, fied as a teratogen [176, 177]. Finasteride is not FDA-
• In the rare case that there is no evident improvement upon approved for females. It is classified as pregnancy category
Finasteride addition, the patient may remain on MTS 5% X and is contraindicated in women of childbearing potential
treatment alone and discontinue Finasteride, unless they are informed of the potential risks and use ade-
• Finally, some patients want to switch from MTS 5% to quate contraceptive measures.
Finasteride without waiting to see Finasteride’s results first. Finasteride in premenopausal women carries the risk of
Combination therapy is advised for at least 3 months -but feminization of a male fetus, with outcomes similar to those
Fig. 24.8 Schematic No treatment Discontinuation of MTS treatment

representation of Finasteride’s MTS + Finasteride Discontinuation of Finasteride treatment
hair-growth effects, MTS 5%,
their combined effect, and the 100% Finasteride
consequence of MTS
discontinuation Start of treatment Discontinuation of treatment
50%
0%
66 24 Finasteride
reported in male infants with genetic 5α-R deficiency [5]. increased from a mean baseline count of 15.5 to 20.9 after
Women of reproductive age should even avoid touching 12 months of Finasteride, vs. 17.3 to 18.3 in the placebo
Finasteride tablets since the intact skin might absorb group. Simultaneously, the miniaturized hairs decreased
Finasteride [178]. In order to prevent unintentional exposure from 26.7 to 23.6 with Finasteride vs. 21.3 to 20.3 with pla-
of women of reproductive age to Finasteride, Propecia® tab- cebo. In contrast, in the female study, no significant differ-
lets are covered in a hard capsule, and unless crushed or bro- ences in follicular counts were found between Finasteride
ken, normal handling of intact capsules is safe. Men under and placebo groups [184].
Finasteride treatment should not donate blood earlier than Price et al. (2000) conducted a 1-year long, double-blind,
6 months after treatment discontinuation [179], since the placebo-controlled, randomized, multicenter trial on 137
donated blood may be transfused to a pregnant woman. postmenopausal women with FPHL and evaluated the effi-
The amount of Finasteride in the semen is insignificant, cacy of oral Finasteride 1 mg/day vs. placebo. Finasteride
even with a regular intake of 5 mg/day Finasteride, and there 1 mg/day showed a further progression of hair loss and no
is no risk for a pregnant woman. The use of a condom is not significant difference in hair count from the placebo-control
necessary for this reason. Notably, the quantities of the drug group. After 1 year, there was a mean change from baseline
in the semen are 50- to 100-fold less than in serum [180]. hair count at −8.7 hairs/cm2 in women taking Finasteride
Merck and Co. reported that men treated with Finasteride and − 6.6 hairs/cm2 in the control group. None of the 44
1 mg for 6 weeks had levels of the drug 750 times lower than postmenopausal women in the Finasteride group experi-
the “no effect” level for developmental abnormalities in rhe- enced an increase in hair growth but only reduced hair loss
sus monkeys [213]. Notably, more than 4lt of semen (assum- compared to placebo, yet not statistically significant [185]
ing a 5-mL ejaculate) would be needed for Finasteride to (Fig. 24.7).
reach an unsafe amount inside the female genital tract These two studies were the reason why researchers first
(Fig. 24.6). challenged the prior assumption that male AGA and “female
There are no reproductive risks for postmenopausal AGA” (today named FPHL) were both androgen-depen-
women, and general adverse effects might apply, such as dent conditions. Further research on the topic led to the
decreased libido, headaches, dizziness, gastrointestinal dis- conclusion that non-androgenic mechanisms are involved
comfort, isolated reports of menstruation changes, and acne. in the etiology of “female AGA,” which was soon renamed
Independent studies evaluating Finasteride 5 mg daily for to Female Pattern Hair Loss, FPHL (see Chap. 12, Vol. 1).
6 months in women with hirsutism found no adverse effects, Other research teams experimented with higher
and there are also several published case reports and case Finasteride doses in women with FPHL and reported mixed
series with similar results showing a lack of side effects, as results. Shum et al. (2002) described 4 cases of hair loss with
reviewed by Hirshburg et al. [181] However, drug-induced characteristics of both male and female patterns in women
abortion and uterine disorders were associated with with hyperandrogenism in which Finasteride 1.25 mg
Finasteride according to Wu et al. who examined the clinical improved or stabilized the condition [186]. Trüeb et al.
reports submitted to the Adverse Event Reporting System (2004) treated five normoandrogenic postmenopausal
(FAERS) of the FDA from 2004 to 2014 and published a women with FPHL with 2.5 or 5 mg/day oral Finasteride.
fascinating review [182]. Both schemes improved scalp hair by all evaluation tech-
niques. The patients’ self-assessment demonstrated that
Finasteride decreased hair loss, increased hair growth, and
Finasteride has been used as an off-label treatment for
improved hair appearance. These improvements were con-
FPHL for years, even though data is limited and con-
firmed by an investigator and photographic assessments,
troversial. Also, there is no standard minimal effective
demonstrating that Finasteride 2.5 mg/day or more may be
dosage of finasteride in FPHL [183], and very few
effective for the treatment of FPHL in postmenopausal
publications have addressed the off-label use of
women in the absence of clinical or laboratory signs of
Finasteride in FPHL.
hyperandrogenism [187].
Iorizzo et al. (2006) studied 37 premenopausal women
Whiting et al. (1999) took serial 4 mm punch biopsies at aged 19–50 years old and demonstrated low to significant
baseline and after 12 months of treatment with Finasteride or efficacy of Finasteride 2.5 mg in combination with contra-
placebo in 26 men with AGA (n = 14 on Finasteride 1 mg ceptive treatment for 62% of women. These findings raised
daily, n = 12 on placebo) and 94 postmenopausal women suspicions on the necessity of a higher dose of Finasteride
(n = 44 on Finasteride 1 mg daily, n = 50 on placebo, aged in pre- or postmenopausal women with or without hyper-
41–60 years old). In the male study, the terminal hairs androgenic signs [188]. Indeed, Yeon et al. (2011) con-
24.11 Finasteride and FPHL 67
ducted an uncontrolled study on 87 pre- and photos. The authors found that 33 (29.5%) of the 112 patients
postmenopausal, normoandrogenic Asian women with showed slight improvement, 73 (65.2%) showed significant
FPHL and reported that administration of Finasteride 5 mg improvement, whereas no change was recorded in 6 (5.4%).
for 12 months had significant positive effects. The average They also demonstrated the efficacy of Finasteride at a dose
increase in density was 107 ± 23 hairs/cm2 (p < 0.001) of 2.5 mg/day for patients with FPHL and that Finasteride
while the average hair caliber was increased by 9.4 μm had a better effect on hair growth when patients had a lower
(14.7%), reaching 70 ± 9 μm (p < 0.02). The photographic Ludwig score and an older age at onset [192].
evaluation indicated that 70 out of the 86 patients (81.4%) According to Rushton et al., the reason why women with
improved in terms of cosmetic coverage and hair density FPHL and evident excess of androgens respond favorably to
[189]. Finasteride and normoandrogenic women with FPHL do not
Kim et al. (2012) conducted a 28 week, open-label, pro- is not related to serum androgen levels [193]. Efficacy of
spective study on 18 normoandrogenic FPHL patients to Finasteride in women seems to depend on parameters such
determine whether 1.25 mg Finasteride is the minimal as age, serum androgens, signs of hyperandrogenism, and
effective dosage on FPHL. Fourteen patients completed the menstrual cycle parameters. The only off-label indication of
study, and after 28 weeks of treatment, phototrichogram Finasteride in FPHL that seems to “make sense” is in women
assessment demonstrated a 5.87% mean increase in hair who do not respond to Minoxidil and have proven androgen
density and an 11.8% mean increase in hair thickness, both sensitivity, but caution is required until more experience with
non-significant. At the end of the study, 10 of these 14 higher doses of Finasteride in FPHL is gained [194].
patients (71.4%) rated their condition as “no change”; the Meanwhile, Bayram et al. (2002) compared a high-dose
physicians also recorded “no change” in 9 (64.3%) patients, Finasteride (5 mg/day) vs. low-dose Finasteride (2.5 mg/
demonstrating that a Finasteride dose higher than 1.25 mg/ day) in the treatment of hirsutism in 56 hirsute women with
day is needed for positive results in normoandrogenic moderate to severe hirsutism. They reported that both doses
FPHL patients [183]. were well-tolerated and safe. Both schemes had similar effi-
Oliveira-Soares et al. (2013) treated 40 normoandrogenic cacy, but estradiol levels increased significantly at 6 and
postmenopausal women with FPHL with oral Finasteride 12 months in the Finasteride 5 mg group [195].
5 mg/day for 18 months, and efficacy was evaluated by the A review of 20 peer-reviewed articles by Seale et al. (2016)
patient’s satisfaction and global photographic assessment. found that very few side effects or adverse events related to
The authors reported a “major’ improvement in 55% of sexual function have been reported in studies in which
patients, and a “moderate” improvement in 37.5% of patients, Finasteride has been used to treat hair loss in women [196].
as assessed by global photography. The percentage of greatly Iamsumang et al. (2020) reviewed the pharmacology and
improved patients was higher in patients <60 years (12/20) efficacy of Finasteride in women, especially in the
and in patients 60–70 years (4/13), than in the group of postmenopausal-aged group, including 9 studies on oral and
>70 years [190] (Fig. 24.8). 2 on topical Finasteride. They also reported that systemic
In contrast, Boersma et al. (2014) conducted a retrospec- side effects of oral Finasteride appeared only in high doses
tive study -without a placebo-control group or a double-blind but were minimal and transient and that no systemic adverse
data collection methodology. They recruited a random sam- effects have been reported with the use of topical Finasteride
ple of 120 women who had been taking Finasteride 1.25 mg in FPHL patients except suppression of serum DHT levels
or Dutasteride 0.15 mg for three consecutive years (anytime [197].
between 2002 and 2012) and separated them into 4 groups of Future publications should investigate not only the effi-
30 women and in two age categories: below and above cacy but the side effect profile in female patients as well
50 years, and for each drug. Researchers measured the hair [189]. Concerning the effects of Finasteride in FPHL, Kanti
caliber of the three thinnest hairs from standardized micro- et al. [45] included one study assessing the efficacy of
scopic images at three sites of the scalp at the start of the Finasteride 1 mg daily [185] and two studies evaluating the
treatment and after 3 years of continuous medication. A total efficacy of Finasteride 5 mg daily [188, 189]. The grades of
of 49 (81.7%) women in the Finasteride group and 50 evidence were A2, C, C, respectively, resulting in an Evidence
(83.3%) in the Dutasteride group had hair thickness increase Level 3 [45].
under this evaluation protocol [191]. Emerging evidence suggests that 5ARIs may also be
Won et al. (2018) retrospectively investigated 112 pre- among the most effective treatments for Frontal Fibrosing
menopausal or postmenopausal patients with FPHL who Alopecia (FFA) in postmenopausal females [198], and they
were administered Finasteride at a 2.5 mg/day dose. Patients are increasingly used in an off-label fashion with this indica-
were evaluated based on their medical records and global tion [199].
68 24 Finasteride
Overall, Finasteride’s off-label use in FPHL and FFA appearance of secondary male characteristics, such as beard
treatment in women is on the rise, and this practice appears and chest hairiness, jaw contour, and muscle development.
safe and efficacious. The physician should explain with patience and clarity to
these patients the benefits and safety profile of Finasteride.
Since extensive, well-designed safety and efficacy studies
The prescribing physician should always be aware that have included very young balding patients of 18 years of age,
the off-label prescription of drugs occurs at the discre- it is acceptable to prescribe Finasteride to these patients, as
tion of the prescribing physician and that even though well. However, it might be wise to start younger patients
the off-label use of drugs is legal, but the promotion of with MTS as a first line treatment and only later add topical
drugs toward unapproved indications can be illegal. Finasteride as a second line treatment and, upon failure, oral
Finasteride.
Even though the safety of Finasteride is considered very
24.12 Final Notes high by most experts, since 2015, there has been an increased
number of reviews and meta-analyses on the safety of
Finasteride is effective, well-tolerated, and safe. However, Finasteride and other 5ARIs [196, 201–203].
media attention, nocebo effect, and internet notoriety have Recent meta-analyses that assessed the incidence of sex-
made Finasteride prescription increasingly challenging for ual adverse effects did not directly address the persistence of
physicians. symptoms (Table 24.2).
One crucial issue is the earliest age one may safely start Belknap et al. (2015) meta-analyzed 34 clinical trials of
treatment with Finasteride. Secondary efficacy analysis was Finasteride in AGA treatment and found systematic inade-
conducted to determine the effects of Finasteride 1 mg on quate safety reporting and underreporting of adverse events.
scalp hair growth by the Finasteride Male Pattern Hair Loss
Study Group, published in JAAD in September 2012. The Table 24.2 Adverse reactions to oral Finasteride 1 mg. (From Trüeb
study initially included 1553 patients, aged 18–41, separated [212])
in Finasteride and placebo groups, who were randomly Common (frequency • Sexual dysfunction (finasteride 3.8%
selected in 27 centers in the USA and 15 other countries. The between ≥1/100 and 1/10): vs. 2.1% within first 12 months of
original study lasted 12 months, and 1215 patients were also treatment; 1% of men withdrew
finasteride because of SAEs within
included in the 12-month extension study, with a crossover first 12 months of treatment; thereafter,
of the two teams in a ratio of 9:1 (Finasteride/placebo) [200]. frequency decreased to 0.6% during
During the same period, a replicate study was conducted in following 4 years of treatment)
32 centers in the USA, including 424 AGA patients aged • Diminished libido (finasteride 1.8%
vs. placebo 1.3%)
41–60. These three well-designed studies confirmed that • Erectile dysfunction (finasteride 1.3%
when Finasteride treatment starts early, it results in a signifi- vs. placebo 0.7%)
cant hair growth increase in all areas of the scalp. When Occasional (frequency • Abnormal ejaculation
treatment begins at middle age, the overall response is between (≥1/1000 • Decreased ejaculatory volume
and < 1/100):
decreased and limited mostly to the vertex. Even though
Rare (frequency between • Testicular pain
younger patients had consistently shown better results, these ≥1/10,000 and < 1/1000): • Breast tenderness
younger patients exhibited lower compliance with • Gynecomastia (may persist for
Finasteride. They discontinued Finasteride more frequently months to years after cessation of
due to adverse effects than placebo, which has been reported finasteride treatment)
• Allergic reactions: Rash, itching,
previously for younger subjects [35] and not observed in hives, swelling of the mouth, face,
older men [65]. lips, or tongue (angioedema)
Very rare • Depression
(frequency < 1/10,000): • Male breast cancer
Despite these promising findings, younger patients are Unknown (frequency • Persistent diminished libido or
terrified of what they read on the internet and in “hair cannot be estimated from erectile dysfunction (after cessation
loss forums” regarding SAEs and other adverse effects existing data): of finasteride treatment)
• Male infertility (usually in association
of finasteride and usually are very resistant to opt-in with preexistent subfertility)
for finasteride treatment. • Decrease in quality of semen (there
are reports on normalization or
improvement of semen quality
Some patients even worry whether early initiation of following withdrawal of drug)
Finasteride treatment might interfere with the long-term • Post-finasteride syndrome
24.12 Final Notes 69
None of these clinical trials had adequate safety reporting, Therefore, the current literature data remains controver-
19/34 were partially adequate, 12/34 were inadequate, and sial, and it is not yet possible to establish a causal relation-
3/34 reported no adverse events at all. A meta-analysis found ship between 5ARIs and the persistence of sexual symptoms.
that adverse event reporting was of poor quality, systemati- Further large-scale prospective pharmacoepidemiologic
cally biased, not generalizable to routine practice and that studies explicitly designed to evaluate these potential SAEs
most subjects had ≤1 year of Finasteride exposure [201]. in young patients using Finasteride for treatment of AGA are
According to Kiguradze et al., who analyzed fifteen system- needed [76].
atic reviews or meta-analyses of 5ARIs trial reports, most on Finally, an important issue that physicians must be aware
Finasteride 5 mg, each concluded that 5ARIs-associated of is that some individuals, in an effort to save money, will
SAEs are infrequent, mild, and reversible. However, none of split Finasteride 5 mg pills (Proscar®) instead of buying the
these prior meta-analyses assessed the adequacy of evaluat- original Finasteride 1 mg Propecia®. Studies have shown
ing adverse events in primary clinical trial reports [202]. high variability in the dosage of pieces of tablets ranging
Overall, available data are too limited and of poor quality, from 0.49 mg to 1.81 mg of Finasteride, only 10% being
and, therefore, insufficient for establishing real safety. within the dosage range, which is ±5%, as compared with the
A systematic review and meta-analysis by Liu et al. authorized 1 mg dose. However, according to Epstein, split-
(2016) observed a significantly greater risk of SAEs among ting the generic Finasteride 5 mg tablet should be an equally
patients with BPH, but not in those undergoing AGA treat- effective alternative to the Finasteride 1 mg, or to the brand-
ment. The two divergent factors between the two groups that name drug, despite the potential for fragment loss during
probably influenced these findings were the mean age and splitting [208]. However, physicians should be aware of legal
the daily dose used for each disease. Moreover, persistent actions that can result from suggesting these practices.
symptoms were not evaluated [203]. Also, generic Finasteride 1 mg capsules formulated with
Another meta-analysis by Lee et al. (2019) found con- an active ingredient of unknown origin are marketed unoffi-
flicting results. The authors b identified a two-fold increased cially. This has raised issues of dosage variability and bio-
risk of SAEs in AGA cases treated with Finasteride com- equivalence. Interesting articles have addressed the issues of
pared to placebo [204]. bioequivalence of all these practices [207] and several
However, observations of Finasteride-related SAE are experts have reported different efficacy of branded vs.
much less prevalent in the actual clinical experience com- generic Finasteride. Regarding generic Finasteride 1 mg cap-
pared to reports in the literature. In order to address the dis- sules, any formulation purportedly similar to the reference
crepancies, Haber et al. (2019) conducted a single-center, proprietary drug must prove its bioequivalence or inter-
survey-based study using the Arizona Sexual Experience changeability with respect to the availability of the active
Scale (ASEX), a reliable, valid, and sensitive tool for mea- ingredient.
suring sexual dysfunction. The authors investigated
Finasteride-associated sexual dysfunction claims in 663 men Synopsis
reporting they were taking Finasteride for varying lengths of Finasteride 1 mg is a selective, potent inhibitor of the
time and compare this to sexual dysfunction in 99 age- 5α-Reductase isotype ΙΙ. Finasteride is the only FDA-
matched non-users. The percentage of men self-reporting approved oral treatment for AGA, and it reduces serum DHT
loss of libido (p = 0.805) or reduced sexual performance levels by 64–70% and scalp levels by 54–65%. Finasteride
(p = 0.332) did not significantly differ between men taking has been proven the most efficacious treatment for AGA in
Finasteride and the control group. Interestingly, for all dura- terms of hair growth and remains effective on a long-term
tions of Finasteride use, ASEX score was predicted to be, on basis for most patients (>93%). Off-label use of Finasteride
average, less than that of no Finasteride use, meaning that in women with FPHL can only be beneficial in a percent of
two individuals of the same age with libido loss and reduced women with a diagnosed androgen disorder. Premenopausal
sexual performance, the individual taking Finasteride is pre- women must take all necessary contraceptive measures when
dicted to have a lower ASEX score (better sexual perfor- using Finasteride since it is a known teratogen.
mance) [205]. Discontinuation of Finasteride results in total regression of
Another controversy is that most clinicians who fre- results over the course of 1 year and progression to the AGA
quently prescribe Finasteride seriously doubt the existence stage the patient would have reached if Finasteride has never
of PFS, suggesting that it is very uncommon, if at all, an been used. A small percentage of patients experience Sexual
issue. Trüeb et al. reported in 2019 the first case of PFS in Adverse Effects (SAEs), which are typically reversible upon
their 20-year prescription practice of 5ARIs for the treatment treatment discontinuation or even while staying on treat-
of AGA. The authors considered that PFS might represent an ment. Physicians are required to inform patients on SAEs,
“induced delusional disorder of the somatic type,” possibly even though knowledge of these adverse effects might trig-
on a background of a histrionic personality disorder [206]. ger a psychological exacerbation of SAEs, a phenomenon
70 24 Finasteride
known as the “nocebo effect.” Recently, concerns have been 8. Russell DW, Wilson JD. Steroid 5 alpha-reductase: two genes/two
raised after a few, small, low-quality, and strongly biased enzymes. Annu Rev Biochem. 1994;63:25–61.
9. Andriole G, Bruchovsky N, Chung LW, et al. Dihydrotestosterone
studies reporting persistent SAEs (“Post-Finasteride and the prostate: the scientific rationale for 5alpha-reductase
Syndrome,” PFS) even after Finasteride discontinuation. As inhibitors in the treatment of benign prostatic hyperplasia. J Urol.
yet, the condition is not recognized by the scientific commu- 2004;172(4 Pt 1):1399–403.
nity, although individuals who claim to suffer from PFS 10. Harris G, Azzolina B, Baginsky W, Cimis G, Rasmusson GH,
Tolman RL, Raetz CR, Ellsworth K. Identification and selective
present with distinctive and relatively homogenous symp- inhibition of an isozyme of steroid 5 alpha-reductase in human
toms. However, the findings have not been confirmed in scalp. Proc Natl Acad Sci U S A. 1992;89(22):10787–91.
high-quality studies and are questionable. Even though 11. Waldstreicher J, Fiedler V, Hordinsky M, Swinehart JM, Thiboutot
emerging clinical evidence suggests a vulnerable cohort of D, Unger W, et al. Effects of finasteride on dihydrotestosterone
content of scalp skin in men with male pattern baldness. J Invest
patients in whom Finasteride can result in long-term persis- Dermatol. 1994;102:615.
tence of SAEs, whether PFS is an actual consequence of 12. Kaufman KD, DeVillez R, Roberts J, Fiedler V, Olsen E, Imperato-
Finasteride treatment remains poorly understood and largely McGinley J, et al. A 12-month pilot clinical study of the effects of
controversial. Further, properly designed long-term, placebo- finasteride on men with male pattern baldness. J Invest Dermatol.
1994;102:615.
controlled, and ideally prospective in nature, clinical studies 13. Kaufman KD, Gormley GJ, Binkowitz B, Jacobsen CA, Bruno K,
using objective methods for evaluating sexual function and the Finasteride Male Pattern Baldness Study Group. The effects
reliable questionnaires are needed to prove or exclude the of oral finasteride on scalp hair growth in men with male pat-
causality between Finasteride and SAEs. We also need to tern baldness [abstract]. 77th Annual Meeting of the Endocrine
Society, Program and Abstracts, Washington, DC, June 14–17,
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tify those patients at particular risk, and how best to treat 14. Roberts JL, Fiedler V, et al. Clinical dose ranging studies with
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199. Holmes S, MacDonald A. Frontal fibrosing alopecia. J Am Acad Product Insert. Issued May 2007. Distributed by Merck and Co,
Dermatol. 2014;71(3):593–4. Inc, Whitehouse Station, NJ 08889, USA.
200. Olsen EA, Whiting DA, Savin R, et al. Male pattern hair loss 214. Steers WD. 5alpha-reductase activity in the prostate. Urology.
study group. Global photographic assessment of men aged 18 to 2001;58(6 Suppl 1):17–24.
60 years with male pattern hair loss receiving finasteride 1 mg or 215. Yanagisawa M, Fujimaki H, Takeda A, Nemoto M, Sugimoto T,
placebo. J Am Acad Dermatol. 2012;67(3):379–86. et al. Long-term (10-year) efficacy of finasteride in 523 Japanese
201. Belknap SM, Aslam I, Kiguradze T, et al. Adverse event reporting men with androgenetic alopecia. Clin Res Trials. 2019;5:1–5.
in clinical trials of finasteride for androgenic alopecia: a meta- https://doi.org/10.15761/CRT.1000273.
analysis. JAMA Dermatol. 2015;151(6):600–6. 216. Welk B, McArthur E, Ordon M, Anderson KK, Hayward J, Dixon
202. Kiguradze T, Temps WH, Yarnold PR, Cashy J, Brannigan RE, S. Association of suicidality and depression with 5α-reductase
Nardone B, Micali G, West DP, Belknap SM. Persistent erectile inhibitors. JAMA Intern Med. 2017;177(5):683–91.
Dutasteride
25
Basic Concepts reporting in early clinical trials. However, specific

• Dutasteride is a second generation, competitive, data on Dutasteride are sparse.
irreversible, and potent inhibitor of all isotypes of • There is no pending application on the FDA for the
5α-R. It is twice as effective as Finasteride in inhib- approval of oral Dutasteride for AGA/FPHL, and its
iting isotype 5α-R ΙΙ and 45 times more potent in use with that indication is off-label even if very effi-
inhibiting isotype 5α-R I. It decreases the systemic cient, while topical Dutasteride in combination with
levels of DHT by almost 95% without having any oral Finasteride is an attractive treatment option.
direct hormonal, estrogenic, progesteronic, or anti-
androgen activity.
• The hair growth effect of 0.5 mg Dutasteride is Dutasteride is a synthetic 4-azasteroid, developed by
higher than 5 mg Finasteride, while doses up to 5 GlaxoSmithKline, and it is an orally-administered, second
times higher than those recommended for BPH generation inhibitor of the 5α-R enzymatic complex that
(2.5 mg Dutasteride o.d.) score significantly better leads to near-maximal Dihydrotestosterone (DHT) suppres-
than lower ones in hair growth. sion. The compound appeared in the medical literature ini-
• Dutasteride’s profile of adverse effects is similar to tially under the name GG-745, later as GI198745, and was
that of Finasteride and reported sexual adverse finally named Dutasteride [1]. Dutasteride is commercially
events (SAEs), such as erectile dysfunction, libido available under the brand name Avodart® (Dutasteride
decrease, and ejaculatory disorders, are rare (<4%) 0.5 mg), containing soft capsules of a mixture of mono- and
and usually self-limited upon treatment continua- diglycerides of capric/caprylic acid. Dutasteride is soluble in
tion, unlike semen parameters which might be sig- organic solvents, such as ethanol (44 mg/mL), methanol
nificantly affected for longer periods. SAEs might (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it
remain for months after discontinuation since is insoluble in water (<0.038 ng/mL) [2].
Dutasteride has a half-life of >240 h and a washout Dutasteride was patented in 1996, and after completion of
period of >680 h. Phase III trials, it was approved by the FDA for the treatment
• Dutasteride is now becoming a popular “off-label” of Benign Prostatic Hyperplasia (BPH) in November 2001
treatment option in AGA due to its tolerability and and introduced into the U.S. market under this indication. In
good response shown by various randomized con- December 2002, Dutasteride was also approved in the
trol studies and meta-analyses. In most studies, European market with the same indication.
Dutasteride scored better than Finasteride with
comparable adverse effects and could become a
treatment of choice for AGA in the near future. 25.1 Mechanism of Action
• Recent clinical studies, case studies, and meta- and Pharmacodynamics
analyses report an increased incidence of SAEs and
CNS adverse effects (depression, mood disorders, Dutasteride is a synthetic steroid with a chemical structure
etc.) for both Finasteride and Dutasteride, and the similar to that of Finasteride, with one essential difference
authors criticize the inadequacy of adverse effect concerning action: it is a selective, competitive, irreversible
inhibitor of all three isotypes of 5α-R, namely I, II, and

78 25 Dutasteride
III. Finasteride, which is also an irreversible inhibitor of ≈24 weeks of continued treatment with 0.5 mg o.d. The
5α-R, only inhibits the type II isoenzyme by 70% and mini- absolute bioavailability of Dutasteride is ≈60% and is
mally the isotype I, as analyzed in Chap. 24. In vitro studies highly bound to plasma proteins, 99% to plasma albumin,
comparing the potency of Dutasteride and Finasteride and 96.6% to the α-1 acid glycoprotein [16, 17]. Dutasteride
reported that Dutasteride was threefold more potent than is extensively metabolized in the liver and is mainly
Finasteride in inhibition of 5α-R isotype ΙΙ and 45 times excreted in the feces [18].
more potent in 5α-R isotype Ι inhibition [3, 4]. Dutasteride is Dutasteride’s mean half-life is remarkably long, esti-
the first and only, so far, complete inhibitor of the enzyme mated at 247 h [19, 20], and the necessary washout period is
5α-R [5], to which it binds irreversibly in a time-dependent >670 h or approx. 28 days [21]. Dutasteride has a large vol-
manner. It forms a stable complex that dissociated extremely ume of distribution (300–500 L) [16, 22] and is extensively
slowly both in vitro and in vivo, thus inhibiting Testosterone distributed throughout central and peripheral compartments,
(T) from binding to 5α-R and converting into DHT [6]. including semen. After one month of Dutasteride 0.5 mg o.d.
Therefore, theoretically, Dutasteride would be expected to treatment, the average concentration in the semen of healthy
have superior efficacy to Finasteride for treating males with volunteers was 3.4 ng/mL (range 0.4–14 ng/mL vs.
AGA. (more on that later). Finasteride 0.26 ng/mL), while 11.5% of the serum concen-
Among the recognized 5α-R isoenzymes, type I and type tration of Dutasteride was found in semen. The steady-state
II contribute to approximately 30% and 70%, respectively, of concentration of the drug in semen is achieved after six
the DHT in circulation [7]. Type I isoenzyme is mainly pres- months of administration.
ent in the skin, including the hair follicle and sebaceous Dutasteride is metabolized by isoenzyme CYP3A4 of
glands [8], whereas type II is predominantly found in the the Ρ-450 enzymic system, and co-administration with
male genitalia, including the prostate, but it is also found in compounds metabolized by the same coenzyme, such as
the inner root sheath of hair follicles [9]. Since Dutasteride Cimetidine, Ciprofloxacin, Ketoconazole, and
blocks both isoenzymes efficiently, it induces a near-maximal Verapamil, might increase their serum concentration.
DHT suppression, which was expected to be a revolutionary Since Dutasteride is metabolized in the liver, caution is
treatment for BPH [10, 11]. As early as the first week of advised in individuals with hepatic disease. The phar-
treatment, Dutasteride results in a median serum DHT levels macokinetic effect due to consumed food is of no clini-
reduction of 85%, increasing to 90% during the second week cal importance, and Dutasteride may be taken both
and reaches 94% DHT suppression during the first year of before or after meals [23].
treatment, remaining at this level thereafter. Respectively,
there is an impressive decrease in the intraprostatic DHT
concentration to levels achieved only with surgical castration 25.3 Dutasteride in BPH
[12], with the only difference being that surgical castration
practically eliminates serum T levels. Three identical, multicenter, randomized, placebo-controlled,
double-blind, large-scale, 2-year-long clinical trials were
conducted to assess Dutasteride’s efficacy and safety profile
Conversely, Dutasteride administration does not influ-
in BPH. Two of the trials were conducted in the U.S. and the
ence T production and will even increase serum T by
third one in 19 other countries [24]. In total, 4325 men were
≈20%, since T that would normally convert to DHT
enrolled and randomized (2951 completed the trials), 2167
will remain in the circulation [13]. However, serum T
received Dutasteride 0.5 mg, and 2158 received a placebo.
remains within the normal range.
Patients were aged 47–94 (average age 66yo), with diag-
nosed BPH and reporting moderate to severe symptoms.
At the same time, PSA values, a powerful indicator of After 24 months, results were quite encouraging since the
prostate size, are decreased by ≈50% after six months of risk of acute urinary retention in the Dutasteride group was
Dutasteride therapy, while the prostate itself eventually reduced by 57% compared to placebo, while the risk of
reduces in size by 25% at 12 months [14], whereas bone den- BPH-related surgical intervention was reduced by 48%.
sity [15], HDL, LDL, and cholesterol remain unaffected. Additionally, the total prostate and transition zone volumes
decreased by a mean of 25.7% and 20.4%, respectively, com-
pared to just 2.2% in the placebo group. During the two years
25.2 Pharmacokinetics of Dutasteride of the study, 376 patients (9% in each group) discontinued
treatment due to adverse effects, mainly relating to the repro-
Mean peak serum Dutasteride concentration is achieved ductive system. In patients reporting adverse effects, these
1–3 h after oral administration of a single 0.5 mg dose, were mostly self-limited over time and while remaining on
with steady-state concentrations being achieved after treatment (Table 25.1).
25.4 Dutasteride and ΑGΑ 79
Table 25.1 Adverse effects of Dutasteride. (Adapted with permission (Finasteride 1 mg) was not commercially available yet. The
from Roehrborn et al. [24]) results demonstrated Dutasteride’s efficacy as a hair-growth
Adverse reaction time of onset drug (Table 25.2), (Figs. 25.1 and 25.2), and results were
Adverse Months Months Months Months published in 2006. Dutasteride 0.1 mg (1/5 of the dose used
reaction 0–6 7–12 13–18 19–24
in BPH) resulted in similar hair counts and serum DHT
Dutasteride (n) (n = 2167) (n = 1901) (n = 1725) (n = 1605)
Placebo (n) (n = 2158) (n = 1922) (n = 1714) (n = 1555) reduction with Finasteride 5 mg, while the highest hair
Impotence a counts were achieved with Dutasteride 2.5 mg. The mean
Dutasteride 4.7% 1.4% 1.0% 0.8% change in total hair counts with Finasteride 5 mg was signifi-
Placebo 1.7% 1.5% 0.5% 0.9% cantly different compared to Dutasteride 2.5 mg (14.8 hairs/
Decreased cm2, 8.4%, vs. 21.5 hairs/cm2, 11.3%, p = 0.009) [27].
libidoa
The promising results of this dose-finding study encour-
Dutasteride 3.0% 0.7% 0.3% 0.3%
Placebo 1.4% 0.6% 0.2% 0.1% aged GlaxoSmithKline initially to announce future large-
Ejaculation scale Phase III trials, which, however, were soon called off
disordersa for publicly unknown reasons. Industry sources speculate
Dutasteride 1.4% 0.5% 0.5% 0.1% that Dutasteride would have been considered as too similar
Placebo 0.5% 0.3% 0.1% 0.0% to Propecia®. It is also assumed that since the most effec-
Breast
tive dosage of Dutasteride 2.5 mg was five times higher
disordersb
Dutasteride 0.5% 0.8% 1.1% 0.6% than the standard dosage in the treatment BPH (Dutasteride
Placebo 0.2% 0.3% 0.3% 0.1% 0.5 mg corresponds to Finasteride 5 mg in BPH), more
a
These sexual adverse reactions are associated with dutasteride treat- side effects would be seen in this group, which worried the
ment (including monotherapy and combination with tamsulosin). These manufacturing company that it would be a reason to get
adverse reactions may persist after treatment discontinuation. The role rejected by the FDA.
of dutasteride in this persistence is unknown
Nevertheless, years later, in February 2007,
b
Includes breast tenderness and breast enlargement
GlaxoSmithKline recruited male volunteers with AGA for a
Phase ΙΙΙ trial to be conducted in Korea (Identifier:
These Phase ΙΙΙ studies on Dutasteride’s efficacy and NCT00441116). The study was conducted by Eun et al., was
safety proved that it is effective, safe, and generally well- completed by January 2008, and results were announced in
tolerated. The 2-year open-label extension of the studies the Journal of the American Academy of Dermatology in
mentioned above to 4 years (1570 subjects were enrolled) August 2010. A total of 153 men, age range 18–49 years old,
demonstrated that Dutasteride retained its efficacy and were randomized to receive 0.5 mg of Dutasteride or placebo
safety, while the frequency of adverse effects was further daily for six months. The mean change of hair counts from
decreased [25, 26]. baseline to 6 months was +12.2/cm2 in the Dutasteride group
vs. 4.7/cm2 for the placebo (p = 0.0319). Dutasteride showed
significantly higher efficacy than placebo by subject self-
25.4 Dutasteride and ΑGΑ assessment and by investigator panel photographic assess-
ment. However, there was no statistically significant
GlaxoSmithKline probably expected Dutasteride to be a difference between groups during the first three months of
game-changer in AGA treatment. In March 1999, the first treatment. There was no major difference in adverse events
small-scale clinical trials on Dutasteride’s effect on AGA in between groups, and only 3 of 73 patients (4.1%) who
humans were completed (Phase ΙΙ, GSK study ARIA2004), received Dutasteride reported Sexual Adverse Effects
examining whether Dutasteride could take after Finasteride (SAEs), vs. 2 of 75 patients in the placebo group (2.7%) [28].
and become the next treatment for AGA. Therefore, the This study allowed Dutasteride to get officially approved
Dutasteride Alopecia Research Team was founded, com- in Korea in 2009 for the treatment of AGA. The study was
prised of leading Dermatologists and Urologists, and a tar- later extended to a multicenter, open-label, non-
geted study protocol was designed to test the hypothesis. interventional, prospective, post-marketing surveillance
A multicenter (21 centers), double-blind, dose-finding study on 712 males with AGA, aged 18–41, supervised by
study was designed and conducted by Olsen et al. (2006), the Korean Food and Drugs Administration Agency (proto-
enrolling 416 men, aged 21–45, classified as Norwood- col ID 113797). The study was conducted by Choi et al.
Hamilton III vertex-V, randomized into six groups: placebo, (2016) and aimed to evaluate the safety and tolerability of
Finasteride 5 mg (Proscar®) and four different dosage Dutasteride. The authors noted that adverse effects of special
schemes of Dutasteride: 0.05 mg, 0.1 mg, 0.5 mg, and interest, such as decreased libido, were reported by nine sub-
2.5 mg. In this study, Finasteride 5 mg had to be used as a jects (1.3%), impotence by 7 (1.0%), sexual function abnor-
benchmark to Dutasteride groups since Propecia® mality by 4 (0.6%), ejaculatory disorder by one subject
80 25 Dutasteride
Table 25.2 Mean changes from baseline after 24 weeks for placebo, Dutasteride (0.05 mg–2.5 mg), and Finasteride 5 mg. (Adapted with permis-
sion from Olsen et al. [27])
Dutasteride Dutasteride Dutasteride Dutasteride Finasteride
Placebo 0.05 mg 0.01 mg 0.5 mg 2.5 mg 5 mg
Increase in number of hairs in −32.3 n/a 78.5 94.6 109.6 75.6
predetermined area
Decrease in serum DHT 0 −42% −69.8% −92% −96.4% −73%
Decrease in scalp DHT n/a −32% −51% −79% −41%
Increase in serum testosterone 15% 18% 23.8% 27.5% 10.4%
Increase in scalp testosterone 23% 39% 99% 222% 23%
Fig. 25.1 Median percentage 20 Serum DHT % change

changes from baseline in from baseline
serum DHT for placebo, 10
Dutasteride (DUT) (0.05– Baseline 0
2.5 mg), and Finasteride
-10
(FIN). Treatment was stopped
after 24 weeks. All active Serum DHT % -20
groups were significantly change from
-30
different from placebo for baseline
DHT and Testosterone at 6, -40
12, and 24 weeks (p < 0.001). Placebo -50
(Adapted with permission -60
from Olsen et al. [27]) 0.05
-70
0.1
DUT -80
0.5 (mg) -90
2.5 -100
-110
FIN
-120
Baseline Week 6 Week 12 Week 24 Week 36
Time
Change from baseline (0.1%), and gynecomastia by two subjects (0.3%).

in haircount Concerning hair growth, subjects evaluated as “improved”
250 were n = 261 (78.6%), sixty-nine subjects (20.8%) were
Week 12
200 **
** classified as “no change,” and only two subjects (0.6%) dete-
Week 24 ** **
**
**
riorated [29].
150 ** **
The efficacy of Dutasteride also has been demonstrated in
100 *
**
monozygotic twins.
50
0 It is recognized from the work of Christian & Kang

-50
(1972) that studies on monozygotic twins can examine
the influence of genetic and environmental factors on
-100
phenotypic traits. Similarly, monozygotic twins are
0.05 0.1 0.5 2.5
-150 Placebo Finasteride ideally suited to determine the extent of drug efficacy
Dutasteride (mg) in treating a condition such as AGA, the expression of
Treatment group
which is genetically determined [30].
Fig. 25.2 Mean changes in hair counts after 12 and 24 weeks, com-
pared with baseline, for placebo, Dutasteride (0.05–2.5 mg), and
Stough (2007) conducted a randomized, double-blind,
Finasteride (FIN). *: p < 0.05; **: p < 0.001 compared with placebo;
† p < 0.05; ǂ: p < 0.001 compared with Finasteride. (Adapted with per- placebo-controlled, single-center study on 17 pairs of mono-
mission from Olsen et al. [27]) zygotic twins, with one twin from each pair receiving
25.4 Dutasteride and ΑGΑ 81
Dutasteride 0.5 mg/day for 12 months while the other receiv- Since the issue of adverse effects related to Dutasteride was
ing placebo for 12 months. Hair growth was evaluated using increasingly “hot,” Tsunemi et al. [33] further investigated the
standardized clinical photographs, hair counts, and patient long-term safety and efficacy of Dutasteride. They published
self-assessment questionnaires, and 16 out of 17 sets of twins in 2016 the results of a multicenter, open-label, prospective,
completed the study. Dutasteride resulted in a significant single-arm, outpatient study conducted at five centers in Japan
cosmetic improvement in 15 of 16 twins on Dutasteride vs. (NCT01831791, GSK identifier ARI114264) in which patients
their twin brother on placebo and increased satisfaction on were administered Dutasteride 0.5 mg/day for 52 weeks.
hair appearance compared to placebo. At month 6, there was Primary endpoints included adverse event assessment, inci-
an average of 11 fewer hairs/cm2 in the placebo-treated group dence of drug-related adverse events, and premature discon-
vs. 6.8 more hairs/cm2 in the Dutasteride-treated subjects. At tinuation of treatment. Secondary endpoints included hair
month 12, there were 3.8 fewer hairs/cm2 in the placebo- growth, hair restoration, and global hair improvement. A total
treated vs. 16.5 more hairs/cm2 in the Dutasteride-treated of 120 patients were enrolled, of whom 110 completed all
subjects, resulting in an overall net gain of +20.3 hairs/cm2 in 52 weeks of treatment. Nasopharyngitis, erectile dysfunction,
the Dutasteride group subjects [31]. and decreased libido were the most frequently reported
Until 2014, there were no available comparative, clinical adverse events, and most adverse events were mild. The inci-
studies of Dutasteride with Finasteride 1 mg. Gubelin Harcha dence of reported drug-related adverse events was 17%, none
et al. (2014) conducted a global Phase II/III study of of which led to the study’s withdrawal. Hair growth (mean
Dutasteride (NCT01231607; GSK study identifier target area hair count at week 52), hair restoration (mean target
ARI114263), which was a randomized, double-blind, area hair caliber at week 52), and global appearance of hair
double-dummy, parallel-group, 24-week study at 39 centers (mean of the median score at week 52) significantly improved
(academic and private) in 9 countries (Argentina, Chile, from baseline until the end of the study (Fig. 25.3). According
Japan, Mexico, Philippines, Peru, Russian Federation, to the authors, Dutasteride 0.5 mg demonstrated long-term
Taiwan, and Thailand). In total, 917 men were randomized to safety, high tolerability, and efficacy within the study popula-
receive Dutasteride in various doses: Dutasteride 0.02 mg/ tion. Concerning the efficacy of Dutasteride, between weeks
day (n = 179), 0.1 mg/day, (n = 184), or 0.5 mg/day (n = 188), 26 and 52 of the study, patients experienced further improve-
Finasteride 1 mg/day (n = 185), or placebo (n = 181) for ment from baseline in photographic assessment, implying that
24 weeks. Overall, 761 patients completed the study, and the the efficacy of Dutasteride does not reach a plateau early dur-
primary endpoint was hair count (2.54 cm diameter) at week ing treatment, and therefore, longer studies were needed.
24. Other assessments included hair count (1.13 cm diame- Adverse effects of special interest were reported in 19 (15.8%)
ter) and width, photographic assessments (investigators and patients in total, namely decreased libido n = 14 (11.7%), sex-
panel), change in stage, and health outcomes. The increase in ual dysfunction n = 4 (3.3%), impotence n = 14 (11.7%), erec-
baseline hair count, terminal hair count, and increased hair tile dysfunction n = 14 (11.7%) and ejaculatory disorders
caliber were all superior in the Dutasteride 0.1 mg, n = 6 (5.0%). Sexual adverse effects (SAEs) reported in six of
Dutasteride 0.5 mg, and Finasteride groups vs. placebo at these patients resolved during the 52-week treatment period.
week 24 (all p < 0.001). However, only Dutasteride 0.5 mg In the 13 patients with SAEs that persisted until the end of the
demonstrated a significant increase in target area hair count treatment period, they all resolved within the 6-month follow-
and hair caliber compared to Finasteride at weeks 12 and 24 up period of treatment cessation. This was the most reassuring
(both p = 0.003). Additionally, there was a fair to moderate finding from this study since there was a concern that some
agreement on individual scores assigned by three patients would experience long-term persistence of SAEs.
Dermatologists for global photographic assessment of Interestingly, in the earlier double-blind ARI114263 study of
improvement in hair growth at week 24, that Dutasteride Gubelin Harcha et al. (2014), the reported frequencies of these
0.5 mg was superior to Finasteride at promoting hair growth events were lower (erectile dysfunction was reported at 3.9%
in the frontal/superior view but not in the vertex at week 24 in the placebo group and 5.4% in the Dutasteride 0.5 mg
(p = 0.002). Finally, the number and severity of adverse group; decreased libido was 1.1% in the placebo group and
events of special interest, such as decreased libido, impo- 3.3% in the Dutasteride 0.5 mg group) [32].
tence, ejaculation disorders, breast enlargement, and breast
tenderness, were similar among treatment groups, except for
decreased libido. These adverse effects were reported by just Tsunemi et al. [33] commented that the increased fre-
3 patients in the placebo group (1.7%) vs. 15 patients (8.1%), quency of reported SAEs might be due to the open-
13 (6.9%), 9 (4.9%) and 12 (6.7%) in Dutasteride 0.02 mg/ label study design since patients were fully informed
day, 0.1 mg/day, 0.5 mg/day and Finasteride 1 mg/day of the effects and side effects of the active compound
respectively, demonstrating no dose-response relationship in might have affected the reporting of SAEs.
different Dutasteride doses [32].
82 25 Dutasteride
Fig. 25.3 Hair restoration as a b

assessed by (a) hair width and 180
(b) terminal hair count in a 14
Mean change from baseline in target

160
2.54-cm diameter circle. Error
12
Mean change from baseline

area hair width (µm × 1e-3)
bars represent the standard 140
in terminal hair count

deviation. (From Tsunemi 10 120
et al. [33])
100
8
80
6 60
4 40
20
2
0
0 −20
Week 26 Week 52 Week 26 Week 52
In addition, the reporting of these SAEs might have been Shanshanwal et al. [36] (2017) conducted a 24-week pro-
influenced by their subjective nature and the fact that, after spective, parallel, randomized, open-label, superiority study
reading and hearing about the possibility of SAEs during the on 90 male patients aged 18–40 years, randomized to receive
informed consent process, the patients were frequently ques- either Dutasteride 0.5 mg or Finasteride 1 mg daily for
tioned directly about sexual dysfunction during the study. A 24 weeks. Results were assessed with global photography,
similar effect was reported by Mondaini et al. (2007), who phototrichogram, and subjective patient evaluation. Seventy-
demonstrated that the information given by physicians when two patients completed the study, and the mean change in
administrating Finasteride under clinical trial conditions terminal hair count compared to baseline was significantly
resulted in an unexplained threefold increase in the report of higher in the Dutasteride group (30.51/cm2, 24%) vs. the
SAEs for the informed group, a phenomenon designated as Finasteride group (5.57/cm2, 4%), as was the mean change
“nocebo effect” [34] (see Chap. 24). in total hair count. Thin hair counts decreased significantly
Jung et al. (2014) evaluated the clinical efficacy and toler- (7.37/cm2) in the Dutasteride group at 24 weeks as com-
ability of Dutasteride in 35 Korean men (33.7 ± 7.9 years of pared to the Finasteride group (1.27/cm2, p = 0.0156).
age) with mild to moderate AGA who did not show clinical Global photographs (5 sets of before-and-after) included in
improvement to the conventional Finasteride treatment for at the article are of high quality and precisely describe the
least six months (402.4 ± 235.9 days of Finasteride treatment level of improvement achieved. The increase in the number
duration). A total of 35 men received Dutasteride at a dose of of thin hairs at the end of treatment in the Finasteride group
0.5 mg/day for six months, and 31 completed the study. suggested that Finasteride failed to reverse the miniaturiza-
Efficacy was evaluated by global photograph assessment and tion process. The proportion of patients with marked
phototrichogram at a target area of a 70 mm2 circle marked improvement was higher in the Dutasteride group, in both
by a central tattoo. Safety assessment was performed through blinded and non-blinded evaluations and in patient self-
physical examination and adverse event reports. Of the 31 assessments (p < 0.001). The authors commented that even
patients who completed the treatment, 24 patients (77.4%) though the change in hair counts in the Dutasteride group
were improved by the global photography (17 slightly, six was comparable to previously published data [27, 32], the
moderately, and one improved markedly) compared to the change in hair counts in the Finasteride group was compara-
post-Finasteride treatment period. There was no significant bly lower. This finding could be related to 5α-R polypeptide
change in seven patients (22.6%), and no patient deterio- two gene polymorphism in the V89L site (leucine substitu-
rated. Compared to the post-Finasteride period, hair density tion of valine at codon 89 polymorphism), which reduces
increased by 10.3% (87 ± 12 to 96 ± 12/cm2) and caliber in vivo 5α-R activity [37] and is highly polymorphic in the
increased by 18.9% (0.053 ± 0.012 to 0.063 ± 0.011 mm), Indian population [38].
respectively, in phototrichogram assessment. Adverse effects Chung et al. (2017) were the first to evaluate Dutasteride’s
included transient sexual dysfunction in six patients (17.1%). efficacy and safety when used for a duration longer than
Global photographs included in the publication are of high 52 weeks. They conducted a retrospective chart review study
quality, and results are indicative of supporting the hypothe- in a small number of patients from a single-center, between
sis that switching Finasteride slow-responders to Dutasteride November 2009 to April 2016 in Wonju Christian Severance
provides an incremental improvement in hair growth. Hospital in Korea. In total, 26 male AGA patients aged
However, due to the absence of a parallel control group of 21–66 years were prescribed Dutasteride for longer than
patients who continued on Finasteride, the study has limita- 52 weeks. Thirteen were prescribed the drug for 1–3 years,
tions to prove the hypothesis clearly [35]. seven for 3–5 years, and six for longer than 5 years. The
25.5 Dutasteride and FPHL 83
mean prescription duration was 43.61 months. According to grade A2 evidence (placebo-controlled) and one a grade C
the subject self-assessment, the overall effectiveness was evidence, resulting in an overall Level of Evidence 1 [27, 28,
84.62% (22/26), and laboratory results showed no significant 31, 32, 34].
changes except in cholesterol levels [39]. The authors also
evaluated subjective and objective satisfaction and quality of
life using the hair-specific Skindex-29 questionnaire, and, The authors concluded that oral Dutasteride 0.5 mg/
notably, emotional scale scores decreased significantly day could be considered in case of previously ineffec-
(−5.87, p = 0.014). Even though this study was small and tive treatment with 1 mg Finasteride over 12 months as
non-randomized, it had the advantage of providing data on a second-line treatment to improve or to prevent pro-
Dutasteride’s long-term outcomes by taking into account the gression of AGA in male patients above 18 years with
self-assessments of hair regrowth and quality of life. mild to moderate AGA (Hamilton-Norwood IIIv–V)
Vañó-Galván et al. (2019) conducted a retrospective, [42].
monocentric, descriptive study to describe the effectiveness
and safety of oral Dutasteride for AGA in real clinical prac-
tice. Overall, 307 patients with a mean age of 35.3 years
(range 18–79) with AGA were included. All the patients 25.5 Dutasteride and FPHL
received oral Dutasteride for a mean time of 17 months
(range 12–60 months). Dutasteride was used at a dosage Dutasteride is not approved for the treatment of FPHL, and
between 1 to 7 capsules per week, with 7 capsules per week data regarding adverse effects in women are extremely lim-
being the most frequent dosage (175 patients, 57%). ited. One should stress that exposure of pregnant women to
Dutasteride-related adverse effects were observed in 20 out Dutasteride increases the risk of abnormal male external
of 307 patients (6.5%): decrease libido (n = 9), erectile dys- genital development, including hypospadias. Due to this
function (n = 4), mood disorders (n = 3), gynecomastia risk, Dutasteride is contraindicated in pregnancy (category
(n = 2) and lower ejaculation volume (n = 2). Eight patients X), with most authors advocating testing to rule out preg-
(2.6%) required the discontinuation of the drug due to nancy before starting off-label Dutasteride and concomitant
decreased libido (n = 4), gynecomastia (n = 2), mood disor- effective contraception measures are necessary for women of
der (n = 1) and erectile dysfunction (n = 1). No adverse childbearing potential.
effects were detected in patients receiving low doses. The Experience with the use of Dutasteride on FPHL is mini-
effectiveness was evaluated in the subgroup of 42 patients: mal, and the same restrictions as on Finasteride administra-
38 patients improved (90%), 10 of them (23.8%) presenting tion to women of childbearing age apply. Camacho et al.
a marked improvement, 4 patients (9.5%) were stable, and (2007) demonstrated significant efficacy during a study on
no patient deteriorated. Eight out of twelve (66%) patients 25 postmenopausal women with FPHL, who received
receiving low doses of Dutasteride improved. The marked Dutasteride 0.25 mg/day and proved to be effective on 60%
improvement was statistically associated with the use of of them during the first year and on 80% at two years [43]. In
higher doses of the drug (p = 0.030) [40]. another study by the same research team, Dutasteride 0.5 mg/
From all these data, Dutasteride seems to be very effec- day, together with Finasteride 2.5 mg/day, was administered
tive in the treatment of AGA. In the meta-analysis of in 19 women with FPHL for six months, aiming to block
Blumeyer et al. (2011), two studies investigating Dutasteride both 5α-R enzymes entirely. It was reported that all women
in AGA with grade A2 evidence were included in the in the study (100%) improved [44]. Olszewska et al. (2005)
evidence-based evaluation, resulting in a level of evidence 2 published a case study of a 46-year-old female, non-
for Dutasteride administration in AGA, in men >18 years, responsive to Minoxidil, who showed significant improve-
with mild to moderate AGA (Hamilton-Norwood IIv-V) ment after six months of Dutasteride treatment. Interestingly,
[41]. The authors remarked that since comparison studies of after nine months, the clinical diagnosis of FPHL could no
Dutasteride 0.5 mg vs. Finasteride 1 mg daily were not avail- longer be made in this patient [45].
able at the time, there was no reason to use Dutasteride The most extended trial of Dutasteride in women is by
0.5 mg instead of Finasteride 1 mg, as higher dosages are Boersma et al. (2014), who conducted a retrospective study.
needed to reach comparable efficacy. However, the study by However, the study had no placebo-control group nor a
Gubelin Harcha et al. [32] answered this issue, and probably double-blind data collection methodology [46]. They
the off-label use of Dutasteride 0.5 mg is safe and more recruited a random sample of 120 women who had been tak-
effective than Finasteride 1 mg in AGA. ing Finasteride 1.25 mg or Dutasteride 0.15 mg for three con-
Kanti et al. (2018) issued newer S3 guidelines and secutive years between 2002 and 2012 and separated them
included five studies investigating Dutasteride in AGA in into 4 groups of 30 women each according to age -below and
their evidence-based evaluation. Four of these studies had a above 50 years- and according to each of the drugs.
84 25 Dutasteride
Researchers measured the hair caliber of the three thinnest Table 25.3 Reported adverse effects of Dutasteride vs. Finasteride
hairs from standardized microscopic images at three predeter- during the double-blind phase of the study, year 1. (Adapted with per-
mission from Nickel et al. [52])
mined areas of the scalp at the start of the treatment and after
three years of continuous medication. A total of 49 (81.7%) Adverse effect Finasteride (n = 817) Dutasteride (n = 813)
women in the Finasteride group and 50 (83.3%) in the Impotence 74 (9%) 63 (8%)
Decreased libido 50 (6%) 41 (5)%
Dutasteride group showed increased hair caliber. Overall, the
Ejaculation disorders 14 (2%) 14 (2%)
only difference between the two compounds was that Gynecomastia 10 (1%) 9 (1%)
Dutasteride performed significantly better than Finasteride in
the age category below 50 years at the midscalp and vertex
areas. Unfortunately, the side effects were not discussed. 5 mg (n = 817). Patients in both treatment groups experi-
Georgala et al. (2009) published the results of an 18-month enced a similar number of adverse events, and no new
long study on 13 postmenopausal women 55–72 years of adverse events were reported in the open-label phase that fol-
age, clinically and histologically diagnosed with frontal lowed [52] (Table 25.3).
fibrosing alopecia (FFA) [47]. Patients were unresponsive to
previously administered potent topical corticosteroids and
used Dutasteride during the study. At 12 months, six patients 25.5.1 Dutasteride and Prostate Cancer (PCa)
(46.1%) showed a complete arrest of the disease, and two
(15.3%) had clinical improvement with moderate hair Concerning PCa, the analysis of the pooled data from the
regrowth, an overall response rate of 61.5%. Furthermore, in three Phase III clinical trials of Dutasteride on BPH revealed
women considered as non-responders, the average progres- that Dutasteride significantly lowered the cumulative inci-
sion rate of the frontotemporal recession per month was sig- dence of PCa vs. placebo at 24 months (1.1% vs. 1.9%,
nificantly lower (0.2 vs. 0.9 mm) than in other reports [48]. p < 0.025) and 27 months (1.2% vs. 2.5%, p < 0.002). This
The same research team reported a case study of a 55-year- was the most decisive clinical evidence until that time, sup-
old female with an asymptomatic recession of the frontotem- porting the hypothesis that Dutasteride could reduce PCa
poral hairline due to FFA, marked thinning of the eyebrows risk. However, these studies were not designed to study risk
of 1-year duration, and partial loss of the axillary hair. She reduction, and the diagnosis of PCa was only reported as an
was treated with oral Dutasteride 0.5 mg/day for six months adverse event [53].
and Pimecrolimus 1% cream twice daily for three months, Regarding Dutasteride’s long-term safety, but mostly the
resulting in a significant regrowth in the eyebrows and axil- fear of correlation of Dutasteride with PCa [54], the
lae, and a moderate improvement on the scalp [49]. REDUCE trial (Reduction by Dutasteride of Prostate Cancer
Ever since Dutasteride got approved by the FDA for the Events) was designed. Andriole et al. (2004) conducted this
treatment of BPH, more than 5500.000 patient-years of 4-year long, multicenter, randomized, double-blind, placebo-
exposure using Avodart® are recorded with a low adverse controlled with parallel groups study, including more than
event profile [50], similar to that of Finasteride. 8200 men in 42 countries, aged 50–75yo. REDUCE aimed to
From the Finasteride studies, it is known that lowering examine Dutasteride’s effects on the natural history of PCa
DHT has been correlated with general adverse effects, in men at increased risk, with no evidence of the disease at
adverse effects of particular interest (mostly SAEs, which baseline and whether Dutasteride could reduce the risk of
will be analyzed further), and Prostate Cancer (PCa). One of biopsy-detectable PCa [55]. The final results of the REDUCE
the first research studies (2001) of GlaxoSmithKline on trial were published in the New England Journal of Medicine
Dutasteride involving 1976 patients in 134 centers in 27 [56] in April 2010 and, unsurprisingly, demonstrated simi-
countries compared the efficacy, safety, and tolerance of larities with the Finasteride’s Prostate Cancer Prevention
Dutasteride 0.5 mg vs. Finasteride 5 mg. During the Trial (PCPT) (see Chap. 24). Final results supported that the
12 months of the trial, the tolerance and safety of both com- incidence of PCa was lower in the Dutasteride arm in every
pounds were comparable, even when followed by an optional subgroup. During the 4-year duration of the trial, PCa was
24 months open-label phase [51]. Later, Nickel et al. (2011) diagnosed in 659 of 3305 patients (19.9%) in the Dutasteride
conducted a multicenter, randomized, double-blind, arm and in 858 of 3424 patients (25.1%) in the placebo arm,
12-month long, parallel-group study on 1650 patients with an absolute risk reduction of 5.1% and a relative risk reduc-
BPH, the Enlarged Prostate International Comparator Study tion of 22.8%. Most tumors were low grade, with 70% of the
(EPICS). EPICS aimed to assess the efficacy and safety of total number of PCa scoring 5 or 6 at the Gleason scale. The
Dutasteride 0.5 mg compared to Finasteride 5 mg in treating number of tumors with Gleason score 7–10 did not differ
men with symptomatic BPH. At study completion, there was significantly throughout the 4-year study or within the sub-
no significant difference concerning prostate size reduction group of biopsies taken at any one-year point. The promise
in subjects on Dutasteride 0.5 mg (n = 813) vs. Finasteride of an absence of a higher number of tumors with Gleason
25.5 Dutasteride and FPHL 85
grade 8–10 at the end of 1–2 years in the Dutasteride group unknown whether this also occurs with Dutasteride. In the
was counteracted by a significant difference detected in the 4-year follow-up of the Phase III trials in BPH, the incidence
number of tumors with Gleason grade 8–10 in the last fol- of SAEs was low and further decreased over time as treat-
low-up (years 3–4) (12 and 1, Dutasteride vs. the placebo ment continued for 4 years [25, 26]. However, lately, there
group, respectively, p < 0.003). After 2 years, REDUCE has been a rising concern about the possibility of Dutasteride
showed a 23% decrease of the relative risk for biopsy- leading to erectile dysfunction and reduced sex drive in sub-
detectable PCa, for Dutasteride compared to placebo jects with BPH, and whether these can persist even after
(p < 0.0001), without significant difference in the percent- treatment discontinuation [63, 64].
ages of high malignancy tumors (Gleason score 7–10) The mechanisms underlining the adverse effects of
between study groups (6.8% Dutasteride vs. 6.7% placebo, Dutasteride on sexual function remain to be elucidated. One
p = 0.81). intriguing theory was presented by Pinsky et al. (2011), who
demonstrated in adult male Sprague-Dawley rats that
Dutasteride 0.5 mg/day decreased serum DHT by 86.5%
However, some years later (2014), Lacy and Kyprianou (range 64.2–94.8%) after 30 days [65]. Immunohistochemical
demonstrated that both the PCPT and the REDUCE studies demonstrated significantly increased collagen depo-
trials had an inherent bias that potentially led to ele- sition in the cavernosal smooth muscle of the treatment arm
vated Gleason scores. When computer models as well as altered expression of neuronal NOS (nNOS) and
attempted to correct for these stated biases, there was inducible NOS (iNOS), which are both necessary for proper
no significant difference found in high-grade PCa erectile function [66]. However, these results have not been
between the Finasteride/Dutasteride group and con- replicated in humans.
trol [57]. Nevertheless, several placebo-controlled studies in
humans have addressed the subject of SAEs during the treat-
ment of BPH with Dutasteride. Debruyne et al. [26] (2004)
25.5.2 Dutasteride, Gynecomastia and Breast published a report on the efficacy and safety using data col-
Cancer lected from all three randomized, placebo-controlled, large-
scale, 2-year long, Phase III clinical studies (ARIA3001,
Subjects have also experienced gynecomastia prescribed ARIA3002, ARIA3003) with a 2-year open-label extension.
Dutasteride 0.5 mg for BPH [26, 56, 58, 59]. Study results Overall, 4325 men were enrolled, and 1667 men completed
obtained by Kaplan et al. (2011) compared the safety and the 4-year study. The onset of new drug-related adverse
efficacy of BPH patients treated with Finasteride or events was reported most frequently at the start of therapy
Dutasteride and suggested that the incidence of gynecomastia and declined over time in patients receiving Dutasteride.
was higher in Dutasteride users [60]. In this retrospective Patients on Dutasteride had more frequent symptoms of
5-year study, the incidence of self-reported breast tenderness erectile dysfunction and impotence during the first year com-
and breast enlargement was significantly higher in the pared to the placebo group (6.1% vs. 3.0% and 4.7% vs.
Dutasteride (3.5%) group compared to the Finasteride (1.2%) 1.7%, respectively), while percentages in both groups were
group (p < 0.01) [60]. comparable during the second year (1.3% vs. 1.3% and 0.8%
vs. 0.9%, respectively) (Table 25.1).
Roehrborn et al. (2010) conducted a 4-year, multicenter,
25.5.3 Dutasteride and Sexual Adverse randomized, double-blind, parallel-group study in 4844 men
Experiences (SAEs) > or = 50 years of age with a clinical diagnosis of BPH
examining the effectiveness, safety and tolerability of the
Finasteride and Dutasteride make up 30% of the medical Combination of Avodart and Tamsulosin (the CombAT
prescriptions for AGA and have become an important staple study). Dutasteride monotherapy was given to n = 1623
for treating this widespread condition [61]. Despite the fre- patients and only 7 reported erectile dysfunction (0.43%), 7
quency of use of these medications, there is a paucity of altered (decreased) libido (0.43%) and 3 gynaecomastia
accurate information available regarding the frequency, (0.18%). Notably, similar percentages were reported in all 3
severity, and persistence of their adverse effects [62]. Sexual groups, even though Tamsulosin is an α1-blocker with no
Adverse Experiences (SAEs) due to Dutasteride use is of the anti-androgenic properties [58].
deepest concern for both patients and doctors and is further Chi et al. (2011) investigated the changes in sexual func-
perpetuated by the conflicting results on SAEs and fertility tion occurring with Dutasteride treatment during a 1-year
issues associated with Dutasteride. Additionally, there have follow-up period in 55 Korean (mean age 62.3 ± 7.2 years)
been reports of persistent, irreversible SAEs with Finasteride with BPH (mean volume 48.9 ± 16.0 g) and previously good
(see Chap. 24), but causality remains uncertain, and it is erectile function. Using the International Index of Erectile
86 25 Dutasteride
Function, they prospectively evaluated, after 1, 3, 6, 9, and function were 0.66 (95% CI: 0.20–2.25) in men with AGA,
12 months of treatment, the changes in sexual function of and those for decreased libido were 1.16 (95% CI: 0.50–2.72)
these 55 outpatients who were treated with Dutasteride for at in men with AGA. The authors concluded that evidence from
least one year. They reported that erectile function scores the randomized controlled trials suggested that 5ARIs were
showed the most significant decrease at one month (p < 0.01) not associated in a statistically significant manner with
and gradually recovered after that but were still significantly increased SAEs in men with AGA, in contrast to men with
decreased after 12 months of treatment (p < 0.05). The orgas- BPH, where scores were significantly increased [70].
mic function and sexual desire scores also showed the most Corona et al. (2017) performed a systematic review, and
significant reduction at one month but were restored to the meta-analysis of all randomized, placebo-controlled trials,
baseline level at six months [67]. evaluating the rate of SAEs in men treated with 5ARIs for
BPH. The authors retrieved 383 articles and included only 17
randomized controlled trials in their study. Randomized clin-
However, these results can be circumstantial. A recent
ical trials enrolled 24,463 in the active and 22,270 patients in
meta-analysis of Traish et al. (2017) reported that
the placebo arms, respectively, with a mean age of 64.0 years
many men in Dutasteride studies report extensive erec-
and a mean follow-up of 99 weeks. Overall, the odds ratio
tile dysfunction and/or decreased libido, but no causal-
for Dutasteride-induced reduced libido over placebo was
ity has been demonstrated [68].
OR = 1.61, and for erectile dysfunction was OR = 1.60; a not
statistically significant difference was reported over
Na et al. (2012) conducted a randomized, double-blind, Finasteride 5 mg. The authors concluded that the use of
parallel-group, placebo-controlled, 6-month long study, fol- 5ARIs significantly increases the risk of erectile dysfunction
lowed by an open-label extension of 12 months. The authors and hypoactive sexual desire in subjects with BPH but did
aimed to evaluate Dutasteride’s efficacy and safety in 253 not comment on patients using Dutasteride for AGA [71].
Chinese adults with symptomatic BPH, randomized to Tsai et al. (2018) conducted a prospective randomized
Dutasteride 0.5 mg/day orally, or matching placebo treat- study of sexual function in 117 sexually active men aged
ment in a 1:1 ratio. After six months, eligible subjects who 18–50 years taking Dutasteride to treat AGA over 24 and
volunteered to enter the open-label extension received 48 weeks. (ClinicalTrials.gov Identifier: NCT02014584)
Dutasteride 0.5 mg/day for another 12 months. Overall, sub- This international, multicenter, parallel-group study com-
jects who initially received Dutasteride and continued to take prised a 4-week participant-blinded placebo run-in period
Dutasteride were depicted as D/D group, while those who and a 24-week double-blind (DB) treatment period where
initially received placebo and switched to open-label participants were randomized (1:1 ratio) using a centralized
Dutasteride 0.5 mg belonged to the P/D group. The incidence computer system to once-daily Dutasteride 0.5 mg or pla-
of treatment-related SAEs was 7.14% in the D/D group vs. cebo. This was followed by a 24-week open-label, active
7.09% in the P/D group during the double-blind phase and treatment period in which all participants received once-
7.22% vs. 3.70%, respectively, during the open-label exten- daily Dutasteride 0.5 mg and a 4-week post-treatment fol-
sion. Decreased libido, erectile dysfunction, and gynecomas- low- up visit. The incidence of SAEs was approximately
tia were reported in similar incidence (1%) in both groups, twofold higher in the Dutasteride group (16%) than the pla-
whereas, during the open-phase trial, incidence increased to cebo group (8%) during the double-blind period; the overall
2% for all SAEs, again in both groups [69]. incidence of SAEs was lower (5%) during the open-label
Choi et al. (2016) monitored SAEs of Dutasteride 0.5 mg period. All adverse events were mild to moderate in severity
in 712 Korean AGA male patients (18 to 41 years old) in a and considered treatment-related. The study was not pow-
clinical practice environment in an open-label, multicenter, ered to detect a significant difference between groups but
non-interventional observational study, the results of which was adequate to assess the persistence and reversibility of
are presented earlier [29]. SAEs. The adverse events resolved while on treatment or
Liu et al. (2016) reviewed all the available data on the after the end of treatment and did not lead to treatment dis-
effect of both 5α-R inhibitors (5ARIs) (Dutasteride and continuation. Notably, this study (NCT02014584) was
Finasteride) on sexual function and assessed whether 5ARIs funded by GlaxoSmithKline (GSK) Research &
increase the risk of sexual dysfunction. After screening 493 Development, and all authors are affiliated with GSK [72].
articles, the authors included 17 randomized controlled trials Lee et al. (2019) conducted a meta-analysis investigating
with 17,494 patients. Nine studies evaluated the efficacy of the risk of SAEs due to Finasteride 1 mg/day or Dutasteride
5ARIs in men with BPH. The other eight reported using 0.5 mg/day in men with AGA. Fifteen randomized double-
5ARIs in the treatment of men with AGA. The pooled relative blinded placebo-controlled trials (4495 subjects) were meta-
risks for sexual dysfunction were 1.21 (95% confidence inter- analyzed. The authors reported that the use of 5ARIs carried
val, CI: 0.85–1.72) in men with AGA; those for erectile dys- a 1.57-fold risk of sexual dysfunction (95% CI: 1.19–2.08).
25.6 Topical Use of Dutasteride 87
The relative risk was 1.66 (95% CI: 1.20–2.30) for Finasteride Considering the similarities of these 2 drugs concerning
and 1.37 (95% CI: 0.81–2.32) for Dutasteride. Both drugs pharmacologic properties, adverse effects profile, and pre-
were associated with an increased risk, although the increase scription indications, one would expect similar reporting of
was not statistically significant for Dutasteride [73]. adverse events associated with Dutasteride and Finasteride.
Overall, as with Finasteride, a direct link between SAEs Interestingly, even though Dutasteride blocks isotype 5α-R Ι,
and Dutasteride is difficult to establish. For the interested which is extensively expressed in the entire CNS and the
reader, Traish has published many comprehensive reviews human brain [77] disproportional reporting of suicidality
on the subject that can assist in further understanding the associated with Finasteride instead. As explained by Nguyen
conflicting results [59, 63, 68, 74]. et al., Dutasteride has received far less attention from the
media or any organization and therefore did not trigger
reporting bias or stimulated reporting by health care profes-
25.5.4 Dutasteride and Fertility sionals or induced a nocebo effect in patients [78].
Fertility issues are another concern in patients on Dutasteride

treatment. Amori et al. (2007) conducted a randomized, 25.6 Topical Use of Dutasteride
double-blind, placebo-controlled trial in 99 healthy men,
aged 18–55 years, randomly assigned to receive Dutasteride Many physicians and patients are reluctant to the off-label
0.5 mg (n = 33), Finasteride 5 mg (n = 34), or placebo use of Dutasteride in the treatment of AGA. The fear of per-
(n = 32), once daily for 52 weeks [75]. The authors investi- sistent SAEs combined with Dutasteride’s very long half-life
gated the effects of the drugs on serum testosterone (T), in the serum makes matters even more complicated. However,
DHT, spermatogenesis, and semen parameters. In both active using Dutasteride topically on the scalp could be an effective
treatment groups, total sperm count, compared with baseline, drug-delivery strategy to minimize systemic side effects.
was significantly decreased at 26 weeks (Dutasteride, Dutasteride could be an exceptionally promising topical
−28.6%; Finasteride, −34.3%) but not at 52 weeks product since proper formulation could lead to adequate
(Dutasteride, −24.9%; Finasteride, −16.2%) or the 24 weeks transcutaneous absorption and would allow local effect on
follow-up (Dutasteride, −23.3%; Finasteride, −6.2%) during the 5α-R enzymic system, acting also on the sebaceous gland
which all treatments were discontinued. At 52 weeks, semen of the scalp, that bears mostly isotype 5α-R Ι [8, 9, 79] (see
volume was decreased significantly for Dutasteride (−29.7%) Chap. 15, Vol. 1).
but not for Finasteride (−14.5%), but significant reductions Sharma et al. (2011) showed in ex vivo skin that the topi-
in mean sperm count from baseline vs. placebo seen with cal use of Dutasteride solution 32 mg/mL in the form of
both 5ARIs at 26 weeks (both p < 0.013) were no longer loaded liposomal system, with a mean vesicle size of
evident at study completion, neither was sperm concentra- 1.82 ± 0.15 μm, led to a 700% increase of substance deposi-
tion (Dutasteride, −3.2%; Finasteride, −7.4%, neither sig- tion in the skin, vs. hydro-alcoholic solution and gels.
nificant). There was a considerable reduction of −6% to Stability studies indicated that the liposomal formulations
−12% in sperm motility during treatment with both were relatively stable in the refrigerated conditions for up to
Dutasteride and Finasteride and at follow-up. At follow-up 10 weeks [80]. Xie et al. (2014) studied Dutasteride’s release
(24 weeks after discontinuing treatment), reductions in from biodegradable microspheres in cultures and in male
semen parameters had partially or almost totally recovered, Sprague-Dawley rats. A steady, long-term (28 days) release
and neither Dutasteride nor Finasteride had any persistent, of Dutasteride from the microspheres was observed in vitro.
significant effect on sperm morphology. Notably, 5% of indi- Similarly, after the subcutaneous injection of drug-loaded
viduals on active treatment showed dramatic declines in total microspheres to rats, about 1-month long plasma drug con-
sperm count during treatment, although they recovered dur- centration vs. time profile was observed, showing similar
ing the follow-up period. The overall impact on fertility of therapeutic efficacy on BPH inhibition when compared to
these modest effects on semen parameters in normal men the oral Dutasteride solution that was administered once
under Dutasteride treatment is currently unknown [76]. daily for 28 consecutive days [81].
Madheswaran et al. (2015) used monoolein to produce
liquid crystalline nanoparticles of Dutasteride, surface-
25.5.5 Dutasteride, Depression and CNS modified with chitosan (low molecular weight) to give a
Effects positive charge. The mean particle size was 239–259 nm,
and the surface-modified nanoparticles enhanced the trans-
Dutasteride’s potential psychiatric side effects have not been dermal delivery of Dutasteride by 4.2-fold compared to liq-
explicitly examined and have been reported collectively with uid crystalline nanoparticles [82]. The same research team
Finasteride on patients using 5ARIs for BPH treatment (see published their latest (2017) results on topical Dutasteride
Chap. 24). delivery in vitro and in vivo using positively charged liquid
88 25 Dutasteride
crystalline nanoparticles (LCN) and LCN-coated with chito- although experimental research on topical Dutasteride for-
san (CHI-LCN), observing skin distribution through fluores- mulations is on-going, when it comes to actual clinical appli-
cence studies. Fluorescence intensity was higher with cations, very few reports are available. Most published data
CHI-LCNs throughout the skin, whereas more intense fluo- concern locally injected Dutasteride, using a method called
rescence was seen only in the epidermis for LCN. CHI-LCN “mesotherapy,” which is popular in cosmetic treatments and
showed greater cellular uptake than LCN, resulting in inter- has received much publicity in the media and internet [95],
nalization of 98.5 ± 1.9% of nanoparticles into human kera- despite being generally useless and even potentially danger-
tinocyte cells (HaCaT) [83]. ous [96].
Noor et al. (2017) also developed various Dutasteride-
loaded nanostructured lipid carriers (DST-NLCs), coated
and uncoated with different concentrations of chitosan 25.6.1 Intralesional Dutasteride
oligomer-stearic acid (CSO-SA). The amount of Dutasteride and Mesotherapy
in the skin was significantly different for DST-NLCs
(6.09 ± 1.09 μg/cm2) without coating (p < 0.05) and those In mesotherapy (from Greek word meso = in between, thera-
coated with 5% CSO-SA (2.82 ± 0.4 μg/cm2), 10% CSO-SA peia = treat), active substances are injected intradermally
(2.70 ± 0.35 μg/cm2) and CSO (2.11 ± 0.64 μg/cm2). DST- into a depth of approx. 3–4 mm using 30–32G needles. This
NLCs coated and uncoated with CSO-SA increased the max- type of intralesional route can be an attractive alternative to
imum non-toxic concentration by 20-fold compared to avoid systemic effects if it proves to possess a similar or
Dutasteride alone. These less cytotoxic, positively-charged, superior efficacy as well as a better safety profile than the
Dutasteride-loaded nanostructured lipid carriers, with stearic oral route.
acid-chitosan oligomer conjugate, are probably appropriate Mesotherapy involves using multiple intradermal or sub-
for topical delivery and have interesting potential for promo- cutaneous injections of a mixture of compounds in minute
tion of hair growth [84]. doses, using very fine needles, directly over/near the affected
Ushirobira et al. (2020) compared two strategies that sites. Mesotherapy in the treatment of AGA/FPHL has
allegedly promote further Dutasteride follicular-targeted received much publicity in the media and the Internet but the
delivery: the chemical modulation of nanosystem surface subject remains controversial in view of the lack of docu-
properties by coating with the natural polymer chitosan and mented evidence.
the application of a massage. They developed poly-(ɛ-
caprolactone)-lipid-core nanocapsules (NC) containing
Nevertheless, all risks and nuisances of frequent scalp
Dutasteride and had their permeation profile compared to
injections apply and should be considered
chitosan-coated nanocapsules (NC-CS). Both coated and
accordingly.
non-coated nanoparticles targeted the hair follicles com-
pared to a drug solution. Enhanced hair follicle targeting was
observed after the massage procedure, with 5 and twofold Abdallah et al. (2009) studied 28 men with AGA Stage
increases relative to NC and NC-CS, respectively. This find- III-V, and patients were randomly assigned to two groups:
ing is exciting since a simple physical stimulation can group I was the actively treated group (n = 14), and group II
enhance 5-times the drug amount accumulated [85]. were placebo controls (n = 14). Patients in both groups
Noor et al. (2020) successfully synthesized chitosan received seven injections at weeks 0, 1, 2, 3, 5, 7, and 11 and
oligomers (CSO) with lauric acid as a coating (CSO-LA) for were evaluated at week 12 by three assessment methods: hair
a dutasteride-loaded nanostructured lipid carriers (DST- pull test, professional independent observer assessment, and
NLCs) system. These negatively charged NLCs, with a mean patient self-assessment. At week 12 of the study, the mean
particle size of ~184 nm were reported by the authors to rep- hair count in the placebo group decreased by 0.173 ± 0.940
resent a promising formulation strategy for Dutasteride hairs, while hair counts in the actively treated group increased
delivery for the treatment of AGA, with reduced cytotoxicity by 7.739 ± 1.104 hairs (p < 0.001). Thirteen cases out of 14
compared to that of the drug alone and lower irritancy than (92.9%) in the active group and 4 out of 14 in the placebo
an ethanolic solution of Dutasteride [86]. group (28.6%) showed improvement. Regarding increases in
Other researchers have published results on incorporating hair density or scalp coverage self-assessed by patients, these
Dutasteride into various formulations, such as Eudragit E were reported by 13 of 14 (92.9%) individuals in the active
nanosuspension, hydroxypropyl-β-cyclodextrin (HP-β-CD) group and by just 1 of 14 (7.1%) in the placebo group. The
nanostructures, silica nanomatrices, self-microemulsifying authors noted a reverse correlation between AGA duration
drug delivery systems (SMEDDS), iron oxide nanocarriers, and response to treatment since patients with shorter AGA
and solid dispersions for their ability to enhance the solubil- duration had a more pronounced improvement. However, the
ity and bioavailability of Dutasteride [87–94]. However, single set of before and after pictures in the full-text article
25.6 Topical Use of Dutasteride 89
that scored grade 4 by observer assessment and grade 3 by tory dysfunction, there was a decline in semen volume in
self-assessment (hair count change from 29 to 37, 27.6%) is group A, a decline in sperm concentration in group B, and a
of bad quality, low resolution, blurry, and shows mostly vel- decline in sperm motility in group A and B. These results
lus or intermediate hair growth instead of thick terminal probably translate into a degree of systemic absorption that
growth [97]. took place and affected spermatogenesis [99].
Moftah et al. (2013) evaluated the efficacy and safety of An appealing prospective clinical study, including six
mesotherapy using a Dutasteride-containing preparation on patients (five males and one female) diagnosed with AGA/
126 female patients with FPHL, classified into two groups; FPHL, was conducted by Saceda-Corralo et al. (2017). They
group I (n = 86) was injected with Dutasteride-containing injected 1 mL of intradermal Dutasteride 0.01% injections
preparation, and group II (n = 40) was injected with saline. every three months during 9 months, in a total of just three
Patients received 12 sessions and were evaluated on the 18th sessions, reporting an increase of hair density and hair diam-
week by photographic assessment, hair pull test, hair caliber eter in trichoscopy in all cases. However, besides a before
change, and patient self-assessment. Photographic improve- and after picture of one 33-year-old patient depicting moder-
ment was noticed in 62.8% of group I patients compared to ate improvement, no trichoscopic or other data are included
17.5% in the control group (p < 0.05). Variable degrees of in the full-text article. According to the authors, mesotherapy
improvement were noted in group I; 26 patients (30.2%) with Dutasteride may be an effective therapy for patients
showed mild improvement, 13 patients (15.1%) showed with AGA even with less intensive treatment schedules, as
moderate improvement, 13 patients (15.1%) showed good sessions once every three months [100].
improvement, and two patients (2.4%) showed excellent Moftah et al. (2019) conducted a prospective cohort
improvement. Three sets of before and after pictures present- study to investigate the impact of metabolic syndrome
ing patients with good improvement and two sets of patients (MetS) on the treatment response of FPHL to intradermal
with excellent improvement depict objectively good and Dutasteride 0.02% injections. Fifty-one adult participants
excellent cosmetic results, respectively. The mean baseline with FPHL were classified into study cohorts with MetS
of hair diameter increased from 25.8 ± 7.6 μm in group I and comparison cohorts without MetS. There was a signifi-
before treatment to 34.6 ± 11.8 after treatment, while in cant reduction in the mean percentage of terminal and vel-
group II there was no change. The authors noted that better lus hairs (p = 0.000), with a substantial reduction in the
response was evident with a shorter duration of FPHL, and mean hair thickness (p = 0.002) in participants with MetS
adverse effects reported were pain on the injection site, head- compared with participants without MetS. The authors con-
ache, and itching with no significant difference between the cluded that MetS negatively impacted FPHL in terms of
two groups [98]. response to intradermal injection of Dutasteride 0.02% and
In a study by Sobhy et al. (2013), ninety male AGA severity [101].
patients aged 18–55 years were divided into three groups: Herz-Ruelas et al. (2020) perform a systematic review
group A (30 patients) received mesotherapy injections of comparing the efficacy of oral and intralesional administra-
pure Dutasteride 0.005%, group B (30 patients) received tion routes of Dutasteride in AGA. Overall, 8 clinical trials
Dutasteride containing solution (Dutasteride 5 mg, dexpan- met the inclusion criteria (5 clinical using an oral route and 3
thenol 500 mg, biotin 20 mg, pyridoxine 200 mg per vial of an intralesional route) and were selected for data synthesis.
10 mL), and group C (30 patients) received saline injec- Selected studies comprised a total of 1627 patients (1487
tions. Interestingly, there was a statistically significant were men), including 480 participants in the placebo group
increase in anagen hair, a decrease in telogen hair, and an and 1147 in the active treatment groups. Out of the 1627
increase in anagen/telogen ratio just in group B, and only patients included in the analysis, 987 were receiving oral
the mean hair shaft diameter was significantly increased in Dutasteride and 160 intralesional administration. The range
both groups A and B. Group C demonstrated no changes in of the treatment period was from 12 to 48 weeks. No study
any parameter. The authors suggested that hair growth pro- directly compared the effects of oral and intralesional
moters contained in the preparation injected to group B Dutasteride, and pooled analysis of 4 studies evaluating oral
could have a synergistic role with Dutasteride or that the Dutasteride estimated a mean change in hair growth of 15.92
difference in concentration of the active ingredient -being hairs/cm2, when indirectly compared to a mean change of 7.9
higher in the Dutasteride containing solution- resulted in hairs/cm2 in the 1 study of intralesional Dutasteride. No
enhanced results. Despite the statistically significant study with intralesional treatment reported any type of sex-
improvement noted in the trichogram of patients in the ual adverse events, but one should consider that half of the
actively treated groups (A and B), this improvement was not studies included for this systematic review were classified as
so evident clinically. In addition, even though none of the having “high risk of bias,” limiting the credibility of the
patients complained of decreased libido, erectile or ejacula- results [102].
90 25 Dutasteride
25.7 Dutasteride + Finasteride, 1. The effects of Finasteride on 5α-R II inhibition have a

Dutasteride + Minoxidil corresponding biological model. There are individuals
with congenital 5α-R II deficiency that are otherwise per-
There is only one report on the combined use of Dutasteride fectly healthy, with a normal life expectancy, morbidity,
and Finasteride. Boyapati et al. (2012) published a case study and mortality rates [107–109]. In contrast, there is no bio-
of a man with AGA, who had moderate results by Finasteride logical model that mimics Dutasteride’s effects since
treatment, and the addition of Dutasteride 0.5 mg o.d. had an congenital 5α-R I deficiency has not been described.
impressive improvement in his cosmetic appearance [103]. Consequently, the potential long-term effects of the
almost complete inhibition of this enzymic system are
still unknown. It is worth noting that isotype 5α-R Ι is
At present, there are no reports on the combined use of
extensively expressed in the entire human CNS and brain
Dutasteride and Minoxidil. However, since
[77], in contrast to type ΙΙ that is absent. The long-term
Dutasteride’s mechanism of action on the miniaturized
neurological potential effects of the inhibition of isotype
AGA hair follicles is entirely different from
5α-R I enzyme remain unknown.
Minoxidil’s, these compounds can be combined for an
2. Since approx. 30% of patients treated with Dutasteride
enhanced result in various ways.
for six months revealed “no global change” as determined
by investigator photographic assessment and subject self-
One interesting strategy would be to add Dutasteride assessment [27, 28]. Rhie et al. (2019) identified genetic
powder into 5% Minoxidil Topical Solution (MTS), since variants associated with response to Dutasteride treat-
Dutasteride is soluble in organic solvents. The patient could ment for AGA on a total of 42 men with moderate
achieve complete inhibition of local 5α-R activity, since AGA. They concluded that the synonymous single nucle-
Dutasteride is moderately absorbed by the intact scalp skin otide polymorphism (SNP) rs72623193 in DHRS9 was
and can act on the sebaceous gland and dermal papilla [8, 9]. most significantly associated with response to Dutasteride,
It has been demonstrated that both 5α-R isotypes are highly followed by the non-synonymous SNP rs2241057 in
expressed in the sebaceous glands of balding hair follicles of CYP26B1. Additionally, potential candidate variants are
the hairline and the frontal area, compared to the occipital located on DHRS9, CYP26B1, ESR1, SRD5A1,
area in men with AGA and, to a lesser extent, in women with CYP19A1, and RXRG are suggested to be associated
FPHL and might be involved in the pathophysiology of with response to Dutasteride. These genes encode pro-
AGA/FPHL [104] (see Chap. 15, Vol. 1). teins involved in the backdoor pathway of DHT synthe-
Combining oral Finasteride with a topical combination of sis, Retinoic Acid metabolism and signaling pathway, and
MTS/Dutasteride has been reported anecdotally to offer steroid hormone metabolism [110].
impressive results. However, one should consider the s trategy 3. The most effective dosage of Dutasteride in AGA is
of such a combo treatment and how to have a reliable mea- 2.5 mg, which is five times higher than the standard dos-
sure of what is the benefit of each compound on the patient age used in BPH treatment [27]. The exact reverse is true
(see Chap. 24). for Finasteride, which acts efficiently enough in the scalp
at dosage five times lower (1 mg o.d.) than the one used
in BPH (5 mg o.d.) (see Chap. 24).
25.8 Concerns Over the Use of Dutasteride 4. Dutasteride’s regular administration will soon result in
in AGA steady-state levels in the plasma lasting for extended peri-
ods after treatment discontinuation due to Dutasteride’s
According to Phase II and III studies, Dutasteride could be pharmacokinetic profile [4]. The mean half-life of
very effective in AGA, even if not officially approved by the Dutasteride is 247 h [19, 20] and the necessary washout
FDA. Dutasteride is becoming a popular “off-label” treat- period is >670 h or >28 days [21]. In comparison,
ment option in AGA [105], due to its good response shown Finasteride has a half-life of only 6–8 h [110, 111].
by various randomized control studies and meta-analyses. Metabolites of Dutasteride are very stable and resistant to
Also, in most of these studies and systematic reviews, further metabolism [112]. Thus, Dutasteride remains in
Dutasteride seems to provide a better efficacy compared with measurable concentrations in the plasma (>0.1 ng/mL)
Finasteride in treating AGA. The two drugs appear to show for 4–6 months after treatment discontinuation, and sup-
similar rates of adverse reactions, especially in sexual dys- pression of DHT persists for months after Dutasteride
function [41, 42], according to a recent meta-analysis [106]. cessation. This pharmacokinetic property of Dutasteride
Nevertheless, there are specific concerns regarding the may become troublesome in patients who report SAEs,
use of Dutasteride in AGA: since these could persist for months after discontinuation.
25.9 Conclusion 91
However, in most cases, SAEs are self-limited even with ate AGA (Hamilton-Norwood IIIv-V) [42]. Also, guidelines
treatment continuation [24–29, 32, 33, 113]. issued by Manabe et al. (2017) conclude that oral adminis-
5. The off-label use of Dutasteride in AGA will make it tration of Dutasteride is strongly recommended for AGA,
harder for patients to attain the drug without a prescrip- while, conversely, it is contraindicated for FPHL [117]. As
tion, and even if they do, it is more expensive that with all hair growth drugs, continued use is recommended to
Finasteride. It will be even more expensive if the patient sustain benefit, which should be re-evaluated periodically,
aims for the highest efficacy of the 2.5 mg/day dosage. and discontinuation leads to reversal of effects within
However, Dutasteride’s patent protection expired in 12 months.
November 2015, and the drug has since become available As is the case with Finasteride, physicians prescribing
in the U.S. in a variety of low-cost generic formulations, Dutasteride for AGA treatment should engage their patients
which will probably be much cheaper but might raise bio- in a productive discussion regarding the potential adverse
equivalence concerns. side effects on their overall health and quality of life.
6. As with Finasteride, women of reproductive age must Although uncommon, adverse sexual and reproductive out-
avoid even skin contact with Dutasteride because of the comes associated with the use of Dutasteride, such as erec-
potential feminization or undervirilization of a male fetus tile dysfunction, decreased ejaculate volume, decreased
should the woman become pregnant. Dutasteride is a libido, and infertility, are often reported. Most events are
teratogen and a category X compound, and in order to mild, occur early, and resolve during continuing treatment or
prevent unintentional exposure of women of reproductive upon treatment cessation but rarely can be serious and per-
age to Dutasteride, Avodart® is marketed in a soft, liquid- sistent [118]. The potential for SAEs with Dutasteride may
containing capsule, and unless crushed or broken, normal require careful consideration in younger men initiating AGA
handling of intact capsules is safe [114]. Use of treatment, and the risk should be communicated appropri-
Dutasteride by women of reproductive age with FPHL is ately to patients.
forbidden unless these women are informed about the
potential risks and use adequate contraceptive measures.
There are no reproductive risks for postmenopausal The prescribing physician should always be aware that
women, and general adverse effects might apply, such as the off-label prescription of drugs occurs at the discre-
decreased libido, headaches, dizziness, gastrointestinal tion of the prescribing physician and that even though
discomfort, isolated reports of changes in menstruation, the off-label use of drugs is legal, but the promotion of
and acne. Men under Dutasteride treatment should not drugs toward unapproved indications can be illegal.
donate blood earlier than six months after treatment dis-
continuation since the donated blood may be transfused
to a pregnant woman carrying a male fetus and cause Synopsis
abnormal development of external genitalia [115]. Even though the FDA has not approved Dutasteride for the
Research has shown that semen contains approx. 200 treatment of AGA, high-quality clinical studies and system-
times less Dutasteride amount than the required mini- atic reviews are showing excellent hair-growth efficacy,
mum for fetal anomalies to occur [116]. Accordingly, and many clinicians recommend Dutasteride with this off-
exposure of pregnant women to the seminal fluids of a label indication. The high potency and the long half-life of
man in Dutasteride treatment has not been linked with Dutasteride should keep the prescribing physician alert for
risk for the fetus, and condom use is not necessary for this sexual adverse effects (SAEs), such as decreased libido,
indication. erectile dysfunction, and ejaculatory disorders that have
been reported in as many as 3.4–15.8% of men of various
age groups. Fortunately, these effects are usually mild,
25.9 Conclusion occur early, resolve during treatment, and are fully revers-
ible upon treatment cessation. Recently there have been
Despite these valid concerns and challenges, Dutasteride low-quality reports of non-reversible SAEs but have not
remains probably the most effective compound for the treat- been confirmed yet in well designed, larger studies.
ment of AGA. Even though its use is “off-label,” recent Dutasteride use in postmenopausal women is on the rise;
guidelines recommend its use. Kanti et al. report that oral however, very few studies evaluate its use in this specific
Dutasteride 0.5 mg/day can be considered in case of previous population. Women of childbearing potential should avoid
ineffective treatment with 1 mg Finasteride over 12 months Dutasteride, and if they choose to use it, all necessary con-
as a second-line treatment to improve or prevent AGA pro- traceptive measures must be taken since Dutasteride is a
gression in male patients above 18 years with mild to moder- known teratogen. Combining Dutasteride with the FDA-
92 25 Dutasteride
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Spironolactone
26
Spironolactone is marketed under the brand name

Basic Concepts Aldactone® (Pfizer Inc., New York, USA) in tablets of
• Spironolactone is a potassium-sparing diuretic with 25 mg and 100 mg [2].
antiandrogenic effects since it decreases
Testosterone levels, competitively blocks the cyto-
solic androgen receptor, reduces DHT effects in tar- 26.1 Mechanism of Action
get tissues, and inhibits the mineralocorticoid
receptor. The ingested drug is absorbed rapidly and metabolized by
• Spironolactone is the most widely used antiandro- the liver to canrenone and potassium canrenoate, the active
gen in Dermatology in the USA, primarily used in antagonist of aldosterone, and contributes to the potassium-
female acne and as a first-line antiandrogen in hir- sparing diuretic action [3]. Besides being a diuretic, acting
sutism. It is more rarely used in FPHL, though it through the competitive inhibition of aldosterone in the dis-
does not have any indication in men with AGA due tal nephron, Spironolactone also exhibits moderate antian-
to the potential for feminization drogenic activity. Spironolactone acts by directly inhibiting
• The moderate hair growth potential of Spironolactone cytochrome P-450-dependent hydroxylating enzymes in the
is apparent only in high doses, and even though it is liver (17β-hydroxylase and 17,20-desmolase), the adrenals,
generally tolerable, it is not favored by patients since and the gonads [4], resulting in the reduction of Testosterone
adverse effects are common (T) synthesis [5]. Additionally, Spironolactone competes
• Topical Spironolactone is safe and may be mildly with T and Dihydrotestosterone (DHT) for binding on the
effective as an adjunctive treatment, is not intracellular androgen receptors and other steroid enzyme
absorbed systemically through the skin, but its systems in target tissues [6]. Spironolactone occupies the
hair growth potential has not been proven in stud- androgen receptor competitively with an affinity of 67–70%
ies, while it has an unpleasant smell when applied compared to DHT, thus decreasing DHT effects accordingly
to human skin. [7]. Moreover, Spironolactone has been reported to inhibit
5α-Reductase enzymes on genital skin directly [8] and is
considered to exhibit mild progestational and anti-estro-
Spironolactone is the prototypic mineralocorticoid recep- genic properties [9]. In vitro, Spironolactone has been
tor antagonist (MRA), is structurally a synthetic derivative shown to inhibit the growth of cultured human sebocytes
of progesterone, patented over 50 years ago and still in directly [10].
widespread clinical use [1]. It is a potassium-sparing Besides the direct antiandrogenic activity, Spironolactone
diuretic, developed in 1960, and is mostly used to manage is considered to act through other pathways, as well. In 1994,
hypervolemia, congestive heart failure, and arterial hyper- Kenouch et al. (1994) demonstrated that the human skin is
tension. It functions as a competitive aldosterone antago- equipped with the complete set of mineralocorticoid path-
nist, resulting in a moderate reduction of arterial pressure, way enzymes and that human skin is a target-organ for aldo-
and it is FDA-approved for the treatment of primary hyper- sterone [11]. A subsequent study by Ahouansou et al. (2007)
aldosteronism, for managing different edematous condi- associated arterial hypertension with AGA and reported that
tions secondary to liver failure, heart failure, nephrotic Spironolactone’s primary effect on hair follicles is not
syndrome, and hypertension. Lately, in Cardiology, it is through its moderate antiandrogenic properties but by inhib-
only used in terminal stages of heart failure and ascites. iting the mineralocorticoid receptor [12]. This conclusion

98 26 Spironolactone
was confirmed by Arias-Santiago et al. (2009), who have Rushton et al. (1991) studied a group of 12 Caucasian
repeatedly associated aldosterone excess with AGA and females with FPHL. Six women were treated for 12 months
FPHL [13, 14]. with Spironolactone (75 or 100 mg/day), and six remained
untreated. Untreated group patients continued to lose hair,
while Spironolactone stabilized hair loss in treated women,
Although not currently officially approved for any der-
without signs of new hair growth, however. In 2 of these
matologic condition, Spironolactone has been more
women, dosages were increased to 150 mg/day, and the
commonly used in an “off-label“fashion in the treat-
study was extended to 24 months, resulting in both women
ment of acne, hirsutism, and FPHL in selected women.
having increased total hair density and increased meaningful
It is the most-widely used antiandrogen in Dermatology
hair density [26]. In a very small-scale study conducted by
in the USA due to its long-term safety profile and effi-
Adamopoulos et al. (1997) on four women with FPHL,
cacy at low doses [15, 16]. It has also been used suc-
Spironolactone reduced hair loss by 62.9% and increased the
cessfully at 100- to 200 mg daily doses to treat FPHL
amount of anagen hair by 50% [27]. Yazdabadi et al. (2009)
[17].
treated a 9-year-old pre-pubertal girl with FPHL with
Spironolactone 100 mg/day and reported objective improve-
ment demonstrated by hair regrowth in 6 months [28].
26.2 Spironolactone as an Antiandrogen Hoedemaker et al. (2007) published a case study of a
53-year-old FPHL patient who was administered 200 mg of
In 1981, Blum et al. published a case-study of a woman who Spironolactone for 24 weeks and showed moderate improve-
was administered Spironolactone for the treatment of poly- ment. When further hair growth reached a plateau, the addi-
cystic ovary syndrome and associated hypertension. tion of 5% Minoxidil Topical Solution (MTS) twice daily
Surprisingly, hirsutism in that woman improved s ignificantly, resulted in new growth [29]. Famenini et al. (2015) con-
demonstrating that Spironolactone could affect androgen- ducted a retrospective study of 166 female patients diag-
induced hair growth [18]. Since this accidental discovery of nosed with FPHL between September 2010 and June 2012,
Spironolactone’s antiandrogenic actions, it has gained popu- including 19 women taking Spironolactone for 7 to
larity in treating many dermatologic androgen- dependent 20 months. A survey study was also performed on 64 patients
conditions, especially in the USA, since the other first-line (ages 20–88) with FPHL who visited the clinic between
antiandrogen, Cyproterone acetate, is not available there November 2012 to June 2013, including 20 women already
[19]. Off-label Spironolactone has been used as a first-line on Spironolactone. Combined results showed that 74.3% of
treatment for female hirsutism since it both reduces adrenal patients (n = 29 of 39) receiving Spironolactone reported sta-
androgen production and exerts competitive occupation of bilization or improvement of hair loss; there was no correla-
androgen receptors in target tissues [20]. The antiandrogenic tion between dose and response in either study (mean
efficacy of Spironolactone has been demonstrated in the dose = 110 mg). However, patients with concomitant hirsut-
management of hirsutism and acne in women [21–24] since ism or acne showed a significantly better response to
the pathophysiological mechanisms of these conditions Spironolactone (p = 0.05) [30]. A retrospective study con-
resemble those of AGA/FPHL. ducted by Κarrer-Voegeli et al. (2009) compared the effects
of common antiandrogens in 228 consecutive female patients
with signs of hyperandrogenism followed for six years, and
26.3 Spironolactone and FPHL reported that Spironolactone was effective only in treating
isolated alopecia in patients with FPHL and normal levels of
As already mentioned, Spironolactone has also been studied androgens [22].
in the management of FPHL [17]. However, no randomized The only studies offering higher than low-quality data on
controlled trials have evaluated the efficacy of Spironolactone Spironolactone’s effects on FPHL have been published by
in FPHL. There are only case reports, series, and one open- Sinclair et al. (2005), who initially conducted an open-label,
label trial to support this indication. Additionally, there are no single-center study, including 80 women, aged 12–79 years,
studies to address a dose-dependent effect in FPHL. Published with biopsy-confirmed FPHL, who received 12 months of
results on the efficacy of doses >100 mg/day are primarily on oral antiandrogen therapy. Forty women received
cohorts of fewer than ten women, such as in the study of Spironolactone 200 mg/day, and 40 women received
Burke et al. in 1985 [25]. The authors in that study used spi- Cyproterone acetate, either 50 mg daily or 100 mg for ten
ronolactone 200 mg daily to treat 12 female patients with hir- days per month, if premenopausal. According to standard-
sutism, acne, 7 of which also had FPHL and after six months, ized photographs evaluated by three blinded experienced cli-
six of these seven patients were well pleased with hair growth, nicians, there was no significant difference in the results
but this assessment was subjective. between Spironolactone and Cyproterone acetate; 44%
26.4 Topical Spironolactone 99
(n = 35) of patients experienced visible hair growth, another pair of low-quality before-and-after photos of a patient
44% (n = 35) of patients had no apparent change in hair den- receiving Spironolactone 50 mg b.i.d. monotherapy at base-
sity before and after treatment, and only 12% (n = 10) had line and 6 months after with significant hair growth [33].
persistence of hair loss. Predictors of response revealed no Despite a lack of further high-quality documentation on
influence of patient age, menopause status, serum ferritin, efficacy, Spironolactone is often used in the treatment of
serum hormone levels, clinical stage (Ludwig), or histologi- FPHL, particularly in those women with documented hyper-
cal parameters, and the only significant predictor was mid- androgenism [34]. Other authors prefer to use Spironolactone
scalp clinical grade, with higher-scale values associated with in FPHL patients with normal serum androgens [17, 18, 35,
a greater response (p = 0.013) [31]. 36]. The minimally effective dose of Spironolactone appears
Sinclair (2018) also conducted a prospective, uncon- to be 100 mg/day, but this dosage is based more on the treat-
trolled, open-label observational case series study of 100 ment of hirsutism than alopecia. In FPHL, the usual doses
women with FPHL treated once daily with capsules contain- empirically reported as being effective are between 100 and
ing Minoxidil 0.25 mg and Spironolactone 25 mg. To avoid 200 mg/day [37].
hypotensive events, 50 mg of sodium chloride was added to
the capsule for women with a baseline blood pressure of
The starting dose of Spironolactone is usually 50 mg/
≤90/60 mmHg. The mean age was 48.44 years (range
day, and monthly increases of 50 mg [38] may take it
18–80), mean hair loss severity at baseline was Sinclair 2.79
up to 200 mg/day, which, however, is not easily toler-
(range 2–5), and mean hair shedding score at baseline was
able by patients.
4.82. The mean reduction in hair loss severity score was 0.85
at 6 months and 1.3 at 12 months. The mean reduction in hair
shedding score was 2.3 at 6 months and 2.6 at 12 months. Treatment with Spironolactone should be administered
The mean change in blood pressure was −4.52 mmHg in sys- for at least 6 months before its efficacy can be evaluated [39].
tolic and −6.48 mmHg in diastolic pressure. Side effects
were seen in eight women but were generally mild. No
patients developed hyperkalemia or any other blood test 26.4 Topical Spironolactone
abnormality. Six of these eight women continued treatment,
and two women who developed urticaria discontinued treat- The efficacy of Spironolactone in the treatment of FPHL as
ment [32]. well as in other androgen-dependent disorders (e.g., acne,
Burns et al. (2020) conducted a retrospective observa- hirsutism), naturally resulted in efforts to produce a topical
tional study to evaluate Spironolactone’s efficacy and adverse Spironolactone solution hoping that the systemic absorption
effect profile as combination therapy or monotherapy in would be low enough to avoid systemic antiandrogenic
FPHL. Data from 79 women with a mean age of 50 years effects in men.
(range, 21–79 years) were analyzed. Patients receiving con- The mechanism of action topical of Spironolactone has
comitant hair loss treatments were divided into 2 groups: been extensively studied, both in lab animals [40] and
those who had been using MTS or a low-level laser light humans [41]. The primary mechanism of action is the com-
device for longer than 6 months experiencing a plateau in petitive occupation of the androgen receptor [10, 42].
hair density and those who started concomitant treatment at Spironolactone occupies androgen receptors, leaving fewer
the time of spironolactone initiation. Overall, 87% of patients DHT binding positions, resulting in lowered local androgen
were receiving Spironolactone monotherapy or added effects. Spironolactone acts on the sebaceous gland, as well,
Spironolactone to a long-term hair loss treatment regimen. decreasing sebocyte proliferation and reducing sebum secre-
The average spironolactone dose was 100 mg daily (range, tion rates [43].
25-200 mg daily) for a minimum of 6 months. All patients Several studies have been published on the antiandrogen
maintained or improved initial Sinclair score (SS), with an effects of Spironolactone used as a topical solution, and its
average overall change of 0.65. Additionally, of the 45 efficacy in severe acne in both sexes has been documented
patients using Spironolactone for longer than 6 months, 29 [41, 43]. Topical use of Spironolactone leads to 23% reduc-
(64%) had the best recorded SS at 1 year of use or longer. tion in sebaceous gland secretion; however, its onset of
Twenty-six patients (33%) reported an adverse event, and action is relatively slow and will appear not earlier than
overall, 3.8% of patients discontinued Spironolactone sec- 12 weeks into treatment [41]. In order to compare the percu-
ondary to reported adverse events; 82% of patients main- taneous absorption of Spironolactone with that of placebo,
tained or increased their dose of Spironolactone without Rey et al. (1988) was the first to conduct a double-blind
issue. The authors reported that Spironolactone, either as crossover study in six healthy male volunteers who applied
monotherapy or adjunct therapy, is an effective and well- either a cream containing 5% Spironolactone or placebo, on
tolerated option for FPHL. The full-text article includes one a well-defined skin area, equivalent to 55% of the body area,
which is approximately 10 times larger than the scalp. life of Spironolactone is 1 h, and the sulfated metabolites,
Topically administered Spironolactone resulted only in local canrenone and 7α-thiospirolactone have half-lives of
skin impregnation, despite the large application surface and 16.5 h and 13.8 h, respectively [15].
no traces of canrenone, the major metabolite of • Spironolactone has an inherent unpleasant, garlic-like
Spironolactone, were detected in blood and urine [44]. The odor due to the Sulfur molecule it contains and body heat
finding that topical Spironolactone remains on the skin, accentuates the smell, so sun or perspiration should be
exerts its action there, and has no systemic antiandrogenic avoided. This egg-like odor on the hair can be both embar-
effects has been documented in other reports as well [45, 46]. rassing and inconvenient.
However, so far, there has been only one published study • Spironolactone will interact with Minoxidil when in the
on the efficacy of topical Spironolactone solution in AGA or same solution and will result in decreased efficacy of both
FPHL. Abdel-Raouf et al. (2020) conducted a 12-month, compounds. Since this chemical interaction is very slow
randomized, comparative study to evaluate the effect of a (>24 h), the separate application of the two substances is
newly prepared topical 5% Minoxidil topical gel (MTG) and safe. The most appropriate application method is to use
1% Spironolactone gel (SG) on 39 males with AGA, and 21 Spironolactone and Minoxidil from separate solutions:
were females with FPHL. The mean age of the patients was first, Minoxidil should be applied, and later, Spironolactone
30.96 ± 7.3 years, and they were classified into 3 equal solution or cream.
groups (20 patients each) according to the treatment modali- • No more than a thin layer of cream should be applied,
ties: group I was treated with 5% MTG, group II with 1% preferably wearing a glove; otherwise, it is necessary to
SG, and group III treated with a combination of 5% MTG wash the hands thoroughly following application.
and 1% SG. The patients used the gel twice daily by gently • Topical Spironolactone may be combined with other hair-
massaging their scalps. Patients were examined were fol- growth treatments. More particularly, topical
lowed-up every month for 1 year with global photographs Spironolactone might act synergistically with Finasteride
and biopsies before and after treatment. In group I (5% as it is speculated that topical Spironolactone will inhibit
MTG), 90% of patients had a positive clinical response; four any remaining DHT reaching the hair follicle since
had an excellent response, six had a good response, two had Finasteride 1% reduces scalp DHT levels by no more than
a fair response, and six had a poor response. In group II (1% 64.1% [49]. Anecdotal sources report that the efficacy of
SG), 80% of patients had a positive clinical response; five the combination Minoxidil and Spironolactone is
had an excellent response, four had a good response, and 70–80%. The combination of Minoxidil-Finasteride-
seven patients had a poor response. In group III (5% Spironolactone is even more efficient. However, there is
MTG + 1% SG), clinical improvement was noticeable in no published evidence for this.
100% of the patients, eight had an excellent response, ten • The preparation of a topical solution of Spironolactone
had a good response, and two patients had a fair response. can be simple, should the unpleasant smell of the solu-
Among group I and group II there was a non-significant dif- tion pose no concern. Spironolactone 5% in a solution
ference in results (p = 0.516), while there was a significant of 40% alcohol and water is reported as the most active
difference between group I and group III, group II and group concentration, but these data refer to lab animals [50],
III (p = 0.035, p = 0.003, respectively). The full-text article and there are no human trials. A 100 mL solution of 5%
includes 3 small pairs of before-and-after global photos of will contain 5gr of Spironolactone, which corresponds
medium quality. The photos depict one subject from each to 50 tablets of Aldactone 100 mg. Any pharmacist
group, 2 males and one female, presenting significant growth. may prepare this solution. It is necessary to keep the
The authors concluded that 5% MTG and 1% SG were effec- solution in the fridge to avoid the unpleasant, egg-like
tive in the treatment of AGA, while the combination of two odor.
agents was better in treatment [47]. • There are commercially available Spironolactone formu-
There have been previous efforts to incorporate lations claiming to be odorless and more convenient to
Spironolactone into nanostructured lipid carriers to increase use. If the patient prefers to use Spironolactone cream, it
absorption and treat hair loss [48]. Nevertheless, despite the should be water-based. According to the study of
lack of evidence on topically applied Spironolactone’s hair Mortazavi et al. (2001), 2% aqueous base Spironolactone
growth potential, its use is quite “popular” among hair-loss cream demonstrated the greatest stability and most desir-
Forum members, who report positive results, outlining prep- able physicochemical properties [41]. However, in this
aration methods and details of use. Anecdotal reports on the split-face study, including 12 patients aged 17–50 years
use of topical Spironolactone include the following: who suffered from mild to moderate hirsutism of the face,
3 months of treatment showed lack of efficacy of the for-
• Topical solution Spironolactone should be used twice mulation on hair growth compared with the other side of
daily, allowing at least 8 h between doses. The serum half- the face [51].
References 101
26.5 Adverse Effects

Spironolactone’s antiandrogenic effects in men are
After oral administration, the absorption of Spironolactone is associated with breast tenderness, breast enlargement,
40–70% and reaches peak plasma levels within 30–60 min. testicular atrophy, decreased libido, and occasionally
Most Spironolactone is excreted in the urine and eliminated with impotence [62]. Therefore, oral Spironolactone is
via the biliary route, and food intake promotes absorption not indicated in men with AGA under any circum-
and reduces the first-pass effect. Spironolactone is metabo- stances because of the risk of feminization [19]. This is
lized in the liver into primary metabolites canrenone and a primary reason Spironolactone in Cardiology is used
7α-thiospirolactone [52]. only as a last-resort drug.
Spironolactone’s side effect profile is perhaps more However, in women, Spironolactone’s long-term safety is
varied than other anti-androgens, and oral administra- acceptable, and even though side effects are common, they are
tion of Spironolactone causes several dose-dependent not usually the cause for stopping the drug [63]. On a final
adverse effects due to its diuretic effects and its antian- note, suspicion on Spironolactone’s potential correlation with
drogen effects. breast cancer [64] was proven to be unsubstantiated [65].
Topical use of Spironolactone has been known to cause
adverse effects only on the application site, including erythema,
The diuretic effect of Spironolactone has been associated burning sensation, and pruritus, while there have been no reports
with polyuria, polydipsia, electrolyte disturbances, weak- of systemic adverse effects induced by systemic absorption [66].
ness, fatigue, nausea, dizziness, vomiting, diarrhea, mild Should the patient present any symptoms indicating systemic
postural hypotension, and urticaria, whereas the antiandro- adverse effects, the treatment is discontinued immediately. Only
gen effects with irregular menses, spotting, breast tender- four case-reports of allergic dermatitis to topical Spironolactone
ness, and mood swings [53, 54]. There have also been reports have been reported so far [67]. However, there is no available
of rare cases of pharmaceutical hepatitis [55]. Menstrual data concerning the long-term safety profile of topically applied
irregularities is a critical issue in 80% of women using Spironolactone. Considering the minimal skin absorption of
Spironolactone [56]; however, most will tolerate long-term Spironolactone, topical use is considered generally safe.
Spironolactone use [57]. On a final note, in the recent (2018) exceptional system-
Hyperkalemia is a potential side-effect related to atic review (Evidence-based (S3) guideline for the treatment
Spironolactone’s aldosterone antagonist/potassium-sparing of androgenetic alopecia in women and men) issued for the
effect in the distal nephron [58]. Therefore, some authors European Dermatology Forum, Kanti et al. state that they
recommend that women under Spironolactone have normal cannot make a recommendation for the use of oral spirono-
blood pressure and electrolyte monitoring, especially in the lactone to improve or prevent progression of AGA in nor-
first 6 months of treatment. Plovanich et al. (2015) mea- moandrogenic female patients at present [68].
sured the baseline rate of hyperkalemia in 974 healthy
young women using Spironolactone for acne or other endo- Synopsis
crine disorders with associated acne, and in 1165 healthy Orally administered Spironοlactone arrests hair loss progres-
young women taking and not taking Spironolactone. The sion with a favorable long-term safety profile in FPHL, but
authors concluded that the rate of hyperkalemia in healthy its use in AGA is completely unjustified due to the risk of
young women taking Spironolactone for acne was equiva- feminization. Topical use of Spironοlactone seems to be safe
lent to the baseline rate of hyperkalemia in this population, in both sexes and may be mildly effective as an adjunctive
suggesting that frequent potassium monitoring is not neces- treatment in combination with MTS + Finasteride. However,
sary for healthy young women receiving Spironolactone evidence for its efficacy is extremely limited. It can also be
[59]. This information may also be applied to the treatment inconvenient due to the topical formulation’s garlic-like
of FPHL in young, healthy women, reducing concerns odor, further discouraging many patients from using the topi-
regarding hyperkalemia monitoring during Spironolactone cal Spironolactone products found online.
use [60].
Caution is needed in patients with renal disorders since
Spironolactone can potentially cause severe electrolyte dis- References
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Cimetidine
27
or vagotomy), which was often necessary [2]. Although

Basic Concepts cimetidine is the most popular member of the Η2-blocker cat-
• Cimetidine is histamine H2-receptor antagonist (H2- egory, it has the highest rate of adverse effects, one of which,
blocker) but also exerts weak antiandrogenic activ- upon administration of high doses (>1200 mg/day) or long-
ity in high doses (1200–1600 mg/day) by term administration, is gynecomastia [3].
competitively inhibiting DHT and other androgens This particular adverse effect raised suspicions that
from binding to the cytosolic androgen receptor. Cimetidine has antiandrogenic properties, which were soon
• Although Cimetidine has been proven to be both demonstrated in mice. Cimetidine was reported to competi-
safe and well-tolerated, its antiandrogenic potential tively inhibit the binding of DHT and other androgens on the
in hirsutism and FPHL is limited, and it is contrain- cytosolic androgen receptor [4], and this property was later
dicated in high doses in males with AGA due to confirmed in cultured human fibroblasts [5]. Antiandrogen
feminization and potential for various adverse effects are rare when cimetidine is administered in doses
effects. within the therapeutic range for gastric ulcer treatment
(150 mg/b.i.d.) and occur only at high doses of 1200-
1600 mg/day. The antiandrogenic actions of Cimetidine are
not related to its H2-receptor antagonism [6].
Cimetidine was discovered in 1971 and came into commercial
use in 1977. It belongs in the imidazole-group of molecules,
and more specifically to the category of histamine H2-receptor
antagonists, which, until the beginning of the twenty-first cen- 27.2 Use of Cimetidine
tury, constituted the highest selling pharmaceutical category
worldwide. The development of longer- acting H2-receptor Cimetidine’s potential as an antiandrogen was first demon-
antagonists (H2-blockers) with fewer drug interactions and strated in lab animals, on which it significantly reduced sebum
adverse effects, such as ranitidine and famotidine, decreased production in the hamster flank organ [7]. In humans with
Cimetidine’s use. Although it is still often used, is no longer acne, oral administration of Cimetidine provided conflicting
among the most popular H2-blockers. results. Two studies were published in Lancet in the early
1980s; one reported moderate efficacy [8] and the other negli-
gible [9]. The use of Cimetidine in a topical solution form for
27.1 Mechanism of Action acne treatment was first suggested back in 1986 by Schmidt
et al. [10] Subsequent experiments by Lieb et al. (1994), who
The action of H2-blockers is exerted through the occupation tested a phospholipid-based liposomal formulation of
of Η2 histamine receptors on the membrane of the parietal Cimetidine, reported significant follicular deposition of the
cells of the stomach and duodenum, resulting in the inhibi- active compound [11]. More recent studies have shown higher
tion of gastric acid secretion [1]. When Η2−blockers were efficacy of Cimetidine in verruca vulgaris rather than acne
first introduced, they were mostly used to treat gastric ulcers, [12]. The use of Cimetidine in female hirsutism did not yield
with numerous advantages over previous drugs, resulting in satisfactory results, and all studies reported that Cimetidine,
rapid remission and healing of chronic or relapsing ulcers. even at doses of 1500 mg/day for 3 months, was not effective
This drug category’s discovery has led to a significant reduc- in the treatment of hirsutism and did not result in a statistically
tion of the standard –amputating- ulcer surgery (gastrectomy significant cosmetic improvement in hirsute women [13–16].
106 27 Cimetidine
27.3 Cimetidine and ΑGΑ/FPHL tem’s activity by 45%, which usually leads to the reduced
metabolism of xenobiotics by the liver [25]. Interestingly,
Regarding Cimetidine’s effects on hair loss, there is a single, cimetidine seems to have a dual role, acting both as an inhib-
small-scale study by Homayoun Aram (1987), examining the itor and inducer of the cytochrome P-450 system, accounting
effects of Cimetidine in FPHL. The study was conducted on for the impaired oxidative metabolism of some drugs during
10 FPHL patients receiving Cimetidine 300 mg/five times a co-administration with Cimetidine [26]. The highest inhibi-
day for a duration of therapy ranging from 1.5 to 9 months, tion occurs in phase I reactions, and substances whose
with a median of 5 months. The evaluation of this trial’s metabolism is impaired by the concomitant administration of
results was based on serial photography, subjective apprecia- cimetidine are the following: Antipyrine, warfarin, diaze-
tion of the patient, and objective evaluation of the author. pam, desmethyldiazepam, chlordiazepoxide, propranolol,
Eight patients completed the study, and seven patients labetalol, metoprolol, phenytoin, carbamazepine, chlorme-
showed good to excellent regrowth of hair. Regrowth of hair thiazole, theophylline, and caffeine [27, 28]. Nevertheless,
was noted from 10 to 18 weeks (with a median of 12 weeks) some experts believe that inhibition of P-450 by Cimetidine
after the beginning of therapy. However, three of the eight may have a long-term liver-protective effect since it prevents
patients who completed the study had a mild recurrence of extensive metabolism of potentially harmful molecules, such
hair loss within 2–3 months after therapy cessation. Acne, as acetaminophen [29].
seborrhea, and hirsutism, which were present in 3 of the Safety of cimetidine, following toxicological studies in
patients, showed significant improvement. Despite the high lab animals [30] but also long-term and very extensive clini-
efficacy, the authors noted that Cimetidine should not be a cal experience as an anti-ulcer drug, is considered very high
first-line treatment for FPHL and should be used only in [31]. Cimetidine appears to be very safe in overdose, produc-
selected cases [17]. ing no symptoms even with massive overdoses of more than
20 g [32].
On a final note, in the recent (2018) systematic review
Based on this minimal evidence, Cimetidine could be (evidence-based (S3) guideline for the treatment of andro-
used in FPHL, but its use is prohibited in AGA due to genetic alopecia in women and men) issued for the
its antiandrogenic effects in high doses. Notably, European dermatology forum, Kanti et al. make no mention
Camacho et al. (2000) claimed that Cimetidine might of cimetidine to improve or prevent progression of AGA/
even have a negative impact on AGA, as it can increase FPHL [33].
the production of systemic androgens through a nega-
tive feedback mechanism [18]. Synopsis
Cimetidine is a weak antiandrogen, and oral administration
of the necessary high doses (>1200 mg/day) to treat AGA in
males is under no circumstances recommended. Its use as an
27.4 Adverse Effects antiandrogen in women has been demonstrated in very few
studies, and reports of limited potential are only available.
Reported side effects of cimetidine include diarrhea, rashes, Therefore, it is not recommended for the treatment of FPHL
dizziness, fatigue, constipation, and myalgia, all of which are or other androgen-dependent disorders, either.
usually mild and transient, while there have been reports of
mental confusion in elderly patients. Rarely, interstitial
nephritis, urticaria, and angioedema have been reported. References
Because of its hormonal effects, cimetidine may cause sex-
ual dysfunction, including loss of libido, erectile dysfunc- 1. Henn RM, Isenberg JI, Maxwell V, Sturdevant RA. Inhibition of
gastric acid secretion by cimetidine in patients with duodenal ulcer.
tion, and gynecomastia (0.1–0.2%) in males during long-term N Engl J Med. 1975;293(8):371–5.
treatment [19]. Administration of 1200–1600 mg of 2. Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman
Cimetidine for 3 months will cause mild prolactin increase in D. Pharmacological interventions for non-ulcer dyspepsia.
both sexes [20], whereas, in males, it will cause Testosterone Cochrane Database Syst Rev. 2003;(1) CD001960
3. Spence RW, Celestin LR. Gynaecomastia associated with cimeti-
reduction [21] reduction of 43% in sperm count [22], even dine. Gut. 1979;20(2):154–7.
impotence [23]. Cimetidine is also commonly associated 4. Winters SJ, banks JL, Loriaux DL. Cimetidine is an antiandrogen in
with transient raised aminotransferase activity, while hepato- the rat. Gastroenterology. 1979;76(3):504–8.
toxicity is rare [24]. 5. Sultan C, Terraza A, Descomps B, Crastes de Paulet A. Cimetidine
competition with androgens for binding to human sex skin fibro-
An important detail of Cimetidine’s pharmacodynamics blasts androgen receptors. J Steroid Biochem. 1980;13(7):839–40.
is that it is metabolized by the cytochrome P-450 system. 6. Sivelle PC, Underwood AH, Jelly JA. The effects of histamine H2
The binding of cimetidine to P-450 inhibits the enzymic sys- receptor antagonists on androgen action in vivo and dihydrotes-
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Biochem Pharmacol. 1982;31(5):677–84. axis in man. Curr Med Res Opin. 1986;10(5):285–90.
7. Gloor M, Wirth H, Swoboda U. Is sebosuppression by cimetidine 22. Van Thiel DH, Gavaler JS, Smith WI Jr, Paul G. Hypothalamic-
an antiandrogenic effect? Acta Derm Venereol. 1981;61(3):262–4. pituitary-gonadal dysfunction in men using cimetidine. N Engl J
8. Lyons F, Cook J, Shuster S. inhibition of sebum excretion by an H2 Med. 1979;300(18):1012–5.
blocker. Lancet. 1979;1(8131):1376. 23. Jensen RT, Collen MJ, Pandol SJ, Allende HD, Raufman JP,
9. Jones H, Simpson NB, Blanc D, Forster RA, Cunliffe WJ. Lack of Bissonnette BM, Duncan WC, Durgin PL, Gillin JC, Gardner
effect of cimetidine in acne. Lancet. 1980;2(8205):1201–2. JD. Cimetidine-induced impotence and breast changes in
10. Schmidt JB, Spona J. Topical cimetidine treatment of acne. Z patients with gastric hypersecretory states. N Engl J Med.
Hautkr. 1986;61(15):1065–72. 1983;308(15):883–7.
11. Lieb LM, Flynn G, Weiner N. follicular (pilosebaceous unit) depo- 24. Sabesin SM. Safety issues relating to long-term treatment with
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formulation. Pharm Res. 1994;11(10):1419–23. 1993;7(Suppl 2):35–40.
12. Fit KE, Williams PC. Use of histamine2-antagonists for the treat- 25. Ioannoni B, Mason SR, Reilly PE, Winzor DJ. Evidence for
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13. Grandesso R, Spandri P, Gangemi M, Nardelli GB, Ambrosio GB, dine: Binding and kinetic studies. Arch Biochem Biophys.
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Cyclosporin
28
plantation and preventing rejection of kidney, heart, and liver

Basic Concepts transplants [1]. Before the introduction of CyA, even with
• Cyclosporin A (CyA) is naturally occurring fungal impeccable surgical techniques, organ transplants were
product and the archetype immunosuppressive drug doomed to fail due to acute graft-vs.-host reactions. CyA
used to suppress graft-vs.-host reactions in solid changed all that forever. CyA was approved in 1983 as an
organ transplantation; one of its most common side immunosuppressant and allowed successful allotransplanta-
effects is dose-dependent hypertrichosis, which tion and xeno-transplantations, both now considered “rou-
affects 80% of patients. tine surgery.” It is also approved in the US for the treatment
• The hypertrichotic mechanisms of CyA have not of rheumatoid arthritis and psoriasis [2], as an ophthalmic
been fully elucidated and are not linked to andro- emulsion for the treatment of ocular symptoms of Sjögren’s
gens but to its action on IL-2, TGF-β1, NF-kB, NO, syndrome and persistent nummular keratitis following ade-
and calcineurin. noviral keratoconjunctivitis [3].
• The adverse effects of oral CyA are numerous and
severe, and the cost/benefit ratio is positive for the
patient only in cases of grave or life-threatening 28.1 Mechanism of Action on the Hair
conditions. Follicle
• Topical CyA nanoparticle application has not
yielded positive results in AGA or FPHL and larger One of the most common dermatological side effects of oral
studies will be probably designed in the future. or IV CyA is dose-dependent hypertrichosis, which was first
noticed during Phase II trials, occurring in >40% of subjects
in the active group [4, 5]. In subsequent studies, it was
In 1970, several new strains of fungi were isolated from soil reported in 80% of cases. Hypertrichosis is usually noted
samples taken from Norway and from Wisconsin in the USA approximately 8 weeks after initiation of therapy and slowly
by employees of the pharmaceutical company Sandoz Inc. resolves after treatment. The observation of this adverse
(today Novartis). Both strains produced a family of natural effect raised the question of the hair growth potential of
products called Cyclosporins. Cyclosporin A (CyA) was first CyA. Indeed, it was found that in high doses (10–100 mg/kg
isolated in 1972, and it is a highly lipophilic, cyclic undeca- body weight/day), CyA increased the growth rate of hair fol-
peptide, produced by the fungus Trichoderma polysporum. licles, and CyA-treated mice showed three to four times lon-
Soon it demonstrated a variety of physiologic actions, such ger hair than control mice [6]. Even the use of a topical CyA
as antiparasitic, fungicidal, anti-inflammatory, and immuno- solution yielded positive hair growth results in lab animals
suppressive properties. In contrast to glucocorticoids and [7]. Gilhar et al. [8] demonstrated the systemic effects of
cytostatics, CyA exerted its activity in its effective dosage CyA on hair growth using an experimental human scalp skin
range towards T lymphocytes. CyA affected the synthesis of graft model transplanted onto nude mice and rats. Later, they
immunological modulators of the interleukin-2 (IL-2) with- investigated the role of topical CyA in the murine transplan-
out suppressing the bone marrow, allowing it to be used in tation model, using human split-thickness skin grafts and
bone marrow transplants. reported terminal anagen hair growth only on the grafted
Most importantly, CyA exhibited impressive efficacy in skin of the CyA-treated group [8] and delayed apoptosis,
managing acute graft-vs.-host disease in bone-marrow trans- probably due to anagen prolongation [9].
110 28 Cyclosporin
naling pathways [23] and, consequently, severely delays the

CyA is considered the most potent known anagen anagen-to-catagen transition in hair follicles, without block-
inducer. The rate of anagen induction is dependent on ing it entirely [24, 25]. CyA is also thought to act by form-
the dose, time course, route of administration and is ing a complex with cyclophilin A, which binds to and
mediated through a direct action of CsA on the skin inhibits calcineurin, preventing the dephosphorylation of
and its appendages [10]. target proteins include ion channels, receptors, and tran-
scription factors. Among the latter, members of the NFAT
family, which controls a wide range of cellular functions
that include proliferation, apoptosis, and differentiation, are
most important [26].
In vitro experiments have shown that CyA at a concen- CyA also prevents the secretion of apoptosis-inducing
tration no >10−7 M—which is within the therapeutic factor (AIF) from mitochondria. Whether AIF, a protein that
plasma range—maintained hair growth for longer than induces caspase-independent apoptosis, can regulate the hair
control and resulted in a 42% greater mean follicle follicle cycle in response to CyA is currently unclear.
elongation after 15 days (p < 0.05). It was also observed However, latest reports by Lan et al. [27] claim that CyA
that hair follicles in CyA solution remained in anagen enhances hair growth through caspase-dependent pathways
for longer than the corresponding control hair follicles by retarding anagen-to-catagen transition and that these pro-
[11]. Shirai et al. [12] administered the anti-tumor drug hair growth properties of CyA are in part due to blockage of
cyclophosphamide (known for causing anagen efflu- AIF nuclear translocation [27].
vium) to adult mice, and 0.5% CyA or Minoxidil 1%
were topically applied to the mice daily. The authors
reported that very thick and long hairs were evident 28.2 Cyclosporin A in Alopecia Areata
after 21 days of cyclophosphamide administration in
the 0.5% CyA group, while vehicle and 1% MTS Cyclosporin has been used in the treatment of alopecia areata
induced sparsely visible, short hairs. Additionally, (AA) with varying success. The oral administration of CyA
damaged anagen hair follicles demonstrated the poten- (10 mg/kg; 5 days/week for 7 weeks) on Dundee experimen-
tial of remodeling themselves, which was promoted by tal bald rats, which typically serve as models for AA, on
topical CyA administration [12]. established lesional DEBR rats displaying extensive areas of
hair loss, yielded impressive results: Within 5 weeks, their
fur had fully grown back [28].
CyA acts as a hair growth agent through different mecha- However, results in humans were not favorable. The effi-
nisms than Minoxidil [13], but the exact mechanisms are still cacy of CyA alone or in conjunction with systemic steroids
unknown. CyA reduces the expression of the IL-2 gene, in AA was investigated in clinical trials and offered variable
decreasing the levels of γ-INF and the activity of Langerhans results. Initial case studies showed negligible [29] or moder-
cells [14]. Besides this mechanism, the hair growth potential ate response [30, 31]. The clinical application of a topical
of CyA is not related to any effects on the androgen metabo- CyA solution on patients suffering from AA also yielded
lism or other hormonal effects. More recent studies correlate results inferior to those expected, since local CyA applica-
the hair growth potential of CyA with the inhibition of tion was ineffective even in concentrations up to 10% CyA
nuclear factor in activated T cells (NFAT) via calcineurin [32, 33]. Oral CyA at 6 mg/kg/day for 12 weeks was studied
inhibition [15]. Other possible mechanisms are -at least par- by Gupta et al. [34] on six patients with AA, and a response
tially attributable- to its growth-promoting effects on hair rate of 50% was reported, whereas significant hair loss re-
epithelial cells through the downregulation of several protein occurred in all patients within 3 months of CyA discontinua-
kinase C (PKC) isozymes in hair epithelial cells or the inhi- tion [34]. Shapiro et al. [35] reported a poor 25% response
bition of translocation PKC isozymes to the membrane or rate when oral CyA was combined with low-dose oral pred-
cytoskeleton of hair epithelial cells [16] since PKC is a nisolone on eight patients (five women, three men) with
known inhibitor of follicular growth [17]. Other regulatory severe Alopecia Totalis [35]. Kim et al. [36] conducted a
molecules that have been described to be modulated by CyA study on 43 patients with severe AA and reported that the
are TGF-β1 [18, 19], NF-kB [20], and nitric oxide NO [21]. combination of oral CyA (200 mg twice daily) and methyl-
Notably, CyA can restore mitochondrial membrane prednisolone (20–24 mg twice daily) for 12 months resulted
potential, attenuate the mitochondria membrane permeabil- in 38 (88.4%) patients with significant hair regrowth and
ity transition, and prevent cytochrome c release from mito- only five (11.6%) non-responders [36]. Rallis et al. [37] also
chondria [22]. CyA is also an excellent inhibitor of reported positive results in a small series of patients with
caspase-dependent and caspase-independent apoptosis sig- severe AA treated systemically with CyA at a dose of
28.3 Cyclosporin A in AGA/FPHL 111
3–5 mg/kg for 6 months, as well as during their 3-month

follow-up after CyA discontinuation [37]. Jang et al. [38] Given its highly lipophilic nature, cyclic molecular
compared CyA and betamethasone minipulse therapy on 88 structure, and large molecular weight, the transcutane-
AA patients who received at least 3 months of oral CyA ous permeation of CyA is challenging, explaining the
(n = 51) or betamethasone minipulse therapy (n = 37). They failure to produce clinically acceptable results in the
reported a 54.9% response in the CyA (vs. betamethasone treatment of alopecias by topical administration [45].
37.8%), with patients with mild AA responding better and
with a 70.6% positive patient self-assessment in the CyA
group (vs. betamethasone 43.2%) [38]. Açıkgöz et al. [39] Various vehicles and enhancers on the topical delivery
evaluated the efficacy of oral CyA in 2.5–6 mg/kg/day doses across rat or human skin have been tested [46], with liposo-
for 2–12 months on 22 young male patients (mean age matic formulations of CyA being the most widely researched
21.92 ± 3.56) with severe AA and reported significant hair [47]. However, the beneficial effect of topical application is
growth in 10 (45.4%) patients, with shorter disease duration very limited in both AA and AGA, and efforts to treat AA or
correlating positively with better treatment response [39]. AGA with a topical CyA solution were unsuccessful, also
Overall, the success rate of oral CyA in AA ranges from due to the limited bioavailability of CyA.
25% to 76.7% in published studies. Notably, CyA has not Mauduit et al. [48] treated 14 patients with severe AA
been found to “protect” patients from developing AA since (ranging from bald plaques to alopecia universalis) for
AA has been reported in several organ transplant patients 6 months with topical CyA and although no CyA was
already into chronic CyA treatment [40]. detected in the patients’ serum. Only three patients demon-
Nowaczyk et al. [41] conducted a retrospective system- strated moderate hair growth, being the less severe cases,
atic review to investigate the efficacy of CyA with and with- with only bald plaques [48]. Gilhar et al. [49] conducted a
out systemic corticosteroids for AA. Fourteen papers were small double-blind trial on 10 subjects with AGA treated
eligible for the systematic review, including 340 reported with 5% CyA and three control patients treated with olive oil
cases. The authors concluded that CyA in combination with for 4 months. Hair growth was evaluated by photographs and
oral systemic corticosteroids is more effective than in mono- hair counts and showed that only two of eight patients in the
therapy for severe AA [41]. active group who completed the study had any measurable
hair growth, and only in one patient was hair growth cos-
metically satisfactory [49]. In another study by Lutz et al.
28.3 Cyclosporin A in AGA/FPHL [50], topical 0.1% CyA solution was used on 10 males with
AGA and showed no change in hair counts after 4 months of
While oral CyA has demonstrated low to moderate success treatment [50]. According to Alkhalifah et al. [51], oral CyA,
in AA, it has failed in treating patients with AGA/ even though unable to modify the natural history of AGA, it
FPHL. Picascia et al. published in 1987 a case-report of a 48 does have some hair growth effect on the rest of the body,
year old male with chronic psoriasis and stage II AGA, who which is not linked to any hormonal action [51].
was treated with CyA and grew back the hair in his temples, Fernandes et al. [45] investigated the skin permeation
which were lost upon CyA discontinuation [42]. The same potential of CyA-loaded poly(d,l-lactide) (PLA) nanoparti-
research team failed to demonstrate hair-growth effects in a cles in ex vivo porcine skin. These nanoparticles had good
small study of oral vs. topical CyA in men with AGA [43]. physicochemical stability and good storage stability for over
Green and Sinclair reported a 41-old male with severe pso- 6 months since no significant changes were observed in their
riasis who received 250 mg oral CyA daily and grew signifi- main physical and chemical properties. The authors reported
cant body hair that required regular trimming. However, his an increased CyA skin permeation/hair follicles accumula-
AGA progressed from stage III to stage VI during the 5 years tion compared with a noncolloidal formulation. CyA bio-
of high oral dose CyA treatment [44]. This demonstrated that compatibility in NCTC2455 keratinocytes (reference skin
CyA could not modify AGA’s natural history and could not cell line) was clearly improved when encapsulated in PLA
benefit AGA/FPHL patients. nanoparticles. In vitro studies suggested that nanoparticles
The severe side effects of long-term systemic administra- will not present toxicity to the skin and will maintain a sus-
tion of CyA (e.g., nephrotoxicity) forced researchers to tained release of the drug for over 48 h, prolonging its thera-
explore topical delivery options, hoping to treat autoimmune peutic effect. The authors considered that in vivo investigation
skin disorders safely. Unfortunately, the skin application of of these CsA-loaded PLA nanoparticles might evolve into a
CyA has produced inconsistent results. promising new strategy to treat alopecias [45].
112 28 Cyclosporin
On a final note, in the recent (2017) systematic review 4. Page EH, Wexler DM, Guenther LC. Cyclosporin A. J Am Acad
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27. Lan S, Liu F, Zhao G, Zhou T, et al. Cyclosporine A increases cia. Arch Dermatol. 1987;123:1432.
hair follicle growth by suppressing apoptosis-inducing factor 43. Picascia DD, Roenigk HH Jr. Effects of oral and topical cyclospo-
nuclear translocation: a new mechanism. Fundam Clin Pharmacol. rine in male pattern alopecia. Transplant Proc. 1988;20(3 Suppl.
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cyclosporine A. Dermatology. 1999;199(1):67–9. enhancers on the topical delivery of cyclosporin A. Int J Pharm.
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Cyproterone Acetate (CPA)
29
tions of the USA and Japan. In the USA, CPA is available

Basic Concepts only as an orphan drug for the treatment of hirsutism since
• Cyproterone acetate (CPA) is a powerful antiandro- the FDA has not approved it yet.
gen with potent progestogen and antigonadotropic CPA is the progestogen with the highest anti-androgenic
properties that directly competes with testosterone activity and is therefore used exclusively in women. In
and DHT for the occupation of the androgen recep- women of child-bearing potential, estrogens, such as Ethinyl
tor in target tissues. Estradiol (EE), are usually given with CPA to ensure regular
• CPA is one of the most frequently used antiandro- menses. This scheme is necessary since CPA is a known
gens in Europe but is not available in the USA. It is teratogen, and pregnancy during treatment would carry a
used exclusively on women, mostly in combination very high-risk of male fetus feminization [2]. CPA 2 mg + EE
with oral contraceptive treatment on certain days of 35 μg is marketed under the brand name Diane-35®, which
the menstrual cycle (Hammerstein regimen), since replaced the older formulation of CPA 2 mg + EE 50 μg
it is a potent teratogen. (Diane-50® or Dianette). Diane-35® has fewer adverse effects
• CPA has been used in FPHL, even though its effi- and similar anti-androgenic efficacy to the previous formula-
cacy is considerably limited compared to other tion [3]. Diane-35® is often used for treating acne in women
compounds, and is probably more helpful in women but has also been utilized for treating other androgen-based
with hyperandrogenism. Topical CPA treatment conditions, such as hirsutism and FPHL.
might be promising when incorporated in an effi-
cient skin delivery vehicle.
29.1 Mechanism of Action
• Adverse effects are frequent but rarely severe, the
long-term safety is satisfactory, but all forms of
CPA acts through several mechanisms. CPA has moderate
administration of CPA to men are strictly forbidden
anti-gonadotropic and potent progesteronic properties. It
for the treatment of AGA because of the potent anti-
inhibits the gonadotropin-releasing hormone (GnRH) and
androgenic, castrating-like effects. In women under
effectively depresses the production of androgens by the
chronic CPA treatments, Fe, ferritin levels, and Vit
adrenals and ovaries. CPA acts by decreasing the release of
B12 should be frequently tested and supplemented
luteinizing and follicle-stimulating hormones through
is necessary.
pituitary-mediated suppression [4]. Moreover, it competi-
tively inhibits the binding of Testosterone (T) and dihy-
drotestosterone (DHT) on the cytosolic androgen receptor
Cyproterone acetate (CPA) is a very potent synthetic analog (AR) and prevents the transfer of the AR-T complex or the
of progesterone, classified as a progestin. It was discovered AR-DHT complex into the cell nucleus [5]. More specifi-
in 1962 by the German company Schering. CPA was devel- cally, CPA binds to the AR with an affinity of 6–21% com-
oped from 17α-hydroxyprogesterone, and it is estimated to pared to T and competes with other androgens for binding on
be approximately 1200 times more potent as an antiandrogen the intracellular AR [6]. It decreases the activity of the
than 17α-acetoxyprogesterone [1]. CPA is marketed under 5α-Reductase enzymic system in the skin, a common prop-
the brand name Androcur® since 1964. It is currently used erty of all progesteronic antiandrogens [1, 7] and accelerates
widely in most countries, representing the first specific anti- the metabolic inactivation of T due to a partial enzymatic
androgen of clinical interest, with the notable major excep- inducer effect on the liver [8]. Absorption of CPA is poor
116 29 Cyproterone Acetate (CPA)
after oral dosing (5–30%), peak plasma concentration is for FPHL, which is hosted in the Cochrane database of sys-
reached in 4 h, bioavailability is ≈90%, and serum half-life tematic Reviews [19], there are no extensive or high-quality
is ≈38 h [9, 10]. studies on the efficacy of CPA in FPHL available.
All these properties render CPA one of the most potent Ekoe et al. [20] administered CPA combined with EE
antiandrogens. between days 5 and 15 of the menstrual cycle in 60 females
(mean age 25 years) suffering from hirsutism, acne, and
FPHL. Treatment was administered for various periods
29.2 Uses of CPA among patients, ranging between 3 and 39 months. The suc-
cess rate was 94% for acne, 85% for hirsutism, and just 55%
CPA has been introduced in clinical practice since 1964 and for FPHL. Side effects were rare and similar in frequency
is the first example of an antiandrogen designed explicitly and nature to those encountered during treatment with
for clinical use against androgen-dependent conditions [11]. estrogen-only containing contraceptives [20]. Dawber et al.
Clinical indications of CPA include contraception, hirsutism, [21] examined 29 women with FPHL and suggested a mini-
acne, seborrhea, polycystic ovaries, FPHL, prostate cancer, mally effective dose of CPA. Twenty-four of twenty-nine
precocious puberty, male hypersexuality, and sexual devia- women had improvement in FPHL when treated with 50 μg
tions [12, 13]. It is the most commonly used antiandrogen for EE and 200 mg CPA daily, but 14 of 17 who remained on
the treatment of hirsutism in Europe, almost always com- Diane® (2 mg CPA) failed to maintain that response [21].
bined with oral contraceptive treatment [14]. In the treatment In a small-scale, 12-month long study by Peereboom-
of acne, CPA results in responses as high as 100% at doses Wynia et al. [22], CPA 2 mg + 50 μg EE was administered
considerably lower than those required for hirsutism, and the daily and an additional 20 mg CPA on days 5 to 20 of the
results become evident in 3–6 months after treatment onset menstrual cycle on 20 women with FPHL, while the control
[4, 15]. Although CPA has not been approved by the FDA for group (n = 8) received no treatment. The parameters used to
the treatment of hirsutism due to its potential cardiovascular evaluate therapeutic results were trichogram, anagen hair
and hepatotoxic adverse effects, its off-label use in FPHL is shaft diameter, and the number of hairs measuring <40 μm.
nonetheless recommended by prominent specialists [16]. At study completion, there was a statistically significant
Hammerstein was the first to describe the use of CPA for increase in anagen hair follicles, a corresponding decrease in
anti-androgenic indications, combining CPA with EE, back telogen ones, a reduction of dysplastic forms, and an increase
in 1969. in the mean caliber of anagen hairs. Reported trichogram
data showed a mean change in anagen percent from 49.7% at
baseline to 74.4% after 1 year in the treated group compared
The original “Hammerstein regimen” included
to a drop from 60.4% to 48.8% in controls. However, the
50–100 mg/day of CPA from the 5th to the 15th day of
study’s serious flaws include that subjects were not random-
the menstrual cycle, for a 6-month period, which is the
ized to treatment or control groups, and hair counts were not
period required for the initial glucocorticoid
performed [22].
suppression.
Mortimer et al. [23] reported a positive response to treat-
ment with cyclical antiandrogen therapy with CPA for
An alternative regimen utilizes CPA 2 mg/day from the 42 weeks in three women with established FPHL of 2, 13,
first day of the menstrual cycle to the 21st, with a week of and 23 years duration. All three patients showed an increase
rest, for 18 additional months [17]. There have been many in hair density (hairs/cm2), in the percentage of hair in ana-
modifications with lower CPA doses or Hammerstein reverse gen, and in the number of hairs greater than 40 μm diameter/
sequential regimens, and all seem to have varying efficacy, cm2 (meaningful density) after 24–28 weeks. Three control
depending on several endocrinological parameters. However, patients who were left untreated for 26 weeks showed no sig-
the original “Hammerstein regimen” is considered the most nificant improvement in any of these parameters [23].
efficacious treatment for FPHL, according to Camacho [18]. Rushton et al. [24] treated 20 women between 18 and
47 years of age who presented with diffuse androgen-
dependent alopecia for 12 months. They administered a
29.3 CPA and FPHL reverse sequential regimen of CPA 50 mg/daily from day 5 to
day 15 and EE 30 μg/daily from day 5 to day 24 of the men-
The few existing studies addressing the therapeutic efficacy strual cycle. Another 20 women were left untreated, serving
of CPA to treat FPHL are controversial, even though research as controls, and half of the patients in each group had serum
on the field dates back to 1980. CPA is generally less effec- ferritin concentrations above or below 40 μg/L, comprising
tive in managing FPHL than hirsutism. According to Van altogether four groups that were investigated. In the treated
Zuuren et al.’s [19] thorough meta-analysis on interventions groups, a significant (p < 0.01) mean increase in total hair
29.3 CPA and FPHL 117
density (16.8% ± 3.3 hair/cm2, SEM, mean + standard error or absence of other hyperandrogenism symptoms, whereas in
of the mean) and meaningful hair density (19.9% + 2.9 non- the MTS group, the total number of new hairs was higher in
vellus hair/cm2) was found in patients in whom the serum patients with isolated alopecia (p < 0.05) [28].
ferritin was above 40 μg/L. In contrast, significant (p < 0.05) Sinclair et al. [29] conducted an open-label, single-center
decreases in total hair density, and meaningful hair density study, including 80 women, aged 12–79 years, with biopsy-
were found in both control groups 12 months later, repre- confirmed FPHL, who received 12 months of oral antiandro-
senting decreases of 6.7% ± 2.6 and 8.9% ± 3.1 for total hair gen therapy. Forty women received Spironolactone 200 mg/
density in controls with serum ferritin levels above and day, and 40 women received CPA, either 50 mg daily or
below 40 μg/L, respectively. The mean decreases of mean- 100 mg for 10 days per month, if premenopausal. According
ingful hair density were 6.9% ± 3.1 and 10.2% ± 4.3 in con- to standardized photographs evaluated by three blinded
trols with serum ferritin levels above and below 40 μg/L, experienced clinicians, there was no significant difference in
respectively. The authors demonstrated that CPA can be use- the results between Spironolactone and CPA. However, the
ful in FPHL and that patients treated with the CPA and EE authors reported that 44% (n = 35) of patients experienced
responded best when serum ferritin was above 40 μg/L [24]. visible hair growth, another 44% (n = 35) had no evident
Minozzi et al. [25] conducted a 12-month long, random- change in hair density before and after treatment, and only
ized, active-controlled trial on 63 postmenopausal women 12% (n = 10) had reduced hair density. Predictors of response
(52–63 years old) with excessive hair loss, randomized into revealed no influence of patient age, menopause status,
three groups (group I = 21, group II = 21, group III = 21). serum ferritin, serum hormone levels, clinical stage (Ludwig),
Group I and II received oral and transdermal contraceptives, or histological parameters. The only significant predictor
respectively, while group III received a modified was midscalp clinical grade, with higher-scale values associ-
Hammerstein regimen of 12.5 mg of CPA + EE 20 μg/daily ated with a greater response (p = 0.013) [29].
from day 1 to day 25 of the menstrual cycle. Women in A more recent retrospective study by Κarrer-Voegeli et al.
group I had the greatest trichogram changes, with baseline [30] compared the action of common antiandrogens in 228
percentage values of anagen 74.1 ± 4.6 and telogen consecutive female patients with signs of hyperandrogenism
23.7 ± 3.8 reaching 85.2 ± 3.6 and 14.0 ± 4.1, respectively investigated over 6 years. They reported that CPA lowered
after 12 months (all p < 0.05) [25]. Carmina et al. [26] con- the hirsutism score to 53.5% of baseline at 1 year and effec-
ducted a randomized, unmasked trial in 48 hyperandrogenic tively treated acne and alopecia, but they did not include fur-
women with alopecia (mean age 30 years), testing the effi- ther details [30]. The latest report on the use of CPA in FPHL
cacy of three treatments in 36 women and observing 12 is the open trial by Kapadia et al. [31], which included 26
untreated women with similar hyperandrogenic signs. CPA females with FPHL, aged 20–54 years. It was a six-month
(50 mg) with EE in a reverse sequential regimen, Flutamide open trial of 2 mg CPA and 35 μg ethinyl estradiol (Diane35®)
(250 mg) or Finasteride (5 mg) daily, all were administered for 21 days of each cycle and 50 mg CPA for 10 days along
for 1 year in 12 women each. Results showed that only with Diane35® and 5% MTS 1 mL twice daily for all days of
Flutamide resulted in a reduction of 21% in Ludwig scores, treatment. Subject assessment of improvement was rated at
while CPA resulted in a reduction of 10%, which was con- the completion of treatment by a questionnaire filled by the
sidered not statistically significant [26]. Another study by patient and by clinical examination by the dermatologists
Brzezinska-Wcislo et al. [27] included 25 FPHL patients (authors). Twenty-two patients completed the study, and sig-
(aged 31–35), demonstrated that Diane-35® administered nificant regrowth was noticed on 16 (72%) in the frontal area
for 6–9 months significantly reduced hair loss, hair thinning and 11 (50%) in the vertex area. Six (27%) patients in the
and seborrhea, while increasing scalp coverage [27]. frontal area and 11 (50%) in the vertex had no clear differ-
The most thorough and extensive study on the efficacy of ence after treatment. Both treatment regimens were well-
CPA in FPHL is the randomized, 12-month long, controlled tolerated, with four drop-outs due to adverse effects [31].
study by Vexiau et al. [28] in a total of 66 women with
FPHL. The authors compared the hair growth effects of CPA
50 mg + EE 35 μg for 20 of 28 days, CPA 2 mg for 21 of It appears that the balance of evidence supports a role
28 days (n = 33), and 2% Minoxidil topical solution (MTS) in for CPA in FPHL. According to most experts, further
association with combined oral contraceptive consisting of EE research would be necessary to clarify whether CPA
30 μg and gestodene 75 μg/day for 21 of 28 days (n = 33). They has a more significant role in those patients with evi-
reported a mean reduction of 2.4 ± 6.2 per 0.36 cm2 in hairs of dence of hyperandrogenism [32]. Treatment doses
diameter > 40 μm observed in the CPA group (p = 0.05) and a vary, but it appears the most effective scheme is
mean increase of 6.5 ± 9 per 0.36 cm2 in the MTS group 100 mg/day on days 5–15 of the menstrual cycle sup-
(p < 0.001). No significant difference was observed in the total plemented by 50 μg EE on days 5–25.
number of hairs among CPA patients according to the presence
In the recent (2018) systematic review (evidence-based lation capacity in hair follicles. This could be a promising
(S3) guideline for the treatment of FPHL in women and topical novel drug delivery system for specific targeting of
AGA in men) issued for the European dermatology forum, hair follicles and sebaceous glands to treat androgenic skin
Kanti et al. commented that in subgroup analysis, patients disorders such as acne, hirsutism, and alopecia [39].
having clinical signs of hyperandrogenism who were treated However, to date, there is no data on the use or efficacy of
with CPA, tended to show increased hair counts at month 12 any kind of topical CPA formulation in FPHL.
compared to those without hyperandrogenism, although the
results were not statically significant. Consequently, there is
insufficient evidence that CPA prevents progression or 29.5 Adverse Effects
improves FPHL, but subgroup analysis suggests improve-
ment of FPHL in female patients with hyperandrogenism CPA can cause feminization of a male fetus and is therefore
[33]. Therefore, the authors stated that they could make a listed as pregnancy category X. Thus, an effective means of
recommendation for the use of oral CPA to improve or pre- contraception must be in place at the time of initiating treat-
vent the progression of AGA in normoandrogenic female ment. In postmenopausal and hysterectomized women, CPA
patients. can be administered in doses of 50 mg as monotherapy con-
tinuously, unlike women of child-bearing potential who must
use it intermittently [40].
29.4 Topical CPA Solution The use of the CPA-EE combination by women of repro-
ductive age is generally safe and does not affect the bio-
The anti-androgenic effects of topical CPA ethanol solu- chemical test values, nor does it induce tachyphylaxis or
tions have been demonstrated both in lab animals and tolerance after long-term use, according to a study of van
humans but not directly on patients with FPHL. Ebling Wayjen et al. [41] in 143 of a total group of 188 women
et al. [34] reported that the daily application of a topical treated from 1968 to 1995 with CPA as monotherapy [41].
ethanol CPA formulation significantly reduced sebum pro- However, it is necessary to exercise caution when adminis-
duction on the treated flank organ of rats but not on the tering CPA to women with predisposing risk factors for
contralateral side, thus excluding a systemic effect [34]. thromboembolism. CPA increases fourfold the risk of venous
The first attempts to treat acne using topical CPA in humans thromboembolism in women taking oral contraceptives con-
failed because the vehicles used (alcohol, DMSO) were not taining CPA compared to levonorgestrel [42].
suitable for adequate transdermal delivery [35]. At the same Adverse events are recorded in approximately 20–30%
time, there was indirect evidence that the action of CPA on of cases, with most being mild and transient. The side effect
the skin was due to a liver metabolite of CPA, rather than profile of long-term use of CPA includes menstrual distur-
CPA itself. CPA 1% solution did not decrease the sebum bances, weight gain, loss of libido, depression, mood
excretion rate (SER) when applied to the forehead skin of swings, fatigue, hypertension, breast tenderness (30%),
acne patients, although SER was reduced when the drug headaches (20%), and gastrointestinal upsets [21, 43]. A
was given systemically [36]. decrease in libido (10%) has been reported in women with
Ekerdt et al. [37] conducted a study on lab animals and hyperandrogenism under CPA treatment [44], although an
discovered that the addition of isopropylmyristate 5% in an extensive study by Adamopoulos et al. questioned these
ethanol solution increased CPA absorption from 0.6% to results [45].
7.8% [37]. Gruber et al. [38] conducted a 3-month long, The most serious potential side effect of CPA is hepato-
placebo- controlled trial on 40 women with moderate to toxicity, and it is most common in elderly patients who are
severe acne. Topical CPA was administered in a liposomatic treated with high doses of the drug for prolonged periods.
carrier in a group of 12 women with acne, oral CPA was The risk of hepatotoxicity and death associated with CPA
administered in another group of 12 women, and 16 women treatment is reportedly the reason that the FDA has not
received a placebo liposomatic cream. The efficacy and clin- approved CPA for use in the United States. However, in a
ical response of liposomatic CPA were comparable to that of multicenter surveillance study of long-term CPA use in 2506
oral CPA. In addition, the risk of adverse effects was reduced, patients for 50 months (11,000 patient-years), not a single
and high serum CPA concentrations were avoided since case of hepatocellular carcinoma or benign of proliferative
serum concentration of topical liposomatic CPA was only liver change has been observed [46]. CPA is contraindicated
10% of the oral administration [38]. in liver disease, in past thromboembolic disease, and in
Ghasemiyeh et al. [39] experimented with nanostructured smokers, while less strict contraindications apply in obese
lipid carriers (NLCs) of different size ranges to enhance skin patients. Moreover, long-term use of CPA, in the form of
penetration and target hair follicles. Follicular targeting Diane-35®, increases glucose tolerance, thus partially impair-
results revealed that NLC at 300 nm had the highest accumu- ing insulin secretion from the pancreas [47].
References 119
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FSH and LH synthesis and release, demonstrating a stronger lism in hirsute patients treated with cyproterone acetate. J Steroid
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gestagen effect than the antiandrogen effect of CPA. There is
9. Humpel M, Wendt H, Schulze PE, Dogs G, Weiss C, Speck
an even greater reduction in plasma T and DHT levels since U. Bioavailability and pharmacokinetics of cyproterone acetate
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libido occurs more rapidly under CPA treatment than even nation with 50 micrograms ethinyloestradiol to 6 young women.
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after surgical castration [50], and spermatogenesis is fully
10. Huber J, Zeillinger R, Schmidt J, Tauber U, Kuhnz W, Spona
inhibited, inducing infertility in all mammalian species, J. Pharmacokinetics of cyproterone acetate and its main metabolite
including humans [51]. 15 beta-hydroxy-cyproterone acetate in young healthy women. Int
Other adverse effects include muscle loss, fatigue, masto- J Clin Pharmacol Ther Toxicol. 1988;26:555–61.
11. Hammerstein J, Meckies J, Leo-Rossberg I, Moltz L, Zielske F. Use
dynia, nausea, and weight gain, while there are reports of
of cyproterone acetate (CPA) in the treatment of acne, hirsutism
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Steril. 2002;77(5):919–27.
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tive compared to MTS 5%. In a single case study that was 14. Camacho-Martínez FM. Hair loss in women. Semin Cutan Med
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conducted, a male volunteer received both treatments, grew
15. Pugeat M, Nicolas MH, Dechaud H, Elmidani M. Combination
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though CPA treatment was continued [54]. ment of Hirsutism. J Gynecol Obstet Biol Reprod (Paris).
1991;20(8):1057–62.
16. Olsen EA, Messenger AG, Shapiro J, Bergfeld WF, Hordinsky
Synopsis
MK, Roberts JL, Stough D, Washenik K, Whiting DA. Evaluation
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the evidence that it prevents progression or improves FPHL Dermatol. 2005;52(2):301–11.
is insufficient. The studies addressing its therapeutic efficacy 17. Hammerstein J, Cupceancu B. Management of hirsutism using
cyproterone acetate. Dtsch Med Wochenschr. 1969;94(16):829–34.
to treat FPHL are very few and controversial. Subgroup anal-
18. Camacho F. Tratamiento del hirsutismo. Actas Dermosifiliogr.
ysis suggests that CPA can be effective in FPHL in women 2006;97(Suppl. 1):33–44.
with hyperandrogenism and high ferritin levels, although 19. van Zuuren EJ, Fedorowicz Z, Schoones J. Interventions
adverse effects are frequent. More extensive studies are for female pattern hair loss. Cochrane Database Syst Rev.
2016;26(5):CD007628.
needed to confirm whether CPA can improve FPHL, regard-
20. Ekoe JM, Burckhardt P, Ruedi B. Treatment of hirsutism,
less of hormone levels. The topical use of CPA in liposo- acne and alopecia with cyproterone acetate. Dermatologica.
matic carriers may have positive results without the adverse 1980;160(6):398–404.
systemic effects of CPA. However, there is no clinical expe- 21. Dawber RP, Sonnex T, Ralfs I. Oral antiandrogen treatment of com-
mon baldness in women. Br J Dermatol. 1982;107(Suppl):20–1.
rience in the use of topical CPA in FPHL or AGA. The use of
22. Peereboom-Wynia JD, van der Willigen AH, van Joost T, Stolz
oral CPA on men with AGA is strictly forbidden. E. The effect of cyproterone acetate on hair roots and hair shaft
diameter in androgenetic alopecia in females. Acta Derm Venereol. 39. Ghasemiyeh P, Azadi A, Daneshamouz S, Heidari R, Azarpira N,
1989;69(5):395–8. Mohammadi-Samani S. Cyproterone acetate-loaded nanostruc-
23. Mortimer CH, Rushton H, James KC. Effective medical treat- tured lipid carriers: effect of particle size on skin penetration and
ment of common baldness in women. Clin Exp Dermatol. follicular targeting. Pharm Dev Technol. 2019;24(7):812–23.
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24. Rushton DH, Ramsay ID. The importance of adequate serum fer- JL, Rapini RP, editors. Dermatology. 2nd ed. London: Mosby Ed;
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treatment of diffuse androgen-dependent alopecia in women. Clin 41. van Wayjen RG, van den Ende A. Experience in the long-term
Endocrinol (Oxf). 1992;36(4):421–7. treatment of patients with hirsutism and/or acne with cyproterone
25. Minozzi M, Unfer V, Constabile L. Alopecia androgenetica in post– acetate-containing preparations: efficacy, metabolic and endocrine
menopausa. G Ital Ostet e Ginecol. 1997;19(6):341–4. effects. Exp Clin Endocrinol Diabetes. 1995;103(4):241–51.
26. Carmina E, Lobo RA. Treatment of hyperandrogenic alopecia in 42. Vasilakis-Scaramozza C, Jick H. Risk of venous thromboembo-
women. Fertil Steril. 2003;79(1):91–5. lism with cyproterone or levonorgestrel contraceptives. Lancet.
27. Brzezinska-Wcislo L. Assessment of efficacy of Diane-35 in andro- 2001;358:1427–9.
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28. Vexiau P, Chaspoux C, Boudou P, Fiet J, Jouanique C, Hardy N, women. Curr Pharm Des. 1999;5(9):707–23.
Reygagne P. Effects of minoxidil 2% vs. cyproterone acetate treat- 44. Appelt H, Strauss B. Effects of antiandrogen treatment on the sexu-
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domized trial. Br J Dermatol. 2002;146(6):992–9. 1984;42(1–4):177–81.
29. Sinclair R, Wewerinke M, Jolley D. Treatment of female pattern hair 45. Adamopoulos DA, Kampyli S, Georgiacodis F, Kapolla N,
loss with oral antiandrogens. Br J Dermatol. 2005;152(3):466–73. Abrahamian-Michalakis A. Effects of antiandrogen-estrogen treat-
30. Karrer-Voegeli S, Rey F, Reymond MJ, Meuwly JY, Gaillard RC, ment on sexual and endocrine parameters in hirsute women. Arch
Gomez F. Androgen dependence of hirsutism, acne, and alopecia Sex Behav. 1988;17(5):421–9.
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loss. J Pak Assoc Dermatol. 2009;19:216–9. tive ethinylestradiol (30 microg) and dienogest (2 mg) on carbohy-
32. Dinh QQ, Sinclair R. Female pattern hair loss: current treatment drate metabolism during 1 year of conventional or extended-cycle
concepts. Clin Interv Aging. 2007;2(2):189–99. use. Horm Metab Res. 2010;42(5):358–63.
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34. Ebling FJ, Randall VA, Skinner J. Local suppression of sebum Suppl):S70–80.
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placebo-controlled trial. Arch Dermatol. 1998;134(4):459–63.
Topical Corticosteroids
30
pounds A to F, according to the chronological order of their

Basic Concepts discovery. He distinguished compound E as a molecule with
• Topical corticosteroids (TCs) are the most exten- “…significant anti-rheumatic properties…” That molecule
sively prescribed compounds in Dermatology, and was named cortisone, and in September 1948, cortisone was
their clinical utility and value are immeasurable. the first glucocorticoid ever to be administered to a patient
• Despite their minimal transcutaneous absorption with rheumatoid arthritis [2], a condition that remained
(0.05%–0.3%), all TCs, ranging from weak to very incurable.
potent, are associated with local and systemic The anti-inflammatory action of cortisone proved
adverse effects and must be administered judi- impressive, and in September 1949, cortisone was launched
ciously and only when indicated. as a pharmaceutical compound by Merck & Company.
• The efficacy of TCs as monotherapy in Alopecia Kendall and his associates, Hench and Reichstein, were
Areata is highly debated, while the application of rightfully awarded the Nobel prize in Physiology-Medicine
TCs on patients with AGA or FPHL has neither in 1950 for having discovered the adrenal cortex hormones,
documented positive effects on the parameter of their chemical structure, and, most importantly, their prop-
micro-inflammation in AGA nor will it halt hair loss erties. The most valuable among these hormones is corti-
nor grow new hair. sone [3].
• Mixing MTS with TC lotions will result in dilution
of both solutions to sub-therapeutic concentration
levels and should not be prescribed to any patient 30.1 The Chemical Structure
with AGA or FPHL since it is undocumented. of Corticosteroids
Corticosteroids have a basic skeletal structure comprising of

If It’s Dry, Wet It; 17 carbon atoms arranged in 4 rings: three rings of six carbon
If It’s Wet, Dry It; atoms (A, B, C) and one ring of five carbon atoms (D)
If you don’t know what it is, (Fig. 30.1). Minor modifications of this basic steroid struc-
use steroids [1].
ture have led to compounds with varying potencies and
In 1849, Thomas Addison discovered the link between adverse effects. Further modifications to the cortisone mole-
chronic insufficiency of the adrenals and certain—unclear at cule, such as the insertion of double bonds and fluoro groups
the time—systemic features. This condition was later named at positions 6 and/or 9, have led to the synthesis of more
Addison’s disease, but the mechanism of this deadly condi- potent, synthetic corticosteroids, characterized by a consis-
tion remained elusive. By 1894, other researchers concluded tently stronger mineralocorticoid activity, which was not,
that the adrenal cortex produced a hormone, which they however, desirable. The addition of α-hydroxyl, α-methyl, or
named cortin. During the 1930s, Edward Calvin Kendall, a β-methyl group in position 16 eliminated this problem, and
researcher at Mayo Clinic, isolated six different substances newer corticosteroids have more targeted glucocorticoid and
produced by the adrenal cortex, which he coined as com- fewer mineralocorticoid properties.
122 30 Topical Corticosteroids
12 Table 30.1 Vasoconstrictor potency of nine common TCs compared to

17 fluocinolone acetonide, which has been assigned with the arbitrary
13 value 100. (From Wilson [17])
11
Topical corticosteroids Vasoconstrictor potency
C D 16 Fluocinolone acetonide 100
1 9 Hydrocortisone <1
Betamethasone <1
10 8
2 14 Flurandrenolone 46
15 Triamcinolone acetonide 75
Clobetasone butyrate 263
A B
5 Betamethasone valerate 360
3 7 Fluoclorolone acetonide 413
Clobetasol propionate 1869
4 6
The principal functions of the GR are transactivation,
Fig. 30.1 Basic stereochemical structure of corticosteroids DNA binding, and ligand binding processes localized in
specific genome domains. The GR is maintained inside the
cytoplasm as an inactive multi-protein complex consisting
30.2 Topical Corticosteroids (TCs) of heat shock proteins, immunophilins, cyclophilins, and
calreticulin. When cortisol (or a synthetic steroid) binds to
To take advantage of the impressive anti-inflammatory prop- the GR, the complex is activated, it dissociates, and the
erties of corticosteroids on a local scale, transcutaneously receptor migrates to the nucleus. There, it binds to DNA
absorbed corticosteroids had to be synthesized, which would sequences known as glucocorticoid response elements
have optimized potency and minimal adverse effects [4]. (GREs), causing upregulation or downregulation of respon-
Initially, cortisone was devoid of local skin activity [5], but sive genes.
the simple reduction of the carbonyl group on position 11 led It is widely accepted that the potent anti-inflammatory
to the synthesis of hydrocortisone [6], which remains one of and immunomodulatory actions of corticosteroids are based
the most commonly prescribed topical corticosteroids (TCs). on the inhibition of transcription factors, such as NF-κB and
The advent of TCs in Clinical Dermatology increased the activator protein-1, which are involved in the activation of
therapeutic potency of Dermatologists tremendously. pro-inflammatory genes. Examples of genes that are upregu-
lated by corticosteroids and are involved in the resolution of
In just a few days of treatment, patients suffering from the inflammatory process are lipocortin I and the p11/
previously severe, extensive, incapacitating, chronic calpactin-binding protein, which play a role in suppressing
inflammatory dermatoses were transformed from arachidonic acid release [9, 10] Lipocortin I inhibits phos-
exhausted, persistently itchy, social cripples into indi- pholipase A2, decreasing the amount of arachidonic acid
viduals leading a normal life, even if periodically still released from phospholipids [11, 12]. Corticosteroids also
troubled by their condition. reduce the release of interleukin IL-1α from keratinocytes
[13], an important pro-inflammatory cytokine.
TCs possess all the properties of systemic corticosteroids
and can even exert additional skin actions since they exhibit
30.3 Actions of Corticosteroids antimitotic and vasoconstrictive effects. The antimitotic
effects are secondary to the general reduction of protein syn-
Corticosteroids act on most tissues, on various cell types in thesis, which may explain the therapeutic action of TCs in
each tissue, and both on a cellular and intracellular level. scaling dermatoses, such as psoriasis [14, 15]. The vasocon-
Natural cortisol controls the intermediary carbohydrate, pro- strictive properties have been demonstrated on vascular beds
tein, and lipid metabolism, and affects numerous enzyme sys- and may contribute to the anti-inflammatory activity of TCs.
tems, while it also acts on electrolyte and water metabolism. However, even though the mechanism used by corticoste-
Its effect on protein metabolism is antianabolic even though roids to induce vasoconstriction was initially observed and
the exact molecular mechanism of corticosteroids on gene measured by McKenzie & Stoughton [16] as early as 1962,
expression regulation is not fully known. However, we recog- and extensively assessed by Wilson [17], the exact mecha-
nize that the effects of corticosteroids on cells are mediated nism remains unclear (Table 30.1). The prevailing theory is
through the glucocorticoid receptor (GR), a protein consisting that TC-induced vasoconstriction is related to the inhibition
of 777 amino acids with a modular structure belonging to the of natural vasodilators, such as histamine, bradykinins, and
super-family of ligand-regulated nuclear receptors [7, 8]. prostaglandins [18, 19].
30.5 Systemic Adverse Effects of TCs 123
During the decades following the discovery of TC, scale, which consists of four (classes) categories: very potent,
researchers focused on finding ways to optimize the anti- potent, moderately potent, and mild [21].
inflammatory and immunomodulatory actions of TCs, paral-
lel to limiting their adverse effects.
30.4 Adverse Effects of TCs
Ideally, a TC should be readily absorbable by the skin,
Unfortunately, as is so frequently the case with “wonder
should retain high concentrations in the epidermis and
drugs,” corticosteroids would have some very unpleasant
dermis, without, however, being systemically absorbed,
side effects [22]. Initially, their “miraculous” therapeutic
while it should not induce topical or systemic adverse
potential led to uncritical overuse. As a result, severe prob-
effects.
lems emerged due to overdosing and “over-treatment” since,
during the first years of TC use, every skin problem was
Unfortunately, this ideal TC has not yet been found, and treated with TCs [23, 24] . Soon enough, the initial “cortico-
until today, the primary way to enhance the properties of TC worship” turned into “cortico-phobia” due to adverse
is to increase their lipophilicity via esterification. According effects, and it took years until physicians would avoid TCs
to the guidelines of care for the use of TCs of the American when not necessary and prescribe TCs only when needed
Academy of Dermatology American [20], there are seven [25]. TCs started to be used more judiciously, and indica-
groups of topical steroids according to potency, ranging from tions became clear. Notably, systemic absorption of TCs,
low potency (group VII) to ultra-high potency (group I) which does not generally exceed 0.05–0.3%, is sufficient to
(Table 30.2). Other countries use a similar classification cause topical and systemic adverse effects [26], which will
be further analyzed in detail.
Table 30.2 Relative potency (concentration as % weight/weight) of
topical corticosteroid formulations. (Adapted with permission from
Brazzini et al. [4]) 30.5 Systemic Adverse Effects of TCs
Potency, group Generic
Ultra high, Class I Augmented betamethasone Systemic adverse effects caused by TCs depend on the
dipropionate 0.05% amount of the compound, which is absorbed. The frequency
Clobetasol propionate 0.05%
and magnitude of adverse effects are strongly related to
Diflorasone diacetate 0.05%
Fluocinonide 0.1% many parameters, and the potency of the TC is probably the
Halobetasol propionate 0.05% most important one. Weak TCs (e.g., hydrocortisone) will
High, Class II Amcinonide 0.1% rarely cause systemic adverse effects compared to potent
Augmented betamethasone (e.g., triamcinolone acetonide) or very potent TCs (e.g., clo-
dipropionate 0.05% betasol propionate) [27]. Nonetheless, studies on the percu-
Betamethasone dipropionate 0.05%
taneous permeation of TCs are complex, and depend on
Desoximetasone
Diflorasone diacetate 0.05%
several skin parameters, as well as the composition of the TC
Fluocinonide 0.05% formulation, including, but not limited to the:
Halcinonide 0.1%
Medium to high, Class III Amcinonide 0.1% • potency of the TC [28],
Betamethasone dipropionate 0.05% • concentration of the active compound [29],
Fluticasone propionate 0.005% • excipients of the active compound [30],
Triamcinolone acetonide 0.5% • condition of the epidermal barrier [31],
Moderate potency, Class Betamethasone valerate
IV & V
• age of the patient [32],
Desoximetasone 0.05%
Fluocinolone acetonide 0.025% • size of the application area [33],
Fluticasone propionate 0.05% • open or under occlusion application [34],
Hydrocortisone butyrate 0.1% • presence or absence of local inflammation [35],
Hydrocortisone probutate 0.1% • frequency of application [36], as some active compounds
Hydrocortisone valerate 0.2% can modify their own absorption when applied repeatedly
Mometasone furoate 0.1% [37], e.g., salicylic acid increases its own absorption by its
Triamcinolone acetonide 0.025%
keratolytic action [37] and TCs do the same by causing
Triamcinolone acetonide 0.1%
Weak potency, Class VI Alclometasone dipropionate 0.05% epidermal thinning [38],
Desonide 0.05% • chemical details of the active compound, since the amount
Fluocinolone 0.01% of betamethasone 17-valerate found in circulation is
Hydrocortisone butyrate 0.1% 400% higher than plain betamethasone, even when the
Very weak potency, VI Hydrocortisone 1%, 2.5% same quantity has been applied [39],
amount of the drug applied, since clobetasol can induce Table 30.3 Principal systemic adverse effects associated with TCs
adrenal suppression even if applied in small amounts of [49–55]
<15 g/week, while optimized betamethasone dipropionate or Systemic, generalized adverse effects
difluorosone require over 50 g/week in order to reduce serum Suppression of HPA axis
cortisol levels significantly [40, 41]. Iatrogenic Cushing syndrome (Diabetes mellitus, Arterial
hypertension, edema, etc.)
Hypogonadism
Most TCs are absorbed in quantities that can produce Hypothyroidism
both systemic and topical adverse effects. Amenorrhea
Electrolytic imbalance—water balance disorders—swelling/edema
Weight gain—obesity
Information on the distribution of corticosteroids into Infection susceptibility
Growth disorders (children)
various tissues and body compartments has been obtained
Osteoporosis, tendon ruptures, necrosis of the femoral head
using labeled TC compounds, which permit radioactivity Gastrointestinal ulcers
measurement in body fluids [42, 43]. Maibach et al. [44] Stomatitis
measured the secretion of C14-labeled hydrocortisone and Cataracts, glaucoma deterioration, retinopathy
found extensive local absorption and renal elimination of Ectopic topical adverse effects
the compound [44]. Subsequent studies also proved that the Striae distense
stratum corneum acts both as a reservoir and as a barrier for Telangiectasia
Ectopic skin atrophy
the penetration of TCs [45, 46]. As far as the systemic
Dermatitis—folliculitis
adverse effects of TCs are concerned, these are primarily Ectopic acneic features
related to water/electrolyte balance, neoglycogenesis, and Tinea incognito, bullous impetigo
tissue repair, as well as an inhibitory effect on the HPA
axis.
In one of their first reports, Scoggins et al. [40] reported 30.6 Topical Adverse Effects of TCs
the suppression of the HPA axis and the reduction of nor-
mal endogenous cortisol levels in patients following the TCs will mostly cause local adverse effects, notably total
application of TCs [40]. Mizuchi et al. [26] reported that skin atrophy, i.e., atrophy of both the epidermal and dermal
3 ng/ml of betamethasone 17-benzoate induced over 90% component, resulting in skin appearing thin, shiny, and telan-
inhibition of plasma cortisol and that plasma betametha- giectatic. This local adverse effect was first observed as early
sone 17-benzoate levels ranged between 0.3 and 5 ng/ml, as 1950 during lab studies, showing that cortisone’s topical
indicating that no more than 0.05–0.3% of the amount application produced changes in the skin architecture of rats
applied to the skin was detected in plasma [26]. Application [57]. At first, it was speculated that well-known, marked ana-
of potent TCs under occlusion resulted in hyperglycemia tomic differences between rat skin and human skin, such as
and glycosuria in patients with pre-existing glucose intoler- the increased number of skin appendages and the absence of
ance [47], while Cushing syndrome has been reported after papillary dermis in rats, may have significantly affected the
treatment with TCs, even with open application [48]. Other reliability of the study [58]. Nevertheless, other researchers
common systemic adverse effects are listed in Table 30.3. considered unlikely that rodent skin behaved in a totally dif-
Adverse effects occurring in skin areas other than the appli- ferent way from human skin when treated with TCs and fur-
cation sites are considered ectopic topical adverse effects ther studied this “hot issue.” Initially, clinical reports
and are included in the systemic adverse effects list [56]. described skin atrophy occurring after months or years of
However, it must be emphasized that severe HPA axis sup- regular use of TC. However, it was later recognized that atro-
pression can be an actual threat when administering TCs phic changes may occur rapidly and quite early into treat-
only if these drugs are misused and not when used as ment and that many parameters can influence their
indicated. occurrence.
30.7 TCs and Alopecia Areata 125
Very frequently, skin atrophy can occur after just a few Table 30.4 Potential pathophysiological skin atrophy mechanisms
weeks of TC application, and some individuals are more induced by the use of TCs. (From Tan et al. [78])
prone to this adverse effect. Even very short-term therapeu- Epidermal thinning
tic regimens of just a few days may cause significant skin Antimitotic effect on epidermis [71]
atrophy in these individuals [59, 60]. Winter et al. [60] con- Anti-synthetic effect on epidermis [72]
Dermal papilla thinning
ducted an experimental study on 15 male volunteers and
Antimitotic effect on fibroblasts [79]
reported that daily application of fluocinolone acetonide Anti-synthetic effect on fibroblasts [70]
0.025% under occlusion to forearm skin could result in the Stimulation of collagenase [80]
loss of the granular layer thinning of the epidermis and the
disappearance of epidermal ridges and dermal papillae all
within seven days [60]. These results, that skin atrophy may Table 30.5 Ranking of the dermal thinning potential of the various
also be caused after short-term TC administration, were also preparations according to the mean percentage of thinning produced
after 6 weeks of treatment as determined by ultrasound and xeroradiog-
replicated and confirmed with labeled radioisotopes [61, raphy. (From Tan et al. [78])
62]. In another small-scale study, Jones investigated the
Topical corticosteroid Reduction of skin thickness
effects of a one-month-long application of TCs on nine male
Clobetasol propionate 0.05% 22%
volunteers. Betamethasone 17-valerate resulted in a high Betamethasone valerate 0.1% 15%–16%
degree of epidermal atrophy, hydrocortisone 17-butyrate Hydrocortisone 17-butyrate 0.01% 15%–16%
resulted in a moderate, and hydrocortisone in a low degree Hydrocortisone 1.0% 13%
of atrophy, but dermal changes were minimal or absent [63]. Clobetasone butyrate 0.1% 9%
According to later clinical experience, very potent, fluori-
nated TCs, are the ones that can cause the most extensive
Table 30.6 Principal local adverse effects associated with TCs.
epidermal atrophy [64]. (Adapted with permission from Brazzini et al. [4])
The atrophogenic properties of TCs in skin connective Skin atrophy
tissue have been studied under optical [65–67] and elec- Steroid face
tronic microscopy, showing a reduced diameter of collagen Rosacea
fibrils [68], but the exact mechanism of skin atrophy and Perioral dermatitis
thinning remained unknown for decades. Since collagen is Corticoid acne
the major extracellular component of the dermis, consisting Allergic contact dermatitis
Worsening of cutaneous infections
of approximately 80% of the dry weight of the skin [69], it Hypertrichosis
was logically assumed that TC-induced dermal atrophy Hypopigmentation
should be accompanied by collagen loss. Sim et al. [70] and Ocular hypertension, glaucoma, cataract
Marks et al. [71, 72] showed that all fractions of dermal col- Eczema craquelé (chapped skin)
lagen are involved in reducing collagen after TC use [73].
Later, it was demonstrated that TC application impaired col-
lagen’s local metabolic balance, either by reducing collagen 30.7 TCs and Alopecia Areata
synthesis or by increasing collagen degradation [74], or
both [75–77] (Table 30.4). Nowadays, the atrophogenic The effects of systemic and intralesional corticosteroids in
potential of TCs is known to every Dermatologist and prob- alopecias are confirmed and go beyond this chapter’s scope,
ably to every physician (Table 30.5). Skin atrophy is an in which only the effects of TCs on hair growth will be pre-
inevitable effect of TCs, provided they penetrate the epider- sented [83].
mal barrier. An interesting adverse effect noticed with high potency
TCs is hypertrichosis in areas of application, resulting from
the conversion of vellus hair follicles to intermediate or ter-
If a TC does not cause skin atrophy, it is safe to assume
minal ones [84, 85]. This iatrogenic hypertrichosis mostly
that it cannot positively impact the skin either.
affects women or children who apply potent TCs on the face,
and the exact mechanism leading to hypertrichosis is still
Choosing the right TC is a complex and multifactorial unknown [4]. Schell et al. [86] investigated the mechanism
decision, and the physician should be very familiar with the by topically applying betamethasone-17-valerate (0.1%
anticipated actions and expected adverse effects of any TC solution and cream) twice daily on the scalp skin of 47
[81] (Table 30.6). Further information on the systemic or healthy volunteers. After 7 and 14 days of treatment, anagen
local adverse effects of TCs can be found in the excellent hairs were plucked from both treated and untreated contralat-
review by Hengge et al. [82] eral scalp areas of each volunteer. Cell cycle analysis of
plucked anagen hairs was performed by means of DNA flow also be useful in the treatment of AGA/FPHL. However, a
cytometry. After the topical application of betamethasone- thorough review of all relevant literature dating several
17-valerate for just seven days, cell kinetic changes were decades back reveals no more than four papers on the issue.
apparent, showing a slightly significant decrease of S and After an early parer in 1974, with all remaining three
G2 + M cell percentages and a considerable increase of G0/1 appeared in 2020.
cell percentage [86]. Wustner and Orfanos [108] treated 50 male and female
Several researchers and clinical investigators have tried to patients with AGA/FPHL (aged 19–52 years) with topical
take advantage of this “trichogenic” adverse effect to treat estrogens and TCs. They reported a decrease in the telogen
common follicular disorders. Several TCs have been used to rate in 52% of the patients and a minimal increase in the
treat mostly Alopecia Areata (AA) [87] with variable effi- anagen hair count. They suggested that estrogens may have
cacy, and some prominent authors have tried TCs of moder- positive effects on hair growth, but the role of TCs has not
ate to high potency as monotherapy to treat AA. However, been elucidated [108].
evidence about the effectiveness of TCs in AA remains very Pazoki-Toroudi et al. [109] conducted a study in 59 male
limited [88]. Very few studies have used the split-head tech- patients with AGA stage I-IV in the Hamilton-Norwood
nique, which allows exclusion of spontaneous hair regrowth scale and 55 females with FPHL stage I-III in the Ludwig
as well as proving at the same time that the action of the scale. They compared the hair growth effects of 5% MTS
investigated TC is topical and not systemic [89]. Studies (n = 49) b.i.d., a combination solution (MHEC) containing
reporting mild to moderate efficacy of TCs in treating AA MTS 12.5%, azelaic acid 5% and betamethasone valerate
first appear in the relevant literature from Pascher et al. [90] 0.025% (n = 57) o.d. vs. placebo topical solution b.i.d.
and Montes et al. [91], later from Camacho et al. [92], (n = 18). Patients were assessed by wash test, which they
Mancuso et al. [93], Tosti et al. [89, 94, 95] and Kuldeep performed by themselves at home, and collected the shed
et al. [96]. hairs to be counted at the dermatologist’s office. Compared
Until today, the efficacy of TCs in AA remains controver- with baseline values, both 5% MTS and MHEC reduced hair
sial [97], and there is no consensus on the efficacy of TCs in shedding in men (p < 0.05 and p < 0.01) and women
the treatment of alopecia areata and alopecias in general (p < 0.05) at 24 weeks. Mean differences in shed hair showed
[98–100]. Not surprisingly, many experts consider TCs to be a significant difference between 5% MTS and MHEC in men
just a placebo treatment in AA [91, 101–103]. Latest guide- (−33.47 ± 3.22 vs. -63.6 ± 4.54, p < 0.01) and women
lines on the treatment of AA, issued by the British Association (−28.62 ± 6.19 vs. -53.44 ± 5.82, p < 0.05). At 24 weeks,
of Dermatologists [104] (2012) report that even though TCs according to the investigator’s assessment, moderate
are extensively used, there is limited evidence that they are in improvement was evident in 35% and marked improvement
any way useful as a monotherapy in AA. Similarly, the con- in 6.25% of male patients in the MTS group (p < 0.001 vs.
clusions that have been drawn by the Cochrane Database placebo). In the MHEC group, moderate improvement was
meta-analysis report that TCs are safe. However, there is no evident in 42.86% and marked improvement in 23.81% of
convincing evidence that they are beneficial in the long-term male patients. The results in female patients treated with
treatment of AA [98]. MHEC were only significant compared with the placebo
Studies reporting negligible efficacy of TCs are rare, and group (p < 0.001). Only one pair of before-and-after photos,
very few authors seem to be interested in getting involved in of very poor quality, is included in the full-text article. The
these studies since the efficacy of intralesional corticoste- severe methodological flaws (e.g., home wash-test) of the
roids is well-documented. Moreover, according to a review study render the claim of the authors that betamethasone val-
by Alkhalifah et al. [105] on the updated guidelines for the erate can induce hair growth through immunosuppression as
management of AA, the use of TCs is associated with relapse unsubstantiated [109].
of the disease in 37–63% of patients, even with continuous Gheisari et al. [110] tested the hypothesis that topical
treatment [105]. anti-inflammatory medications combined with MTS might
TCs of moderate potency can be only considered a treat- help improve hair growth in AGA patients. Sixty men with
ment of choice only for children with AA, either as mono- AGA (stage II–IV, Norwood-Hamilton scale) between 25
therapy [106] or in combination with 5% MTS [107]. and 40 years were recruited. Participants were randomized
into group I, in which participants applied 1 ml of 5% MTS
b.i.d. and group II, in which participants applied 1 ml of a
30.8 TCs and AGA/FPHL solution containing 5% MTS + 0.1% betamethasone dipro-
pionate b.i.d. At baseline and at weeks 8, 16, and 24, tricho-
The fact that some TCs induce, mostly temporary, hair grams of the 2 × 2 cm marked area on the vertex were taken
regrowth in AA patients may be responsible for the unfortu- and evaluated by two experienced, blinded, dermatologists
nate, erroneous, and simplistic assumption that TCs may and a self-assessment questionnaire was given to every
30.8 TCs and AGA/FPHL 127
patient. At baseline and 24 weeks, the terminal hair counts applying TCs on a balding scalp will most probably exac-
in group I was 114 ± 5.14 and 32.76 ± 7.27, respectively, erbate rather than improve hair loss through PGD2
and the terminal to vellus ratio was 1.30 ± 0.11 and upregulation,
0.83 ± 0.21, respectively (all p < 0.001); in group II, it was • According to Paus et al. [116, 117], corticosteroids induce
120 ± 6.04 and 33.82 ± 8.22, respectively and the terminal the entry of hair follicles to catagen, exacerbating hair loss.
to vellus ratio was 1.26 ± 0.129 and 0.96 ± 0.27, respec- Recent studies have actually confirmed this, elucidating the
tively (all p < 0.001). Both study groups showed significant exact mechanism as well. Kwack et al. [118] found that the
hair growth at the end of the study, but the difference glucocorticoid receptor is strongly expressed in the inner
between the two groups was not significant. The authors and outer root sheath of hair follicles and more weakly
concluded that reducing micro-inflammation does not alter expressed in the matrix, dermal papilla cells (DPCs), and
hair growth patterns in AGA [110]. dermal sheath. They also described for the first time the
Rossi et al. (2020) conducted a single-blind study, retro- mechanism by which Dexamethasone, and probably natu-
spective study to investigate the efficacy of topical 0.05% ral cortisol, inhibit hair growth. They found that
17α-estradiol solution vs. 0.5% Finasteride lotion in the Dexamethasone induces DKK1 in human DPCs, but not in
treatment of FPHL in 119 postmenopausal female patients follicular keratinocytes, suggesting that the induction of
split into two groups. Both solutions included 0.08% hydro- DKK1 by Dex is cell type-specific and that Dexamethasone
cortisone butyrate that was used (quote) “to block the inflam- inhibits keratinocyte growth via the paracrine effect of
matory process” (see Chap. 36, Ref. [111]). DKK1 from DPCs. Overall, their data strongly suggest that
Despite the complete lack of credible evidence suggesting stress-related neurohormones induce DPCs to secrete
the use of any TC in the treatment of AGA or FPHL, some DKK1, which in turn inhibits hair growth [118],
physicians prescribe galenic formulations of 5% MTS with • Corticosteroids increase the likelihood of local infections
added mometasone furoate 0.1% or other TC lotion. [119] or the extensive colonization by Demodex [120],
Propionibacterium [121], and Staphylococcus [122]
which are considered the most common microbial factors
Some even suggest the “bizarre” combination of 5%
involved in the process of follicular microinflammation in
MTS + ATRA + TC lotion, adopting a simplistic ratio-
ΑGΑ [123, 124],
nale that the adverse effects of the TCs (atrophy and
• Systemic absorption of TCs will result in numerous topi-
skin thinning) will be counterbalanced by the effects of
cal and systemic adverse effects, as presented in Tables
ATRA (collagen production) and that the adverse
30.3 and 30.6.
effect of ATRA (irritation, burning) might be “regu-
lated” by the action of the TC (antiphlogistic effect).
Many patients will be lost in follow-up and will not
discontinue the TC after a few days or weeks as
Concerning the in vivo prevention of TC-induced atrophy
instructed, especially if he/she believes that by con-
by the use of ATRA (see Chap. 32), it has been demonstrated in
tinuing to use the original prescription, more hair will
the hairless mouse model by Schwartz et al. [111], but no
grow! In countries where the pharmacist does not
human studies have replicated these results [111]. Mixing MTS
require an updated prescription, some patients might
with TCs is a practice also based on the unsubstantiated asser-
not show up for a scheduled physician visit, during
tion that the inflammatory parameter of AGA is responsible for
which the physician would discontinue or tapper-out
some of the clinical features of AGA. As already analyzed in
the TCs. These patients will often continue using the
Chap. 14, Vol. 1, there is a huge controversy on this issue.
same potent TC-containing formulation for months or
Another explanation for this common practice is that
even years with devastating effects.
since mild dermatitis, itching, and trichodynia [112] often
coexist during AGA’s active phase, physicians supporting
this regimen are also trying to relieve the patient from these Most importantly, mixing lotions or active substances in
symptoms. Although having good intentions, this practice one container involves two additional, significant risks: the
can backfire for many reasons: possibility of interaction between compounds and the overall
dilution of both active substances. In particular, a galenic
• TCs cause local vasoconstriction, and as a result, hair fol- formulation containing two or three lotions in one bottle
licle vascularization in AGA-affected areas is further reduces the concentration of all substances to sub-therapeutic
decreased, levels. When a lotion of 30 ml of 0.1% mometasone furoate
• Corticosteroids increase Prostaglandin D2 (PGD2) [113, is added to 60 ml of 5% MTS, the end product is a 90 mL
114], which, according to Garza et al. [115], is the key solution that contains Elocon 0.03% and Minoxidil 3.5%,
molecule in the pathophysiology of AGA [115]. Therefore, both diluted.
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Ketoconazole
31
antifungal agents, such as Itraconazole, because of

Basic Concepts Ketoconazole’s higher toxicity, lower absorption, and more
• Ketoconazole was the first orally-active azole medi- limited spectrum of activity. These properties are extensively
cation and a potent inhibitor of gonadal and adrenal covered in the relevant bibliography [2] and will not be ana-
steroidogenesis, used primarily to treat systemic lyzed further herein. This chapter will focus on the antian-
fungal infections. drogenic and anti-inflammatory properties of Ketoconazole.
• Ketoconazole in high oral doses has antiandrogenic
and anti-glucocorticoid properties, inhibits the pro-
duction of Testosterone and other androgens in both 31.1 Pharmacology of Ketoconazole
gonads and adrenals. It has even has been employed
to treat Cushing syndrome, prostate cancer, and The primary antiandrogenic mechanism of Ketoconazole—
precocious puberty. and all azoles—is the inhibition of several enzymes neces-
• Topical Ketoconazole shampoo has documented sary for the conversion of cholesterol to steroid hormones,
antifungal, antibacterial, and anti-inflammatory such as Testosterone (T) and cortisol [3]. These enzymes
properties, mostly against the Pityrosporum ovale and, more particularly, the enzymes sterol 14-adimethylase
of the normal scalp flora. Therefore it is used to [4], 17,20-desmolase, 17,20-lyase, and 17-alpha-hydroxylase
treat seborrheic dermatitis and dandruff with high [5] in the liver, gonads, adrenals, and renal tissue belong to
efficacy and negligible transcutaneous absorption. the P-450 enzymatic system. They are involved in the syn-
• Small, uncontrolled clinical trials have demon- thesis and degradation of steroids, including the precursors
strated mild to moderate positive effects of the of T [6]. Other azoles, such as clotrimazole and miconazole,
Ketoconazole shampoo in AGA, with unknown exert their fungicidal action by interfering with the fungal
mechanism of action, and its use in AGA/FPHL is synthesis of ergosterol, which is a constituent of fungal cell
“off-label”. membranes [7]. Ketoconazole does not exert any action on
• Ketoconazole shampoo acts synergistically with the cellular membrane, and this is why resistant strains
Finasteride and MTS, it is considered very safe, tol- emerge less frequently [8]. The effect of Ketoconazole on
erable, and valuable addition to every AGA/FPHL these P-450 enzymes results in the inhibition of T (and
patient even though the quality of evidence of its androgen) production in the gonads [9] and adrenals [10],
efficacy is still poor. granting strong antiandrogenic properties to Ketoconazole.
Quickly achieved therapeutic concentrations of
Ketoconazole virtually eliminate corticosterone produc-
tion, and therefore it has been used as a means of adjunc-
Ketoconazole is an antifungal agent, which belongs to the tive pharmaceutical castration in patients with prostate
group of azoles (imidazole) [1], was discovered in 1976 by cancer after surgical castration [11]. In healthy men,
Janssen Pharmaceutica, and was first introduced in 1977. Ketoconazole induces a significant elevation of the estra-
Ketoconazole has a prominent place in Clinical Dermatology, diol-T ratio since it depresses serum T concentrations
as the first orally-active antifungal azole, used both orally markedly, while serum estradiol is reduced to a much
and topically to combat numerous types of moderate or lesser degree [12]. Ketoconazole appears to be the first
severe fungal infections. Ketoconazole has mostly been example of a non-steroidal compound that binds competi-
replaced as a first-line systemic antifungal by other azole tively to both SHBG (sex hormone-binding globulin) and
134 31 Ketoconazole
multiple steroid hormone receptors. However, the dose of

Ketoconazole required for 50% occupancy of the androgen Ketoconazole has been used with moderate success as
receptor (AR) is not likely to be achieved in vivo, at least a second-line treatment in certain forms of advanced
not in plasma [13]. androgen-dependent prostate cancer [19].
31.2 Oral Ketoconazole Since Ketoconazole inhibits the production of androgens

by the adrenals [20], it has been found useful even in
Oral Ketoconazole is most frequently administered in doses hormone- refractory prostate cancer, even in low doses
of 200 or 400 mg, is readily absorbed, and result in plasma (200 mg t.i.d.). It is usually administered in combination
levels of 10–12 μg/ml within 1–2 h. At least 85% of either with hydrocortisone [21] or immunosuppressive com-
Ketoconazole is bound to plasma proteins, and 14% is bound pounds [22]. Overall, Ketoconazole is commercially avail-
to other blood elements, leaving less than 1% free in the able as a tablet for oral administration, but this use has been
plasma. After a single dose of 200 mg, detectable levels are discontinued in several countries. FDA issued a warning that
found in the cerebrospinal fluid, urine, saliva, and sebum. oral Ketoconazole can cause severe liver injury and adrenal
When repeated doses of oral Ketoconazole were adminis- gland dysfunction and recommends that Ketoconazole oral
tered in men treated for chronic mycotic infections, they tablets should not be a first-line treatment for any systemic
often produced androgen deficiency features, including fungal infection.
decreased libido, gynecomastia, impotence, oligospermia,
and decreased T levels [13].
These initially unexpected adverse effects intrigued 31.3 Ketoconazole Shampoo
researchers to conduct studies on Ketoconazole’s potential
use as an antiandrogen as soon as the compound was dis- Nowadays, Ketoconazole is mostly available in various topi-
covered. Oral Ketoconazole was initially tested on women cal formulations, used to treat tinea and cutaneous candidia-
who suffered from typical androgen-dependent diseases, sis, including candidal paronychia and pityriasis versicolor.
such as acne and hirsutism. It has been tried as secondary Ketoconazole is also available as a shampoo, which is the
hormonal therapy in castration-refractory prostate cancer, most popular formulation of Ketoconazole, used against seb-
combined with Dutasteride in men [14]. Additionally, its orrheic dermatitis and dandruff. Ketoconazole shampoo may
use has been proposed for the inhibition of early adre- initially act paradoxically by increasing scalp “oiliness”,
narche, and its anticortisolic effect has been found useful in since it improves sebum delivery onto the skin surface, which
most Cushing’s syndromes in both sexes [6]. Another inter- was hindered by follicular occlusion. However, this effect
esting effect of Ketoconazole on the skin is the regulatory soon balances with the reduced sebum production levels, and
effect on sebum production. A statistically significant overall sebum production and delivery remain lower than
decrease in sebum secretion rate in all patients, even with a before treatment [23].
single daily oral dose of Ketoconazole (200 mg) has been The efficacy of 1% Ketoconazole shampoo in dandruff
reported [15]. treatment has been demonstrated by Go et al. [24] in a
Studies in women with hirsutism or acne who were double- blind, placebo-controlled trial on 176 patients.
administered oral Ketoconazole reported satisfactory effi- Patients used a shampoo twice weekly, and after 4 weeks,
cacy. Venturoli et al. [16] conducted a study on 42 females 80% of patients using Ketoconazole reported good to excel-
patients with acne and/or hirsutism who were treated with lent results vs 23% who used the placebo shampoo [24].
400 mg/day for 3–6 months. All patients (100%) reported Danby et al. [25] evaluated the safety and efficacy of 2%
improved acne, while Ketoconazole had a therapeutic effect Ketoconazole shampoo vs a selenium sulfide 2.5% sham-
on just 14 of hirsute patients (35%). Sonino et al. [17] con- poo and a placebo shampoo in 246 patients with moderate
ducted a similar study in 16 women with a spectrum of dis- to severe dandruff. They reported that both active sham-
orders, ranging from idiopathic hirsutism to polycystic poos were effective in the treatment of moderate to severe
ovaries. They reported that Ketoconazole 400 mg/day for 3 dandruff; however, 2% Ketoconazole shampoo was better
months resulted in 11 women (70%) reporting moderate tolerated [25]. Squire et al. [26] compared the therapeutic
improvement of hirsutism, whereas patients treated for 6 efficacy of a shampoo containing 1.5% ciclopirox olamine
months showed even further improvement [17]. Gokmen and 3% salicylic acid (CPO/SA) with 2% Ketoconazole
et al. [18] conducted a prospectively-designed study on 24 shampoo in a study involving 154 subjects with dandruff.
hirsute females who were administered 400 mg/day Shampoos were used three times a week for 4 weeks, and
Ketoconazole for 6 months and reported significant scored comparably [26].
improvement in 22 of them and a slight improvement in 2 Peter et al. [27] conducted a multicenter, double-blind,
patients [18]. placebo-controlled trial to investigate 2% Ketoconazole
31.4 Ketoconazole and ΑGΑ/FPHL 135
shampoo’s efficacy in the treatment and prophylaxis of seb- strated that topical 2% Ketoconazole was effective on the
orrhoeic dermatitis and dandruff on 575 patients presenting androgen-insensitive coat hairs of mice and behaved as an
with moderate to severe seborrhoeic dermatitis and dandruff androgen-independent biological response modifier.
of the scalp. Patients were treated with 2% Ketoconazole However, its action on hair growth and hair follicle diameter
shampoo twice weekly for 2–4 weeks, producing an excel- was inferior to that of Minoxidil [33].
lent response in 88%, and 312 of initial patients were
included in a prophylactic phase, lasting another 6 months.
As far as studies on humans are concerned, the objec-
In the placebo group, 47% of patients experienced a relapse
tivity and reliability of relevant publications are
of seborrhoeic dermatitis, compared with 19% of patients in
dubious.
the active treatment group and 31% of patients in the active/
placebo group. The authors concluded that 2% Ketoconazole
shampoo is highly effective in clearing scalp seborrhoeic The earliest study was published by the research team of
dermatitis and dandruff and also in preventing relapse of the Piérard-Franchimont et al. in cooperation with Janssen
disease when used prophylactically once weekly [27]. Pharmaceutica, the manufacturer of Nizoral® shampoo, the
Overall, the antimicrobial [28] and anti-inflammatory initial brand name of 2% Ketoconazole shampoo.
properties of 2% Ketoconazole shampoo have been docu- Piérard-Franchimont et al. [34] conducted a 21-weeks
mented both in vitro [29] and in vivo [30]. Concomitant seb- long prospective study on 39 men (aged 21–33) to determine
orrheic dermatitis is common in AGA and may further whether Ketoconazole shampoo, known for being normaliz-
aggravate hair loss. Therefore, Ketoconazole shampoo’s ing scalp microflora and showing intrinsic anti-inflammatory
positive impact on AGA, even though hard to measure, did activity, could help in the treatment of AGA. Ketoconazole
not come as a surprise. shampoo was compared to an unmedicated shampoo used in
combination with or without 2% Minoxidil (MTS).
Ketoconazole shampoo alone led to a reduction of the vol-
31.4 Ketoconazole and ΑGΑ/FPHL ume of the sebaceous glands by −19.4% as early as 6 months,
to a 7% increase of the median hair diameter in balding
The efficacy of oral Ketoconazole for the treatment of AGA areas, and an 18% increase in the number of hairs. Subjects
or FPHL has not been reported in the literature and probably in the group of 2% MTS + unmedicated shampoo showed
has never been tested. This is probably because Ketoconazole, less improvement compared to that of the Ketoconazole
besides inhibiting androgen synthesis, also inhibits numer- group, both concerning the increase in the amount of hair
ous other enzymes [31], making it an unsuitable drug for (11%) and the decrease of the volume of the sebaceous
AGA/FPHL. Also, Ketoconazole requires high serum con- glands (−5.3%) [34]. The authors commented that the anti-
centrations to be efficacious as an antiandrogen, making it an bacterial action of Ketoconazole against Pityrosporum ovale
unsafe choice for oral treatment in AGA/FPHL. and Malassezia spp. found in the scalp’s normal flora is the
However, when treating AGA, the only tissue that requires hair growth mechanism of Ketoconazole. They hypothesized
a relatively high concentration of a compound is the hair fol- that the colonization of the follicular isthmus by strains of
licle, and the topical application of Ketoconazole could be these bacteria contributes to the micro-inflammation
sufficient. Ketoconazole’s topical formulations include 2% observed in the outer sheath of balding follicles [35] (see
ointments and 1% and 2% shampoos, with the shampoo for- Chap. 14, Vol. 1).
mulation been the only one reported having moderate hair The study conducted by Khandpur et al. [36] was an open,
growth potential. The positive effect of Ketoconazole sham- randomized, parallel-group study designed to evaluate and
poo has been demonstrated in two animal studies and five compare the efficacy of various AGA treatments in a total of
clinical studies. It remains unclear how exactly this antifun- 100 patients. Subjects were randomized into four groups:
gal shampoo induces hair growth. The antibacterial and anti- group Ι (n = 30) received only oral Finasteride 1 mg o.d.,
inflammatory properties are the strongest “candidates” for group ΙΙ (n = 36) received Finasteride 1 mg + topical 2%
Ketoconazole’s hair growth effects, probably by down- MTS b.i.d., group ΙΙΙ (n = 24) received only 2% MTS b.i.d.
regulating the inflammatory aspect of AGA/FPHL (see Chap. and group ΙV (n = 10) received Finasteride 1 mg
14, Vol. 1). o.d. + Ketoconazole shampoo 2%, three times/week. After 6
Jiang et al. [32] reported that a topical lotion of 2% months of treatment, Finasteride + MTS and
Ketoconazole had a macroscopically significant stimulatory Finasteride + Ketoconazole groups showed similar efficacy
effect on hair regrowth in C3H/HeN mice compared to the in decreasing hair loss and encouraging new hair growth. At
vehicle group [32]. Aldhalimi et al. [33] compared the stimu- the end of 12 months, hair growth was observed in all the
latory effect of Ketoconazole, Minoxidil, and Minoxidil + groups with slightly better results recorded with the combi-
Tretinoin on hair growth in the mouse model. They demon- nation of Finasteride-MTS (Group II) followed by groups IV,
136 31 Ketoconazole
I, and then III. Group Ι (Finasteride monotherapy) and ΙΙΙ Ketoconazole can be useful in some but not all men with
(MTS monotherapy) were clearly less effective than combo AGA. Hair loss recurred in one patient when he stopped
treatments. However, according to physician evaluation, the using Ketoconazole, but growth began again upon resump-
Finasteride-Ketoconazole group IV had the highest efficacy, tion of use. Additionally, researchers performed transient
since n = 8 subjects (80%) exhibited moderate improvement transection essays and demonstrated that Ketoconazole
compared to the Finasteride-MTS group II, in which n = 24 improves AGA by suppressing the AR activity. The study’s
subjects (66.67%) showed moderate improvement. limitations included the lack of a control group, quantitative
Respective values for group Ι were n = 10 (33.34%) and for outcome measurements, inconsistent follow-up, and incon-
group ΙΙΙ, n = 3 subjects (8.34%). The authors speculated that sistent use of the lotion by subjects [39].
Ketoconazole is effective due to its actions against the lipo- Rafi et al. [40] conducted a prospective study on 15 men
philic fungus Pityrosporum ovale [36]. This fungus is part of (24–72 years old) who were treated with a combination of
the scalp’s normal flora and is found in 90–100% of adults “NuH hair formulation” (unknown contents, since the
worldwide, regardless of whether they suffer from AGA or authors proclaimed the formula a trade secret). All patients
not [37]. Ketoconazole efficacy was not assessed indepen- were given the option to add Finasteride, Minoxidil topical
dently in this study, limiting results, and the authors used a foam, oral Finasteride, and Ketoconazole shampoo. All 15
protocol without objective criteria for hair measurement, patients experienced significant new hair growth. Ten of the
including only photo-based evaluations. 15 patients used 2% Ketoconazole as part of their therapy,
Piérard-Franchimont et al. [38] conducted a prospective and 8 had known seborrheic dermatitis improvement signifi-
study on 150 men presenting with telogen effluvium related cantly after 1 month of therapy with 2% ketoconazole sham-
to AGA and dandruff. They were randomly assigned to three poo. Only one patient used NuH Hair and ketoconazole
groups receiving either 1% Ketoconazole (KTZ), 1% piroc- alone, and no patients used ketoconazole alone, limiting the
tone olamine (PTO), or 1% zinc pyrithione shampoos (ZPT) ability to discern the effect of topical ketoconazole on hair
2–3 times a week for 6 months. Hair shedding during sham- growth. The study was also limited by subjective evaluation
poo was evaluated semiquantitatively, and hair density on the of hair growth and the varied combinations of products used
vertex was evaluated on photographs. Trichograms were by individual patients [40]. The full-text paper includes vari-
used for determining the anagen hair percentage and the ous very low-quality before-and-after pictures of patients,
mean proximal hair shaft diameter using computerized taken without a standard protocol of photography (light,
image analysis, and the sebum excretion rate (SER) was also position, hair length, etc.)
measured using a Sebumeter. All three treatments cleared In support of the theory of Khandpur et al. is the finding
pruritus and dandruff rapidly. At endpoint, hair density was that P. ovale has been associated with the induction of skin
unchanged, although hair shedding was decreased (KTZ: inflammation in seborrheic dermatitis and atopic eczema
−17.3%, PTO: −16.5%, ZPT: −10.1%), and the anagen hair [41]. It is believed that this fungus-induced skin inflamma-
percentage was increased (KTZ: 4.9%, PTO: 7.9%, ZPT: tion is caused by the skin’s abnormal reaction to the fungus.
6.8%). The effect on the mean hair shaft diameter was con- The number of P. ovale fungi is of minor importance and has
trasted between the three groups of volunteers (KTZ: 5.4%, been found to be similar in patients with dermatitis and
PTO: 7.7%, ZPT: −2.2%). Hair density was unchanged, healthy adults [42]. P. ovale possesses lipase activity and
although hair shedding was decreased in all groups at the end may generate free fatty acids, which could also contribute to
of the study period (ketoconazole group by 17.3%, piroctone the inflammatory response in addition to several other fac-
olamine group by 16.5%, and the zinc pyrithione group by tors that are probably important in the pathogenesis of sebor-
10.1%). The anagen hair percentage was also increased in all rhoeic dermatitis, such as skin lipids, immune function,
groups. Mean hair shaft diameter was increased in the keto- heredity, atmospheric humidity, and emotional state [43].
conazole (+5.4%) and piroctone olamine (+7.7%) groups Nevertheless, the mechanism of this relationship of P. ovale
and decreased in the zinc pyrithione group (−2.2%). Severe and seborrheic dermatitis had not been identified until 2001.
limitations of the study include the use of very imprecise Faergemann et al. [44] published a study on the results of
measurement techniques, whereas the full-text paper skin biopsies from normal and lesional skin from the trunk
includes various detailed figures but no before-and-after pic- and scalp in patients with seborrhoeic dermatitis and reported
tures of patients [38]. that skin colonization by P. ovale causes an irritant non-
Inui et al. [39] conducted a 10-month long open, small immunogenic stimulation of the immune via the secretion of
trial on six males with AGA, aged 23–51, who used 2% IL-4 and IL-10 and complement activation to susceptible
Ketoconazole lotion daily after washing their hair. All three subjects [44].
younger subjects showed “remarkable hair growth” (no data Another theory on the hair-growth mechanism of
on hair counts are available, though), unlike older males who Ketoconazole has been presented by Hugo Perez [45], who
did not show significant improvement, suggesting that hypothesized that it plays a role in the local disruption of the
DHT pathway rather than having an anti-inflammatory 31.5 How to Use the Ketoconazole
effect. In rat studies, Ketoconazole has been shown to inhibit Shampoo
the binding of 5α-Reductase to sex binding hormone globu-
lins [46] and that unlike Finasteride, it also binds to the Anecdotal reports indicate that both the 1% and 2% dosages
human AR [13]. According to the author, the effect of of Ketoconazole shampoo have hair loss effects; however,
Ketoconazole on the DHT pathway may be twofold: through the more potent 2% formulation likely produces better
the inhibition of DHT and/or inhibition of DHT binding to results.
AR. They suggested that when used in conjunction with To ensure maximum efficacy of 2% Ketoconazole in any
Finasteride, Ketoconazole may help achieve a complete pharmaceutical form, the scalp should be preferably clean
reduction of DHT [45]. since intense and persisting greasiness decreases absorption
Ketoconazole shampoo has been approved by the FDA of active substances by the follicular ducts. Lademann et al.
only for the treatment of dandruff and seborrheic dermatitis [51] demonstrated with the use of laser scanning microscopy
of the scalp. Therefore, it cannot be endorsed or marketed as and cyanoacrylate skin surface biopsies that not all hair fol-
a hair loss remedy to the general public. licles are “available” to absorb substances at any given
moment and that some follicular ducts are “open,” while
some others are “closed” [51]. “Closed” follicles are due to
However, according to an extensive review by Rogers plugs of shed corneocytes pushed out of the follicular ori-
et al., published in the JAAD in 2008, Ketoconazole is fices by growing hair or emerging sebum that blocks the duct
an important addition to the toolkit of every physician [52]. Washing can actually “open” more follicles, and since
treating AGA/FPHL patients [47]. follicular penetration is the key route of absorption in the
scalp, the scalp must be washed first with ordinary shampoo,
and then to use the Ketoconazole shampoo 2%.
Even though it has not been demonstrated actually to
grow hair, anecdotal reports claim that it helps maintain
existing numbers of hair. Most experts believe that medica- The 2% Ketoconazole shampoo has to be used 2–3
tions capable of maintaining the existing hair population, times per week. Patients must scrub into the scalp for
even in the absence of hair regrowth, should be regarded as 60–90 s and then leave the foam on the scalp for
effective treatments for AGA and FPHL. Ketoconazole 5–10 min before rinsing, as is recommended for the
shampoo might be precisely that, even though according to treatment of dandruff and seborrheic dermatitis.
the latest issued guidelines for the diagnosis and treatment Excessive usage has not been shown to produce better
of AGA/FPHL by Manabe et al. [48], evidence supporting results.
its use is considered of poor quality (level III to IV evi-
dence) [48].
In the recent (2018) systematic review by Kanti et al.
(Evidence-based (S3) guideline for the treatment of andro- 31.6 Adverse Effects
genetic alopecia in women and in men) issued for the
European Dermatology Forum, authors included only the Oral Ketoconazole, even in low doses, is accompanied by
study of Khandpur et al. [36], which was attributed Level frequent and severe adverse effects, such as nausea and vom-
of Evidence 3 and grade of evidence B. They considered iting (50%), gynecomastia (21%), a decrease of libido (13%),
that no recommendation for the use of Ketoconazole to elevated liver function tests (5%), pruritus (5%), and rash
improve or prevent progression of AGA/FPHL could be (4%). The frequency of these adverse effects has been found
made [49]. to be directly proportional to the administered dosage [53].
In contrast, Fields et al. [50], who conducted a systematic In contrast, topical Ketoconazole is considered perfectly
review to evaluate topical Ketoconazole’s efficacy in AGA safe, and its transcutaneous absorption is minimal. Studies
treatment, reached different results. Overall, 47 papers were with Ketoconazole cream 2% in infants with extensive seb-
screened for inclusion, of which 9 were assessed for eligibil- orrhoeic dermatitis (>50% of the body area) showed that
ity. Seven articles were included in the qualitative synthesis, despite the large surface of application, plasma levels rang-
including 2 animal studies (total of 40 participants) and 5 ing from 0.018 to 0.133 μg/ml were measured, which are
human studies (total of 318 participants). The authors con- negligible compared to oral administration values (4–9 μg/
cluded that topical Ketoconazole is a promising adjunctive or ml), and suggest that the occurrence of systemic dose-
alternative treatment of AGA [50]. dependent side effects is very unlikely [54]. In another open
138 31 Ketoconazole
study, 19 infants with a bipolar seborrhoeic rash were treated 3. Finkel R, Cubeddu LX, Clark MA. Pharmacology. 4th ed.
with 2% Ketoconazole cream o.d. for 10 days, and no plasma Baltimore: Lippincott Williams & Wilkins; 2009. p. 411.
4. Sud IJ, Feingold DS. Mechanisms of action of the antimycotic
Ketoconazole accumulation over the 10-day treatment period imidazoles. J Invest Dermatol. 1981;76(6):438–41.
was detected [55]. 5. Santen RJ, Van den Bossche H, Symoens J, Brugmans J, DeCoster
Adverse effects with the use of Ketoconazole shampoo R. Site of action of low dose ketoconazole on androgen biosynthe-
are rare, mild, and tolerable to most patients, namely abnor- sis in men. J Clin Endocrinol Metab. 1983;57(4):732–6.
6. Miossec P, Archambeaud-Mouveroux F, Teissier MP. Inhibition of
mal hair texture, discoloration, irritation, or pimple-like steroidogenesis by ketoconazole. Therapeutic uses. Ann Endocrinol
bumps on the scalp. At the same time, there are no reports of (Paris). 1997;58(6):494–502.
interactions with other topical Ketoconazole formulations. 7. Sud IJ, Feingold DS. Heterogeneity of action mechanisms
Since Ketoconazole shampoo is an antifungal formulation among antimycotic imidazoles. Antimicrob Agents Chemother.
1981;20(1):71–4.
that addresses the scalp sebum and scale removal aspects of 8. Playford EG, Webster AC, Sorrell TC, Craig JC. Antifungal
dandruff, over time, it might excessively remove sebum, agents for preventing fungal infections in non-neutropenic
resulting in hair that is dry and subject to static electricity, critically ill and surgical patients: systematic review and meta-
degrading its cosmetic value. This has been demonstrated in analysis of randomized clinical trials. J Antimicrob Chemother.
2006;57(4):628–38.
a comparative study by Draelos et al. [56] on 40 females 9. Pont A, Williams PL, Azhar S, Reitz RE, Bochra C, Smith ER,
aged 18–50 with mild to moderate dandruff. The study Stevens DA. Ketoconazole blocks testosterone synthesis. Arch
assessed a pyrithione zinc 1% conditioning shampoo and 2% Intern Med. 1982;142(12):2137–40.
Ketoconazole shampoo and reported that after 2 weeks, 75% 10. Pont A, Williams PL, Loose DS, Feldman D, Reitz RE, Bochra C,
Stevens DA. Ketoconazole blocks adrenal steroid synthesis. Ann
of patients with dandruff preferred the pyrithione zinc 1% Intern Med. 1982;97(3):370–2.
conditioning shampoo over the 2% Ketoconazole shampoo 11. De Coster R, Wouters W, Bruynseels J. P450-dependent enzymes
in terms of overall performance [56]. as targets for prostate cancer therapy. J Steroid Biochem Mol Biol.
Recently, a new product, Ketoconazole anhydrous gel 2%, 1996;56(1–6 Spec):133–43.
12. Pont A, Goldman ES, Sugar AM, Siiteri PK, Stevens
was launched to treat seborrheic dermatitis [57]. This formula- DA. Ketoconazole-induced increase in estradiol-testosterone
tion optimized the features and effectiveness of Ketoconazole ratio. Probable explanation for gynecomastia. Arch Intern Med.
locally and could also be useful in AGA/FPHL. 1985;145(8):1429–31.
13. Eil C. Ketoconazole binds to the human androgen receptor. Horm
Metab Res. 1992;24(8):367–70.
Synopsis 14. Sartor O, Nakabayashi M, Taplin ME, Ross RW, Kantoff PW, Balk
Ketoconazole shampoo is FDA-approved only for the treat- SP, Oh WK. Activity of Dutasteride plus ketoconazole in castration-
ment of dandruff and seborrheic dermatitis of the scalp. refractory prostate cancer after progression on ketoconazole alone.
Though large-scale prospective studies are lacking, the exist- Clin Genitourin Cancer. 2009;7(3):E90–2.
15. De Pedrini P, Rapisarda R, Span G. The effect of ketoconazole on
ing literature shows promise for the use of Ketoconazole in sebum secretion in patients suffering from acne and seborrhoea. Int
AGA. It has been demonstrated in small trials to have a hair J Tissue React. 1988;10(2):111–3.
growth potential, with a mechanism of action that is proba- 16. Venturoli S, Fabbri R, Dal Prato L, Mantovani B, Capelli M,
bly different from Finasteride or Minoxidil. Though large- Magrini O, Flamigni C. Ketoconazole therapy for women with acne
and/or hirsutism. J Clin Endocrinol Metab. 1990;71(2):335–9.
scale prospective controlled studies are lacking, the existing 17. Sonino N, Scaroni C, Biason A, Boscaro M, Mantero F. Low-dose
literature shows promise for the use of ketoconazole in ketoconazole treatment in hirsute women. J Endocrinol Investig.
AGA. Its regulatory effect on the sebaceous gland makes it a 1990;13(1):35–40.
necessary addition in every treatment scheme for AGA and 18. Gokmen O, Senoz S, Gulekli B, Isik AZ. Comparison of four dif-
ferent treatment regimes in hirsutism related to polycystic ovary
FPHL, even though such recommendation is off-label and syndrome. Gynecol Endocrinol. 1996;10(4):249–55.
most physicians cannot endorse it as a hair loss remedy to the 19. Small EJ, Baron AD, Fippin L, Apodaca D. Ketoconazole retains
general public. The 2% Ketoconazole shampoo is used every activity in advanced prostate cancer patients with progression
third day, on pre-washed hair, with foam remaining on the despite flutamide withdrawal. J Urol. 1997;157(4):1204–7.
20. Oh WK. Secondary hormonal therapies in the treatment of prostate
scalp for 5–10 min before rinsing. cancer. Urology. 2002;60(3 Suppl. 1):87–92.
21. Harris KA, Weinberg V, Bok RA, Kakefuda M, Small EJ. Low dose
ketoconazole with replacement doses of hydrocortisone in patients
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Retinoic Acid
32
List of Essential Medicines along with the most effective and

Basic Concepts safe medicines needed in a health system [4].
• Retinoids are a mainstay in the treatment of acne Retinoids are ingested in precursor forms, with animal
vulgaris; they act via specific nuclear receptors, sources containing retinyl-esters and plant sources contain-
RXRα, RARβ, and RARγ, they induce protein syn- ing carotenoids. Tissue cells convert these organic precur-
thesis and cell turnover modulating the proliferation sors to retinοl and then either to retinal or RA [5]. Both
and differentiation of epidermal and follicular cells. retinal and RA possess potent effects on the growth, matu-
• Tretinoin, or all-trans-retinoic acid (ATRA), con- ration, and differentiation of many cell types, both in vivo
trols the hair growth cycle, increases the duration of and in vitro [6]. The synthesis of RA from circulating reti-
anagen, decreases the duration of telogen, increase nol occurs through the action of two enzyme families: reti-
angiogenesis of the skin, and decrease the size of nol dehydrogenase (Roldhs), which catalyzes the reaction
the sebaceous glands. of retinol to retinal and is the rate-limiting step, and retinal
• ATRA has been suggested to act synergistically dehydrogenase (Raldh/Aldh1a), which catalyzes the reac-
with Minoxidil Topical Solution (MTS), producing tion of retinal to RA [7]. Retinoic acid is insoluble in water
more hairs than either compound alone, and but soluble in numerous organic solvents (ethyl alcohol,
enhances the percutaneous absorption of Minoxidil propyl glycol, etc.); in its pure crystalline form, it has a
by up to 300%, via stratum corneum permeability bright yellow color.
increase. Retinoic acid is prone to further oxidation towards form-
• MTS 5% + ATRA 0.01% o.d. has been reported to ing an inactive ester, primarily upon exposure to intense
be equally effective to 5% MTS b.i.d. allowing a light. Topical use of ΑΤRΑ on facial skin leads to percutane-
simpler dose regimen, which might increase long- ous absorption of less than 2%, whereas repeated applica-
term compliance to treatment. tions are not increasing percutaneous uptake [8]. Other
• Evidence on this combined treatment is weak and authors have reported that the percutaneous absorption of
mostly anecdotal, and patients must undergo fre- ATRA can occasionally reach 5–7% [9]. The systemically
quent re-evaluation for topical adverse effects. absorbed ATRA is metabolized by the liver, leaving no resi-
dues in the body, even after long-term use [10].
Vit Α and its derivatives (retinoids) have been known since 32.1 Mechanism of Action of Retinoids
the beginning of the twentieth century to be essential for and ATRA
developing and maintaining various tissues, including the
skin and hair [1, 2]. Retinoic acid, also known as Tretinoin, Despite the wealth of clinical and experimental data, the pre-
or all-trans-retinoic acid (ATRA) in its pharmaceutical form, cise mode of action of retinoids remains to be determined.
is the carboxylic acid, an acidic, active metabolite of Vit ATRA, which is generally thought to exert most biologic
A. Retinoic acid (RA), and retinoids, in general, are the most actions of retinoids, is no exception. ATRA affects several
extensively studied class of drugs for acne treatment [3]. physiological and biological activities, including prolifera-
ATRA was patented in 1957, got approved for medical use in tion, cell cycle, angiogenesis, migration, apoptosis, and
1962, and notably, it is on the World Health Organization’s fibrosis in a plethora of cell types.
142 32 Retinoic Acid
Retinoids act via specific nuclear receptors and belong to keratoses, uniform dispersion of melanin granules, new col-
ligand-dependent transcriptional regulators [11]. There are lagen formation in the papillary dermis, new vessel forma-
two types of retinoid receptors: Retinoic acid receptor (RAR) tion (angiogenesis), and exfoliation of retained horn in the
and Retinoid X receptor (RXR) [12]. Each type of receptor follicles [21].
can be divided into three subtypes: α, β, and γ [13]. The
human sebaceous glands express RXRα and RARγ [14] pri-
ATRA on healthy, non-photo-aged skin promotes kera-
marily, while dermal papilla cells (DPCs) mainly express
tinocyte proliferation, induces epidermal thickening,
RARβ [15]. ATRA binds to RARα, RARβ, and RARγ with
and alleviates skin aging signs without any significant
similar affinity.
adverse reaction [22]. Therefore, ATRA is frequently
The activation of RARα, RARβ, and RARγ results in
used as a potent skin rejuvenation compound [23].
gene expression modifications, subsequent protein synthesis,
and epithelial cell growth and differentiation. However, it
has not been established whether ATRA’s clinical effects are
mediated through activation of RARs, other mechanisms, or 32.2 ATRA and the Hair Follicle
both. RAR genes have been identified in almost every por-
tion of the hair follicle. RARs differ depending on the spe- The hair growth potential of ATRA was accidentally discov-
cific portion of the hair follicle. There is a complex interaction ered, as is often the case with most scientific discoveries.
between RA and cellular RA-binding protein (CRABP). RA When ATRA was initially tested in acne treatment, increased
can increase CRABP, but excess CRABP can increase the vellus or lanugo hair growth was reported in areas where
amount of RA within the cell. RA binds to the CRABP ATRA was applied for prolonged periods. Subsequent stud-
within the cell nucleus, inducing protein synthesis and cell ies demonstrated that ATRA affects follicular physiology
turnover, modulating the proliferation and differentiation of through various, intricate mechanisms and that its action is
epidermal cells [16]. Research has established that ATRA synergistic to that of Minoxidil. Eventually, more light has
plays an essential role in hair follicle formation and pattern- been shed on the hair growth potential of ATRA and reti-
ing through the homeobox gene proteins Hox C8 and Hox noids in general, especially in patients with AGA/FPHL:
C6. ATRA has been found to both up- and down-regulate the
homeobox genes, which consequently influence hair follicle 1. Retinoids can have a significant effect on the hair follicle
generation, initiation, differentiation, and inhibition [17, 18]. during the various growth and regression phases, nota-
ATRA has been used for more than 50 years in the treat- bly increasing anagen duration and decreasing that of
ment of acne vulgaris [19]. Although the exact mode of telogen [24],
action of ATRA is still largely unknown, the evidence sug- 2. In general, retinoids exert anti-inflammatory effects via
gests its efficacy is due to the ability to modify abnormal the inhibition of leukotriene B4 (LTB4)-induced
follicular keratinization. Comedones form in follicles with migration of polymorphonuclear leukocytes to the
an excess of keratinized epithelial cells. ATRA promotes the skin [25], which might reduce the AGA-related
detachment of cornified cells and the enhanced shedding of microinflammation,
corneocytes from the follicle. By increasing the mitotic 3. Moreover, retinoids decrease the expression of the ara-
activity of follicular epithelia, ATRA also increases the turn- chidonic acid-induced secretion of pro-matrix metallo-
over rate of thin, loosely-adherent corneocytes. Through proteinase (MMP)-9 and (MMP)-13 [26],
these actions, the comedo contents are extruded, and the for- 4. Retinoids can promote and regulate cell proliferation
mation of the microcomedo, the precursor lesion of acne vul- and differentiation in the epithelium [27] and may pro-
garis, is reduced. mote vascular proliferation factors important for hair
The main pharmaceutical action of ATRA is that of chem- growth promotion [28],
ical peeling. ATRA is a compound with keratolytic proper- 5. Retinoids dramatically reduce the size of the sebaceous
ties and effectively dissolves the stratum corneum, and like glands (by even 90%) and lower sebum production both
all such compounds, it is mildly caustic. ATRA decreases the in vitro [29, 30] and in vivo, equally in lab animals [31]
coherence of the stratum corneum’s epithelial cells, thus and humans [32, 33]. The exact mechanism by which
causing its lysis and, consequently, the formation of a dry, retinoids suppress lipid synthesis in the sebaceous gland
flaky skin (peeling) [20]. Besides treating acne, ATRA can is still unknown [34]. It is speculated that they either
be used to treat photo-aged skin, in which daily topical appli- decrease the action of lipogenetic enzymes or decrease
cation of 0.05% ATRA results in impressive positive effects the gland’s cellular proliferation [35]. As analyzed in
on photoaged skin, which include the following: replace- Chap. 15, Vol. 1, the sebaceous glands contain all
ment of the atrophic epidermis by hyperplasia, elimination upstream enzymes of androgen metabolism that catalyze
of dysplasia, and atypia, eradication of microscopic actinic weaker androgen conversion to more potent ones.
32.2 ATRA and the Hair Follicle 143
Balding hair follicles contain hypertrophic glands in Recently, in vitro studies in follicle organ cultures, cultured
which all these enzymes are over-expressed compared to human DPCs, and normal human epidermal keratinocytes
occipital control follicles [36–38]. Consequently, the have confirmed that the combination of Minoxidil plus
sebosuppresive effect of retinoids might indirectly exert ATRA has the following advantages [47, 48]:
a positive impact on balding hair follicles. There is no
direct proof, but since sebum contains DHT, the amount 1. Minoxidil plus ATRA enhances proliferation of human
of sebum-containing DHT reabsorption by the follicle in DPCs and epidermal keratinocytes to a greater extent
balding areas might also be decreased, exerting less of a than Minoxidil or ATRA alone,
negative effect in AGA hair follicles, 2. Minoxidil plus ATRA elevate the phosphorylations of
6. Preliminary studies of cellular retinoic acid-binding pro- Erk and Akt in cultured human DPCs and epidermal kera-
tein (cRABP) levels in whole scalp skin of human sub- tinocytes more effectively than Minoxidil or ATRA alone,
jects with AGA indicated that, in the scalp areas not which increases growth and survival of DPCs and epider-
affected by AGA, levels of cRABPs were higher than in mal keratinocytes,
areas with AGA and that the levels of cRABPs in whole 3. Minoxidil plus ATRA increases Bcl-2 expression and
skin were increased by topical application of decreases Bax expression and TUNEL-positive cells
RA. However, this finding has not been further explained more than Minoxidil or ATRA alone,
[39], 4. Minoxidil plus ATRA enhances hair growth more effi-
7. Initially, it was considered that retinoids do not exert any ciently than Minoxidil or ATRA alone in human hair fol-
anti-androgenic or other hormonal action [40]. It was licle organ culture,
later discovered that 13-cis-retinoic acid is a potent com- 5. Minoxidil plus ATRA downregulates the expressions of
petitor of 3α-HSD and RoDH-4 enzymes, which are P53 and P21 in DPCs and NHK more efficiently than
related to the conversion of 3-androstenediol into DHT Minoxidil alone.
occurring in the sebaceous gland. The reduced local pro-
duction of DHT from 3-androstenediol might explain These results suggest that Minoxidil plus ATRA could have
the unique sebosuppressive effect of retinoids when an additive effect on human hair growth and that the actual
treating acne [41] and the hair growth potential of reti- hair growth modulatory effects of the combination of
noids in AGA, Minoxidil plus ATRA would be derived from different mech-
8. ATRA, in combination with Minoxidil, elevates phos- anisms, i.e., via the activation of Erk-and Akt-dependent
phorylated Erk, phosphorylated Akt, and the ratio of pathways and via the prevention of apoptosis, by increasing
Bcl-2/Bax. Simultaneously, ATRA decreases P53 and the Bcl-2/Bax ratio, and the number of TUNEL negative
P21 proteins more effectively than Minoxidil alone, thus cells [47, 48].
preventing cellular apoptosis of the dermal papilla These in vitro results have been tested in lab animals by
in vitro [42], Aldhalimi et al. [49], but results did not agree with in vitro
9. ATRA modulates nitric oxide pathways, inhibiting the studies. Researchers divided mice into four groups of five
secretion of nitric oxide and TNF-α [43], and treated them with topical application of 95% ethanol,
10. ATRA has been reported to increase threefold 2% Ketoconazole solution, 5% Minoxidil topical solution
Μinoxidil’s percutaneous absorption, probably due to (MTS), and MTS with Tretinoin solution 0.1%, respectively.
the increased stratum corneum permeability. Minoxidil The results demonstrated that Ketoconazole, MTS, and MTS
reaches the target-organ, the hair-follicle, faster and with Tretinoin had a significant stimulatory effect on hair
more efficiently and ultimately exhibits a higher concen- growth compared with the control group. However, Minoxidil
tration in the dermal papilla [44]. Combining ATRA and was the most effective drug and the results obtained from the
Μinoxidil has been found to increase the hair-growth combination of Minoxidil with low dose Tretinoin were sig-
effect of both compounds. It is considered that this is due nificant, yet less than that of MTS [49].
to both the direct hair-growth effects of ATRA and to the
increased absorption of Minoxidil [45],
Overall, retinoids seem to initiate cell growth and dif-
11. Sharma et al. [46] reported that topical ATRA applica-
ferentiation that Minoxidil does not stimulate.
tion influences follicular sulfotransferase expression,
Likewise, Minoxidil can promote mitogenic and vaso-
which converts Minoxidil to its active sulfated metabo-
dilatory action not obtained with the retinoids [48].
lite, Minoxidil sulfate. In a cohort of ten males and ten
females patients with AGA/FPHL (average age 32),
43% of subjects initially predicted to be non-responders However, ATRA can have both positively and negatively
to Minoxidil were converted to responders following 5 regulating function in hair growth. ATRA induces TGF-β2
days of topical tretinoin application [46]. expression in a variety of cells and organs, such as human
pancreatic cells and rat keratinocytes [50]. Further study has synergistically with Minoxidil to produce more dense hair
shown that exogenous ATRA can inhibit hair follicle growth regrowth from regressing follicles than either compound
by inducing catagen with TGF-β2 expression in human hair alone [54].
follicle DPCs [51]. Additionally, ATRA activates TGF-β/ Shin et al. conducted a randomized, double-blind, com-
Smad signaling and function in several cell types and organs parative clinical trial to compare the efficacy of a 5% MTS
for cell differentiation, proliferation, and apoptosis [52]. plus 0.01% ATRA solution with that of conventional 5%
Lately, Nan et al. [53] demonstrated that ATRA inhibited MTS [55]. Thirty-one male patients with AGA (stage III–V)
mink hair follicle growth and DPCs proliferation and induced were randomly assigned into two groups, one group in which
apoptosis of DPCs in vitro and ATRA functioned its role 5% MTS and 0.01% ATRA was applied to the scalp once
might be partially through TGF-β2/Smad2/3 pathway [53]. daily at night, together with a vehicle placebo in the morn-
ing, and the other group in which 5% MTS was applied twice
daily. The efficacy parameters were total hair count changes
32.3 ATRA and AGA/FPHL in a 1.5 cm diameter circular target area, non-vellus hair
count, anagen hair ratio, linear hair growth rate, mean hair
Published data on the effects of retinoids and specifically of diameter assessed by macrophotographic image analysis,
ATRA in AGA/FPHL are very limited, and results of just and patient and investigator subjective assessments. After
three small-scale trials are available, which are unfortunately therapy, there were no statistically significant differences
inconclusive and conflicting. Nevertheless, adding ATRA in between the two treatment groups concerning changes in
MTS is a popular galenic mixture that many Dermatologists macrophotographic variables or scores on global subjective
use in everyday practice. evaluations by patients and the investigator. The mean
Bazzano et al. [27] were the first to publish on the hair changes from baseline total hair count did not differ signifi-
growth potential of ATRA. Both worked in the Department cantly at 18 weeks, though the 5% MTS and 0.01% ATRA
of Dermatology of Tulane University Medical School, New solution led to slightly elevated values (15.9 hairs/cm2 vs.
Orleans, Louisiana, and had already significant work on reti- 18.2 hairs/cm2), which were statistically insignificant.
noids. Bazzano et al. [27] assessed the effect of ATRA + Overall, the treatment effect of both schemes was equivalent,
MTS on hair growth and regrowth on 56 patients in several with the advantage of once-daily application for the combi-
small pilot studies conducted between 1983 and 1986. In one nation scheme [55].
of these studies, 56 males were separated into 4 groups, Gugle et al. [56] published their study in which they com-
using various treatment schemes, all applied twice daily: pared the efficacy of 5% MTS vs. the efficacy of a combina-
0.025% ATRA was used alone (n = 12), 0.025% ATRA was tion of 5% MTS, topical 1.5% Azelaic acid, and topical
used in combination with 0.5% MTS (n = 36), 0.5% MTS 0.01% Tretinoin in the treatment of AGA. They recruited and
was used alone (n = 3) and a control group that used vehicle randomized 46 equally distributed males aged 23–56 years
solution was also included (n = 5). After 12 months of treat- old. The authors reported that both 5% MTS and combina-
ment, the 0.5% MTS + ATRA group reportedly had the best tion treatment were equally effective in AGA treatment and
results since 16 patients had a good response, and 8 had a that combination treatment had no added advantage over 5%
moderate response; altogether, 66% of patients in that group MTS monotherapy. The mean number of hairs increased by
showed an increase in terminal hair growth. The smaller 27.7%, and average hair thickness increased by 38.8% in the
ATRA group included two men with good response and 5 monotherapy group, vs. 25% and 41% in the combination
with a moderate response. Altogether, 58% of patients in that treatment group, respectively [56].
group showed an increase in terminal hair growth, whereas There is also one case report by Walsh et al. [57] who treated
the other two groups had 0% response. a 32-year-old healthy white male with AGA (stage V) with
However, the trial was not blinded, nor randomized. Also, 3.75% MTS combined with 0.05% ATRA (4:1 vol/vol) for
the authors reported that evaluation was done with target final concentrations of 3% MTS and 0.01% ATRA, together
area hair counts (1-in. diameter) and global photographs with oral Finasteride 5 mg daily. The patient was reported to
evaluation, no data on hair counts were included in the arti- have an excellent response, even after discontinuing Finasteride
cle, and only photographs of selected cases with impressive 5 mg on month 8, and that he continued to grow hair until
response were included. A striking example of an impressive month 12 when he had reportedly improved from Norwood-
response was that of a 43-year-old woman with extensive hamilton stage V pretreatment to stage III [57]. The full-text
FPHL since she was 20 years old, who had increased hair article contains pre- and post-treatment photos revealing a
counts of 1100% within 18 months of ATRA monotherapy marked increase in terminal hair density. The mechanism of
[27]. The same researchers claimed that retinoids increased continued improvement after Finasteride’s discontinuation was
the rate of hair growth, prolonged the anagen duration, recently explained by Van Neste et al. [58] and should not be
played a role in converting vellus to terminal hairs, and acted attributed to Ketoconazole (see Chap. 23).
32.5 Combining ATRA and Minoxidil 145
From the limited and low to moderate quality clinical data

available for the efficacy of the MTS + ATRA combination It is important to remember that ATRA enhances the
treatment in AGA, there seems to be only one advantage: percutaneous absorption of Minoxidil due to the
adding ATRA into 5% MTS and using it once daily might increased stratum corneum permeability [44]. This
have a similar treatment effect to the twice-daily scheme of might contribute to the higher incidence of Minoxidil-
conventional 5% MTS. related adverse effects, most commonly hypotension,
dizziness, tachycardia, and water retention [69].
There is a known, fully substantiated, reversely pro-
portional relationship between the frequency of dose
Intense redness and local irritation, change of skin pig-
regimens and medication compliance [59]. Thus, the
mentation, and photosensitivity have sporadically been
use of 5% MTS + 0.01% ATRA o.d. could be an effi-
reported as a result of ATRA use but are fully reversible upon
cient hair growth modulatory strategy in the manage-
treatment discontinuation. Application of MTS + ATRA to
ment of AGA, since 5% MTS b.i.d., seems to have very
the scalp using single-use gloves is recommended in order to
high discontinuation rates in real-life clinical practice,
avoid the absorption of ATRA through the digital skin, which
even when results are satisfactory [60–62].
might lead to skin peeling of the fingers. Topical ATRA
safety during pregnancy or breastfeeding is undocumented,
and oral ATRA is a potent teratogen. ATRA is pregnancy
32.3.1 Use of ATRA in AGA/FPHL category D, categorized as “suspected to have caused or may
be expected to cause, an increased incidence of human fetal
Patients using an MTS + ATRA solution must be advised to malformations or irreversible damage”. Anecdotally, topical
avoid excessive sun exposure since 70% of ATRA degrades ATRA formulations are considered safe due to low systemic
after even brief sun exposure [63]. Avoiding the sun, using absorption [9].
sunscreen or a hat is necessary when MTS + ATRA is Finally, there are no reports of the use of topical ATRA
applied to the scalp, especially for individuals with occupa- causing CNS symptoms, in contrast to Isotretinoin’s oral
tional chronic sun exposure [64]. Also, due to ATRA- use, which has been linked to neurological and psychiatric
induced epidermal peeling, ATRA-treated scalp skin is symptoms, such as depression, psychotic syndrome, mood
more susceptible to sunburns and more sensitive to the cold swings, aggressive behavior, and suicidal tendencies [70].
and wind. ATRA-thinned scalp skin results in a stinging There is, however, an overall lack of concrete scientific
sensation when exposed to the sun [65], which, however, data that limits any conclusion that can be drawn about a
attenuates over time [66]. Concomitant use of other phar- causal relationship between ATRA and psychiatric adverse
maceutical formulations, such as scalp cleansers or “strong” events [71].
shampoos, should be cautious, especially for compounds
containing sulfur, resorcinol, or salicylic acid. The com-
bined effects of irritant compounds affecting the stratum 32.5 Combining ATRA and Minoxidil
corneum are complex, and severe skin irritation may be
induced [67]. Users should be gentle when washing their Choosing the appropriate ATRA concentration is a critical
hair, use a mild shampoo, and avoid vigorous scalp scrub- challenge. Multiple studies within the literature have sought
bing or brushing [27]. to determine the optimal concentration of ATRA to balance
its beneficial and deleterious effects; however, published
data concerning its use in AGA/FPHL are very limited. It is
32.4 Adverse Effects a delicate balancing act between using too much and too lit-
tle ATRA in treating AGA. A too low concentration will be
Adverse effects caused by ATRA are rare and mostly ineffective in inducing hair growth, while a too high concen-
restricted to local effects. The topical use of ATRA is associ- tration may result in telogen effluvium. This phenomenon
ated with local irritation, desquamation, redness, a burning can present both through hormonal [72, 73] and a mechani-
sensation, and local discomfort. Collectively, this side effect cal mode of action, since ATRA loosens follicular attach-
profile is termed “retinoid reaction”. However, these symp- ment to the skin, making hair to shed more easily due to
toms and clinical signs do not constitute side effects per se mechanical causes, like brushing or pulling [74]. The appro-
but actual ATRA effects. Typically, the retinoid reaction is priate concentration of ATRA is mostly idiosyncratic.
dose-dependent, will occur at the beginning of treatment, Therefore, most physicians prefer a “safe” MTS + ATRA
and will last for 7–10 days before subsiding over time. Actual 0.025%w/v solution. Others may start with even a lower con-
allergic dermatitis to ATRA is very rare [68]. centration and will gradually increase it until a maximum
tolerable dose, in terms of local adverse effects, is reached; Novel marketed formulations of ATRA clearly more tol-
this is usually no more than ATRA 0.1%w/v. erable [87] and to reach the hair follicle more efficiently than
Formulating the combined solution is another key issue. conventional ATRA [85]. The same applies to the newer,
Shapiro and Price have reported that Rogaine® and Retin-A® third, and fourth generation retinoids that are significantly
(the proprietary products) are incompatible and become inef- more tolerable than ATRA. A newer retinoid, Tazarotene,
fective if compounded in the same solution [75]. Therefore, has been demonstrated even to reverse corticosteroid-
the pharmacist should prepare the combined solution by add- induced epidermal atrophy since it can increase the thickness
ing pure ATRA in generic powder form in the 5% MTS con- of the epidermis by 62% [88]. Adapalene was introduced in
tainer. Propyl glycol and isopropyl alcohol already contained 1995, and it is another third generation retinoid, formulated
in MTS are ideal ATRA solvents and for optimizing percuta- as a 0.1% gel which has unique properties in terms of chemi-
neous absorption [76]. cal rigidity and photostability [89]. Adapalene has an ideal
size of 3–10 μm, which allows it to penetrate freely deep into
the pilosebaceous unit, has anti-inflammatory skin proper-
ATRA and Minoxidil are both concentration-dependent
ties, superior to those of ATRA [90], and comparable to beta-
compounds. Thus, mixing an ATRA lotion and MTS
methasone-17 valerate and indomethacin.
will dilute both solutions and lower the concentration
Recently, Kochar et al. [91] developed a liposomal hydro-
of both active molecules in the end solution. Instead,
gel system for simultaneous delivery of Minoxidil and
ATRA powder should be added to MTS in order to
ATRA. They reported that prepared liposomes were stable,
achieve the desirable ATRA concentration without
homogenous, capable of holding both the drugs within. The
affecting the concentration of Minoxidil in the
liposome-loaded hydrogel carrier was found to be non-
solution.
irritant to the skin, enhanced the permeation of Minoxidil
through skin ex vivo but ATRA retained on the skin [91]. In
Caution should be exerted in patients under treatment the future, liposomes could serve as a great alternative plat-
with MTS + ATRA since case studies of serious adverse form for simultaneous administration of both drugs in a sin-
effects have been reported in the literature, even though very gle system with ease of administration and minimal
rare [77, 78]. In the recent (2018) systematic review irritancy.
(Evidence-based (S3) guideline for the treatment of androge- Even though newer retinoids seem to combine the best of
netic alopecia in women and men) issued for the European both worlds in terms of efficacy and low rate of adverse
Dermatology Forum, Kanti et al. included only two studies effects, no studies are substantiating the compatibility of
[27, 50] investigating ATRA in AGA, one of which was newer retinoids with MTS or the synergism of such a combi-
attributed with grade A2 evidence (placebo-controlled) and nation in AGA treatment. Consequently, to avoid cross-
one with grade B evidence, resulting in an overall level of reactions or incompatibilities between MTS and any newer
evidence 2 [79]. retinoid, one should apply these compounds on the scalp
separately from MTS, making this an impractical option for
most patients. Moreover, no studies are proving that any of
32.6 New Pharmaceutical Formulations these substances has hair growth potential.
of ATRA and Newer Retinoids
Synopsis
Although ATRA is, in many respects, an ideal topical formu- Combining 5% Minoxidil topical solution (MTS) and ATRA
lation, it occasionally causes disturbing skin irritation, dry- might be a useful addition to the toolkit of physicians treat-
ness, erythema, and peeling, and these adverse effects make ing patients with AGA/FPHL. Simultaneous administration
patients less compliant to treatment. Since the desired effect of MTS with ATRA may enhance the response of follicles to
is to induce preferential accumulation of ATRA in appenda- Minoxidil. Synergism of these two compounds has been
geal structures, more sophisticated ATRA formulations have reported, resulting in superior results than using any of the
been developed. One such example is Retin-A® Micro, con- compounds alone. Additionally, the combination treatment
taining ATRA microspheres, which allow gradual release of can be used once daily with reportedly similar results to 5%
the compound in the skin, resulting in significantly higher MTS used twice daily, which increases patient compliance
efficacy, faster onset, longer duration of action (>48 h), and and, therefore, efficacy compared to monotherapy with each
increased safety of use [80]. compound. ATRA-induced local adverse effects, such as
Other experimental examples include liposomes [81], mild skin irritation and exfoliation, might be challenging for
solid lipid nanoparticles [82], transferosomes [83], pronio- some patients. Direct sun exposure of the scalp must be
somes [84], polymeric micelles [85], and niosomes [86]. avoided, and mild shampoo is needed for washing. Mixing a
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Azelaic Acid
33
Basic Concepts
33.1 Mechanism of Action
• Azelaic acid has bacteriostatic and anti-
The primary use of AzA in Dermatology is in the treatment
inflammatory properties, and it is used locally to
of mild to moderate acne and, more recently, rosacea [3].
treat mild to moderate comedonal and inflamma-
However, the mechanism of action has not been clarified
tory acne. It is also used as a topical gel treatment
AzA exhibits the following properties [4]:
for rosacea and to treat melasma and post-
inflammatory hyperpigmentation.
1. It demonstrates bacteriostatic activity to both aerobic and
• Azelaic acid has been reported in an one early
anaerobic bacteria, including Propionibacterium acnes
in vitro study to effectively inhibit the 5a-R enzyme
and Staphylococcus epidermidis. Notably, the bacteri-
and, when combined with Zinc and Vit B6, to
cidal effect of AzA is considerably reduced in the pres-
induce a complete inhibition of the enzyme. This
ence of nutrients in vitro [5],
report has not, however, been replicated in vitro,
2. It is an anti-keratinizing agent, displaying antiprolifera-
nor the effects verified in vivo.
tive/cytostatic effects on keratinocytes and modulating
• Azelaic acid has not been reported to have any hair-
the early and terminal phases of epidermal differentiation
growth effects in any controlled, randomized trials
by reducing the thickness of stratum corneum [6],
during the three decades it is on the market since the
3. AzA is a disodium salt (C(9)2Na) and has potent scav-
FDA approved its use, lately with an indication for
enging properties on free radicals [7],
the treatment of rosacea.
4. It has been speculated to regulate sebum secretion [8], but
this theory has been met with scepticism [9],
5. AzA has been reported to possess a variety of anti-
Azelaic acid (AzA) is an organic compound found in abun- inflammatory and antioxidant properties, the former
dance in nature and physiologically in low systemic levels in including downregulation of cathelicidin (LL-37) and
humans. Many food sources, such as wheat, barley, and rye, activation via inhibition of serine protease (kallikrein-5)
regularly expose humans to AzA through dietary intake. AzA [10–12],
is a saturated dicarboxylic acid, much weaker than house- 6. In vitro, it has been reported as a potent inhibitor of
hold vinegar. Available data show that AzA appears to be 5α-Reductase (5α-R), preventing the conversion of
devoid of acute or chronic toxicity, is not mutagenic or tera- Testosterone to dihydrotestosterone (DHT) [13]. This
togenic [1]. The daily oral tolerable dose exceeds 20gr, mak- property could render it an attractive potential treatment
ing it very safe, even when used orally, for extended periods for AGA, and Price and Shapiro, in an older (1998) semi-
[2]. AzA is industrially produced by the ozonolysis of oleic nal review, have mentioned AzA as a possible future adju-
acid, the side product being a nonanoic acid. Naturally, it is vant treatment of AGA/FPHL [14].
produced by Pityrosporum ovale, which is part of the normal 7. Recently, Amirfakhryan et al. investigated the protective
skin flora of humans, and the bacterial degradation of nona- effects of AzA against ultraviolet B (UVB) irradiation in
noic acid gives AzA. cultured bulb and bulge cells by determining catalase
152 33 Azelaic Acid
activity and Sonic hedgehog (Shh) protein expression. This was followed by a subsequent 8-week follow-up period,
Catalase activity significantly (p < 0.05) increased in the during which no cream was applied. The authors reported
bulge cells after exposure AzA and led to Shh protein that AzA exhibited similar degrees of efficacy in encourag-
overexpression in the hair follicles in vitro and in organ ing hair growth to anthralin [21]. At week 20, the terminal
culture. Overall, AzA protected the bulge cells from UVB hair regrowth score was 1.27 ± 0.9 in the AzA group vs.
damage and its combination with Minoxidil may activate 1.37 ± 0.8 in the anthralin group (p > 0.05). A complete
hair growth through overexpression of Shh protein [15]. response was observed in 53.3% of cases in the AzA group
(8 of 15 patients) compared to 56.2% (9 of 16 patients) in the
After local application of AzA, approximately 10% of the anthralin group (p > 0.05), overall showing that AzA can be
compound remains in the epidermis and dermis, and within an effective topical therapy for patchy AA. Nevertheless,
4 h, only 3–5% penetrates the skin barrier, mostly through spontaneous regrowth cannot be excluded in this study popu-
hair ducts (transfollicularly) [16]. Before using AzA, the lation, as Hordinsky et al. commented in their excellent
skin must be thoroughly cleaned with water to remove sur- review [22].
face cells of the stratum corneum. This will increase There are only three literature reports on the effects of
absorption, which is maximized at pH = 5 [17]. The percu- AzA in AGA patients.
taneous absorption of a 20% AzA cream has been assessed Gugle et al. compared the efficacy of topical 5% Minoxidil
to be no more than 3.6%, and AzA metabolites are readily solution (MTS) versus efficacy of the combination of 5%
excreted in the urine, making AzA very safe, even for long- MTS, topical 1.5% AzA, and topical 0.01% Tretinoin in the
term use [18, 19]. treatment of AGA on 46 randomized and equally distributed
males aged 23–56 years old. The authors reported that 5%
MTS and combination treatment were equally effective in
33.2 Azelaic Acid and AGA/FPHL the treatment of AGA, and that combination treatment had
no added advantage over 5% MTS monotherapy. The mean
A hair growth effect has been attributed to AzA due to a sin- hair number increased by 27.7%, and average hair thickness
gle, early, in vitro study and another small, randomized trial increased by 38.8% in the monotherapy group compared to
on Alopecia Areata (AA) patients. 25% and 41% values respectively in the combination treat-
In their study on foreskin samples, Stamatiadis et al. ment group [23].
tested the effects of AzA, Zinc sulfate (ZnSO4), and Vit Β6 Pazoki-Toroudi et al. conducted a double-blind, random-
on the inhibition of 5α-R. At a concentration as low as ized controlled trial evaluating the efficacy of a combined
3 mmol/L, AzA inhibited 5α-R by 98%, while ZnSO4 topical solution (5% MTS, 1.5% AzA, and 1% caffeine) on
required a concentration of 15 mmol/L to achieve a 98% hair growth in comparison to a 5% MTS or a placebo solu-
inhibition. When both compounds were combined, just tion. Seventy-one Iranian men aged ≥23 years with AGA
0.5 mmol/L of AzA and 3 mmol/L of ZnSO4 could achieve a were divided into three groups: combined solution group
95% inhibition. Adding Vit Β6 (0.025%) to ZnSO4 resulted (n = 40), 5% MTS group (n = 20), or placebo (n = 11) group,
in a two-fold increase in the inhibition of the 5α-R enzyme for a total period of 32 weeks. Each treatment’s efficacy was
activity, whereas Vit Β6 alone or combined with AzA had no evaluated every 6 weeks by wash test (number of hairs shed),
inhibitory effect. The additive effect of all three compounds subjective patient self-assessment, and objective dermatolo-
in concentrations that had no inhibitory activity when used gist assessment. After 12 weeks of treatment, both combined
alone (Vit Β6 0.025%, 0.1 mmol/L of AzA, and 0.5 mmol/L and 5% MTS solutions significantly reduced hair shedding
of ZnSO4) resulted in 90% inhibition of 5α-R [13]. compared to the placebo group (p < 0.05). Also, the efficacy
of the combined topical solution at 12 weeks was as good as
the efficacy of 5% MTS at 32 weeks (p < 0.05). In both the
However, these in vitro results on human homogenates
dermatologist’s objective assessment and patient subjective
have not been confirmed in any clinical study ever
self-assessment of the combined topical solution group,
since.
moderate and marked response rates were significantly
higher than the two other groups (p < 0.001 vs. placebo and
The only other in vitro data available on the allegedly p < 0.05 vs. 5% MTS). The authors commented that the com-
anti-androgenic effect of Vit B6 is that it reduces the extent bined topical solution resulted in a faster and better clinical
of protein synthesis observed after androgen receptor activa- result in comparison to 5% MTS and had the same side effect
tion by 35–40% [20]. profile [24]. This study is available only as an abstract.
Sasmaz et al. conducted a randomized controlled trial on Pazoki-Toroudi et al. conducted a study on 59 male
31 patients with AA on whom 20% AzA (n = 15) or 0.5% patients with AGA (stage I-IV in the Hamilton-Norwood
anthralin (n = 16) was applied for 12 consecutive weeks. scale) and 55 females with FPHL (stage I-III in the Ludwig
References 153
scale). They compared the hair growth effects of 5% MTS Dermatology Forum, Kanti et al. included only the study by
(n = 49) b.i.d., a combination solution (MHEC) containing Pazoki-Toroudi et al. [25] However, they made clear that
12.5% MTS, 5% AzA and 0.025% betamethasone valerate they cannot make a recommendation for combination ther-
(n = 57) o.d. and placebo topical solution b.i.d. (n = 18). apy of MTS with topical AzA and Betamethasone valerate
Patients were assessed by wash test, which they performed and that further studies are needed to confirm the superiority
by themselves at home, and collected the shed hairs to be of combination therapies to improve or prevent progression
counted at the dermatologist’s office. Compared with base- of AGA/FPHL [31].
line values, both 5% MTS and MHEC reduced hair shedding
in men (p < 0.05 and p < 0.01) and women (p < 0.05) at
24 weeks. Mean differences in shed hair showed a significant 33.3 Adverse Effects
difference between 5% MTS and MHEC in men
(−33.47 ± 3.22 vs. -63.6 ± 4.54, p < 0.01) and women AzA is well tolerated on topical application, with adverse
(−28.62 ± 6.19 vs. -53.44 ± 5.82, p < 0.05). At 24 weeks, effects limited to mild and transient local cutaneous irritation,
according to the investigator’s assessment, moderate soreness, burning, dryness, and pruritus. Rarely, depigmenta-
improvement was evident in 35% and marked improvement tion at the application surface has been reported, although AzA
in 6.25% of male patients in the MTS group (p < 0.001 vs. does not affect normal skin melanocytes, except in melasma
placebo). In the MHEC group, moderate improvement was and skin discoloration areas [31]. There are rare reports of local
evident in 42.86% and marked improvement in 23.81% of allergic reactions and exacerbation of herpes labialis when
male patients. The results in female patients treated with AzA is used. Azelaic Acid is non-teratogenic and has not been
MHEC were significant only when compared with the pla- related to any systemic effects, even in chronic use of 20% AzA
cebo group (p < 0.001). Only one pair of before-and-after topical formulations [32]. Additionally, no systemic safety
photographs of very poor quality is included in the full-text issues have been associated with the application of 20% cream,
article. 15% gel, and/or 15% foam formulations. All three formula-
tions have been extensively studied in research trials and col-
Besides the severe methodological weaknesses (home lectively have been available in the United States market for
wash-test), the claim of the authors that “…AzA approximately three decades [33].
potentiates the effects of Minoxidil, especially in
males” is totally unsubstantiated [25]. Synopsis
Azelaic acid (AzA) is a safe, well-tolerated compound that
has been reported in an early (1988), single in vitro study to
As already mentioned, the results of Stamatiadis et al. inhibit 5α-R enzymes in vitro when combined with Ζinc and
have not been replicated by any other team since 1988. The Vit Β6. No clinical studies support the speculated hair growth
preparation of a solution containing AzA, Zinc, and Vit B6 is properties for AzA, whereas the combined solution with
challenging since Zinc and Vit B6, when added in the same Ζinc and Vit Β6 is hard to formulate, and only anecdotal
solution, precipitate in the form of white-colored flakes. The patients’ stories on the internet perpetuate the value of AzA
combination of all three substances is not commercially as a hair-growth agent.
available. Until 2011, the topical preparation Xandrox® was
available. It contained Minoxidil, Retinoic acid, and AzA,
but the FDA withdrew it due to violation of FDA issues, References
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Bimatoprost
34
of an isopropyl-ester on the C-1 carbon of the α-chain [5].

Basic Concepts Lumigan® ophthalmic solution containing Bimatoprost
• Bimatoprost is a synthetic analog of prostaglandin, 0.03%, was approved by the FDA in 2001 for the treatment
initially developed to treat glaucoma. It exhibits of elevated IOP in patients with ocular hypertension or open-
hypertrichotic adverse effects on eyelash hair folli- angle glaucoma [6]. It is considered as the most potent and
cles, most likely by interacting with the prostaglan- effective anti-glaucoma agent [7]. Its safety and efficacy in
din receptors in the dermal papilla and the outer the reduction of IOP have been well documented in clinical
epithelial sheath of the hair follicles. trials lasting up to 4 years, as well as extensive clinical expe-
• Bimatoprost stimulates telogen follicles to enter rience totaling >9 million patient-years of exposure [8].
early into anagen, prolongs anagen, decreases the
duration of telogen, increases dermal papilla size,
and enhances melanin production, resulting in lon- 34.1 Mechanism of Action
ger, thicker, and darker eyelashes, an overall effect
named hypertrichosis. Bimatoprost resembles a class of naturally-occurring fatty
• The FDA has approved Latisse® (Bimatoprost acid amides, known as prostaglandin ethanolamides or pros-
0.03%) for increasing eyelash length, thickness, tamides [9]. Although prostamides are structurally similar to
and pigmentation in patients with hypotrichosis of prostaglandins, they exert no meaningful activity on pros-
the eyelashes while results in eyelash and scalp alo- tanoid receptors [10] and constitute a separate class of com-
pecia areata are conflicting. pounds formed from anandamide, which is catalyzed by
• Phase I and Phase II trials to determine how cyclooxygenase-2 (COX-2) [3]. Anandamide is an endoge-
Bimatoprost could affect scalp hair growth in nous, naturally occurring, cannabis-like ligand (endocan-
patients with AGA/FPHL have been completed in nabinoid), derived from arachidonic acid. Bimatoprost
2016, and (unpublished) results are positive, even probably exerts its effects by stimulating the prostamide
though topical Bimatoprost 0.03% seems to be infe- receptor, which is pharmacologically distinct from F pros-
rior to 5% minoxidil topical solution in all outcome tanoid (FP) receptors [3, 7]. The mechanism through which
measures. Nevertheless, Bimatoprost will likely be Bimatoprost reduces IOP involves the secretion of metallo-
the third FDA-approved drug in the fight against proteinases by ciliary smooth muscle cells and remodeling
hair loss. of the extracellular matrix. These result in the widening of
the intermuscular spaces, ultimately increasing the uveo-
scleral outflow of aqueous humor [1–4].
Bimatoprost (Lumigan®, Allergan Inc., Irvine, CA) is a syn-
thetic analog of prostamide and prostaglandin. It was ini-
tially developed to reduce intraocular pressure (IOP) in 34.2 Bimatoprost and Hair Follicles
glaucoma by increasing the outflow of aqueous humor
through both the trabecular meshwork and the uveoscleral Several prostaglandin analogs increase the number, length,
route [1–4]. Bimatoprost is stereo-chemically similar to thickness, and pigmentation of eyelashes. This phenomenon
other prostaglandin-F2α (PGF2α) analogs, including is coined hypertrichosis and has been extensively reported
Latanoprost, Travoprost, and Unoprostone. The only chemi- earlier with Latanoprost [11–16] and Minoxidil [17].
cal difference is that Bimatoprost has an ethyl amide instead Hypertrichosis is known to be a common adverse effect of
156 34 Bimatoprost
prostaglandin and prostamide ophthalmic solution analogs

a
[10]. The eyelash growth effect of the Bimatoprost ophthal-
mic solution 0.03% was a serendipitous discovery, based on
reports of patients using the compound during Phase III trials
that assessed its anti-glaucoma properties [18, 19]. Initially,
hypertrichosis was reported by Higginbotham et al. [20],
who conducted two identical, multicenter, randomized,
double-masked, 1-year long clinical trials in which patients
were treated with Bimatoprost 0.03% o.d. (n = 474),
Bimatoprost 0.03% b.i.d. (n = 483) or 0.5% timolol maleate
b.i.d. (n = 241). It was reported that in 42.6% of patients who
applied Bimatoprost for 1 year, the number, length, and pig-
mentation of eyelashes was increased [20]. However, since
eyelash properties were not specifically examined in those
trials, these reports failed to capture the true incidence and b
impact of these interesting adverse effects. Subsequent clini-
cal trials on the effect of Bimatoprost on eyelash growth
were conducted by Allergan Inc. and demonstrated that it
promoted eyelash growth effectively.
This outcome, initially reported as an adverse effect,

soon became a desirable outcome for patients who suf-
fered from eyelash hypotrichosis or simply preferred
to have longer, thicker, and darker eyelashes [21]
(Fig. 34.1).
Eyelash hypotrichosis is a condition characterized by an Fig. 34.1 Considerable eyelash hypertrichosis of the left eye (b) in
inadequate amount of eyelashes caused by multiple factors, comparison with the untreated right eye (a). (From Tosti et al. [22])
including aging, heredity, physical trauma, eye surgery,
trichotillomania, alopecia areata, chemotherapy, or
unknown causes [23]. It is a condition that has a negative 34.3 Bimatoprost Mechanism of Action
impact on self-image and increases the risk of ocular injury on Hair Follicles
[24]. Based on these data, numerous cosmetics companies
soon launched products for the “enhancement” of eye- The exact mechanism of Bimatoprost’s action on the hair fol-
lashes, some of which contained prostaglandin analogs, licles remains elusive, and most probably, it involves interac-
which were not regulated by the FDA, though [25]. tion with the FP receptors of the hair follicle. The FP receptors
However, at least one of these products was seized by the are present in the dermal papilla and the outer epithelial sheath
FDA in November 2007, as an “unapproved and mis- of the hair follicle and appear to be involved in the hair folli-
branded drug” [26, 27]. cle’s development and regrowth, at least in mice [28, 29].
34.6 Bimatoprost and AGA/FPHL 157
Prostaglandin analogs were initially believed to act by 34.5 Bimatoprost Vs. Latanoprost
stimulating telogen hair follicles into entering anagen [30].
In 2010, Cohen demonstrated that Bimatoprost increased Even though Bimatoprost and Latanoprost share a similar
anagen hair follicles, decreased telogen hair follicles, and adverse-effects profile, Bimatoprost has demonstrated an
prolonged anagen duration. That same study provided evi- overall greater capacity for increasing the length of eye-
dence that the caliber of treated eyelashes increased by 20% lashes. A randomized, 6-month clinical study conducted by
compared to untreated ones and that melanin content also Noecker et al. [40] compared the two compounds and
increased. These effects probably occurred due to reported increased growth of eyelashes in 14 of 133 patients
Bimatoprost’s overall positive trophic action on the dermal in the Bimatoprost group, vs. no patients (n = 0) in the
papilla and on multiple follicular cell lines. Since Bimatoprost Latanoprost group [40]. A similar, 3-month study by Gandolfi
does not cause follicle neogenesis [31], the increase in the et al. [41] concluded that the increase in eyelash growth was
number of eyelashes is consistent with the precipitation of more common in the Bimatoprost group compared to the
anagen in follicles that would normally be in telogen. Latanoprost group (13% vs. 4%) and that hypertrichosis
Additionally, the longer anagen duration -consistent with occurred earlier with Bimatoprost [41]. Other studies by
longer lashes- together with thicker and darker lashes, create Eisenberg et al. [42] and Tosti et al. [22] have found similar
a pleasing, thicker effect. Hypertrichosis in eyelashes results, reporting that hypertrichosis usually appears earlier
inspired other promising alternative clinical uses of with Bimatoprost than with Latanoprost.
Bimatoprost to arise [32]. These results could probably be explained by the fact that
Bimatoprost, unlike Latanoprost, is not a pro-drug and does
not need to be converted into an active metabolite in order to
34.4 Effect of Bimatoprost in Healthy extend its potent pharmacological action. Another possible
Eyelashes explanation is that the response of Bimatoprost may be con-
ferred by interacting with FP-altFP heterodimer receptor and
Longer, thicker, and darker eyelashes are a sign of feminin- the additional secondary calcium signaling pathway elicited
ity and beauty in all cultures, and based on the high volume by Bimatoprost may translate into a higher hair growth
of mascara sales, Allergan Inc. and independent research response [23].
groups have conducted several randomized clinical trials
on the effects of Bimatoprost on the growth of eyelashes.
Since the detailed results of these studies go beyond this 34.6 Bimatoprost and AGA/FPHL
chapter’s scope, one should note that in all trials,
Bimatoprost use was associated with a significant increase Prostaglandin analogs are currently studied as alternate ther-
in the number of eyelashes and in longer, thicker and darker apies for scalp alopecia areata (AA) in adults and children
hairs within just a few months of treatment [25, 33–36]. [43]. As anyone would expect, Bimatoprost has also been
Pigmentation of the periocular skin and eyelid skin [36], tested on AGA and FPHL.
probably through the stimulation of tyrosinase enzyme [37, Data on AA are minimal and include one small study
38] was the only notable side effect which is understand- and one case report. Zaher et al. [44] were the first to
ably welcomed by female patients, since it achieved an study Bimatoprost’s effects on patients with AA of the
additional “eyeliner effect.” scalp. Thirty adult patients with patchy AA were included
In December 2008, FDA reviewed the extensive safety in the study; two AA patches were randomly assigned to
database for Bimatoprost for the treatment of glaucoma. It treatment, either by mometasone furoate 0.1% cream o.d.
included nine Phase I and Phase II studies and two pivotal or Bimatoprost 0.03% solution b.i.d., both administered
Phase III studies, including more than 6000 subjects. for 3 months. The authors reported that in the Bimatoprost
Additional data included clinical data, post-marketing sur- 0.03% group, they noticed a higher percentage of hair
veillance data, and one additional pivotal confirmatory regrowth (p = 0.001), earlier onset of response (p = 0.005),
study to assess eyelash growth. A new drug application and lower incidence of relapses (p = 0.03) [44]. Li and
(NDA) on Bimatoprost for the treatment for hypotrichosis Antaya also presented a case of steroid-resistant multifo-
of eyelashes, named Latisse®, was approved by the cal AA that was successfully treated with topical
FDA. Latisse® is a topical solution containing Bimatoprost Bimatoprost [45].
0.03% FDA-approved for increasing eyelash length, thick- Published data on the potential effects of Bimatoprost in
ness, and darkness in patients with hypotrichosis of the AGA and FPHL is even more limited, with only one case
eyelashes [39]. study by Emer et al. [46]. They reported a case of a 59-year-
158 34 Bimatoprost
old female suffering from FPHL who failed to respond to cm2): (A: 13.1; B: 6.1; C: 6.3; vehicle: 4.1 and 5% MTS:
scalp injections of Bimatoprost 0.03% weekly for 12 weeks 21.9), target area hair width, TAHW: (A: 0.76; B: 0.25; C:
and then biweekly for 4 weeks [46]. 0.12; vehicle: 0.13 and 5% MTS: 1.29) and target area hair
darkness, TAHD: (A: 1.19; B: 2.92; C: 4.04; vehicle: 0.65
and 5% MTS: 3.40) [50]. The second trial was a Phase II,
However, a more recent, excellent review by Barrón-
randomized, double-blind study (NCT01904721), including
Hernández and Tosti, included the unpublished details
244 males with mild to moderate AGA, aiming to compare
of Phase I and Phase II trials on Bimatoprost’s effect in
two formulations of Bimatoprost solution with the vehicle.
androgen-sensitive hair follicles [47].
The patients applied Bimatoprost and vehicle initially o.d.
for 4 weeks and then b.i.d. for 6 months. The preliminary
These included the following: results showed a more significant change in TAHC in both
Allergan Inc. filed on August 25th, 2010, the protocol of the Bimatoprost groups compared to vehicle (solution 1:
the Phase I trial (NCT01189279) on the safety, tolerance, 12.7, solution 2: 9.3, vehicle 5.8 terminal hairs/cm2) [51].
and pharmacokinetics of a topical Bimatoprost solution of Finally, a Phase II, randomized, double-blind study
unspecified concentration for the treatment of AGA [48]. (NCT01325350) evaluated the safety and efficacy of
Forty-two men and women with moderate AGA/FPHL Bimatoprost topical solution in 306 women with mild to
respectively were included in the study. Two Bimatoprost moderate FPHL. Three formulations of Bimatoprost topical
products were studied during the first part of the study, and a solution (A, B, C) were compared with vehicle and 2% MTS.
third product was studied in the second part. During the first Once again, 2% MTS was superior to all Bimatoprost solu-
part, Bimatoprost was applied in predetermined areas of the tions since results showed a greater change from baseline in
scalp, and its local tolerance was studied, as well as the most outcome measures in the 2% MTS group compared to
occurrence of any clinically significant electrocardiogram vehicle and Bimatoprost groups. More specifically, TAHC:
(ECG) findings. The second part of the study begun upon (A: −0.4; B: −3.5; C: 4.3; vehicle: 1.1 and 2% MTS: 13.6
completion of the first part. However, even though both parts terminal hairs/cm2) and TAHW: (A: 0.13; B: −0.19; C: 0.30;
were completed by June 24th, 2013, no results have been vehicle: 0.07 and 2% MTS: 0.87) were both in favor of
published. Nevertheless, Phase ΙΙ studies had already been MTS. Interestingly, in TAHD, Bimatoprost solutions were
scheduled, probably because the Phase I studies were comparable or significantly superior to 2% MTS (A: 2.94; B:
successful. 4.22; C: 2.11; vehicle: 2.07 and 2% MTS: 2.12) [52].
A Phase II, randomized, double-blind, interventional,
crossover study (NCT02170662) was designed to determine
how Bimatoprost could affect scalp hair growth. Nine men According to these Phase II results, Bimatoprost seems
with moderate AGA (stages Hamilton-Norwood IIIv, -Va) to be effective in both AGA and FPHL and will likely
were included in the study, with three patients topically be soon the third FDA-approved pharmaceutical in the
applying a placebo solution for 16 weeks and then switching fight against hair loss [53].
to Bimatoprost 0.03% solution for another 16 weeks. Another
six patients applied Bimatoprost 0.03% solution for 16 weeks
and then switched to placebo for another 16 weeks. The On a final note, in the recent (2018) systematic review
results showed that after the first 16 weeks, the change in (evidence-based (S3) guideline for the treatment of androge-
target area total hair count was significantly greater in the netic alopecia in women and in men) issued for the European
active group (27.4 vs. −2.6), while results were reversed Dermatology Forum, Kanti et al. make no mention of
when both teams switched treatments (4.9 vs. −5.8) [49]. Bimatoprost in the treatment of AGA/FPHL [54].
Two more trials were designed to evaluate the safety and
efficacy of topical Bimatoprost in men with mild to moderate
AGA. The first trial (NCT01325337) was a Phase II, ran- 34.7 Adverse Effects
domized, double-blind, 6-month long study, including 307
males with moderate AGA, aiming to compare three Application of Latisse® once daily to increase eyelashes
Bimatoprost formulations (A, B, C) with vehicle and 5% growth has shown to be safe and well-tolerated in both adult
Minoxidil topical solution (MTS). Bimatoprost formulations and pediatric populations, with few discontinuations due to
were applied at a dosage scheme of 1 ml o.d., while 5% MTS adverse effects. Bimatoprost is generally safe when applied
was applied at a dosage scheme of 1 ml b.i.d. results showed to the base of the eyelash (at the lid margin). However, a long
a greater change from baseline in all outcome measures in list of infrequent, mild, local adverse effects has been clini-
the 5% MTS group compared to vehicle and Bimatoprost cally reported, which is beyond this chapter’s scope and can
groups: Target area hair count, TAHC (in terminal hairs/ be traced in the relevant literature [55–59].
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Latanoprost
35
to aqueous humor, thus lowering intraocular pressure.

Basic Concepts Latanoprost reduces both the diurnal and nocturnal intraocu-
• Latanoprost is a synthetic analog of prostaglandin lar pressure and has been shown to act synergistically with
and was initially used in the treatment of glaucoma. other anti-glaucoma medications. Latanoprost also acts as a
It exhibits hypertrichotic adverse effects on eyelash selective agonist of the prostaglandin receptor FR of the cel-
hair follicles, most likely by interacting with the lular membrane [4]. The action of Latanoprost to the FP
prostaglandin receptors in the dermal papilla and receptor of the cellular membrane causes the release of Ca+2
the outer root sheath cells. to the cytosol and concomitant activation of PK-C (protein
• Latanoprost stimulates telogen follicles to enter kinase C) [5]. Both these actions result in increased trophic
early into anagen, prolongs anagen, decreases the metabolic activity fundamental to cell growth and prolifera-
duration of telogen, increases dermal papilla size, tion [5].
and enhances melanin production, resulting in lon-
ger, thicker, and darker eyelashes, an overall effect
named hypertrichosis. 35.1 Latanoprost and Hair Follicles
• Latanoprost has been tested in eyelash Alopecia
Areata with conflicting results, and one small study The serendipitous discovery that Latanoprost ophthalmic
has assessed the compound in AGA/FPHL. solution could influence eyelash growth was initially reported
during preliminary Latanoprost Phase II trials. Latanoprost
was reported to have a positive trophic effect on eyelashes,
and this effect was later termed hypertrichosis, comprising
Latanoprost (Xalatan®, Pharmacia Upjohn Co.) is a
an increase in the number, length, thickness, and pigmenta-
prostaglandin-F2α (PGF2α) analog discovered in the early
tion of eyelashes [6]. Moreover, Wand was the first to report
1990s. It was explicitly developed as an ocular hypotensive
a case study of a patient with eyelashes exiting from the eye-
agent for the treatment of open-angle glaucoma. The FDA ini-
lid at a more acute angle and canthal and eyelid hypertrophy
tially approved it as a second-line drug with that indication in
after Latanoprost treatment [7].
1996. However, in 2003, after reviewing the 5-year safety data
of the molecule, the FDA approved the once-daily prescription
Latanoprost 0.005% w/v eye drop as a first-line treatment for Altogether, Latanoprost induced several anatomic and
elevated intraocular pressure (IOP) associated with open- cosmetic ocular and periocular effects. Some of these
angle glaucoma or ocular hypertension [1]. Moreover, data effects were highly desirable, especially to female
soon demonstrated that regardless of the higher cost compared patients, while others were not welcome [8].
to β-blockers, it could provide superior clinical outcomes at a
small additional cost in actual clinical practice [2].
Latanoprost is an esterified prodrug of PGF2α that is acti- Some patients described persistent hypertrichosis for up
vated to the free acid in the cornea and then is fully hydro- to 14 months following even a brief treatment course with
lyzed into the active Latanoprost acid [3]. Latanoprost acts Latanoprost, and Johnstone et al. (2002) reported that even
as a selective F prostanoid (FP) receptor agonist, with the very brief exposure to Latanoprost could produce a similar
primary mode of action being the increased uveoscleral out- effect of eyelash growth as compared to chronic exposure [9]
flow of aqueous humor. It increases the sclera’s permeability (Table 35.1).
162 35 Latanoprost
Table 35.1 Latanoprost-induced hair growth manifestations. (Adapted of microfilaments in the dendritic processes of melanocytes
with permission from Johnstone et al. [9]) and promote complexing of melanosomes [20]. This action
Eyelashes of Latanoprost is also responsible for the frequent reporting
Increased eyelashes number in eyelashes row (7–10%) of darkening of the iris and periocular skin during
Additional eyelash rows treatment [21].
Increased eyelash length
Some of these in vitro mechanisms of action of
Increased eyelash thickness
Increased eyelash curling Latanoprost have also been demonstrated in vivo.
Steeper lash angulation from skin Preliminary studies with Latanoprost applied topically to
Increased pigmentation the C57/B16 mouse model indicated that it promoted the
Medial and lateral canthal hair rapid induction of anagen, and showed moderate growth
Increased number of visible hairs stimulatory effects on early anagen hair follicles and
Vellus and intermediate hairs develop into terminal hairs induced melanogenesis [22]. Similar effects were found in
Increased pigmentation
the bald scalp of the stump-tailed macaque. Uno et al.
Skin of lid
Vellus hair treated one group of four macaques once daily with a topi-
Thickening of hair cal solution of 50 mg/mL of Latanoprost (0.005%) for 5
Hair elongation months and treated a control group with a daily application
Increased pigmentation of a vehicle [23]. For an additional 3 months, two monkeys
from each group were treated topically with 500 mg/mL
Latanoprost (0.05%), while the remaining monkeys
35.1.1 Latanoprost Mechanism of Action remained in the initial treatment.
on Hair Follicles
The exact mechanism through which Latanoprost causes Latanoprost 0.005% induced mild hair regrowth, while
hypertrichosis has not been fully elucidated. Latanoprost’s Latanoprost 0.05% induced moderate to significant
vasodilatory effect, acting mostly on the venous network hair regrowth, with 5–10% conversion of vellus hairs
[10], does not seem to be the primary mode of action. to terminal hairs. This efficacy was comparable to 5%
Another theory was that Latanoprost had a similar mecha- Minoxidil Topical Solution (MTS) in the same animal
nism of action to Minoxidil through the activation of the model [24].
enzyme prostaglandin endoperoxide synthase-1 (PGHS-1)
in the dermal papilla cells. The effect results in the produc-
tion of prostaglandin E2 (PGE2), which has known cytopro- Overall, Latanoprost has been reported to induce the fol-
tective effects and induces hair growth [11]. However, other lowing effects in hair follicles, in vitro, in animal models,
theories were also presented. and in human eyelashes:
Latanoprost is a PGF2α analog, and this class of com-
pounds has been known to stimulate the initiation of DNA 1. It increases in the number of visible hairs: given that the
synthesis in resting cells and to act as potent mitogens [12]. number of hair follicles does not increase after birth [25]
They also induce gene expression, prevent cellular apoptosis and that no compound can induce true follicle neogenesis
[13], and stimulate cell receptors linked to phosphorylase C [26], the increase in the number of hairs in eyelash hyper-
that trigger activation of protein kinases, which play a key trichosis is consistent with the early conversion of telogen
role in cell growth. Since Latanoprost acts as a PGF2α analog, follicles to anagen ones. The increased anagen duration
it is a potent activator of PGHS-1 and therefore increases the has been hypothesized to be determined at the anagen’s
production of PGE2, which has been found to play a protec- initiation and is probably controlled by the dermal papilla
tive role against radiation-induced alopecia [14] and per se.
Doxoribucin-induced alopecia [15]. 2. It increases the hair length: longer hairs are consistent
Moreover, Latanoprost has been found to increase the with both longer anagen duration and delayed telogen.
transcription of nuclear material and protein synthesis [16], 3. It increases the hair caliber: this effect is consistent with
which alter the extracellular matrix of cells [17]. Since this is the conversion of vellus and intermediate hairs to terminal
a necessary process for the entry of the hair follicle in anagen ones, demonstrating a direct positive trophic and mito-
[18], Latanoprost’s effects on the expression of matrix metal- genic effect [27].
loproteinases in hair follicle cells might be implicated in its 4. It increases the hair pigmentation: this is consistent with
hair-growth effects [19]. Concerning the melanogenic prop- the increased amounts of melanin within the melanocytes
erties of Latanoprost, these are possibly attributed to prosta- but was not associated with an increase in the actual mela-
glandins’ intrinsic property to induce peripheral orientation nocyte number [5].
35.3 Effects of Latanoprost on The Scalp 163
35.2 Effects of Latanoprost in Eyelashes reported in just 3 weeks [9]. Another interesting difference
with the FDA-approved drugs Minoxidil and Finasteride is
35.2.1 Latanoprost and Healthy Eyelashes that Latanoprost’s results on eyelash hair follicles lasted for
up to 14 months after treatment discontinuation [4]. Even
During the initial Phase II & III studies on Latanoprost’s though Latanoprost’s unique traits would be interesting to
safety and efficacy, conjunctival hyperemia, sporadic epi- test in scalp hair loss disorders, there is only one published
sodes of mild punctate corneal epithelial erosions, and study on the use of Latanoprost on the scalp of patients with
increased pigmentation of the iris were the most common AGA.
adverse effects [28]. In three Phase III multicenter clinical Blume-Peytavi et al. published a small-scale, double-
trials in Europe, Scandinavia, and the US, in which 829 blind, randomized study assessing the safety efficacy of
patients were included, just one case of darker eyelashes and Latanoprost solution 0.1% on hair growth, hair pigmenta-
no hypertrichosis cases were reported [28]. The paucity of tion, and scalp pigmentation on 16 young men aged
hypertrichosis reports following Latanoprost therapy sug- 23–35 years with mild AGA (Norwood Hamilton stage
gested that these findings were spurious and represented II-III). Each subject received either 0.1% Latanoprost
mostly idiosyncratic or rare events. However, a closer look at lotion or placebo lotion packaged in droppers (flasks) with
eyelash features led to the discovery that Latanoprost’s hair the dose of one drop (50 μL) daily for 24 weeks on two
growth action was actually identified in 60–100% of patients symmetric locations on the scalp according to randomiza-
[29]. Johnstone had already presented evidence that tion. At 24 weeks at the Latanoprost-treated site, the den-
hypertrichosis in response to Latanoprost was a generalized sity was significantly higher than baseline and placebo
phenomenon, rather than a rare or idiosyncratic one [6]. The (p < 0.001). However, the anagen/telogen ratio did not
detailed results of these studies go beyond the scope of this change, which might indicate that Latanoprost does not
chapter. In summary, several studies reported that Latanoprost modify the length of anagen and telogen of individual hair
resulted in eyelashes having a fuller appearance, being lon- follicles. However, as the absolute number of both anagen
ger, thicker, more heavily pigmented, and exiting at a more and telogen hairs increased, it seems Latanoprost recruits
acute angle from the skin than before or compared to the new hairs into anagen. The authors commented that results
control eye [30–33]. might not apply to other patient groups of older age or in
However, the discovery of Bimatoprost set new standards higher AGA stage [41].
for the hypertrichotic effects of prostaglandin analogs. Even Concerning AA of the scalp, there is only one published
though Bimatoprost and Latanoprost share a similar adverse article by El-Ashmawy et al. who recruited 100 patients with
effects profile, Bimatoprost soon demonstrated a greater AA, randomized them into five groups of 20 subjects each,
capacity for increasing the size, number, and length of the and treated them as follows: Group I, Latanoprost 0.1%
eyelashes [34, 35]. lotion; Group II, MTS 5%; Group III, Betamethasone valer-
ate 0.1% solution; Group IV, combination of Latanoprost
lotion and Betamethasone valerate solution and Group V, a
35.2.2 Latanoprost and Eyelash Alopecia vehicle lotion control group. All active groups showed sig-
nificant differences in the mean score for scalp and beard
The first report on Latanoprost’s effect on eyelash regrowth regrowth (SALT score) between before and after treatment
was presented by Mansberger et al. [36] in 2000. Since then, (p values 0.044–0.001), with group IV showing the most sig-
studies evaluating whether the topical use of Latanoprost can nificant changes (p = 0.001) [42].
be effective in alopecia areata (AA) of eyebrows and eye- There are no other published studies or scheduled Phase
lashes, produced conflicting results that go beyond the scope I-III trials on the use of Latanoprost for the treatment of
of this chapter. Some authors reported eyelash regrowth in AGA or FPHL. In 2020, Oliveira et al. published their
AA [37, 38] or even Alopecia universalis [39], while others research on developing polymeric nanocapsules containing
reported negligible results [40]. Latanoprost. The authors presented in vitro data of formula-
tion stability and ex-vivo data on the increased accumulation
of Latanoprost into the hair follicles of porcine skin [43].
35.3 Effects of Latanoprost on The Scalp In the recent (2018) systematic review (Evidence-based
(S3) guideline for the treatment of androgenetic alopecia in
According to data from Phase II and III trials, the hair growth women and men) issued for the European Dermatology
appears earlier with Latanoprost than with Minoxidil or Forum, Kanti et al. make no mention of Latanoprost in the
Finasteride since the first signs of hair growth have been treatment of AGA/FPHL [44].
164 35 Latanoprost
Synopsis 16. Ocklind A. Effect of latanoprost on the extracellular matrix of the

Latanoprost has demonstrated positive effects on eyelash ciliary muscle. A study on cultured cells and tissue sections. Exp
Eye Res. 1998;67(2):179–91.
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FM. Latanoprost in the treatment of eyelash alopecia in alopecia A, Trakatelli M, Tosti A, Del Marmol V, Piraccini BM, Nast A,
areata universalis. J Eur Acad Dermatol Venereol. 2010;24(4):481–5. Blume-Peytavi U. Evidence-based (S3) guideline for the treatment
40. Roseborough I, Lee H, Chwalek J, Stamper RL, Price VH. Lack of androgenetic alopecia in women and in men – short version. J
of efficacy of topical latanoprost and bimatoprost ophthalmic solu- Eur Acad Dermatol Venereol. 2018;32(1):11–22.
Estrogens
36
Estrogens are hormones with wide-ranging and significant

Basic Concepts biological effects on many tissues. Major target organs are
• Estrogens influence most tissues and have numer- the reproductive tract, genitals, bone, blood vessels, and
ous biological effects on all skin elements, includ- skin. In humans, estrogens influence all skin elements in
ing hair follicles, in both lab animals and humans. various ways, but mostly the dermal papilla (DP) and the
• Estrogens act through estrogen receptors ERα and connective tissue are affected. Estrogens increase overall
ERβ. ERβ is most important in human skin, while skin thickness, increase the collagen content of the dermis,
ERα is of primary importance in lab animals. This increase hair and skin pigmentation, enhance vascularization
difference initially resulted in contradicting experi- of the dermis [1], augment the mitotic activity of the epider-
mental data that were non-applicable to humans. mis [2], reduce the activity of the sebaceous glands, delay
• The control of hair growth by estrogens is very skin aging [3] and increase the water and hyaluronic acid
complex and differs between distinct integumental content of the skin [4]. After menopause, the dramatic
sites, genders, and species. In humans, estrogens decrease in the amount of estrogens in the serum results in
might even have paradoxical “site-dependent” significant “catabolic” processes in the female skin and body.
effects on hair growth, resembling the paradoxical These include a decline by 1–2% per year of skin collagen
effects of androgens. content, reduction in skin thickness, in the metacarpal index,
• It very tempting to speculate that estrogens may act and forearm bone mineral content [5, 6]. However, there is
as androgen-antagonists in follicular biology and still a huge disparity in our understanding of how estrogens
AGA pathobiology, but exact effects await exert their actions, particularly in non-reproductive tissues,
clarification. such as the skin [3].
• Oral administration of estrogens in males with AGA
is obviously contraindicated, and it is neither rec-
ommended in FPHL, both due to the increased risk 36.1 Mechanism of Action of Estrogens
for thromboembolism and other potential severe
side-effects and the low efficacy compared to other The most important naturally occurring estrogen is
antiandrogens or topical treatments such as 17β-estradiol, which is responsible for most normal physio-
Minoxidil. logical processes of this class of compounds. 17β-estradiol
• Topical estrogens have been traditionally employed stimulates the proliferation of human keratinocytes by pro-
for topical treatment of hair diseases in Europe moting the expression of cyclin D2. This protein induces G1
since the 1950s in both females and males, despite to S phase progression in the cell cycle and inhibits oxidative
the unclear rationale of use and the absence of high- stress-induced apoptosis in keratinocytes by promoting
quality studies supporting their use. Bcl-2 expression [7, 8]. Moreover, 17β-estradiol stimulates
• Hair growth effects of topical estrogens have con- collagen synthesis, increases mRNA expression of both
sistently been much lower than that of Minoxidil in estrogen receptors (ERα and ERβ) and expression of IGF-1R
both sexes. All available studies are of low-quality in cultures of fibroblasts [9]. Surprisingly, 17β-estradiol is as
and poor-design, and overall, there is no evidence to effective as ATRA (All-Trans Retinoic Acid) in stimulating
support their use to improve or prevent the progres- the development of new connective repair zones in photo-
sion of AGA/FPHL. damaged skin and in inducing skin thickening through water
accumulation, resulting from an estrogen-induced hyaluro-
168 36 Estrogens
nan synthesis [10]. The stereo-isomer of 17β-estradiol is potent hair growth inhibitor in mammalian species as diverse
17α-estradiol, which has approximately half the affinity for as mice, rats, guinea pigs, and dogs [26–29]. In 1996, Oh
ERα and one-tenth of the affinity for ERβ compared to et al. reported that topical application of 17β-estradiol on
17β-estradiol. Therefore, is considered an inactive stereo- female CD-1 mice, arrested hair follicles in telogen, block-
isomer of 17β-estradiol [4]. Naturally occurring 17α-estradiol ing their transition in anagen and resulting in hair growth
has been found in serum and urine only in rare cases [11, 12] inhibition. Conversely, Fulvestrant’s topical application
and is possibly synthesized by the aromatization of epites- (ICI182,780), a pure antagonist of ERα and ERβ, caused
tosterone [13]. telogen follicles to enter anagen, thereby inducing hair
Estrogens act through a designated receptor, which is a growth. They also demonstrated that the ER is expressed in
member of the nuclear hormone receptor superfamily, the nuclei of the DPCs of the telogen hair follicle in CD-1
namely, the Estrogen Receptor (ER). ER was cloned for the mice [30]. In contrast to these results, the use of 17α-estradiol,
first time in 1986 from MCF-7 cells [14], and for years it was topically or orally, had no results in mice [31], while it was
considered that only one ER existed. In 1996, it was demon- found to prolong anagen in guinea pigs [32]. These results
strated in cultures of rat prostate cells [15] that a second renewed the interest in estrogens’ role in hair growth, and
estrogen receptor exists, with a similar amino acid sequence studies were undertaken to determine how estrogens are
with the initially discovered one, and some months later, involved in the regulation of the hair follicle cycle and growth
these results were confirmed in human testicular cells [16]. in different species [33–39].
That “second” receptor was named ERβ, while the former The mechanism by which estrogens influence the DPC
receptor was named ERα. These two estrogen receptors are signals that initiate and terminate the hair cycle remained
not located on the same chromosome, unlike progesterone poorly understood and research results did not match with
receptors [17]. ERβ is located in chromosome 14 and ERα in clinical experience in humans [40, 41]. One fundamental dif-
chromosome 6, and even though they had a similar chemical ference between lab animals and humans is that ERα is
affinity for 17β-estradiol [18], their tissue distribution differs expressed in the skin of both humans and rodents, but ERβ is
significantly [19]. ERβ is the predominant receptor in human absent from the skin and hair follicles of most lab animals
scalp skin [20], with strong expression in epidermis, dermal [42]. The murine hair follicle cycle is regulated through an
fibroblasts, blood vessels, and hair follicle [21], while human ERα pathway [43], whereas the human hair follicle cycle is
keratinocytes are reported to express both ERβ and ERα, most likely regulated via an ERβ pathway [21, 39]. Movérare
possibly including a membrane ERα [20]. ERβ is widely et al. demonstrated in lab animals subjected to genetic elimi-
expressed in the hair follicles of both sexes, mainly in the nation of either ERα receptors (ERKO mice) or ERβ recep-
dermal papilla cells (DPCs), inner sheath cells, matrix cells, tors (BERKO mice), that the effect on hair follicle cycling is
and outer sheath cells, including the bulge region. ERα is caused exclusively by an ERα mediated inhibition of telogen-
poorly expressed, being restricted to only sebocytes [22]. anagen transition [43]. So, even though the action of estro-
Interestingly, estrogens have been found to be produced by gens is mostly inhibitory for hair follicle growth in mice,
the hair follicle itself, and the fact that estrogen receptors are guinea pigs, and dogs [44–46], in humans, estrogen action is
mostly expressed in the DP both suggest that estrogens act as not straight-forward.
endogenous paracrine regulators of hair follicle cycling [23].
Overall, the control of hair growth by estrogens is
much more complicated than previously appreciated
36.2 Estrogens and Hair Follicles in Lab and differs between different integumental sites, gen-
Animals ders, and species and might even be paradoxically dif-
ferent depending on gender and site [38].
Estrogens are known for almost a century to play a pivotal
role in skin physiology and hair growth control in animals. In
the early 1930s, Dawson first recognized that hair growth Finally, estrogens in very high concentrations have been
and sexual hormones in animals are closely connected since reported to inhibit the metabolism of Testosterone (T) in
the regrowth of the hair was faster in spayed than in breeding mice [47], and to inhibit 5α-Reductase (5α-R) in vitro
female guinea pigs [24]. directly [48]. 17β-estradiol has been found to be a non-
The first experimental data by Gardner et al. [25], dating competitive inhibitor of 5α-R in ovarian cells of mice [49] in
back to 1940, reported inhibitory hair growth effects of very high concentrations (20 μΜ/L); however, at physiologi-
estrogens in dogs. Soon, 17β-estradiol was recognized to cal levels ranging from 10−8 to 10−4 mol/L, it fails to inhibit
profoundly modulate hair growth, acting primarily as a 5α-R activity [50].
36.3 Estrogens and Hair Follicles in Humans 169
36.3 Estrogens and Hair Follicles Months before During Months after
in Humans pregnancy pregnancy labour
8 6 4 2 2 4 6 8 2 4 6 8
100
The systemic effects of estrogens in women are well-known
and will not be discussed herein, besides the fact that estro-
gens increase SHBG levels, resulting in an indirect reduction
of free T levels. They also send negative feedback signals 90
that suppress the hypothalamic secretion of gonadotropin
and the pituitary secretion of luteinizing and follicular-
stimulating hormones, which result in a decreased androgen 80
%
production by the adrenals.
Beginning of gestation
However, the exact effects of estrogens in human hair fol-
licles have not been fully elucidated due to the conflicting
70
results of estrogen administration in humans.
Labour
Estrogen could have a protective role on human hair
60
growth, suggested by the increased prevalence of
Months
FAGA following menopause, the prolongation of ana-
gen during pregnancy [51], the hair loss in women tak- Fig. 36.1 Schematic representation of the percentage of anagen hair
ing tamoxifen or aromatase inhibitors for the treatment on a 25-year-old primipara before, during, and after pregnancy. During
of breast cancer [52], and the documented complete the second and third trimesters, the proportion of anagen hairs rose con-
siderably above her non-pregnant baseline and persisted 6 days postpar-
hair regrowth in transsexual individuals with AGA on tum but decreased significantly by 3 weeks postpartum. Lactation was
estrogen [53, 54]. abruptly discontinued 5 weeks postpartum. Six weeks postpartum,
there was an even greater decrease in the percentage of anagen hairs.
This low level persisted until 6 months postpartum. Hair loss, clinically
evident because of a large amount of shed hair, with slight diffuse alo-
It is considered that 17β-estradiol inhibits hair shaft for- pecia, began 4 months postpartum and lasted for 2 months. By 8 months
mation, thus lowering the rate of hair growth, but at the same postpartum, the differential count of hair roots was back to normal.
time, it prolongs anagen duration in vitro, thus decreasing (From Lynfield [51])
telogen rate [55]. Ohnemus et al. studied the effects of
17β-estradiol at various concentrations (1–1 mM) on female gradual increase in progesterone during gestation, an eight-
occipital scalp hair follicles and confirmed the inhibitory fold rise in estrogens [60], whereas prolactin also rises sig-
properties of 17β-estradiol in hair shaft elongation, which nificantly, reaching a 20-fold increase at term [61]. Once the
were maximal at 1 mM [56]. However, when Conrad et al. placenta is removed at birth, estrogen and progesterone lev-
investigated a single, large, frontotemporal scalp skin sample els return to normal within 2–4 days [62]. It is believed that
obtained during routine facelift plastic surgery from a healthy changes in hair physiology can be explained with these vari-
46-year-old male individual, results were different. ations in hormone levels in pregnant and postpartum women,
Compared to the vehicle control, the hair shaft elongation of as initially presented in 1960 by Lynfield. He reported that
those male frontotemporal scalp hair follicles were signifi- during pregnancy the percentage of anagen follicles is sig-
cantly stimulated by 1–100 nM of 17β-estradiol already as nificantly increased (from 85% to 95%) and that sebum pro-
early as 1 day after the start of organ culture. This stimula- duction is reduced [51] (Fig. 36.1). In later years, it was
tion became even more pronounced at the end of organ cul- reported by Pecoraro et al. that increased rates of thick to
ture (days 7 and 9) [57]. Even though these remain to be medium or thin hairs are evident in pregnancy [63]. Nissimov
unequivocally proven in vivo, these contradictory results et al. studied hair samples from 12 pregnant and 13 non-
suggest that estrogens might even have paradoxical “site- pregnant women and were the first to report that the major-
dependent” effects on human hair growth, just like andro- axis hair diameter is increased by 10% during pregnancy due
gens [58]. In vitro experiments in DPCs and human to the action of estrogens on DPCs [64]. However, it remains
fibroblasts demonstrated that ethinyl estradiol at concentra- to be determined which pregnancy-associated factors are
tions higher than 10 ng/mL significantly increased the growth responsible for these effects.
of both cell types as shown by [3H]thymidine uptake [59]. After parturition, the abrupt reduction in the concentra-
Naturally circulating estrogens seem to affect human hair tion of circulating estrogens seems to result in an accelera-
follicles in general positively, and their actions are pro- tion of the transition to telogen in the follicles in which
foundly manifested during pregnancy. There is a ninefold, anagen has been prolonged, accounting for the decrease in
170 36 Estrogens
the percentage of anagen, clinically evident as “postpartum

telogen effluvium”, “postpartum hair loss”, or PTE [51]. Even though all the mechanisms of action of estrogens
PTE manifests 2–6 months after delivery, it is attributed to on human hair follicles are still mostly unknown, they
the postponed telogen, usually lasts 3 months, and shedding have multiple positive effects: Increase in anagen vs
may be dramatic [65]. telogen rates, increase in aromatase activity, synthesis
of VEGF, IGF-1, nitric oxide, and decrease in sebum
production.
Most women will return to their usual hair growth
cycle between 6 and 12 months after birth. Postpartum
hair loss usually returns the hair to pre-pregnancy
thickness, but in some women it leads over to FPHL
and will never fully recover.
36.4 Estrogens, AGA and FPHL
From the in vitro studies in human hair follicles, it has been

Gizlenti et al. studied 28 women at the 24th week of preg- hypothesized that estrogens could be useful in treating hair
nancy, 30 pregnant women at term gestation, 29 women in follicle disorders [42]. Orentreich observed in females a
the fourth postpartum month, and 29 in the first postnatal decrease in daily effluvium during therapy with systemic
year (overall 116 women), and reported that the anagen rate estrogens [79], and he reported an increased proliferation
increases during pregnancy and telogen rate rise after deliv- rate, slowed down differentiation, and postponed telogen
ery [66]. However, other researchers doubt the very exis- effluvium [57]. Studies by Orfanos et al. have also reported
tence of PTE and consider it an ill-defined entity with very increased anagen and decreased telogen rates after treatment
low incidence [67]. with estrogens, compared to placebo [80, 81]. The questions
The alleged inhibitory effect of estrogens on the 5α-R that immediately arise are whether estrogens can be effective
enzyme system has not been confirmed in human male fore- in androgen-sensitive areas of the scalp, whether they can be
skin fibroblasts [68]. Ethinyl estradiol had no efficacy what- used both by males and females, and what would be the pre-
soever in inhibiting 5α-R in ex vivo skin of the female breast, ferred and efficient administration route.
which shares similar features with the human scalp [1].
Therefore, the positive action of estrogens in hair growth in
humans is not associated with this mechanism [69]. 36.4.1 Oral Estrogens
Estradiol also induces aromatase activity, which converts
T and weaker androgens into estrogens [70], and also inhib- Oral administration of estrogens in males with AGA is obvi-
its the expression of the androgenic receptor [17]. Yet, there ously contraindicated, but it is not considered ideal for
are other mechanisms, which have been proposed to explain women with FPHL, either. Estrogens are known to increase
the action of estrogens on hair follicles. It has been known the levels of serum lipoproteins (VLDL, LDL, triglycerides),
since the early 1980s that estrogens enhance the proliferation to increase threefold the risk for venous thromboembolism
of human keratinocytes [71]. In addition, 17β-estradiol has [82], while there are reports of estrogenic contraception-
been reported by Sawada et al. (2000) to provide protection induced hair loss. Oral estrogens have minimal systemic bio-
against nigral neuronal apoptosis [72] and provide neuropro- availability (2–10%) due to gut and liver metabolism [83]
tective antioxidant activity independent of the activation of (first-pass), limiting their oral use.
estrogen receptors [73]. Reportedly, 17β-estradiol even stim-
ulates human hair follicle synthesis of VEGF [23]. Another
Moreover, estrogens are known for their genotoxic and
possible mechanism of action is the estrogen-induced
mutagenic metabolites that stimulate tissue growth and
increase of IGF-1 [74], while another significant feature is
participate in the pathogenesis of breast cancer [84].
the reduction of size and activity of sebaceous glands, which
is evident with per os ethinyl estradiol 35 μg/day used in
treating moderate acne vulgaris [75]. The sebaceous glands In the relevant literature, there have been very few clinical
are responsible for most cutaneous androgen metabolism studies on the efficacy of oral estrogens in FPHL and Kanti
and for producing in situ unknown amounts of DHT directly et al. in their recent systematic review (Evidence-based (S3)
from cholesterol [76]. Thus, it is possible that the sebo- guideline for the treatment of androgenetic alopecia in
suppressive effect of estrogens is of high significance in the women and in men) issued for the European Dermatology
androgen-sensitive follicles [77]. Finally, estrogens increase Forum, considered that only two studies met their inclusion
endothelial nitric oxide by a receptor-mediated system, criteria [85]. Peereboom-Wynia compared a group of 20
inducing vasodilation, which may also exert positive effects women with FPHL treated for 1 year with Diane® (50 μg
in hair follicles [78]. estradiol+2 mg CPA) + 20 mg CPA for days 1–14, with an
36.4 Estrogens, ΑGΑ and FPHL 171
untreated control group of 28 women with FPHL. Trichogram higher concentration of estradiol has been found in the seba-
data showed a mean increase in anagen follicles from 49.7% ceous gland, and the DP and estradiol may reach deep
at baseline to 74.4% after year in the treated group, com- enough in the skin to exert its action on the hair follicles [94].
pared to a decrease in anagen follicles from 60.4% to 48.8% The limited trichogram evidence that is currently avail-
in the control group. However, the study’s essential flaws able suggests that, in androgen-sensitive hair follicles of the
were that subjects were not randomized to treatment or con- female scalp, topical 17β-estradiol decreases the telogen
trol groups, and no hair counts were performed [86]. rate, prolongs anagen duration, and inhibits hair shaft elon-
Vexiau et al. reported a mean change of baseline total gation of occipital follicles in vitro [95]. However,
hair count of −2.8 hairs/cm2 (−1.4%) at 6 months and 17β-estradiol-effects on human frontotemporal scalp hair
−7.8% hairs/cm2 (−3.9%) at 12 months in 33 females with follicles show differences between genders, namely, stimula-
FPHL receiving oral contraceptive +50 mg CPA. Subjects tion of hair shaft elongation in males and inhibition in
treated with a combination of Minoxidil Topical Solution females. Therefore, not only species-, but also sex-, and
2% (MTS) twice daily and an oral contraceptive showed a location-dependent differences in the hair follicle response
mean increase in hair count of 16.1 hair/cm2 (8.6%) at to estrogens must be taken into account [43]. Although it
6 months and 16.9 hair/cm2 (9.1%) at 12 months. The total remains to be unequivocally demonstrated in vivo,
hair count differences at 12 months were statistically sig- 17β-estradiol has been proposed to decrease the telogen rate
nificant between groups (p < 0.0001). In subgroup analysis, and to prolong the anagen duration in human scalp skin, jus-
patients under treatment with CPA and clinical signs of tifying the use of topical 17β-estradiol in the management of
hyperandrogenism showed increased hair counts at month hair loss characterized by premature catagen, such as AGA,
12 compared to those without hyperandrogenism, although FPHL and telogen effluvium [67, 91]. Moreover, no litera-
the results were not statistically significant. Consequently, ture exists comparing efficacy and safety of topical vs. sys-
according to Kanti et al., the overall evidence that oral hor- temic estrogens.
monal treatment prevents progression or improves FPHL in
female patients is insufficient, and studies meeting the
Despite the low level of evidence, estrogens have been
inclusion criteria obtained a grade of evidence B and level
traditionally employed for topical treatment of hair
of evidence 3 [87].
diseases in Europe since the 1950s and constitute a
firm staple of management strategies [96], especially
in women with FPHL in central and Western Europe
36.4.2 Topical Estrogens [57, 97, 98]. 17β-estradiol and 17α-estradiol are the
most popular agents, and 17β-estradiol containing top-
Estrogens are primarily marketed to address problems related ical preparations are frequently used in everyday tri-
to hypoestrogenism. Fortunately, estrogens are among the chological practice [99].
very few compounds in pharmacopeia that can effectively
surpass transcutaneously [88, 89]. Therefore, according to
the indication, oral, transdermal, and topical preparations are Very high doses seem to be necessary in order to obtain
available. Transdermal administration of estrogens can be measurable hair growth effects. Therefore, due to the
achieved with diverse formulations, such as gels, patches, unwanted side effects, such as gynecomastia and loss of
creams, all with intersubject variability in bioavailability and libido, 17β-estradiol is contraindicated in males with
bioequivalence. Nevertheless, absorption levels of 90% can AGA. However, the systemically inactive stereoisomer
be attained, suggesting that individual dose adjustments may 17α-estradiol is frequently prescribed in men with AGA
be needed when switching between different administration [100]. Interestingly, 17α-estradiol has been reported to
forms of percutaneous estrogen therapy [90]. induce aromatase activity in organ-cultured human anagen
Estrogen absorption by the scalp skin is higher than in all hair follicles, resulting in increased conversion of T to estra-
other areas of the body surface [91]. Therefore, in an attempt diol and Androstenedione, which certainly encourages one to
to circumvent problems related to systemic hormonal treat- explore the use of 17α-estradiol for AGA in men and FPHL
ments the topical application of estrogens on the scalp might women [70]. Nevertheless, its claimed efficacy for AGA or
seem ideal in hair follicle disorders since it has not be found FPHL remains still unsupported by reliable, well-designed,
to increase serum estrogen levels or to affect lipoprotein syn- prospective, double-blind, placebo-controlled, long-term
thesis [92]. The human skin can absorb estrogens and ste- clinical trials. Consequently, Kanti et al. make a recommen-
roids extensively [93], and it has been observed that the dation for the use of topical natural estrogens to improve or
human skin may act as a reservoir of estradiol, which allows prevent the progression only of FPHL in female patients at
it to exert its actions for several hours after application. A the present time.
172 36 Estrogens
36.4.2.1 Topical Estrogens in Men

Topical formulations of estradiol benzoate, estradiol valer- Unfortunately, these few available studies have serious
ate, 17β-estradiol, and 17α-estradiol have been commer- methodological flaws, and the results must be viewed
cially available in European countries since the 1980s. Most with skepticism.
published articles on estrogen scalp solutions can be traced
in German scientific literature. There are four early studies
on the safety and efficacy of the topical estrogen Alfatradiol Researchers either did not measure efficacy [101], or no
(17α-estradiol) in men [80, 81, 101, 102]. control group was included [80, 81] and/or the results were
Orfanos et al. conducted a small study in 30 male patients not reported separately for each sex [101, 102], whereas in
with AGA, aged 17–37, and measured the total plasma uri- one study, topical corticosteroid was also included [101].
nary estrogen levels before and after 6 months of topical Consequently, Kanti et al. [85] considered that no studies on
estrogen treatment. In 18 patients, 0.05% dienestroldiacetate the use of Alfatradiol as a treatment for AGA in male patients
in an alcoholic vehicle was daily applied on the scalp skin, met the inclusion criteria for their guideline, resulting in evi-
whereas 12 controls were treated with the same preparation dence level 4.
without estrogen content. In 3 and 6 months after treatment,
plasma and urinary estrogen levels were slightly elevated but 36.4.2.2 Topical Estrogens in Women
still within normal range and, similarly, no clinical side- Available data on the efficacy of topical estrogens in females
effects of the estrogen application (i.e., gynecomastia) were with FPHL are conflicting. A 32-week open trial by Abadjieva
recorded in the study [80]. However, case reports of persis- (2000), published in a Polish dermatological journal,
tent gynecomastia and loss of libido in AGA-affected men, included 45 females with FPHL, aged 18–42 years, who
resulting from scalp inunction of 17α-estradiol, have been used a topical solution of estradiol benzoate, prednisolone,
published by other authors [103, 104]. and salicylic acid. Results showed that 33.33 ± 7.27% pre-
Orfanos et al. conducted a controlled, randomized, sented with minimal and 7.14 ± 3.97% with moderate hair
double-blind study in 51 men with AGA and investigated growth, whereas the mean count of non-vellus hair increased
the effects of a topical treatment with 17α-estradiol 0.025% by 15.79 ± 1.35%. The authors claimed that the tested solu-
solution for 6 months. The authors reported that 63% of tion was an efficacious and safe treatment of FPHL [105].
the treated patients displayed a reduction of the number of Blume-Peytavi et al. randomized 103 females with FPHL
telogen hairs (vs. placebo 37%), 11% reported deteriora- into group I (n = 52) who applied 2% MTS b.i.d. for
tion vs 50% in the placebo group, showing an increased 12 months and group II (n = 51) who applied an Alfatradiol
telogen rate by more than 10%. Even though no regrowth 0.025% solution o.d. for 6 months and then switched to 2%
of new hairs was reported, the authors considered that MTS for months 7–12. The authors reported a decreased
17α-estradiol might have a therapeutic value similar to total hair count after 6 months of Alfatradiol 0.025% (mean
17β-estradiol if applied topically for an extended period in change from baseline −7.8 hairs/cm2, −4.3%, p < 0.0005)
men with AGA [81]. whereas subjects treated with 2% MTS showed increased
Wüstner et al. conducted a 6-month-long study on 50 total hair counts at 6 months (15.3 hairs/cm2; 8.7%). Non-
female and male patients with hair loss, treating them with a vellus hair counts and cumulative hair thickness were also
topical solution combination of estrogen + corticosteroid. decreased in the Alfatradiol group and increased in the MTS
They reported a slight decrease in the telogen rate in 52% of group at 6 months (−6.0 hairs/cm2 vs. 14.0 hairs/cm2,
the patients and considered this as a clinical improvement p < 0.001; −0.5 mm/cm2 vs. 1.8 mm/cm2, p < 0.0001) [106].
[101]. No further details on the segmentation of patients or Similar results were reported by Georgala et al., who ran-
agents used are available, though. Several decades later, domized 75 postmenopausal women into three groups and
Wozel et al. conducted a drug monitoring study, assessing studied them for 3 years (1998–2000). Patients in group 1
the efficacy and safety of Alfatradiol 0.025% in 233 patients (G1) applied estradiol valerate 0.03% for 12 weeks, patients
with AGA (192 women, aged 14–76 years, and 41 men, aged in G2 applied estradiol valerate 0.03% for 24 weeks, while
17–56 years). After 7.5 months of treatment, trichograms of patients in G3 applied placebo treatment containing only the
112 patients (92 women, 20 men) were evaluated. In patients vehicle for 24 weeks. There was a change of the anagen/telo-
treated with Alfatradiol, the proportion of frontal anagen hair gen hair follicles ratio (G1: 1.68 to 2.33, G2: 1.57 to 2.27,
increased significantly in women from an average of 69% to G3: 1.61 to 1.57, all p < 0.01), while in the placebo group,
77% and men from 56% to 65%. In 12% of women and 21% 7/20 patients noticed a further progression of their condition.
of men, a further decline in the number of anagen hairs was No new hair growth was reported in any group [107].
observed, concluding that Alfatradiol is effective and safe in Kim et al. conducted an open-labeled, single-arm, single-
AGA’s topical treatment in both men and women since up to institution clinical trial in 51 women with FPHL, who applied
88% of female treated patients retained their hair [102]. a topical solution of 17α-estradiol 0.025% o.d. for 8 months
[108]. The authors reported a mean increase of 31.57 ± 34.63 scopic and trichoscopy pictures of one patient from each
hair/cm2 in hair counts after 8 months of treatment, compa- group showing minor and moderate improvement, respec-
rable to that of 2% MTS [109]. However, the large standard tively [112].
deviation, lack of placebo arm, and the short duration of the The only available controlled trial of a topical hormonal
study, which did not eliminate the effect of seasonal changes treatment that has employed modern methods of assess-
in hair growth, are important limitations of this study. ment was published by Gassmueller et al. (2008). They
Choe et al. [110] published in 2017 the results of a non- conducted two randomized, phase II, proof-of-concept
comparative, retrospective, single-institution study on 34 studies to evaluate the efficacy of Fulvestrant solution, an
women with mild to moderate FPHL who applied 3% MTS estrogen receptor antagonist, in stimulating hair growth in
and 17α-estradiol o.d. (1 ml/application and 3 ml/applica- 102 men with AGA and 70 postmenopausal women with
tion, respectively) for 6 months. The authors claimed that FPHL. Male patients were randomized to receive
hair number and thickness changes as assessed by phototri- Fulvestrant solution 70 mg/ml b.i.d. or 2% MTS b.i.d. for
chogram were statistically significant (p < 0.001) and attrib- 16 weeks, while female patients received Fulvestrant solu-
uted these changes to the 17α-estradiol component. tion 70 mg/ml b.i.d. or vehicle b.i.d. for 16 weeks. No dif-
However, they acknowledged that photos and phototricho- ferences in efficacy between topically applied Fulvestrant
grams had not been performed on the same areas due to the and vehicle were seen for any of the key endpoints of hair
absence of tattooing on the scalp. Also, the data were density, cumulative hair thickness, or hair growth rate in
reviewed retrospectively, which may have created some men with AGA or women with FPHL, whereas statistically
limitations concerning the comparison of efficacy. The significant advantages for 2% MTS over Fulvestrant were
authors tried to determine the efficacy of the simultaneous seen in men even as soon as the eighth week of the study.
use of these two medications. Therefore, it is impossible to Although well-tolerated, Fulvestrant solution was ineffec-
attribute the positive effects solely to the 17α-estradiol ele- tive in the management of either AGA or FPHL in this well-
ment of the treatment since MTS alone has produced similar designed study. This remains the only study to date
results in females with FPHL in terms of total hair density evaluating the hair-growth effects of an estrogen compound
and hair parameters [111]. Overall, this study’s data failed objectively by measuring hair density, cumulative hair
to provide definitive information as to whether the single thickness, and hair growth rate in men [113].
use of either MTS or 17α-estradiol is more effective than the Kanti et al. [85] considered that results on the efficacy of
combination. topical estrogens to improve or prevent progression of FPHL
Rossi et al. conducted a single-blind study, retrospective in female patients are contrary and insufficient to support
study to investigate the efficacy of topical 0.05% 17α-estradiol their use in FPHL, resulting in evidence level 4. Naturally,
solution vs 0.5% Finasteride lotion in the treatment of FPHL they strongly do not recommend the use of oral estrogens or
in 119 postmenopausal female patients split into two groups. androgen-receptor antagonists to improve or prevent the pro-
The first group comprised 69 women treated with 0.5% gression of AGA in male patients. They also recommend not
Finasteride, 2% MTS, and 0.08% hydrocortisone butyrate. using fulvestrant, fluridil, or alfatradiol in males.
The second group included 50 women treated with
17α-estradiol 0.05%, 2% MTS, and 0.08% hydrocortisone
butyrate. Global photographs were systematically taken at 36.5 Adverse Effects
baseline and at 6- and 12- to 18-month follow-up and were
evaluated using the 7-point rating scale. All patients were Transdermal delivery of estrogens is a promising field of
instructed to apply 1 mL of the assigned topical solution pharmacology [114]: novel topical spray vehicles for
every night on the vertex and frontal region. The improve- enhanced transdermal delivery of estradiol have been inves-
ment was statistically significant from 6 months to tigated and developed for decades already [115], topical
12–18 months, both for Finasteride (p < 0.005) and solutions that prevent the local conversion of estradiol to the
17α-estradiol (p < 0.05) galenic formulations. More impor- less potent estrone [116], use of penetration enhancers [117]
tantly, the efficacy of topical Finasteride was significantly and “sophisticated” gels may allow higher efficacy with less
greater than that of the 17α-estradiol solution, both at the adverse effects in the near future.
6-month (p < 0.05) and at the 12- to 18-month follow-up Only 17α-estradiol may be safely used in men since all
(p < 0.005). The greatest improvement was observed after other estrogens bear the risk of gynecomastia and other anti-
12–18 months of treatment with topical Finasteride and min- androgenic adverse effects [103, 104]. After oral administra-
oxidil therapy. Using a 7-point scale, the improvement was tion, 17α-estradiol is rapidly and intensively conjugated,
statistically significant from 6 months to 12–18 months, both with only tiny quantities of the free steroid (<1% of total)
for Finasteride (p < 0.0027) and 17α-estradiol (p < 0.02). appearing in serum, whereas the half-life is <10 h [118].
The full-text article includes 2 sets of high-quality macro- Topical 17α-estradiol should be administered with caution in
174 36 Estrogens
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Progestins
37
ing the follicular phase (1 ng/mL), but and rise up to >18 ng/
Basic Concepts mL during the luteal phase [5].
• Progesterone is a natural hormone found in both Progestins are synthetic steroid compounds that mimic
sexes, and progestins are synthetic molecules the actions of endogenous progesterone. In contrast to pro-
with progesterone properties. Interestingly, cer- gesterone, they can be orally administered, which is sub-
tain progestins can be extensively absorbed jected to rapid and extensive gut and liver metabolism
transcutaneously. (first-pass) that results in irregular plasma levels and incon-
• Progesterone is a potent in vitro inhibitor of the sistent biological activity.
5α-R enzyme family, and certain progestins inhibit Progesterone has a complex metabolism, and it may form
5α-R isoenzymes even more efficiently than more than 35 different unconjugated metabolites when it is
Finasteride, but strangely enough, oral administra- ingested orally, while its terminal half-life in circulation is
tion of progestins is related to hair loss, frequently less than 5 min [6]. In contrast, progestins are metabolized at
reported by females under oral contraceptives. a slower rate and remain in circulation for several hours [6].
• There is only one small study published back in The metabolism of progesterone occurs primarily in the liver
1987 addressing the topical application of proges- [7], though enzymes metabolizing progesterone are also
terone in AGA or FPHL, reporting not statistically expressed widely in the brain, skin, and various other extra-
significant results but recent research might change hepatic tissues [8].
this. Progestogens are used most commonly in oral contracep-
tives and in menopausal hormone therapy.
Progesterone is a natural hormone synthesized in the human

body and is found in the serum of both sexes. In many spe- 37.1 Categories of Progestins
cies, including humans, progesterone is involved in the men-
strual cycle, pregnancy and embryogenesis [1]. It is also an Progestins were initially developed for two purposes:
essential metabolic intermediate in the production of other
endogenous steroids, including sex hormones and mineralo- 1. To overcome certain pharmacokinetic disadvantages of
corticoids, while also playing an essential role in brain func- natural progesterone,
tion as a neurosteroid [2]. 2. For patenting purposes, natural progesterone is a natural
Progesterone is synthesized from pregnenolone, which is compound and cannot be patented to generate profit.
derived from cholesterol [3]. In women, progesterone is pro-
duced by the ovary’s corpus luteum, from the onset of Progestins are synthetic derivatives of one of the following
puberty (adrenarche) to menopause. After adrenarche, pro- molecules [9] (Fig. 37.1):
gesterone is also produced in smaller amounts by the adre-
nals of both males and females. To a lesser extent, • natural progesterone,
progesterone is produced in the nervous tissue, mostly in the • 17alpha-hydroxyprogesterone (e.g., chlormadinone ace-
brain and in the adipose tissue. In men, 0.2–0.3 mg of pro- tate, Cyproterone acetate, medroxyprogesterone acetate,
gesterone is produced daily by the adrenals (60%) and megestrol acetate),
Leydig cells (40%), resulting in serum progesterone levels of • 19-norprogesterone (e.g., nomegestrol, promegestone,
≤0.9 ng/mL [4]. In females, progesterone levels are low dur- trimegestone, nesterone),
180 37 Progestins
Fig. 37.1 Classification of synthetic progestins. (From Edelman et al. [10])
• 19-nortestosterone norethisterone (NET) (e.g., lynestre- Differences in interactions with various hormone receptors
nol, levonorgestrel, desogestrel, gestodene, norgestimate, result in differing effects across progestin generations [12, 14].
dienogest)
• Spironolactone (i.e., drospirenone). • First-generation progestins have higher androgenic index
and more adverse reactions than second-generation and
third-generation progestins [7, 8]. A higher androgen
Progestins are commonly categorized by generation [11].
index leads to an increase in DHT.
The older progestins, synthesized in the 1960s and 1970s,
• Second-generation progestins also bind to the AR and are
were designed for use in oral contraceptives. For this rea-
considered higher in androgen index than the third-
son, a major design target was the antigonadotropic action.
generation and newer classes of progestins.
By convention, the older progestins are divided into three
• Third-generation progestins have very low androgen indexes.
generations and can be classified according to the steroid
• The newest progestins, such as chlormadinone acetate
from which they derive. The newer generation of proges-
(not available in the United States) and drospirenone,
tins has been designed to bind very specifically to the pro-
have mild antiandrogenic activity.
gesterone receptor (PR) and not to other steroid receptors
to avoid androgenic, estrogenic, or glucocorticoid side
effects [12]. Contraceptives with androgenic effects, especially
Progestins interact with the PR and interact with the first-generation and second-generation progestins, can
androgen and estrogen receptors. Progestins that bind to the induce chronic telogen effluvium, and can worsen the
androgen receptor (AR) are considered to have androgen effects for women who already have FPHL [11].
activity, though the level, or index, varies between older and
newer progestins.
Two mechanisms mediate the androgenic activity of
androgenic progestins: 37.2 Mechanism of Action
1. direct binding to and activation of the AR, The physiological effects of progesterone are mediated mostly
2. displacement of T from sex hormone-binding globulin by the PR but also with other steroid hormone receptors. Some
(SHBG), thereby increasing free (and thus bioactive) progestins interact with the AR, the estrogen receptor, the glu-
Testosterone (T) levels [13]. cocorticoid receptor, or the mineralocorticoid receptor.
37.3 Actions in the Skin and Hair Follicles 181
The PR belongs to the type-1 nuclear receptor subfamily. most likely to the skin as well, and it functions as a biologic
Like other family members, the PR contains three main func- switch in hair follicles, overseeing the entry and exit from
tional domains, an N-terminal domain, a centrally located anagen [29].
ligand-binding domain (LBD), which is involved in DNA Progesterone has also been found to be a potent indirect
binding, and a C-terminal domain, which is involved in inhibitor of 5α-Reductase [30] (5α-R) in microsomal prepa-
ligand binding and transcriptional activation [15]. PR is a rations of human skin. Progesterone was converted into
hormone-inducible transcription factor activated by a multi- 5a-pregnane-3,20-dione in these preparations and competed
step mechanism. After progesterone (or an agonist) binds to effectively with Testosterone (T) for the enzyme’s active site
the PR, a major conformational change within the LBD is [31]. In later ex vivo studies on human skin, progesterone
induced, promoting the recruitment of transcriptional coacti- was found to inhibit the 5α-R enzyme system by up to 93.3%
vators and multiprotein assembly complexes with chromatin- [32–34]. This function is probably due to the chemical
modifying activities [16]. It was recently confirmed that resemblance of progesterone and T, which allows these mol-
progesterone could also act directly (nongenomic action) ecules to compete for the 5α-R enzyme for the production of
without binding to the PR but through the activation of tran- Dihydroprogesterone or Dihydrotestosterone (DHT), respec-
scriptional factors. There are several rapid non-nuclear sig- tively. Even though Dihydroprogesterone does not have
naling pathways known to be activated by progesterone. androgenic properties, is metabolically inert, and is elimi-
These include the extracellular signal-related kinase (ERK) nated through the kidneys [35], it will still compete with
pathways, Ca2+ influx/PKC activation, phosphatidylinositol DHT for cell receptor sites [36].
3-kinases (PI3 K)/Akt pathway enzymes of the tyrosine
kinase family [17], protein kinase A (PKA), protein kinase C
Therefore, it is speculated that by having available
(PKC), and other signal transduction cascades [18].
excess numbers of molecules of progesterone com-
Progesterone is involved in various physiological pro-
pared to T, 5α-R will produce fewer DHT molecules in
cesses besides reproduction, and since the biological func-
favor of more Dihydroprogesterone molecules [37].
tions of progesterone in the reproductive system, nervous
system, and other systems are beyond the scope of this chap-
ter, only the role of progesterone and progestins in skin and Synthetic progestins, such as norgestimate, have been
hair follicles will be presented. found to inhibit 5α-R potently [38]. There are reports that
certain modern progestins inhibit the 5α-R enzyme system in
the hamster seminal vesicles and flank organs more power-
37.3 Actions in the Skin and Hair Follicles fully than Finasteride [39]. Similar results were reported by
Niiyama et al. on dermal papilla cells (DPCs) derived from
The PR has been detected in the human skin, and it is present human scalp biopsies. DPCs were incubated in the presence
in keratinocytes and fibroblasts, indicating that both are tar- of [3] H-testosterone (T), 17α-Estradiol, 17β-Estradiol, pro-
gets for progesterone activity [19]. Even though progester- gesterone, or Finasteride for up to 48 h. Finasteride 1 nM
one does not have the impressive positive effects of estrogens inhibited DHT synthesis in DPCs by 86%, 1 nM progester-
on skin morphology (collagen and water content, surface one by 75%, 100 nM 17α-Estradiol by 20%, and 100 nM of
lipids, elasticity, skin thickness, blood flow, etc.), it is well 17β-Estradiol by 60% [40].
documented that progesterone has positive effects on skin Research on synthetic progestins is extensive, and numer-
and has even been used as an anti-aging compound [20]. ous new compounds with potent antiandrogenic properties
At a cellular level, progesterone at very low concentra- have been discovered, with the hope to use them in the ther-
tions (3 × 10−10 M) has been found to increase the prolifera- apy of prostate diseases and other conditions [40–43].
tion of keratinocytes in vitro. Paradoxically, progesterone Progesterone also partially inhibits binding of androgens to
has an inhibitory keratinocyte effect at higher concentrations the AR in vitro, but this is not considered significant in vivo
(3 × 10−7 M) [21], while some progestins have been found to [44].
increase the proliferation of dermal papilla cells in vivo [22]. Regarding the action of progestins on the sebaceous
Moreover, progesterone has been known to induce localized gland, studies have generated conflicting results. Early stud-
suppression of the immune response [23] and regulate cyto- ies claimed that progesterone did not affect sebum produc-
kine production in tumor cells, such as interleukin IL-6 [24], tion in lab animals [45, 46]. Others found marked hyperplasia
which has been implicated in the pathogenesis of alopecia when progesterone was administered to oophoreetomized
areata. It also inhibits the activity of matrix metalloprotein- rats [47], whereas other researchers reported that progester-
ases in fibroblasts, thus suppressing collagenolysis and one increased sebum production minimally [48]. Concerning
maintaining skin thickness [25–27]. Furthermore, progester- human studies, results were also conflicting. Zeligman et al.
one enhances EGF expression in the endometrium [28] and reported the experimental induction of acne in adult females
182 37 Progestins
with progesterone administration [49]. In contrast, Strauss Burry et al. reported that when estradiol 0.05 mg patches and
et al. reported that the administration of natural progesterone progesterone cream 30 mg were applied on the skin of six
in physiologic amounts to prepubertal and postpubertal postmenopausal women, the serum concentrations of pro-
males and females and to aged females did not change the gesterone was significantly increased and correlated strongly
sebaceous gland size or function [50]. with the absorption of transdermal estradiol [60].
The reason for the qualitative and quantitative differ-
ences in the results between human and animals concerning
the androgenicity of progestins is mostly due to the extrap- 37.5 Progestins and AGA/FPHL
olation of data from rat studies to humans and the use of
different progestins. Progestins differ widely in their chem- Progesterone has been widely used as a topical antiandrogen
ical structures, structure–function relationships, metabo- according to anecdotal reports and uncontrolled studies,
lism, pharmacokinetics, and potencies; they are not created yielding mixed results [61]. The scientific rationale behind
equal [51]. this questionable practice originates from studies in the adult
male hamster with fully developed flank organs. In this
model, repeated progesterone injections to one flank organ
37.4 Topical Progestin Solutions resulted in shrinkage of the flank organ to the female flank
organ’s size and weight [62]. This finding “convinced” many
The transdermal uptake of progestins by the skin of lab ani- clinicians that progesterone is a potent antiandrogen and that
mals and the tissue distribution following local application it could be useful in androgen-dependent disorders.
have been extensively studied, first by Scheuplein et al. [52]
(1969) and decades later (1995) by Johnson et al. [53]. Consequently, many physicians probably experi-
Progesterone levels in the serum and in other organs in lab mented with progesterone topical solutions or injec-
animals after skin application of a progesterone solution is tions on the scalp in patients with AGA or FPHL in the
extensive. The tissue/plasma concentration ratio for “pre-Minoxidil” era, during a time that anything that
progesterone exceeded 1 in all tissues, most notably in the could help in the fight against hair loss seemed promis-
uterus (8.4) and lungs (9.6), whereas urinary progesterone ing and useful.
levels were only half of those in plasma [54]. However, the
pharmacokinetics of topical progesterone solution in the
human skin markedly differ from those of lab animals. Since The topical application of progestins for the treatment of
progesterone is a lipophilic compound, it is extensively AGA and FPHL has been studied, but studies are very lim-
absorbed by the human skin, both transepidermally and ited in number and scale [63–65]. Only 1 article published in
through the follicular ducts and sebaceous glands [55]. The 1987 by van der Willigen et al. has directly addressed the use
absorption of topically applied progesterone in healthy male of topical progestins for the management of AGA63, and thus
volunteers was 33 ± 8.9% under occlusion, 13 ± 6.3% under far, no well-controlled studies of topical progesterone have
protected conditions [56] and 10.8 ± 5.8% in open applica- been published in the English literature. Nav der Willigen
tion [57]. et al. treated 10 male AGA patients for 12 months with a
Several studies have addressed the use of topical proges- topical lotion containing 1% of 11a-hydroxyprogesterone
tins in pre- and postmenopausal women. Nevertheless, and included eight untreated patients in the study who served
results on the absorption and efficacy of this mode of admin- as the control group. Hair root diameters were measured
istration are contradictory. under 100× magnification, and the anagen/telogen ratio was
O’Leary et al. investigated six pre- and six postmeno- calculated before and after treatment. Even though the ana-
pausal women to determine the short-term changes in serum, gen/telogen ratio and the mean hair shaft diameter were both
urinary, and salivary progesterone concentrations following reported as slightly increased, the difference was not statisti-
a single 64 mg progesterone topical application. They cally significant, and since the control group was left
reported that even though serum progesterone concentra- untreated, the “placebo effect” could not be determined [63].
tions did not increase, salivary values increased 10-fold, con- The other two relevant studies did not address AGA spe-
firming that topically applied progesterone is extensively cifically. Tamm et al. treated three groups of subjects, Group
absorbed, despite the lack of change in serum progesterone 1 included five normal males who applied vehicle only for
concentrations [58]. Carey et al., who studied 24 postmeno- 15 days, Group 2 included 11 normal males who applied 1%
pausal women aged 40–65 years of age, reported a mild of 11a-hydroxyprogesterone b.i.d. on the forehead for
increase in progesterone’s mean concentration in the serum 15 days, and Group 3 included nine females with FPHL
and of pregnadiol-3-glucoronide in the urine and also noticed treated with 15 mL of 0.5% of 11a-hydroxyprogesterone
a wide intersubject variation [59]. Contrary to these results, b.i.d. for 2,5–4 years. Researchers measured sebum produc-
References 183
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all three groups. Group 1 had no change in sebum produc- ating natural progesterone with breast cancer [72], but there
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duction and −62% in cholesterol content, whereas women in
Group 3 reported diminished greasiness, a −42% reduction Synopsis
in sebum production, and −56% in cholesterol content. From Progesterone and synthetic progestins have been reported to
these results, the authors speculated that progesterone could exert potent antiandrogenic effects in hair follicles in vitro,
slow the progression of FPHL in women but presented no which have not been demonstrated in clinical practice. There
findings whatsoever to support their claims [64]. is no solid evidence to support their use to improve or pre-
Tromovitch et al., in a review article, mentioned the ratio- vent the progression of AGA in males or FPHL in females.
nale of injecting dilute suspensions of aqueous progesterone Therefore, these agents should be avoided when treating
3-5 mg/mL with or without triamcinolone acetonide 1 mg/ these disorders.
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Hormonal Contraceptives
38
In general, hormone contraception compounds include

Basic Concepts those containing estrogen (ethinyl estradiol) combined with
• Oral Contraceptives (OCs) can have both positive a progestin, and those containing only a progestin [3]. OCs
and negatives effects on hair follicles. Hair loss is a are available in both these types of formulations, whereas
recognized adverse reaction of Combined Oral intrauterine devices (IUD), subcutaneous implants, and
Contraceptives (COCs) due to the androgen activity injections contain only progestins. OCs containing estrogen
caused by the progestin component and can occur and a progestin are called combined OCs (COCs) [4].
to 10–12% of users. The OC pill is one of the most extensively studied pre-
• This androgen action may be counteracted by the scribed medications. As one would expect, the primary func-
activity involving estrogen receptors credited to the tion of OCs is to prevent pregnancy, and the primary
estrogen component of the COCs, but the overall mechanism of action is the prevention of ovulation by alter-
effects on the hair will depend on the potency of the ing estrogen and progesterone levels to arrest fertility.
progestin component and the amount of estrogen in Progesterone is primarily responsible for the inhibition of
the COC. follicular development [5]. Progestins are synthetic steroid
• Hair loss in the form of shedding or thinning due to compounds that mimic the actions of endogenous progester-
COCs can occur on several occasions: during the one (see Chap. 37). Progestins in COCs are generally classi-
initiation of treatment, 3–4 months into treatment, fied according to the androgen index three earlier generations
due to switching of a compound to another, or after (first to third) and a fourth, newer generation [4] (see
the discontinuation of treatment with an estrogen- Table 38.1).
only OC taken for a long time. Besides the primary function, OCs have become essential
• Women with a medical or family history of hair loss medications for many other functional or organic distur-
or/and FPHL are more vulnerable to an exacerba- bances. They are used with several off-label indications such
tion of hair loss and should be thoroughly consulted as dysmenorrhea, irregular uterine bleeding [6], premen-
to make informed decisions on the contraception strual syndrome, premenstrual dysphoric disorder [7], poly-
method they will choose. cystic ovaries [8], endometriosis, pelvic inflammatory
• Modern COCs contain progestins of low andro- disease, rheumatoid arthritis, menstrual migraine, and the
genic potential or with antiandrogenic effects and onset of multiple sclerosis. All these are prevented, treated,
are therefore safer for use by those susceptible or delayed with OC therapy [9].
women. These COCs can be even used to treat As will be explained, OCs can also reduce the negative
FPHL. actions of endogenous androgens on sebaceous glands and
hair follicles. They can treat the symptoms of androgeniza-
tion and offer numerous benefits to the skin [10], such as
Oral contraceptives (OCs) were first approved for use in the acne regulation [11], management of hypertrichosis and hir-
U.S. in 1960 [1]. The OC pill is colloquially referred to as sutism [12], and treatment of specific causes of hair loss
“the pill,” and it is the second most popular form of contra- [13].
ception in the Western world. It is used by more than 100 Despite the undeniable popularity and benefits of hor-
million women worldwide, and according to the U.S. Center monal contraception, some women experience adverse
for Disease Control (CDC), 12.6% of the 72.2 million effects caused by the androgenic properties of progestins in
women aged 15–49 in the U.S. are currently using OCs [2]. COCs or in progestin-only hormonal contraceptives of any
188 38 Hormonal Contraceptives
Table 38.1 Commonly prescribed progestins by androgen index normo-androgenic and hyper-androgenic women. Three pos-
Generation Drug sible underlying mechanisms may be held responsible for
First (high) Norethindrone this effect:
Ethynodiol acetate
Norethindrone acetate • Suppression of ovarian androgen synthesis,
Second (medium) Levonorgestrel • Increased SHBG levels,
Norgestrel
• Suppression of adrenal androgen synthesis.
Norethisterone
Third (low) Desogestrel
Etonogestrel The details of different types of COCs on the suppression of
Norgestimate gonadotrophin secretion, adrenal androgen synthesis, and
Norelgestromin the metabolism of SHBG, go beyond the scope of this chap-
New progestins (antiandrogenic) Drospirenone ter, and the interested reader is advised to seek further infor-
Gestodene mation in the relevant literature [23–25].
Norethisterone acetate
Chlormadinone acetate
38.2 Hormonal Effects of OCs in Hair

type (oral, cutaneous of IUD). These women experience Follicles
adverse effects, including breast sensitivity, headaches, nau-
sea, and loss of libido [14–16]. Moreover, epidemiological Estrogens and progesterone/progestins are actively involved in
studies have shown a relation between OCs and increased the physiology of the hair follicle. The estrogen component of
risk of arterial and venous thrombotic events [17]. COCs prolongs anagen duration, decreases the telogen rate,
and has an overall positive effect on the female scalp hair [26]
(see Chap. 36). Progesterone enhances Epidermal Growth
External androgenic manifestations of COCs include Factor (EGF) expression, and it functions as a biologic switch,
oily skin, acne, hirsutism, android obesity, excessive guarding the entry and exit from anagen [27] (see Chap. 37).
telogen hair loss, or exacerbation of FPHL [18]. However, several synthetic progestin components of
COCs have high-androgenic potential and bear the risk of
adverse effects on the hair follicles of the female scalp.
Androgen activity may be counteracted by activity involv- Significantly, the first- and second-generation progestins
ing estrogen receptors credited to the estrogen component of included in older COCs, can induce telogen effluvium and
the COC. In general, progestin-only hormonal contracep- can exacerbate shedding and miniaturization in women who
tives of any type will have more pronounced adverse effects already have FPHL [18, 22, 28].
compared to COCs, since the former lack estrogen to coun- The adverse effects of COCs in hair follicles have been
teract the androgen effects of certain progestins. reported in the literature very early. Cormia was the first to
describe five women who had diffuse hair loss, which was
attributed to COCs. The hair loss started in three patients
38.1 General Hormonal Effects of OCs when they stopped taking the COC. One had been continu-
ously taking a very high estrogen dose for endometriosis
In normo-ovulatory women, Testosterone (T) arises from when the hair loss started, and another was taking a sequen-
three sources: 50–60% is derived from the peripheral con- tial COC [29]. Greenwald reported two patients who devel-
version of the pro-hormones androstenedione, dehydroepi- oped diffuse alopecia after stopping the COC and three more
androsterone (DHEA), and its sulfate (DHEA-S), whereas who lost hair while still taking the COC [30]. Both studies
25% is secreted by the ovary and 25% by the adrenal gland lacked controls and did not state whether other causes of
[19, 20]. Around 65–70% of circulating T is bound and thinning hair were excluded. Dawber et al. reported diffuse
inactivated by sex-hormone-binding globulin (SHBG). hair loss occurring in a woman 2 months after stopping a
Most of the remaining 30–35% is bound by albumin, and COC. The hair fall ceased when she became pregnant but
only 0.5–3% represents freely circulating T (free T). Since restarted 2 months after delivery and continued after
the binding of T to albumin is relatively weak, the free- and 4 months [31, 32]. Griffiths studied a series of 31 women
albumin-bound T together are defined as the bioavailable T seen consecutively for diffuse thinning of scalp hair and con-
[20–22]. firmed that diffuse scalp hair loss occurred in some women
COCs can reduce the serum levels of T -and consequently after they stop taking COCs and that others noticed thinning
the dihydrotestosterone (DHT) levels- by up to 50% in both while still taking COCs [32].
38.3 Clinical Image 189
Hair loss may also emerge due to IUDs [33] and subcu- treatment might not correlate it to the OC and will often pre-
taneous contraceptive methods [34]. Alopecia is listed as fer other explanations, such as stress- or seasonal-induced
an adverse event of progestin-only OCs [35] and has been hair loss.
reported with progestin implants with incidence rates of
1.1–11.8% [36, 37]. Backman et al. studied approximately
18,000 women in Finland and observed contraception- 38.3 Clinical Image
related hair loss in 15.7% of the women who are were
using an IUD containing levonorgestrel. More particularly, Hair loss in the form of shedding or thinning due to COCs
17.7% of women <33 years old reported hair loss and up to can occur in several distinct circumstances. It can occur dur-
13.5% in women aged 39–47 who were using IUD. Details ing the treatment initiation, later, several weeks into treat-
of the onset of hair loss concerning insertion and removal ment, due to switching from one COC to another or after the
were not given [38]. Paterson et al. reported on a case discontinuation of treatment with an estrogen-only OC that
series of five women in New Zealand who have experi- was taken for a long time.
enced hair loss while using the levonorgestrel IUD, identi-
fied by Prescription Event Monitoring [39]. Hair loss has • Telogen effluvium precipitated by COCs containing a
also been identified as a secondary outcome measure in the progestin with a high androgenic potential generally
Cochrane review of hormonally impregnated IDUs, but no occurs 3–4 months after treatment initiation in genetically
studies were identified that provided data on this outcome predisposed women. It has been proposed that in the pres-
[40]. ence of a genetic susceptibility, it is the estrogen to andro-
gen ratio that might be responsible for triggering hair loss
Despite the massive popularity of OCs, hair loss as an in women. In the same line is the observation of hair loss
adverse effect of specific OCs is commonly acknowl- induced in susceptible women by treatment with aroma-
edged in medical textbooks. However, many physi- tase inhibitors for breast cancer [43].
cians do not address it when prescribing OCs as it • Telogen effluvium precipitated by the discontinuation of
might be seen as favoring individual pharmaceutical an estrogen-only OC resembles post-partum hair loss. In
companies or compounds. OC-induced telogen effluvium, the percentage of hair fol-
licles massively entering telogen can reach even 50%
compared to the physiological 5–10%. This form of hair
Accurate hair loss rates due to hormonal contraceptives of loss may occur 6 weeks to 3 months after discontinuation
all types are difficult to find due to differing methodologies, of a COC, but normal hair growth usually returns within
studies funded by pharmaceutical companies, and hair loss 3–6 months [44]. The observation that many women show
often being combined with hirsutism when categorizing increased shedding of hair from 2 weeks to 3–4 months
adverse reactions [4]. after they stop taking an oral contraceptive probably sim-
Hair loss as an adverse effect of OCs is also underreported ulates that which is commonly seen after parturition [45].
in the literature. This is probably due to insufficient knowl- • Interestingly, some patients may experience an exacerba-
edge on the pathophysiology of FPHL and because hair loss tion of telogen effluvium as a result of initiating a COC as
must be severe enough before it is clinically evident. well as during the change of the prescribed COC, mostly
Therefore, many women suffer from hair loss and not real- when the previous pill was used for long periods of time.
izing it is from their OCs since they do not become “too Fortunately, this process is reversible most of the time
thin.” when the patient is re-administered the previous compound
Another reason for the underreporting is the confusing or when the hair follicles “adjust” to the new molecule.
anamnesis since most women will report that hair growth With time, the amount of lost hair is generally restored.
accelerated when first starting the OCs and that their hair • Patients susceptible to FPHL, or already afflicted by
actually got thicker. These same women, however, may FPHL or with a positive family history of hair loss and/or
describe an increased rate of hair loss several months after FPHL are more susceptible to exacerbation of hair loss
starting the OC. due to COCs. In these women, both the administration
Signs of hair loss are also reported by teenagers who start and the discontinuation of a COC can exacerbate the con-
OCs [40]. During the initial stage of OCs administration, dition. These women should be forewarned that taking
they do not observe increased growth and hair thickening as COCs may result in shedding or thinning to make
easily as an older, post-menopausal woman with thinner hair informed decisions about how to approach birth control.
would, but clumps of hair in the brush hardly go unnoticed If hair loss occurs, these cases tend to reverse partially
several months after initiation of OCs [41, 42]. These teenag- and not entirely [46]. Progestin-only hormonal contracep-
ers who notice increased shedding after months into OC tives (such as levonorgestrel, and tibolone) may have even
worse results on the hair of these women than COCs mended to use a non-hormonal contraceptive method.
because they lack estrogen to counteract the androgen According to the American Hair Loss Association, a list of
effects [40–42]. These COCs may precipitate alopecia COCs with a significant potential of exacerbating or causing
and often with a male pattern. hair loss ranked according to their androgen index from the
lowest to highest [53] follows:
38.4 How to Avoid OCs-Mediated Hair • Desogen,

Loss? • Ortho-Cept,
• Ortho-Cyclen,
Progestin-only hormonal contraceptives should be avoided • Ortho Tri-Cyclen,
in females susceptible to FPHL unless absolutely necessary. • Micronor,
Therefore, a medical and family history concerning hair • Nor-Q D,
health should be acquired before the prescription of any OC • Ovcon-35,
to these groups of women. The same applies to high- • Brevicon/Modicon,
progestin-content COCs and IDUs. • Ortho Norvum 7/7/7,
If a female patient complains of hair loss and is con- • Ortho Novum 10–11,
comitantly using any hormonal contraception method, • Tri-Norinyl, Norinyl,
the physician should consider the androgen index of the • Ortho 1/35,
progestin as well as the level of ethinyl estradiol in the • Demulen 1/35,
COC since estrogenic effects can counteract androgenic • Triphasil/Tri-Levien,
effects. Women experiencing an exacerbation of hair • Nordette,
loss, whether due to hormonal contraception or not, may • Lo/Ovral,
find more benefit from COCs containing 30mcg ethinyl • Ovrette,
estradiol [47]. If a patient has been experiencing chronic • Ovral,
shedding (6 months or more) or hair thinning and is on a • Loestrin 1/20,
high androgen index contraceptive, the physician should • Loestrin 1.5/30.
consider prescribing a less androgenic COC. Patients
COCs that contain third-generation progestins or drospi-
renone may be at increased risk of venous thromboembo- 38.5 COCs as a Treatment for FPHL
lism [48].
COCs higher in estrogen or containing progestins with
antiandrogenic effects may stimulate hair growth, prolong
For patients who develop increased hair shedding
anagen, and reduce the effects of DHT both systemically
3–4 months after starting a high androgen index COC,
and locally. Cyproterone acetate (see Chap. 29),
and for whom other potential causes have been ruled
Chlormadinone acetate, and Dienogest are progestins with
out, switching to a low androgen index COC may be
purely antiandrogenic effects. There is long-standing expe-
beneficial if the shedding does not resolve in 6 months
rience with COCs and progestogen-only OCs containing
[49].
Chlormadinone acetate in Germany and France; however,
familiarity with these agents is limited in most other coun-
Gradual hair thinning in a patient using a high androgen tries [28]. Schindler reported on a female patient with
index contraceptive, in the absence of other causes, indicates FPHL without underlying hyperandrogenism, treated with
FPHL [50]. ethinylestradiol/chlormadinone acetate (EE/CMA)
Low-progestin-content COCs are less likely to cause hair 0.03 mg/2 mg for 6 months and experienced stabilization of
loss. However, several women are still using older COCs that hair loss [9].
contain high amounts of older progestins because these pills Fourth-generation progestins, unlike progestins from the
are much cheaper. These older formulations contain proges- first three generations, have mild antiandrogenic activity.
tins with high androgenic potential, resulting in a higher Norethisterone acetate, gestodene, chlormadinone acetate
incidence of hair loss. (not available in the U.S.), and drospirenone also possess
The American Hair Loss Association recommends to antiandrogenic properties [54].
women interested in using COCs regardless of the indication Newer COCs, such as Yasmin [55], Yaz [56], Desogen
to prefer medications with low androgenic potential, such as [57], Mircette [58], OrthoCyclen [59], Ortho-TriCyclen [18],
desogestrel [51] and gestodene [52]. If there is a strong pre- and Ortho-TriCyclen Lo [60], and Yasmin [61] are more suit-
disposition for hair loss/FPHL in the family, it is recom- able for women concerned about the likelihood of hair loss.
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Flutamide
39
largely replaced by newer NSAAs, namely Bicalutamide and

Basic Concepts Enzalutamide, mostly due to their superior safety, tolerabil-
• Flutamide is a potent nonsteroidal antiandrogen, ity, and pharmacokinetic profiles [7].
competing with androgens on the androgen recep- The “off-label” dermatologic uses of Flutamide include
tor level. Its off-label use in Dermatology focuses hirsutism, with or without excessive androgens [2, 8], acne,
on hirsutism and acne in women, while, so far, there and FPHL. In these cases, it is used alone or in combination
is limited evidence supporting its use in the treat- with oral contraceptives (OCs).
ment of FPHL.
• A few low-quality studies have demonstrated the
efficacy of oral Flutamide in FPHL, but there is a 39.1 Mechanism of Action
high risk of severe hepatotoxicity, which is occa-
sionally lethal, while its use in males is indicated The exact mechanism of action of Flutamide has not been
only in hormone-sensitive prostate tumors and it is fully elucidated yet. Both Flutamide and its active metabo-
contraindicated in healthy males. lite, HF, act as selective, competitive, silent AR antagonists.
• Topical flutamide could be interesting in the treat- Neither Flutamide nor HF possess any intrinsic androgenic
ment of AGA but early experimental results await activity but still compete with androgens for binding on the
confirmation. AR and inhibit the translocation of the androgen-AR com-
plex towards the cell nucleus. In Flutamide’s presence, fewer
androgen molecules bind to the AR and therefore do not
fully exert their action [9]. The active metabolite HF has a
Flutamide (Eulexin™, Schering-Plough Int.) was initially half-life of 5–6 h, possesses 10- to 25-fold higher affinity for
synthesized as a bacteriostatic agent, and it was later was the AR than Flutamide, but its affinity for the AR is only 5%
found to possess potent antiandrogenic properties [1]. compared to that of Testosterone (T). Flutamide has a far
Flutamide is a weak nonsteroidal, antiandrogen (NSAA) lower affinity for the AR than other steroidal antiandrogens,
with a nitroaromatic chemical structure. When orally admin- such as Spironolactone and Cyproterone Acetate (CPA). It is
istered, it undergoes extensive first-pass metabolism into an a relatively weak antiandrogen in terms of potency by weight,
active, potent, antiandrogen metabolite, 2-hydroxy-but the large dosages at which Flutamide is usually adminis-
Flutamide (HF) [2]. Both molecules act by competitive inhi- tered, compensate for this [10].
bition of androgen binding on the androgen receptor (AR) in By inhibiting T’s binding to the AR, Flutamide amplifies
target tissues, and Flutamide reaches steady-state concentra- the negative feedback of gonadal steroids at the hypothalamic-
tions after 2–4 days of oral administration [3]. pituitary level and inhibits adrenal 17,20-desmolase. This
Since the 1980s, oral Flutamide has been used off-label as inhibition reduces levels of DHEA and DHEA-S [11], evi-
a palliative treatment in hormone-sensitive prostatic tumors dent mostly in young women with polycystic ovary syn-
since early studies showed encouraging results [4]. A decade drome (PCOS) [12, 13]. Flutamide has no progesteronic,
later, these were confirmed by extensive studies [5], and the estrogenic, corticoid, or gonadotropin properties [14]. Also,
FDA finally approved Flutamide for the treatment of meta- Flutamide has been reported to decrease the release and
static prostatic carcinoma, combined with a luteinizing expression of EGF in prostatic cells in patients with benign
hormone-releasing agonist [6]. Lately, Flutamide has been prostatic hyperplasia [15] and prostatic cancer [16].
194 39 Flutamide
39.2 Flutamide and Hair Follicles Carmina et al. conducted a randomized, unmasked trial in
4 groups of 12 hyperandrogenic women with FPHL each
The use of Flutamide in Dermatology is focused on hirsut- (overall n = 48). They evaluated three treatments: Flutamide
ism and acne in women [11, 17], who usually receive the 250 mg/day, CPA 50 mg/day, Finasteride 5 mg/day, and they
lowest effective dose while having their liver enzymes also included an untreated control group of similar patients.
closely monitored [18]. Flutamide in this off-label use is Flutamide induced a modest improvement in FPHL after
considered the most effective antiandrogen for treating adre- 1 year of treatment and resulted in a statistically significant
nal seborrhea, acne, and hirsutism syndrome (SAHA), or improvement by 21% in Ludwig scores (2.3 ± 0.2 to
hirsutism alone in women with normal ovaries [19, 20]. In 1.8 ± 0.1), whereas other treatment effects offered no statisti-
these cases, low doses of 62.5–125 mg daily can be used cally significant improvement [30].
with high efficacy, according to several authors [21, 22]. Yazdabadi and Sinclair published a case report of a
Numerous studies have also demonstrated that 35-year-old female with normal androgen levels and a long-
Flutamide + OCs have impressive efficacy in the manage- term (>15 years) diffuse hair loss with widening of the mid-
ment of SAHA [23]. According to Camacho, Flutamide is line part (Sinclair grade 4). The patient has been treated with
the best antiandrogen for the treatment of PCOS at a dose of Spironolactone 200 mg/day for 5 years without improve-
125–250 mg/d and adrenal hirsutism at a dose of 250– ment, despite evidence of cutaneous antiandrogen effects of
750 mg/day. Higher doses carry the risk of severe hepatotox- the drug and almost complete loss of secondary sexual hair.
icity in >13% of patients [24]. Regarding these androgenic The addition of Minoxidil Topical Solution 5% (MTS) daily
disorders, Flutamide + OCs are recommended as a third line for 6 months did not improve the clinical picture signifi-
treatment reserved for milder refractory cases or upon failure cantly. The patient remained on MTS 5%, Spironolactone
of other modalities [25–27]. OCs alone are the first line treat- was discontinued, and Flutamide 250 mg/day was initiated.
ment, and Spironolactone/CPA the second line treatment. Then, the patient reported decreased hair shedding, increased
The hair growth potential of Flutamide has been evalu- hair density over the frontal area during the next 12 months,
ated almost exclusively in hyperandrogenic women with hair and upon examination, the hair loss score was improved
loss. According to some authors, Flutamide is the treatment from Sinclair grade 4 to grade 2 [31].
of choice when hair loss and hirsutism co-exist [28]. The only researchers who conducted a long-term (15-
years long) cohort study, including a large number of
women with FPHL (n = 101), were Paradisi et al. They
Olsen argues that most studies supporting this treat- evaluated Flutamide’s long-term effects, safety, and tolera-
ment modality suffer from the same severe method- bility in a prospective cohort study conducted in a tertiary
ological flaws as many other antiandrogen studies in care university hospital [32]. Thirty-three patients were
women: the effect on FPHL initially has not been eval- treated with Flutamide alone, and sixty-eight were treated
uated separately but was rolled into a single evaluation with Flutamide combined with an OC, and all received
of cutaneous androgen-related disorders, including yearly reducing doses (250, 125, and 62.5 mg/d) of
acne and seborrhea [29]. Flutamide during 4 years. Both groups showed a marked
decrease in alopecia scores after 12 months of Flutamide
Cusan et al. compared the clinical efficacy and safety of therapy, compared with baseline values. Approximately
Flutamide 250 mg b.i.d. and Spironolactone 50 mg b.i.d. in 80% of patients were satisfied or highly satisfied with their
the treatment of 53 premenopausal women suffering from treatment effect, regardless of whether they were taking
moderate to severe hirsutism. An independent investigator concomitant OCs or not. The maximum drug effect
monitored hirsutism, acne, seborrhea, alopecia, and side occurred after 2 years and was maintained during the fol-
effects during a treatment period of 9 months and a follow- lowing 2 years of treatment. However, during the first year
up period of 6 months. Flutamide caused the highest reduc- of high-dose therapy, 4% of patients dropped out of the
tion in the hirsutism score, reaching score values within the study due to hepatic dysfunction related to the drug,
normal range in 6 months. Moreover, 6 out of 7 women with whereas during the following lower-dose years, no patient
FPHL demonstrated an increase in cosmetically acceptable dropped out. The authors reported that the use of very low
hair density during the study period. Still, the authors did not Flutamide doses (62.5 mg/d) was associated with moderate
present further details or objective measurements of their efficacy in hair growth, excellent hepatic tolerability, and
claims. Subjects in the Spironolactone group had no improve- high adherence. However, results were only based on clini-
ment in hair appearance, and one subject in the group cal examination and not on objective measurements, such
reported further increased hair loss [21]. as total hair count or total hair weight [33].
Even though these studies seem to yield positive results, measured at 5.82 ± 0.50 mm and 4.50 ± 0.32 mm, respec-
according to extensive meta-analyses and reviews, no ran- tively, vs. 2.83 ± 0.18 mm for the vehicle-treated grafts.
domized placebo-controlled studies support the use of According to the authors, these results were similar or supe-
Flutamide in FPHL [34, 35]. rior to those obtained by oral Finasteride and oral Flutamide,
In the recent (2018) systematic review (Evidence-based without been associated with any systemic side effects, as
(S3) guideline for the treatment of androgenetic alopecia in demonstrated by T/DHT monitoring. Since 2000, no other
women and men) issued for the European Dermatology researchers have addressed the topical use of Flutamide solu-
Forum, Kanti et al. report that there is not enough evidence- tion as a potential hair growth treatment. There has been only
based data to support the routine use of Flutamide to improve a histological and in vivo study on male hamsters by
or prevent progression of FPHL in normoandrogenic female Hamishehkar et al. (2016), who developed Flutamide-loaded
patients at present [36]. solid lipid nanoparticles (SLNs) for follicular targeting and
demonstrated more new hair follicle growth with Flutamide-
loaded SLNs than Flutamide hydroalcoholic solution [43].
39.3 Topical Use of Flutamide
Due to Flutamide’s potent anti-androgen effects, its use is 39.4 Adverse Effects
strictly contraindicated in healthy males and is only limited
to the palliative treatment of hormone-sensitive prostatic Adverse effects due to Flutamide are potentially severe, and
tumors [37]. A topical Flutamide formulation would seem a off-label Flutamide remains limited because it can cause
logical step to avoid the systemic toxicity of Flutamide and dose-dependent, severe liver toxicity. Flutamide necessitates
allow males with AGA to benefit from its antiandrogenic serial monitoring of liver function tests (every 3 months)
effects only on the affected scalp regions, during treatment [44]. After the launch of Flutamide in the
Early tests were conducted in lab animals and comprised USA, between February 1989 and December 1994, the FDA
of Flutamide’s unilateral topical application to the flank received reports of 20 patients who died and 26 hospitalized
organs of Testosterone-treated female hamsters and to the for hepatotoxicity due to Flutamide Induced Liver Injury
flank organs of intact male hamsters for 14 days. Significant (FILI). [45] FILI is initially revealed and monitored by ele-
bilateral reductions of flank organ weight at doses as low as vation of aspartate and alanine aminotransferases concentra-
0.375 mg/d (the lowest dose tested), inhibition of lipogene- tion in plasma [46], and treatment should be stopped or not
sis, and a marked reduction in sebaceous gland size was evi- commenced if levels exceed twice the normal limits [47].
dent [38]. This confirmed the topical action of Flutamide in However, harm to hepatic tissue can range from fully devel-
androgen-dependent tissues. It also demonstrated that oped and severe manifestations [48] (e.g., ascites, hypoalbu-
Flutamide could be absorbed extensively and exert signifi- minemia, hyperammonemic encephalopathy, lethargy,
cant systemic effects even when topically applied [39]. confusion, bleeding, and clotting disorders) to mild, isolated
Katchen et al. determined Flutamide’s fate in men following biochemical alterations [49].
a single 6 h topical application of 5 mg 14C-labeled According to some earlier studies, both short [50] and
Flutamide, dissolved in 50% ethanol/50% propylene glycol. prolonged [51] Flutamide treatment of females with hirsut-
Urine analysis showed that at least 16% of the applied ism has not been related to serious adverse effects, and
Flutamide was systemically absorbed [40]. Interestingly, Sinclair et al. estimated the rate of hepatotoxicity at 3 in
while it has been found that topical Flutamide solution 2% 10,000 users [52]. In contrast, Giorgetti et al. [53] published
decreased sebum production in men, it paradoxically a thorough meta-analysis on 23 human-based studies target-
increased sebum secretion in women [41]. ing adverse Flutamide effects in hepatic and reproductive
The only article which correlated topical application of function. They reported several publications documenting a
Flutamide with hair growth was published in 2000 by Sintov high incidence of hepatic side effects of Flutamide, espe-
et al. [42], who used an experimental model of human scalp cially in women using the drug in an off-label indication.
skin graft transplanted onto SCID (severe combined immu-
nodeficiency) mice. Topical formulations containing
Finasteride, Flutamide, and a vehicle formulation were com-
pared in terms of mean hairs per graft, length, the diameter of According to the authors, treatment of hirsutism with
the shafts, and structures of the hair’s growth stages. The Flutamide in women is not appropriate, nor does it
number of hairs per graft for Flutamide and Finasteride meet the fundamental ethical principle “beneficence
groups was 1.22 ± 0.47 and 0.88 ± 0.95 hairs/graft, respec- non-maleficence,” since the risk/benefit ratio is
tively, vs. 0.35 ± 0.6 hairs/graft for vehicle-treated graft. strongly tilted toward the risk [53].
Similarly, hair lengths for Flutamide and Finasteride were
196 39 Flutamide
In men, similarly, Flutamide is the anti-androgen with the often used in FPHL. The efficacy of topical Flutamide solu-
highest incidence of hepatotoxicity. Abnormal liver function tion in AGA/FPHL has not been tested, and other researchers
test results have been reported to vary between 4% and 62% have not replicated that one study that demonstrated the effi-
in Flutamide groups, even when the drug is used with a cacy of topical Flutamide in rats. Oral administration of
proper indication [49, 54]. Flutamide in men with AGA is under no circumstances rec-
FILI is generally considered to be dose-dependent. ommended due to the castration-like antiandrogenic effects
However, Bruni et al. conducted a 10-year surveillance study it produces.
on 203 hyperandrogenic young females using low (125 mg/
day) and ultra-low (62.5 mg/day) dose regimens of Flutamide.
They reported a 10% incidence of hepatotoxicity, similar in References
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25. Cumming DC, Yang JC, Rebar RW, Yen SS. Treatment of hirsutism 48. Andrade RJ, Lucena MI, Fernández MC, Suárez F, Montero JL,
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Portier MB. Anti-androgen treatments. Ann Endocrinol (Paris). 49. Gomez JL, Dupont A, Cusan L, Tremblay M, Suburu R,
2010;71(1):19–24. Lemay M, Labrie F. Incidence of liver toxicity associated with
27. Camacho-Martinez FM. Hair loss in women. Semin Cutan Med the use of flutamide in prostate cancer patients. Am J Med.
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Dermosifiliogr. 1995;86:327–34. 51. Pucci E, Genazzani AD, Monzani F, Lippi F, Angelini F, Gargani
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Suppl):S70–80. sutism with flutamide alone in patients affected by polycystic ovary
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Recently Reported Hair Growth Drugs
40
The following pharmaceuticals/cosmetics have also been relative recovery rate did not change within or between the
reported to possess hair-growth properties in a few studies. groups (p = 0.99) at 6 months. After 6 months, none of the
Therefore their results are reported in summary. patients achieved complete recovery. However, the patient
satisfaction rate was significantly higher in the adenosine
group (p = 0.003) because of the reported faster prevention
40.1 Adenosine of hair loss and appearance of the newly grown hairs [7]. In
the full-text article, no before-and-after treatment photos are
Adenosine is an endogenous purine nucleoside composed of included.
a molecule of adenine which is attached to a ribose sugar In another RCT authored by Watanabe et al., 102 Japanese
molecule (ribofuranose) moiety via a β-N9-glycosidic bond male subjects were recruited; 51 volunteers used an 0.75%
[1]. Derivatives of Adenosine are widely found in nature and adenosine-containing lotion, and 51 used a placebo lotion,
are crucial in multiple energy-transfer biochemical pro- both during an observation period of 6 months. The number
cesses. These include adenosine diphosphate (ADP) and of those that experienced a moderate or higher improvement
adenosine triphosphate (ATP), as well as in signal transduc- in hair diameter was 41 of 51 subjects (80.4%) in the active
tion as cyclic adenosine monophosphate (cAMP) [2]. group vs. 16 of 50 (32.0%) in the control group (p < 0.05)
Adenosine itself is a neuromodulator, believed to play a [8]. The full-text article includes three sets of good quality
role in promoting sleep and suppressing arousal [3]. In clini- global before-and-after photos of adenosine-treated subjects
cal practice, Adenosine is the drug of choice for terminating that show minimal and moderate vertex improvement.
stable, regular narrow-complex tachycardias, including par- In the latest RCT to-date, Iwabuchi et al. recruited 38
oxysmal supraventricular tachycardia (PSVT) due to AV Caucasian male subjects; 19 volunteers used an 0.75%
nodal reentrant tachycardia and AV reentrant tachycardia adenosine-containing lotion, and 19 used a placebo lotion,
(AVRT) [4]. Adenosine also plays a role in the regulation of both during an observation period of 6 months. Hair diame-
blood flow to various organs through vasodilation [5]. ter was compared between the groups after 6 months. The
Since 2005, an adenosine-mediated signal transduction number of vellus hairs thinner than 40 μm in diameter sig-
pathway has been proposed to be involved in Minoxidil- nificantly decreased (p = 0.0154), the number of thick hairs
induced VEGF production (see Chap. 23). Therefore, equal to or thicker than 60 μm significantly increased
researchers decided to experiment on the potential hair- (p < 0.0001), and hair density significantly increased
growth effects of Adenosine. Concerning the efficacy of (p = 0.0470) in the adenosine-containing lotion group com-
Adenosine, 3 RCTs on AGA and one RCT on FPHL have pared vs. the control group [9]. The full-text article includes
been conducted, as Manabe et al. summarize in their excel- one set of low quality, global, before-and-after photos of an
lent review [6]. adenosine-treated subject that shows minimal vertex
Professor Gita Faghihi et al. (Department of Dermatology improvement.
Isfahan University of Medical Sciences Isfahan, Iran) con- Concerning FPHL, Oura et al. conducted an RCT, includ-
ducted a prospective RCT involving 110 adult male patients ing 30 female subjects (mean age 38.9), who used a 0.75%
(94 subjects completed the study) with a mean age of adenosine-containing lotion during an observation period of
30.46 ± 6.28 years. Subjects were randomized in to two 12 months. A significant improvement was found in the
groups, 53 patients (56.4%) received Minoxidil topical solu- growth rate of anagen hair and thick hair ratio in the
tion 5% (MTS 5%), and 41 (43.6%) received a 0.75% adenosine-containing lotion group vs. the placebo group. In
adenosine-containing lotion. According to the authors, the the adenosine-containing lotion group, 11 of 13 subjects
200 40 Recently Reported Hair Growth Drugs
(85%) experienced a moderate or higher improvement, that cetirizine had no notable side effects, allowing excellent
whereas 5 of 14 subjects (36%) experienced a mild or better patient compliance. Also, females of any age with FPHL can
improvement in the placebo group. The growth rate of ana- safely use it (pregnancy B2 category) [14].
gen hairs and the ratio of thick hairs ≥80 μm in diameter
significantly increased at 6 and 12 months in the adenosine-
containing lotion group. The authors suggested that Topical cetirizine may be a promising therapy for AGA
Adenosine promotes hair growth by modulating the expres- with an excellent safety profile. Further studies are
sion of genes encoding growth factors such as FGF-7 and warranted to assess the drug’s insight action, the pos-
VEGF, or TGF-β1 in dermal papilla cells [10]. In the full- sible role of other H1-blockers in AGA/FPHL, and
text article, no before-and-after treatment photos are whether it is useful in other forms of alopecias [15].
included.
According to Manabe et al., there is sufficient evidence
concerning Adenosine’s hair growth effects in men, and topi-
cal application is recommended as an alternative to MTS 5% 40.3 Roxithromycin
(grade of recommendation: B). In contrast, there is insuffi-
cient evidence regarding its efficacy in women, and given its Roxithromycin (RXM) is a 14-member anti-microbial, semi-
minor adverse reactions and the fact that products for women synthetic macrolide that prevents bacterial growth by inter-
are commercially available, topical application is permissi- fering with their protein synthesis [16]. RXM has a variety of
ble (grade of recommendation, C1) [6]. bioregulatory functions over many cell types, including anti-
Kanti et al. in their recent (2018) systematic review inflammatory and antioxidant effects [17, 18]. Roxithromycin
(Evidence-based (S3) guideline for the treatment of androge- is not available in the United States.
netic alopecia in women and in men) issued for the European In 2005, a preliminary (unpublished) clinical study sug-
Dermatology Forum make no mention of adenosine [11]. gested favorable results of topical RXM in AGA. Based on
these preliminary results, Ito et al. cultured murine (Balb/c
mice) vibrissae hair follicles (HFs) and human scalp skin
40.2 Cetirizine anagen HFs and examined the in vitro effect of RXM in
comparison to other 14-member macrolides, namely clar-
Cetirizine is sold under the brand name Zyrtec® (among oth- ithromycin, and erythromycin. They reported significant
ers), and it is a second-generation antihistamine used to treat acceleration of murine vibrissae HFs elongation by only
allergic rhinitis, dermatitis, and urticaria [12]. According to RXM (p < 0.05), an anti-catagen effect (p < 0.01), anti-
the findings of Garza et al., prostaglandin E (PGE) and apoptotic effect of RXM on murine HF keratinocytes
PGF2a play a generally positive role on hair growth, while (p < 0.05), increased proliferation of murine HF cells
PGD2 plays a potent inhibitory role on hair growth [13] (see (p < 0.05) and increased hair elongation in cultured human
Chap. 11, Vol. 1). Therefore, the researchers decided to HFs (p < 0.01).
experiment on the potential hair-growth effects of antihista- In order to test the clinical effects and safety of topically
mines and cetirizine in particular. applied RXM on hair restoration in AGA, researchers
Rossi et al. conducted a preliminary study on the efficacy recruited a total of 24 adult Japanese men with AGA (18 to
and tolerability of a topical lotion containing cetirizine 1% 40-years of age) at stages Norwood/Hamilton grade II and
for the treatment of AGA and FPHL. They recruited 85 vol- III; 13 volunteers used an 0.5% RXM containing lotion, and
unteers (male and female aged between 22 and 60), of which 11 used a placebo lotion, both during an observation period
67 were used to assess the treatment’s effectiveness with of 24 weeks. Vertex global photographic assessment scores
topical cetirizine 1%, while 18 were control patients. at 24 weeks were 2.08 ± 1.03 and 0.09 for RXM-treated and
Researchers evaluated the following variables: total hair den- control patients, respectively (p < 0.01). The hair shaft thick-
sity, vellus hair density, terminal hair density, and hair diam- ness was significantly increased after 24 weeks
eter. After 6 months of treatment with cetirizine, the patients (86.8 ± 10.5 μm) from baseline (55.9 ± 3.47 μm) in RXM
showed an 11% increase in the average total hair density, an group (p < 0.01) vs. no difference in the control group. No
18% increase in the average terminal density, a 15% decrease patients treated with RXM lotion experienced any topical
in the vellus hair density, and a 10% increase in the average adverse effects, such as irritation and inflammation. The full-
diameter (all p > 0.05). In contrast, in the control group, the text article includes two sets of tiny global before-and-after
authors observed variations of 1% for the total density and photos that show minimal and moderate vertex improve-
3% for the terminal density. The full-text article includes ment. The authors concluded that the clinical effect of topi-
four sets of global before-and-after photos that show moder- cal RXM seemed to be associated with the thickening of
ate to significant positive response. The authors commented growing hairs [19].
40.4 Botulinum Toxin 201
The only relevant publication is the in-vitro and ex-vivo results reported with Propecia® (see Chap. 24). The authors
study by Główka et al. They developed and evaluated a plu- hypothesized that Botox® “loosens” the scalp, reducing pres-
ronic lecithin organogel (PLO) with topical roxithromycin sure on the perforating vasculature, thereby increasing blood
(ROX)-loaded nanoparticles (NPs) for follicular targeting. flow and oxygen concentration. They also argued that enzy-
Encapsulation of ROX into biodegradable, biocompatible matic conversion of Testosterone to DHT is oxygen depen-
and inexpensive polymeric NPs of appropriate size (300 nm) dent and that in low-oxygen environments, the conversion of
resulted in preferential targeting to the pilosebaceous unit in T to DHT is favored; in contrast, in a high-oxygen environ-
ex vivo human scalp skin penetration studies [20]. ment, more T is converted to estradiol. However, these argu-
Finally, in April 2005, an interventional, randomized, ments are not supported by studies (see Chaps. 11 and 16,
crossover, open-label, clinical trial enrolling 20 participants Vol. 1). The full-text article includes two sets of global
was sponsored by the Hamamatsu University, Japan. The before-and-after photos that show minimum to moderate
“Estimated Study Completion Date” of the trial (ClinicalTrials. improvement in AGA stage [27].
gov Identifier: NCT00197379) was set in January 2007. Singh et al. conducted a pilot study in a tertiary care cen-
However, the results were never published [21]. ter enrolling ten male patients aged 22–42 years with AGA,
Norwood–Hamilton stage II–IV. The authors injected intra-
muscularly 5 U of Botox® in 30 different sites along the fron-
40.4 Botulinum Toxin talis, occipitalis, temporalis, and periauricular muscles, in a
total of 150 U. Of these ten patients, eight had good to excel-
Botulinum toxin is a neurotoxic protein produced by the bac- lent response on photographic assessment. One patient had
terium Clostridium botulinum and related species [22]. It poor, and one showed a fair response to treatment at the end
prevents the release of the neurotransmitter acetylcholine of 24 weeks. The full-text article includes four sets of high-
from axon endings at the neuromuscular junction, thus caus- quality, large-size global before-and-after photos that show
ing flaccid paralysis [23]. poor to truly excellent response [28].
The rational use of botulinum toxin in alopecia’s treat- Zhang et al. experimented with a smaller dose of diluted
ment was initially explored in the idea that it would act by Botox® (50 U) on 25 Chinese male outpatients aged
two distinct pathophysiological mechanisms: a vasodilator 30–45 years with AGA. All subjects were injected with 50 U
effect on the vessels irrigating the scalp by decreasing the of Botox® into the muscles surrounding the scalp, including
tone of the surrounding muscles and/or inhibition of certain the frontalis, temporalis, periauricular, and occipitalis mus-
neuromodulators, which would act on AGA, such as sub- cles, in equally divided doses at a minimum of 30 injection
stance P and CGRP (calcitonin gene-related peptide) [24]. sites. The trial was completed in 24 patients, and one patient
dropped. After 6 months of treatment, 11 patients exhibited
significant hair regrowth (>10% increase from baseline), 8
However, one should remember that there are no per-
showed minimal improvement, and 5 showed no response to
forating branches from the scalp’s underlying muscles
treatment. Furthermore, sebum secretion gradually restored
to the scalp [25].
to the normal state in 19 patients who had shown a signifi-
cant decrease in sebum secretion at 3 months. Importantly,
Freund et al. conducted a prospective, single-center, no patient experienced adverse effects. The full-text article
open-label, proof of principle study to assess the efficacy and includes 1 set of low-quality, small-size, global before-and-
safety of 150 units of botulinum toxin-a (Botox®; Allergan, after photos that shows excellent response [29].
Inc., Irvine, Calif.) injected intramuscularly in the prevention Zhou et al. recruited 63 patients with AGA (mean age
of hair loss in men with AGA (ClinicalTrials.gov Identifier: 38.47 ± 10.13 years) and treated them with Botox® 100 U
NCT00965640) [26]. The researchers enrolled 50 male sub- injection (n = 30) or Botox® 100 U injection combined with
jects aged between 19 and 57 years with Norwood/Hamilton 1 mg oral Finasteride (FNS) (n = 33). Thirty injection target
AGA stage of II to IV. The study was 60 weeks long, with sites (1.5–2 cm apart, located in the frontal muscle, temporal
12 weeks of run-in followed by two treatment cycles of muscle, periauricular muscle, and occipital muscle) were
24 weeks each. Subjects were injected with 150 U of Botox® injected with Botox® every 3 months for a total of 4 times.
(5 units per 0.1 mL saline) into the muscles surrounding the Hair counts, head photographs, evaluation scores, and self-
scalp, including frontalis, temporalis, periauricular, and assessment were assessed in patients with AGA. After an
occipitalis muscles, in equally divided doses over 30 injec- overall treatment for 4 times, hair counts in the BTA + FNS
tion sites. Forty subjects completed the study, and no adverse group were 234.01 ± 27.35 root/cm2 (vs. 178.21 ± 24.33 at
effects were reported. Mean hair counts for the entire group baseline) and 218.26 ± 30.59 root/cm2 in the BTA group (vs.
showed a statistically significant (p > 0.0001) increase of 180.57 ± 26.53 at baseline). The hair counts of both groups
18% between baseline and week 48, comparable to the were significantly different from the start of the study
202 40 Recently Reported Hair Growth Drugs
(p < 0.001) and between groups at 12 months (p < 0.035). the treatment of male AGA [35]. The active ingredients con-
However, no significant difference was observed in hair tained in the product supposedly obtained three main effects:
counts between the two groups when measured after treat- proliferation of the stem cells of both the bulge and the der-
ment for once, twice, and three times. After 12 months, 16 mal papilla, keratinization, and stimulation of microcircula-
AGA patients in the Botox® group and 23 patients in tion. Stem cell and dermal papilla stem cell proliferation are
Botox® + FNS group reported moderate and marked improve- allegedly achieved by the actions of hydrolyzed rice protein
ment in scalp oil secretion, pruritus, and dandruff. Moreover, and corosolic acid, respectively. Keratinization is supposed to
23 AGA patients in Botox® group and 27 AGA patients in be stimulated by cysteine, lysine, a glycoprotein (lectin), and
Botox® + FNS group experienced a moderate and marked microcirculation is stimulated by benzyl nicotinate.
reduction in hair loss as compared with before treatment. Buonocore et al. [36] conducted a placebo-controlled, ran-
The evaluation score of the photographs of the head before domized trial on 46 healthy males suffering from AGA grade
and after treatment by dermatologists revealed that the effec- II to IV; 23 males applied one vial (5 mL) of the active prod-
tive rates of Botox® and Botox® + FNS groups were 73.3% uct for every day for five consecutive days, no the treatment
and 84.8%, respectively, following 4 times treatment for 2 days, and then continue the application for 4 months; 23
(p < 0.259). The full-text paper contains several low-quality, males similarly applied the placebo vials. Anagen rate and
tiny-size before-and-after pictures of patients from both hair resistance to traction (pull test) were assessed after 2 and
groups that show moderate to high efficacy of both treat- 4 months of treatment using phototrichogram and the pull
ments. In this study, it seems that the efficacy of Botox® test. Baseline mean anagen hair rate was similar between
injections is comparable to 1 mg oral Finasteride up to active (63.8 ± 4.2%) and placebo (62.8 ± 4.3%) groups. At
9 months and that the combination treatment will offer opti- 4 months, the active product group showed a statistically sig-
mal results [30]. nificant increment of the mean anagen rate (74.5 ± 5.6%) vs.
the placebo group (65.0 ± 5.2%) (p < 0.001), both higher than
at 2 months. Baseline mean pulled hairs in the pull test was
Botulinum toxin has been found to be a safe and effec-
similar between the active (9.2 ± 1.3) and placebo (9.1 ± 1.8)
tive therapy for the management of AGA in small-
groups; at 4 months, the active product group showed an
sized pilot studies. More extensive, randomized
additional statistically significant increment of 46.8% of hair
controlled trials are required to establish the role of
resistance (4.8 ± 1.5). A slight statistical improvement of
botulinum toxin in the management of AGA and
16.6% was also seen in the placebo group (7.6 ± 1.9)
FPHL, though.
(p < 0.001), both higher than at 2 months [36]. The authors
commented that the active product was effective in stimulat-
According to the latest systematic review of Carloni et al., ing hair follicles in a time-dependent manner. The full-text
these results should be interpreted with caution, especially article includes 3 sets of low-quality, global before-and-after
since three publications reporting alopecia of the face or photos showing a minimal positive response, mostly attrib-
scalp following injections of botulinum toxin for the treat- uted to the different hairstyles. Other weaknesses of the study
ment of oromandibular dystonia, blepharospasm, or frontal were the short duration, the small number of subjects, that no
wrinkles [31–33]. The authors concluded that their system- women with FPHL were included, and that the study was
atic review of the literature did not allow them to demon- sponsored by the manufacturer. There are no further studies
strate with certainty the interest of the use of botulinum toxin or publications on this product.
in the treatment of alopecia because of a low level of evi-
dence from the majority of the included studies, even if four
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Caffeine
41
Caffeine is rapidly and extensively absorbed after inges-

Basic Concepts tion. It crosses cell membranes, including the blood-brain
• Caffeine is a naturally occurring pesticide found in barrier, and freely distributes throughout the body. Although
seeds, leaves, and nuts of numerous plants, and bil- best known as a CNS stimulant, caffeine also acts on myo-
lions of humans consume caffeine as a stimulant, cardial tissue, respiration, smooth muscles, and kidneys [3].
making it the world’s most widely consumed psy-
choactive compound.
• Caffeine has been used in Dermatology mostly as a 41.1 Caffeine in Dermatology
means of studying skin permeation, and lately, it
has been shown to possess in vitro hair-growth pro- Caffeine, particularly after ingestion, is well known to exert
moting properties in low concentrations. various pharmacological effects. Concerning caffeine appli-
• Studies on the effects of caffeine combined with cations in Dermatology, until 2007, caffeine has only been
Minoxidil or in shampoos have shown variable effi- used as a means to measure the transcutaneous absorption
cacy in AGA. However, all available studies have under ex vivo [4] and in vivo [5] conditions. It is still often
considerable methodological limitations, and data used to predict the transdermal permeation through the fol-
on the effects of topical caffeine on the hair follicle licular pathway [6].
is insufficient. Transdermal absorption of caffeine through human skin
• Concerning increased caffeine consumption and has offered interesting findings. Caffeine, being an amphi-
effects on hair growth, studies have demonstrated philic compound, when applied under occlusion, does not
protective role of caffeine against all the demonstrate increased permeation [7] but rather a constant
Corticotropin-releasing hormone-induced events in absorption rate, regardless of skin thickness. In contrast, the
AGA. skin permeability of caffeine varies substantially, depending
on the anatomical location [8].
Caffeine is a bitter, white crystalline purine, a methylxan- These features urged the research team of Lademann
thine alkaloid, chemically related to the adenine and guanine et al. to design and carry out a series of ingenious
bases of deoxyribonucleic acid (DNA) and ribonucleic acid experiments. They proved that although terminal hair
(RNA). Caffeine is found in different concentrations in follicular ostia occupy no more than <0.1% of the
seeds, leaves, and nuts of more than 60 different plant spe- skin’s surface, their diffusion coefficient can be orders
cies. It acts as a naturally occurring pesticide since it can of magnitude higher than that of the stratum corneum.
paralyze and kill predator insects feeding on the plant [1].
Humans consume caffeine as a stimulant, mainly in coffee
beans, tea extracts, in products containing kola or guarana Lademann et al. calculated that terminal hair follicles
seeds, in the form of soft drinks or energy drinks, or even in contribute significantly (>50%) to the penetration of
everyday food. Caffeine is the world’s most widely con- locally applied substances [8–10], mainly on the male
sumed psychoactive compound or central nervous system scalp and face. They also reported that not all hair follicles
(CNS) stimulant, and in the USA, more than 90% of adults are “available” to absorb compounds and that some follic-
consume an average of 2.4 mg/kg of caffeine daily [2]. ular ducts are “open” and some are “closed” during the day
[11]. These experiments demonstrated that the human
206 41 Caffeine
scalp absorbs caffeine extensively and rapidly -within inhibition of growth, possibly via a “hyper-stimulation” and
minutes of application- and absorption is completed within depletion of cellular Ca2+ deposits [17].
1–2 h [12]. Further studies by Fischer et al. demonstrated that caf-
Regarding its biochemical actions, caffeine is known to feine enhanced hair shaft elongation, prolonged anagen
increase intracellular Ca2+, thus stimulating nitric oxide pro- duration, and stimulated hair matrix keratinocyte prolifera-
duction through the expression of the endothelial nitric oxide tion. It also counteracted T-enhanced TGF-β2 protein expres-
synthase enzyme. Nitric oxide is diffused to the vascular sion in male hair follicles and reduced physiological TGF-β2
smooth muscle cell to increase Ca2+ release from vascular expression in female hair follicles. Additionally, caffeine
smooth muscle cells, resulting in vasodilation [13]. Moreover, enhanced IGF-1 gene and protein expression revealing new
caffeine is an inhibitor of phosphodiesterase [14] and is bio- growth-promoting effects of caffeine on human hair follicles
logically mediated by cyclic AMP (cAMP) increase in cells, in both sexes at different levels (molecular, cellular, and
resulting in stimulatory effects on cell metabolism and organ) [18]. All in all, this study provided clear evidence that
proliferation. caffeine can counteract testosterone-induced growth sup-
Caffeine has a combined action on two levels: pression of hair follicles while at the same time highlighting
the importance of selecting the optimal caffeine dose to pro-
1. Increased synthesis of cAMP, since it blocks the inhibitor duce the best physiological response while avoiding inhibi-
of adenylate cyclase enzyme, which converts ATP into tory effects [19].
cAMP, Caffeine has also been reported to possess anti-apoptotic
2. Slowing of the cAMP degradation by inhibiting the phos- properties demonstrated in macrophages and reduce super-
phodiesterase enzyme, which converts cAMP to oxide dismutase production [20, 21]. Thus, it is speculated
AMP. Through these actions, caffeine promotes prolifera- that this mechanism could have a positive effect on AGA hair
tion by stimulating cellular metabolism [15], a mecha- follicles, which exhibit typical steps of cellular apoptosis
nism that some authors have speculated could potentially [22].
counteract the miniaturization of the hair follicle induced Concerning other effects of caffeine on human skin,
by Testosterone (T) and dihydrotestosterone (DHT). Brandner et al. reported that caffeine application signifi-
cantly reduced the transepidermal water loss in male forearm
skin and that caffeine is beneficial for overall barrier function
41.2 Caffeine and the Hair Follicles in male skin [23].
Fischer et al. considered that since the skin and HFs can
Caffeine’s ability to inhibit the harmful effects of T on kera- manage locally occurring stress, they can serve excellently
tinocyte proliferation has been demonstrated in culture mod- as a human ex-vivo hair stress organ culture model. They
els of male skin and hair follicles from men with AGA. cultured human hair follicles from the balding vertex region
In vitro experiments of Tsianakas et al. in the male skin of AGA patients and investigated the effects of a possible
organ culture model (MSOCM) proved that caffeine reverses counteracting substance, the well-known phosphodiesterase
the inhibitory effect of T in keratinocyte proliferation [16]. inhibitor, caffeine. The HFs were incubated with
Fischer et al. studied whether results in MSOCM were appli- Corticotropin-releasing hormone, CRH (10−7 mol/L) with or
cable in hair organ culture models and were the first team to without caffeine (0.001% or 0.005%). Compared to controls,
report the positive action of caffeine in human hair follicles. CRH significantly enhanced the expression of catagen-
Hair follicles from 14 biopsies, taken from the vertex of male inducing TGF-β2 (p < 0.001), CRH receptors 1 and 2 (CRH-
AGA patients, were cultivated for 120–192 h in vitro with R1/2) (p < 0.01), ACTH (p < 0.001) and melanocortin
normal William’s E medium (control) or William’s E medium receptor 2 (MC-R2) (p < 0,001), and additional stress-
containing different concentrations of T and/or caffeine. Hair associated parameters, substance P and p75 neurotrophin
shaft elongation was measured daily, and at the end of the receptor (p75NTR). CRH inhibited matrix keratinocyte prolif-
culture time, cryosections of follicles were stained with eration and expression of anagen-promoting insulin-like
Ki-67 to evaluate the degree and localization of keratinocyte growth factor-1 (IGF-1) and the pro-proliferative nerve
proliferation. The authors noted that significant growth sup- growth factor receptor NGF-tyrosine kinase receptor A
pression was found in hair follicles treated with 5 μg/mL T, (TrkA). Caffeine significantly counteracted all described
which was counteracted by caffeine in concentrations of stress effects and enhanced inositol trisphosphate receptor
0.001% and 0.005%. Moreover, caffeine alone led to a sig- (IP3-R), for the first time detected in human HFs. These find-
nificant stimulation of hair follicle growth, and these results ings also provided the first evidence in ex vivo human AGA
were confirmed immunohistochemically by Ki-67 staining. HFs that the stress mediator CRH induces a complex intra-
On the contrary, higher (toxic) caffeine concentrations, follicular HPA response and a non-HPA-related stress
0.01% and 0.05%, which are unachievable in vivo, induced response.
41.3 Caffeine and AGA/FPHL 207
One year later, in the same, non-indexed Journal,

Overall, the authors demonstrated the protective role Bussoletti et al. published the results of an open-label, spon-
of caffeine against all the aforementioned CRH- sored, monocentric study on 40 male volunteers, again with
induced events in AGA HFs, further supporting a a mean age of 37 years, suffering from mild-moderate AGA
potential benefit of caffeine in the management of (stages of Hamilton-Norwood II–IV) who used once daily a
AGA [24]. topical Caffeine lotion for 4 months. Results were again
evaluated through pull-tests and subjective patient self-
evaluation. The authors reported an average 15.33% decrease
Since the publication of these findings on the positive in the number of hairs extracted with the pull-test after four
effects of caffeine, a growing number of cosmetic hair- months of treatment, with 83% of volunteers having a
products appeared containing caffeine, while there are at decreased number of hairs on the pull test. The subjective
least two filed patents concerning topical products against evaluation of the cosmetic effectiveness showed that 80% of
hair loss based on caffeine [25]. volunteers were satisfied with the product. They reported a
decrease in hair loss and improved hair and scalp conditions
after four months of treatment. However, this study did not
41.3 Caffeine and AGA/FPHL include any before-after photos, no objective measurements,
nor other credible data, and conflicts of interest were not dis-
From the results of in vitro and in vivo penetration studies, closed [33].
the effects of caffeine on hair follicles, as well as penetration Sisto et al. published in the journal mentioned above a
and accumulation of topical caffeine, have been confirmed randomized, controlled, double-blind, parallel-group study
[26–29]. However, the efficient penetration and accumulation conducted to assess the skin compatibility and hair growth
of caffeine, which can result in a penetration depth of efficacy of a caffeine-containing shampoo vs. placebo. The
200 μm, cannot be equated with stimulation of the dermal treatment period lasted for six consecutive months on 66
papilla. Up to date, data on the effects of topical caffeine on men (n = 33 in the active group, n = 33 in the placebo group),
the hair root is insufficient and weak [18, 30]. Nevertheless, all with mild to moderate AGA (grade II-IV according to
these do not discourage several researchers from investigat- Hamilton and Norwood). After six months of treatment,
ing and publishing on the potential efficacy of caffeine in patient satisfaction was reported at 84.8% in the active treat-
promoting hair growth [31]. ment group and 36.4% in the placebo group. In three other
Published trials on products containing caffeine, used patient-assessed outcomes regarding hair loss intensity,
for the treatment of AGA/FPHL date back to 2010, when speed of progression of hair loss, and the number of hairs
Bussoletti et al. published in the Journal of Applied shed while combing, a greater improvement (statistically
Cosmetology, an Italian journal with a very low impact fac- significant) was reported in the active treatment group com-
tor (<0.2), which is not even indexed in Pubmed. Initially, pared to placebo. Once again, before-and-after photos,
they conducted an open-label, uncontrolled, sponsored, objective measurements, or other credible data were not pro-
monocentric, six-month-long study on 30 male volunteers, vided, and conflicts of interest were not disclosed [34].
mean age 37 years, suffering from mild-moderate AGA Golpour et al. conducted a double-blind, randomized
(stages of Hamilton-Norwood II–IV). Subjects washed clinical trial study on 60 patients with advanced AGA (stages
their hair once daily with a topical caffeine shampoo and of Hamilton-Norwood >V), comparing the effect of
kept the foam on the scalp for 2 min before rinsing off. Minoxidil Topical Solution 2.5% (MTS) + caffeine (n = 30)
Results were evaluated through pull-tests and subjective and MTS 2.5% alone in AGA treatment (n = 30), both b.i.d.
patient self-evaluation. According to these non-specific, 1/mL. The study was published in the Iranian Journal of
non-sensitive, and non-objective tests, the authors reported Mazandaran University of Medical Sciences (not index in
that the pull-test results showed a decrease of 7.17 % after Pubmed), and the methodology included measurements of
three months and 13.15% after six months of treatment, hair density in three alopecia areas (1 cm2 each) on days 0, 7,
with 67% of volunteers being satisfied with the product. 30, 60, 90, 120, and 150. From day 120 onward, the com-
They also reported that the extent of the falling out of hair bined treatment showed better results (statistically signifi-
was significantly reduced (p < 0.001), and the progression cant), and 58.33% of patients (14/24) were very satisfied
of balding was improved considerably (p = 0.004). with the treatment vs. 41.38% (12/29) on MTS alone [35].
However, no before-after photos, no objective measure- Again, before-and-after photos were not provided.
ment techniques (total hair counts, hair weight, etc.), or Pazoki-Toroudi et al. conducted a randomized, controlled,
other credible data were provided, and no conflicts of inter- double-blind, parallel-group study to assess the combination
est were disclosed [32]. of caffeine 1 %, MTS 5 % and azelaic acid 1.5% (n = 40) vs
208 41 Caffeine
MTS 5% monotherapy (n = 20) or placebo (n = 11). Study publication, and the very short duration of the study does not
endpoints included a reduction in lost hairs in the “hair wash compensate for seasonal variations. Most importantly, the
test,” self-assessment by patients, and assessment by a “original” technique of evaluating hair loss by having
Dermatologist. The solution consisting of caffeine 1% plus patients comb their hair and measure the fallen hair is hugely
MTS 5% plus azelaic acid 1.5% was shown to be superior to imprecise.
MTS5 % alone and placebo at 12 weeks. The results of the Dhurat et al. conducted a randomized, open-label,
study were presented in the 2013 International Investigative active-controlled, multicenter (at five centers in India),
Dermatology Meeting. Here, too, considerable limitations in noninferiority study to determine whether a caffeine-based
terms of methodological study quality and reporting of 0.2% topical liquid (Alpecin® Liquid) would be no less
results were obvious [36]. effective than MTS 5%. Subjects were 210 males with
AGA (stage of III-V on the Hamilton-Norwood scale),
aged between 18 and 55 years. The primary endpoint was
All these studies on caffeine have significant method-
the percentage change in the proportion of anagen hairs
ological limitations and are all based on assessments
from baseline to 6 months using a frontal and occipital
by patients themselves or investigators, which are,
trichogram. At six months, the 5% MTS group showed a
obviously, of limited value.
mean improvement in anagen ratio of the trichogram of
11.68%, and the group of the 0.2% caffeine solution had an
Dressler et al. published a systematic review of the avail- anagen improvement of 10.59%. The difference of mean
able evidence regarding the efficacy and tolerability of the values between both groups was 1.09% and therefore was
topical application of caffeine-containing products on hairs considered as not inferior to MTS 5%. Even though this
or follicles. They reviewed all available studies and noted study was longer in duration and larger than the previous
that even in all the randomized, controlled trials, the risk of ones, it also had severe limitations: its open-label design,
bias was assessed as “high” [37]. the use of trichogram to measure anagen hairs instead of a
Alonso et al. evaluated the efficacy of a commercial prod- more precise technique (e.g., hair counts), and the lack of
uct containing a combination of 2 extracts of Coffea arabica before-and-after photos to support the claims [40].
and Larrea divaricate. This combination had previously been Bussoletti et al. conducted a single-center, double-blind,
reported to affect hair growth on C3H mice by inducing ana- parallel trial to determine the efficacy of a phytocaffeine-
gen and has been registered under the name of Ecohair® [38]. containing shampoo used over 6 months in female subjects
Authors conducted an open, prospective, cohort study apply- with FPHL. The primary endpoint was the change from
ing Ecohair® spray lotion in 25 women (48.1%) and 27 men baseline in the number of hairs pulled in a hair pull test at six
(51.9%) with non-cicatricial alopecia during a daily admin- months. Hair loss intensity, hair strength, subject satisfac-
istration period of 3 months. The efficacy was determined by tion, and tolerability were also assessed. Results showed that
assessing an increase in hair volume, improvement in hair subjects using the active shampoo had significantly fewer
looks, growth of new hair, a decrease in hair loss by the test hairs pulled in a hair pull test at six months than subjects
of hair count, and hair traction. The capacity to decrease the using the control shampoo (−3.1 vs. −0.5 hairs; p < 0.001).
amount of dandruff was also evaluated. To determine the The majority of pre-specified secondary endpoints were also
effect on hair loss, patients were trained during the first visit significantly improved for subjects using the active sham-
of the trial to count the hair lost after brushing for 1 min dur- poo, compared with controls, whereas both products were
ing three consecutive days with a fine-tooth comb. The num- very well tolerated [41].
ber of fallen hairs was registered in the charts that were given Völker et al. explain in their recent review on the pharma-
to each patient. According to the authors, on day 90, fifty cological benefits of caffeine in the management of AGA,
patients (96.2%) improved, and two patients (3.8%) did not that caffeine has successfully undergone the critical valida-
show any improvement, while this effect was more marked tion steps, from proof of principle (in vitro) to controlled
in women. Patients and doctors agreed that the treatment was clinical trials (in vivo). The in vitro effects of caffeine on hair
effective in 84.6% of patients and that there was an improve- follicles, hair shaft elongation, and hair growth’s critical reg-
ment in hair features (p = 0.056). Overall, the authors claimed ulatory factors have been found to be dose and gender-
that the spray improved the overall hair volume and appear- dependent. Caffeine penetrates efficiently via the follicular
ance, that it increased its thickness, induced hair growth, and route, and in vivo studies have shown that hair loss is reduced
decreased hair loss, while no local adverse reactions were using caffeine-containing topical formulations as long as
observed upon treatment with the product [39]. However, the caffeine is dosed properly to support the biological activity
impressive results of this study leave plenty of room for scru- of male and female hair follicles best [19].
tiny. Once again, before-and-after photos, objective mea- However, the recent (2018) systematic review of Kanti
surements, or other credible data were not provided in the et al. (Evidence-based (S3) guideline for the treatment of
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Cysteine and Cystine
42
Cysteine is a sulfur-containing, α-amino acid with the

Basic Concepts chemical formula O2CCH(NH2)CH2SH. Cysteine is unique
• Cysteine is the primary structural amino acid of amongst the 20 natural amino acids as it contains a thiol
human keratin, it is naturally synthesized in the group. It is classified as a conditionally non-essential amino
human body from other amino acids, which are acid since the human body can naturally synthesize it [1, 2].
found in abundance in everyday diet, and cysteine Like other amino acids, cysteine has an amphoteric character
deficiency can occur only in congenital disorders of and is extensively used as an additive in the food industry,
methionine metabolism and in severely malnour- mainly in bakery, in the production of flavors, and as a pro-
ished patients. cessing aid [3]. When used as a food additive, it is labeled as
• Cysteine as a food supplement is mainly produced E920 [4].
from the chemical processing of human hair, prob- Cystine is the oxidized dimer form of cysteine with the
ably collected from barbershops in China and India, chemical formula [SCH2CH(NH2)CO2H)2]. It derives from
but that does not render it unsafe since cysteine is a the oxidation of two molecules of cysteine, which bind
popular food additive (E920) of minimal toxicity. through a disulfide bond (Fig. 42.1). It was isolated in
• Considering the source of industrial cysteine prod- 1810 by William Hyde Wollaston from a new, at that time,
ucts and the insufficient evidence, the administra- type of bladder stone that he named cystic oxide stone
tion of cysteine supplements in patients with hair (later called cysteine). It was not recognized as deriving of
loss is comparable to believing that if a bald man proteins until it was isolated from cow’s horn in 1899 [6].
eats another man with luxurious hair, he will Cystine’s disulfide bonds are crucial in defining the ter-
improve his hair image. tiary structures of many proteins, as well as of their spatial
• The few studies investigating the effects of oral folding. Human hair and skin contain approximately
administration of cysteine in patients with hair loss 8–17% cystine by mass [7, 8], which is significantly higher
are old, small-sized, of poor quality, biased at mul- than the amount found in feathers or hairs of other
tiple levels, and with conflicts of interest. However, mammals.
anecdotal stories on the positive action of cysteine Cysteine has numerous biological actions, mainly related
supplements on hair are very popular among to its antioxidant effects and the fact it is the precursor of the
physicians. tripeptide Glutathione [9] (Fig. 42.2). It is vital in collagen
production, as well as skin elasticity and texture. Also
required in the manufacture of amino acid taurine, Cysteine
plays a role in the metabolism of essential biochemicals such
Due to the popularity of the practice to prescribe cyste- as coenzyme A, heparin, and biotin. Nevertheless, herein,
ine/cystine products in patients with any cause of hair only the reported actions on hair follicles will be discussed
loss, the chapter on this particular food supplement has since cysteine is a vital component of the keratin protein by
been included in the OTC treatments. its ability to form disulfide bridges that confer strength and
rigidity to the protein [10].
212 42 Cysteine and Cystine
formation of cystine stones in the kidneys, ureter, and

bladder [18].
Cysteine is found in most high-protein-containing foods,
especially in foods containing proteins of high nutritional
value, namely all types of red and white meat, dairy prod-
ucts, and eggs. Plant sources carrying adequate cysteine
amounts include red peppers, onion, garlic, broccoli, and
cereals [19]. Cysteine is catabolized in the gastrointestinal
tract and plasma. In contrast, cystine travels safely through
Fig. 42.1 Disulfide bond formation. The formation of a disulfide bond the GI tract and plasma and is promptly reduced to two cys-
from two cysteine residues is a redox half reaction. Filled black circle, teine molecules upon cell entry [20].
C atom. (Christian Appenzeller-Herzog & Jan Riemer [5])
Consequently, if a patient with hair loss does not suffer

from severe malnutrition, methionine metabolism dis-
orders, or is not on total parental nutrition unsuper-
vised for months, he/she cannot suffer from cysteine
deficiency since his/her body produces enough cyste-
ine under all other circumstances.
Nevertheless, several articles are claiming that cysteine-

rich proteins, such as keratin or nutraceuticals, may have
advantages over the pure amino acid or its derivatives to
Fig. 42.2 The non-conventional tripeptide glutathione. Glutathione is safely and beneficially improve antioxidant status in health
an essential compound composed of the amino acids glycine, cysteine and disease [21]. Others claim that cysteine supplementation
and glutamate. Between cysteine and glutamate, an unusual peptide
bond between the γ-carboxyl group of glutamate and the α-amino group
promotes a significant upregulation of keratin expression due
of cysteine is present. This peptide bond renders the tripeptide stable to de novo protein synthesis. Also, it supposedly counteracts
inside cells. (Christian Appenzeller-Herzog & Jan Riemer [5]) the adverse effect of iron deficiency on cellular keratin
expression and enhances the metabolic iron availability for
DNA synthesis without creating a detrimental condition of
42.1 Sources of Cysteine iron overload [22].
Under normal physiological conditions, Cysteine is synthe-

sized in the human body as long as a sufficient quantity of 42.2 Cystine/Cysteine Dietary
serine and methionine are available as chemical substrates Supplements
[11]. Cysteine is conditionally essential in the human diet,
meaning its synthesis can be limited under specific patho- Nine uses of cysteine are reported in cosmetics, eight of
physiological conditions [12]. Ordinary, even the so-called which are in hair care products [23]. Yet, every physician
Western/unhealthy diet contains adequate amounts of methi- should be aware of some very compelling information con-
onine for cysteine synthesis [13], and the physiological cys- cerning the origin of cysteine in oral food supplements.
teine production can only be affected in the following Cysteine and cystine found in food supplements originate
disorders: mostly from two sources [24]:
1. In individuals who suffer from congenital defects of • Hydrolysis of poultry feathers or hog’s hair,
methionine metabolism [14], or other rare inborn errors • Hydrolysis of real human hair.
of metabolism of sulfated amino acids,
2. In severely malnourished neonates and adults [15] or neo-
nates and adults under long-term, unsupervised, total Cysteine content of prescribed cysteine capsules, so
parental nutrition [16, 17], often administered to patients suffering from hair loss,
3. In neonates and adults who suffer from inherited autoso- in many—if not most—cases will originate from pro-
mal recessive malabsorption syndromes, such as cystino- cessed human hair. Human hair hydrolysis with hydro-
sis. These result in cystinuria, which is characterized by chloric acid will deliver l-cysteine hydrochloride or
high concentrations of cystine in the urine and leads to the
42.3 Cystine and the Hair Follicle 213
lished in the medical literature, both in German medical

hydrochloride monohydrate [25, 26]. The “raw mate- journals, reporting on the effects on human hair of food sup-
rial” usually comes from barbershops in China and plements containing cysteine. These studies examined
India, and manufacturers of industrial cysteine prefer cysteine-based multi-supplement effects containing cyste-
human hair due to the higher content in cysteine, in ine, retinol, gelatin, B-complex vitamins, and medicinal
comparison to poultry feathers [27], as well as due to yeast, a rich natural source of B-complex vitamins and trace
the minimum cost of the raw material’s collection, i.e., elements.
just by wiping the floor of barbershops. In one of these trials, conducted by Hertel and Orfanos
(1989), the efficacy of new combination therapy for diffuse
hair loss was initially tested in 36 patients, followed by a
Even though using human hair as source material for cys- double-blind study on 47 patients. The daily dosage was
teine is explicitly banned in the European Union [28], it is 18,000 IE retinol, 70 mg L-cystine, and 7000 mg gelatin.
impossible to discern the origin of l-cysteine through post- Gelatin is a mixture of peptides and proteins produced by
production chemical analysis. It is questionable whether this partial irreversible hydrolysis of collagen extracted from
legislation is strictly adhered to by manufacturers. various by-products of the meat and leather industry, such as
Synthetically produced l-cysteine, compliant with Jewish the skin, horns, hoof and bones, connective tissues, organs,
kosher and Muslim halal laws, is also available, albeit at a and intestines.
significantly higher price. The synthetic route involves fer-
mentation using a mutant E. coli strain, implicating a path- Although gelatin is 98–99% protein by dry weight, it
way from substituted thiazolines. Following this technology, has low nutritional value since it lacks certain essential
l-cysteine is produced by the hydrolysis of racemic 2-amino- amino acids, such as tryptophan, and it is also deficient
Δ2-thiazoline-4-carboxylic acid using Pseudomonas thiazo- in isoleucine, threonine, and methionine.
linophilum [29]. This synthetically produced l-cysteine has
found limited applications due to the high cost and is mostly
consumed by those with raised awareness of human-sourced The clinical efficacy was evaluated by trichogram and
cysteine consumption [30]. hair density measurement before and after treatment. The
pilot study demonstrated a reduction of the telogen rate by
8.3%, an increase of the anagen rate by 11%, and an increase
42.3 Cystine and the Hair Follicle of the hair density by 6.9%. In the following double-blind
study, the trichogram showed a significant decrease in the
In the 1960s, the role of supplementation of cystine and other telogen rate by 13.5%, while there were no changes in the
sulfur-containing amino acids in the diet of sheep for the pro- placebo group. The baseline lowered anagen rate of 47.2%
duction of wool was extensively studied. It was discovered was improved by 8%, whereas the placebo group’s mean
that supplementing a diet deficient in cysteine [31–33] or value decreased from 47.7% to 39.9% (7.8%). In addition,
adding cysteine in otherwise well-fed sheep [34] led to the percentage of dysplastic anagen hairs improved by 7.4%,
increased wool growth rate and wool yield. Since then, trans- as against further impairment with an increase of 26% in the
genic sheep that can synthesize cysteine have been devel- placebo group. During oral therapy, no systemic side-effects
oped, with an improved wool growth rate [35]. A more recent were detected. The authors concluded that long-term oral
discovery was offered by the in vitro study of Thomas et al. therapy with high doses of L-cystine and gelatin in combina-
in 2007, who pointed out that diets designed to maximize tion with Vit A might have beneficial effects on diffuse hair
wool growth of animals should provide specific amino acid loss [39].
profiles and suggested the relative rates of cysteine, lysine, In the study of Petri and Tronnier (1990), growth and
alanine, and leucine [36]. quality of hair were studied after treatment with Pantogar®
The cystine supplementation research in animals bred for (Merz Pharmaceuticals GmbH) vs another prescription com-
wool production prompted some researchers to consider pound (Verum-2®) and placebo for 4 months, in 60 patients
l-cystine as a potential dietary supplement that could be with diffuse effluvium and structural alternations of hair.
used to improve hair growth in humans. Of course, in con- Pantogar® contained Calcium pantothenate 60 mg, cystine
trast to ruminants, humans will usually consume through 20 mg, thiamine 60 mg, yeast 100 mg, keratin 20 mg and
their diet adequate amounts of high-quality proteins contain- para-amino-benzoic acid 20 mg (PABA). Concerning hair-
ing plenty of cysteine or methionine, and only in cases of quality, the efficacy was assessed by measurements of
severe malnutrition or starvation will they exhibit signs of “swelling of hairs”, dye-binding and thickness, and hair-
nutritional disorders in hair [15, 37, 38]. Nevertheless, dur- density measurements and trichograms evaluated hair-
ing the early 1990s, two clinical trials [39, 40] were pub- growth. Statistical analysis of “swelling properties” and
trichogram data indicated that Pantogar® was effective and Except from these German studies, two more publications
tolerable; the second preparation improved the quality of report positive effects of cystine supplementation in subjects
hair and retarded hair loss, whereas placebo was ineffective with hair loss. However, besides the fact that these studies
[40]. These trials and an anecdotal report were included in a are not indexed in international scientific databases, there are
German review on the systematic treatment of diffuse hair apparent conflicts of interest of the authors and severe meth-
loss published in 1994 by Ahrens [41]. odological limitations: lack of dose-relationship effect, the
However, these studies had methodological limitations methods employed are not reliable or standardized, and the
and flaws, did not include only patients with AGA or FPHL, study design does not take the placebo group into account.
and did not perform the necessary intention-to-treat analysis. There is an allegedly double-blind, placebo-controlled
Moreover, the duration of the studies was too short and, trial by Morganti et al. (1998), which included 60 volunteers
therefore, could not eliminate any potential seasonal changes (30 men with ΑGΑ and 30 women with FPHL, aged 21–38),
in hair growth [42]. The study of Petri et al. examined a com- randomized in 5 groups of 12 subjects each. Groups received
mercial product that was sponsored by the manufacturing different combinations of an “active lotion” (Mavi-ceuticals
company, and authors probably had conflicts of interest that Bioesse Lozione, containing disodium cystinyl disuccinate,
were not required to be stated at that time [40]. castor oil, panthenol, ginkgo biloba extract, saw palmetto
Later, in 2000, Gehring et al. published a double-blind, extract, azelaic acid, piroctone olamine, ethyl nicotinate), a
randomized study on the hair growth effects of another oral placebo lotion (similar with the “active” lotion, except diso-
hair growth supplement tested on 40 female patients. The dium cystinyl disuccinate), an “active” orally administered
preparation (Priorin®, Bayer AG) is composed of a combi- food supplement (Mavi-ceuticals Bioesse Plus containing
nation of millet fruit extract, l-cystine, and Calcium panto- gelatin, l-cystine, l-methionine, Cu, Zn) and an orally
thenate and used twice daily for 6 months. The authors administered placebo supplement. The researchers reported
reported that the anagen rate was increased by 16% accord- a significant average increase of hair numbers in men and
ing to phototrichogram measurements (p = 0.0225 vs. pla- women using in the “active” lotion group compared to pla-
cebo). However, the supplement did not affect terminal hair cebo (30% vs 11% placebo, p < 0.005) and a 29% increase in
counts, hair density, and cumulative hair shaft diameter. It the number of hairs after a 50-week treatment only with the
thus would not seem to be indicated for the treatment of “active” per os administered food supplement that patients
alopecia due to cycle shortening, such as AGA or FPHL, received 4 times/day [46]. This study is not indexed in
whereas the short duration of the study was a significant PubMed and was presented in the “Singapore Clinical
limitation [43]. Dermatology 2000″ meeting, Singapore, 18–20 June 1998.
Budde and Tronnier conducted a controlled, randomized, The products used in the trial were manufactured by Mavì
double-blind study in 72 women with hair loss of unknown Sud S.r.l., Italy, the president and CEO being Morganti him-
etiology to compare the tolerance and efficacy of two thera- self. The same team has published additional articles [47–50]
peutic agents containing B-complex vitamins and l-cystine of dubious credibility on the positive action of similar prod-
in different compositions vs placebo. The study only lasted ucts containing gelatin and cysteine, but none of these arti-
4 months [44]. The study protocol closely resembled the ear- cles is indexed in any credible international scientific
lier study of Petri and Tronnier [40], measuring “hair swell- database.
ing” as a criterion of improved hair quality. The authors
reported that treatment with “active medication 1” was supe-
This portfolio of non-indexed studies, published in
rior to treatment with “active medication 2”, and both were
non-peer-reviewed Journals has been used for market-
superior to placebo. They also claimed that the additional
ing purposes for decades.
active ingredients contained in the active medication 1, but
not contained in the active medication 2, could not be com-
pensated by the higher amounts of l-cystine contained in the There is also a study of Lengg et al. examining the effect
active medication 2 [44]. of the dietary supplement Pantogar® containing Calcium
Besides the short-duration limitation, both studies [43, pantothenate 60 mg, cystine 20 mg, thiamine 60 mg, medici-
44] had numerous methodological flaws. Also, the impact nal yeast 100 mg, keratin 20 mg, and PABA 20 mg on 30
on scientific judgment due to industry sponsorship, present healthy women suffering from telogen effluvium. The study
in both studies, was unclear, as aptly reported in the was reported as randomized, double-blind, placebo-
Cochrane systematic review by van Zuuren et al. [45] These controlled, lasted for 6 months, and the efficacy of the sup-
authors concluded that the studies have low referential plement was evaluated by TrichoScan® and global
value and cannot substantiate, under no circumstances, an photographs evaluated by independent investigators. Results
indication for the administration of cystine in individuals stated that treatment with this food supplement led to a sta-
with hair loss [45]. tistically significant increase in the mean anagen hair rate
42.3 Cystine and the Hair Follicle 215
(p = 0.003), while there was no significant change in the pla- authors work for Merz Pharmaceuticals GmbH, which also
cebo group (p = 0.85) [51]. However, the study of Lengg funded the study [53].
et al. was published in a journal not indexed in Pubmed and Riegel et al. investigated how the Pantogar® oral formula-
was funded by Merz Pharmaceuticals GmbH, which manu- tion’s active components affect cellular processes, which
factures the product used in the trial. The article includes two might be relevant for hair-growth. They studied which com-
before-and-after Trichoscan photos, but there is no tattoo to pounds could positively impact the proliferation and viabil-
establish that it is the same area or even the same patient. ity of human hair follicular keratinocytes (HHFKs) and
Also, two global before-and-after photos of a female with contribute to higher protection against endogenous oxidative
different hairstyles among the two photos show practically stress. They reported that the compounds had a supportive
minimal improvement. effect on cell viability by lower sensitivity to solar-simulated
Beer and Veghte (2014) evaluated the effects of a supple- UV-radiation and increased protection against oxidative
ment named Cynatine HNS (produced by Roxlor Global, stress. They reported a central role for l-cystine, as changes
LLC) for improving various aspects of hair and nails. This in the expression of the anti-oxidative gene hmox1 were
was an single-center, randomized, parallel-group, double- l-cystine-dependent and that to reach a maximal stimulating
blind, placebo-controlled, 90-day intervention trial in 50 effect on proliferation, the combination of all four com-
women with signs of damaged hair and nails, conducted at a pounds was necessary. All the authors declared being
single site in Italy (Farcoderm, University of Pavia). Cynatine employees of Merz Pharmaceuticals GmbH during the con-
HNS contained 250 mg Cynatine (keratin), in a peptide form duct of the study, and only Kristina Riegel worked temporar-
obtained by proprietary processing of New Zealand sheep ily for the company. Merz Pharmaceuticals GmbH also
wool as well as 7.5 mg Zinc, 9.0 mg Vit B3, 0.825 mg Copper, funded the study [54].
6.84 mg Vit B5, 1.0 mg Vit B6, and 0.150 mg Vit B8 (Biotin) A meta-analysis of clinical studies performed with
The active group (n = 25) received two Cynatine HNS cap- Pantogar® was presented as poster by Andreas Finner, MD,
sules per day and the placebo group (n = 25) received two Berlin, Germany, at the 15th EHRS annual meeting, July
identical capsules of maltodextrin per day, for 90 days. 6–9, 2011, in Jerusalem, Israel [55]. Three endpoints (inves-
Interestingly, all hair measurement parameters, including tigator satisfaction, patient satisfaction and anagen hair rate)
hair pull test, anagen/telogen test, hair tensile strength, and were analyzed. For the endpoint of investigator satisfaction,
hair appearance, were reported as improved in a statistically three studies with 1682 patients were included [44, 56, 57].
significant way (p < 0.001), according to the authors. Even For 84% of patients, the treatment results were evaluated as
the amino acid profile of the hairs in the active group was very good or good (p < 0.0001). For the endpoint anagen
reported to have changed: the mean percent increase of ser- rate, four randomized, placebo-controlled studies with 180
ine was 3.2% (p < 0.001), glutamic acid 3.5% (p < 0.001), subjects were analyzed [40, 44, 51, 58]. A full analysis was
cystine 8.6% (p < 0.001), and methionine 4.8% (p < 0.001) performed, which reduced the bias compared to an analysis
compared to baseline [52]. However, no before-and-after of completers only. The anagen rate in the Pantogar® group
photos were included in the article. In addition, analyzing the improved by 3.83 absolute points (p = 0.00006) compared to
amino acid profile of hairs just 90 days into treatment would placebo. For the endpoint patient satisfaction, four studies
be extremely difficult due to practical issues. The hairs would with 2047 patients were included [44, 50, 56, 57]. 83% of
not have grown more than 30 mm from the scalp surface, and treated patients rated the effect as very good or good
even so, it would require clipping to the surface of the scalp, (p < 0.0001). The results of this meta-analyses must be inter-
something that most subjects would not be happy with. preted with caution. First, investigator satisfaction in
Robert H. Veghte (primary author) is the General Manager of manufacturer-sponsored trials is rarely considered as con-
Roxlor Global, LLC, which funded this study, and the other crete evidence. Patient satisfaction is a subjective metric that
two authors, Christina Beer and Simon Wood, received con- is not considered accurate or valid. Mostly, the huge majority
sulting fees on a per-job basis from Roxlor Global, LLC. of patients included in the meta-analysis come from “manu-
Hengl et al. (2018) assessed the capacity of ingredients of facturer studies”.
the Pantogar® oral formulation, both separately and in com- From the 1682 patients used for “end-point 1” result,
bination, to modulate the effects of UVR in growth-limited 1658 are included in studies that have never been peer-
normal human epidermal keratinocytes (NHEKs) in vitro. reviewed or publicly published, and were included under
They reported that L-cystine and thiamin are essential for the the condition that results were declared as (quoting) “data
proliferation of epidermal keratinocytes and suggest a novel, on file”.
UV-protective potential of formulations combining l-cystine From the 2047 patients used for “end-point 3” result,
and thiamin in growth-limited inter-follicular NHEKs 2023 are included in studies that have never been peer-
in vitro. However, one should consider that almost all of the reviewed or publicly published, and were included under
the condition that results were declared as (quoting) “data et al. [43], which was attributed “level of evidence 3 and
on file”. grade B” [50].
From the 180 patients used for “end-point 2” result, 45 On a final note, one should keep in mind that Cysteine -and
are included in studies that have never been peer-reviewed or methionine- are not stored in the body. Any dietary excess is
publicly published. This end-point result is probably the only readily oxidized to sulfate, excreted in the urine (or reab-
one that can withstand scrutiny. However, the statistically sorbed depending on dietary levels), or stored in the form of
significant result (p = 0.00006) of 3.83 absolute points glutathione [59]. This fact makes cysteine or cysteine sup-
increase in anagen rate has minimal clinical significance. plementation on healthy adults even more absurd.
Synopsis
Many of these studies mentioned above have obvious
Cysteine is traditionally prescribed as a food supplement in
methodological limitations, were not published in
individuals with hair loss of any etiology, and this practice
peer-reviewed journals (besides [53, 54]), were short
has mistakenly acquired a status of solid scientific truth in
in duration, the products studied contained multiple
everyday clinical practice. Interestingly, the primary source
compounds, and results could not be safely attributed
of supplementary cysteine is hydrolyzed human hair col-
to cystine or to any other ingredient. Moreover, they
lected from barbershops. However, there are only low qual-
did not refer to cases of AGA or FPHL, while the
ity, small, fundamentally biased, unreliable studies on the
conflict-of-interest present in many of these articles
use of these supplements since almost all clinical trials are
raises questions on the conclusions.
sponsored by manufacturers and suffer from conflicts of
interest in multiple levels. The fact that human hair contains
According to the author’s understanding, the only scien- cysteine should not be confused or associated with the imag-
tifically reliable publications on the effects of supplementary ined effects of orally administered cysteine for hair growth,
cystine administration are actually on lab animals. Chatterjee especially in otherwise healthy and well-nourished individu-
et al. demonstrated that prior administration of als. This practice takes us back to ancient beliefs when the
N-acetylcysteine prevented hair loss in guinea pigs exposed hunter would eat a wild animal’s heart to obtain some of the
to 2-chloroethyl ethyl sulfide (CEES), an analog of mustard spirits of the animal, or the fighter would eat his opponent’s
gas, the notorious chemical warfare agent [55]. D’Agostini heart to acquire his courage. It is sad that in the twenty-first
et al. reported that while high-dose environmental cigarette century, some still believe that eating products of human hair
smoke (ECS) induced apoptosis-related alopecia in mice. will help to grow back their own hair!
Also, oral administration of L-cystine/Vit B6 effectively
inhibited alopecia in a dose-dependent fashion [56].
Moreover, in 2013, D’Agostini et al. reported that the References
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B. 2018;189:318–25.
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that there is insufficient to missing evidence for the assump- mate antiporter, system x (c) (−) : cystine supplier and beyond.
tion that these products improve or prevent progression of Amino Acids. 2012;42(1):231–46.
10. Fraser RD, Parry DA. Structural transition of trichocyte keratin
AGA/FPHL (evidence level 4). Kanti et al. who updated the intermediate filaments during development in the hair follicle.
S3 guideline (2018), included only the study by Gehring Subcell Biochem. 2017;82:131–49.
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2013;305(1):25–34. 68. Trüeb RM. 2010. (data on file) as cited in Ref. 61
Free Fatty Acids
43
43.1 Free Fatty Acids (FFAs)

Basic Concepts
• Free Fatty Acids (FFAs) are carboxylic acids with Fatty acids are carboxylic acids containing a saturated or an
no other molecules bound to the aliphatic chain and unsaturated aliphatic chain. Most naturally occurring fatty
can either be obtained through the diet, synthesized acids have an unbranched chain of an even number of carbon
endogenously, or produced by gut microbiota. atoms, from 4 to 28 [8]. When there are no other molecules
• FFAs are natural components of human sebum and bound to the aliphatic chain, these acids are called Free Fatty
possess anti-inflammatory and antimicrobial prop- Acids, or FFAs.
erties to a wide range of gram-positive bacteria FFAs are metabolic intermediates that may be obtained
in vitro, with lauric acid exhibiting antimicrobial through the diet, synthesized endogenously, or produced via
activity even against methicillin-resistant fermentation of carbohydrates by gut microbiota. Since the
Staphylococcus aureus. 1950s, there were reports on the antimicrobial, anti-
• Certain unsaturated FFAs have antiandrogenic inflammatory, and antiandrogenic properties of FFAs, and
properties, and their action is selective; some FFAs these conclusions have later been confirmed by numerous
inhibit 5α-Reductase isotype I, and others inhibit in vitro studies. The most extensive and impressive initial
isotype IΙ, with linoleic acid demonstrating the analysis was that of Nieman et al., who first addressed the
highest antiandrogenic potency of all FFAs. antimicrobial properties of FFAs. Moreover, they identified
• Clinical data on the effects of FFAs in AGA/FPHL synergies between different FFAs and “selectivity” against
data are minimal, with just two published trials, specific bacterial strains, depending on the number of unsat-
both utilizing supplements containing multiple fatty urated bonds of the FFA aliphatic chain [9].
acids and antioxidants, from which very limited It took almost 20 years until Kabara et al. re-addressed the
conclusions may be drawn. issue, publishing their findings and confirming previous
results [10]. Some years later, Morello et al. reported that the
scalp surface lipids of individuals with severe acne contained
lower quantities of linoleic acid than healthy subjects [11]
Products classified as cosmeceuticals [1] are skincare prod- and expressed a hypothesis of a causative correlation [12]. A
ucts that lie in a gray area between cosmetics and drugs. few years later, Heczko et al. reported on the potent antimi-
Most ingredients have been added to these products based on crobial properties of FFAs against strains of Staphylococcus
the theoretical benefits discovered from in vitro studies [2]. aureus and Streptococci group A, B, C, and G [13]. Speert
Most of these ingredients are of botanical origin, and their et al. identified the bactericidal effect of oleic acid on group
use is not supported by evidence-based science [3]. A streptococci [14]. Knapp et al. eventually demonstrated
Even though cosmeceuticals have never been well-defined that the toxicity of polyunsaturated fatty acids on
and are typically characterized by myths and misconceptions Staphylococcus aureus was dependent upon time, concentra-
[4], nevertheless, they represent the most rapidly expanding tion and FFA unsaturation [15]. Overall, the antimicrobial
frontier in Dermatology [5]. Regarding cosmeceuticals, phy- activity of several FFAs has been proven to a wide range of
sicians are primarily- and justifiably- concerned about safety Gram-positive bacteria [16]. Lauric acid, a minor sebum
issues [6], since credible studies substantiating their safety ingredient, exhibits the most potent antimicrobial activity
are lacking, whereas the public is mostly concerned on in vitro, even against methicillin-resistant Staphylococcus
whether they actually work and to what extent [7]. aureus [10, 17–19].
220 43 Free Fatty Acids
Natural FFAs are secreted initially by the sebaceous α-linolenic acid > than linoleic acid > than palmitoleic acid
glands as triglycerides, and they are catabolized on the skin > than oleic acid > than myristoleic acid [33].
surface by lipases [20], which are produced by the local flora A subsequent study of Liang et al. proved that the topical
[21]. It has been reported that FFAs at the skin surface application of γ-linolenic acid to the T-treated flank organ of
underly at least a part of an antimicrobial barrier, they are rats suppressed the anabolic effects of T. In contrast, the
partially responsible for the resistance of human skin to bac- DHT-dependent activity on the organ was not significantly
terial colonization [22, 23] and that their antimicrobial prop- affected, suggesting that flank organ growth was dependent
erties can be traced in various mechanisms of action affecting on DHT and that γ-linolenic acid acted by inhibiting
bacterial physiology [24]. 5α-R. They also demonstrated that the effect of γ-linolenic
acid was localized at the site of application and did not affect
the androgen-dependent growth of other organs, such as tes-
Lauric acid, found in the human sebum at a concentra- tis, epididymis, seminal vesicles, and prostate [34]. Later
tion of 1–2%, is a typical example [25] and has potent experiments by Liu et al. confirmed that both lauric acid
bactericidal properties against even methicillin- (saturated FFA), and α-linolenic acid and oleic acid (unsatu-
resistant Staphylococcus aureus (MRSA) [26]. rated FFAs) demonstrated an inhibitory effect on the prolif-
eration of LNCaP cells (androgen-sensitive human prostate
adenocarcinoma cells). Simultaneously, the expression of
PSA mRNA was down-regulated, suggesting that these FFAs
Nakatsui et al. proved that the incubation of the skin bac- blocked the conversion of T to DHT and inhibited the prolif-
teria P. acnes, S. aureus, and S. epidermidis with lauric acid eration of prostate cancer cells [35].
yielded minimal inhibitory concentration values against the Subsequent studies by Raynaud et al. [36] and Abe et al.
bacterial growth more than 15 times lower than those of ben- [37, 38] confirmed earlier findings on the high antiandro-
zoyl peroxide (BPO) [27]. At the same time, it also exerted genic potency of γ-linolenic acid. Researchers concluded
therapeutic action against a Propionibacterium acnes- that several other FFAs, namely myristoleic, lauric and oleic
induced skin inflammation in vivo. A double-blind, placebo- acids, are pharmacologically active compounds, with moder-
controlled, randomized study comparing the active lotion ate to potent inhibitory activity on both isotypes of 5α-R
containing triethyl citrate and ethyl linoleate with its vehicle in vitro. Later experiments using herbal extracts that con-
as a placebo control was conducted by Charakida et al. in 40 tained FFAs were also reported to exert measurable antian-
patients with mild to moderate acne vulgaris. Results showed drogenic activity. Fujita et al. noted that the extract prepared
a rapid response, an apparent reduction in lesion counts, and from Ganoderma lucidum significantly inhibited the
acne grading, while a mean reduction of 53% in sebum pro- T-induced growth of the ventral prostate in castrated rats due
duction was noted in the actively treated group, compared to its FFA content [39]. In their extensive (55 pages-long)
with baseline [28]. These findings have sparked vivid scien- review on the pharmacological effects of Saw Palmetto
tific interest, and there are ongoing and forthcoming studies extract in the lower urinary tract, Suzuki et al. reported that
of topically-acting antimicrobial products based on FFAs the content of Saw Palmetto extracts in saturated and unsatu-
[29, 30]. rated FFAs ranged from 40.7% to 80.7% [40]. Abe et al.
Another significant property of FFAs is their antiandro- reported that the total FFA content of Saw Palmetto extract
genic activity. Experiments of Watanabe et al. demonstrated was composed of 30.2% lauric, 28.5% oleic, 12.1% myristic,
a strong enhancing effect of FFA on the binding of progester- 9.5% palmitic, and 4.6% linoleic acids [37] (see Chap. 71).
one, androsterone, and testosterone (T) to bovine serum They argued that the antiandrogenic potential was propor-
albumin binding [31]. However, in the case of human serum tional to the concentration of each FFA in the extract, with
albumin, the binding affinities of progesterone and T were that of linoleic acid, oleic acid, and myristic acid being 1.7–
not greatly affected by bound FFA [32]. Yet, the first report 4.5 times more potent than the activity of the saw palmetto
of the direct antiandrogenic properties of FFAs was provided extract per se.
by Liang et al. on cultures of human prostate cancer cells. However, given that the concentration of linoleic acid,
Researchers reported that certain unsaturated FFAs have which is the FFA with the highest antiandrogenic potency,
antiandrogenic properties and that their action is selective, does not exceed 4.6% in the standardized Saw Palmetto
with some FFAs inhibiting isotype 5α-R I and others inhibit- extract, this might explain why Saw Palmetto extract is not
ing isotype 5α-R IΙ. The relative inhibitory potencies of an efficient anti-androgen. Matsuda et al. showed that the
unsaturated FFAs in decreasing order were as follows: lipophilic components of Lygodii Spora, namely oleic, lin-
γ-linolenic acid > than cis-4,7,10,13,16,19-docosahexaenoic oleic, and palmitic acids, demonstrated in-vitro 5α-R inhibi-
acid = cis-6,9,12,15-octatetraenoic acid = arachidonic acid = tory activity and in vivo antiandrogenic activity in the flank
43.2 FFAs, Hair Follicles, AGA and FPHL 221
organ of castrated Syrian hamsters. Additionally, they raises questions on the direct participation of FFAs in hair
induced hair regrowth on shaved, T-treated C57Black/6CrSlc follicle physiology [56].
mice with the application of Lygodii Spora extract [41]. Most recently, Munkhbayar et al. [57] investigated the
Finally, the antiandrogenic activity of certain FFAs has been effect of arachidonic acid (AA) on hair growth by using both
confirmed in cultures of prostatic adenocarcinoma cells, in in vivo (C57BL/6 mice) and in vitro (human scalp hair fol-
which long-chain unsaturated FFAs (oleic and linolenic licles) models. They demonstrated that AA enhanced the
acids) potently suppressed conversion of T to DHT [38, 42]. viability of human dermal papilla cells (hDPCs) and pro-
moted the expression of several factors responsible for hair
growth, including fibroblast growth factor-7 (FGF-7), FGF-
Unfortunately, the in vivo antiandrogenic effects after 10, and HGF. Western blotting identified the role of AA in
oral FFAs have not been found in accord with the the phosphorylation of various transcription factors (ERK,
in vitro results. CREB, and AKT) and increased expression of Bcl-2 in
hDPCs, factors that are known to promote survival and pre-
vent cell death. In addition, AA significantly promoted hair
shaft elongation, with increased proliferation of matrix kera-
A randomized, double-blind, placebo-controlled study tinocytes, during ex vivo hair follicle culture. AA was also
by Giltay et al. assessing the effects of eicosapentaenoic found to promote hair growth by induction and prolongation
acid (EPA), docosahexaenoic acid (DHA) (400 mg/day), of anagen phase in telogen-stage C57BL/6 mice.
and alpha-linolenic acid ALA (2 g/day) on serum T levels
during 41 months of follow-up in 1850 male patients who
survived a myocardial infarction (MI), reported that no 43.2 FFAs, Hair Follicles, AGA and FPHL
effect of EPA-DHA and ALA supplementation on changes
in serum total T [43]. Concerning the clinical effects of FFAs in AGA and FPHL,
In contrast, the anti-inflammatory properties of FFAs, data are minimal.
both in vitro and in vivο, have also been demonstrated in Skolnik et al. published in 1977 a case-report of a 19-year-
clinical studies. Oral FFAs supplementation has beneficial old man who was being maintained on a long-term regimen
effects in rheumatoid arthritis and patients with asthma, of fat-free, intravenous hyperalimentation fluids and devel-
supporting the idea that FFAs are potent anti-inflammatory oped essential fatty acid deficiency and hair loss. The cutane-
agents. There are indications that the inclusion of n-3 PUFA ous manifestations (scalp dermatitis, alopecia, and
(polyunsaturated fatty acids) in enteral and parenteral for- depigmentation of hair) were reversed after 21 days by daily
mulas might be beneficial to patients in intensive care or topical application of sunflower oil, which contained 60–70%
post-surgery [44]. The hypothesis behind the anti-inflamma- linoleic acid [58].
tory activity of FFAs is that they act both directly (i.e., by There is an unpublished, controlled, clinical trial by
replacing arachidonic acid as an eicosanoid substrate and Khadavi et al. [59] testing a commercial product (Revivogen®
inhibiting arachidonic acid metabolism) and indirectly (i.e., Scalp Therapy) that contains γ-linolenic acid (GLA),
by altering the expression of inflammatory genes through α-linolenic acid (ALA), linoleic acid and OLEIC acid, and
effects on transcription factor activation) [45]. The anti- numerous other ingredients with potential hair-growth
inflammatory activity of FFAs is produced through intracel- effects. These ingredients are caffeine, saw palmetto extract,
lular targets, such as peroxisome proliferator-activated β-sitosterol, Azelaic acid, Vit B6, Vit Ε, and zinc. The hair
receptors (PPARs). For the interested reader, the anti- growth potential of each compound is extensively discussed
inflammatory properties of FFAs and their significance in in dedicated chapters. The study was a small-scale, 1-year
cutaneous biology have been extensively studied and long, randomized trial on 84 male and female patients with
reported by Ziboh et al. [20, 46–48]. AGA and FPHL, aged 18–52. Two groups were randomized;
Extensive research has been conducted to evaluate the the active group included 25 males and 25 females, suffering
potential therapeutic effects of fish oils in numerous inflam- from AGA and FPHL respectively, who received a topical
matory conditions [49, 50], such as rheumatoid arthritis [51], product containing FFAs (1 mL o.d.), and the control group,
inflammatory bowel disease [52, 53], cardiovascular disease which included 17 men and 17 women who received topical
[54], and autoimmune diseases [49]. At the same time, it is placebo (1 cc o.d.). All enrolled patients suffered from mild
speculated that FFAs might even have cancer-protective to moderately severe AGA, according to a modified Norwood/
properties [55]. The findings of Cunnane et al. in lab animals Hamilton (II-V) and Savin (II-V) classification scales.
are worth mentioning, who reported that deprivation of lino- Patients visited the clinic every **3 months, where they
leate from the diet of mice led to the loss of their fur, which completed a hair growth questionnaire, and investigators
completed assessments of scalp hair growth by examining acids from fish and blackcurrant seed oils and antioxidants
scalp photographs taken with the head in stereotactic posi- [65]. According to the authors, the main ingredients of the
tioning. According to the authors, the results in the active tested supplement were fish oils, rich in omega-3 PUFAs
group were superior to placebo at all time points (p < 0.02), (Eicosapentaenoic and docosahexaenoic acids), and black-
and by month 12, 88% of patients in the active group were currant seed oil, containing a balance of omega-6 (linoleic
rated as improved by the investigators, vs. 8% of the placebo- and γ-linoleic acid) and omega-3 acids (α-linolenic and, to a
treated patients. Accordingly, 86% of patients in the active lesser degree, stearidonic acids). Women with any hair loss
group were satisfied with their overall hair appearance vs. condition were randomly assigned either to the nutritional
18% of the placebo-treated patients. Assessment of hair supplement group (n = 80 subjects, of those, 40 were pre-
growth by blinded investigators confirmed that progressive menopausal and 40 postmenopausal) or to the control group
improvement in hair growth at 3, 6, 9, and 12 months was (n = 40 subjects, of those, 20 were premenopausal and 20
evident in the active group in terms of thickness, pigment, postmenopausal). Supplemented subjects received a nutri-
length, and/or growth rate of hair vs. no significant improve- tional supplement providing a daily dose of 460 mg fish oil,
ment in the placebo-treated patients. Regarding self- 460 mg blackcurrant seed oil, 5 mg Vit E, 30 mg Vit C, and
evaluation individual questions, active treatment was 1 mg Lycopene for 6 months whereas control subjects did
superior to placebo for all seven questions (all p values not receive any product. According to global photographs
<0.003). The methodology used in this trial has been reported that both investigators and patients assessed, after 6 months,
to be reliable and valid, both as far as patient evaluation is 62% of supplemented subjects had an increased hair density
concerned [60, 61] but also concerning objectivity and compared to only 28.2% of subjects in the control group
reproducibility of results of specialist observers in older (p < 0.001). In the supplemented group, 88.6% of women
studies for AGA [62]. observed increased hair density on their scalp photographs
In 2007, an in vitro study was performed by BIOalternatives vs. 51.3% of women in the control group. Although the per-
S.a.s. on behalf of Advanced Skin And Hair Inc. to assess the centage of telogen hair decreased in both groups during the
effects of the test product (Revivogen® Scalp Therapy) on the study, the decrease was significantly more marked (p < 0.001)
metabolism of T in reconstructed human epidermis [63]. The in the supplemented group, according to trichogram results.
study’s protocol included a comparison of inhibition of the The proportion of non-vellus anagen hair (>40 μm diameter),
5α-R enzymic system between a control group (T), representing 79.7% of the anagen hair at baseline in the sup-
Finasteride, Dutasteride, and the test product in reconstructed plemented group, increased significantly (p < 0.001) after
human epidermis. The various molecular species (T metabo- 6 months of supplementation, reaching 87.7%, also accord-
lites) were separated by thin-layer chromatography, and ing to trichogram results vs. no change in the control group
plates were autoradiographed with [14C]-T and quantified. (81.5% of anagen hair at baseline; 81.1% after 6 months).
This model has been shown earlier in a publication by The majority of supplemented subjects reported a reduction
Bernard et al., who was working at BIOalternatives S.a.s., to in hair loss (89.9% of subjects at 6 months vs. 69.2% of the
be useful for the evaluation of inhibitors of this metabolism control group), as well as an improvement in hair diameter
[64]. In the control samples, 74% of T had metabolized in (78.5% vs. 33.3%) and hair density (87.3% vs. 64.1%).
DHT within 24 h. Correspondingly, Finasteride 10−5 M One severe limitation that the authors themselves
inhibited the transformation of T into DHT by 67% com- acknowledged was that the study design did not allow
pared to the control group, and Dutasteride 10−5 M and determining to what extent the observed beneficial effects
10−6 M inhibited the transformation of T into DHT by 80% may be attributed to each of these active ingredients.
and 86%, respectively. Besides, the standard trichogram is a non-specific, non-
precise test, and it is unreliable for the determination of the
hair growth efficacy of products (see Chap. 9, Vol. 1),
unlike digital trichoscopy. The report did not provide details
The test product (5 mg/cm2) strongly reduced DHT
about the measures used to blind study personnel, while
production by 90%, testing favorably to finasteride and
both investigators and participants were the outcomes
Dutasteride.
assessors, both prone to bias. Participants did not receive a
substitute for the nutritional supplement, which is likely to
influence their outcome assessment. Funding source and
Le Floc’h et al. conducted a 6-month, comparative, ran- declaration of interest were not reported, but the first author
domized, expert-blinded study on 120 healthy female sub- is employed by Innéov (L’Oréal), the manufacturer of the
jects aged 18–65 years (60 premenopausal and 60 supplement. Concerning outcomes, the three sets of before-
postmenopausal). They evaluated the efficacy of a nutritional and-after photos of patients after 6 months of supplementa-
supplement containing specific omega-3 and omega-6 fatty tion show mild changes in coverage. Van Zuuren et al., who
References 223
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Copper Tripeptides
44
Basic Concepts 44.1 Mechanism of Action and Properties

• Tripeptide GHK-Cu participates in the physiologi- of GHK-Cu
cal metabolism of Cu and is endowed with a wide
range of biological activities. These include angio- GHK-Cu was initially discovered in the human serum in
genesis, acceleration of wound healing, enhanced 1973 by Pickart et al. they described it as a growth factor for
bone repair, stimulation of collagen synthesis, and various differentiated cells and a modulator of the extracel-
superoxide dismutase-like activity. lular matrix [1]. Since then, the GHK peptide has been estab-
• GHK-Cu has been reported to exert positive effects lished to possess stimulating and growth-promoting effects
on hair follicles in vitro and in vivo, probably by on many cells and tissues. GHK forms complexes with tran-
stimulating VEGF expression, suppressing TGF- sition metals cu and Fe before they interact with cells and
β1, IL-1, and caspase-3, as well as increasing Bcl-2 facilitates the delivery of metallic elements required for cel-
and Bax secretion and activity. lular growth and survival in forms that are both non-toxic
• Commercially available products containing copper and readily utilizable by the cells [6].
tripeptides have been reported to have positive hair- There are numerous and diverse properties attributed to
growth effects in AGA patients in one small-scale, GHK-Cu, namely significant antioxidant, anti-inflammatory,
sponsored, unpublished study. and healing properties. Even though considerable research
• Similar products have been used extensively in hair effort has been conducted for decades to discover the proper-
restoration surgery during the post-operative period ties of GHK-Cu, the exact molecular mechanisms of action
as agents for improved healing, despite the minimal of tripeptide GHK-Cu remain mostly unknown. Its actions in
scientific data supporting this indication. many tissues and organs are fascinating, with the most
important reported positive effects being those on the skin,
vessels, gastrointestinal tract, and nerve tissue:
Tripeptide Glycyl-L-histidyl-L-lysine (GHK) is a naturally • the property initially attributed to the GHK-Cu complex
occurring tripeptide that was initially isolated in the human was being a hepatic and cellular growth factor [7–9], as
serum [1] at a concentration of 200 ng/mL and was later iso- well as being an efficient replacement for serum in cell
lated in the saliva and urine [2]. GHK is a matrix-derived culture media [10, 11]
tripeptide which may originate from several extracellular • the role of GHK-Cu in the human body seems to be
matrix macromolecules. It spontaneously forms a high- related to cellular Cu+2 transfer, absorption, and distribu-
affinity tripeptide- Cu+2 complex with one Cu+2 (II) ion, tion to cells [3, 4]. In particular, GHK-Cu is reported to
forming GHK-Cu. provide free Cu+2 ions to intracellular metallochaperones,
Besides being recognized as a metal ion carrier in biologi- which, in their turn, deliver Cu+2 ions to intracellular
cal fluids, GHK mediates essential biochemical functions Cu+2-dependent enzymes [12, 13]. It naturally occurs at a
common to many types of cells. It has also been known to concentration of 200 ng/mL (10−7 mol/L) by 20 years of
play a vital role in Cu uptake and distribution into cells, in
+2
age, whereas, by 60 years of age, the concentration has
the form that Cu+2 is not toxic [3–5]. dropped to 80 ng/mL.
226 44 Copper Tripeptides
• positive actions of GHK-Cu in the healing process were even suggested that GHK-Cu may be a potential thera-
demonstrated a decade after its isolation [14]. GHK-Cu peutic agent against age-associated neurodegeneration
accelerates healing and induces direct, critical tissue and cognitive decline [38].
reconstruction steps, such as neo-angiogenesis -both in • The anti-inflammatory activity of GHK-Cu is exerted by
vitro [15] and in vivo [16] chemo-attraction of cells nec- preventing the inhibitory effect of IL-1 beta [39] and the
essary for tissue healing, such as macrophages, mono- suppression of TGF-β1 (Transforming Growth Factor-β1)
cytes, mastocytes [17] and endothelial cells [18–20] and secretion and activity [40]. GHK-Cu has been shown to
enhancement of extracellular matrix in vivo [21]. During reduce TNF-β induced secretion of proinflammatory
wound healing, GHK-Cu may be freed from existing cytokine interleukin IL-6 in normal human dermal fibro-
extracellular proteins via proteolysis and can serve as a blasts, and GHK-Cu can be used as a topical agent in the
chemoattractant for inflammatory and endothelial cells treatment of inflammatory skin conditions in the place of
[20]. corticosteroids [41]. Zhai et al. studied patients with
• GHK-Cu modulates the expression and activation of nickel skin allergy and showed that topical use of GHK-Cu
matrix metalloproteinase-2 in vivo [22], stimulates cul- gel was comparably effective with topical steroids in
tured fibroblasts to synthesize collagen [23], and induces reducing inflammation and erythema [42].
a dose-dependent increase in the synthesis of glycosami- • GHK-Cu is capable of upregulating or downregulating at
noglycans [24]. Cell culture studies [18] have shown that least 4000 genes in the human genome. Studies using the
GHK-Cu exerts its maximal biological effect at broad Institute’s connectivity map found that GHK sig-
10−9 mol/L. At this concentration, GHK-Cu has been nificantly increased DNA repair gene expression, with 47
shown to increase mRNA production for collagen, elastin, genes stimulated and five genes suppressed, with an aver-
proteoglycans, and glycosaminoglycans in fibroblasts age increase or decrease more than or equal to 50% [43,
[18, 22, 24]. 44].
• In vivo injection of GHK-Cu accelerates tissue recon- • In 2009, Kang et al. showed that treatment with GHK-Cu
struction [25, 26] and healing [18, 27], especially in at concentrations of 0.1–10 μM increases the proliferative
superficial wounds [28, 29]. It has also been shown that potential of basal keratinocytes by modulating the expres-
extracellular matrix accumulation increases in the rat sion of integrins, of p63 and PCNA. Also, increased lev-
wound model due to the GHK-Cu application [21]. GHK els of p63, a putative stem cell marker of the skin, suggest
facilitates essential steps in wound healing in humans as that GHK-Cu promotes the survival of basal stem cells in
well, such as cell migration, neo-angiogenesis, tissue the skin [45].
remodeling, and accelerating all tissue repair processes
[21]. Pilot studies have demonstrated the efficacy of
GHK-Cu preparations in facilitating an increased rate of
However, not all Copper tripeptides exert positive
wound healing and re-epithelization of skin ulcers in dia-
actions on human cells, and, actually, some Copper tri-
betic patients [30] and in patients who have undergone
peptides might even have adverse effects on human
Mohs surgery [31]. Mulder et al. demonstrated in a ran-
cells [46]. Interestingly, even the role of Cu+2 concern-
domized, double-blind, placebo-controlled study that the
ing the properties of GHK-Cu is uncertain.
application of GHK-Cu in diabetic foot ulcers resulted in
a threefold faster rate of healing compared to standard
care and vehicle [32].
• GHK-Cu contributes to the restoration of blood flow in Maquart et al. reported that GHK induced a similar
injured tissue through three overlapping mechanisms: enhancement of collagen synthesis as GHK-Cu. The lack of
neo-angiogenesis, thrombolysis, and vasodilation. In enhancement of collagen synthesis by Cu+2 indicated that the
vivo, GHK-Cu induces angiogenesis and new capillary tripeptide alone might be responsible for the GHK-Cu tri-
growth in rabbit models at 10−12 mol/L by acting as a che- peptide effects [14]. The chemical structure of the GHK-Cu
moattractant for capillary cells [18]. Pollard et al. reported tripeptide initially (1979) led to the hypothesis that its activ-
that fibroblasts on GHK-Cu produced significantly larger ity was based on the His-Lys sequence and that the side chain
b-FGF and VEGF quantities compared to standard fibro- of Lys plays a vital role in the biological activity of the mol-
blasts cultures [33]. ecule [47]. Several years later (2001), Conato et al. con-
• GHK-Cu exerts direct superoxide dismutase-like (SOD) firmed this theory proving that the role of the first (Gly)
effects since it neutralizes effectively reactive oxygen residue is necessary and that the second residue (His) does
species (ROS) in vitro [34, 35]. not appear to play a role. In contrast, the presence of the free
• GHK-Cu has been reported to accelerate the regeneration side chain of the third residue (Lys) appears to be of funda-
of nervous [36] and bony tissue [37] in vitro. Pickart et al. mental importance [48].
44.3 Clinical Studies 227
44.2 GHK-Cu and Hair Follicles growth was dependent on the dose administered, on the cop-
per peptide complex structure, and did not exhibit by copper
GHK-Cu seems to be endowed with various properties that salts or the peptides alone, without copper.
could positively affect the physiology of the hair follicle: It Trachy et al. (1996) were the first to present the positive
stimulates the proliferation of dermal fibroblasts, elevates action of GHK-Cu on hair follicles in vivo in a pilot study on
the production of vascular endothelial growth factor (VEGF) human volunteers with AGA. Their pilot study demonstrated
by dermal fibroblasts [33], decreases the secretion of TGF- through the use of phototrichogram that GHK-Cu accelerated
β1 from dermal fibroblasts [40], and has potent anti- the entry of hair follicles into the anagen. The details of the
inflammatory and anti-oxidative properties [49]. VEGF is study can be found only in the first edition of the Dermatologic
strongly associated with the hair follicle cycle [50], enhanc- Research Techniques textbook, by Howard I. Maibach [61].
ing the vascularity around the hair follicle [51], and increas- Pyo et al. studied an alternative peptide, L-alanyI-L-
ing the size of the dermal papilla and the caliber of the histidyI-L-lysine-Cu (AHK-Cu), and reported on the hair
produced hair [52–54] (see Chap. 11, Vol. 1) growth potential in dermal papilla cells and human hair fol-
Androgen-inducible TGF-β1 deriving from dermal papilla licles ex vivo. They concluded that AHK-Cu at a concentra-
cells of AGA patients is involved in the suppression of epi- tion between 10−12 and 10−9 M induced the proliferation of
thelial cell growth, as presented in the seminal publication by DPCs, elevated the ratio of Bcl-2/Bax, and reduced levels of
Inui et al. in 2002 [55]. Additionally, the histologically estab- the cleaved forms of caspase-3 and PARP, resulting in low-
lished micro-inflammation component of AGA/FPHL has ered apoptosis on different cell types. Pyo et al. hypothesized
been shown to play a crucial role in the progression of the that AHK-Cu might function by slowing the programmed
condition [56] (see Chap. 14, Vol. 1) cell death rate in human hair follicles that ultimately halts
human hair growth [62].
Regarding the percutaneous permeation of the human
skin by copper complexes, it is subject to dynamic ligand
Since GHK-Cu can affect all these parameters,
exchange in the process of diffusion through skin [63].
researchers investigated whether GHK-Cu could have
Hostynek et al. conducted experiments in ex vivo conditions
a stimulating effect on hair growth.
[64, 65] and found that human skin absorbs Cu+2 efficiently
from these molecules, acting as a reservoir. Copper deposi-
tion through GHK-Cu was high, initially towards the epider-
Trachy et al. initially studied the effects of GHK-Cu analogs mis and then into deeper layers. Results were impressive
with hydrophobic residues in C3H mice and provided histologi- enough to report that topical administration of Cu+2 in the
cal evidence of the hair follicle-stimulating properties of copper tripeptide form may offer an effective alternative to injection
peptide complexes [57]. Later, Uno et al. conducted an in-vivo in copper deficiency cases.
study on the back skin of fuzzy rats and reported that the hair
growth effect of GHK-Cu (compound PC1020, ProCyte
Corporation) was comparable to those of topical Minoxidil. The 44.3 Clinical Studies
details of hair stimulation by GHK-Cu was studied by phototri-
chogram, folliculogram (micro- morphometric analysis), and The hair growth potential of GHK-Cu has been tested in a
the rate of DNA synthesis in the follicular cells. The reported single, small-scale Phase II clinical study, sponsored by
effects were essentially a stimulation of the follicular cell prolif- ProCyte Corp., who holds the patent for the proprietary exper-
eration, resulting in an enlargement of the anagen follicles from imental peptide-copper complex, PC1358 [66]. The study was
vellus to terminal or maintenance of the pre-bald terminal folli- conducted in 1997 as a controlled, single-center, double-blind,
cles (prevention) [58]. Phase II clinical study of the experimental product PC1358,
Pickart and Lovejoy injected GHK-Cu intradermally in which was later named Tricomin® Solution. The study investi-
the back skin of mice and observed improved and faster (12 gated the hair growth potential of PC1358 at concentrations of
vs. 20 days) growth of new hair. The addition of fatty acids 1.25% and 2.5% on 33 of the men with ΑGΑ, aged 18–40,
or hydrophobic amino acids in the GHK-Cu solution further with mild to moderate AGA, randomly assigned to either one
improved efficacy [59]. Awa et al. reported that topical of two dose groups or the vehicle formulation. The study’s
GHK-Cu significantly reduced chemotherapy-induced hair prospectively designed endpoints included determination of
loss due to cytosine, arabinoside, and doxorubicin in lab ani- the effect of 1.25% and 2.5% doses of PC1358 vs. vehicle on
mals, while administration of GHK-Cu after chemotherapy total hair count and hair weight measured in a 1 cm2 treatment
accelerated fur regrowth [60]. Overall, the model studies area located on the vertex. An additional endpoint included a
showed that copper peptides stimulated shifts from telogen general cosmetic assessment of the treated area. Treatment
to anagen, resulting in increased and earlier hair growth. This with 2.5% PC1358 resulted in a statistically significant
increase in the total hair count compared to vehicle treatment 6 months was: poor (26.7%), fair (46.7%), good (20.0%),
during the study. Appreciable increases in total hair weight and excellent (6.7%) in group A, poor (42.9%), fair (42.9%),
were not found over the study’s treatment phase, whereas 90% and good (14.3%) in the group B, and poor (50.0%), fair
of patients on 2.5% PC1358 evaluated that they grew new hair (42.9%), and good (7.1%) in the group C. The proportion
or that AGA did not progress. No significant adverse effects above good satisfaction was higher in group A (26.7%) than
were reported, while 50% of subjects in the placebo group in the other groups (group B: 14.3%, group C: 7.1%). There
reported hair loss progression [67]. was no statistically significant difference in hair length and
hair thickness among the three groups at 6 months, and there
were no adverse events in any group.
However, this study has never been published in a
peer-reviewed journal, there are no photos or other
objective data, and the full article of the study cannot 44.4 GHK-Cu and in Hair Restoration
be traced in any database. Surgery
Copper peptides have been used extensively in the hair resto-

In another unpublished study, Dr. Pickart, founder of Skin ration surgery field since 1998, mostly in the form of com-
Biology, Inc., a manufacturer of copper peptide products for mercially available products, such as GraftCyte® or Iamin®.
hair loss and skin care, allegedly conducted a direct compari- Several authors have reported [72] on using GraftCyte®
son of Tricomin® and Minoxidil 2% Topical Solution. shampoo, GraftCyte® Moist Dressings, and GraftCyte®
Application of MTS 2% for 4 months resulted in +73 new Concentrate Spray during the immediate post-operative
hairs (nonvellus hair count) vs. -31 for placebo, whereas period. They have reported improved healing of both the
Tricomin® 2.5% after 3 months resulted in +97 new hairs donor and recipient areas, reduced incidence of graft telogen
(nonvellus hair count) vs. -51 for placebo. According to effluvium, and accelerated regrowth of new hair in the recipi-
Pickart, in this direct comparison of Tricomin® with MTS ent area [73, 74]. A controlled study by Perez-Meza et al.
2%, Tricomin® produced slightly more hair growth than MTS (1998) on the effects of GraftCyte® Moist Dressing reported
2% and thicker hair shafts. However, there are no data what- that hairs from transplanted hair follicles regrow within
soever on this “trial,” such as the number of subjects, stage of 6 weeks instead of the usual 10–14 weeks after surgery,
AGA, study design, photos, objective, or subjective data, while there was a reduction in post-surgical crusting [75].
besides the claims of Dr. Pickart himself [68]. ProCyte Corp. Another study by Hitzig in 30 surgical hair restoration
discontinued an announced preclinical trial of Tricomin® for patients reported that the use of Graftcyte® spray in the recip-
alopecia in Japan (11 Jun 1997) and an announced Phase-II ient area reduced the post-surgical shedding of grafts by
trial for alopecia in USA (30 Nov 2000) therefore, Tricomin® 60%, reduced the healing period of the donor and recipient
Solution 2.5% is available only as a cosmetic, containing the areas by 30–50%, induced faster hair growth of grafts by
patented Triamino Copper Nutritional Complex™ [69]. 30% in the recipient area, while patient satisfaction increased
The only other relevant publication found in the scientific from 80% to >95% [76].
literature is of Lee et al. (2016). They conducted a random- Other surgeons have not found the GraftCyte® protocol to
ized, double-blind, 6-month prospective study examining the be useful in promoting wound healing, and consider that it
efficacy and safety on hair growth of a complex (ALAVAX) does not provide the moist environment around the sutured
of 5-aminolevulinic acid (5-ALA) and glycyl-histidyl-lysine donor incision that is optimal for healing. Additionally, since
(GHK) peptide in 45 AGA patients [70]. 5-ALA is a photo- GraftCyte® gel is drying and seems to accumulate in the hair,
sensitizer compound widely used in photodynamic therapy, 5–10% of patients seem to get irritated from the treatment,
which has demonstrated hair growth properties [71]. Patients and the recipient site can become pruritic and hyperemic [77].
were randomized into 3 groups: group A was treated with
ALAVAX 100 mg/mL, group B was treated with ALAVAX Synopsis
50 mg/mL, and group C served as the control group and was GHK-Cu tripeptide seems to possess a plethora of regenera-
treated with placebo, all for 6 months. Total hair count on a tive and protective features, including antioxidant, anti-
1 cm-diameter circle at the frontal scalp using a phototricho- inflammatory, and wound healing properties. The hair growth
gram technique, hair length, hair thickness, patient assess- potential of GHK-Cu tripeptide cosmeceutical products has
ment, and adverse events were evaluated at months 1, 3, and been demonstrated in a single, small-scale, sponsored, and
6. An increase in hair count for 6 months was 52.6 (p < 0.05) unpublished clinical trial, while documentation on their effi-
in group A, 71.5 (p < 0.05) in group B, and 9.6 in group cacy in AGA/FPHL patients is missing. Therefore, GHK-Cu
C. The ratio of changes in hair count between group B (2.38) tripeptide compounds are not recommended for AGA/FPHL
and group C (1.21) at 6 months showed a statistically signifi- treatment, and minimal evidence exists on the effects of cop-
cant difference (p < 0.05). Patient satisfaction assessment at per peptides in the hair restoration field.
References 229
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Melatonin
45
by the pineal gland, usually at night. The onset of melatonin

Basic Concepts at dusk promotes sleep in diurnal animals, including humans,
• Melatonin is a ubiquitous molecule, widely distrib- and activity in nocturnal animals [6].
uted in nature with astoundingly diverse pleiotro- In vertebrates, besides being a synchronizer of the bio-
pic, physiological effects. logical clock, melatonin has multiple functions: it is a neuro-
• Melatonin is a neurohormone released by the pineal modulator, a hormone, a cytokine, a biological response
gland regulating seasonal biorhythms, daily sleep modifier, possesses anti-apoptotic properties [7–9], and can
cycles, and the aging process. Along with circadian even induce DNA repair [10]. It also affects neural, immune,
rhythm function, melatonin is a potent radical scav- gastrointestinal, cardiovascular, renal, bone, and endocrine
enger maintaining the functional integrity of cells functions; it also acts as an oncostatic and anti-aging mole-
with its antioxidant properties. cule [11]. Melatonin is also a potent free-radical scavenger
• Melatonin demonstrates anabolic effects in hair fol- and wide-spectrum antioxidant [12, 13], both intracellularly
licle cultures in vitro and in wool-producing ani- and extracellularly [14, 15], and works with other antioxi-
mals in vivo. dants to improve the overall effectiveness of each antioxidant
• Regarding the in vivo action of melatonin on human [16].
hair follicles, data are limited, and trials on topical Melatonin has been proven to be twice as active as Vit E,
effects of melatonin in AGA/FPHL and diffuse alo- and it is considered the most effective lipophilic antioxidant
pecia are small, poorly designed, biased, suffering [17]. Melatonin differs from other known radical scavengers
from conflicts of interest and the reported results in producing metabolites that are scavengers themselves, in
are suspiciously “impressive”. what is referred to as the “cascade reaction” [18]. Melatonin
reacts with agents to form products that are not recycled back
to melatonin, making it a “suicidal antioxidant“ [19]. In
addition to being a broad-spectrum antioxidant, it can also
Melatonin was first isolated from bovine pineal gland activate cytoprotective enzymes [20]. Also, topical melato-
extracts in 1958 by the distinguished researcher and profes- nin, has been found to suppress UV-induced erythema and
sor of Dermatology Aaron B. Lerner, who also described the UV-induced reactive oxygen species in a dose-dependent
chemical structure as N-acetyl-5-methoxytrypamine [1, 2]. manner [21, 22].
The functions of melatonin were not initially evident, but it Lately, data are accumulated regarding melatonin’s sig-
was soon discovered that it is a ubiquitous molecule, widely nificant effects in skin physiology, both for the endogenously
distributed in nature [3], with functional activity occurring in produced and exogenously administered melatonin [23–25].
vertebrates, invertebrates, plants, fungi, even in bacteria [4, Melatonin works by activating one of two pharmacological
5]. Melatonin is now recognized as a phylogenetically receptors, MT1 (MTNR1A) and MT2 (MTNR1B). Both
ancient, highly conserved indole, demonstrating uncom- receptors are distributed widely throughout the human body,
monly wide distribution and astoundingly diverse pleiotro- and receptor expression varies among different target organs
pic, physiological effects. [26]. Human skin expresses both receptors, with ΜΤ1 being
In animals, melatonin’s primary function is regulating the the predominant receptor, found in both whole skin and cul-
body’s physiological response to natural cycles of light and tured cells [27]. MT1 receptor expression has been detected
darkness, called circadian rhythms. In vertebrates, melato- by immunocytochemistry in the stratum granulosum and spi-
nin, also known as “the hormone of darkness”, is produced nosum, in the outer and inner root sheath, in eccrine sweat
232 45 Melatonin
gland, and blood vessel endothelium [28]. There is compel- Even though significant progress has been achieved, the
ling evidence that the human skin is not just the target of understanding of the role of melatonin in hair follicle biol-
biological actions of melatonin but also contains the entire ogy is still limited, mostly due to the complexity of melato-
molecular and biochemical machinery necessary to trans- nin’s interactions and metabolism. Due to the substantial and
form L-tryptophan to melatonin through serotonin and often contradictory species-, gender-, and dose-dependency
N-acetylserotonin (NAS) intermediates [29, 30]. Production of melatonin-related hair effects [39, 47–50], the exact func-
of Melatonin per se has been demonstrated in skin cell and tions of melatonin in hair biology remain confusing.
organ cultures, making the skin a vital, extrapineal tissue for
the regulation and metabolism of melatonin [31].
45.2 The Effects of Melatonin in Human
Hair Follicles
45.1 The Effects of Melatonin in the Hair
Follicles of Animals Findings on the effects of melatonin in cultures of human
hair follicles are largely contradictory. An organ culture
Hair follicles of both animals [32] and humans [33] are not study of Fischer et al. using human scalp hair follicles
just targets of melatonin bioactivity but also important extrap- showed that the maximum stimulating effect of melatonin on
ineal sites of its synthesis, regulation, and metabolism. the growth of hair follicles was at 30 μΜ. In contrast, increas-
An early study by Houssay et al. claimed that melatonin ing the concentration of melatonin to 1–5 mM had a reverse
had an inhibitory effect on the hair growth of mice [34]. inhibitory effect [51]. The stimulatory effect was seen only
However, a few years later (1969), melatonin was reported to during the early culture period (day 1–5) and could reflect
initiate molting and development of the white winter pelage enhanced protection of melatonin-treated organ-culture hair
in male weasels [35], and these effects were reproduced in follicles from the consequences of general tissue damage
other species [36, 37]. This melatonin action in hair follicles after microdissection/wounding. This interpretation concurs
was “expected” since its secretion is associated with circa- with the results of a subsequent extensive in vitro study of
dian and circannual rhythms [38]. Subsequent studies on Kobayashi et al. reporting no effects of melatonin on human
farm animals contributed significantly to our understanding scalp hair growth or hair matrix proliferation in vitro over a
of basic melatonin-related physiological mechanisms in the wide range of melatonin concentrations [32].
regulation of reproduction and pelage in individual domestic Regarding the in vivo action of melatonin on human hair
species. The neuroendocrine action of melatonin has been follicles, even though there are reports on topical absorption
related to the increase in wool growth of goats [39], to sea- of melatonin by the human skin [52, 53], the depth of pene-
sonal loss and regrowth of fur [40], even to fur pigmentation tration and achieved concentration in the dermal papilla and
in other species [35, 41, 42]. epithelial keratinocytes remain unknown. Clinical data on
the in vivo action of melatonin in the human scalp hair folli-
cles are limited to an older (2004) publication by Fischer
Overall, melatonin modulates hair growth and pigmen- et al. published in the British Journal of Dermatology [54], a
tation, presumably as a key neuroendocrine regulator subsequent study by Fischer et al. published in the
that couples coat phenotype and function to International Journal of Trichology [55] and a later study
photoperiod-dependent environmental and reproduc- (2017) by Nichols et al., published in the Journal of Clinical
tive changes [43]. and Aesthetic Dermatology [56].
Fischer et al. conducted a double-blind, randomized,
placebo-controlled pilot study in 40 women with hair loss,
Even though initial results showed a negative effect of between 20 and 70 of age, randomized into two groups. In
melatonin on hair growth [34], subsequent evidence sug- group A, 14 patients were diagnosed with diffuse alopecia
gested otherwise. When Ibraheem et al. added melatonin at and 6 with FPHL, and in group B (control group), 14 women
various concentrations (50–300 ng/L) to a culture of hair fol- had diffuse alopecia, and six suffered from FPHL. In this
licles collected from goats, hair growth was promoted [44]. study, 1 mL of a 0.1% melatonin-containing alcohol solution
Also, melatonin promoted anagen of the murine hair cycle, or a placebo solution were topically applied each evening for
mediated by the MT2 receptor [32, 45]. Various researchers 6 months, and trichograms (hair-pluck test) were performed
reported the anabolic effects of melatonin supplementation to assess anagen and telogen hair rates. After 6 months, the
in the diet of goats and other ruminants. Supplemented mela- researchers reported an increase in the anagen rate of the
tonin results in the transition of hair follicles from telogen to occipital trichograms from 76.3% to 85% in women with
anagen [46] and an increased growth rate, explained by the FPHL and in the control group from 78.22% to 82.11%
stimulation of dermal papilla cells [39, 44]. (p = 0.012). There was an increase from 82.2% to 83.8% in
45.2 The Effects of Melatonin in Human Hair Follicles 233
women with diffuse alopecia and a reduction from 83.16% to [55]. ASATONA AG funded all studies. The results were
81.13% in the placebo group (p = 0.046). Plasma melatonin published in the “International Journal of Trichology”, a
levels increased under treatment with melatonin but did not peer-reviewed, open-access medical journal published on
exceed the physiological night peak. These effects were behalf of the Hair Research Society of India, whereas the
slightly relevant in FPHL and only marginal in diffuse alope- journal’s impact factor is undisclosed [63].
cia. Nevertheless, they were interpreted by the authors as The studies coded MEL-COS-1 [64], MEL-COS-AS01
evidence of the induction of hair growth by prolongation of [65], MEL-COS-AS03 [66], MEL-COS-AS04 [67], and
anagen, in part via retardation of the transition to catagen MEL-COS-AS05 [68], results were evaluated by standard-
and/or by the promotion of the transition from telogen to ized questionnaires, TrichoScan®, 60-second hair count test,
anagen. However, these results referred only to the occipital and hair pull test. It was reported that melatonin 0.0033%
area, and during the study, melatonin did not influence the solution had a (quoting) “impressive hair growth potential,
rate of anagen hair growth in hair follicles located in the significantly higher than Minoxidil or Finasteride“. However,
frontal scalp area. The authors considered these results as a closer look at the methodology of the studies reveals meth-
evidence of a positive effect of melatonin in human hair odological flaws, such as short duration (3 months), absence
growth, indicating that melatonin receptors are realistic tar- of a placebo group in most studies, open-label protocol, non-
gets for hair growth regulation in humans [54]. objective measuring techniques, and asymmetric group sizes.
However, this publication had critical methodological
flaws, as Sladden et al. [57] aptly commented in a following
paper in the British Journal of Dermatology. The authors had However, even these cannot explain the reported
not followed the typical, general conditions for the conduc- results, approximately threefold better than the offi-
tion of an unbiased, randomized research (CONSORT state- cially published results of 5% Minoxidil Topical
ment) [58], nor did they fulfill the requirements for the Solution (MTS) (see Chap. 23) and Finasteride 1 mg
publication of an article in the prestigious British Journal of (see Chap. 24).
Dermatology [59]. Additional flaws of the study as presented
by Sladden et al. were the following:
• A very small number of subjects was enrolled, and most In detail for each study:
importantly, different size of groups with FPHL (n = 6)
and telogen effluvium (n = 14), • MEL-COS-1 [64]: Pharmacodynamics study, under once-
• It refered only to women with FPHL, and there is no sam- daily topical application of melatonin 0.0033% solution
ple of men with AGA, in the evening, which showed no significant influence on
• Instead of using hair weight measurements or any other endogenous serum melatonin levels and that treatment
objective and precise hair evaluation technique, the was well tolerated.
researchers used the hair-pluck test, which is an outdated, • MEL-COS-AS01 [65]: An open-label observational study
non-specific, non-sensitive technique, completely unreli- on 15 women with Stage I or II Ludwig scale and on 15
able for diagnosis of AGA or FPHL, let alone document- men with Stage I or II AGA Hamilton/Norwood scale, aged
ing the response to a hair loss treatment [60], 18–40 years who applied melatonin 0.0033% solution each
• The short duration of the study did not account for sea- evening. Results showed a significant reduction in the
sonal physiological changes in the percentage of hair fol- degree of severity of alopecia after 30 and 90 days
licles in anagen or telogen [61, 62], (p < 0.001) based on questionnaires completed by investi-
• Positive results were reported only for the occipital area gators and patients. One should note that reduction in the
and not on the androgen-sensitive frontal areas or the ver- severity of alopecia in Stage I or stage II AGA in Hamilton/
tex, where FPHL occurs, Norwood scale is questionable. These patients already have
• There was no reference to the hallmark parameter of a practically full head of hair, whereas any kind of positive
AGA/FPHL, i.e., hair follicle miniaturization and whether results in 30 days would be extremely unlikely. Even with
melatonin could influence this vital parameter of AGA/ Minoxidil, and Finasteride, positive effects will not appear
FPHL. earlier than 8–12 weeks, according to Price, who was a
leading investigator in both drugs, and according to well-
At the end of 2012, Fischer et al. published the results of 5 known physiological facts on hair-cycle dynamics [69, 70].
studies (one pharmacodynamic and four pre-post studies) • MEL-COS-AS03 [66]: an open-label, clinically con-
conducted by his team during January 2003–October 2006, trolled study was carried out based on a digital software-
on behalf of the Swiss company ASATONA AG, studying supported epiluminescence technique (TrichoScan®) to
the effects of a melatonin 0.0033% topical scalp solution determine the efficacy and tolerability of the melatonin
234 45 Melatonin
0.0033% hair solution, which was applied to the scalp 61.6% at baseline to 7.8% after 3 months, while the pro-
each evening by 35 men (aged 18–41 years) with Stage I portion with negative hair pull tests (no hair loss) increased
or II AGA (Hamilton/Norwood scale) for 3 months. After from 12.2% to 61.5%. Interestingly, only this inexpensive,
3 and 6 months in 54.8% to 58.1% of the patients, a sig- non-specific, non-sensitive, semi-invasive technique with
nificant increase in hair density of 29% and 41%, respec- important limitations and demerits [59, 73] was used to
tively, were measured. The increase in the hair count was evaluate the efficacy of the treatment instead of an objec-
29.2% (3 months vs. 0 month) and 42.7% (6 months vs. tive, measurable, reproducible, sensitive, and controlled
0 month); both values were statistically significant method that could provide detailed information, statistics,
(p < 0.001) (Month 0: 85.76 ± 27.0; Month 3: and data [74]. Since this technique has never been used in
110.82 ± 31.7; Month 6: 122.35 ± 40.5). Concerning hair clinical trials on any other compound, it is impossible to
density, increase of 29.1% and 40.9% was determined compare results with FDA-approved or other compounds.
after 3 and 6 months, respectively (Month 0: 123.15 ± 39.0;
Month 3: 159.03 ± 46.8; Month 6: 173.56 ± 58). The dif- These industrially sponsored, privately conducted, uncon-
ferences among the hair density values were also signifi- trolled, and poorly designed studies should be compared
cant (p < 0.001). Once again, including males with Stage them to the methodology and objective results of trials on
I or stage II AGA in Hamilton/Norwood scale is a ques- FDA-approved drugs Minoxidil and Finasteride.
tionable practice. On top of that, FDA-approved Additionally, considering that the reported results of these
compounds Minoxidil and Finasteride have reported
studies were impressively superior to Minoxidil and
much lower efficacy than these results: MTS 5% treat- Finasteride’s results, leaves no room for further scrutiny.
ment twice daily for 48 weeks [71] resulted in 18.6 new In 2017, Nichols et al. [55] conducted an open-label, pro-
terminal hairs/cm2 whereas during the Phase III, 1-year spective, proof-of-concept 24-week long study on six
long, double-blind, placebo-controlled, randomized, mul- females with FPHL and four males with AGA, aged 35–62.
ticenter trials testing the efficacy of Finasteride on the They investigated the efficacy and safety of the oral supple-
crown of 1553 men, aged 18–41 with mild to moderate ment Forti5® (produced by Q-SkinScience®, Miami, Florida),
AGA, no more than 20.9 new terminal hairs/cm2 were containing cholecalciferol, omega 3 and 6 fatty acids, mela-
measured [72]. tonin, antioxidants, and botanical 5-α Reductase inhibitors).
• MEL-COS-AS04 [67]: This open-label observational Efficacy was evaluated using hair-mass-index, measured by
(quoting) “non-FDA-related” cosmetic study was con- a cross-section trichometer, whereas the terminal hair count
ducted at four hair salons in Tampa, FL, USA, included was measured with dermoscopy and Investigator Global
40 male and 20 female patients (mean age 41 years) with Photography Assessment. Eighty percent of subjects (8/10)
early-stage hair loss or hair-thinning, who applied the were rated as improved after 24 weeks of supplementation.
melatonin 0.0033% hair solution each evening for Overall there was a significant improvement in terminal hair
90 days. Based on a 4-point scale, the hairstylists reported count (mean increase of 5.9% or 4.2 more terminal hairs in
an improvement in hair texture and identified a reduction the area examined, p = 0.014) and in HMI (mean increase of
in hair loss, both statistically significant among both 9.5% or 4.5 higher HMI, p = 0.003). Even though the
women and men. Mean hair loss, as determined by the employed assessment techniques generally offer high speci-
patients during a timed 60-second hair count test per- ficity and sensitivity results, there were several methodologi-
formed while combing their hair each morning, a signifi- cal flaws: there was no placebo group, the number of subjects
cant reduction in hair loss was observed by hairstylists in was very small, results on male and female patients were not
the hair salons in women, while hair loss in men remained presented separately. Dr. Martin Zaiac, the senior author in
constant (p < 0.001). Scientific scrutiny of the reported is the article, is a shareholder in Q-SkinScience® and declared
meaningless. However, the methodology of the study is conflicts of interest.
quite original, namely, recruiting hairstylists to assess the Beyond the academically exciting actions of melatonin on
hair texture and the reduction in hair loss in clients. hair follicles, the actual clinical results are not at all encour-
• MEL-COS-AS05 [68]: A large, open-label, multicenter aging. Blumeyer et al. [75] in their systematic review
study was carried out at 200 dermatology centers and (Evidence-based (S3) guideline for the treatment of androge-
included 901 men (47.6%) at stage I or II AGA (Hamilton netic alopecia in women and in men, 2011) issued for the
scale) and 990 women (52.4%) with stage I or II FPHL European Dermatology Forum, considered that the trails of
(Ludwig scale). All subjects applied a cosmetic hair solu- Fischer et al. [55] did not fulfill the inclusion criteria of the
tion containing melatonin each evening for 90 days. guideline and did not comment on it. In the more recent
Clinical response was evaluated based on hair pull tests, (2018) update of this S3 guideline, Kanti et al. included the
and authors reported that the proportion of patients with Fischer et al. trial, which was attributed a level of evidence 4
two- and three-fold positive hair pull tests dropped from and grade of evidence C [76].
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2004;17(4):190–4. 74. Blume-Peytavi U, Blumeyer A, Tosti A, Finner A, Marmol V,
54. Fischer TW, Burmeister G, Schmidt HW, Elsner P. Melatonin Trakatelli M, Reygagne P, Messenger A, European Consensus
increases anagen hair rate in women with androgenetic alopecia or Group. S1 guideline for diagnostic evaluation in androge-
diffuse alopecia: results of a pilot randomized controlled trial. Br J netic alopecia in men, women and adolescents. Br J Dermatol.
Dermatol. 2004;150(2):341–5. 2011;164(1):5–15.
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Spuls PI, Trakatelli M, Finner A, Kiesewetter F, Trüeb R, Rzany B, A, Trakatelli M, Tosti A, Del Marmol V, Piraccini BM, Nast A,
Blume-Peytavi U, European Dermatology Forum (EDF). Evidence- Blume-Peytavi U. Evidence-based (S3) guideline for the treatment
based (S3) guideline for the treatment of androgenetic alopecia in of androgenetic alopecia in women and in men – short version. J
women and in men. J Dtsch Dermatol Ges. 2011;9(Suppl 6):S1–57. Eur Acad Dermatol Venereol. 2018;32(1):11–22.
Marine Extract Compounds
46
Even though these studies claim unprecedented results

Basic Concepts and zero adverse effects, most have never been published,
• Products based on marine extract compounds have not even in pay-per-page journals. Nevertheless, these
been advertised for decades as anti-aging skin treat- unpublished, private studies are cited in the marketing mate-
ments and hair growth agents. rial of companies manufacturing these products, who inform
• All these products seem to originate from physicians and the public with their impressive results, creat-
Scandinavian countries, claim to have impressive ing for themselves “scientific credibility.”
hair growth efficacy, but early “scientific” studies of Therefore, the author needs to ask the readers to appreci-
seemingly competing products share, more or less, ate the entertaining value the claims in the reviewed articles.
a very limited number of authors. Some of these The reader is asked to excuse the extensive quoting in this
authors have been accused of manufacturing results chapter. It is the only way to propagate the exact language,
and forging credentials, and all studies are pub- claims, and mentality of the authors.
lished in the same pay-per-page journals instead of
peer-reviewed ones.
• Latest research on these products seems to be more
authentic and focuses almost exclusively in female Finally, it shall be clarified that this present chapter
diffuse hair loss, still claiming excellent to incredi- does not suggest the use or non-use of the products
ble results but minimal effects in AGA/FPHL. mentioned herewith and focuses on presenting, in a
critical way, the studies on such products and their
respective flaws.
Marine extract compounds are products that have appeared

in the scientific literature since the early 1990s. Even though
their ingredients are not fully disclosed and are allegedly 46.1 Nourkrin®
based on patented, “secret” formulas, they share too many
similarities. Some of these similarities are the similar design Nourkrin® (Pharma Medico International, Aarhus,
of the published studies, the unknown -but speculated- Denmark) is a product containing a proprietary marine-
mechanism of action, and that almost all studies are pub- based extract ingredient, exclusive to Nourkrin® products,
lished exclusively on the same pay-per-page journal. Another called Marilex®. Other ingredients include acerola cherry
similarity these products share is having designated authors extract, silica, horsetail extract, vitamins, trace elements,
who publish studies that look solid to the inexperienced and immunoglobulins. Initially, this product was reported
reader but actually suffer from severe limitations, conflicts of to protect the skin and support its (quoting) “repair pro-
interest, and flaws. Most importantly, these products claimed cesses” [1].
to be impressively efficacious, with the authors typically Concerning the hair growth potential of the product, there
reporting results two to threefold superior to FDA-approved is a single study published in “The Journal of International
compounds, 5% Minoxidil topical solution (MTS), and Medical Research” on the effects and tolerability of
Finasteride 1 mg. Notably, claims of (quoting) “complete Nourkrin® authored by Erling Thom [2], in which he claimed
cure” of AGA, FPHL, alopecia Areata, even of alopecia that (quoting): “Nourkrin® is intended to supply the hair fol-
Universalis are boldly reported in several of these articles. licles with nutrients that are important for the growth and
240 46 Marine Extract Compounds
quality of the hair. The product’s active ingredients are meant What is even more impressive is that the reported results
to nourish the follicles and ‘awaken’ the dormant hair folli- were approximately two- to three-fold superior to the offi-
cles, thereby stopping hair loss, stimulating regrowth of new cially published results of 5% Minoxidil topical solution
hair, and strengthening the existing hair. The mechanism of (MTS) and Finasteride 1 mg. Since the added surface of all
action of Nourkrin® is not known, but it might be related to four areas was 25 cm2, and the mean increase in hair count
the production of dihydrotestosterone in the hair follicle.” was 1064 hairs, this would equate to an increase of 42.56
Even though this phrase seems very inappropriate for a sci- new hairs/cm2 in the active group. For comparison, during
entific publication, the authors allegedly conducted a ran- Phase III trials, 5% MTS treatment b.i.d. for 48 weeks [3,
domized, double-blind, placebo-controlled study with two 4] resulted in 18.6 new terminal hairs/cm2, whereas during
arms, followed by an open phase on active treatment. The the Phase III, 1-year long, double-blind, placebo-con-
trial included 51 male subjects and 4 females with hair loss trolled, randomized, multicenter trials testing the efficacy
of different etiologies, without discerning how many sub- of finasteride on the crown on 1553 men, aged 18–41 with
jects suffered from AGA and FPHL. The subjects were first mild to moderate AGA, 20.9 new terminal hairs/cm2 were
randomized to receive either two capsules per day of measured [5].
Nourkrin® for subjects below 80 kg in body weight and three
capsules per day for those above this weight or placebo dur-
ing the study’s blinded phase, which lasted 6 months. In the This study by was published in “Τhe Journal of
open phase, participants who had been taking Nourkrin® dur- International Medical Research.” This journal has an
ing the blinded phase continued with the treatment for a fur- undeniably attractive and scientific-sounding title. Of
ther 6 months, and participants who had been in the placebo course, their landing webpage explains: “The Journal
group during the blinded phase were switched to Nourkrin® of International Medical Research is a leading interna-
for 12 months. The mean total hair counts in four predefined tional journal for rapid publication of original medical,
areas were investigated: Vertex, forehead, and the area sur- pre-clinical and clinical research, reviews, preliminary
rounding the ear on both sides of the head, each area being and pilot studies on a page charge basis” [6].
6.25 cm2. According to the author, the average total hair
counts increased from 2980 hairs to 4044 hairs in 6 months
of Nourkrin® treatment (+35.7%) vs. 2735 hairs to 2776
hairs (+1.5%) in 6 months of placebo administration Therefore, since “Τhe Journal of International Medical
(p < 0.001). At 6 months, there was a highly significant dif- Research” is not peer-reviewed and almost any scientist can
ference between the groups in the self-evaluation score in publish as long as the page fee is honored- that leaves plenty
favor of the Nourkrin® treatment group (p < 0.001). There of room for doubt on the scientific value and credibility on
was also a significant increase in the visual analog scale any study published there. Notably, no conflicts of interest
score after a treatment period of 6 months (p < 0.01). The were declared in relation to this article by Erling Thom.
score also improved significantly from 6 to 12 months Notably, most of his publications have been hosted in this
(p < 0.05), and tolerability was excellent, with no reports of journal. Even more interesting is that most articles authored
adverse effects. by Erling Thom are very similarly designed, randomized,
However, a closer look at the methodology of the study placebo-controlled, double-blind studies on alternative, nat-
reveals serious methodological flaws. There is no report on ural products on hair growth, weight loss, and wrinkle-
whether these new hairs were vellus or terminal. Since vellus reduction, all claiming “miraculous” efficacy and no adverse
hairs have no actual cosmetic value, the increased number of effects whatsoever [7–13].
hairs does not translate to an actual cosmetic improvement. Interestingly, in 2016, a very extensive article on Dr.
The size of the predefined areas was too large and prone to Erling Thom was published in www.forskning.no, an Oslo-
significant counting errors since the only scientific tools that based online newspaper established by “The Research
were used in the study were a magnifying glass and a lamp. Council of Norway,” which is a non-profit organization with
Imagine how challenging it would be for the patient to stand 65 research institutions as members. This extensive and
still and for the examiner to manually measure every single detailed article was based on an investigation by journalists
hair in four areas of 6.25 cm2 surface each, which would add of www.forskning.no. Dr. Erling Thom’s name is included in
to approximately 4000 hairs for each patient under active a list of researchers who have conducted studies and present
treatment. Anyone who has tried to measure total hair counts themselves as having impressive academic titles and affilia-
understands how unlikely this task is, even with modern skin tions to research institutions that they do not have. Reports of
scanning equipment. Additionally, there were no before-and- dubious academic credentials, of too suspicious similarities
after photos of patients in the article and no independent or in results between different studies, on publishing exclu-
blinded researchers to evaluate the claimed results. sively in pay-per-publish journals, and not disclosing con-
46.3 Viviscal® 241
flicts of interest are only some of the credibility issues that

cebo for the initial 6 months, whose hair growth improved by
were revealed during this investigation [14]. 60.8% after 12 months of active treatment, a highly signifi-
In 2017, Erling Thom published a review on the etiology cant improvement (p < 0.001). The subjects were also asked
and management of postpartum effluvium, actually criticiz- at each visit to score their satisfaction with the treatment on a
ing earlier studies on the subject (quoting): “All the available
10-cm visual analogue scale (VAS) ranging from 0 (not at all
studies have significant limitations in their scientific basis,
satisfied) to 10 (very satisfied). After 6 months, the mean VAS
such as small sample size, absence of control group, or score of the treated group (5.7) was significantly higher than
highly subjective measurement of treatment response. that of the placebo group (0.9) (p < 0.001), whereas, at
Therefore, a clinically proven, anagen-inducing supplement 12 months, the mean VAS score of the treated group climbed
classified as a proteoglycan replacement therapy (Nourkrin® to 7.9. The author claimed that the exact mechanism of action
with Marilex® from Pharma Medico) seems to be an effec- of the product was unknown, and (quoting) “we do not know
tive and targeted treatment option in this regard.” Interestingly,
what will happen when the treatment is stopped. It may be
these limitations are precisely the same ones found in his necessary to continue with maintenance treatment at a lower
earlier study [2]. According to Erling Thom, the solution to dose.” The reported tolerability was excellent, with no reports
postpartum effluvium is the product he endorses in his study, of adverse effects whatsoever.
without disclosing any conflicts of interest [15], even though The article does not include any before-and-after photos
he is prominently included in the “Nourkrin® Expert’s Panel” or details regarding the number, type, color, and weight of
on the product’s website [16]. hair, there is no conflict of interest disclosed by the author,
and the results were so impressive that the author stated
(quoting): “The results obtained in the present study com-
46.2 Hairgain ®
pare favorably with the results obtained in studies with drugs.
In a study with Finasteride in 1533 men, the increase in the
Erling Thom has authored an earlier study, also published in number of hairs was reported to be 11% compared with a
“Τhe Journal of International Medical Research,” investigat- 2.5% decrease in the placebo group.” He even cited the rele-
ing containing another marine-protein product [8], Hairgain® vant articles [17, 18]. The statement “compares favorably”
(Parexel Medstat AS, Lillestrøm, Norway), which is a food seems like an understatement, since the -reported- average
supplement from Norway. improvement of hair growth with Hairgain® was 63.9% vs.
This study was once again a placebo-controlled, double- 11% of finasteride 1 mg. However, no other research team
blind, randomized study investigating the efficacy and toler- has ever studied this product ever since to replicate the
ability of Hairgain®. The product contained (quoting) “… results.
minerals and vitamins in addition to a marine protein extract
from a deep-sea fish living along the Norwegian coastline”
on 60 volunteers, 28 males and 2 females in the active group 46.3 Viviscal®
and 27 males and 3 females in the placebo group. Most vol-
unteers suffered from AGA or FPHL (56 and 60, respec- A third oral compound against hair loss, consisting of pro-
tively), while four subjects had alopecia totalis (AT). The teins and glycosaminoglycans of marine origin, is Viviscal®.
dosage scheme was 2 capsules/day for subjects below 80 kg Viviscal® contains proprietary AminoMar C™ marine com-
in body weight and 3 capsules/day for those above this plex, shark, and mollusk powder derived from sustainable
weight, a posology which strongly reminds Nourkrin® stud- marine sources, an organic form of silica derived from
ies, even though Hairgain® was supposedly a competing Equisetum sp. (horsetail), and vitamin C derived from
product. The subjects receiving active treatment in the Malpighia emarginata (acerola cherry) stearate.
blinded phase (6 months) were followed for another 6 months Initial researchers that authored publications on this spe-
in an open study on active treatment. Participants receiving cific product were Lassus A. and Eskelinen E., and their
placebo in the blinded phase were followed for an additional studies on the effects of Viviscal® on skin and hair date back
12 months on active treatment. All subjects were thus to 1992. The first study on Viviscal®, was published in “The
exposed to the active treatment for 12 months. Journal of International Medical Research” and was also a
Hair counting based on close-up pictures (none included controlled, randomized, double-blind study with parallel
in the article) showed a significant average increase in hair groups [19]. This study evaluated the efficacy and tolerabil-
growth of 32.4% during the blinded phase in the active group, ity of Viviscal® in 40 randomized young men with AGA,
whereas only 0.9% increase was reported in the placebo with a mean age of 25.1 ± 2.9, at stages AGA II-V, in the
group. The study’s extension to 12 months resulted in an Norwood-Hamilton scale. The study included 20 subjects
average improvement of hair growth by 63.9% for the active who received two tablets of Viviscal® once daily and 20 sub-
group. A similar effect was seen in the group exposed to pla- jects who received two tablets of a fish extract once daily,
both for 6 months. The comparison with the fish extract was both lotion and shampoo containing 1% of the same active
decided since the fish extract product has been reported pre- ingredients as the tablets. According to the authors, after
viously to improve hair growth in women treated for photo- 2 months of treatment, hair loss had halted in all subjects.
aged skin [20, 21]. Out of the 40 randomized males, 37 were Before the study, the mean area of baldness of the total scalp
evaluable after 6 months, 20 in the Viviscal® treatment group was 39% (11–52%), and at the end of the treatment period, it
and 17 in the fish extract group. A template with a 2.5 cm had dropped to a mean 9% (4–25%). Thirteen patients showed
diameter hole was centered over the posterior vertex, and 100% regrowth (43%), seven showed >75% regrowth (23%),
non-vellus hairs within the hole (total area 7.9 cm2) were four showed 50–75% regrowth (13%), another four showed
counted with the aid of magnification and bright illumina- 30–50% regrowth, and two (7%) patients had no regrowth.
tion. Additionally, 5 mm punch biopsies were taken at base- The mechanism by which Viviscal® stimulated regrowth of
line, and the end of the study, 6 months later. hair was again reported as unclear; however, the authors
The authors reported an increase of 38.1% (+472 new stated that weight-dependent dosing of the oral treatment and
hairs) in hair growth in the Viviscal® group and only 2.1% the combination with topical treatment is the most efficient
(+17 new hairs) in the fish extract group. The authors claimed mode of using Viviscal® [22]. It includes a pair of very poor
(quoting): “With 19 of the 20 patients being completely cured quality, before-and-after photos of the vertex of a 40-year old
as shown by non-vellus hair count and histological examina- man before and after treatment showing some hair growth.
tion.” This study was received for publication at the “Τhe Since then, other studies of the same research group have
Journal of International Medical Research” on August 20th, also reported on the impressive efficacy of Viviscal® against
1992, was accepted on August 26th, 1992, and published on alopecia areata (AA) and even against alopecia totalis (AT),
November 20th, 1992, fully adhering to the journal’s commit- but neither these studies are indexed in Pubmed. However, at
ment for “rapid publication on a page charge basis.” least one of these studies was submitted for publication in
“The Journal of American Academy of Dermatology,” and
was rejected [23]. The results of Lassus A and Eskelinen E
[23]. on the effects of Viviscal® on 20 patients with AA
Such a swift publication-process would probably not
(mean duration of disease 9 years, 10 females and 10 males)
occur in a peer-review journal, considering that curing
and 20 patients with AT (mean duration of disease 7 years,
AGA claims in 19 of 20 patients are no less than mirac-
10 females and 10 males) who were treated with 2 pills of
ulous since a claim like this has never been reported in
Viviscal® liniment once daily and Viviscal® shampoo 2–3
the scientific literature [6].
times/week for 8 months were the following:
• Seventeen patients with AA (85%) were (quoting) “com-

Once again, no adverse effects were reported by the pletely cured,” and two (10%) showed significant
researchers or patients. The article includes a pair of suppos- improvement. Only one of the patients in this group dete-
edly before-and-after photos of histology specimens show- riorated during the treatment period,
ing a section of completely bald skin and a section of hairy • Five (25%) patients with AT were (quoting) “completely
skin, claiming that bald skin became hairy. It also includes a cured,” and four (20%) showed significant improvement,
pair of close-up, very poor quality, before-and-after photos while 11 patients developed only minimal vellus hair.
of scalp skin with long, overlapping hair. There is no tattoo,
the hair is not cut, the size of the area is not disclosed, and the
numbers of hair in each area are not presented. The only dif-
According to these results, Viviscal® products could
ference is that hair in the first photo is parted, and in the
cure much more than just AGA and FPHL; they could
second photo, it overlaps, appearing slightly denser.
also incite full and permanent hair regrowth in up to
A following, 8-month long, open-label, single-arm, private
95% of AA patients.
study which is not indexed in Pubmed (and can be found only
in the manufacturer’s website) was conducted by the same
authors, reporting even more impressive results. The study
included 30 middle-aged men (34–48 years old) with mild to The study’s methodology flaws were that no placebo
moderate AGA (stages Norwood-Hamilton ΙΙ-IV) who were group was included since AA has a high and unpredictable
administered an oral dose of Viviscal® (2 tablets daily if spontaneous remission rate [24] and that no photos and no
<80 kg and 3 tablets daily if >80 kg, a similar posology to the other objective data on these unprecedented results have
other two competing products). Also, a Viviscal® lotion was been used or presented.
rubbed onto the bald areas every evening, and a Viviscal® Majass et al. [25] took it even further and in 1996 con-
shampoo was used for hair washing 2–3 times/week, with ducted a study (also unpublished) in collaboration with the
46.3 Viviscal® 243
Swedish Alopecia Society, a “society” actually consisting of ies. In all these trials, besides one, women with temporary
patients with AA. They investigated the effects of oral hair loss were enrolled, and cases of FPHL were excluded.
Viviscal® for 12 months on 84 volunteers of the society, Most of these studies are irrelevant to the effects of Viviscal®
themselves suffering from AA (n = 50), AT (n = 12), and on AGA/FPHL, but since most physicians do treat patients
Alopecia Universalis (AU) (n = 22). In the AA group, the with diffuse hair loss, they are still interesting. Another rea-
average time until signs of regrowth of permanent hair was son to present the exact methodology and the results of these
evident was 6 months, in the AT group (10 patients) was studies is to reveal the limitations, flaws, and claims that can
4 months, and in the AU group (7 patients) it was 5 months. seem reliable to the “inexperienced” reader of hair growth
A (quoting) “complete cure” was reported in 7 AA patients studies but not to the experienced one.
(14%), in three AT patients (25%), and one (5%) AU patient. The earliest study (2012) authored by Glynis Ablon [29]
An “excellent result” was obtained in 54% of the patients was a small-size, randomized, double-blind, placebo-
with AA, in 32% of AT patients and 23% of AU patients. controlled study testing the hair growth effects of the twice-
Treatment failure (poor regrowth of scalp hair) was reported daily administration of Viviscal® maximum strength
by 12% of AA patients, 24% of AT patients, and 72% of AU (Lifes2good, Inc., Chicago, IL) compared to placebo. Fifteen
patients. So, according to these results, Viviscal® products women, 21–75 years of age, with self-perceived thinning
could cure approximately 30% of Alopecia Universalis hair, associated with poor diet, stress, hormonal influences,
patients as early as 1996. or abnormal menstrual cycles were investigated over 6
In 1997, Jose Marcos Pereira et al. published in a Brazilian months.
journal a private, 6-month long, open-label, single-arm study,
including 200 male AGA patients aged between 17 and 45
who were treated twice a day with a 300 mg tablet of
True alopecia cases, as the author called them, includ-
Viviscal®. The authors reported that even though hair density
ing AA, scarring alopecia, FPHL, and telogen efflu-
did not increase, 75.3% of patients observed a significant
vium, were excluded.
decrease in hair loss, and 14.6% showed partial hair regrowth.
The authors reported that less severe cases, independently of
the duration of hair loss and age of the patients, had signifi-
cantly superior results as compared to patients with long- Subjects were randomized to receive the active medica-
term, severe baldness [26]. This study was the first one tion (n = 10) or placebo (n = 5), and the investigator selected
reporting modest and plausible results; however, still favor- a 4 cm2 area of the scalp along the frontalis bone at the junc-
ing the use of the tested product without providing pictures tion of the frontal and lateral hairlines. According to the
or using any objective measurement techniques. reported results, at baseline, the mean number of terminal
Summarizing these studies, Lassus A. and Eskelinen E. hairs among placebo-treated subjects was 256.0 and
published astounding results on the effects of Viviscal® in remained at 245.0 and 242.2 after 90 and 180 days, respec-
AGA, FPHL, AA, and AT, whereas two more researchers tively. In the active group, the mean number of terminal hairs
published impressive efficacy in AGA and even on AU. It is was 271.0 at baseline, increased to 571.0, and reached 609.6
noteworthy that almost all articles authored by Lassus A. and after 90 and 180 days, respectively. This was an impressive
Eskelinen E. spanning their whole careers have been pub- +125% increase at the end of 6 months (for each, p < 0.001
lished in the “Τhe Journal of International Medical Research,” vs. placebo). Self-perceived improvements after 90 days
investigating exclusively “miraculous,” polysaccharide were further increased after 180 days of additional treatment.
marine product against hair loss or aging skin [27, 28]. The author included digital photos of non-permanently
marked selected areas, marked with a black thick-tip skin
marker instead of a permanent tattoo, most of them blurry,
46.3.1 Viviscal® in the Twenty-First Century and all photos with overlapping long hairs. The small num-
ber of subjects, the arbitrary etiology of hair loss in the inclu-
For almost 15 years, no other studies on this product were sion criteria, an undisclosed technique of measuring the
published. Suddenly, in 2012, the legacy of Lassus A. And number of hairs (hopefully not the low-quality photos, of
Eskelinen E. was taken over by Glynis Ablon, MD, FAAD of non-permanently marked areas, with overlapping hairs) are
Ablon Skin Institute Research Center. He published several some of the numerous limitations of the study that render the
studies, and submitted them simultaneously (all in November already overly optimistic result of +125% increase in hair
2014) in ClinicalTrials.gov. All trails were funded by grants counts even more questionable. However, the author reported
from Lifes2good, Inc., Chicago, IL, the new manufacturers that (quoting): “These results may represent the first descrip-
of Viviscal®. Glynis Ablon disclosed that he received a tion of increased hair growth in women associated with the
research grant from Lifes2good, Inc. for most of these stud- use of a nutritional supplement.” At many points in the arti-
cle, he referred to this proprietary nutritional supplement as challenging it is to treat long-standing diffuse hair loss in
(quoting) “the new drug,” and he informed readers that otherwise healthy women, this +80%, seems extremely
“additional clinical studies designed to further assess the use unlikely.
of Viviscal® to increase hair thickness and hair counts using The same author published another, shorter this time,
larger patient populations are currently underway.” 3-month long, randomized, double-blind, placebo-controlled
Keeping his promise, Ablon et al. published in 2015 a ran- study, evaluating the ability of another Viviscal® product
domized, double-blind, placebo-controlled, multicenter (two (Viviscal® Extra Strength) to promote hair growth and
private centers), extension trial, evaluating the efficacy of a decrease shedding in women with self-perceived thinning
twice-daily administration of a new oral supplement (New hair (ClinicalTrials.gov identifier: NCT02297360, first
Viviscal® Professional Strength Oral Tablets). This product received: November 18, 2014). Once again, true alopecia
was also tested in women with self-perceived thinning hair cases and FPHL cases were excluded [32]. Subjects were
associated with poor diet, stress, hormonal influences, or randomized to receive treatment with the active product
abnormal menstrual cycles. Once again, (quoting) “true alo- (n = 30) or placebo (n = 30), and all other methodological
pecia cases were excluded” (ClinicalTrials.gov identifier: parameters, including the low-resolution digital camera,
NCT02302053, first received: November 24, 2014) [30]. were identical to the previous studies. The mean terminal
Thirty-six female subjects, aged 25–66, completed the hair count increased from 178.3 to 235.8 in the active group
6-month long study (n = 17 in the active group, n = 19 in the while it remained unchanged in the placebo group (178.2–
placebo group. The only difference from the previous study’s 180.9) after 3 months. The increase in the number of termi-
protocol was that 10 terminal hairs in the target area were nal hairs in the active group represented a +32.5% increase at
randomly chosen and cut at the surface of the scalp at base- the end of 3 months, a much more plausible (yet still impres-
line visit and in 90 and 180 days, to measure changes in hair sive by clinical standards) result compared to the previous
diameter. The secondary endpoints were changes in terminal reports (+125% and +80%). The active-treated subjects also
hair diameter and responses to Quality of Life and Self- had a significant decrease in the mean numbers of shed hairs
Assessment Questionnaires. Mean terminal hair counts from 27.1 at baseline to 16.5 at day 90 vs. 23.4 at baseline for
reported were 189.88 at baseline, 297.35 at 90 days, and placebo-treated subjects and 21.9 at day 90. Strangely, in
341.00 at 180 days in the treatment group (p < 0.0001) and contrast to the high expectations set by previous publications
190.26, 189.21, and 192.68 for the placebo group, respec- on these products, the mean hair diameter did not increase in
tively. The increase in the number of terminal hairs in the any group. However, the author reported improved hair qual-
active group represented an 80% increase at the end of ity, including overall hair growth and increased hair strength.
6 months. The mean number of vellus hairs increased as well Later in 2015, Ablon was the senior author in another
as the hair diameter from 0.060 to 0.067 (p = 0.006) in the double-blind, placebo-controlled clinical study involving
active group and did not change in the placebo group. female subjects with self-perceived thinning hair associated
with poor diet, stress, lifestyle, while “true alopecia cases”
were again excluded (ClinicalTrials.gov identifier:
Some macro-photographs of the target area are pre- NCT02288858, first received: November 7, 2014) [33]. A
sented in the article, but all photos have overlapping contract research organization conducted the study (Thomas
long hairs, and most photos are blurry. The researchers J. Stephens and Associates, Inc., TX, USA) with board certi-
used a 4 megapixels camera, even though in 2015, fied dermatologists as study investigators at two sites
cameras with a resolution up to 20.7 megapixels were (Carrollton, TX, USA, and Colorado Springs, CO, USA).
available on cellphones [31]. Ninety-six females, 21–55 years of age enrolled, and 71
completed the study, 36 subjects in the active group and
35 in the placebo group. The study investigated the impact
on hair shedding rate and hair fiber diameter, assessed by
Among the 13 items in the self-assessment questionnaire, phototrichogram. In this study, a small tattoo dot was applied
there were significant improvements in five areas, reporting to a target 1 cm2 area of the scalp, which was shaved to 1 mm
improvement in feelings of embarrassment, self-esteem, in length and dyed black for measurements. Results from
self-consciousness, and attractiveness. The authors con- shed hair count analysis indicated that hair shedding was
cluded that (quoting) “this new oral supplement increased reduced in the active group, from 52 shed hairs at baseline to
both hair density and hair diameter and improved the quality 43 hairs at 3 months. This finding was statistically significant
of life in women with self-perceived hair loss.” the limita- only when compared to the increased shedding of the pla-
tions of this study are similar to those of the previous study. cebo group at 3 months (46 at baseline to 70 shed hairs at
The reported increase in the number of hairs in the target 3 months) but not anymore at 6 months, where the active
area was +80%. To those clinicians who are aware of how groups were losing 43 hairs, and the placebo groups were
46.3 Viviscal® 245
losing 49 hairs. Additionally, an 8% increase in mean vellus- However, even though macrophotographs of two subjects
like hair diameter after 6 months was reported, which, even with the highest response in the active group are provided in
though small in magnitude, it attained a statistical signifi- the article, results are cosmetically minimal. Trichoscan®
cance (p = 0.02), whereas an opposite trend was observed in images provided in the article have not been tattooed at the
placebo-treated individuals both at month 3 and 6. According start of the study in order to prove that the same area is
to the authors (quote) “overall, >60% of subjects’ vellus-like depicted and compared. Nevertheless, the authors consid-
hairs got a bit thicker after using the oral supplement, ered that the study demonstrated significant improvements in
whereas about 60% of subjects’ vellus-like hairs were finer hair growth and total hair count, and several quality of life
after using the placebo.” Overall, the authors reported that measures.
those taking the oral supplement exhibited a statistically sig- Summarizing the results of these studies, they share the
nificant favorable change in their overall hair volume at same limitations, the same flaws, and weaknesses.
6 months (p < 0.007) compared to placebo (p = 0.238). Clinicaltrials.gov allegedly received all these trials in
However, these results are statistically marginally signifi- November 2014, and according to the website, on the results
cant, and even then, they are irrelevant since the “thickening” page of each study, the message “No Study Results Posted
of vellus hairs, that still remain vellus hairs, does not add to on ClinicalTrials.gov for this Study” appears. Interestingly,
the cosmetic coverage of the scalp. The only photos in the from 2012 to 2016, the efficacy reported dropped from the
article are before-and-after photothrichogram ones, which remarkable +125%, to +80%, then to +35%, and ended-up in
do not even include the tattoo to demonstrated that the same +7.5%, which was a hardly statistically significant increase
area is depicted and compared. in hair counts.
Carl S. Hornfeldt, Ph.D., has authored two reviews of all
the studies mentioned above on Viviscal®. He published in
2015 the results of a panel discussion [35] and a summary of
This is the first study that includes third-party, inde-
research on Viviscal® published in 2017, presenting all the
pendent investigators, and the results are extremely
results and none of the flaws and limitations that most prob-
less favorable than previous reports and marginally
ably nullify these studies [36]. Interestingly, Carl
positive.
S. Hornfeldt, Ph.D. works for Apothekon, Inc., which is
(quoting) “…an independent medical writing service spe-
cializing in the pharmaceutical, medical device, and allied
The latest study on Viviscal®, once again by Glynis Ablon, industries.”
MD, is a 6-month, randomized, double-blind, placebo-
controlled study evaluating the ability of yet another Synopsis
Viviscal® product, Viviscal® man. This is a reformulated Products based on marine extract compounds have been
product for use by men [34]. Sixty healthy males with a available for decades and are accompanied by enthusiastic
mean age of 44.5 years and with mild AGA (stages Norwood- online patient testimonials and weighty expert opinions on
Hamilton ΙΙ-III) were randomized into two groups of 30 their efficacy. They are “supported” by published studies that
subjects each and instructed to take two tablets of their the inexperienced eye will not easily discern that are of very
assigned treatment every day for 180 days (ClinicalTrials. low quality and hardly believable. Most studies on these
gov identifier: NCT02302053, first received: November 24, products, even on seemingly competing products, are
2014). This was the first Viviscal® study that high-quality authored by the same researchers with dubious credentials
macro-photographs with standardized lighting were and no further scientific work, have identical “methodology
obtained, and computerized trichogram images with designs” and similar, and always impressive, results on hair
TrichoScan® were taken. The objective, automated measure- growth. Most importantly, though, all studies are published
ments of Trichoscan®, showed an impressively more modest in the same pay-per-page journal. These early studies claimed
response to treatment compared to previous efficacy reports. efficacy that is two to threefold superior to oral finasteride
Even though still statistically significant, according to the 1 mg for men with AGA and Minoxidil 2% in women with
authors, total hair count with the active product increased FPHL. These incredible -claimed- results have naturally
from 162.2 to 169.08 and reached 174.89 from baseline in sparked the interest of physicians and the public, scoring
90 days and 180 days respectively (7.5% increase in hair impressive sales worldwide. However, the latest studies,
counts this time), compared to non-significant results in the published in peer-reviewed journals, report very modest to
placebo group (152.2, 151.33, and 146.92, baseline, 90 days statistically insignificant results in AGA or FPHL patients.
and 180 days respectively). Subjects indicated a significant These products seem to be helpful only in diffuse alopecia
overall improvement in quality of life at days 90 and 180 and cases in women, associated with poor diet, stress, hormonal
substantial improvement in overall satisfaction at day 180. influences, or abnormal menstrual cycles. However, even
these studies are not well-designed and are subject to severe hereditary androgenic alopecia in young males. J Int Med Res.
1992;20(6):445–53.
scrutiny on the reported results.
20. Eskelinin A, Santalahti J. Special natural cartilage polysaccharides
for the treatment of sun-damaged skin in females. J Int Med Res.
1992;20(2):99–105.
References 21. Eskelinen A, Santalahti J. Natural cartilage polysaccharides for the
treatment of sun-damaged skin in females: a double-blind compari-
son of Vivida and Imedeen. J Int Med Res. 1992;20(3):227–33.
1. Béguin A. A novel micronutrient supplement in skin aging: a
22. Lassus A, Santalahti J, Sellmann M. Viviscal scientific hair loss
randomized placebo-controlled double-blind study. J Cosmet
product study number 2. Treatment of hereditary androgenic alope-
Dermatol. 2005;4(4):277–84.
cia in middle-aged males by combined oral and topical administra-
2. Nourkrin TE. Objective and subjective effects and tolerability in
tion of special marine extract-compound. Helsinki Research Center
persons with air loss. J Int Med Res. 2006;34(5):514–9.
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3. Price VH, Menefee E, Sanchez M, Ruane P, Kaufman KD. Changes
23. Lassus A, Santalahti J, Sellmann M Treatment of alopecia areata and
in hair weight and hair count in men with androgenetic alopecia
alopecia totalis with viviscal (special marine extract compound).
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Clinic, Leverkusen, Germany; 1993
4. Οlsen EA, Dunlap FE, Funicella T. A randomized clinical trial of
24. Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro
5% topical Minoxidil versus 2% topical Minoxidil and placebo in
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25. Majass M, Puuste O, Prästbacka B, Brorsdotter-Johansson
5. Kaufman KD, Olsen EA, et al. Finasteride in the treatment of men
P. Treatment of Alopecia areata, Alopecia totalis and Alopecia
with androgenetic alopecia. Finasteride Male Pattern Hair Loss
Universalis with Oral Viviscal® for 12 months. Swedish Alopecia
Study Group. J Am Acad Dermatol. 1998;39(4 Pt. 1):578–89.
Society; 1996.
6. http://journals.sagepub.com/home/imr
26. Pereira JM. Treatment of androgenetic alopecia with a marine-
7. Thom E, Wadstein J, Gudmundsen O. Conjugated linoleic acid
based extract of proteins and polysaccharides, vol. 54. Sao Paulo
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8. Thom E. Efficacy and tolerability of hairgain in individuals with
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2000;28(5):229–33.
efficacy of an Oral supplement in women with self-perceived thin-
10. Thom EA. Randomized, double-blind, placebo-controlled study on
ning hair. J Clin Aesthet Dermatol. 2012;5:28–34.
the clinical efficacy of oral treatment with DermaVite on ageing
30. Ablon G, Dayan S. A randomized, double-blind, placebo-
symptoms of the skin. J Int Med Res. 2005;33(3):267–72.
controlled, multi-center, extension trial evaluating the efficacy of a
11. Wadstein J, Thom E. A randomized, placebo-controlled double-
new oral supplement in women with self-perceived thinning hair. J
blind parallel group study in the treatment of aging symptoms
Clin Aesthet Dermatol. 2015;8:15–21.
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against hair growth disruption using Nourkrin(®) with Marilex(®),
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The Helsinki Formula®: Polysorbate 60
and Polysorbate 80 47
• Polysorbate 60 (polyoxyethylene (20) sorbitan

Basic Concepts monostearate)
• Polysorbate 60 is a popular emulsifier used in the • Polysorbate 80 (polyoxyethylene (20) sorbitan
cosmetic industry to solubilize essential oils into monooleate).
water-based products and is also a popular additive
in the food industry. The number following the “polyoxyethylene” part refers to
• In 1974, an uncontrolled, poorly designed clinical the total number of oxyethylene -(CH2CH2O)- groups found
study was published by two Finnish pathologists in the molecule. The number following the “polysorbate”
claiming that Polysorbate 60 had hair growth prop- part is related to the type of fatty acid associated with the
erties. Commercial products based on an extraordi- molecule’s sorbitan part. Monolaurate is indicated by 20,
narily cheap and easy-to-make formula were monopalmitate by 40, monostearate by 60, and monooleate
advertised aggressively, resulting in a hair craze by 80. Accordingly, Polysorbate 60 is an ester of sorbitan
phenomenon that lasted for almost two decades. and stearic acid, and Polysorbate 80 is an ester of sorbitan
• The hair growth potential of Polysorbate 60 was and oleic acid. Both are non-ionic, multi-purpose emulsifi-
later proved to be comparable to placebo and the ers, which enable water and oil to mix, and this effect is
claims of manufacturers that their products could amplified when they are combined with cetyl alcohol or sor-
actually “cure” AGA in 70% of patients were false bitan stearate.
and deceptive. These products became the center of Polysorbate 60 is also a dispersing agent, a thickener, an
a long-drawn-out legal battle with U.S. authorities antistat, a solubilizer, and a stabilizer of essential oils. It is
that ended up in huge fines, withdrawal from the used in the food industry as a foaming agent in beverages to
market, and millions of deceived patients. help chocolate coatings not taste greasy and aids in the
absorption of fat-soluble vitamins in supplements [3]. It is
also used to manufacture synthetic fibers, as a stabilizer for
color materials and emulsion polymerizations, as an emulsi-
Polysorbates are oily liquids deriving from Polyethylene fier for adjuvant of agrochemicals, an emulsifier for water-
glycol and sorbitan (a sorbitol derivative), esterified based metal process cutting oils, surface coating type
with fatty acids. Sorbitan esters, also known as Spans [1] antistatic agents, additive to pesticides, and in various other
or Polysorbates, contain less than 20 moles of ethylene applications. It has been approved in the European Union as
oxide per mole of ester, according to the Food Chemicals a food additive (emulsifier-E491) and is widely used in
Codex (FCC) [2]. Polysorbates are emulsifiers used in lotions, creams, hair loss treatments, skin cleansers, and
the food and pharmaceutical industries and often used in make-up products when emulsification is required. It is one
cosmetics to solubilize essential oils into water-based of the best emulsifiers in the cosmetics industry [4, 5],
products. mainly due to its rheological properties [6] and its chemical
Typical examples of polysorbates are: stability [7].
Since the late 1990s, Polysorbate 60 has been used in sev-
• Polysorbate 20 (polyoxyethylene (20) sorbitan eral medical applications, including the topical application
monolaurate), and controlled release of doxoribucin [8], diclofenac [9],
• Polysorbate 40 (polyoxyethylene (20) sorbitan antigens [10], and imiquimod for the treatment of warts of
monopalmitate), external genital and perianal organs [11], as well as a sub-
248 47 The Helsinki Formula®: Polysorbate 60 and Polysorbate 80
stance in innovative pharmaceutical molecules such as altering the interphase transport of cholesterol, according
organogels [12] and amphiphilogels [13]. Polysorbate 60 has to another unrelated publication [22]. The sebaceous
also been effectively used in emulsifiers used for the intrave- gland is a steroidogenic tissue, capable of synthesizing in
nous administration of heparin [14] and ribavirin [15]. situ steroid hormones de novo from cholesterol, but this
Polysorbate 80 also has numerous applications. It contains was discovered no <27 years later by Thiboutot et al. [23].
oleic acid, which is why it was considered to have a higher In hindsight, Polysorbate 60 might have mildly decreased
hair growth potential than Polysorbate 60, which is possibly both the production of DHT by sebocytes and the reab-
explained by oleic acid’s antiandrogenic potential [16, 17]. sorption of DHT by the hair follicles.
Polysorbate 60 contains stearic acid, which has a mild antian- 2. Polysorbate 60, and later Polysorbate 80, have been
drogenic [18] and COX-2-inhibitory potential [19]. reported to produce hemodynamic responses in humans
and dogs similar to those produced by histamine infusion.
In lab animals, administration of Polysorbate 80 causes
47.1 Polysorbate 60 and Hair Follicles histamine production in mastocytes and increases serum
histamine concentrations [24], which could result in vaso-
The story of Polysorbate 60 as a remedy for hair loss initiated dilation and increased blood flow. Dr. Schreck-Purola ini-
by Dr. Ilona Schreck-Purola, MD, a pathologist assistant in the tially used Polysorbate 60 in her original formula, but
first Internal Medicine Clinic of Helsinki University. Dr. some years later, she switched to Polysorbate 80 because
Schreck-Purola was conducting skin cancer research on mice it (supposedly) worked even better as a hair growth
for her mentor, Dr. Kai Setälä, an esteemed Finnish patholo- promoter.
gist. As Dr. Schreck-Purola has mentioned in several inter-
views, every morning, she would clean the white mice using a However, Dr. Schreck-Purola gave several other, dubious
solution called Polysorbate 60. She noticed that mice seemed explanations in her interviews, such as (quote): “excessive
to be growing more fur after some weeks of cleaning with cholesterol reduces cellular proliferation, cells of the hair fol-
Polysorbate 60. It was an ordinary compound that she knew licle harden or become rigid and cannot grow properly” [25].
derived from corn and was commonly used as an additive in
cleansing solutions and food products, like in salad dressings
and in ice creams as a binder. When she mentioned her seren- Even though the scientific community would never
dipitous findings to Dr. Kai Setälä, himself, as an internation- agree with these proclaimed mechanisms, hair loss
ally acclaimed scientist, he was initially skeptical about doing patients at that pre-Minoxidil times, were desperate for
any further research on the matter. The risk of losing presti- hair regrowth and willing to believe and try anything
gious grant money researching whether a common food addi- on their thinning scalp.
tive was an efficient hair growth agent was just too high.
Nevertheless, Dr. Schreck-Purola and Dr. Setälä (1974)
conducted an uncontrolled study at the University of Helsinki
and published the results. They reported that, out of 110 47.2 Polysorbate 60 and the Hair Growth
males with AGA who were treated with topical Polysorbate Craze
60, 42% showed gross hair growth after 16 weeks [20].
Unfortunately, further details on that study are impossible to For years, the Polysorbate experiment of Dr. Schreck-Purola
trace. In February 1976, Dr. Setälä and Dr. Schreck-Purola went unnoticed until Robert E. Murphy, the—later—founder
published another article on their findings, this time in an of Pacific Research, Inc., “rediscovered” it. He initially pro-
obscure British journal, the Journal of Environmental Studies. duced his own formula since the ingredients—Polysorbate
They claimed that Polysorbate 60 was highly effective in pro- 60, purified water and preservatives—were available at any
moting hair growth in 1200 mice [21]. Strangely, the authors pharmaceutical supply house. Then, he started experiment-
in the abstract of their study concluded that cholesterol might ing on volunteers with hair loss, to whom he offered the topi-
play an essential role in the development of AGA, even cal lotion free of charge, and just requested users to answer
though in the full-text publication, this conclusion was irrel- questionnaires on the effects the product had on their hair.
evant to their findings. Nevertheless, two theories have been After some months of this “back-yard testing”, Murphy
proposed by Dr. Setälä and Dr. Schreck-Purola to explain the reported that 80% of the participants would recover 60% of
reported hair growth potential of Polysorbate 60 on mice: their hair within a year, and almost 100% of users reported
cessation of shedding within 3–4 weeks. In 1981, he decided
1. Polysorbate 60, as a known nonionic detergent, emulsi- to launch the formula under the name “New Generation” and
fier, and surfactant, would enhance the mechanical threw together a low-budget 30-min T.V. infomercial to tell
removal of cholesterol from the follicular environment by his entire story on the U.S. national television. This was
47.3 Was Polysorbate 60 Effective Against Hair Loss? 249
probably the first late-night infomercial in history and soon Both fiercely claimed that theirs was the original formula
allowed him to reach record sales. Shortly, Durk Pearson and the most effective one. Nevertheless, both proceeded to
would enthusiastically state in the Marv Griffin television further lengths in their obsession to win and sell more.
show that Polysorbate 60 (quote): “…will grow hair on a Initially, it was Lederman who befriended Dr. Schreck-
head bald as a billiard ball in about 6 weeks. Pearson pro- Purola and invited her to California. They agreed to tinker
claimed that Polysorbate 60 regrew his hair and went on to with the original formula to make it more commercially
support the product as an effective baldness treatment in his appealing, and he started sending her quarterly checks for a
popular best-seller “Life Extension” [26]. Since that show few thousand dollars. In a desperate attempt at damage con-
and the effect of Pearson’s bestselling book, the reputation of trol, Murphy flew to Helsinki, and to his astonishment, he
Polysorbate 60 treatment became legendary all too fast. learned that Lederman had never signed any agreement with
However, Murphy was not the only one to produce this Dr. Schreck-Purola. So, he persuaded Schreck-Purola to sign
new, “miraculous hair tonic”. Hal Z. Lederman, the CEO a 10-year, $25,000-a-year contract for exclusive world rights
of Los Angeles-based, Pantron I Corp., used a similar to the original “Mouse Formula” [27].
formula -allegedly as “original” as the one Murphy used- The publicity generated by Murphy’s and Lederman’s
and manufactured a series of products against hair loss, products did not go unnoticed by other industrious
namely a shampoo, a scalp cleanser lotion, and pills. He also Californians throughout the 1980s and 1990s. One of
claimed to have run a test on volunteers who were treated for Murphy’s employees quit in order to sell his own Polysorbate
3 months with his products and that “60% of subjects product called Growthplus. Small companies with their own
reported some sort of hair growth”. He later admitted that it hybrids of the University of Helsinki formula began to pop
was not a “strictly” scientific test; nevertheless, he probably up. They had names like Biotin, Folliplex, P/80, and Bio-
knew this did not actually matter since hair loss patients Prima II. Furthermore, while Polysorbate manufacturers
would believe anything that was marketed under the claim of were making millions of promises of “new, thick hair”, Dr.
a “study”. Lederman was insightful enough to name the Schreck-Purola was not particularly interested in money.
product “The Helsinki Formula” and automatically—yet Therefore, she did not patent her discovery, and she had even
totally unworthily—his product line “inherited” the credibil- given the rights of her formula away in Sweden, free of
ity of an outstanding University with 350 years of history charge, to Dr. Setälä’s son-in-law. Years after the initial pub-
and multiple Nobel nominations. lication, she gave the German rights to her Polysorbate for-
mula to a German company called Bioscalin for just $8000.
She would also share her formula with anybody who would
Just because Dr. Schreck-Purola worked in the Helsinki
come to her for help develop their own Polysorbate product,
University when she published her results on
and only if they remembered her financially down the line,
Polysorbate 60, the “The Helsinki Formula” became
she would accept any remuneration [27]. Hal Lederman and
credible by association.
Robert Murphy spent a considerable part of their careers
threatening lawsuits and in court carrying them out, yet have
altogether sold nearly six million bottles of their tonics
“The Helsinki Formula” was also sold through late-night worldwide and have grossed an estimated quarter of a billion
infomercials, which aired in 1985 under the title “Discover dollars during the first “hair-growth fever” in history.
with Robert Vaughn”, with actor Robert Vaughn interview-
ing enthusiastic users, Hal Lederman himself and even fea-
tured the testimony of Dr. Schreck-Purola claiming that 47.3 Was Polysorbate 60 Effective Against
(quote:) “it is very safe and has an 80% success.” The info- Hair Loss?
mercials ran until 1991, and actor Robert Vaughan managed
to sell more than $100 million worth of products (at $50 a Looking back on it now, the whole Polysorbate 60 experi-
bottle) during the infomercial’s run until the Pantron I Corp. ence seems comical. However, this entire hair-growth phe-
was convicted for fraud by the Federal Trade Commission. nomenon that exploded in the 1980s with these products
However, judging from the thousands of unsolicited testimo- needs some context.
nial letters, both Polysorbate 60 products have attracted a Until the 1980s, there were no solutions for baldness.
cult of balding men so devoted to one product or the other Since Minoxidil has not been marketed yet, all treatments
that no amount of government legal action could diminish against AGA till then had no credible, scientific “competi-
the products’ sales [27]. tor,” and most over-the-counter products were based on big-
Hal Lederman and Robert Murphy competed against each otry or plain trickery. In the 1920s, for instance, a U.S.
other in the market and had a decade-long feud over the legal congressional committee analyzed dozens of reputed formu-
rights to the main ingredient of the product, Polysorbate 60. las, including Lucky Tiger (with arsenic as the hair-saving
ingredient), Hair-A-Gain (kerosene and lanolin), Hall’s Hair women with FPHL and 3 with diffuse hair loss, whereas
Renewer (red pepper and borax) and Ultrasol (lemon juice, altogether, 13 patients reported seborrhea at baseline.
eggs, sulfur, and human pituitary-gland extract) [27]. Patients applied a combo treatment lotion made of
Even though there were patients who would quickly Polysorbate 60 and Polysorbate 80 every second day and
swear by the efficacy of “The Helsinki Formula” or “New were evaluated through expert assessment and a series of
Generation”, no actual scientific study has been conducted three trichograms, at baseline, at 3, and at 6 months. Overall,
until 1985, that Groveman et al. published their results [28]. 10 patients were reported as significantly improved (10–50%
They conducted a double-blind, placebo-controlled trial and increase in anagen hairs), three were moderately improved
actually demonstrated that Polysorbate 60 was utterly use- (3–10% increase in anagen hairs), six did not benefit, and
less as a hair growth treatment. In their well-designed clini- only one patient lost more hair during the 6 months of treat-
cal trial, 174 men with AGA, aged 18–65, were randomized ment. Out of 13 patients with seborrhea at baseline, 12
in a treatment group receiving a commercially available (92.3%) were reported as improved. Overall, the authors
lotion (claiming 70% response rate on T.V.) containing 25% claimed that the mixture of Polysorbate 60 and Polysorbate
Polysorbate 60 in water and a control group receiving a 80 was an effective treatment for AGA. However, severe
lotion containing 25% glycerin in water. Patients were evalu- limitations of the study include the small size of the tested
ated with an objective scalp measuring system developed for group, the lack of control group, results were not reported
the study that measured the hairline “regression” with respect separately for each sex and that 10 out of the 17 patients had
to a fixed point on the head. The authors obtained five scalp AGA/FPHL for just 1–3 years, and these were the ones with
hairline measurements depending on the balding pattern and a better response (77.7%) compared to the those with longer-
also used global photographs. Out of the 141 men who com- standing (>5 years, response 43%) AGA/FPHL [29].
pleted the trial, 24.8% reported new hair growth (27.9% with
Polysorbate 60 and 21.9% with placebo), 67% did not report
new hair growth, and 8% were uncertain. When both the 47.4 What Happened with Polysorbate 60
measurement data and the photographic data were analyzed, Products?
no statistically significant difference was observed between
the treatment and the control group. Additionally, subjects “The Helsinki Formula” and “New Generation” products
reporting new hair growth were not positively correlated were much in the news in the 1980s and 1990s: first as mira-
with objective measurements, thus excluding the possibility cle cures for hair loss and then as the center of a long-drawn-
of Polysorbate 60 being an effective remedy for AGA. out legal battle and media circus. More specifically, both
manufacturers of hair loss products based on Polysorbate 60
were prosecuted by the US Postal Service (USPS) on the
grounds of unfounded claims for their products, using the
Until that time, the “placebo effect” was well-described
USPS to market them. Many of these conflicting federal and
only in subjective symptoms such as pain. Groveman
state government lawsuits, however, dragged on for years,
et al. were the first to demonstrate that it can be an
and one might ask why the federal government should
essential factor also in hair-growth studies.
expend so much energy and resources against a hair-growth
formula that consumers seemed happy with [27].
The primary reason was false advertising since both man-
Groveman et al. rightfully noted that AGA is an emotion- ufacturers bluntly claimed that their products would cure
ally charged condition, and patients who remain in a study AGA. However, when Postal Inspector William F. Powers
long-term (vs. those who drop out soon) are usually eager for interviewed Drs. Setälä and Schreck-Purola in Finland
positive results. Therefore, they represent the well-meaning regarding the products, both emphatically stated that their
advocates of any baldness “cure” that could become con- formula did not affect AGA and that they have never claimed
vinced of its efficacy and believe they grew hair when actu- that their product would cure baldness that it will decrease
ally they had not. the rate of loss of hair and might stop excessive hair loss in
Since 1985, the only other scientific publication address- some instances [30].
ing Polysorbate 60 as a potential hair growth agent is a study After several FTC lawsuits and subsequent appeals, on
by Georgala et al. published in Greek in 1995. Georgala et al. September 10, 1991, a federal district court ordered Robert
conducted a small, uncontrolled clinical trial testing the ther- Murphy to pay $2 million-plus court costs for falsely and
apeutic effects of Polysorbate 60 and Polysorbate 80 and deceptively claiming that their “New Generation” products
published the results in the Hellenic Dermato-Veneological prevented baldness and stimulated hair regrowth in those
Review. The trial included seven men, aged 21–33, with mild who had male pattern baldness. Moreover, Judge Bruce
to moderate AGA and 13 women aged 17–64, including 10 R. Thompson noted, the Food and Drug Administration has
References 251
determined that baldness remedy claims for non-prescription two separate companies competed furiously to convince des-
products like “New Generation” are false, misleading, or perate men that products containing Polysorbate 60 not only
unsupported by scientific data. Robert Murphy settled and cleaned what was left of their hair but allowed new growth to
backed down on his spurious claims [31]. However, he had spring up miraculously. “The Helsinki Formula” was proba-
managed to generate dozens of millions of profits until then. bly the most iconic of all Polysorbate 60 products and was a
In 1988, the Federal Trade Commission filed suit against marketing triumph that used consumers’ blind trust in sci-
Hal Z. Lederman, the manufacturer of “The Helsinki ence to convince them that this product actually regrew hair.
Formula”, who did not give up easily and fought the govern- Even when 3-month trial users discovered the scam, an entire
ment through trial and appeals for years while selling his country of new prospects remained vulnerable until the U.S.
products. In 1996, a judge ruled that Pantron I Corp. was authorities won the lawsuits and forced these products out of
making false and misleading claims and that there was no the market.
credible evidence that “The Helsinki Formula” stopped or
reversed hair loss, as claimed. The Pantron I Corp. was
ordered to pay a settlement of $27 million and soon filled References
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decisions/1981/8–1.htm.
Part VI
Nutrition, Lifestyle Factors and AGA/FPHL
Modern lifestyle is characterized by abundance in most aspects of life. When one considers
technological progress, typically, the rapid evolution of technology, transportation, or telecom-
munications comes to mind. However, the evolution from an agrarian to an industrialized
society had another striking effect: the dramatic upgrade in the quality and quantity of food
ordinary people can access. Modern families do not base their nutrition on older staple foods,
such as cereals and beans, neither have to wait until Sunday to eat meat or fish. Quality food is
cheaper than ever before, and therefore, previously frequent manifestations of nutritional defi-
ciencies, such as pellagra, rickets, goiter, etc.) are sporadic in industrialized countries.
Of course, this did not come overnight. Decades of research were needed to overcome these
nutritional diseases that occurred throughout the world. Sophisticate agricultural, livestock,
fishing, and aquaculture practices, provide modern humans with the luxury of nutritious diver-
sity and quality that was a privilege only of the elite less than a century ago. Sophisticated
agronomics, synthetic chemistry, and food fortification with essential nutrients have also revo-
lutionized human and animal nutrition. Public health policies and food system strategies man-
aged to decrease the incidence of nutrient deficiencies at the global level.
In earlier times, legumes, cereals, fruits, and vegetables covered dietary caloric needs, while
today, meat and refined carbohydrates have increased sharply as components of the modern
diet. The “Western pattern diet”, based on saturated fats, meat, and sugar, has caused a corre-
sponding increase in the prevalence of obesity in most western societies. Reports that nutrition-
related diseases—directly or indirectly—have increased dramatically are widespread; coronary
heart disease, arterial hypertension, cholesterol-related conditions, diabetes mellitus, and isch-
emic strokes are rising alarmingly.
In the next chapter, the general effects of nutrition on hair and skin health will be discussed.
The effects of nutrition in the progress of AGA/FPHL will also be presented. More specifically,
the impact of excessive caloric intake, mainly from fat and those of caloric deprivation, will be
demonstrated. In previous parts of this book (Part IV, Vol. 1), there are extensive reports on
diseases having a causal or epidemiological association with AGA/FPHL. Finally, we will
elaborate on the potential effects of the supplementary intake of vitamins, minerals, and other
dietary elements in patients with AGA/FPHL.
Diet, Lifestyle, and AGA/FPHL
48
able decrease or an—unwanted—increase in overall andro-

Basic Concepts gen availability. The consumption of androgen-containing
• Individuals with AGA/FPHL have higher plasma foods could exacerbate FPHL in some women, but it is
androgen levels and significantly increased local unlikely that men would experience any detrimental effects
response to androgens, which, together with the— because of high endogenous androgen levels. In the follow-
still unknown—AGA genes, result in balding. ing sections, those lifestyle factors that could impact the
• Under normal conditions, individuals with AGA course of AGA/FPHL, either by affecting androgen metabo-
might be predisposed to produce higher amounts of lism or by directly influencing the hair follicle physiology,
androgens, but there are lifestyle and dietary factors will be examined.
that can increase the androgenic “burden” even fur-
ther and precipitate the rate of hair loss in AGA.
• Chronic emotional stress, obesity, a high-fat diet, 48.1 Are Systemic Androgens Increased
glucose intolerance, alcohol abuse, and smoking are in AGA/FPHL?
all adjustable factors that can disrupt the hormonal
balance in the human body and result in higher sys- Laboratory studies on—otherwise healthy—men with early
temic androgen levels or have directly damaging AGA and females with FPHL have repeatedly demonstrated
effects on the balding hair follicles. higher plasma levels of potent androgens. In most studies, higher
• Early intervention in any of these preventable levels of plasma Testosterone (T) and Dehydrotestosterone
parameters may positively impact the rate of pro- (DHT) have been reported in AGA/FPHL cases compared to
gression and course of ΑGΑ/FPHL. controls [1–7]. Additionally, higher levels of weaker andro-
gens, such as DHEA-S, Androstenedione, and Epitestosterone,
which are precursors of DHT, are typically measured [3, 6, 8].
Lower levels of sex hormone-binding globulin (SHBG) are
Genetic factors, androgens, and follicular micro-inflammation reported in AGA/FPHL patients, allowing for higher free T lev-
play key roles in causing “androgenic” hair loss (see Chaps. els in plasma and increased overall bioavailable plasma andro-
11 and 14, Vol. 1) In order to affect the course and progres- gens [9–14]. Nevertheless, other factors are clearly involved
sion of AGA through diet or lifestyle, the only parameter in since not all men develop AGA, despite having similar andro-
AGA that could be “manipulated” is the hormonal one, which gen levels to those that do (see Chap. 11, Vol. 1).
includes several sub-components: In most of these studies, plasma androgen levels of AGA/
FPHL patients—even though significantly higher compared
1. Production of androgens (gonads, adrenals, local), to controls—still remain within the reference range, meaning
2. Transfer of androgens, they fall within the normal distribution curve of values taken
3. Production-conversion of androgens in peripheral tissues from the general population [15]. However, there is enor-
(skin, sebaceous glands, and hair follicles), mous variability in the use of androgen assays, and reference
4. Metabolism in the target-organ, ranges by academic and community clinical laboratories are
5. Cellular response to androgens. established without clinical considerations [16]. Notably,
reference values used to categorize values as high or low
Only the production and transfer steps could be modified have been found to differ as much as threefold between labo-
through dietary and lifestyle changes, either towards a favor- ratories [17].
256 48 Diet, Lifestyle, and AGA/FPHL
fully elucidated and are sometimes strikingly contradictory

So, since the actual clinical significance of comparably when explaining the adaptive mechanisms in play. Interesting
higher androgen levels in AGA/FPHL patients—but examples of how complex the major physiological stress
still not outside the undeniably wide reference response system in the human body might be are the follow-
ranges—cannot be determined, one should simply try ing theories:
to avoid a further increase in androgen levels in these
patients. 1. Drapeau et al. [22] suggest that visceral obesity could
also be a source of stress promoting visceral fat accumu-
lation since visceral fat is able to release cytokines that
48.2 Adrenal Hormones and Androgens stimulate the HPA axis, representing a non-optimal phys-
iological adaptation to stress [22].
Corticosteroids are essential stress-hormones. They are 2. Rosmond et al. [23] claim that after long-term stress
secreted along with adrenocorticotropic hormone (ACTH) exposure, the HPA axis will eventually become dishabitu-
in response to the pulsatile secretion of corticotropin- ated, resulting in a disruption of central regulatory sys-
releasing hormone (CRH), which is secreted from the para- tems and a net decrease of cortisol output [23].
ventricular nucleus of the hypothalamus. The secretion of
androgens from adrenals depends on ACTH secretion from Besides from these ambiguous (for now) stress adaptation
the pituitary, and levels of androgens follow those of cor- theories, a significant shift from cortisol to DHEA occurs
tisol secretion. The adrenal glands have a key role in hor- during stress exposure [24]. Increased DHEA may result in
monal reactions to stress as they are involved both in the increased DHT production, with the known negative conse-
hypothalamic-
pituitary-
adrenocortical axis (HPA) and the quences for the hair follicles in AGA predisposed individu-
symphatho-adrenomedullary system. Adverse situations trig- als. Other pathophysiological mechanisms associating
ger responses of the adrenals, which result in an increase biochemical stress with hair follicles may be found in Chap.
in glucocorticoid and/or catecholamine secretion. These 17, Vol. 1.
responses are the front-line endocrine mechanisms to defend
the organism against stressful situations. However, chroni- 48.2.1.2 Obesity
cally increased secretion of cortisol is followed by an increase Obesity is another vital cortisol regulator, and it is well
in DHEA and Androstenedione production, which derive known that cortisol secretion or production is commonly
from the enzymic conversion of cortisol [18]. While DHEA increased in obesity [25]. Additionally, cortisol clearance is
is a weak androgen, DHEA-S is more potent, and it can con- disturbed in obesity, which may account for further activa-
vert directly to DHT in the dermal papilla cells (DPCs) [19]. tion of the HPA axis [26]. In particular, subjects with visceral
adiposity depict increased cortisol secretion rates, whereas
urinary free cortisol and glucocorticoid metabolite excretion
48.2.1 What Can Cause Chronically Increased rates are frequently elevated in obese subjects [27]. The fre-
Cortisol Secretion in Otherwise Healthy quent occurrence of psychosomatic reactions and psycho-
Adults? logical stress due to the “social stigma” that is often reported
in obesity is likely to aggravate the condition even further
Factors associated with increased serum cortisol and not [28]. Self-perceived increased body weight or exposure to a
related to pathological conditions (diseases, tumors, etc.) are “weight stigma” is stressful and has adverse physiological
chronic emotional stress and obesity. consequences on the stress-responsive HPA axis [29].
However, obesity, besides increasing cortisol levels, has a
48.2.1.1 Stress potent negative effect on androgen production. Tajar et al.
Disruptions in homeostasis (i.e., stress) place demands on [30] conducted a cross-sectional survey on 3369 community-
the body that are met by the activation of two systems, the dwelling men aged 40–79 years old in 8 European centers
HPA axis and the sympathetic nervous system (SNS). and reported that Body Mass Index (BMI) of >30 kg/m2 was
Stressor-induced activation of the HPA axis and the SNS strongly associated with secondary hypogonadism (Relative
results in a series of neural and endocrine adaptations known risk, RR: 8.74; p < 0.001) [30]. This conclusion was con-
as the “stress response” or “stress cascade.” The stress firmed by Dhindsa et al. [31], who determined the prevalence
response is responsible for allowing the body to make the of subnormal T concentrations in 1849 men (1451 nondia-
necessary physiological and metabolic changes required to betics and 398 diabetics) with and without obesity among a
cope with the demands of a homeostatic challenge [20, 21]. primary care clinic population. The prevalence of subnormal
The correlations between stress and obesity, cortisol and free T concentrations in lean (n = 275), overweight (n = 687),
Testosterone, cortisol and AGA or other conditions are not or obese nondiabetic men (n = 489) was 26%, 29%, and
48.2 Adrenal Hormones and Androgens 257
40%, respectively (p < 0.001 for trend). The authors claimed From these, it is safe to assume that obesity is associated:
that obesity is probably the most frequently associated con-
dition with subnormal free T concentrations in males [31]. • with increased cortisol in both sexes,
Other studies have confirmed these findings, both in adoles- • with hyperinsulinemia in both sexes,
cents and young adults [32, 33] as well as in elderly obese • with increased levels of DHEA and weak androgens in
men [34]. Similar findings have been demonstrated in healthy both sexes and reduction of T and SHBG in men,
adults under severe stress conditions (e.g., internal medicine • with hyperandrogenism in women and possibly hypogo-
residents [35], athletes [36], or men under severe anticipa- nadism in men,
tory stress [37]), who—strangely—exhibit decreased T and • with increased peripheral DHT production in both sexes.
cortisol levels [38].
Marked increased weight in young adulthood adversely Additionally, hyperinsulinemia and IGF-1 have been found
disrupts glucose and insulin metabolism, and if not reversed, to enhance lipogenesis in sebocytes [53], resulting in an
may lead to both insulin increase and glucose intolerance increase of sebum production in the scalp hair follicles.
[39]. Insulin increase negatively affects hepatic SHBG pro- Sebum contains potent androgens, which are reabsorbed by
duction [40], enhances ovarian steroidogenesis, which mani- the hair follicle and exert further adverse trophic effects [54].
fests clinically as hyperandrogenism in women [41] and, (See Chap. 15, Vol. 1).
conversely, results in chronically lowered T production in Concerning the epidemiological association and dose-
males [42]. Insulin is also considered a potent androgen response relation between AGA and cardiovascular disease
secretion regulator [43]. High insulin levels following (CVD), metabolic syndrome (MetS), hypertension, and IR,
consumption of meals high in refined carbohydrates or insu- the reader should refer to Chap. 21, Vol. 1.
lin secretion stimulators [44] (e.g., coffee, smoking) result in
a transient increase in serum androgens [45]. Tsai et al. [46]
calculated the bioavailable and free T of 221 middle-aged 48.2.2 Other Factors that Increase Androgens
nondiabetic men and reported an inverse association between in the Serum
free T and insulin resistance (IR), mediated through body fat
and independent of SHBG [46]. These effects result in Additional factors that may increase androgen levels in both
increased serum T and androgens in obese women [47], sexes are:
while strangely, the levels of total T in obese men are propor-
tionally diminished with both the increase of BMI and IR 1. high-fat diets,
index [48]. 2. crash diets,
3. alcohol abuse,
4. smoking.
These effects might be explained by the fact that
abdominal, breast, and axillary adipose tissue are sig-
nificant extra-gonadal estrogen sources, having the
48.2.3 High-Fat Diets and Androgens
ability to convert androgens into estrogens.
Diets rich in saturated fat of animal origin can impact serum
androgen levels, and Inaba et al., in their textbook (1996),
This peripheral aromatization of T to estrogens in obese hypothesized a definite contributory cause of AGA/FPHL in
men has been found to result in a mean reduction of plasma the excess animal fat consumption [55]. However, their inter-
T levels by 40% and to >50% increase in estrone and estra- esting theoretical correlation between different ethnic diets,
diol plasma levels [49]. Surprisingly, even though the adi- the prevalence of AGA/FPHL, and the caliber of hair was not
pose tissue is an essential extra-gonadal source of estrogens, supported by any study.
obesity is mostly linked to androgenic effects in women [47] Similarly, several reports have been published concerning
and to lower T levels in men [50]. the relationship between AGA and nutrition. Most of these stud-
Nevertheless, adipose tissue also exhibits ies concluded that excessive intake of certain nutrients might
5α-Reductase activity and readily converts weak andro- cause an increase in blood cholesterol and reduction of blood
gens into potent ones [51]. Obese men likely undergo a flow in the peripheral capillary vessels [56–58]. The capillary
higher local conversion of T or DHEA-S to DHT com- vessels that circulate blood to the dermal papilla of the hair root
pared to the non-obese. Fortunately, this effect of obesity thus exhibit this decrease of blood flow and the hair follicle is
on the hormone profile of obese men has been found to subsequently deprived of sufficient nutrition. However, these
reverse with weight loss [52]. conclusions fail to explain why women, who ingest the same
kinds of nutrients as men, do not grow bald. If cholesterol plays Also, the saturated fatty acid contained in animal fats seems
an active role in the onset of baldness, why don’t women grow to induce enlargement of sebaceous glands that could precipi-
bald as early or as frequently as men? Hypernutrition may be a tate the progression of AGA/FPHL (see Chap. 15, Vol. 1).
causative factor in baldness, but the causal process must be con-
sidered apart from the cholesterol intake.
Fatty acids have been shown to decrease the binding of T Overall, there is very limited available data indicating
to SHBG in vitro [59]. Studies have demonstrated that high that diets rich in fat and animal proteins can increase
dietary lipid intake (>100 g/day) is an additional factor androgens in the serum, decrease levels of SHBG,
involved in the reduction of plasma levels of SHBG [60]. It increase insulin levels, and overall exert adverse effects
can also increase the levels of total and free Τ [61] and the on hair follicle physiology. These effects can be even
free serum androgens in healthy men [62]. The effects of more pronounced in women with FPHL [69].
fatty acids on hormone production and serum hormone lev-
els have been confirmed in studies on male monozygotic and
dizygotic twins, showing an increase of androgen levels on
individuals who had a diet rich in fat vs their twin brothers 48.2.4 Deprivation (Crash) Diets
who were on a regular diet [63]. In contrast, a low-fat diet and Androgens
reduces free Τ down to normal levels, and even to subnormal
levels [61]. Similar studies in women have shown that a Deprivation (crash) diets can have a significant negative
high-fat diet decreases the production of SHBG [64], while a impact on the endocrinological balance of the human body,
low-fat and high-fiber diet decreases plasma androgens [65]. resembling those of high-fat/high-calorie diets. Starvation
A very interesting study was published by Pathomvanich diets can severely disturb pancreatic function and physiolog-
et al. [66], possibly exhibiting the direct adverse effects of a ical insulin secretion, induce glucose intolerance, overt
high-fat diet on AGA. A total of 1124 men were randomized to Diabetes Mellitus [70], and even result in cardiovascular
assess the prevalence of AGA in Bangkok, Thailand, and com- complications [71]. Moreover, serum cortisol concentrations
pare the prevalence of previous studies conducted on Asians and are increased in fasted or malnourished human subjects. This
Caucasians. The prevalence of cosmetically significant AGA starvation-induced enhancement of cortisol secretion is
(Norwood III-VII) was 38.52% and steadily increasing with mediated by an increased glucocorticoid secretory burst
age, which was found to be comparable to that of Caucasian mass [72]. Interestingly, Tomiyama et al. [73] demonstrated
populations. However, in previous studies, it was reported as on 121 female participants that restricting calories not only
being 2–3 times lower. The authors speculated that the novel increased the total output of cortisol but that monitoring cal-
socioeconomic environment and westernized diet (fat-rich) ories increased perceived stress and increased cortisol output
might have contributed to this significant increase [66]. even further [73]. Studies have also reported potential asso-
Fortes et al. [67] conducted a hospital-based case-control ciations between crash diets, nutritional deficiency, chronic
on 104 males with AGA and 108 healthy controls to investi- telogen effluvium, AGA, and FPHL (see Part VII. Dietary
gate the role of the “Mediterranean diet” in determining the supplements and Androgenetic Alopecia).
risk of AGA. After controlling for age, education, BMI, and A typical consequence of crash diets on hair growth is
family history of AGA, protective effects for AGA were massive hair loss in the form of telogen effluvium [74–78],
found for high consumption of raw vegetables (OR = 0.43; and even telogen counts of 25–50% have been reported.
95% CI: 0.21–0.89) and high consumption of fresh herbs Fortunately, regrowth of hair typically occurred within sev-
(OR = 0.44; 95% CI: 0.22–0.87). The authors supported the eral months [79]. Telogen effluvium will routinely appear
hypothesis that some fresh herbs and salad included in the 2–3 months after the initial trigger and long before any actual
Mediterranean diet, rich in phytochemicals such as carot- deficiency is established [80]. It is believed that a sudden
enoids and polyphenols, may reduce the risk of AGA but are decrease in energy and nutrient supply of the highly energy-
not correlated with androgen levels [67]. consuming hair follicle is the cause of this phenomenon [81].
Yi et al. [68] conducted a web-based cross-sectional sur- Moreover, sudden telogen effluvium has been reported in
vey with a structured questionnaire. They investigated the severe cases of eating disorders, such as anorexia nervosa
association between dietary factors such as meat and vegeta- and bulimia nervosa.
ble consumption, junk food and alcohol intake, and other
factors, including stress, sleep habits, smoking, scalp health,
and AGA severity. They reported that factors increasing the Therefore, deprivation diets disturb serum androgen
odds of a more severe type of AGA are carnivorous eating concentration [82] and can frequently precipitate telo-
(OR = 1.23, 95% CI: 1.05, 1.45) and consumption of junk gen effluvium and diffuse alopecia.
food (OR = 1.63, 95% CI: 1.39, 1.90) [68].
Nonetheless, expert yogis, who fast for 1–3 months with dione, and estrone concentrations were 10–20% higher in
no food and only sips of water in preparation for spiritual women consuming more than 25 g/day of alcohol com-
pursuits, do not have noticeable hair loss or gross changes; pared to non-consumers. Estradiol and free estradiol were
these extreme examples seem to contradict commonly not associated with alcohol intake at all. SHBG levels were
accepted observations [55]. about 15% lower in alcohol consumers compared to non-
consumers [96]. Overall, endocrine disorders caused in
women by alcohol abuse are more severe than those in men,
48.2.5 Alcohol Abuse and Androgens and they are due to the differences in ethanol metabolism
between sexes [97].
Alcohol intake has been shown to affect many hormonal Extensive research in animals and humans also has docu-
pathways, including the HPA axis, the hypothalamic- mented the deleterious effects of alcohol on male reproduc-
pituitary-gonadal (HPG) axis, the hypothalamic-pituitary- tive function, including reduced T levels. Acute alcohol intake
thyroid (HPT) axis, the hypothalamic-pituitary-growth decreases the circulating levels of LH and T due to the dimin-
hormone/insulin-like growth factor-1 (GH/IGF-1) axis, and ished release of hypothalamic LHRH [98]. In contrast,
the hypothalamic-posterior pituitary (HPP) axis [83]. The chronic alcohol intake significantly increases FSH, LH, and
activities of these axes are regulated through several negative estrogen levels but still decreases T and progesterone levels in
or positive feedback mechanisms, the complexities of which men [99]. Additionally, the aromatization of androgens to
go beyond the scope of this chapter. estrogens in the liver is increased [100], and reactive oxygen
Multiple lines of evidence indicate that alcohol con- species (ROS) produced during alcohol metabolism may
sumption affects the stress-response pathways. Gonadal cause testicular cell damage [101]. Interestingly, Shiels et al.
and stress hormones interact with alcohol, which results in [102] evaluated 1275 men ≥20 years old who participated in
differential neurobiological responses between males and the Third National Health and Nutrition Examination Survey
females [84]. The same applies to the effects of alcohol on (NHANES III) and reported that men who consumed ≥1
the HPG axis and the hormonal homeostasis in general. drink/day had lower SHBG than men who drank less fre-
Even though there is still no consensus, it is generally quently (31.5 vs. 34.8 nmol/L, p = 0.01). Also, total T
accepted that alcohol alters serum levels of sex steroids by (p-trend = 0.08) and free T (p-trend = 0.06) increased with the
modifying hepatic, gonadal, and, possibly, adrenal metab- number of drinks per day [102]. Severi et al. [103] conducted
olism [85–87]. a case-control study on 1390 men aged 40–69 years in
Several studies, both in lab animals and humans, confirm Australia to determine AGA risk factors. They reported that
that alcohol abuse affects the function of the HPA axis [88] drinking alcoholic beverages more than once a month on
as well as the HPG axis [89] by inhibition of GnRH and LH average was associated with a significantly increased risk of
hypothalamic secretion [90]. Furthermore, alcohol exerts its 50–60% for frontal and vertex AGA, unlike full AGA, but
harmful effects directly on the testis by reducing the testicu- there was little evidence of a dose-response with increasing
lar biosynthesis of T [91]. Alcohol abuse in premenopausal alcohol consumption [103].
women has been associated with gonadal dysfunction, sec- Gatherwright et al. [104] conducted a study on 46 pairs of
ondary amenorrhea, libido decrease, and infertility [92, 93]. monozygotic twins with a mean age of 51.05 ± 16.30 years
Heavy alcohol intake has been found to increase ACTH pro- (range, 23 to 84 years) to examine the putative contributions
duction, cortisol, DHEA-S, and Τ in young women and can of genetics, environment, and specific behaviors. The sub-
result in hyperandrogenism and loss of female sexual charac- jects completed a comprehensive questionnaire followed by
teristics [94, 95]. standardized digital photographs at preset distances and set-
Rinaldi et al. [96] investigated the relationships between tings. Regarding alcohol use, twins who refrained from
alcohol intake and serum levels of sex steroids and SHBG drinking had significantly more vertex hair loss (0.036;
in 790 pre- and 1291 post-menopausal women, who were p = 0.030; n = 6), but those who drank more than four drinks
part of the European Prospective Investigation into Cancer per week also had more vertex hair loss (0.033; p = 0.004;
and Nutrition (EPIC). Premenopausal women who con- n = 28). The full-text paper includes two sets of high-quality,
sumed more than 25 g/day of alcohol had >30% higher before-and-after photos of 2 pairs of twins with significant
DHEA-S, total T and free T, 20% higher δ-4-androstene- hair loss differences due to non-genetic factors, including
3,17-dione, and about 40% higher estrone concentrations alcohol abuse. These authors found that alcohol can be both
compared to women who were non-consumers. In contrast, beneficial and detrimental to hair preservation, depending on
estradiol, free estradiol, and SHBG concentrations showed the amount consumed. However, this study presented only
no association with alcohol intake. In post-menopausal correlations, and results should not be translated into causal-
women, DHEA-S, free T, total T, δ-4-androstene-3,17- ity [104].
15% higher total and 13% higher free T levels compared

Based on the above, we can assume that alcohol- with men who never smoked [109].
consumption-induced endocrinological disorders are Halmenschlager et al. [110] studied 90 smokers and
more pronounced in women and are associated with a 165 nonsmokers but failed to reproduce the results men-
direct or indirect increase in circulating androgens. It tioned above. They reported no significant difference
is unclear how alcohol consumption is involved in dis- observed in the mean values of total T (p = 0.580), free T
orders caused in the HPA and HPG axis in both sexes. (p = 0.869), bioavailable T (p = 0.933), SHBG (p = 0.279),
LH (p = 0.573), and FSH (p = 0.693) in the different lev-
els of pack-years when compared to nonsmokers [110].
48.2.6 Smoking Shiels et al. [102] evaluated the associations of smoking,
alcohol consumption, and physical activity with sex ste-
Smoking is the single most preventable cause of significant roid hormone concentrations among 1275 men >20 years
cardiovascular and pulmonary morbidity and a major cause old who participated in the NHANES III. They reported
of death in the general population. It has also been associated that active smokers had higher total T (5.42, 5.10, and
with various adverse effects on the skin and hair follicles. 5.26 ng/mL in current, former, and never smokers), free T
(0.110, 0.102, and 0.104 ng/mL), total estradiol (40.0,
48.2.6.1 Smoking and Androgens 34.5, and 33.5 pg/mL), and free estradiol (1.05, 0.88, and
Field et al. [45] cross-sectionally examined 1241 randomly 0.84 pg/mL) compared with former and never smokers
sampled middle-aged U.S. men. They reported that com- (all p ≤ 0.05) [102].
pared with nonsmokers and independent of BMI and age, Wang et al. [111] evaluated the associations of cigarette
cigarette smokers had increased serum levels of DHEA (18% smoking and serum androgen levels in 2021 men (989 non-
higher, p = 0.0002), DHEA-S (13% higher, p = 0.0007), cor- smokers and 1032 smokers), aged 20–69, collected from the
tisol (5% higher, p = 0.01), androstenedione (33% higher, Fangchenggang Area Male Health and Examination survey.
p = 0.0001), T (9% higher, p = 0.009), DHT (14% higher, They reported that smokers had significantly higher total T
p = 0.004), and SHBG (8% higher, p = 0.004) [45]. Vermeulen and free T levels compared to nonsmokers, even after strati-
et al. [105] examined a non-obese healthy population fication as per age, BMI, triglycerides, and alcohol consump-
(n = 250), and an obese population (n = 50) before and after tion. Also, both total T (p < 0.001) and free T (p < 0.001)
weight loss and reported that smoking appeared to be accom- levels were negatively correlated to the amount of tobacco
panied by higher free T levels [105]. exposure [111].
Alen et al. [106], based on a sample of 696 men, reported
that smoking +10 cigarettes/day was associated with 15%
higher T, 22% higher SHBG, and 17% higher LH concentra- Based on the above, even though there is no consensus,
tions. In contrast, free T and 3α-androstanediol glucuronide we can assume that cigarette smoking is associated
were not associated with smoking [106]. Svartberg et al. with increased plasma levels of androgens in males.
[107] conducted a population-based, cross-sectional study
on 1563 men participating in the Tromsø study in 1994/1995
and reported that both total and free T were positively associ-
ated with tobacco consumption (p < 0.001 and p = 0.004), 48.2.6.2 Smoking, Hair Follicles, and AGA
whereas SHBG, was also positively associated with smoking The mechanisms by which smoking accelerates hair loss
(p = 0.004) adjusted for age and BMI [107]. have not been examined, but they are likely similar to the
Ponholzer et al. [107] conducted a prospective study of effects on the skin, i.e., the cutaneous microvasculature is
375 men aged 45–85 years to evaluate the association constricted by long-term smoking, causing transient local
between lifestyle, serum levels of total T, and free T, in aging ischemia. However, Prof. Ralph Trüeb speculates that the
males. They reported that after adjustment for age and BMI, mechanisms by which smoking can cause or increase hair
nicotine consumption showed a significant positive correla- loss are multifactorial [112]. These are probably related to:
tion to total and free T levels (p < 0.01) [108]. Svartberg et al.
conducted a cross-sectional population-based study on 3427 • effects of cigarette smoke on the microvasculature of the
men participating in the fifth Tromsø study (2001) and dermal papilla,
reported that smoking men had significantly higher levels of • smoke genotoxicants causing damage to DNA of the hair
total and free T compared with men who never smoked follicle,
(p < 0.001 and p < 0.01 respectively). Both total T and free T • smoke-induced imbalance in the follicular protease/anti-
levels increased significantly with the increasing number of protease systems controlling tissue remodeling during the
cigarettes smoked daily (p < 0.001), and smoking men had hair growth cycle,
• pro-oxidant effects of smoking leading to the release of et al. [122] cultured DPCs from the balding and non-balding
pro-inflammatory cytokines resulting in follicular human scalp and demonstrated that balding DPCs are particu-
micro-inflammation, larly sensitive to environmental stress [122], a theory that
• fibrosis and finally increased hydroxylation of estradiol, Trüeb has supported for many years [112, 113, 123]. They
as well as inhibition of the enzyme aromatase creating a discovered that cultured dermal hair DPCs from balding scalp
relative hypo-estrogenic state [113]. grow slower in vitro than non-balding DPCs. The loss of pro-
liferative capacity of balding DPCs was associated with
Smoke genotoxicants metabolized in hair follicle cells may changes in cell morphology, expression of senescence- associ-
cause DNA damage through DNA adducts production, and ated beta-galactosidase, decreased expression of proliferating
smoking-associated mitochondrial DNA mutations have cell nuclearantigen and Bmi-1, upregulation of p16(INK4a)/
been shown in human hair follicles, though the relevance of pRb, and nuclear expression of markers of oxidative stress and
these for hair follicle pathology is as yet unknown. Since DNA damage including heat shock protein-27, superoxide
substantial extracellular matrix remodeling is involved in the dismutase catalase, ataxia- telangiectasia- mutated kinase
hair follicle growth cycle, especially during catagen- (ATM), and ATM- and Rad3-related protein [122].
associated hair follicle regression, it is conceivable that ciga-
rette smoke-induced imbalance in the intra- and perifollicular
protease/antiprotease systems controlling tissue remodeling
Although cigarette smoking-related premature skin
may also affect the hair follicle growth cycle. Finally,
aging has attracted the medical community’s attention
smoking-induced oxidative stress and disequilibrium of anti-
since the 1960s, it was just in 1996 that Mosley et al.
oxidant systems may lead to the release of pro-inflammatory
originally reported a relationship between smoking,
cytokines from follicular keratinocytes, which by themselves
male baldness, and premature grey hair. Ever since, the
have been shown to inhibit the growth of isolated hair folli-
association between smoking and AGA has been
cles in culture. Moreover, adjacent fibroblasts are fully
addressed in several studies, with inconsistent results,
equipped to respond to such a pro-inflammatory signal. On
though.
the occasion that the causal agent persists, sustained micro-
inflammation of the hair follicle is the result, together with
connective tissue remodelling, where again collagenases
play an active role and are believed to contribute to perifol- Mosley et al. [124] investigated whether premature hair
licular fibrosis [114]. changes may be causally associated with smoking on 606
Several researchers have contributed to the investigation patients of both sexes (268 men, 338 women, all >30 years
of smoking on the skin and the hair follicles. Leow and old) and reported a strong association of grey hair and smok-
Maibach [115] initially reviewed the effects of smoking on ing (Odds ratio, OR = 4.4, 95% CI: 3.24–5.96, p < 0.0001) in
the cutaneous vasculature and tissue oxygen tension [115]. both sexes and a strong link between AGA and smoking in
On a cellular level, dermal fibroblasts exposed to nicotine men (OR = 1.93, 95% CI: 1.13–3.28, p < 0.01), without,
undergo a significant decrease in their activity, leading to however, claiming a causal relationship [124].
lower migration rates, proliferation, and remodeling [116]. Matilainen et al. [125] conducted a population-based
Liu et al. [117] demonstrated that smoking depletes antioxi- cohort study examining the associations between IR-linked
dants and causes mitochondrial DNA deletions [117] and factors and hair status of 324 women aged >63 years old. The
mutations [118], altering the regulation of mitochondrial life prevalence of smoking was quite low (13.6%), and the sub-
functions [119]. Still, their relevance in hair follicle pathol- groups did not differ from each other in this respect
ogy is unknown. Knuutinen et al. [120] have demonstrated (p = 0.918) [125]. Severi et al. [103] studied 1340 men and
in vivo that the synthesis rates of type I and III collagen reported no association with current cigarette smoking sta-
fibers were lowered by 18% and 22%, and the levels of tus, nor did they find an association with either quantity or
MMP-8 were higher by 100% in smokers compared to non- duration of smoking and AGA prevalence [103].
smokers, resulting in an altered balance of extracellular Su et al. [126] conducted a population-based cross-
matrix turnover of the skin [120]. sectional survey on 740 men aged 40–91 years old in Tainan
Other studies have focused on the role of oxidative stress County, Taiwan, to evaluate AGA’s association with smok-
induced by cigarette smoke since it has been reported to have ing. After controlling for age and family history, statistically
deleterious effects on hair follicles. Naito et al. [121] reported significant positive associations were noted between moder-
that the topical application of linolein hydroperoxides, which ate or severe AGA (Norwood types ≥IV) and smoking status
produce free radicals, led to the early onset of catagen in (OR = 1.77; 95% CI: 1.14–2.76), current cigarette smoking
murine hair cycles and induced the apoptosis of hair follicle of 20 cigarettes or more per day (OR = 2.34; 95% CI: 1.19–
cells by up-regulating apoptosis-related genes [121]. Bahta 4.59), and smoking intensity (OR = 1.78; 95% CI: 1.03–
3.07). The authors reported that the odds ratios of early-onset diagnosis, a designed questionnaire to determine basic phys-
history for AGA grades increased in a dose-response pattern ical and smoking habits was completed, and results were
[126]. interpreted and analyzed. Most smokers (425) had a form of
The monozygotic twins’ study by Gatherwright et al. AGA, while only (200) nonsmokers had a degree of AGA
[104] reported that a positive smoking history had statisti- (p < 0.01). In the smokers group, 235 (47%) had grade III
cally significant effects on frontal hair loss. Although the AGA and 120 subjects (24%) had grade IV AGA. In the non-
quantity of smoking was not statistically significant, the smokers group, 100 subjects (20%) had grade II AGA, and
twins who started smoking earlier (p < 0.001; n = 20) and 50 subjects (10%) had either grade III or IV AGA. The
stopped smoking later (p = 0.097; n = 12) had associated authors concluded that the prevalence of AGA among smok-
increases in frontal hair loss. Twins who smoked had signifi- ers was statistically higher than among nonsmokers, while
cantly more vertex hair loss than their nonsmoking siblings the severity of AGA was not associated with the intensity of
(p = 0.047; n = 20) [104]. smoking [53]. However, these results can be purely circum-
Salman et al. [127] conducted a hospital-based, cross- stantial, and the study is very poorly designed since it attri-
sectional, controlled study on 954 patients (535 women, 419 butes causality without investigating more in-depth into the
men), investigating the frequency of AGA/FPHL, the pres- potential correlations of smoking and AGA, e.g., hair loss or
ence of accompanying systemic diseases, and lifestyle fac- stress due to hair loss could actually be a reason to start
tors. The authors reported no significant difference in alcohol smoking [130].
consumption and smoking habits between patients with and
without AGA in both sexes (p > 0.05) [127].
Based on the above, we can assume that even though
Fortes et al. [128] conducted an outpatient-based, cross-
smoking can theoretically precipitate AGA/FPHL by
sectional study among 351 AGA subjects to investigate risk
several mechanisms, there is no established clinical
factors for AGA severity. AGA subjects that were heavy
association.
smokers (≥10 cigarettes per day) had almost three times
increased risk of having a moderate/severe AGA (OR = 2.56;
95% CI: 1.27–5.16, p < 0.05) compared to never smokers.
Subjects with a BMI ≥25 and current smokers had almost a 48.3 Tips That Could Reduce Further Hair
sevenfold increased risk of having moderate or severe AGA Loss in AGA/FPHL
(OR = 6.72; 95% CI: 2.57–17.6). In the multivariate model,
after controlling for gender, age, education, dyslipidemia, Common sense would consider that the progression of AGA/
dietary supplements, and wine consumption, the effect of FPHL would delay from a well-balanced diet containing
high BMI and smoking on AGA severity remained fats, protein, carbohydrates, vitamins, minerals, and other
(OR = 5.96; 95% CI: 1.65–21.5) [128]. nutrients, all in proper amounts. Nevertheless, studies testing
Danesh-Shakiba et al. [129] conducted a case-control this “conventional wisdom” and the hypotheses mentioned
study evaluating data on lifestyle habits, including smoking above are painfully missing.
and alcohol consumption in 256 men with AGA and 256 age- More extensive epidemiological studies would be neces-
matched healthy controls (mean age 38.5 ± 9 years). The sary to answer whether diet and lifestyle can actually affect
authors reported that although smoking and alcohol con- AGA/FPHL. Until then, practical advice a physician can
sumption were not significantly more common in patients offer to AGA/FPHL patients who are interested in increasing
with mild to moderate AGA compared to those with severe the likelihood of preserving their hair -and general health-,
AGA (p = 0.276, p = 0.313, respectively), hookah (smoking are as follows:
water pipe) use was significantly more prevalent in the for-
mer group (p < 0.001). Their findings did not show a signifi- • Reduce stress by managing stressful situations more effi-
cant association between AGA, hypertension, and smoking. ciently. Emotional stress and the stress response that it
Although lower BMI and lower waist to hip ratio were induces share several mediators, circuitries, and effects
observed in the patient group, these values were within nor- with degenerative and inflammatory disorders, which
mal range and therefore not biologically significant [129]. might further affect balding hair follicles in multiple
Salem et al. [53] conducted a cross-sectional study to ways.
assess the demographic and clinical features of early-onset • Decrease dietary fat intake. A high-fat diet has been cor-
AGA among smokers and nonsmokers and evaluate whether related with increased plasma lipoproteins and increased
AGA’s prevalence was affected by smoking. One thousand scalp sebum production, containing DHT, which is reab-
healthy males aged 20–35 years were recruited for this study sorbed by scalp hair follicles and aggravates AGA [119,
and divided into two groups of 500 each based on their 131]. Men who reduced saturated and increased poly-
smoking attitudes. Trichoscopy was used to confirm the unsaturated fats in their diet demonstrated favorable
References 263
effects in insulin, SHBG androgens, and estrogens [132, men [153]. Men who replaced meat with soybean in their
133]. Similar results have been reported in obese women diet had a minor effect on biologically-active sex hormones
who lowered cholesterol levels and significantly reduced [154]. Lai et al. [155] concluded that regular consumption of
T and dehydroepiandrosterone levels and increased estra- soybean drinks significantly decreased AGA’s risk
diol levels [134, 135]. (OR = 0.23, 95% CI: 0.06–0.85) [155]. Naturally, more stud-
• Decrease in the amount of refined carbohydrates (high ies are needed.
glycemic index) that potently stimulate insulin secretion, Overall, a modified Mediterranean diet may be the perfect
indirectly increase androgens in plasma and peripheral T recommendation for patients with AGA/FPHL since it
conversion to DHT [136]. High-fat foods, fried foods, and includes proportionally high consumption of olive oil,
bakery products are to be avoided. legumes, unrefined cereals, fruits, and vegetables, moderate
• Avoid processed foods with high amounts of food addi- to high consumption of fish, and low consumption of non-fish
tives (preservatives, flavoring agents, colorants, and acid- meat products. Compared to the original Mediterranean diet,
ity regulators) as they could increase systemic ROS levels which allows moderate consumption of dairy products
[137]. (mostly as cheese and yogurt) and moderate wine consump-
• Smoking should be discontinued. Besides being the sin- tion, probably those who want to follow the best dietary
gle most important preventable cardiovascular disease advice for their hair should keep the latter to a minimum
risk factor, it exerts a direct, negative effect on hair folli- [156]. however, on should keep in mind that on a typical
cles, with various -still elusive- mechanisms. Western diet, the hair follicle should have no problem in pro-
• Alcohol intake should be kept to a minimum since it ducing an appropriate hair shaft, as billions of individuals can
affects most hormonal systems. attest.
• Mild to moderate exercise, preferably a combination of
endurance training (cardio) with weight training, is Synopsis
helpful. Endurance training has been reported to sup- Heredity and androgens are the main culprits of AGA/
press basal testicular T production through complicated FPHL. However, factors that just a few years ago were still
adaptation mechanisms of the HPA axis [138], while considered irrelevant with AGA/FPHL or hair loss in general
resistance training increases androgen levels in men today are known to contribute negatively. Diet and lifestyle
[139] and women [140]. So, combined endurance and seem to play a reinforcing role in the rate of AGA progress
resistance training can have the maximum benefit for during a patient’s lifetime. Dietary and lifestyle choices can
health and physical condition and favorable hormonal have a considerable impact on androgen plasma levels,
effects [141, 142]. Interestingly, Choi et al. [143] con- which can precipitate the course of hair follicle miniaturiza-
ducted a survey-based, observational study on 600 male tion. Alcohol abuse can have more generalized hormonal
and 582 female subjects (total of 1182; mean age, repercussions, whereas pathophysiologic mechanisms by
51.38 ± 12.83 years; range, 18–94 years of age). The which smoking can cause or accelerate hair loss are multi-
number of AGA/FPHL patients was 534 (45.2%) in total factorial and not fully clarified. Patients should be informed
and 350 (58.3%), 184 (31.6%) within the male and of these contributing factors and how they can make the right
female subgroups, respectively. The authors reported an choices to have the best chances to keep more hair for a lon-
apparent positive association between exercise and ger time on their heads.
AGA/FPHL. However, as of the result of an observa-
tional study, it cannot be confirmed that alopecia or
exercise preceded one the other, and therefore, results do References
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Part VII
Dietary Supplements and Androgenetic Alopecia
Skin, scalp hair, and body hair require for their integrity and function, among other things, an
adequate and balanced nutrition [1]. Admittedly, most individuals in developed countries have
sufficient nutrients in their diet. However, others do not have access to proper nutrition, and
still, others have medical illnesses that predispose them to nutritional deficiencies.
Food deprivation, malnutrition, partial or complete deficiency of a food group, and an
excess of one particular nutrient over another may all disrupt the human body’s general nutri-
tional balance. The results can be often reflected in changes of scalp and, at times, body hair.
Malnutrition or nutrient deficiencies due to chronic illness, malignancy, alcoholism, and
advanced age can cause hairs to lose color, to weaken, or fall. Overall, cutaneous manifesta-
tions and changes in skin and hair due to malnutrition can often provide clues to the presence
of the underlying deficiency [2].
However, the field of dermatology studying the effects of nutrition on hair loss is probably
one of the most neglected fields of this specialty. Ironically, most of our knowledge on the cor-
relation of nutrition and hair stems from hair changes in those lacking nutrition and the clinical
manifestations of nutritional deficiencies, traced almost exclusively in the old scientific litera-
ture. Modern scientific literature reveals that little is known about dietary factors in hair loss in
otherwise healthy individuals. Aside from cases of particular patient populations that may be
at risk from acquired deficiencies, our knowledge of the effect of nutrition in hair loss is even
more limited due to lack of data [3]. These patient populations include patients with psychiat-
ric morbidities (e.g., anorexia), chronic malnutrition or starvation, chronic vomiting, drug
abuse (such as laxatives and diuretics), chronic conditions, patients receiving long-term total
parenteral feeding, and those with perceived or real food allergy.
How Was Initially Hair Loss Correlated with Malnutrition?
It has long been recognized that diet influences the coat of animals. In lab animals, nutritional
factors and hair loss have been scientifically recorded since 1932 by Cunningham, who noted
hair loss in iron-deficient rats [4]. Later, in 1941, Sullivan and Nichols reported hair loss in
riboflavin deficient rats [5] while other researchers noted hair loss in both rats [6] and mice [7]
due to zinc deficiency. Since the influence of carbohydrates, proteins, fats, trace elements, and
vitamins in various species goes beyond the scope of this chapter, the reader interested in a
historical perspective can refer to the fascinating early review by Ryder et al. [8].
The impact of nutrition on hair growth and skin in humans has been observed since
antiquity, but centuries had to pass before correlating an initial observation with a distinct
nutritional deficiency. Vitamin C is a perfect example. According to Stewart and Gutherie
[9], Vasco da gamma, in the journey around Africa to India and back (1497–1499), recorded
the deaths of 100 out of his 160 sailors from “scurvy“(Vit C deficiency). These unfortunate
270 Dietary Supplements and Androgenetic Alopecia
men suffered from hair loss and skin bleeding before dying. It took no less than 300 years
before James Lind confirmed the empirical correlation between scurvy and a nutrient found
in citrus fruits, much later to be named Vit C. until then, scurvy has resulted in more deaths
in the British fleets than French and Spanish arms combined [10]. Daniel whistler, in 1645,
was the first to clinically describe a nutrient deficiency -that we know today as Vit D- in his
DM thesis on rickets. This condition, however, was not linked to Vit D until 1922, and the
results of the studies by McCollum et al. [11]. It was not until 1991 that the beneficial role
of Vit D and its analogs in psoriasis was established [12].
Besides these impressive examples of severe nutrient deficiencies in humans, the associa-
tion of nutrition and its effects on skin and hair follicles arises mostly from studies on protein
malnutrition and caloric deficiency [13]. In the literature, malnutrition is generally divided into
protein-energy malnutrition and micronutrient deficiency. Protein-energy malnutrition is
defined by the height and weight measurements that fall two standard deviations below normal
[14]. In developed countries, malnutrition is often caused by things other than inadequate food
intake. Since hair follicles are among the most metabolically active organs in the body, hair
growth may be influenced by calorie and protein malnutrition as well as micronutrient defi-
ciency. However, the links are complex, and nutrition effects on hair follicle condition are not
straightforward or easy to assess.
The response of hair follicles to protein malnutrition has been extensively studied in chil-
dren (although adults can also be affected) with marasmus, Kwashiorkor’s disease, and maras-
mic-kwashiorkor conditions which have been reviewed thoroughly by Bradfield and Bailey
[15]. Hair loss has been reported in children under total parenteral nutrition with formulas
deficient in pantothenic acid and riboflavin [16]. Such deficiencies have been recognized for
decades and are, fortunately, much less of a problem now than in the past. Under these condi-
tions of protein-energy malnutrition or micronutrient deficiency, significant changes occur in
skin keratinization and pigmentation (both hyper- or hypo-), while also wound healing is
delayed. Histologically, hair follicles in protein-energy malnutrition exhibit moderate to severe
atrophy [17]. These hairs are easily epilated, they become finer in caliber, lose pigmentation,
and even their curl [10], lose their tensile strength, fall out easily, and have a reduced daily
growth rate [18, 19]. Fortunately, these severe malnutrition cases, which can lead to skin and
hair changes, are very unlikely to occur in developed countries.
An Outrageous Misconception!
There are several reasons to suspect a role for micronutrients in non-scarring alopecia. The
most noteworthy of these is that micronutrients are major elements in the normal hair follicle
cycle, playing a role in the cellular turnover of matrix cells in the follicle bulb that are rapidly
dividing [20, 21]. Nutritional influences in humans can actually affect the skin and hair folli-
cles, a phenomenon that is nowadays, fortunately, observed almost exclusively in patients
under total parenteral nutrition and in very specific patient populations [16].
The problem is that the reverse logic holds strong in popular belief: If an individual suffers
from hair loss, then he/she must have some sort of nutritional deficiency causing the hair loss,
even if he/she is healthy, robust, and youthful! The following simplistic and erroneous associa-
tion is one that most seem to accept all too easily: Every case of “hair loss” has to be related to
some sort of nutritional deficiency, and restoring it through diet or supplementation, will have
a positive impact on hair, will halt shedding or even reverse thinning or balding! To understand
how absurd this argument is, it is similar to suggesting that the compass actually turns the ship.
The fact that some nutrients (amino acids, vitamins, trace elements, etc.) are involved in
the physiology of the hair follicle does not mean that any hair follicle condition or pathol-
ogy is necessarily related to a nutritional deficiency!
Is There Hair Loss Due to Nutritional Disorders? 271
This absurd and childish approach, i.e., that every case of hair loss will benefit from
improved nutrition or dietary supplementation is utterly false. Actually, of all the nutrients
involved in the hair follicle’s physiology and will be reviewed in the following chapters, only
Zinc (Zn) and Iron (Fe) deficiencies may be associated with hair loss and even those, only
under very specific circumstances [22, 23].
Although carbohydrates, proteins, vitamins, and minerals are essential for healthy hair
growth, their absence or deficiency will not exacerbate AGA or FPHL but might cause
diffuse hair loss.
Furthermore, even though hair growth disorders caused by nutritional deficiencies in

healthy individuals are rare in developed countries, they still tend to be overestimated by
patients and physicians, especially concerning the role of vitamins. Patients with hair loss
frequently inquire whether nutritional supplements can help prevent further hair loss or restore
hair growth. Many balding individuals will start dietary supplements without medical advice
in the hope (or belief) that supplements will help. There is very limited research on the role of
nutrient supplementation concerning “hair follicle health” in the absence of a deficiency, and
physicians must counsel their patients on the lack of research supporting these products.
Unfortunately, most patients will not follow their physician’s advice and will typically “fall”
for direct-to-consumer advertising, promoting the use of a wide variety of supplements against
hair loss. The unregulated supplement industry capitalizes on this population’s vulnerability,
and many nutritional supplements are actually advertised as effective hair loss treatments.
Moreover, the FDA does not regulate supplements nor has the authority to review dietary
supplements for safety and effectiveness before they are marketed [24]. Thus, it relies on
the physician and the consumer to review the efficacy and safety of supplements [25].
This lack of oversight and regulation or the need to demonstrate safety or efficacy prior to sales,
manufacturers continue to enter the market. According to a report by Goldstein research, in 2016
the global beauty supplement market was valued at about $3.5 billion, and by the end of 2024 this
market is estimated to reach $6.8 billion [25, 26]. Meanwhile, pharmacy aisles and internet drug-
stores are full of vitamins promising full, thick hair for prices that range from suspiciously cheap
to unreasonably overpriced.
Burns et al. (2020) of the Massachusetts General Hospital, Boston, a retrospective analysis
of patients with hair loss at our academic alopecia clinic showed that 81% of patients were
female and had rates of reported supplement use higher than the national average. This was
most notable among younger people (age 18–39 years), with 63% using supplements com-
pared with the U.S. average of 40% [27]. Patients taking a hair-specific supplement, such as
one labeled “Hair/Skin/Nails” or biotin, also had a higher number of total supplements used
(4.5 supplements) compared with the overall study population (2.5 supplements). The cost of
supplement use extends beyond potential health risks and into women’s wallets. A single hair-
specific vitamin can cost $50 to $100 per month, with costs totaling well over $1000 per year
if multiple supplements are used. Hair loss is often chronic and progressive, and the expense
compounds with years of use [28].
Is There Hair Loss Due to Nutritional Disorders?
Yes, of course, there is. Hair growth may be impacted by calorie and protein malnutrition as
well as micronutrient deficiency; however, the links are complex and still not fully understood.
Nutritional influences in humans can affect the skin and cause scaling disorders resulting in
excessive hair loss, while others can directly affect the pilosebaceous unit without concomitant
scaling. Therefore, it is imperative to separate those nutritional factors that act directly on the
skin from those acting only on the hair follicle. Additionally, one should first distinguish
between hair loss that is actually related to nutritional disorders vs. hair loss not associated
with nutritional disorders. There is a very brief summary of the earlier type of hair loss in the
following lines, both because these disorders are beyond this chapter’s scope and because they
represent a very small percentage of patients with hair loss [29].
Nutritional Disorder-Related Hair Loss with Scaling Problems
It is well-known that some chronic exfoliating scalp disorders lead to increased shedding due to
pruritus and excoriations induced by patients in their effort to alleviate their symptoms [30].
Less recognized is the involvement of nutritional factors in milder scaling conditions, such as
dandruff and seborrheic eczema, except for dairy produce [31]. Biotin deficiency has been
reported to cause dermatitis and hair loss in experimentally induced states but establishing the
presence of a deficiency in humans with a balanced diet has yet to be demonstrated [32]. There
is also sufficient animal data to support the role of essential fatty acids deficiency in dermatitis
and hair loss, with limited evidence established in humans [33, 34]. The clinical manifestations
associated with zinc deficiency are similar to those seen in the notorious but extremely rare
congenital skin disease named acrodermatitis enteropathica [35]. There is a considerable debate
on whether food allergy and food intolerances (hypersensitivity type I mediated reactions) can
affect the hair cycle, and even where there is strong evidence for an immunological involvement
in the skin, strong scientific skepticism surrounds any hair follicle involvement [36].
Nutritional Disorder-Related Hair Loss Without Scaling Problems
Possibly one of the most contentious areas in dermatology is the role of nutritional factors and
hair loss in subjects without any observable scaling disorder. In general, hair loss without scal-
ing problems occurs in diffuse hair loss and chronic telogen effluvium (CTE) [37]. Iodine
deficiency and hypothyroidism may cause CTE, just like biotin, inositol, niacin, and panto-
thenic acid deficiencies have been reported to cause diffuse hair loss without scaling [38].
Studies have also reported potential associations between nutritional deficiency AGA, FPHL,
and alopecia areata [29, 39]. However, there is no causal correlation or even a strong correla-
tion of any kind. All these will be reviewed extensively in the relevant chapters.
Very few disorders can have a subclinical presentation and remain undiagnosed for a
long enough time to cause noticeable hair loss without first causing any other sign that
would drive the patient to the physician.
Iron deficiency is probably the most prominent and is the most common nutritional disorder
in women with CTE [40] and pregnant women [41] while it rarely occurs in men, with or with-
out hair loss (see Chap. 67). According to a study by Rushton et al. (2001) on 200 -apparently-
healthy women complaining of increased hair shedding for longer than six months, the most
frequent abnormal finding was low serum ferritin. Notably, what Rushton considered as “low
ferritin” (<40 μg/L) is much higher than the lower limit of ranges that most labs consider nor-
mal (>10 μg/L). As will be analyzed in Chap. 67, the established normal reference ranges for
Iron in women are probably incorrect and have derived from populations containing a vast
number of iron-deficient women [42]. In an earlier study by Rushton et al.(1990), 65% of these
women had a ferritin concentration <40 μg/L, the lowest control value obtained in women
without hair loss [43] and a level just above the lower limit of normal for males quoted in some
laboratories [44]. Interestingly, 96% had serum ferritin <70 μg/L, the upper 99% confidence
limit for iron staining in the bone marrow [45]. In these women, the role of Iron as an aetiologi-
History of Dietary Standards 273
cal factor in diffuse hair loss in non-anemic, iron-deficient women has been demonstrated by
Hård since 1963 [46].
Another element potentially correlating with hair loss is the essential amino acid L-lysine.
The role of essential amino acids in anemia is well known, but their possible role in hair growth
has not been investigated, probably due to the abundance of body stores making amino acid
deficiency in a well-nourished individual unlikely. However, the rate-limiting essential amino
acid L-lysine is an exception. The bioavailability of L-lysine is restricted primarily to meat,
fish, and eggs, and drastically reducing the consumption of these foods, like strict vegans,
could result in a negative balance between uptake and utilization. While the body could make
up any shortfall from the muscle reserves, it could arguably prioritize their availability for the
essential tissues leaving nonessential tissue such as scalp hair compromised. Rushton et al.
have noted that the addition of L-lysine to iron supplementation resulted in a significant
increase in mean serum ferritin concentration in some women with CTE who failed to respond
to iron supplementation alone. There is limited data available, and the role of L-lysine should
be investigated further [47].
Hair Loss Without Nutritional Disorders
This category includes every hair loss cause that occurs in otherwise well-fed individuals. It
includes individuals following an ordinary Western pattern diet, no matter how unhealthy it
might be, concerning higher intakes of red and processed meat, butter, high-fat products, and
high-sugar drinks. Naturally, AGA falls into this category. This is the category of patients that
clinicians will mostly encounter since the average hair loss patient does not suffer from any
nutritional deficiency relating to their condition.
Marketing and advertising directed to consumers are very aggressive and manage to con-
vince, despite their weak scientific support. Therefore, physicians must be able to answer ques-
tions having a thorough knowledge of the available evidence. One point to emphasize is that
“hair-growth” supplements are not without risks. In the absence of a deficiency, supplementa-
tion may prove harmful to hair. Over-supplementation of certain nutrients, including selenium,
Vit A, and Vit E, has been linked to hair loss [37, 39, 48, 49].
In the following chapters, the available literature on nutrient deficiencies that may result in
hair loss will be reviewed, the risk factors for these deficiencies will be analyzed, and the avail-
able evidence of supplementation effects on hair loss, both beneficial and adverse, will be
presented. Moreover, it is thought-provoking to start with a historical review that might help
disprove some common nutritional myths.
History of Dietary Standards
Dr. Leitch reviewed the evolution of dietary standards in her seminal article in 1942, and it was
the first time the term “recommended daily allowance” (RDA) appeared in the scientific litera-
ture [50]. Before that, the first official “dietary recommendation” was issued by the English
parliament, included in the “merchant shipping amendment act of 1867,” requiring the addi-
tion of lemon juice to the diet of sailors as a means of preventing scurvy [51].
The first genuinely scientific dietary recommendation was introduced even earlier by
Edward Smith during the peak of that time’s economic recession [52]. The British Royal
Council had asked Edward Smith to determine the minimum required food quantity an adult
requires to avoid starvation. Smith measured the amount of exhaled CO2 and nitrogen elimina-
tion in mine workers and estimated that the minimum necessary amount of food for a man
doing manual labor is 80 g of protein and 2800Kcal/day. That was the first time a dietary stan-
dard was based on actual scientific measurements. These results might seem inadequate by
today’s standards, but during the nineteenth century, it was widely accepted that nutrition that
is based only on protein, carbohydrates, lipids, and certain trace elements was sufficient for
survival and, probably, even well-being [53]. Another hundred years had to pass to realize that
food contained additional essential elements that had not been yet determined, such as vita-
mins [54] (see Chap. 50).
During World War I (1914–1918), guidelines were issued regarding the required quantity of
food for soldiers. By then, nutritional deficiency-related diseases were clearly identified, and
foods that prevented them were named “protective foods.” A typical example of a protective
food was milk, since British Authorities -as early as 1911- made recommendations to add milk
in children’s nutrition and green vegetables in all ages [55]. The “Great Depression” of 1929 in
the USA necessitated the introduction of committees to gather information on the human
body’s needs in minerals and vitamins. In 1933, the first dietary U.S. recommendation was
published by Stiebeling [56] on behalf of the U.S. Department of Agriculture and included
recommended values for several vitamins and minerals. In 1939, Sherman stated that these
recommended minimum values should be increased by 50% in order to include individuals
that earlier values may not cover [57]. During World War II, more detailed recommendations
were issued that included several trace elements and vitamins to ensure that the minimum
required nutrient intake is adequate even under war conditions.
All these official recommendations addressed minimum required values in conditions of
starvation, threat, and disease and were the minimum required amounts of nutrients adequate
to keep a man alive in periods of food deprivation. These recommendations were later used as
the basis of legislative provisions on dietary supplements and nutrition in general [58]. Indeed,
current official recommendations, even in the twenty-first century, are not different from those
issued in 1933, and, in some cases, they are even lower.
On may 27, 2016, the FDA updated the regulations and changed the RDIs and daily values
to reflect current scientific information. Until this time, the daily values were still primarily
based on the RDAs established in 1968. The new regulations make several other changes to the
nutrition facts label to facilitate consumer understanding of the calorie and nutrient contents of
their foods [59, 60].
Adequacy of Nutrients
Adequate intake of micronutrients within the range of dietary reference intake (DRI) is consid-
ered to prevent deficiencies and is vital for maintaining health and wellness. DRI are reference
values that are quantitative estimates of nutrient intakes to plan and assess diets for healthy peo-
ple. To determine the exact quantity of a specific micronutrient needed on an everyday basis to
cover an individual’s needs, every five years, the U.S. departments of agriculture (USDA) and
health and human services (HHS) jointly publish a report containing nutritional and dietary infor-
mation and guidelines for the general public.
The dietary guidelines are based on the preponderance of current scientific and medical
knowledge. The 2015–2020 edition of the Dietary Guidelines is based on the Scientific Report
of the 2015 Dietary Guidelines Advisory Committee and consideration of Federal agency and
public comments and has determined 5 DRI values [61]:
1. Estimated average requirement (EAR): EAR is the average daily nutrient intake value
estimated to meet the requirement of 50% of healthy individuals in every demographic
group (age, gender, and overall physical condition) according to international literature.
2. Recommended daily intake (RDΙ): RDΙ is the average daily dietary nutrient intake level
sufficient to meet the nutrient requirement of nearly all (>97%) healthy individuals in every
demographic group (age, gender, and overall physical condition). It is estimated based on
EAR and is usually 20% higher.
3. Adequate intake (AI): AI is used whenever an RDΙ cannot be determined. AI is the intake
level that is considered to cover the needs of 100% of every demographic group. AI is based
on experimentally or clinically determined approximations or estimates of nutrient intake
by a group (or groups) of apparently healthy people without adequate data.
History of Dietary Standards 275
4. Tolerable upper intake level (UL): UL is the highest average daily intake level that is
likely to pose no risk of adverse health effects to almost all individuals in the general popula-
tion. As intake increases above the UL, the potential risk of adverse effects also increases.
This is the most significant difference between the new DRI and the old RDA since the older
RDA did not mention the tolerable upper intake levels.
5. Lower reference nutrient intake (LRNI): It is the lowest intake level under which a per-
son is at risk of suffering from a nutritional disorder.
However, the most commonly used value in scientific literature is an older value, the recom-
mended dietary allowance, RDA. RDAs were developed during world war II by a committee
established by the United States National Academy of Sciences investigating nutritional issues
that might “affect national defense.” RDAs were a set of nutrition recommendations that evolved
into the dietary reference intake (DRI) system of nutrition recommendations (which still defines
RDA values) and the RDIs used for food labeling. The RDAs (and later the RDA values within
the DRI) were regularly revised to reflect the latest scientific information.
Unfortunately, the concept of RDAs (or RDIs) is largely misunderstood, often deliberately,
to create certain “trends” and (fake) “needs” for dietary supplements. People tend to believe
that any value short of RDI is harmful and/or dangerous and that any value above the issued
RDA is safe or even favorable for human health (Fig. 49.4). The scientific truth is much more
complex, and it will be discussed in Chap. 49, which is addressing dietary supplements in
general. Table 1 includes the official values of most essential dietary micronutrients.
Table 1 Table of dietary reference intake (DRI) for essential micronutrients involved in the hair follicle physi-
ology [61, 62]
Best food sources in decreasing
order of content (average
Vitamins Ear RDA/AI UL Units serving portions)
Vitamin A 625 (or 900 (or 3000 IU) 3000 (or mg Sweet potato, spinach, beef
2000 IU) 10,000 IU) liver, pumpkin, cantaloupe,
carrots, black-eyed peas,
mango, fortified cereals
Vitamin C 75 90 (Smokers: An 2000 mg Peppers, citrus fruits, and
additional juices (e.g., oranges,
35 mg) grapefruit), kiwifruit, broccoli,
Brussels sprouts, strawberries,
tomatoes, and tomato juice
Vitamin D 10 (or 400 IU) 15 (or 600 IU) 100 (or μg Cod liver oil, fish (e.g., herring,
4000 IU) mackerel, salmon, trout, and
tuna), fortified products (orange
juice, cereals, dairy, and soy
products)
Vitamin E 12 (or 18 IU) 15 (or 22.5 IU) 1000 (or mg Wheat germ oil, almonds, nuts
1500 IU) and seeds, peanuts and peanut
butter, fortified cereals and
juices, sunflower seeds and oil,
other vegetable oils
Vitamin K NE 120 ND μg Natto (dangerously high
content), dark green vegetables
(e.g., collards, broccoli, kale,
spinach, turnip greens,
collards), soybeans
Vitamin B1, 1 1.2 ND mg Breakfast cereals and other
Thiamine fortified grain products (e.g.,
bread, cereal, pasta, rice),
beans and peas, pork, trout,
tuna, mussels
Vitamin B2, 1.1 1.3 ND mg Beef liver, meats, enriched
Riboflavin grain products (e.g., bread,
cereal, pasta, rice), dairy
products, clams
(continued)
Table 1 (continued)
Vitamin B3, Niacin 12 16 35 mg Beef liver, poultry, pork,
salmon, tuna, enriched grain
products (e.g., bread, cereal,
pasta, rice), nuts
Vitamin B5, NE 5 ND mg Breakfast cereals fortified, beef
Pantothenic acid liver, shitake mushrooms,
sunflower seeds, poultry, tuna,
avocado, dairy products
Vitamin B6, 1.1 1.3 100 mg Chickpeas, beef liver, salmon,
Pyridoxine tuna, chicken breast, potatoes,
fruits (other than citrus)
Vitamin B7, Biotin NE 30 ND mg Beef liver, beef and pork meat,
eggs (cooked only), tuna,
salmon, seeds, and nuts
Vitamin B8, Inositol NE 1000 (unofficial, >18,000 mg Citrus fruits, beans, grains, and
since it is nuts
produced
naturally in
human kidneys)
Vitamin B9, Folic 320 400 1000 μg Beef liver, beans, and peas,
acid enriched grain products (e.g.,
bread, cereal, pasta, rice), dark
green leafy vegetables (e.g.,
spinach, Brussels sprouts,
broccoli)
Vitamin B12, 2 2.4 ND μg Seafood (especially clams,
Cyanocobalamine trout, salmon, and tuna), beef
liver, meats, dairy products,
eggs, fortified cereals
Minerals and trace elements
Calcium 800 1000 2500 mg Cheddar cheese, yogurt, and all
dairy products, canned seafood
with bones (e.g., salmon and
sardines), fortified cereals and
juices, fortified soymilk, tofu
(made with calcium sulfate),
dark green vegetables (e.g.,
spinach, kale, broccoli, turnip
greens)
Copper 700 900 10,000 μg Beef liver and other organ
meats, oysters and shellfish,
sesame and sunflower seeds,
chocolate and cocoa, potatoes
Iodine 95 150 1100 μg Seaweed (dangerously high
content!), seafood, cod, dairy
products, iodized salt, enriched
breads, and cereals
Iron 6 18 45 mg Whole grain, fortified cereals,
breads, oysters, beans and peas,
chocolate, dark green
vegetables, meats, and poultry
Magnesium 330 400 350 mg Almonds, cashews, peanuts,
(Applies only spinach, and other green leafy
to vegetables, avocados, bread,
supplemental wheat bran, potatoes
magnesium)
Phosphorus 580 700 4000 mg Tuna, tofu, pork meat, chicken,
Turkey, dairy products, nuts
and seeds, beans and peas,
whole grain, fortified cereals,
and breads
References 277
Table 1 (continued)
Selenium 45 55 400 μg Brazil nuts (dangerously high
content!), tuna, halibut,
sardines, meats, poultry, dairy
products, eggs, enriched pasta,
and rice
Silicon 24–33 NE NE mg Beer is the best source of Si
(Has not yet been regarding absorption and
established as an bioavailability
essential nutrient) Grains, barley, oats, rice bran,
wheat bran, cereals, flour,
bread, pasta, bread products.
Asparagus, cabbage, cucumber,
olives, radishes, brown rice,
and green beans, bananas
(negligible absorption, <2%)
Zinc 9.4 11 40 mg Oysters (dangerously high
content!), seafood (e.g., clams,
crabs, lobster), beef, dairy
products, poultry, fortified
cereals, nuts, cashews, whole
grains
Sulphur >900 (but diets Estimated NE mg All meats, cereals, corn,
that are 1500–2000 sunflower seeds, oats,
adequate in chocolate, cashews, walnuts,
protein contain almonds, and sesame seeds,
adequate onions, cruciferous vegetables,
sulphur) such as broccoli, cauliflower,
cabbage, etc.
Boron 0.9–1.4 1–13 20 mg Nuts, legumes, tomatoes,
broccoli, avocado, green
peppers, apples, grapes, and
generally vegetables grown in
soil rich or fortified with boron
EAR estimated average requirement, AI adequate intake, RDA recommended dietary allowance, UL tolerable
upper intake level, ND not determinable owing to lack of data of adverse effects in this age group and concern
concerning lack of ability to handle excess amounts, NE not yet been established or not yet evaluated
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The Inconvenient Truth About Food
Supplements (or “Hope in a Capsule”) 49
Basic Concepts • The time-old saying “can’t hurt, might help” con-
• Food (or dietary) supplements are products intended cerning food supplements should be used with cau-
to provide nutrients in high concentration to tion, given the lack of regulatory oversight,
increase the quantity of their consumption or pro- interference with diagnostic laboratory assays,
vide non-nutrient chemicals that claim to have a potential interactions with prescribed pharmaceuti-
biologically beneficial effect. cals, and most of all, the lack of solid evidence on
• Guided by elusive, outrageous, and often false being useful.
claims of manufacturers, the public considers food
supplements useful or even necessary for wellness,
fitness, and longevity. Approximately 50% of adults
chronically consume 1–4 dietary supplements daily Food supplement, according to the Dietary Supplement
in a desire to acquire more control over their health. Health and Education Act (DSHEA) of 1994 (Public Law
• These supplements are exempt from the regulations 103–417) [1], is a product that is not a pharmaceutical drug,
applicable to conventional foods, food additives, a food additive (spice or preservative), or “conventional
and drugs. They can be marketed and sold without food,” and which meets the following criteria:
undergoing a formal FDA approval process for
safety or efficacy; they are not even required to fol- • The product intends to supplement an individual’s diet
low established drug product good manufacturing without being used as a meal replacement.
practices (GMPs). • The product is or contains vitamins, trace elements,
• These products are not intended to prevent or treat enzymes, essential fatty acids, concentrates, metabolites,
any disease, and in some circumstances, they can extracts of glands or organs, ingredients, herbs, amino
even be dangerous, according to the U.S. National acids, or any other substance which contributes to other
Institutes of Health. food eaten or any combination of these.
• Nevertheless, the public considers them more use- • The product is labeled as a dietary supplement, is mar-
ful and safer than pharmaceuticals, and both healthy keted in the form of tablets, pills, capsules, pastilles, soft-
individuals and those with a doctor-informed medi- gels, gelcaps, powders, bars, or liquids, and is orally
cal condition use these products, mostly without administered.
sharing this information with a licensed medical
professional. Multivitamins are the most popular food supplements world-
• Dietary supplements are only useful and indicated wide [2] and represent a significant percentage of health-
in specific, vulnerable groups, and trials indicate no related expenses in the U.S., reaching more than 1/3 of
substantial health benefit to the general population. prescription drug expenses. A multivitamin/mineral supple-
Large meta-analyses have repeatedly demonstrated ment is defined in the U.S. as: “A supplement containing 3 or
that dietary supplements can even increase long- more vitamins and minerals and not herbs, hormones, or
term morbidity and mortality of both healthy indi- drugs, in which, each vitamin and mineral is included at a
viduals and patients with minor or severe dose below the tolerable upper level, as determined by the
conditions. Food and Drug Board, and does not present a risk of adverse
health effects” [3]. Multivitamin supplements are commonly
282 49 The Inconvenient Truth About Food Supplements (or “Hope in a Capsule”)
provided in combination with dietary minerals and the terms U.S. Supplement Market Share
multivitamin and multimineral are often used interchange-
ably. Even though the term multivitamin/multimineral sup-
plements (MVM) regularly appears in scientific literature, Meal Replacement
none of these terms has a precise scientific definition [4]. 11%
MVMs might even contain more than 10 different vitamins
and 7–10 minerals. Vitamin
31%
Sports Supplements
The FDA is responsible for taking action against any 14%
adulterated, unsafe or misbranded dietary supplement
product only after it reaches the market [5].
Specialty/Other
18%
Therefore, some MVMs might contain levels of specific Minerals
7%
vitamins and minerals that are substantially higher than the
RDA or even the established tolerable upper intake level.
Several popular brand supplements in the U.S. contain Herbs/Botanicals
amounts for some vitamins or minerals, often as high as 2–6 19%
times the RDA for minerals and 10–30 times the RDA of the
B vitamin complex. Calcium and Magnesium are the only
Fig. 49.1 U.S. market share by product according to 2018 Survey by
ingredients rarely included at 100% of the RDA because the the Council for Responsible Nutrition (CRN) [7]. (The CRN is trade
pill would be too large. Some MVMs that contain very high association representing 150+ dietary supplement and functional food
doses of one or several vitamins or minerals, or are specifi- manufacturers, ingredient suppliers, and companies providing services
to those manufacturers and suppliers) [7]
cally intended to treat, cure, or prevent disease, require a pre-
scription or medicinal license in the U.S. However, since
such products contain no novel compounds, they do not
require the same testing as would be required by a New Drug 49.1 Why Are These Products So Popular?
Application (NDA). Therefore, they are allowed on the mar-
ket as drugs due to the Drug Efficacy Study Implementation The intended use of dietary supplements is to ensure that a
program [6]. person gets enough essential nutrients. These products are
Americans have been massively consuming MVMs not intended to prevent or treat any disease and, in some cir-
since the early 1940s when the first such products became cumstances, can even be dangerous, according to the
available. Data from 2014 claim that at least half of U.S. National Institutes of Health [10].
American adults ingest at least one dietary supplement
daily and MVMs account for almost 20% of all purchases
of dietary supplements and 40% of all sales of vitamin
The vast majority of supplements used in the U.S. are
and mineral supplements (Fig. 49.1). Sales of all dietary
based on pure personal choice and not because health
supplements in the U.S. totaled an estimated $36.7 billion
care professionals recommend them to prevent or treat
in 2014. This amount included $14.3 billion for all vita-
any condition or disease. Although often taken to
min- and mineral-containing supplements, of which $5.7
improve or maintain health, less than a quarter of all
billion was for MVMs [8]. The U.S. food supplement
supplements are taken at the healthcare provider’s rec-
market is so competitive that according to 2015 data, no
ommendation [11].
single company accounted for more than a 5% share of
value sales [9].
Beauty supplements are big business.
According to a report by Goldstein Research, in 2016, the When investigating the reasons that make these products
global beauty supplement market was valued at about $3.5 are so popular, one should consider the context under which
billion, and by the end of 2024, this market is estimated to this phenomenon has risen. Consumers have been daily
reach $6.8 billion [2]. “bombarded” for decades with advertising messages on the
49.1 Why Are These Products So Popular? 283
Fig. 49.2 The most common

reasons users of different TOP REASONS USERS TAKE SUPPLEMENTS BY AGE GROUP
age-groups take dietary
supplements according to the 55+ years 35–54 years 18–34 years
2018 CRN Consumer Survey
on Dietary Supplements, OVERALL WELLNESS 49% OVERALL WELLNESS 49% OVERALL WELLNESS 49%
which included a national FILL NUTRIENT GAPS 33% ENERGY 33% ENERGY 37%
sample of 2004 adults (1504
were supplement users) aged BONE HEALTH 31% FILL NUTRIENT GAPS 32% HAIR, SKIN, NAILS 28%
>18 living in the U.S. [7]
HEART HEALTH 29% IMMUNE HEALTH 31% IMMUNE HEALTH 25%
HEALTHY AGING 28% HAIR, SKIN, NAILS 23% FILL NUTRIENT GAPS 22%
JOINT HEALTH 23% DIGESTIVE HEALTH 21% WEIGHT MANAGEMENT 21%
2018 CRN Consumer Survey on Dietary Supplements: www.crnusa.org/CRNConsumerSurvey
“risks of poor nutrition,” “free radicals,” “oxidative stress,” be precious for patients who consider their condition some-
and nutrition or lifestyle-related medical conditions [12]. what embarrassing (e.g., erectile dysfunction) or not war-
Food supplements are marketed mostly by evoking guilt ranting a professional opinion (e.g., “feeling of low energy”).
and fear in the consumers for their nutritional and lifestyle • For some consumers, food supplements offer hope when
choices. At the same time, they provide a -false- hope: a ben- conventional drug therapy does not, and many food sup-
efit from a food supplement that will “fix the problem,” will plements are marketed for disorders that are generally
offer overall health/wellness, will increase performance and considered incurable (e.g., psoriasis) or for which con-
energy, and will prevent or even cure health-related problems ventional treatment options are limited. Hair loss falls
[11]. Most individuals will start using food supplements to precisely in that category.
prevent and treat both real and imaginary conditions: arthri-
tis, colds & flu, osteoporosis, lack of energy, chronic fatigue, There are also a couple of more subtle, yet probably stronger,
memory issues, low vision, cholesterol, heartburn, stress, drives that complement the ones mentioned above:
depression, obesity, and others. Even high blood pressure
and cancer are some of the most widespread conditions peo- • It is much easier for the average person to take a pill,
ple believe food supplements will prevent, alleviate, or even believing that it will decrease the likelihood of malig-
cure. Interestingly, whether these individuals are motivated nancy, rather than actually changing his/her lifestyle and
to use food supplements for their alleged benefits or develop harmful lifestyle habits (e.g., smoking).
motivations to justify the use is still unknown. Nevertheless, • People desire more control over their health, especially in
most supplement users will fall into one of the following cat- the modern environment of managed health, and using food
egories [13, 14] (Fig. 49.2): supplements is their way of “seizing control.” In that sense,
food supplement use is “a statement of independence.” This
• According to the public view, food supplements provide false sense of control offered by these products is utterly
added value to one’s nutrition and improve the “quality of tempting, and very few can resist it once introduced to it.
nutrition.” Most people cannot discern between poor food • Especially for aging “baby-boomers” who are still vital
choices and actual nutrient deficiencies, thinking that eating and want to prove that “old does not mean unfit,” food
less of a specific food than official recommendations consti- supplements offer the “magic pill solution,” promising
tutes a “deficiency.” Thus, they will use food supplements to rejuvenation, life prolongation, and improvement of qual-
“correct” that -non-existing problem- with one or more pills. ity of life with “just one pill a day.” These people want to
• Many consider that because most food supplements are take an active role in their own health and perceive sup-
derived from natural sources are intrinsically safer than plements as a type of “insurance” against poor health.
synthetically created conventional drugs. This perception
has been encouraged by advertising and salesmen and has For these reasons, people have firm beliefs about these prod-
reached the status of a self-proclaimed truth. ucts. In addition, the increasing public and medical confusion
• Consumers with some non-threatening conditions may pre- over apparently contradictory results from studies and reports
fer the easy access that food supplements offer, rather than of possible benefits or potential adverse effects in certain cir-
the inconvenient, more expensive, and lengthy process nec- cumstances not only fail to discourage unsupervised food sup-
essary to acquire prescription medication. Easy access can plement use but seem to result in an increasing trend (Fig. 49.3).
Fig. 49.3 Trends in the 70

percentage of persons using
dietary supplements, by 60
gender for adults aged 20 and Women
over in the U.S., 1988–2006 Total
50
(From Gahche et al. [15]) Men
40
Percent
30
20
10
0
1988–1994 1999–2002 2003–2006
Years
NOTES: Significant linear trend from 1988–1994 through 2003–2006. Statistically significant difference for men
compared with women for all time periods, p < 0.05 for comparison between genders within survey periods. Age
adjusted by direct method to the year 2000 projected U.S. population.
SOURCE: CDC/NCHS, National Health and Nutrition Examination Surveys.
49.2 Regulatory Issues Until December 2006, when the U.S. President signed the
Dietary Supplement and Nonprescription Drug Consumer
In the U.S., the FDA regulates drugs, food additives, dietary Protection Act. S. 3546, manufacturers were not even obliged
supplements, and nutritional ingredients. to inform the FDA on reports or complaints about adverse
The pre-market approval process for food additives and effects related to their products [16]. After that, the FDA was
pharmaceuticals is tedious and expensive, requiring rigorous required to establish systems of data collection on serious
testing of the product’s safety. The FDA carefully reviews all adverse reactions (e.g., for those resulting in hospitalization,
evidence before any new product is introduced into the mar- significant disability, or death) that people experience while
ket. Pharmaceuticals must be tested for efficacy as well, using dietary supplements. Since then, manufacturers, pack-
which is required to be demonstrated beyond doubt through ers, and distributors of dietary supplements are obliged by
adequate and well-controlled trials, including human clinical law to submit information to the FDA concerning adverse
trials, proving that the drug will have the effect claimed on its reactions reported to them by the public [4]. This new regula-
labeling. Interestingly, even though the FDA is tasked with tory requirement finally addressed the long-recognized
the oversight of dietary supplements, it regulates these prod- safety concerns over dietary supplement use.
ucts under a completely different regulatory framework than Accordingly, the European Union has issued harmonized
the one covering conventional foods, food additives, and rules on those products under the Food Supplements Directive
drugs. According to the FDA website, under the Dietary (FSD), Directive 2002/46/EC, to protect consumers against
Supplement Health and Education Act of 1994 (DSHEA), potential health risks from food supplements and to ensure
dietary supplements and dietary ingredients are exempt from that they are not provided with misleading information [17].
the food additive regulations applicable to conventional This Directive establishes a definition for food supplements,
foods and may be marketed and sold without undergoing a lays down a harmonized list of vitamins and minerals that
formal FDA approval process. may be added for nutritional purposes in food supplements. It
also contains a list of permitted sources (vitamin and mineral
substances) from which those vitamins and minerals may be
manufactured and sets labeling requirements [18]. However,
Dietary supplement manufacturers are not required by
in the European Union (E.U.), monitoring of food supple-
the FDA to prove safety or efficacy and are not required
ments is the responsibility of each country’s competent
to follow established drug product good manufactur-
authority, and for further details, the reader can address the
ing practices (GMPs). The manufacturers of supple-
respective national legislation. Concerning the labeling of
ments are not required to provide rigorous scientific
food supplements in the E.U., in December 2012, a list of
evidence of safety or efficacy and are only required to
approved functional health claims went into effect [19]. The
provide information to support just labeling claims.
list includes generic claims for substances other than botani-
cals, whereas disease risk reduction claims and claims refer-
49.3 Who Is Using Food Supplements? 285
ring to the health and development of children require Marketing on the Internet is subject to regulation in the same
authorization on a case-by-case basis, following the submis- fashion as promotions through any other media.”
sion of a scientific dossier to the European Food Safety However, even these specific regulations have not discour-
Authority (EFSA). Health claims based on new scientific data aged manufacturers in advertising and labeling their products
will have to be submitted to EFSA for evaluation, but a sim- with claims that may start from general, ambiguous, or pseudo-
plified authorization procedure has been established. scientific statements and can climax to clear-cut outrageous
Concerning the labeling of food supplements in the U.S., health claims. However, as long as these claims remain ambig-
health claims are defined explicitly under the Nutrition uous and do not affirm treatment or cure of disease but remain
Labeling and Education Act of 1990 (NLEA) [20]. These constrained to “maintenance” or “support” of a function, they
statements should characterize the relationship between a can effectively stay “under the radar” of the FDA. These are
food substance and a specific disease or health-related condi- some claims copied from popular food supplements:
tion based on significant scientific agreement. Health claims
on dietary supplement labels must meet the same criteria • Causes muscle mass changes,
established under NLEA for conventional food products • Provides increased energy,
(Commission on Dietary Supplement Labels, 1997) [21]. • Provides increased strength,
DSHEA permits four types of structure/function claims -for- • Will increase physical performance,
merly referred to as nutritional support statements- to appear • Supports general metabolism,
on supplement labels [22]: • Improves recovery,
• Supports fat metabolism,
• a benefit related to a classical nutrient deficiency disease, • Can affect mood swings,
disclosing the prevalence of such disease, • Supports cognitive function,
• a description of the role of a nutrient or dietary ingredient • Serves as a weight-loss or management product,
intended to affect the structure or function in humans, • Removes metabolic by-products,
• a description of the documented mechanism by which a • Serves as an appetite suppressant,
nutrient or dietary ingredient acts to maintain such struc- • Supports glucose metabolism,
ture or function, • Supports testosterone metabolism,
• a description of general well-being from consumption of • Supports the immune system,
a nutrient or dietary ingredient. • Provides antioxidant properties,
• Relieves stress,
• Could alter libido.
Structure/function claims can be distinguished from
Despite the vagueness and the unsubstantiated nature of
the more rigorous health claims in that they are not
these claims, people desperate to improve their health, well-
permitted to state or imply a link between a supple-
ness, and fitness, will voluntarily “fill in” the missing scien-
ment and the treatment, diagnosis, cure, or disease pre-
tific facts with hopes and good-will. Knowing that people are
vention. The following disclaimer must accompany
willing to believe anything regarding health, manufacturers
structure/function claims in the U.S.: “This statement
introduce new food supplements with more “interesting” and
has not been evaluated by the Food and Drug
promising claims. The estimated number of supplement
Administration. This product is not intended to diag-
products increased from 4000 in 1994 to more than 55,000 in
nose, treat, cure, or prevent any disease” [23, 24].
2012, the most recent year for publicly available data [26].
Additionally, in November 1998, the Federal Trade Overall, there is a notable lack of oversight and scien-
Commission (FTC, 1998) issued for the industry an advertis- tific rigor in the manufacturing and marketing of sup-
ing guide on dietary supplements [25] that clarified truthful plements, mostly due to the regulatory framework.
claims for advertising. The guide states that dietary supple-
ment manufacturers must back up explicit claims and implied
benefits made for their products and that (quoting): “The FDA
has primary responsibility for claims on product labeling, 49.3 Who Is Using Food Supplements?
including packaging, inserts, and other promotional materials
distributed at the point of sale. The FTC has primary responsi- Dietary supplement use is widespread among U.S. adults aged
bility for advertising claims, including print and broadcast ads, 20 and over, and similar trends have been reported in Western
infomercials, catalogs, and similar direct marketing materials. European countries and less so in former Eastern Europe. Very
interesting and detailed data have been gathered from the 2008 Working Document, food supplements containing vita-
National Health and Nutrition Examination Survey mins and minerals have a 50% share of the market.
(NHANES), initially designed to monitor the health and nutri- Euromonitor International research published in 2009
tional status of the U.S. population [27, 28]. The NHANES is revealed that the number of substances other than vitamins
a nationally representative, cross-sectional survey that sam- and minerals used in food supplements on the European mar-
ples civilian U.S. residents using a complex, stratified, multi- ket is estimated to be >400 and that significant national vari-
stage probability cluster sampling design, collected by the ation exists: fish oils constitute over 50% of the market of
National Center for Health Statistics (NCHS) [29]. other substances in Denmark, but under 3% in Spain and in
NHANES began querying the use of dietary supplements Italy; probiotics account for 44% of the market in Italy, and
for the first time in 1988 in two-year-long cycles, and each only 0.3% in Denmark; herbal products (ginkgo, ginseng, St
cycle ranged from 4863 to 6213 participants. Each cycle is John’s Wort, echinacea, and garlic) make up 75% of the mar-
considered as an independent sample, and in some studies, ket in the Netherlands, 40% in France, and <5% in Italy [45].
multiple cycles have been analyzed together, reaching fig- Dietary supplement use remains prevalent in patient popu-
ures as high as 37,958 individuals [30]. According to analy- lations with chronic conditions and among those who are fre-
ses of different cycles of the NHANES data, dietary quently hospitalized or at risk of hospitalization. According to
supplement use among adults has increased over the past the meta-analysis of Gardiner et al. on the 2002 National
30 years in the U.S., with over 40% of U.S. adults using sup- Health Interview Survey, 21% of adult prescription medica-
plements between 1988–1994 [2, 31]. Others report a steady tion users in the U.S. reported using food supplements in the
trend [30] in overall supplement use since 1999–2012, and prior 12 months, yet the majority (68%) did not share this
currently the trend appears to have stabilized to approx. 50% information with a physician [46]. According to Farina et al.,
of adults using one or more dietary supplements, of whom approximately one-third (34.3%) of all U.S. adults reported
more than two-thirds use MVMs [15, 32]. concomitant dietary supplements and prescription medica-
Many demographic characteristics of people who choose tion use. The prevalence of use was significantly higher
to use supplements have been revealed in studies: users tend among those with vs. without a doctor-informed medical con-
to be older [33, 34], have a lower body mass index (BMI) [34, dition (47.3% vs. 17.3%). These findings demonstrated that
35], are more physically active [34, 36], are less likely to the presence of a doctor-informed medical condition might
smoke [36, 37], have higher educational attainment and actually be a risk factor for concomitant dietary supplement
socioeconomic status compared to non-users [35, 38]. Almost and prescription medication use among U.S. adults [47].
one-third of the older adults reported using ≥4 types of food Despite available data, little is known about dietary sup-
supplements in the past 30 days, and in most cases, these plement use patterns or how they interact with medications.
products were generally taken regularly and for many years. Nevertheless, one in four Americans uses dietary supple-
Seventy percent of older U.S. adults reported using ≥1 food ments concomitantly with prescription medication, without
supplements, with significantly higher use reported among any kind of control on the indication, compatibility, possible
women (76%) than men (62%). Further, 31% of food supple- interactions, dose, and standardization of these products,
ment users reported taking only one supplement in the past which would make this practice safer [38]. Some authors
30 days, 23% took 2, 17% took 3, and 29% took ≥4 [39]. have even described the concept of dietary supplement poly-
Individuals classified as underweight or obese were less likely pharmacy. While classical polypharmacy has not been pre-
to use supplements than normal and overweight individuals. cisely defined in terms of the specific number of drug products
used, the critical elements for this “diagnosis” are the exces-
sive and inappropriate nature of medications utilized with
increased risk of adverse drug reactions. This increased risk is
These data lend credence to the “inverse supplement
precisely what seems to be happening with users of multiple
hypothesis” that those most likely to use dietary sup-
dietary supplements, rendering this problem a common one
plements are healthy individuals and are also those
and of considerable public health significance [48]. This hid-
least likely to need them [40, 41].
den and growing phenomenon of dietary supplement poly-
pharmacy adds a new layer of complexity to patient care and
poses a significant public health problem [49].
The household expenditures on dietary supplements in
2005 only in the USA were more than $21 billion [42],
increased to $30 billion [43] in 2011, and exploded to $38.8 49.4 Who Really Needs Food
Billion in 2015 [44]. Similar trends have been observed in Supplements?
the United Kingdom and other European countries. In the
E.U., the vitamins and dietary supplements market totaled Very little is known about the efficacy of dietary supplements
nearly €7 billion in 2009, and it is expected to jump to €11 for disease prevention, management, or treatment in nutrient-
billion by 2021. According to the European Commission’s replete and well-nourished populations. It is often complex
49.5 Group …Therapy 287
to study the use of supplements in disease prevention and However, several other prominent scientists recommend
health promotion in epidemiologic research because supple- routine use of multivitamins for most adults to fill known
ment use cannot be disentangled from other health-seeking nutritional deficiencies, ensure physiological body function,
behaviors. Investigating the use of supplements in random- and generally support good health, considering that these
ized clinical trials is also tricky because they tend to be short effects may also provide some protection against chronic
in duration, while most chronic diseases of public health disease [62–64]. Others disagree with the routine use of
concern have a long latency period (e.g., cancer, cardiovas- dietary supplements, mainly because MVMs have not been
cular disease) [11]. shown to provide actual protection against chronic diseases
As commonly stated, supplements are not a substitute [65]. Others believe that daily use of MVMs must be care-
for a balanced healthy diet. A diet that includes plenty of fully considered for most middle-aged and older individuals
fruits, vegetables, whole grains, enough protein, and to ensure adequate dietary intake of essential vitamins and
healthy fats should generally provide all the nutrients minerals and potentially reduce the risk of total cancer with-
needed for good health. However, not everybody has out any evidence of harm [62, 66]. However, disease preven-
access to a balanced diet, and even in developed countries, tion is not the rationale for the existence of MVMs and is not
there are cases of primary or secondary deficiencies, the primary reason consumers give for using MVMs and
mostly of vitamins. other dietary supplements [11, 62, 67]. Naturally, people
have some interest in disease prevention, but the top reason
given by consumers for using dietary supplements is for
overall health and wellness.
A primary deficiency occurs when an individual does
not get enough of a nutrient in its food. A secondary
deficiency may be due to any of the following: an
49.5 Group …Therapy
underlying disorder that prevents or limits the absorp-
tion or use of a nutrient; due to a “lifestyle factor,” such
Briefly, one could summarize that specific food supplements
as smoking, excessive alcohol consumption; the use of
can be medically indicated in the following groups alone:
medications that interfere with the absorption or use of
the nutrient.
1. Individuals with excessive needs: adolescents, pregnant
and breast-feeding females, athletes/soldiers, and anyone
under extreme training/working conditions (professional or
The fundamental question, “who has an actual indication top-level only), critically ill patients, burn and polytrauma
for a food supplement?” has an answer probably more patients, patients receiving medication that increases the
straightforward than one would imagine. One would be metabolism of one or more nutrients, or similar.
tempted to claim that nutrient-replete populations could also 2. Individuals with significantly reduced intake:
benefit from dietary supplements. After all, some dietary sur- undernourished- malnourished individuals of any age,
veys suggest that there are suboptimal intakes for several alcoholics, drug addicts, neglected elderly patients,
micronutrients and that partly due to our modern lifestyle, homeless individuals, mentally disabled individuals,
the typical Western diet does not fully cover human needs in chronically bedridden patients, those on long-term total
vitamins and trace elements [50–57]. However, the reliabil- parenteral/enteral nutrition, neglected psychiatric
ity and applicability of these results in the general population patients, individuals suffering from eating disorders (e.g.,
are dubious since most of these studies suffer from intrinsic anorexia nervosa), individuals under long-term restrictive
flaws, many are severely biased, and results are occasionally diets (e.g., strict vegans), atopics with sensitization to
unsubstantiated. multiple foodstuffs or similar.
The Dietary Reference Intakes and the 2010 Dietary 3. Individuals with significantly reduced absorption:
Guidelines for Americans recommend routine supplemental patients with digestion/absorption syndromes, patients
intakes of certain nutrients for specific population groups who have undergone extensive amputation surgery of the
[58, 59]. These are called “vulnerable groups” [60], and, gastrointestinal tract (tumor or bariatric surgery), intesti-
according to studies, receive less than 1/3 of the RDA of any nal failure, individuals underexposed to solar radiation
essential nutrient. People in these groups are suitable candi- (for Vit D only), and patients receiving medication that
dates for food supplements [61]. These include women of hinders absorption or chelates of one or more nutrients, or
reproductive age, pregnant or lactating women with increased similar (Table 49.1)
needs of folic acid and Iron, post-menopausal women with 4. Individuals with excessive losses: patients with chronic
increased requirements of Vit D and Calcium for prevention bowel inflammatory disease (chronic diarrhea), patients
of osteoporosis, individuals on a strict vegan diet requiring with increased urinary excretion (diuretics, liver cirrho-
vitamin B-12, and a few other groups. Further details go sis, diabetes, nephrosis, malignant tumors, nephrotic syn-
beyond the scope of this chapter. drome, renal failure), persistent vomiting, long-term
hemodialysis, heavily menstruating females (>80 mL/ Therefore, some population groups are advised to consume
menstrual cycle), individuals with sickle cell or other specific supplements. If someone does not belong to one of
types of anemia, and rarely individuals with extreme these groups, even if he/she follows a Western-unhealthy
“lifestyle factors,” such as extreme smoking or alcohol diet, he/she will not benefit from any type of food supple-
consumption, or similar. ments. In contrast, taking supplements will be harmful in
most circumstances (Fig. 49.4).
Table 49.1 Exemplary selection of drugs that may interact with
absorption or activity of nutrients of potential relevance to hair health.
(From Trüeb [68])
49.6 Can Food Supplements
ACE inhibitors Zinc
Be Dangerous?
Antacids Iron
Zinc
Biotin The intended use of dietary supplements is to ensure that an
Vitamin B12 individual gets enough essential nutrients. However, these
Antibiotics Beneficial intestinal bacteria products are not intended to prevent or treat any disease and,
Biotin
Vitamin K in some situations, can even be dangerous, according to the
Aspirin and NSAR Iron U.S. National Institutes of Health.
Diuretics Zinc As with medications and food ingredients, health risks
Isoniazid Niacin from the use of dietary supplements are derived mainly from a
Vitamin B6 consumer’s individual susceptibility, from the dietary supple-
Isotretinoin Biotin
ment’s inherent biological activity, or interactions with medi-
Levodopa Vitamin B6
Metformin Vitamin B12
cations. Some food supplements can be dangerous because of
Methotrexate Folic acid their contents and due to poor manufacturing practices.
Oral contraceptives Vitamin B1 Recently, Katta et al. (2020) published an excellent review
Vitamin B6 explaining every supplement must be treated with the same
Vitamin B12 level of caution as a pharmaceutical medication and that all
Folic acid
Vitamin C
supplements should be evaluated for PPIES: purity, potency,
Orlistat Essential fatty acids (in rats) interactions, efficacy, and safety [70].
Paracetamol (acetaminophen) Sulphur amino acids (in mice)
Penicillamine Copper • The purity of supplements is an important consideration,
Zinc as reported issues have ranged from microbial contamina-
Statins Selenium
tion, heavy metals to adulteration [70].
Coenzyme Q10
Valproic acid Biotin • In terms of potency, two main issues exist. The first is
Zinc Copper ensuring that the supplement contains the dose specified on
Fig. 49.4 Naïve vs. accurate

view of nutrient intakes. The Danger
RDA for a given nutrient of toxicity
represents a point that lies
between a range of
appropriate and reasonable Marginal
intakes between toxicity and > < Tolerable
deficiency. Both RDA and AI Safety Upper
are high enough to provide Intake Level
reserves in times of short-
term dietary inadequacies but Safety
not so high as to approach
toxicity. Nutrient intakes RDA > <
above and below this range
may be equally harmful. > < RDA > < Estimated
(From DeBruyne et al. [69]) Marginal Average
Requirement
Danger
Danger
of deficiency
Native view Accurate view

49.7 Supplements That Can Eventually Kill 289
the label, and that doses are consistent in all packages. The control center or the supplement manufacturer, the numbers
second concern is determining the correct dose, in terms of we have are likely very low estimates of actual events [75].
efficacy and safety, for a particular medical indication [70]. Unfortunately, precise data are lacking to quantify the fre-
• Concerning interactions, it is well documented that supple- quency of adverse events associated with dietary supplements
ments may interact with medications, foods, and other sup- in the U.S. Geller et al. estimate that in the U.S. alone, more
plements. In literature reviews of documented interactions than 23,000 emergency department visits annually -from
between medications and herbs/dietary supplements, the 2004 through 2013- were attributed to adverse events associ-
authors identified a total of over 1400 unique pairs of interac- ated with dietary supplements. These visits resulted in an
tions involving over 200 herbs and supplements. The great- estimated 2154 hospitalizations annually [76]. Rao et al.
est number of documented interactions involved magnesium, conducted a retrospective analysis of out-of-hospital dietary
calcium, iron, St. John’s wort, and Ginkgo biloba [70, 71]. supplement exposures reported to the National Poison Data
• Efficacy can be extremely challenging to determine since System from 2000 through 2012 and reported an overall
most supplements have little to no published scientific increase in the rate of dietary supplement exposures from
research; others have studies with important limitations, 2000 through 2012. Miscellaneous dietary supplements
ranging from poor methodology to a lack of generaliz- accounted for 43.9% of all exposures, followed by botanicals
ability, and most have only been tested in animals. Even (31.9%), hormonal products (15.1%), and other supplements
when human studies are available, there are multiple con- (5.1%). The majority of dietary supplement exposures
siderations, such as risk of bias, studies sponsored by the (70.0%) occurred among children younger than 6 years old
manufacturer and publication bias [70] (see Chap. 68) and were acute (94.0%) and unintentional (82.9%) [77].
• Concerning safety, since warning labels are not legally However, voluntary reporting may substantially underes-
required on most supplements, the consumer must beware. timate the adverse events associated with dietary supple-
Even when of high-quality and delivered in appropriate ments, and even then, accidental, rare, idiosyncratic, or
doses, many “natural” supplements have well-known and spontaneously reported adverse events are not the single
documented side effects, ranging from allergic reactions vital issue [78]. What is probably most important is whether
to gastrointestinal upset to sedation and more. While chronic use of food supplements can actually harm most
some research studies have evaluated short-term safety, users. The answer to this crucial question is precisely what
many lack information on long-term safety [70]. some researchers attempted to approach.
As already analyzed, under DSHEA, the law that regulates

dietary supplements safety [22], neither safety testing nor 49.7 Supplements That Can Eventually Kill
FDA approval is required before marketing a dietary supple-
ment. If a dietary supplement is found to be unsafe, the FDA Bjelakovic et al. in 2008 published the results of their meta-
can have the manufacturer remove the product only after it analysis on the literature findings of the Cochrane Library.
reaches the market [72]. Notably, from 2004 through 2012, They included all primary and secondary prevention ran-
more than 200 recalls were issued for dietary supplements domized clinical trials on all five major antioxidant supple-
containing unapproved regulated substances or impurities ments (beta-carotene, Vit A, Vit C, Vit E, and selenium)
[73], and calls for changes in oversight have followed [74]. versus placebo or no intervention. Included participants were
The FDA also tracks reports of illness, injury, or reactions either healthy (primary prevention trials) or had any disease
from supplements and supplement manufacturers report (secondary prevention trials), and overall, 67 randomized tri-
severe harmful effects to the FDA. FDA information shows als with 232,550 participants met the inclusion criteria. In
that the number of reports has continued to climb each year: the trials with a low risk of bias (47 trials, including 180,938
2010: 1009 reports of dietary supplement adverse events, participants), the antioxidant supplements significantly
2011: 2047 reports, and 2012: 2844 reports. Exposures to increased mortality (RR = 1.05, 95% CI: 1.02–1.08).
supplements accounted for more than 100,000 calls to U.S.
poison control centers in 2013. Of these calls, more than
8000 people were reportedly treated in health care facilities. When the different antioxidants were assessed sepa-
More than 1000 cases were reported to poison control cen- rately, analyses including trials with a low risk of bias
ters as having moderate to severe outcomes. These cases did and excluding selenium trials found significantly
not include electrolyte and mineral supplements, which increased mortality by Vit A (RR = 1.16, 95% CI:
accounted for another 2500 people treated in health facili- 1.10–1.24), beta-carotene (RR = 1.07, 95% CI: 1.02–
ties, with 350 moderate to severe reactions and two deaths 1.11), and Vit E (RR = 1.04, 95% CI: 1.01–1.07), but
reported to poison control centers. However, since most peo- no significant detrimental effect of Vit C (RR = 1.06,
ple who suffer unexpected side effects, illnesses, or drug 95% CI: 0.94–1.20) [79].
interactions from dietary supplements do not call a poison
The same research team updated their systematic review

in 2012 by adding literature findings from MEDLINE, After reviewing three trials of multivitamin supple-
EMBASE, LILACS, the Science Citation Index Expanded, ments and 24 trials of single or paired vitamins that
and Conference Proceedings Citation Index-Science. They randomly included more than 400,000 participants,
even scanned citations of relevant publications and asked they concluded that there was no clear evidence of a
pharmaceutical companies for additional trials. Overall, 78 beneficial effect of supplements on all-cause mortality,
randomized trials with 296,707 participants met the inclu- cardiovascular disease, or cancer [87].
sion criteria, and 56 trials, including 244,056 participants,
had a low risk of bias. In these 56 trials, all antioxidant sup-
plements significantly increased mortality; 18,833 Most, if not all, other reviews and guidelines that have
dead/146,320 (12.9%) versus 10,320 dead/97,736 (10.6%); appraised the role of vitamin and mineral supplements in pri-
RR = 1.04, 95% CI: 1.01 = 1.07). According to the authors, mary or secondary prevention of chronic disease have con-
antioxidant supplements need to be considered medicinal sistently found null results or possible harms.
products and should undergo sufficient evaluation before
marketing [80].
The same research team studied the effect of these five 49.8 Questions Nobody Seems to Ask
antioxidant compounds on hepatic disease [81] and the pre-
vention of gastrointestinal cancers [82]. Antioxidant supple- There is no scientific evidence that food supplements actu-
ments significantly increased the activity of gamma-glutamyl ally provide any real health benefits, and data suggests they
transpeptidase [81], and there was no convincing evidence can even cause harm when chronically ingested. Nevertheless,
that antioxidant supplements prevent gastrointestinal can- users are incredibly reluctant to discontinue these products,
cers. On the contrary, beta-carotene, in combination with Vit convinced that their consumption is beneficial to their health.
A and Vit E, significantly increased mortality [82]. Other Some even consume mega-doses of vitamins hoping to help
research teams have reported that these antioxidants offer their body “clean up” from harmful free radicals, which,
no benefit in preventing lung cancer. In individuals at high according to pop culture, are implicated in cancer and car-
risk of lung cancer, such as smokers and those exposed to diovascular disease [88–90]. Confusion is further intensified
asbestos, beta-carotene intake showed a small but statisti- by conflicting studies on nutrient deficiencies, food supple-
cally significant higher risk of lung cancer incidence, lung ments, novel foods, superfoods, fortified foods, and other
cancer mortality, and all-cause mortality compared to pla- newly found terms for supplements. Even though so many
cebo [83, 84]. Finally, Jiang et al. reviewed nine randomized people consume food supplements, there are so many sim-
controlled trials with 165,056 participants and reported that ple, yet unanswered questions on the benefits, adverse
antioxidant vitamins and selenium supplements did not effects, and details of the administration of food supplements
reduce prostate cancer incidence and mortality [85]. that nobody seems to care about:
Fortunately, they did not find any positive correlations with
mortality. • What happens if you exceed the recommended dose
In 2010, the World Cancer Research Fund and the long-term?
American Institute for Cancer Research (WCRF/AICR) con- • What age groups are eligible for use?
ducted a systematic literature review. It included twelve pro- • What is the minimum adequate dose?
spective observational studies on breast cancer risk and • What adverse effects can occur even with the recom-
folate intake, two on cobalamin, one on riboflavin, one on mended dose?
pyridoxine, and two on B-vitamin supplement use. For all • What are the risks of exceeding the recommended dose?
B-vitamins, the level of proof was judged “limited, non- • What are the possible interactions with pharmaceutical
conclusion” [84]. However, Egnell et al. conducted a large compounds?
prospective cohort study investigating the associations • What are the dose adjustments-requirements for every
between intake of various B-vitamins (dietary, supplemental, medical condition?
and total) and breast cancer risk. Total pyridoxine intake and • What is the significance of adequate hydration?
total thiamin intake were associated with decreased breast • At what time of the day should the product be taken?
cancer risk, suggesting a potential protective effect of these • What is the ideal regimen?
two vitamins in middle-aged women [86]. Fortmann et al. • Should it be taken with food or with an empty stomach,
systematically reviewed trial evidence to update the and when can the user eat again?
U.S. Preventive Services Task Force recommendation on the • Which are the excipients in the formula?
efficacy of vitamin supplements for primary prevention in • What is the potential allergenicity of the product?
adults with no nutritional deficiencies. • What is the potential intolerance of the product?
References 291
• Is the product tolerable by both sexes? time. Impressive packaging and even more impressive,
• Who should not use the product? vague, and often pseudo-scientific claims and health prom-
• Is the product safe during pregnancy or breast-feeding? ises render these products so tempting that no less than 50%
of adults in the U.S. and other countries are chronic volun-
Most doctors cannot answer these or several other -reason- tary users. Most users are typically healthy, following a
able- questions. However, they can quickly answer the same healthful lifestyle, yet ingesting food supplements is their
questions when the product in question is a pharmaceutical way of “seizing control” and a statement of independence
compound. Medical professionals do not have answers to against managed health. Unfortunately, one in four
these questions because there are no actual answers that Americans uses dietary supplements concomitantly with
would be supported by scientific documentation and tangible prescription medication, a phenomenon adding a new layer
evidence. Moreover, even though the public is not really of complexity to patient care and posing a significant public
interested in these answers before deciding to ingest a food health problem. Despite popular belief and confusion among
supplement, this frivolous behavior cannot justify healthcare physicians, supplementing the diet of well-nourished adults
professionals recommending these products to otherwise with multivitamins/multiminerals has no clear benefit and
healthy and well-nourished adults. can even be potentially harmful. Most, if not all, food sup-
The next chapters will discuss the properties, mode of plements do not prevent chronic disease, their use is not jus-
action, indications, needs, recommended doses, and safety of tified, and they should be avoided. This is mostly true for the
major nutritional organic and inorganic components of the general population with no clear evidence of micronutrient
human diet. These molecules also happen to be physiologi- deficiencies, who represent most supplement users in the
cally related to the hair follicle’s function, and for this rea- U.S. and other countries. Healthcare professionals should
son, they have been reported to have a potential positive not recommend these products unless specific nutrient defi-
action in the pilosebaceous unit and skin in general. In the ciencies are present, and they ought to know that no nutrient
next chapters, each vitamin, trace element, and herb that has has a positive effect on the hair follicles of an average,
been found, empirically or clinically, to relate with hair loss healthy, and ordinarily nourished adult with hair loss.
and/or dermatitis-induced hair loss will be discussed sepa-
rately. More specifically, though, each element’s indications
and evidence-based medical recommendations regarding References
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Vitamins: Definition and Types
50
Vitamin “history” started with the works of Frederick (a) It is an organic compound that is not a carbohydrate, fat,
Hopkins in 1912. He demonstrated in a series of animal feed- or protein, and it is necessary to perform a specific meta-
ing experiments that diets consisting of all known food bolic function or to prevent a specific deficiency
groups of milk, i.e., proteins, carbohydrates, fats, minerals, disease,
and water, failed to support animal growth [1]. However, the (b) it cannot be synthesized by the body in sufficient quanti-
addition of just a small quantity of milk reassured their proper ties to maintain health, so that it must be obtained
growth. This observation led him to suggest the existence, through the diet.
both in milk and in regular diets, of tiny quantities of -as yet-
unidentified substances essential for animal growth and sur- Although each vitamin has its specific metabolic profile,
vival. He called these hypothetical substances “accessory general functions of vitamins relevant to the hair include
food factors,” later to be called “vitamins.” It was this work facilitation and contribution to chemical reactions occurring
that led him to share the 1929 Nobel Prize for Medicine with in cells and acting as catalysts in necessary energy-producing
Christiaan Eijkman. and structural chemical reactions.
Polish biochemist Kazimierz Funk is, however, generally An organic chemical compound is classified as a vitamin
credited with formulating in 1912 the concept of vitamins. He when the organism cannot synthesize the compound in suf-
was the first to isolate such a factor, which was later to be known ficient quantities, and it must be obtained through the diet.
as Vitamin B3 (niacin), though he initially described it as “anti-
beriberi-factor” (later to be named Vit B1). Since it chemically
Thus, the term vitamin is conditional upon the circum-
belonged to amines, he invented the term “vitamin” or “vital
stances and the particular organism [3] with 13 vita-
amines,” combining the word vita = life in Latin, since they
mins being universally recognized at present for
were substances indispensable for survival, and the word amine.
humans.
Later, to avoid confusion and after discovering other similar
“factors” that did not belong to the amine group, the suffix -e
was eliminated, and the term vitamin became ubiquitous.
The discovery of vitamins played a crucial role in the sci- For the most part, vitamins are obtained from food, with
entific understanding and expansion of clinical nutrition. Vit just a few being obtained by other means, e.g., gut flora pro-
A was the first vitamin to be described in 1913, and within duces vitamin K and Biotin, while vitamin D3 is synthesized
the next 36 years, all the other vitamins were isolated and in the skin with the help of the natural ultraviolet wavelength
described. Vitamins were isolated in the following chrono- of sunlight. The recommended source of vitamins is a varied
logical order: Vit D, Vit E, Vit C, Vit B1, Vit B2, Pantothenic diet, while food supplements can only benefit individuals
acid, Biotin, Vit K, Vit B6, Nicotinic acid, Folic acid, and the with certain health conditions.
last one was Vit B12 in 1948 [2]. Vitamins are classified by biological and chemical activ-
ity, not by their structure, and each vitamin refers to several
“vitamer” compounds that all show a similar biological
50.1 Vitamins in General activity associated with a particular vitamin. Thus, “Vitamin
A,” includes the compounds retinal, retinol, and four known
Vitamins are organic compounds classified as essential nutri- carotenoids, whereas Vitamin B complex includes eight very
ents and are required in limited amounts. By definition, a different chemical molecules but with similar biological
vitamin is defined by the following two characteristics: activity.
296 50 Vitamins: Definition and Types
Another valid classification is according to whether they In the following chapters, there will be a detailed review of
can be dissolved in water or fat: the general actions, the actions on the hair follicle, the food
sources, dietary recommendations, and deficiency or excess
• There are four fat-soluble vitamins: Vit D, Vit E, Vit K, conditions for each vitamin that has been implicated in the
and Vit A (D, E, K, A). In contrast to water-soluble ones, hair follicle physiology. Vit D is reviewed in Chap. 19, Vol. 1.
fat-soluble vitamins readily penetrate cellular membranes
and accumulate in body tissues, mainly in adipose tissue.
Therefore, their daily intake is not required. References
• All other nine vitamins are water-soluble: vitamins of
complex B (Vit Β1, Vit Β2, Vit Β3, Vit B5, Vit Β6, Vi tΒ7, 1. Hopkins FG. Feeding experiments illustrating the impor-
tance of accessory factors in normal dietaries. J Physiol.
Vit Β9, Vit Β12), and Vit C. The human body cannot store 1912;44(5–6):425–60.
large quantities of water-soluble vitamins since they can- 2. Rosenfeld L. Vitamine—vitamin. The early years of discovery. Clin
not easily penetrate cellular membranes, which are made Chem. 1997;43(4):680–5.
from phospholipids. Since they are not as readily stored, 3. Scott T, Brewer M. Vitamins. In: Scott T, Brewer M, editors.
Concise encyclopedia of biochemistry. Berlin: Walter de Gruyter
more consistent intake is essential. and Co.; 1983. p. 499.
Vit A
51
and several pro-vitamin A carotenoids, which are found in

Basic Concepts plant foods. Vit A occurs in nature in many different forms
• Vit A and its derivatives (retinoids) have numerous (alcohol, aldehyde, acid), but retinol (alcohol) is the most
essential functions, including a paramount role in abundant and potent form [3]. In foods of animal origin, the
vision, maintenance of epithelial tissues, immune primary form of Vit A is that of retinoic ester, while in foods
competence, reproduction, embryonic growth, and of plant origin, it occurs mostly as carotenes [4]. Since the
development. pure alcohol (retinol) form is unstable, Vit A is found in tis-
• Vit A on the skin promotes cellular differentiation, sues of the human body in the form of retinyl ester [5] and
regulates sebaceous gland activity and is critically upon ingestion, it is rapidly transferred and stored mainly in
important in the development and maintenance of the liver (≥80%), within the stellate cells [6].
hair follicles, as shown by the detrimental effects of
either Vit A deficiency or toxicity.
• Deficiency of Vit A is a widespread, major public 51.1 Actions of Vit A
health issue in developing countries but is sporadic
in developed ones in which Vit A hypervitaminosis Vit A is essential for the life of all chordates and functions at
is much more common and mostly due to excessive two levels in their body: one is in the visual cycle in the ret-
intake of Vit A supplements. ina of the eye, and the other is systemic, in all body tissues,
• Topical retinoic acid has been documented to have maintaining growth and integrity of cells. The growth, dif-
positive actions in AGA/FPHL, whereas no data ferentiation, and maintenance of epithelial surface cells
exist on oral Vit A supplementation in non-deficient throughout the body are particularly affected by Vit A. Vit A
adults; in contrast, Vit A chronic toxicity is a situa- is indispensable for the normal embryonic development of
tion that may result in hair loss. the human body, the normal function of eyes, skin, reproduc-
tion, and immune competence [7].
Vit A is also necessary for the functions of the mucous
membranes of the respiratory, urinary, and gastrointestinal
Vit A is a fat-soluble vitamin with a wide range of actions systems for hormonal production and bone metabolism
since it regulates a variety of essential functions throughout while also playing a crucial role in cell division and gene
the human body. The story of Vit A goes back to the Ancient transcription [8].
Egyptians, who recognized that liver consumption, known Moreover, it contributes to cellular and skin health, in
today to be a source of high levels of Vit A, could cure night hematopoiesis, it holds a regulatory role in the immune sys-
blindness. The scientific characterization of Vit A begun in tem, helping lymphocytes fight bacterial and viral infections
the early nineteenth century and spanned over more than [9]. Finally, it acts as an antioxidant, protecting membranes
130 years till the mid-twentieth century [1]. During this long, [10] and has profound effects on keratinization disorders,
incremental process, there was no single event that can be sebaceous gland function, and even cancer [11]. The ability
called the “discovery” of Vit A [2]. of Vit A to regulate the expression of several hundred genes
“Vit A” serves as a generic descriptor for a group of through binding to nuclear transcription factors is considered
unsaturated nutritional organic compounds that includes reti- to mediate most of Vit A’s functions. Vit A’s role may extend
nol, retinal, retinoic acid, which are found in animal foods, beyond the regulation of gene transcription because a large
298 51 Vit A
number of noncoding RNAs are also regulated by retinoic formed Vit A by eating tissues from animals that have already
acid. Additionally, extra-nuclear mechanisms of action of converted the pro-vitamin A carotenoids into retinoids, forti-
retinoids have also been identified [7]. fied foods, pharmaceutical supplements, and eating plants
containing pro-vitamin A carotenoids.
High quantities of preformed Vit A are found almost
The immense scientific interest in Vit A and retinoids
exclusively in animal products, such as whole milk (animal
is illustrated by a steady daily publication of five to six
or human) and dairy products, glandular meats, liver (pri-
articles in international scientific biomedical journals
marily), fish liver oils, and egg yolk. Concerning milk, pre-
over the last ten years (i.e., articles registered by
formed Vit A in the form of retinyl palmitate has been added
PubMed, National Center for biotechnology informa-
to the milk, based on U.S. Food and Drug Administration
tion at the National Library of medicine).
(FDA) fortification requirements. Preformed Vit A is also
used to fortify processed foods that may include sugar, cere-
als, condiments, fats, and oils [21]. Pro-vitamin A carot-
Thus, several thousand scientists are continuously engaged enoids are found in all dark-colored, green leafy vegetables
in unraveling the secrets of this dietary micronutrient [7]. (e.g., spinach, amaranth, and young leaves from various
The effect of Vit A on epidermal dynamics is very pro- sources), yellow vegetables (pumpkins, squash, and carrots),
found and is complicated by many variables. Vit A, and more and yellow and orange non-citrus fruits (mangoes, apricots,
specifically, retinoic acid, appears to maintain normal skin and papaya) [22]. One plant-based group of products -the
health by promoting the differentiation of mesenchymal cells “ready-to-eat cereals”- are also found within the top 10
and keratinocytes into mature epidermal cells [12, 13]. Vit A sources of Vit A retinoids because they have often been forti-
has also been shown to initiate remodeling of the sebaceous fied with Vit A in the form of retinyl palmitate [23].
glands, triggering changes in gene expression that selectively Preformed Vit A is relatively stable in the animal foods
induce apoptosis, resulting in a reduction in the size of the that contain it. Ordinary handling, storage, and cooking
gland and reduction in sebum production [14]. methods for these foods will usually preserve the content of
preformed Vit A. Preformed Vit A is efficiently absorbed and
utilized by humans at absorption rates of 70–90%. In con-
51.2 Vit A and the Hair Follicle trast, Vit A obtained from pro-vitamin A carotenoids in plant
foods is absorbed much less efficiently, at rates of 20–50%,
Wolbach and Howe first reported that Vit A deficiency leads to depending on individual Vit A status and other dietary and
metaplasia of keratinized epithelia, including the hair follicle non-dietary factors [24]. Inside the human body, both retinyl
and atrophy of the sebaceous gland [15]. Follicular hyperkera- esters and pro-vitamin A carotenoids are converted to retinol,
tosis has also been seen in Vit A deficient humans [16], whereas, which is oxidized to retinal and then to retinoic acid [25].
in rodents, it leads to a thin hair coat [17]. Hair loss is a consis-
tent finding during Vit A toxicity in lab animals [18]. Studies
with transgenic mice support a role for retinoic acid in the hair 51.4 Dietary Recommendations
follicle, and dietary Vit A has been shown even to activate hair
follicle stem cells. However, the results from these studies sug- Vit A is usually measured in ΙU (International Units) or
gest that precise levels of retinoic acid are necessitated for the Retinol Activity Equivalents (RAE). Equivalence in weight
optimal function of the hair follicle and sebaceous gland [19]. units is: 1 μg = 1 RAE = 3.3 IU. However, an RAE cannot be
For further details on the effects of endogenous retinoids in the directly converted into an IU without knowing the source(s)
hair follicle and sebaceous gland, the interested reader can refer of Vit A.
to the excellent review by Everts [20]. As of 2001, the Recommended Dietary Allowance (RDA)
Vit A’s actions on the hair follicle in the form of all-trans- for an adult is 3000ΙU or 900 μg, equivalent to 1800 μg of
retinoic acid (ATRA), the hair growth potential, and the ther- β-carotene supplement (3000 IU) or 10,800 μg of β-carotene
apeutic effects in AGA/FPHL when used alone or in in food (18,000 IU). Adequate Intake (AI) is 500 μg
combination with Minoxidil Topical Solution are extensively (1650 IU), and the Tolerable Upper Intake Level (UL) is
discussed in Chap. 32. 3000 μg (10,000 IU) [26].
51.3 Food Sources 51.5 Deficiency- Excess of Vit A
No animal species have the capability for de novo Vit A syn- Deficiency of Vit A is quite common in developing countries
thesis, and all rely on dietary intake to cover their Vit A but rare in developed ones since the ordinary Western diet
requirements. In humans, dietary Vit A is obtained from pre- can easily cover the daily requirements of Vit A of an adult
51.5 Deficiency- Excess of Vit A 299
[27]. It is noteworthy that 100 g of cooked veal liver contains Hypervitaminosis A is due to excessive consumption of food
six times the RDA of retinol for an adult, while a large carrot supplements rich in Vit A. Vit A toxicity is known to be an
contains four times the RDA of carotenoids. ancient phenomenon, and even fossilized skeletal remains of
early humans suggest bone abnormalities may have been
caused by hypervitaminosis A [34].
There are two forms of hypervitaminosis A or Vit A toxic-
Unfortunately, Vit A deficiency remains a major public
ity: acute toxicity occurring over hours or days and chronic
health problem at the clinical level in 45 countries,
toxicity resulting from chronic (for months or years) inges-
which includes overt signs of deficiency, and 122
tion of high amounts of preformed Vit A. Since Vit A is fat-
countries have subclinical levels of Vit A depletion
soluble, disposing of any excess dietary intake is significantly
with marginal liver reserves.
slower than with water-soluble vitamins, allowing toxic lev-
els of Vit A to accumulate. These toxicities only occur with
preformed Vit A, retinoids from animal sources, either from
According to the World Health Organization estimates, supplements or from specific foods, such as eating the liver
between 140 and 250 million pre-school children are at risk of a seal or bear, which may result in lethal Vit A toxicity
of subclinical Vit A deficiency, three million are clinically Vit [35]. Carotenoids themselves cannot produce toxicity, but
A deficient, and more than 670,000 childhood deaths are excessive dietary intake of beta-carotene can lead to caro-
associated with Vit A deficiency annually [28]. tenosis, a harmless orange-yellow discoloration of the skin
Vit A deficiency can occur as either a primary or a sec- [36].
ondary deficiency [29]: Acute Vit A toxicity may occur after the ingestion of
approx. 500,000 IU (over 100 times the RDA) by adults or,
• Primary Vit A deficiency occurs among children and proportionately less, by children [37]. Common symptoms
adults who do not consume an adequate intake of pre- and signs of acute Vit A toxicity include nausea, irritability,
formed Vit A from animal and dairy products or pro- anorexia, vomiting, blurry vision, headaches, hair loss, mus-
vitamin A carotenoids from fruits and vegetables. cle, and abdominal pain, and altered mental status. Chronic
• Secondary Vit A deficiency is associated with very low-fat intake of Vit A supplements, even when not high enough to
diets, chronic malabsorption of lipids, chronic diarrhea, cause toxicity, has been associated with increased risk for
impaired bile production/release, chronic exposure to oxi- osteoporosis and hip fractures [38], severe liver damage [39],
dants, such as cigarette smoke, and chronic alcoholism, hair loss, dry skin, drying of the mucous membranes, fever,
which has been shown to decrease hepatic Vit A stores [30]. insomnia, fatigue, diarrhea, weight loss, and anemia. When
women ingest excessive Vit A at the early stages of gestation,
Still, one should note that the measured levels of Vit A in the fetal anomalies and poor reproductive outcomes can be man-
serum do not reflect plasma and tissue levels, and patients ifested [40]. This is the “Vit A paradox” known in modern
with hypervitaminosis A may actually have high, average, or Medicine [41]: while Vit A is indispensable for the develop-
even low serum levels of Vit A. The liver, which is the pri- ment of mammalian and human embryos [42], at the same
mary storage site for Vit A, contains 80% of total body time, retinoid abuse by pregnant women may result in terato-
reserves during normal Vit A status and may store enough genesis [43]. Moreover, while Vit A administration has sig-
quantity of Vit A to cover the needs of an adult for ≈12 months nificantly decreased the mortality of malnourished children
[31]. Direct measurements of concentrations of Vit A in the [44], it is also associated with immune disorders in healthy
liver would be the indicator of choice for determining children [45].
requirements; however, this cannot be done with the method- Concerning chronic Vit A supplementation without toxic
ology now available for population use [32]. phenomena, Bjelakovic et al. [46] published the results of
The first group of biological indicators of Vit A deficiency their meta-analysis on the literature findings of the Cochrane
is clinical and involves the eye. One of the earliest and dis- Library and included all primary and secondary prevention
tinct manifestations of Vit A deficiency is decreased visual randomized clinical trials on all five major antioxidant sup-
acuity in reduced light, a condition called night blindness plements (beta-carotene, Vit A, Vit C, Vit E, and selenium)
[33]. If it persists, night blindness gives rise to a series of versus placebo or no intervention. Overall, in 67 randomized
devastating ocular changes, progressing into xerophthalmia, trials, including 232,550 participants, researchers found sig-
corneal ulcers, keratomalacia, and resulting in complete nificantly increased mortality correlating with Vit A
blindness. (RR = 1.16, 95% CI: 1.10–1.24) and beta-carotene
In developed countries, hypervitaminosis A is much more (RR = 1.07, 95% CI: 1.02–1.11). The same research team
frequent than Vit A deficiency. Hypervitaminosis A occurs updated their systematic review in 2012 by adding literature
when storage capacity of hepatic stellate cells is exceeded, findings from MEDLINE, EMBASE, LILACS, the Science
and plasma retinol-binding protein is saturated. Citation Index Expanded, and Conference Proceedings
300 51 Vit A
Citation Index-Science. They even scanned the citations of 4. Marks J. The fat-soluble vitamins in modern medicine. Vitam
Horm. 1974;32:131–54.
relevant publications and asked pharmaceutical companies
5. Bangham AD, Dingle JT, Lucy JA. Studies on the mode of action
for additional trials. of excess of vitamin A. 9. Penetration of lipid monolayers by com-
pounds in the vitamin A series. Biochem J. 1964;90(1):133–40.
6. Biesalski HK. Comparative assessment of the toxicology of vita-
min A and retinoids in man. Toxicology. 1989;57(2):117–61.
Overall, 78 randomized trials with 296,707 partici- 7. Blomhoff R, Blomhoff HK. Overview of retinoid metabolism and
pants were included, and 56 trials (244,056 partici- function. J Neurobiol. 2006;66(7):606–30.
pants) had a low risk of bias. In these 56 trials, 8. McGrane MM. Vitamin A regulation of gene expression:
molecular mechanism of a prototype gene. J Nutr Biochem.
beta-carotene (RR = 1.05, 95% CI: 1.01–1.09) and Vit 2007;18(8):497–508.
A (RR = 1.07, 95% CI: 0.97–1.18) were demonstrated 9. Semba RD. The role of vitamin A and related retinoids in immune
to increase mortality significantly [47]. function. Nutr Rev. 1998;56(1 Pt 2):S38–48.
10. Palacios A, Piergiacomi VA, Catal A. Vitamin A supplementa-
tion inhibits chemiluminescence and lipid peroxidation in iso-
lated rat liver microsomes and mitochondria. Mol Cell Biochem.
1996;154(1):77–82.
51.6 Topical Use of Vit A 11. Elias PM, Williams ML. Retinoids, cancer, and the skin. Arch
Dermatol. 1981;117(3):160–8.
Vit A is used in anti-aging products, and numerous, exten- 12. Fuchs E, Green H. Regulation of terminal differentiation of cul-
tured human keratinocytes by vitamin A. Cell. 1981;25(3):617–25.
sive, double-blind studies have demonstrated the positive
13. Logan WS. Vitamin A and keratinization. Arch Dermatol.
effects of retinoids in photoaging and skin-aging [48]. 1972;105(5):748–53.
Topical tretinoin has been shown to induce epidermal hyper- 14. Wróbel A, Seltmann H, Fimmel S, Müller-Decker K, Tsukada M,
plasia and compaction of the papillary dermis, leading to the Bogdanoff B, Mandt N, Blume-Peytavi U, Orfanos CE, Zouboulis
CC. Differentiation and apoptosis in human immortalized sebo-
deposition of a glycosaminoglycan-like substance in the der-
cytes. J Invest Dermatol. 2003 Feb;120(2):175–81.
mis [49]. 15. Wolbach SB, Howe PR. Tissue changes following deprivation of
However, given that ATRA is a medical prescription-only fat-soluble a vitamin. J Exp Med. 1925;42(6):753–77.
pharmaceutical substance, cosmetic products can contain 16. Girard C, Dereure O, Blatière V, Guillot B, Bessis D. Vitamin a
deficiency phrynoderma associated with chronic giardiasis. Pediatr
only Retinol and Retinyl Palmitate [50]. These molecules are
Dermatol. 2006;23(4):346–9.
not biologically active and have to convert to retinoic acid in 17. Everts HB, Berdanier CD. Nutrient-gene interactions in mitochon-
the skin [51]. Concerning the effects of retinoic acid on scalp drial function: vitamin A needs are increased in BHE/Cdb rats.
skin and AGA/FPHL, see Chap. 32. Nevertheless, it should IUBMB Life. 2002 Jun;53(6):289–94.
18. Shih MY, Kane MA, Zhou P, Yen CL, Streeper RS, Napoli JL,
be noted that there is a confirmed association between exces-
Farese RV Jr. Retinol esterification by DGAT1 is essential for reti-
sive intake of Vit A and hair loss [52] and that even topical noid homeostasis in murine skin. J Biol Chem. 2009;284(7):4292–9.
ATRA used on the scalp on AGA/FPHL might cause para- 19. Suo L, Sundberg JP, Everts HB. Dietary vitamin A regulates
doxical hair loss by upregulation of transforming growth wingless-related MMTV integration site signaling to alter the hair
cycle. Exp Biol Med (Maywood). 2015;240(5):618–23.
factor-β2 (TGF-β2) in the dermal papilla [53].
20. Everts HB. Endogenous retinoids in the hair follicle and sebaceous
gland. Biochim Biophys Acta. 2012;1821(1):222–9.
Synopsis 21. Rodriguez-Amaya DB. Carotenoids and food preparation: the
Vit A oral administration does not positively affect individu- retention of pro-vitamin A carotenoids in prepared, processed, and
stored foods. Arlington, VA: John Snow, Inc./OMNI Project; 1997.
als without subclinical or clinical Vit A deficiency, and
22. U.S. Department of Agriculture, Agricultural Research Service.
chronic excessive intake may cause telogen effluvium in oth- USDA Nutrient Database for Standard Reference Nutrient Data
erwise healthy individuals with AGA/FPHL. Benefits and Laboratory Home Page. 2002. http://www.nal.usda.gov/fnic/.
limitations of topical Vit A products (ATRA, all-trans- 23. Priebe MG, McMonagle JR. Effects of ready-to-eat-cereals on key
nutritional and health outcomes: A systematic review. PLoS One.
retinoic acid) on patients with AGA/FPHL may be found in
2016;11(10):e0164931.
Chap. 32. 24. Blomhoff R, Green MH, Green JB, Berg T, Norum KR. Vitamin A
metabolism: new perspectives on absorption, transport, and stor-
age. Physiol Rev. 1991;71(4):951–90.
25. https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/.
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intakes: Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper,
1. Mori S. Primary changes in eyes of rats which result from defi- Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium,
ciency of fat-soluble A in diet. Am Med Ass. 1922;79(3):197–200. and Zinc. Washington, DC: National Academy Press; 2001.
2. Semba RD. On the 'discovery' of vitamin A. Ann Nutr Metab. 27. Vitamin A. Deficiency—a global disease. Nutr Rev.
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A metabolism. Nutrients. 2012 May;4(5):356–71. 43. Soprano DR, Soprano KJ. Retinoids as teratogens. Annu Rev Nutr.
31. Wake K. Perisinusoidal stellate cells (fat-storing cells, interstitial 1995;15:111–32.
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Cytol. 1980;66:303–53. 45. Erkelens MN, Mebius RE. Retinoic acid and immune homeostasis:
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33. Russell RM, Smith VC, Multack R, Krill AE, Rosenberg IH. Dark- C. Antioxidant supplements for prevention of mortality in healthy
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36. Roe DA. Assessment of risk factors for carotenodermia and cuta- 48. Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl
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Semin Dermatol. 1991;10(4):303–8. efficacy and safety. Clin Interv Aging. 2006;1(4):327–48.
37. Bendich A, Langseth L. Safety of vitamin A. Am J Clin Nutr. 49. Voorhees JJ. Clinical effects of long-term therapy with topical treti-
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38. Whiting SJ, Lemke B. Excess retinol intake may explain the 3):26C–8C.
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39. Nollevaux MC, Guiot Y, Horsmans Y, Leclercq I, Rahier J, 51. Sorg O, Didierjean L, Saurat JH. Metabolism of topical retinalde-
Geubel AP, Sempoux C. Hypervitaminosis A-induced liver fibro- hyde. Dermatology. 1999;199(Suppl 1):13–7.
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Vit Β3 (Niacin)
52
and thiamin acting as cofactors in the metabolic conver-

sion [4].
Basic Concepts
• Vit B3 (niacin) is an essential organic compound,
and as the precursor for NAD and NADP, it contrib- 52.1 Actions of Vit B3
utes to a myriad of energy-related processes and
participates in the synthesis of androgens. Vit B3 is the precursor of co-enzymes NAD and NADP,
• Topical use of Vit B3 has beneficial properties, which are involved in redox reactions, carrying electrons
especially on aged skin, is incorporated in numer- from one reaction to another, used as “currency” of energy
ous cosmetics, being one of the very few com- for numerous cellular reactions. Therefore, the biochemical
pounds with natural high transcutaneous role of niacin has been described much before its dietary
absorption. one was discovered. NAD and NADP are the coenzymes of
• Topical use of Vit B3 on the scalp results in vasodi- innumerable dehydrogenases, found mostly in the mito-
lation, and it has been promoted as a hair growth chondria. NAD is essential in the catabolism of fat, carbo-
tonic; however, the induced scalp “flushing” causes hydrate, protein, and alcohol [5], and is also involved in
the secretion of prostaglandin PGD2, which is a key DNA replication and repair [6], calcium intake by cells,
molecule in the pathophysiology of AGA. synthesis of fatty acids [7], and synthesis of androgens [8].
NADP is involved mostly in anabolic reactions, such as
fatty acid synthesis, cholesterol synthesis, and androgen
production [9].
Vit B3, also known as niacin or nicotinic acid, is a water- The principal medical use of oral Vit B3 is as a lipid-
soluble member of the Vit B3 complex, a family of vitamins lowering medication. Altschul et al. were the first to
that includes nicotinamide and nicotinamide riboside. Niacin describe niacin as having lipid-lowering properties in 1955,
was first described by chemist Hugo Weidel in his studies of and as such, niacin can be considered the oldest lipid-low-
nicotine [1]. It was later extracted from liver tissue by bio- ering drug [10]. At pharmacologic doses, niacin, but not
chemist Conrad Elvehjem in 1937, who later identified the nicotinamide, is still playing a role either as an additive to
active ingredient, then referred to as the “pellagra-preventing a statin or as a statin substitute in statin-intolerant patients.
factor” and the “anti-blacktongue factor.” [2] Nowadays, nia- It improves the lipid profile, reduces coronary events and
cin is referred to as Vit B3 because it was the third of the B total mortality in patients at high risk for coronary heart
vitamins to be discovered. Niacin cannot be directly con- disease, and numerous clinical trials have explored the car-
verted to nicotinamide, but since both compounds are pre- diovascular benefit of niacin combined with other lipid-
cursors of the coenzymes nicotinamide adenine dinucleotide lowering medications [11].
(NAD) and nicotinamide adenine dinucleotide phosphate Recent studies have substantiated the beneficial proper-
(NADP) in vivo, the term Vit B3 is used as a blanket term for ties of niacinamide, especially on aged skin. It has been
both [3]. found to improve the properties of the epidermal barrier
In the human body, the liver can synthesize niacin from function, increase keratinocyte differentiation, reduce the
the essential dietary amino acid tryptophan, requiring signs of photoaging, increase skin hydration and smooth-
60 mg of tryptophan to make 1 mg of niacin, with Vit B6 ness, induce improvement in wound healing and reduce
sebum production [12–14]. Numerous cosmetics contain Vit
304 52 Vit Β3 (Niacin)
B3, and niacinamide is used in dozens of cosmetic formula- effect of nicotinic acid derivatives on thinning hair during the
tions, including shampoos, hair tonics, skin moisturizers, study, hopes should be very low
and cleansing formulations. The niacinamide concentration The only other article distantly relevant to Vit B3 is
varies from a low of 0.0001% in night preparations to a high authored by Davis et al., who reported a leave-on product
of 3% in body and hand creams, lotions, powders, and sprays. containing caffeine, niacinamide, panthenol, dimethicone,
Niacin concentrations of use range from 0.01% in body and and an acrylic polymer which increased the diameter of indi-
hand creams, lotions, powders, and sprays to 0.1% in paste vidual, existing terminal scalp hair fibers by 2-5 μm. This
masks (mud packs). Both ingredients are readily absorbed effect yielded an increase in the cross-sectional area of
from the skin, blood, and intestines and are widely distrib- approximately 10%, acting on the hair shaft and not the hair
uted throughout the body [15]. follicle, possibly with the acrylic polymer “adding” external
thickness to the hair shaft [19].
However, one should consider that topical use of niacin
Vit B3 members belong in an “elite group” of very few results in vasodilation through the release of prostaglan-
compounds (less than 15), natural or artificial, that din PGD2 by skin macrophages, as demonstrated by
exhibit considerable transcutaneous absorption [16]. Morrow et al. [20] They reported that topical administra-
tion of methylnicotinate (10−1 M) to the forearms of
human volunteers resulted in a 58- to 122-fold increase in
levels of PGD2. According to the seminal publication of
52.2 Vit B3 and the Hair Follicle Garza et al., PGD2 is considered to be the most crucial
molecule in the pathophysiology of AGA [21] (See Chap.
The actions of Vit B3 on human hair follicles are supposedly 11, Vol. 1).
related to the vasodilating effects of Vit B3 on skin vessels,
whereas tryptophan, as a Vit B3 precursor, has been found to
accumulate among hair fibers with age [17].
Therefore, it is highly probable that the action of topi-
There is only a single publication found in the literature
cally applied Vit B3 on the scalp of AGA patients
on the effect of nicotinic acid derivatives on thinning hair.
might have a negative effect, exacerbating hair loss or
Draelos et al. conducted a pilot study examining the effect of
follicle miniaturization.
topical application of two niacin derivatives (0.5% octyl nic-
otinate and 5.0% myristyl nicotinate) on “hair fullness” in 60
women with FPHL, Ludwig stage I-III. The study was a
double-blind, placebo-controlled (40 active, 20 placebo, Additionally, Haslam et al. investigated the hypothesis
vehicle only) trial, using standardized 35-mm photographic that nicotinamide may be an effective hair growth-inhibitor
analyses to assess efficacy. Subjects were instructed to apply on micro-dissected human scalp hair follicles cultured in the
once daily at night, six metered drops to the scalp, and stan- presence of nicotinamide 10 mM for 6 days. They reported
dardized 35 mm photography was conducted at baseline, 2, that these hair follicles showed significantly decreased hair
4, and 6 months. Overall tolerability of the topical formula- shaft production and entered catagen more rapidly than vehi-
tions was excellent, and of the total subjects enrolled in the cle control hair follicles [22].
study, 32 of 40 active and 12 of 20 placebo subjects com- In the recent (2018) systematic review (Evidence-based
pleted the study. According to the authors, the niacin deriva- (S3) guideline for the treatment of androgenetic alopecia in
tives demonstrated a statistically significant increase in hair women and men) issued for the European Dermatology
fullness since 33% of the placebo group (n = 4) and 69% of Forum, Kanti et al. included two studies [18, 23] with niacin
the active groups (n = 22) scored higher than at baseline derivates and considered that they obtained level of evidence
(p = 0.04 compared to the placebo). However, the authors 2 and grade A2 and B respectively [24].
could not conclude whether the increased hair fullness was
the result of increasing the density of active hair follicles or
increasing the quality of the existing hair shafts. They could 52.3 Food Sources
neither determine whether the benefit was provided by octyl
nicotinate, myristyl nicotinate, or a combination of the two Free Vit B3 has the highest bioavailability for humans
niacin derivatives [18]. Besides the optimistic comments of and is found in liver, fish, and poultry, whereas bound Vit
the authors, there was only one before-after photo included B3, which is absorbed poorly (30%) by the human GI
in the article, exhibiting hardly any higher coverage after tract, is found in cereals and beans [25]. The human body
6 months of treatment. If that was the best example of the may synthesize Vit B3 from tryptophan, and it is esti-
52.5 Deficiency- Excess of Vit B3 305
mated that this mechanism covers 50% of daily needs in Clinical pellagra is extremely rare; however, occasional
Vit B3. Since food processing may decrease Vit B3 con- sporadic outbreaks of pellagra occur in the U.S. [37] and
tent, flour and its derivatives are often artificially forti- other developed countries [38]. In contrast, Vit B3 “hypervi-
fied with Vit B3 [26]. taminosis” is much more frequent and can be dangerous. Vit
B3 is a water-soluble vitamin, and as such, it is unlikely to
reach toxic levels. It is impossible to overdose on niacin by
52.4 Dietary Recommendations eating too many niacin-rich foods, and Vit B3 toxicity can
result only from very high doses of supplemental Vit B3 used
The recommended dietary allowance (RDA) of Vit B3 for an as a lipid-lowering medication [39]. The standard target dose
adult male is 16 mg, the adequate intake (AI) is 12 mg of Vit B3 for both primary and secondary hyperlipidemia
(1650 IU), and the tolerable upper intake level (UL) is 35 mg management and heart disease is 1-2gr per day, although
[27]. doses may range from 2-6gr per day. In general, there is little
danger of niacin toxicity when it is taken orally, even in
megadoses [40], and severe toxicity can occur in individuals
52.5 Deficiency- Excess of Vit B3 who are not carefully monitored throughout treatment. Sadly,
some of these patients may end up with fulminant hepatic
Nowadays, Vit B3 deficiency is mostly seen as a mild defi- failure [41, 42] possibly related to metabolism via amidation
ciency, with loss of appetite, fatigue, skin pigmentation, and resulting in NAD production [43].
ulcers of mucous membranes. Severe deficiency of Vit B3 is Flushing (e.g., warmth, redness, itching, or tingling) is the
clinically manifested as pellagra, a disease initially described most common adverse effect of niacin toxicity, followed by
by Casal in 1735 that remained relevant until the beginning headache, abdominal pain, dyspepsia, nausea, vomiting,
of the twentieth century. Until that time, maize (corn) was diarrhea, rhinitis, pruritus, and rash. Flushing has been found
used as a staple food from poorer classes, and since maize is to occur in daily doses of niacin that do not exceed the toler-
the only grain low in niacin and tryptophan [28], both mole- able upper intake level (≥35 mg) [44]. Nevertheless, acquired
cules were ingested in non-absorbable forms by the human tolerance will also help reduce flushing, and after several
body. In Mexico, where corn was soaked and cooked in an weeks of consistent high doses, most patients no longer
alkaline solution (limewater), the incidence of pellagra was experience flushing with doses up to 100 mg.
extremely low [29]. This cooking technique of pretreating
corn with alkali ingredients is called nixtamalization. It
increases the bioavailability of niacin during maize meal/ Even higher doses may be tolerable, and flushing can
flour preparation and removes up to 97–100% of aflatoxins be blocked by taking 300 mg of aspirin half an hour
from mycotoxin contaminated corn. before niacin intake since aspirin neutralizes PGD2,
Pellagra used to be a global challenge, but improved diets which is the primary cause of the flushing reaction
and supplementation made this severe condition uncommon [45].
in developed countries. At present, pellagra occurs almost
exclusively in developing countries, endemically in areas
where maize and millet form the main diet, in alcoholics or
patients with severe eating disorders [30], in patients with In patients with niacin deficiency, additional daily supple-
tryptophan malabsorption (Hartnup’s disease), impaired mentation with nicotinic acid or nicotinamide is advised
absorption of niacin from Crohn’s disease [31], arising from [46]. Usual doses of Vit B3 in dietary supplements range
interactions with various medications that interfere with nia- from 50-100 mg and are rarely related to adverse effects. If,
cin metabolism (diazepam, mercaptopurine, isoniazid), or in however, the dose received exceeds tolerable limits, then
patients suffering from carcinoid syndrome [32]. In addition, skin flushing occurs within 1–2 hours. The discontinuation
pellagra frequently affects populations of refugees and other of Vit B3 will usually relieve symptoms within 24 hours, and
displaced people due to their unique, long-term residential the administration of aspirin may be useful once flushing has
circumstances and dependence on food aid [33]. occurred. Vit B3, even in high doses, is not a carcinogen,
The clinical manifestations of pellagra are often described teratogen, or mutagen.
as the 4 Ds: dermatitis, diarrhea, dementia [34]. The fourth D
stands for death, which is inevitable if the condition is not Synopsis
corrected by niacin supplementation. The occurrence of clin- Vit B3 deficiency, clinically featured as pellagra, is an
ical pellagra is postulated to require not only Vit B3 defi- extremely rare condition, and very few Dermatologists in the
ciency but also tryptophan, Vit B6 and thiamine [35, 36]. Western world have actually seen a pellagra patient with
306 52 Vit Β3 (Niacin)
their own eyes. Pharmacological doses of niacin induce a 18. Draelos ZD, Jacobson EL, Kim H, Kim M, Jacobson MK. A pilot
study evaluating the efficacy of topically applied niacin deriva-
profound change in the plasma levels of various lipids and
tives for treatment of female pattern alopecia. J Cosmet Dermatol.
lipoproteins but have not been demonstrated to positively 2005;4(4):258–61.
affect hair follicles or in AGA/FPHL. In the literature, a sin- 19. Davis MG, Thomas JH, van de Velde S, Boissy Y, Dawson TL Jr,
gle, small trial supported topical Vit B3 in the treatment of Iveson R, Sutton K. A novel cosmetic approach to treat thinning
hair. Br J Dermatol. 2011;165(Suppl. 3):24–30.
FPHL but with minimal results. However, since topical Vit
20. Morrow JD, Awad JA, Oates JA, Roberts LJ 2nd. Identification
B3 is likely to increase PGD2 production locally, cosmetics, of skin as a major site of prostaglandin D2 release follow-
shampoos, and lotions containing Vit B3 could have a nega- ing oral administration of niacin in humans. J Invest Dermatol.
tive effect on AGA/FPHL rather than a positive one. 1992;98(5):812–5.
21. Garza LA, Liu Y, Yang Z, Alagesan B, Lawson JA, Norberg SM,
Loy DE, Zhao T, Blatt HB, Stanton DC, Carrasco L, Ahluwalia G,
Fischer SM, Fitzgerald GA, Cotsarelis G. Prostaglandin d2 inhib-
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Vit B5 (Pantothenic Acid)
53
mon supplemental form of Vit B5 is calcium pantothe-

Basic Concepts nate, and because it is a salt, it is more stable than
• Vit B5 is necessary to more than 70 enzymes pantothenic acid.
involved in the metabolism of fatty acids, proteins,
carbohydrates, the production of androgens and ste-
roid hormones. 53.1 Actions of Vit B5
• Topical Vit B5 (Dexpanthenol) has significant
regenerative properties through the proliferation Vit B5 is vital to the synthesis and maintenance of coen-
and differentiation of fibroblasts and the induction zyme A (CoA), which is a cofactor and an acyl group car-
of epidermal epithelization. rier for numerous enzyme processes. CoA is a biological
• Dexpanthenol binds to the hair shaft, coats its sur- transport mechanism of carbon atoms within the cell, and
face, offering a more shiny appearance, and there- at least 70 enzymes in the human body are using CoA and
fore, it is a common component of shampoos and its derivatives for their metabolic processes [3]. CoA is
hair conditioners. essential in the biosynthesis and metabolism of many
• Popular orally administered products containing Vit essential compounds, such as proteins, carbohydrates,
B5 have been reported to have a positive effect on fatty acids, cholesterol, sterols, steroid hormones [4],
hair growth exclusively in industry-sponsored trials androgens [5] porphyrins; therefore, it is essential to
of controversial referential value. almost all forms of life. CoA also catalyzes gluconeogen-
esis, the synthesis of fatty acids and sphingolipids, which
are essential for stratum corneum lipid layers [6]. Hence,
pantothenic acid is essential for epithelia to maintain their
Pantothenic acid or Vit B5 is a water-soluble vitamin and an physiological function.
essential nutrient. Vit B5 was discovered in 1933 by Williams
et al. during their studies on microbial growth factors [1].
Pantothenic acid is the amide between pantoic acid and
Even though Vit B5 was discovered decades ago, the
β-alanine, with the latter playing a vital role in the crystalli-
exact mechanisms of action of Vit B5 and, more spe-
zation and subsequent artificial production of Vit B5, first
cifically, of dexpanthenol have not been fully eluci-
achieved in 1940. The name of pantothenic acid derives from
dated yet [7].
the Ancient Greek word “πάντοθεν = from everywhere”,
indicating its widespread occurrence in nature since small
quantities of Vit B5 are found in nearly every known food.
Remarkably, only one of the popular foods lacks pantothenic When applied topically, dexpanthenol is readily absorbed
acid, and that is olive oil. and rapidly converted enzymatically to pantothenic acid
Only the dextrorotatory (D) isomer of pantothenic acid inside the peripheral tissue. Topical Vit B5 has significant
(D-pantothenic acid) possesses biologic activity. regenerative properties through the proliferation and differ-
Dexpanthenol (D-panthenol or Provitamin B5) is the alco- entiation of fibroblasts and epidermal epithelization induc-
holic analog of D-pantothenic acid, is a water-soluble, tion [8, 9]. Dexpanthenol is acclaimed in cosmetology for its
more stable form of Vit B5, and is often used as a source healing, restorative, regenerative, smoothing, beautifying,
of Vit B5 in multivitamin supplements [2]. Another com- invigorating, antidermatitis, and depigmentation properties
310 53 Vit B5 (Pantothenic Acid)
[10]. Numerous topical dexpanthenol preparations exist nicotinate, tested on 60 patients with AGA/FPHL, published
(cream, emollient, drops, gel, lotion, oil, ointment, solution, the results in English but the article is not indexed in Pubmed
and spray), tailored according to individual needs, ranging [23].
from pediatric to adult use [11]. In concentrations of 2–5%, The latest study on a “hair tonic” containing Vit B5 was
topical dexpanthenol ointment is used to treat sunburns, mild authored by Beer and Veghte, who evaluated the effects of a
burns, minor skin injuries, and skin disorders, such as eczema supplement named Cynatine HNS® (Roxlor Global, LLC)
[12]. It improves skin hydration and skin elasticity, reduces containing 6.84 mg Vit B5, 250 mg Cynatine, 7.5 mg zinc,
itching and skin inflammation, and accelerates the rate of 9.0 mg Vit B3, 0.825 mg copper, 1.0 mg Vit B6, and 0.150 mg
epidermal wound healing [13]. Dexpanthenol has also been Vit B8 (Biotin) in 50 women with signs of damaged hair and
demonstrated to readily bind to the hair shaft, coat the hair, nails [24]. The study was a single-center, randomized,
and seal its surface, lubricating the hair shaft and giving it a parallel-
group, double-blind, placebo-controlled 90-day
more shiny appearance [14]. Thus, it is a common compo- intervention, and Cynatine is a keratin-based peptide form
nent of commercial shampoos and hair conditioners [15] obtained by proprietary processing of New Zealand sheep
wool. The authors reported that subjects taking Cynatine
HNS® showed statistically significant improvements in their
53.2 Vit B5 and the Hair Follicle hair and nails compared to placebo.
The only animal study regarding the effects of Vit B5 on the

coat of animals is an old study by Wiese et al. They reported However, all these studies had numerous, severe meth-
that induced experimental Vit B5 deficiency in baby pigs odological limitations; most did not include patients
resulted in severe morbidity and in a poor quality of hair coat with AGA/FPHL and did not perform the necessary
in 30 days [16]. “intention-to-treat analysis”.
Concerning the effects of Vit B5 on the hair follicles of
patients with hair loss, there are only small and low-quality
studies.
There is one early study by Dupré et al. in which inject- Moreover, the duration of most of these studies was too
able pantothenol in combination with biotin has been alleged short and, therefore, could not eliminate any potential sea-
to be effective for treating chronic telogen effluvium. In this sonal changes in hair growth [25]. Additionally, all studies
study, the intravenous route of administration was reported were performed on commercial products and were all spon-
as superior to oral or intramuscular application [17]. Then, sored by the manufacturing companies, and some authors
there are several papers on commercial products that contain probably had conflicts of interest that were not required to
numerous “natural” ingredients, one of which is Vit B5. be stated back at that time. Notably, Morganti was the presi-
However, results cannot be safely attributed to any specific dent and CEO of Mavì Sud S.r.l., the manufacturing com-
ingredient. pany of the product under trial [23], while Robert H. Veghte
In humans, six small-scale studies have tested the effects was the General Manager of Roxlor Global, LLC, manufac-
of oral combination products, with one of the ingredients turing the product Cynatine HNS [24]. In all these studies,
being Vit B5, on patients with hair loss: 4 studies (2 in there only one set of before-and-after photos of a patient
German language [18, 19], one in Bulgarian [20], and one in in the active compound group showing minimal clinical
English [21]) report that oral administration of the product improvement [21].
Pantogar® (Merz Pharmaceuticals GmbH), which contained The impact on scientific judgment due to industry spon-
calcium Pantothenate 60 mg in addition to cystine 20 mg, sorship, present in most (if not all) of these studies, is unclear,
thiamine 60 mg, yeast 100 mg, keratin 20 mg and para- at best, as aptly reported in the Cochrane systematic review
amino- benzoic acid 20 mg, improved quality of hair in by van Zuuren et al. The authors concluded that these studies
patients with telogen or diffuse hair loss. An article in the have low referential value and cannot substantiate, under no
German language by Gehring et al. reported on the hair circumstances, an indication for the administration of cal-
growth effects of another oral hair growth supplement cium pantothenate in individuals with hair loss [26]. For
(Priorin®, Bayer AG) containing calcium pantothenate, mil- more details on these studies and their results, see Chap. 42.
let extract, L-cystine, and biotin, tested on 40 females with Davis et al. reported that a leave-on product containing
hair loss of unknown etiology [22]. Morganti et al. conducted caffeine, niacinamide, panthenol, dimethicone, and an
a study on the topical product Mavi-ceuticals Bioesse acrylic polymer increased the diameter of individual, exist-
Lozione® (Mavì Sud S.r.l.,) containing disodium cystinyl ing terminal scalp hair fibers by 2-5 μm. This yielded an
disuccinate, castor oil, panthenol, Ginkgo Biloba extract, increase in the cross-sectional area of approximately 10%,
saw palmetto extract, azelaic acid, piroctone olamine, ethyl acting on the hair shaft and not the hair follicle, possibly with
53.5 Deficiency- Excess of Vit B5 311
the acrylic polymer “adding” external thickness to the hair tance of the lack of a control group, the small duration of the
shaft. According to the authors, the caffeine, niacinamide, study (subject to seasonal changes), and the small number of
and panthenol trio added flexibility or suppleness as charac- subjects in the study, among others [29].
terized by reduced shear modulus, in addition to the diameter Kutlu et al. conducted another retrospective and descrip-
increase, but they did not claim any actual hair growth effects tive case series to evaluate dexpanthenol’s effect on FPHL
[27]. using the Dermatology Life Quality Index (DLQI) and a
Siavash et al. conducted a prospective, randomized, modified hair growth questionnaire. A total of 21 women
4-month long controlled trial on 73 premenopausal women diagnosed with FPHL were involved in the study with a
with FPHL. Participants were randomized into four groups mean age of 32.05 ± 10.41 years and classified at stages
to receive a) 220 mg zinc sulfate and 100 mg calcium panto- 1–3 in the Sinclair scale. All women were initiated with
thenate, b) zinc sulfate alone, c) calcium pantothenate alone, 500 mg intramuscular dexpanthenol weekly for 2 months.
and d) 2% Minoxidil topical solution (MTS). The primary The authors reported that the overall satisfaction with the
endpoint was the change in hair density and diameter mea- hair’s appearance was 85.7% among patients with FPH and
sured by dermatoscope, and the secondary endpoints that there was a significant increase in quality of life after
included the researcher’s evaluation and a blinded dermatol- DXP treatment. The full-text paper includes 2 sets of large
ogist’s opinion. After 4 months, in the zinc plus pantothenate but low-quality before-and-after photos that show a marginal
group, hair count increased from 118.6 ± 9.9 hairs/cm2 to difference which can be attributed to non-standardized con-
121.9 ± 11.1 hairs/cm2 (3.3 ± 1.2 hairs/cm2, p = 0.042) and ditions (light, combing, etc.). The same limitations as with
thickness changed from 62.2 μm ± 6.6 to 64.0 μm ± 5.0 the previous study apply [30].
(1.8 μm ± 1.6, p = 0.126), respectively. These changes for the
2% MTS group were from 120.1 ± 9.7 hairs/cm2 to
132.3 ± 10.5 hairs/cm2 (12.2 ± 0.8 hairs/cm2, p = 0.001) and 53.3 Food Sources
from 60 μm ± 3.1 to 63 μm ± 3.0 (3.0 μm ± 0.1, p = 0.001),
respectively. Hair density increments were more obvious in The content of Vit B5 varies among manufactured and natu-
the MTS group, then pantothenate, after that in the combina- ral foods. As already mentioned, Vit B5 is found in abun-
tion and finally in the zinc group, respectively. On the other dance in all foods, with major sources being veal, fish, eggs,
hand, hair thickness increment was more obvious in the pan- vegetables, dried mushrooms, yeast, and sunflower seeds
tothenate, then zinc, MTS, and finally, the combination [31]. Whole grains are another source of Vit B5, but milling
group, respectively. However, examining more closely the removes much of the pantothenic acid, as it is found in the
numbers and not the “p values”, the differences in the cover- outer layers of whole grains. Vit B5 is relatively stable when
age (hair density and hair diameter) of patients in any of all it comes to cooking, but foods will lose some pantothenic
groups besides those of MTS are insignificant, and probably acid into cooking water when boiling or when cooked in an
this is why no pictures are provided in the published article. acidic (e.g., vinegar) or alkali (e.g., sodium bicarbonate-
Additionally, due to the differences in medications, the par- soda) environment [32].
ticipants were not blinded to treatment, whereas the stage of
hair loss and the effect of treatment regimens based on each
stage were not determined [28]. 53.4 Dietary Recommendations
Kutlu et al. conducted a retrospective and descriptive case
series including 9 healthy men AGA aged 16 to 46 years pre- At the moment, there is not sufficient information to estab-
sented to the Dermatology outpatient clinic of Uşak lish EARs or RDAs for pantothenic acid. In instances such as
University, Turkey. They were initiated with 500 mg intra- this, the Adequate Intake (AI) is set, with the understanding
muscular dexpanthenol weekly for 2 months and were then that the AI will be replaced by more exact information at
evaluated using a clinical questionnaire on the treatment some later date. The current Vit B5 AI for adults is 5–7 mg/
response. Two-thirds of patients receiving dexpanthenol for day. There are no definitions of tolerable upper intake level
AGA revealed the benefit of treatment overall. In addition, (UL) as there is no human data for adverse effects from high
all of the patients with male AGA stated that they observed doses of Vit B5 [33].
increased hair growth with dexpanthenol. The full-text paper
includes 2 sets of small before-and-after low-quality photos
that show a marginal difference. The authors acknowledged 53.5 Deficiency- Excess of Vit B5
only a couple of limitations in their paper: a fixed dose of
dexpanthenol could affect the results in subjects with a high Given the abundance of Vit B5 in food and its synthesis by
body mass index and that the questionnaire study inevitably intestinal microflora [34], it is practically impossible for
bears recall bias. However, they fail to appreciate the impor- humans to develop primary Vit B5 deficiency naturally, and
312 53 Vit B5 (Pantothenic Acid)
therefore the condition has not been thoroughly studied. Vit 4. Tahiliani AG, Beinlich CJ. Pantothenic acid in health and disease.
Vitam Horm. 1991;46:165–228.
B5 deficiency is exceptionally rare and may only occur arti-
5. Jaroenporn S, Yamamoto T, Itabashi A, Nakamura K, Azumano
ficially with the deliberate omission of Vit B5 from the diet, I, Watanabe G, Taya K. Effects of pantothenic acid supplementa-
as in limited volunteer trials [35] or by the administration of tion on adrenal steroid secretion from male rats. Biol Pharm Bull.
a chemical competitor [36]. In those very few cases where a 2008;31(6):1205–8.
6. Proksch E, Jensen JM. Dexpanthenol. In: Barel AO, Paye M,
severe Vit B5 deficiency has been reported, nearly all symp-
Maibach HI, editors. Handbook of cosmetic science and technol-
toms were reversed with the return of pantothenic acid. Most ogy. 2nd ed. New York, London: Taylor & Francis Group; 2006.
Vit B5 deficiency symptoms are neurological, similar to the p. 399–406.
general symptoms of Vit B complex deficiency [37]: irrita- 7. Proksch E, de Bony R, Trapp S, Boudon S. Topical use of dex-
panthenol: a 70th anniversary article. J Dermatolog Treat.
bility, fatigue, apathy or anxiety, numbness, paresthesia,
2017;14:1–8.
muscle cramps, hypoglycemia, sleep disturbances, nausea 8. Ebner F, Heller A, Rippke F, Tausch I. Topical use of dexpanthenol
and vomiting, and in extremely rare cases, hepatic encepha- in skin disorders. Am J Clin Dermatol. 2002;3(6):427–33.
lopathy [38]. 9. Jerajani HR, Mizoguchi H, Li J, Whittenbarger DJ, Marmor
MJ. The effects of a daily facial lotion containing vitamins B3 and
Toxicity of pantothenic acid is unlikely, and no tolerable
E and provitamin B5 on the facial skin of Indian women: a ran-
upper-level intake (UL) has been established. There are no domized, double-blind trial. Indian J Dermatol Venereol Leprol.
reports of toxic reactions by excessive intake of Vit B5, even 2010;76(1):20–6.
in daily doses of ≥1gr. Most frequently, Vit B5 is available in 10. Gehring W, Gloor M. Effect of topically applied dexpanthe-
nol on epidermal barrier function and stratum corneum hydra-
multivitamin products containing 25-100 mg Vit B5, and
tion. Results of a human in vivo study. Arzneimittelforschung.
there is no risk of toxicity unless the recommended dosage of 2000;50(7):659–63.
the product is not followed [39]. When massive doses (e.g., 11. The United States Pharmacopeia. U.S. Pharmacopeial Convention,
≥10 gr/day) are ingested, these may yield mild intestinal dis- vol. Vol. 1. 38th ed. Rockville, MD: The United States
Pharmacopeia; 2008.
tress and diarrhea, at worst [32, 40]. Excessive consumption
12. Eichenfield LF, Fowler JF Jr, Rigel DS, Taylor SC. Natural advances
of Vit B5 can result in a secondary deficiency of Vit B12 in eczema care. Cutis. 2007;80(6 Suppl):2–16.
since Vit B5 at very high doses competes with other Vit B 13. Heise R, Skazik C, Marquardt Y, Czaja K, Sebastian K, Kurschat
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Baron JM. Dexpanthenol modulates gene expression in skin wound
nol, there are no adverse reactions known following skin
healing in vivo. Skin Pharmacol Physiol. 2012;25(5):241–8.
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Synopsis 15. Schalock PC, Storrs FJ, Morrison L. Contact urticaria from panthe-
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Vit B5 is involved in dozens of biochemical reactions in
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female pattern hair loss. J Cosmet Dermatol. 2020;22. 40. Haslam RH, Dalby JT, Rademaker AW. Effects of megavitamin
31. U.S. Department of Agriculture, Agricultural Research Service. therapy on children with attention deficit disorders. Pediatrics.
USDA Nutrient Database for Standard Reference, Release 13. 1984 Jul;74(1):103–11.
Nutrient Data Laboratory. 1999. http://www.nal.usda.gov/fnic/ 41. Combs GF, McClung JP. The vitamins: fundamental aspects in
foodcomp. Search the database online. nutrition and health. 5th ed. San Diego: Elsevier; 2017.
32. Tarar OM, Ali SA, Jamil K, et al. Study to evaluate the impact of
heat treatment on water soluble vitamins in milk. J Pak Med Assoc.
2010;60:909–12.
Vit B6 (Pyridoxine)
54
Basic Concepts
54.1 Actions of Vit B6
• Vit B6 is an essential cofactor for more than 140
enzymes, and it is the most versatile coenzyme Vit B6 is an essential cofactor required for more than 140
for numerous biological reactions, ranging from biochemical reactions, mostly related to amino acid biosyn-
macronutrient metabolism to gene expression. thesis and degradation, with additional roles in growth,
• Vit B6 has been reported to inhibit 5α-Reductase immune function, and numerous aspects of metabolism.
in vitro and to inhibit the function of the transcrip- Interestingly, all amino acids, except for proline, rely on
tional activation of the androgen receptor, but these Vit B6 for their synthesis and catabolism [3]. Vit B6 gener-
results have never been demonstrated in vivo or in ally serves as a coenzyme for many biological reactions,
clinical trials. including transamination, decarboxylation, racemization,
• There is only an early Polish study supporting the elimination, replacement, and beta-group interconversion
positive role of Vit B6 in human hair, according [4]. Vit B6 is involved in many aspects of macronutrient
to which daily injections of Vit B6 for 30 days in metabolism: in the metabolism of amino acids [3], in the
women with diffuse alopecia of unknown etiol- synthesis and function of hemoglobulin, in neurotransmit-
ogy resulted in an improvement of their ter synthesis, in glucose and lipid metabolism [5]. It also
condition. participates in regulating immune function [6, 7] and even
in gene expression, since it has been implicated in down- or
up-regulation of the expression of genes [8].
Moreover, Vit B6 contributes to single-carbon metabo-
Vit B6 is a water-soluble vitamin, but the name refers to a lism, to the synthesis [9] of Vit B3, in the conversion of
group of at least ten chemically similar pyridine derivatives essential fatty acids to prostaglandins [10] and is an essential
(vitamers), which can be interconverted in biological component of enzymes that facilitate the biosynthesis of
systems. sphingolipids [11].
György [1] first isolated Vit B6 in 1934, and he reported
that it is found in 3 primary forms: pyridoxine, pyridox-
amine, and pyridoxal 5′-phosphate (PLP). These differ in a
variable group present at their 4-position: pyridoxine car- 54.2 Vit B6 and the Hair Follicle
ries a hydroxymethyl group; pyridoxal and pyridoxamine
have an aldehyde and an aminomethyl group, respectively. Even though scientific evidence on the positive effects of Vit
PLP is the biologically most active form of Vit B6, and B6 on human hair follicles is minimal, several popular prod-
80% of this vitamin is stored in the liver and muscles of the ucts use Vit B6 as an ingredient and report having hair growth
human body [2]. activity. Vit B6 has been speculated to have positive effects
in AGA/FPHL because of the in vitro results of an old study
by Stamatiadis et al. [12], published in 1988.
316 54 Vit B6 (Pyridoxine)
In their study on foreskin samples, Stamatiadis et al. lack of financial interest since 2 out of 3 substances are natu-
tested the effects of Azelaic acid (AzA), Zinc sulfate (ZnSO4), ral substances and cannot be patented, while the patent for
and Vit Β6 on the inhibition of 5α-Reductase (5α-R). At a Azelaic acid has long expired. Trusting this theory, many
concentration as low as 3 mmol/L, AzA inhibited 5α-R by forum members try to replicate on themselves the results of
98%, while ZnSO4 required a concentration of 15 mmol/L to that study and become human guinea pigs of “do-it-yourself”
achieve a 98% inhibition. When both compounds were com- topical treatments with AzA, ZnSO4, and Vit Β6.
bined, just 0.5 mmol/L of AzA and 3 mmol/L of ZnSO4 There is only one study by Brzezinska-Wcislo, published
could achieve 95% inhibition. Adding Vit Β6 (0.025%) to in a Polish journal on the action of Vit B6 on human hair fol-
ZnSO4 resulted in a two-fold increase in the inhibition of the licles on 46 women with diffuse alopecia of unknown etiol-
5α-R enzyme activity, whereas Vit Β6 alone or combined ogy. These volunteers were orally given calcium pantothenate
with AzA had no inhibitory effect. The additive effect of all 100 mg b.i.d. for 4–5 months, and Vit B6 was injected every
three compounds in concentrations that had no inhibitory day for 20–30 days and repeated again after 6 months.
activity when used alone (Vit Β6 0.025%, 0.1 mmol/L of According to trichogram and hair loss evaluations, the
AzA, and 0.5 mmol/L of ZnSO4) resulted in 90% inhibition authors reported that parenteral Vit B6 improved the hair
of 5α-R activity. However, these in vitro results on human condition in some women, and it reduced hair loss, whereas
homogenates have not been confirmed in vivo or in clinical calcium pantothenate did not show an apparent positive
studies. effect. However, the claims of this inconvenient treatment
Until 1994, a few other authors researched the anti- presented in the article were not supported by any specific
androgenic potential of Vit B6, but ever since, there have quantitative or qualitative measurements or demonstrated in
been no reports on Vit B6 effects on hair follicles or its before-and-after photos [18].
involvement in the biochemistry of androgens.
Allgood et al. reported that the transcriptional activation
of both the androgen and progesterone receptors was reduced 54.3 Food Sources
by 35–40% under elevated Vit B6 conditions and enhanced
by 60–90% in deficiency [13]. Kniewald et al. reported that Vit B6 is widely distributed in foods in both its free and
pyridoxal hydrochloride showed an in vitro inhibitory effect bound forms. It is absorbed by passive diffusion in the jeju-
on 5α-R in rat pituitary cells, the basal hypothalamus, and num and ileum, and the absorption capacity is so high that
the rat prostate but these findings were never confirmed humans can absorb quantities much greater than necessary
in vivo [14]. It has also been found that moderate variations for physiological demands. After ingestion, free or bound
in the intracellular concentration of Vit B6 can have a signifi- forms are converted to any of several vitamers (pyridox-
cant modulatory effect on steroid-induced gene expression, amine, pyridoxine, and pyridoxal) and PLP.
and the Vit B6 nutritional status of cells modulates their Plant foods contain mostly pyridoxine, while animal
capacity to respond to steroid hormones. According to Tully products are rich in PLP. The main food sources of Vit B6
et al., the elevation of intracellular PLP levels leads to vitamers are red meat, poultry, and fish, such as tuna fish and
decreased transcriptional responses to glucocorticoid, pro- salmon. Significant amounts of Vit Β6 are also found in cere-
gesterone, androgen, or estrogen hormones. Conversely, als, beans, bananas, and soy products [19]. Prolonged heat-
cells in a Vit B6-deficient state exhibit enhanced responsive- ing, milling, or refining grains and food storage contribute to
ness to steroid hormones [15] confirming the results previ- substantial loss of Vit B6 in foods, ranging between 50% and
ously reported by Symes et al. [16] and Bender et al. [17]. 70% [20].
Even though Stamatiadis et al. clearly stated that their 54.3.1 Dietary Recommendations
results had not been confirmed in vivo [12], their study
has become quite “popular” in internet hair loss forums The current Recommended Dietary Allowance (RDA) of Vit
and has even triggered “conspiracy theories”. Β6 for adult men and women up to the age of 50 is 1.3 mg.
However, since individuals over the age of 65 years show
lower blood levels of Vit B6 even at a consistent dietary intake,
RDAs accordingly increase with age, and for adults older than
According to these theories, combining these cheap and 50yo, the RDA is set to 1.7 mg [21]. Adequate intake (AI) is
easy-to-finding compounds could be the long-awaited solu- 1.1 mg, and the UL for Vit B6 is set at a relatively high level of
tion to AGA. The “conspiracy theory” claims that pharma- 100 mg for adults, allowing plenty of room for Vit B6 intake
ceutical companies block further research on the issue due to substantially above the RDA level [22].
54.3 Food Sources 317
54.3.2 Deficiency- Excess of Vit B6 Although Vit B6 is a water-soluble vitamin, pyridoxine

doses in excess of the dietary upper limit (UL) over long
Clinical symptoms and signs of Vit B6 deficiency are usually periods can result in painful and ultimately irreversible neu-
non-specific since it is necessary for the proper functioning rological damage. The primary symptoms are numbness of
of dozens of enzymes. Signs of Vit B6 deficiency can occur the extremities and pain since excessive Vit B6 intake is
within 3 weeks of reduced intake, but >3 months are required related to damage to the dorsal root ganglia of upper and
for signs to develop. Vit Β6 full-blown primary deficiency is lower extremities. Toxicity will cause sensory neuropathy,
extremely rare, even in developing countries. Between 1952 numbness, and itching/tingling of arms and legs [38], pro-
and 1953, in the U.S., a small percentage of infants who were gressing to motor neuropathy, with muscle weakness and
fed a formula lacking in pyridoxine developed severe neuro- instability [39]. Vrolijk et al. [40] have demonstrated that
logical symptoms and intractable convulsions [23]. high concentrations of pyridoxine levels paradoxically lead
Low serum Vit B6 levels often occur in association with to decreased vit B6 function due to competitive inhibition of
other B complex vitamins in severely malnourished individ- active pyridoxal-5′-phosphate by the inactive form of
uals, such as alcoholics and neglected older adults. Moreover, pyridoxine.
individuals with metabolic syndrome, diabetes, or obesity,
have been reported to have a lower Vit B6 status and a higher
prevalence of Vit B6 inadequacy than healthy individuals.
Consequently, symptoms of excessive Vit B6 supple-
Evidence exists for decreased levels of Vit B6 in women with
mentation are similar to those of vitamin B6 deficiency
type 1 diabetes [24], in uremic patients [25], and in liver dis-
[40].
ease patients [26]. Secondary deficiency can develop in
patients on treatment with certain anticonvulsants, such as
isoniazid, hydralazine, penicillamine, phenelzine, cycloser-
ine [27, 28] and in women on oral contraceptive treatment Sensory neuropathy typically develops at doses of Vit
[29]. Lower Vit B6 status has also been reported in patients B6 > 1000 mg/day, but adverse effects can occur with much
with systemic inflammation [30, 31], rheumatoid arthritis, less, and doses >200 mg are not considered safe [41]. Vit B6
and those infected with HIV [32]. Diets very high in protein should not be co-administered with Levodopa [42],
are known to increase the risk of Vit B6 depletion (secondary Phenytoin, and Phenobarbitone due to potential interactions
deficiency), and some researchers have suggested increased [43].
Vit B6 intake when protein intake is exceptionally high [22]. Brasky et al. analyzed the data from a total of 77,118 par-
Signs of Vit B6 deficiency include a seborrhoeic ticipants of the VITAL cohort, 50 to 76 years of age. They
dermatitis-like eruption, atrophic glossitis with ulceration, concluded that the use of supplemental vitamins B6, folate,
angular cheilitis, conjunctivitis, anemia (due to impaired and B12 was not associated with lung cancer risk among
heme synthesis), and neurologic symptoms of somnolence, women. In contrast, the use of vitamin B6 and B12 from indi-
confusion, and neuropathy. Severe Vit B6 deficiency has vidual supplement sources, but not from multivitamins, was
similar skin clinical features with pellagra [33] was first associated with a 30% to 40% increase in lung cancer risk
observed in lab animals by György [34] and later in humans among men. When the 10-year average supplement dose was
by Prasad et al. [35]. In this pellagra-like syndrome, usually evaluated, there was an almost two-fold increase in lung can-
secondary to isoniazid treatment, secretion of sebaceous cer risk among men in the highest categories of vitamin B6
glands is amplified, and seborrheic dermatitis-like occurs on (>20 mg/day; hazard ratio, HR: 1.82; 95% CI, 1.25 to 2.65)
the face, scalp, and body [27]. Notably, it has been suggested and B12 (>55 μg/day; HR: 1.98; 95% CI: 1.32–2.97) com-
that suboptimal Vit B6 status is associated with certain dis- pared with nonusers. For vitamin B6 and B12, the risk was
eases that mainly afflict the elderly population: impaired even higher among men who were smoking at baseline. In
cognitive function, Alzheimer’s disease [36], cardiovascular addition, the B6 and B12 associations were apparent in all his-
disease, and different types of cancer [37]. tologic types except adenocarcinoma, which is the type less
related to smoking. This extensive study provides evidence
that Vitamin B supplements are not chemopreventive for
lung cancer and may be harmful [44].
Vit Β6 toxicity has been documented from Vit B6 sup-
plements but never from food sources, and every report Synopsis
of Vit B6 toxicity involves the use of megadose supple- Even though in vitro studies have reported the potential
mentation in doses >500 mg/day. inhibitory effect of Vit B6 on the 5α-Reductase enzymic sys-
tem, there are no in vivo or clinical reports of this applica-
318 54 Vit B6 (Pyridoxine)
tion. Anti-androgenic actions of Vit B6 have never been 19. U.S. Department of Agriculture, Agricultural Research Service.
USDA Nutrient Database for Standard Reference, Release. Nutrient
confirmed, and clinical studies do not support Vit
Data Laboratory. 1999. http://www.nal.usda.gov/fnic/foodcomp.
B6-containing products that claim to have hair growth activ- Search the database online.
ity. Oral administration of Vit B6 has not been reported to 20. Sareen G, Stepnick A, Smith JL, Groff JL. Advanced nutrition
affect the hair follicle and is therefore not recommended in and human metabolism. Australia: Wadsworth/Cengage Learning;
2009.
patients with AGA/FPHL.
21. Institute of Medicine. Food and nutrition board. Dietary refer-
ence intakes: thiamin, riboflavin, niacin, vitamin B6, folate, vita-
min B12, pantothenic acid, biotin, and choline. Washington, DC:
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Concepts Nutr. 1983;12:1–12.
Vit B7 (Vit H, Biotin, Coenzyme R)
55
Basic Concepts 55.1 Actions of Biotin

• Biotin serves as a cofactor for five essential carbox-
ylation enzymes, has essential roles in amino acid Since biotin is required for normal cellular functions,
metabolism, in the intermediate metabolism of car- growth, and development, all animal cells contain some
bohydrates and fats, and the regulation of the biotin quantity, with higher concentrations found in
expression of more than 2000 genes in humans. hepatic and renal cells. Like other Vit B complex mem-
• Biotin deficiency is exceptionally rare and seen bers, biotin is also involved in the intermediate metabo-
only in cases of congenital or acquired deficiency of lism of carbohydrates and fats. Biotin is a carboxyl carrier
biotinidase or carboxylase, in cases of antibiotic use and acts as a cofactor for five essential carboxylases; four
disrupting the gastrointestinal flora, and in antiepi- are located in the mitochondria and one in the cytoplasm
leptic use. It is related to lower hair quality, hair [4]. These carboxylases have critical roles in the metabo-
loss, and even total alopecia, which are reversed lism of gluconeogenesis, fatty acid synthesis, and amino
upon aggressive biotin supplementation. acid catabolism, mostly that of isoleucine and valine [5].
• Although there is an incredible amount of social Recent studies have suggested an additional role for bio-
media hype and market advertising touting the effi- tin in the regulation of gene expression. Both stimulation
cacy of biotin for the improvement of hair quantity and suppression have been reported, and expression of
and quality, it remains poorly substantiated in sci- over 2000 human genes appears to be affected by biotin
entific literature, and treating hair loss with biotin status [6]. It is also considered to play a vital role in rep-
supplementation in the absence of a deficiency, lication and transcription of DNA [7], since biotin is
acquired or congenital is controversial. closely related to histones, DNA-binding proteins that
package and order DNA into nucleosomes. Through bio-
tinidase, which is able to biotinylate histone proteins, bio-
tin regulates the stability of DNA replication [8]. Further
Biotin is a water-soluble vitamin, also called Vit B7, and for-
evidence suggests that biotin plays a role in causing DNA
merly known as Vit H or Coenzyme R, with the different
strand breaks and modulating the cellular response to
names attesting to the confusion surrounding its role in nor-
strand breaks [9].
mal metabolism. Biotin was initially discovered in 1927 in
In addition, a role for biotin in normal immune func-
raw egg white, where it is bound to the protein avidin [1].
tions and cell proliferation has been cited, and emerging
Even though it has been identified as a necessary nutrient for
evidence has been accumulating, showing a role in the
almost a century, it has only begun to be understood since the
functions of immune cells. Biotin is essential for the
beginning of the twenty-first century. Notably, after the ini-
activity of human natural killer lymphocytes, for the gen-
tial discovery of biotin, nearly 40 years of research were
eration of cytotoxic T lymphocytes, and the maturation
required just to establish it as a vitamin [2].
and responsiveness of immune cells [10]. Lately, it was
Biotin has an unconventional structure with two rings -a
also demonstrated that biotin levels profoundly affect the
ureido ring and a tetrahydrothiophene ring- fused on one of
functions of human monocyte- derived dendritic cells
their ring sides. In nature, the biotin molecule exists in the
[11]. Additionally, transcriptional factors, including
form of 8 stereoisomers, but only the D-biotin isomer is bio-
NF-κB and Sp1/3, are also affected by the status of bio-
logically active [3].
322 55 Vit B7 (Vit H, Biotin, Coenzyme R)
tin, indicating that biotin regulates immunological and

inflammatory functions independently of biotin- Despite the total lack of evidence, and mostly due to its
dependent carboxylases [12]. low cost and minimal toxicity even in mega-doses
[21], biotin is often recommended as a dietary supple-
ment for “strengthening hair and nails” and has become
55.2 Biotin and the Hair Follicle a trend for consumers [22].
Biotin is also called Vit H, with the H representing “Haar und

Haut”, German for “hair and skin.” It got this name because Even in vitro studies have failed to show an effect in nor-
clinical signs of overt biotin deficiency include hair loss and mal human hair follicles. Limat et al. reported that biotin at
brittle, thin fingernails. pharmacological doses did not affect proliferation or differ-
Biotin’s functions in protein synthesis and keratin produc- entiation of outer root cells in human hair follicles [23].
tion explain its contribution to healthy nails and hair, and Concerning clinical trials on oral supplements containing
actually, biotin supplementation has been reported to have biotin, among other ingredients, there is only one relevant
positive effects on brittle fingernails and onychoschizia [13, study (2002), authored by Prager et al. [24] and published in
14]. However, no studies have shown an effect on the hard- the “Journal of Alternative and Complementary Medicine”.
ness of nails in individuals without a biotin deficiency [15, Researchers in this small, allegedly randomized, double-
16]. Concerning human hair, it is documented that biotin blind, placebo-controlled trial wanted to test the botanically-
deficiency relates to trichorrhexis nodosa, in diffuse hair derived 5α-Reductase inhibitors, Serenoa repens, and
loss, and even in total alopecia17, and there are reports upon β-sitosterol, on 26 males with AGA, separated into two
correction of biotin deficiency with supplementation, patients groups of 13 subjects each. The active group received an
get back their lost hair [17]. oral supplement treatment containing lecithin 50 mg, inosi-
The effects of biotin on hair and nail diseases caused tol 100 mg, phosphatidylcholine 25 mg, niacin 15 mg, bio-
by biotin deficiency have been documented in the litera- tin 100 mcg, β-sitosterol, and Saw Palmetto. Overall, 19
ture. Patel et al. in 2017 conducted a PubMed search of all men completed the trial, and 60% (6/10) of men in the active
case reports and randomized clinical trials and found 18 group reported an improvement in the clinical picture vs.
reported cases of biotin use for hair and nail changes. In 11% (1/9) of subjects in the placebo group. Still, the study
all reported cases in the literature, patients receiving bio- had severe methodological errors and limitations, and even
tin supplementation had an underlying pathology for if the reported results were objective and cosmetically sig-
either poor hair or nail growth. Ten of these cases were nificant, they could not be attributed to one ingredient alone,
reports of patients with inherited enzyme deficiency in and there is no way of identifying the impact of each ingre-
either biotinidase or holocarboxylase synthetase. The rest dient separately [24]. Also, the article does not contain any
had either acquired biotin deficiency or irrelevant under- before-and-after photos or any objective method of mea-
lying conditions, such as brittle nail syndrome or uncomb- surement of efficacy to support the claims of the authors
able hair syndrome. Of these 10 reports, 8 cases reported (see Chap. 71).
alopecia that subsequently resolved after varying months Prof. Trüeb conducted a study on 541 female patients
and doses of biotin supplementation. Additionally, the aged between 9 and 92 years (mean age: 45.9 years) to deter-
three reported cases of uncombable hair syndrome showed mine the frequency and significance of biotin deficiency in
improvement in hair quality/combability after a few women complaining of hair loss. Serum biotin levels were
months of treatment [18]. evaluated, and 38% of women complaining of hair loss had
However, no clinical trials have shown efficacy in values consistent with biotin deficiency (<100 ng/L).
treating hair loss with biotin supplementation in the Associated seborrheic-like dermatitis was found in 35% of
absence of a deficiency. A small trial in a group of women women with serum biotin levels <100 ng/L and telogen efflu-
with diffuse hair loss of unknown etiology by Pawlowski vium vs. 0% of women with normal biotin levels and telogen
et al. published in a Polish language in 1966 reported just effluvium in trichograms. Finally, the patient’s history helped
“improvement of hair quality” but no hair regrowth [19]. detect biotin deficiency, though with low sensitivity, since in
There is also one early study by Dupré et al. in which the biotin deficiency group, 11% of patients vs. 1.5% in the
injectable pantothenol in combination with biotin has group with optimal biotin levels presented with a history of
been alleged to be effective for treating chronic telogen risk factors for biotin deficiency. Overall, Prof. Trüeb com-
effluvium. In this study, the intravenous route of adminis- mented that the habitual practice of treating women com-
tration was reported as superior to oral or intramuscular plaining of hair loss with oral biotin supplementation in an
application [20]. indiscriminate manner is to be rejected [25].
El-Esawy et al. conducted a case-control study on 60 initiative, despite optimal blood Biotin levels. Eleven (38%)
AGA patients and 60 age, sex, and body mass index-matched patients reported a remarkable decline in hair loss, 15 patients
healthy volunteers. The serum zinc level (μg/dL) was lower stated a very low benefit, and 3 patients had no benefit. The
significantly in patients compared to controls (mean ± stan- authors concluded that biotin supplementation could be used
dard deviation, SD = 60.267 ± 10.817, 80.8 ± 6.47 respec- to prevent temporary hair loss after LSG. However, these
tively; p = 0.01), suboptimal biotin levels (μg/dL) were found claims are to be taken with extreme caution. To everyone who
in AGA patients while it was within normal values in con- knows about hair follicle physiology, an expected telogen
trols (mean ± SD = 339.4 ± 12.125, 532.82 ± 35.224, respec- effluvium after a surgical injury is the most probable cause of
tively; p = 0.01). There was also a significant positive what the authors reported (see Chap. 17, Vol. 1). Telogen
correlation between serum zinc and serum biotin (r = 0.489, effluvium will routinely appear 2–3 months after the initial
p = 0.001) but nonsignificant correlations as regards the trigger and long before any actual deficiency is established.
AGA clinical grades, BMI, disease duration, or between This shedding is entirely reversible without treatment. The
serum zinc and patients’ age [26]. reports of the patients concerning the efficacy of treatment
Abdel Rahman et al. conducted a case-control study at the were circumstantial since permanent alopecia was not
outpatient clinic of the Dermatology and Andrology observed in any of the patients ultimately. The same applies
Department at Benha University, Egypt, to evaluate biotin to the conclusion of the authors: they attributed a hair growth
serum levels in patients with telogen effluvium (TE). The effect to Biotin just because a Biotin supplement was being
study included 60 patients with TE and 20 healthy subjects used while hair would be growing anyway. Finally, claiming
matched in terms of age (30.65 ± 8.07 years vs. “prevention” would require a pre-surgical administration of
31.0 ± 8.18 years, respectively; p = 0.87) and sex (88.3% vs. Biotin. Overall, the study is was poorly designed and of low-
80% female patients, respectively; p = 0.45). The investiga- quality and does not contain any before-and-after photos [28].
tion did not reveal any significant difference in biotin serum To date, no clinical trials have investigated the efficacy of
levels between the patients and control subjects. Insignificantly biotin supplementation for the treatment of alopecia of any
lower biotin levels in elderly patients, s mokers, athletes, those kind. There have been no randomized controlled trials to study
with a history of recurrent infections, and women who were its effect on hair quality and quantity in human subjects.
pregnant and/or lactating were observed [27].
Şen et al. conducted a prospective cohort study on 156
female patients with a mean age of 39 ± 10.4 years who had
Nevertheless, due to its availability and affordability,
undergone Laparoscopic sleeve gastrectomy (LSG) for mor-
biotin is a popular nutritional supplement for the treat-
bid and completed at least a 1-year follow-up duration.
ment of brittle nails and hair loss. Although there is an
Vitamin D deficiency was detected in 77% of patients in pre-
incredible amount of social media hype and market
operative examinations (<30 ng/mL). The ferritin levels of 26
advertising praising its efficacy for improving hair,
patients with normal hemoglobin levels was <20 g/mL. All
effects remain largely unsubstantiated in the scientific
patients were prescribed post-surgically a multivitamin sup-
literature [29].
plement that contained all vitamins and minerals, including
Biotin 600mcg. The authors reported that hair loss was
observed in 72% of the patients during the first year after sur-
gery (n = 112); 79% of them reported onset of hair loss The custom of treating women complaining of hair loss in
between the third and fourth months and 20% in the fifth to an indiscriminate manner with oral biotin supplementation is
sixth months (n = 88) after LSG, respectively. Hair loss con- inappropriate, unless biotin deficiency and its significance
tinued for an average of 5.5 ± 2.6 months, but permanent alo- for the complaint of hair loss in the individual patient at hand
pecia was not observed in any of the patients. After the have been demonstrated. In fact, treating the patient exclu-
surgery, laboratory tests revealed 4 patients with biotin defi- sively with oral biotin poses the risk of neglect or delay of
ciency (<100 ng/L) and 21 patients with a suboptimal level of appropriate treatment of hair loss of another underlying
biotin (100–200 ng/L). Biotin supplements (1000 mcg/day) cause in the particular case [25].
were prescribed to 22 patients with low Biotin levels for hair
loss for 3 months, in addition to the multivitamin supplement.
Of those patients, 5 (23%) reported a remarkable decline in 55.3 Food Sources
hair loss after the treatment, 14 had a low effect, and 3 patients
reported no effect. In the follow-up period, 29 patients were Biotin is widely distributed in natural foodstuffs, but an
found to take 1000 mcg/day of Biotin supplements for an unknown biotin quantity is contained in most foods. Biotin
average of 2.5 months after the onset of hair loss by their own contents have been determined for a few foods and are not
ordinarily included in food composition tables [30]. The dif- adults ages 19 and up is 30 μg/day [38, 39]. Murphy et al.,
ficulty in determining biotin’s food content lies in the limita- using food intake data from the NHANES II, estimated the
tions of all methods for biotin analysis in the laboratory, and mean biotin intake of young women aged 18–24 years to be
the results of these different methods can be quite inconsis- 39.9 ± 26.9 μg/day (SD). Nevertheless, there are still critical
tent [31]. questions regarding how much biotin is needed to prevent
However, biotin is not equally absorbed from all foods, deficiency [40].
e.g., biotin in corn and soy is completely bioavailable in
comparison to almost none of the biotin in wheat [32]. This
can probably be explained by the fact that biotin in foods 55.5 Deficiency- Excess of Biotin
exists both in a protein-bound, named biocytin, and a free
form, with the former being 50% less bioavailable than the Many foods provide adequate biotin amounts that remain
latter [33]. The concentration of biotin varies substantially in stable at room temperature and are not destroyed by cooking.
foods; liver contains biotin at about 100 μg/100 g, whereas The natural intestinal flora also produces biotin, and since
fruits and most fleshy meats contain less than 1 μg/100 g. the human body effectively scavenges and recycles it [7].
According to the U.S. Department of Agriculture, egg whites, Thus, biotin deficiency is extremely rare in otherwise healthy
beef liver, brewer’s yeast rice, milk, cereals, soybeans, mush- individuals. Serum biotin levels show a wide variability
rooms, pumpkin and sunflower seeds, and most vegetables ranging from 400 to 1200 ng/L, with daily fluctuations in the
are considered to contain large quantities of biotin [34]. magnitude of up to 100%. Therefore, at least two determina-
However, most dietary biotin appears to be protein-bound in tions on two different days are recommended.
meats and cereals, whereas biotin in cereals appears to be Rare cases of biotin deficiency may be present in both
less bioavailable [35]. acquired conditions and congenital disorders:
Still, the human intestine is exposed to another source of
biotin, a bacterial one. The large intestine’s normal microflora • Severe malnourishment and protein deficiency will pre-
synthesizes and releases into the intestinal lumen a substan- dispose to biotin deficiency, among other deficiencies.
tial amount of free biotin [36]. Chronic alcoholism [41], old age and homelessness are
known precipitating factors for all these conditions.
• Signs of acquired biotin deficiency was initially discov-
Notably, the extent to which biotin is absorbed from ered in rats [42] (called “egg white injury”) and later in
the large intestine and relative contribution of this humans have been experimentally induced on individuals
source of biotin toward total human biotin nutrition, who consume raw egg whites over long periods, of
however, is not well defined [37]. months to years [43]. In these cases, the glycoprotein avi-
din found in egg white binds potently with biotin, making
it unavailable for use in enzymatic reactions [25].
Fortunately, avidin is partially denatured through cooking
55.4 Dietary Recommendations and binding to biotin is reduced. However, one study
showed that 30–40% of the avidin activity was still pres-
The U.S. Food and Nutrition Board acknowledges that biotin ent in the white after frying or boiling [44].
requirements are unknown. Consequently, no RDAs are • Prolonged use of broad-band antibiotics has been associ-
available for biotin in the U.S. but only recommendations for ated with biotin deficiency, presumably due to the altera-
Adequate Intake, based solely on biotin intake among the tions in the intestinal flora [45]. This condition of
apparently healthy, general population. Concerning biotin, dysbacteriosis could impair the body to generate biotin on
this approach is considered flawed by experts, and dietary its own.
intake data are only crude estimates [38]. The uncertainty • Total parenteral nutrition (TPN) has been reported during
associated with this approach becomes even more evident the 1980s and 1990s as a cause of biotin deficiency in
when comparing the intake recommendations from 1989 bed-ridden patients [46], even causing hair loss in some
(AI≤100 μg/day) and those from 1998 (AI = 30 μg/day), [47]. However, standard addition of biotin in modern TPN
with both recommendations having been released by the solutions has eliminated this occurrence.
U.S. Food and Nutrition Board at the National Research • Extensive surgical operations of the alimentary tract
Council [38, 39]. (tumor or bariatric surgery) or short-bowel syndrome [48]
Since, at this time, there is not sufficient information to and inflammatory bowel disease [49] can result in reduced
establish RDAs for biotin, the Board set Adequate Intakes biotin absorption.
(AIs), with the understanding that at some later date, AIs will • Prolonged use of certain anticonvulsants [50] (carbam-
be replaced by more exact information. The current AI for azepine, phenobarbitone, phenytoin, and primidone) may
55.5 Deficiency- Excess of Biotin 325
substantially increase requirements in biotin [51], whereas biotin deficiency levels, the dermatological manifestations
valproic acid [52], and isotretinoin [53] may negatively often appear first and can, therefore, be essential indicators
affect the body’s supply with biotin. [18] (Fig. 55.1).
• Marginal biotin deficiency may occur in pregnant women Biotin deficiency-dermatitis presents in the form of scaly,
[54], possibly in up to 50% of them [55]. Also, heavy patchy, red rash around the eyes, nose, mouth (erythematous
smoking can increase biotin catabolism and result in bio- perioro-facial macular rash), and the genital area. Hair signs
tin deficiency [56]. include hair thinning, hair color loss and can even manifest
• Genetic disorders such as biotinidase deficiency, multiple as total alopecia, whereas seborrheic dermatitis of the scalp
carboxylase deficiency, and holocarboxylase synthetase and fungal infections are reported [60]. Most adults with
deficiency can also lead to inborn or late-onset forms of severe biotin deficiency will exhibit neurological symptoms,
biotin deficiency [57, 58]. including mild depression -which may progress to profound
fatigue, lethargy and, eventually, somnolence- hallucina-
When biotin deficiency is suspected, the serum biotin level tions, generalized myalgias and paresthesia of the extremi-
must be determined, and if a diagnosis of biotin deficiency is ties [61].
set (<100 ng/L), the cause must be sought, unless obvious Biotin toxicity has not been reported in patients treated
from the patient history, and treated. Marginal and severe with daily doses of 200 mg/day orally and up to 20 mg intra-
degrees of biotin deficiency lead to a variety of clinical venously to treat biotin-responsive inborn errors of metabo-
abnormalities that include dermatitis, conjunctivitis, hair lism and acquired biotin deficiency. Similarly, the
thinning, alopecia, and central nervous system disorders U.S. National Academy of Sciences was unable to find any
[35]. Biotin deficiency presents with typical neurological evidence for biotin toxicity, even at doses as high as 10,000
manifestations of Vit B complex deficiency and skin and hair times the AI level. Accordingly, there are no reported cases
signs. While the neurological symptoms occur at more severe of adverse effects from receiving high doses of biotin [36].
Fig. 55.1 (a–d) Successful

treatment of biotin deficiency- a b
related alopecia and
dermatitis with 5 mg oral
biotin. (a, b) Before
treatment: (a) alopecia, (b)
redness and scaling of scalp
(dermoscopy). (c, d)
Significant improvement of
symptoms after 3 months of
treatment. (From Trüeb [59])
c d
13. Colombo VE, Gerber F, Bronhofer M, Floersheim GL. Treatment

Additionally, biotin, has been shown to interfere with of brittle fingernails and onychoschizia with biotin: scan-
ning electron microscopy. J Am Acad Dermatol. 1990;23(6 Pt
common diagnostic immunoassays, including thyroid 1):1127–32.
stimulating hormones and troponins and the FDA has 14. Lipner SR, Scher RK. Biotin for the treatment of nail disease: what
issued a warning on the issue. This is exceptionally is the evidence? J Dermatolog Treat. 2017;9:1–4.
concerning given the high prevalence of thyroid dis- 15. Cashman MW, Sloan SB. Nutrition and nail disease. Clin Dermatol.
2010;28(4):420–5.
ease and atypical myocardial infarction presentations 16. Beautiful hair, beautiful nails-even with aging! Rev Med Suisse.
in women [62]. 2009;5(227):2425.
17. Charles BM, Hosking G, Green A, Pollitt R, Bartlett K, Taitz
LS. Biotin-responsive alopecia and developmental regression.
Lancet. 1979;2(8134):118–20.
Synopsis 18. Patel DP, Swink SM, Castelo-Soccio L. A review of the use of
Biotin reverses hair thinning and hair loss only in patients Biotin for hair loss. Skin Appendage Disord. 2017;3(3):166–9.
with biotin deficiency. However, true biotin deficiency out- 19. Pawlowski A, Kostanecki W. Effect of biotin on hair roots and
sebum excretion in women with diffuse alopecia. Pol Med J.
side the pregnancy setting, malnutrition, adverse medication
1966;5(2):447–52.
effects, and biotinidase deficiency in children is exception- 20. Dupré A, Lassere J, Christol B, Bonafé JL, Rumeau H, Arbarel N,
ally uncommon. Biotin supplements are quite “in vogue”, Coberand S, Périole N, Sorbara AM. Traitement des alopecies dif-
without being any real reason to be so. Societal infatuation fuses chroniques par le panthenol et la D-biotine injectables. Rev
Med Toulouse. 1977;13:675–7.
with supplementation of biotin is propagated by its glamor-
21. Fiume MZ. Cosmetic Ingredient Review Expert Panel. Final report
ization in media. The popularity of biotin is vastly dispropor- on the safety assessment of biotin. Int J Toxicol. 2001;20(Suppl
tionate to the insufficient clinical evidence supporting its 4):1–12.
efficacy in hair improvement in individuals who do not pres- 22. Haneke E. Biotin as a therapeutic nail and hair substance? Med
Monatsschr Pharm. 1994;17(6):187.
ent with low biotin levels. Overall, oral or topical biotin will
23. Limat A, Suormala T, Hunziker T, Waelti ER, Braathen LR,
not benefit patients with AGA/FPHL in any way. Baumgartner R. Proliferation and differentiation of cultured human
follicular keratinocytes are not influenced by biotin. Arch Dermatol
Res. 1996;288(1):31–8.
24. Prager N, Bickett K, French N, Marcovici G. A randomized,
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Vit C (L-Ascorbic Acid)
56
to synthesize Vit C [5]. This is due to a mutation which

Basic Concepts occurred approximately 40 million years ago, in the gene
• L-ascorbic acid is the most biologically active and encoding l-gluconolactone oxidase (GULO), the terminal
well-studied form of Vit C, is not synthesized in the enzyme in the Vit C biosynthetic pathway [6]. All these spe-
human body, and has to be provided by diet or phar- cies have a non-functional gene for the enzyme instead, the
macologic means. ψGULO pseudogene [7], and for these species, Vit C is an
• Vit C performs numerous physiological functions, essential nutrient. However, they are able to make do with
including the synthesis of collagen, carnitine, and the lower levels available from their diets by recycling oxi-
neurotransmitters. It also serves as a cofactor dized DHA back into ascorbic acid, which the body can
required for the function of several hydroxylases reuse as Vit C [8].
and monooxygenases. Vit C was discovered in 1912 and isolated in 1928 by
• Vit C has demonstrated significant growth stimula- Albert Szent-Györgyi, who received a Nobel Prize in medi-
tory effects on healthy and balding dermal papilla cine in 1937 for this discovery [9]. Some years later (1933),
cells (DPCs) in vitro, induces versican, and attenu- Vit C was synthesized, and soon after (1934) marketed as a
ates DHT-induced DKK-1 expression in balding dietary supplement [10].
DPCs, suggesting positive effects in hair follicles.
• In vivo studies on the hair growth effects of oral or
topical Vit C in humans are needed, and inherent 56.1 Actions of Vit C
limitations due to minimal topical percutaneous
absorption apply. Since the discovery of Vit C, the number of its known bio-
logical functions is continually expanding. Ascorbic acid
performs a large number of physiological functions in the
human body; however, the primary biological role of Vit C is
Vit C or L-ascorbic acid is a weak sugar acid that can occur to act as a reducing agent, donating electrons to various
in reduced or oxidized form structurally related to glucose. enzymatic and non-enzymatic reactions.
Vit C is a collective term describing several vitamers with Vit Vit C does not directly participate in the enzyme-catalyzed
C activity in animals, including ascorbic acid, ascorbate, conversion of substrate to product. Instead, it regenerates
their salts, and some oxidized forms of the molecule, such as prosthetic metal ions in these enzymes in their required
dehydroascorbic acid (DHA). The name “Vit C” always reduced forms, acting as an electron donor for eight enzymes
refers to the L-enantiomer of ascorbic acid and its oxidized [11, 12]. Other Vit C functions include a vital role in protect-
forms. The D-enantiomer, which does not occur in nature ing cell membranes, as an antioxidant and scavenger for oxi-
and can only be synthesized artificially, lacks biological dizing species [13], including hydrogen peroxide [14],
activity. nitrogen dioxide [15], nitrogen dioxide [16], and peroxyni-
Most animals are able to synthesize Vit C in their liver trite [17]. It has also been shown to repair the tocopheroxyl
from glucose via a series of four enzymic reactions, during (chromanoxyl) radical of Vit E, thereby allowing Vit E to
which glucose is converted to Vit C [1, 2]. However, humans function again as a free radical chain-breaking antioxidant
[3] and a small selection of animal species, such as primates [18].
[4], guinea pigs [4], most bats, teleost fishes (96% of all Vit C contributes to many important enzyme reactions,
extant species of fish) and some birds, have lost the ability including those leading to the synthesis of norepinephrine,
330 56 Vit C (L-Ascorbic Acid)
carnitine, cholesterol, amino acids, and several peptide hor- tinue to prescribe intravenous ascorbic acid to cancer patients
mones [19]. One of the most prominent Vit C functions is as (or healthy individuals) with purely commercial interest.
an essential cofactor for the synthesis of collagen, proteogly- Since these topics are beyond the scope of this chapter,
cans, and other organic components of the intracellular they will not be further analyzed.
matrix of tissues such as bones, skin, capillary walls, and
other connective tissues [20]. Vit C increases the transcrip-
tion rate of procollagen genes and chemically stabilizes pro- Even though the results of studies and meta-analyses
collagen mRNA [21], and it is speculated that the ability of are still contradictory, and there is no final consensus,
Vit C to heal scurvy is likely due to the stimulation of colla- against popular belief and wishful thinking, Vit C is
gen synthesis in connective tissues [22] and keratinocytes most probably useless in the following conditions: for
[23]. The blood vessels are particularly dependent on Vit C’s the prevention or cure of common cold [30], as a
role in collagen synthesis to help maintain wall resistance hepato-protective agent [31], in asthma treatment [32]
and extensibility. The vitamin C-dependent enzymes propyl and for the prevention or cure of cancer [33].
hydroxylase and lysyl hydroxylase are necessary for the
hydroxylation of proline and lysine before they are added
during collagen synthesis. Furthermore, Shirai et al. demon-
strated that collagen remodeling is involved in the hair cycle, 56.2 Food Sources
and collagen, specifically collagen type 17A1/BP180, is
important in the differentiation of hair follicle-associated The best dietary sources of Vit C are raw fruits and vegeta-
pluripotent stem cells [24]. bles [34]. Citrus fruits, potatoes, tomatoes, and tomato juice
An additional significant biological function of Vit C is as are leading contributors of Vit C to the Western diet. All
a reducing agent, donating electrons and preventing oxida- fruits and vegetables contain Vit C: citrus fruits and their
tion by keeping iron and copper atoms in their reduced states juices (40–50 mg/100 g), such as oranges and grapefruit,
[25]. Vit C preserves the active center of metal ions of kiwi, strawberries, blackberries, blueberries, and water-
hydroxylases and oxygenases in a reduced state to maintain melon. Vegetables with the highest concentrations of Vit C
optimal enzymic activity. Vit C has been reported in exten- are the following: wild potatoes (3100 mg/100 g), red and
sive meta-analyses to have a role in plaque stabilization and green peppers (240 mg/100 g), broccoli, Brussels sprouts,
to prevent endothelial dysfunction in atherosclerosis [26]. cauliflower, tomatoes and tomato juice, spinach, sprouts, tur-
Other claims that it can lower the incidence of major cardio- nips, and other leafy greens. Since Vit C is not naturally pres-
vascular events, stroke, myocardial infarction, cardiac death, ent in grains, it is added to fortified breakfast cereals [35].
and total death are false [27]. Prolonged storage and cooking may reduce the Vit C con-
One important function related to hair physiology is that tent of most foods because ascorbic acid is water-soluble and
Vit C is actively involved in the control of iron metabolism. is destroyed by heat [36]. Fortunately, many of the best food
Recent molecular cloning of mammalian duodenal brush- sources of Vit C, such as fruits and vegetables, are usually
border reductase activity and studies in animals and man consumed raw, and consuming five varied servings of fruits
strongly supported ascorbate as the intracellular electron and vegetables a day can provide more than 200 mg of Vit C
donor for duodenal ferri-reductase activity and provided a [35]. Notably, Vit C is readily oxidized upon exposure to air,
molecular mechanism for an intracellular role of ascorbate in and special care must be given to the handling of its food
intestinal iron absorption [28]. sources.
Many other functions and benefits from Vit C supplemen-
tation have been attributed to Vit C. The research (and pub-
lic) interest spiked after Linus Pauling, the two-time awardee 56.3 Dietary Recommendations
of the Nobel Prize (Chemistry Prize, 1954, Peace Prize 1962)
and one of the most influential scientists in human history Recommended Dietary Allowance (RDA) for Vit C is based
[29], popularized the concept of high-dose Vit C as preven- on its known physiological and antioxidant functions in
tion and treatment of the common cold. A few years later he white blood cells and is much higher than the amount
published his research on the potential of Vit C to prevent required for protection from Vit C deficiency. RDAs for Vit
cardiovascular disease, and at 10 g/day initially (for 10 days) C are 90 mg/day for adult men (>19 years of age) and 75 mg/
intravenously and thereafter administered orally to cure late- day for adult women [37]. Smokers or passive smokers of
stage cancer. Subsequent multiple controlled studies, even every age should increase their daily intake of Vit C by an
though inconclusive in results, have mostly discredited this additional 35 mg [38]. Adequate intake (AI) is 75 mg, and
“megadosing” theory. Nevertheless, public interest in the Tolerable Upper Intake Level (UL) is set at 2000 mg.
subject remains high after more than six decades, and is fur- Ascorbic acid is absorbed from the intestinal tract and has
ther fueled by controversial practices of physicians who con- a biological half-life of 30 min. There is no storage site in the
56.5 Vit C Excess 331
human body, but some tissues carry significantly higher con- Initial symptoms of Vit C deficiency are often vague and
centrations of Vit C [39]. Tissues with the highest Vit C con- nonspecific and can mimic a variety of common conditions,
centration (>100 times the plasma concentration) are including fatigue -probably the result of impaired carnitine
adrenals, pituitary, thymus gland, corpus luteum, and the biosynthesis-, malaise, and lethargy. As Vit C deficiency pro-
retina [40]. The brain, spleen, lungs, testicles, lymph glands, gresses, collagen synthesis becomes impaired, and connec-
liver, thyroid gland, intestinal mucous membrane, leuco- tive tissues become weakened. Petechiae, swelling,
cytes, pancreas, kidneys, and salivary glands usually bear ecchymoses, purpura are often first seen in the lower extrem-
10–15 times higher concentration than that of plasma [41]. ities as capillary fragility leads to an inability to withstand
hydrostatic pressure, together with joint pain, poor wound
healing, hyperkeratosis, perifollicular hemorrhages, and
56.4 Vit C Deficiency corkscrew hairs [35, 47]. Iron deficiency anemia can also
occur due to increased bleeding from all mucous membranes
One of the most compelling arguments for the vital role of and decreased non-heme iron absorption secondary to low
Vit C in skin health is the association between Vit C defi- Vit C intake. Late scurvy stages are typically more severe
ciency and the loss of several essential skin functions. Acute and life-threatening; common manifestations include gener-
Vit C deficiency leads to scurvy, but the timeline for scurvy alized edema, severe jaundice, hemolysis, acute spontaneous
development varies, depending on pre-existing Vit C body bleeding, open sores with pus, tooth loss, neuropathy, fever,
stores; signs can appear within one to more than 6 months of convulsions, and if left untreated, scurvy is fatal [48].
little or no Vit C intake (<10 mg/day) [42]. The most common risk factors of Vit C deficiency in the
While Hippocrates described the first record of scurvy literature are alcoholism, low socioeconomic status, and
around 400 BC, the first attempts to provide a scientific severe psychiatric illness leading to poor nutrition [39].
explanation for the causes of this condition were made in Other, less common predisposing factors include severe
1747 by James Lind, a British Royal Navy surgeon. James intestinal malabsorption, cancer [49] and end-stage renal dis-
Lind conducted what was to be considered the first example ease on chronic hemodialysis [50].
of a controlled experiment aboard his ship, since scurvy was
prevalent among people with limited access to fresh fruit and
vegetables, such as seamen and soldiers. Aware of the lethal 56.5 Vit C Excess
effects of scurvy, Lind selected 12 men suffering from the
condition aboard the “HMS Salisbury” and divided them The uptake of ascorbate from the intestinal tract is very
into six groups of two. In addition to the daily rations they tightly controlled, and in conjunction with renal filtration
received, Lind provided two oranges and one lemon per day and re-absorption, both processes determine the bioavailabil-
to one group, while the other groups received cider, vinegar, ity of ascorbate [51]. However, Vit C is the most widely
seawater, or a mixture of garlic, mustard, sulfuric acid, sea- taken nutritional supplement, and many individuals consume
water, and horseradish [39]. Those given the citrus fruits mega doses of Vit C every day. This phenomenon can prob-
quickly and fully recovered from signs of scurvy, leading ably be attributed to a theory described in 1970 in an article
Lind to conclude that oranges and lemons prevented scurvy. by Linus Pauling that for optimal health, humans should be
From that day forward, citrus juices from oranges, lemon, consuming at least 2300 mg/day to compensate for the
and especially limes were used by the “limeys” of the Royal inability to synthesize Vit C [52].
Navy to prevent and cure scurvy [39]. James Lind published Severe adverse effects from excess intake of Vit C
his findings in the “Treatise on the Scurvy” in 1753, saving (>2–3 gr/day) are infrequent since the human body cannot
countless lives [43]. Until that time, it was assumed that 50% store water-soluble vitamins. Dietary excess of Vit C is rap-
of sailors would succumb to scurvy on a given trip, and idly excreted in the urine, so it exhibits remarkably low acute
scurvy is believed to have resulted in more deaths in the toxicity. Vit C is not considered to cause serious adverse
British fleets than French and Spanish arms combined [44]. effects at high intakes, besides been significantly associated
Full-blown scurvy might be rare in industrialized coun- with a higher risk for incident kidney stones in men, but not
tries, but milder Vit C deficiency is not. in women [53]. The most common complaints of excess
intake of Vit C (>2000 mg/day) are indigestion, nausea,
abdominal cramps, osmotic diarrhea, and other gastrointesti-
Contemporary epidemiological evidence indicates 5% nal disturbances due to the osmotic effect of unabsorbed Vit
prevalence for Vit C deficiency and 13% prevalence for C in the gastrointestinal tract [35].
suboptimal status even in industrialized countries [45]. Early human studies have shown that doses up to 6 g for
It takes 8–12 weeks of irregular or inadequate vitamin more than 1400 days were generally well tolerated [54].
C intake in the diet before symptoms occur [46]. LD50 (dose causing the death of 50% of a population) in mice
is 3367 mg/kg of body weight. The mechanism of fatal dam-
age induction in such doses (≈1.2% of body weight) is Asc 2-P. This demonstrated that Asc 2-P-inducible IGF-1
unknown, but it is speculated that it is more mechanical than from DPCs promotes follicular keratinocytes’ proliferation
chemical. Based on animal test data, chronic effects of mega- and stimulates hair follicle growth in vitro via phosphati-
dosing of Vit C may affect genetic material, may cause dylinositol 3-kinase (PI3K) [61].
adverse reproductive effects and birth defects (teratogenic), The research team of Kim and Sung [62], in a similar
whereas, in humans, Vit C passes through the placenta and is experiment, reported that Asc 2-P induced versican expres-
readily excreted in human milk [55]. sion via phosphatidylinositol 3-kinase (PI3K) signaling and
caused nuclear b-catenin accumulation in DPCs. Since versi-
can is known as a target gene of canonical Wnt/b-catenin
56.6 Vit C and Hair Follicles In Vitro signaling pathway [63] suggesting a vital role in anagen
induction and maintenance of the normal growing phase
In the last two decades, it has been reported that Vit C acts [64], Asc 2-P might have an in vivo hair growth potential.
directly to the dermal papilla cells (DPCs) and that it would Later (2008) studies by Sung et al. demonstrated that Asc 2-P
be worthy of evaluating Vit C (or its derivatives) as a novel induced CCN1/Cyr61 and CCN2/CTGF via Wnt/b-catenin
treatment for hair loss. Most research effort has been con- pathway in human DPCs, and they speculated that Asc 2-P
ducted by the research team of Sung et al. and Kwack et al., caused nuclear b-catenin accumulation by inactivation of
both from Korea. GSK-3b [65]. Kwack et al. conducted an in vitro study to
According to early studies by Hata et al. human skin identify factors responsible for balding by screening DHT-
fibroblasts were significantly stimulated by the presence of inducible genes in balding DPCs by cDNA microarray. They
L-ascorbic acid 2-phosphate (Asc 2-P), a long-acting Vit C found that dickkopf 1 (DKK-1) was one of the most upregu-
derivative, which enhanced twofold the relative rate of col- lated genes, providing early evidence that DHT-inducible
lagen synthesis to total protein synthesis and fourfold the cell DKK-1 produced by balding DPCs promotes apoptosis of
growth [56]. Sung et al. (2006) obtained hair biopsy speci- neighboring follicular keratinocytes in vitro. These data,
mens from the non-balding occipital scalp region of patients together with the higher expression of DKK-1 in balding
with AGA during hair transplantation. Then, they isolated scalp compared to the haired scalp, suggest that DKK-1 may
and cultured both the whole anagen follicles and the DPCs be one of the critical factors involved in the pathogenesis of
from anagen bulbs. They observed a significant elongation of AGA [66].
hair shafts in isolated hair follicles when Asc 2-P was added Two years later (2010), Kwack et al. investigated whether
into the growth medium and significant growth stimulation Asc 2-P could attenuate DHT-induced DKK-1 expression in
in DPCs when Asc 2-P was added at 0.25 mM. When they DPCs from the balding scalp. Researchers observed that
applied Asc 2-P at 250 mM by iontophoresis on the shaved DHT-induced DKK-1 mRNA expression was attenuated in
backs of mice for 4 weeks, induction of early conversion the presence of Asc 2-P as examined by RT-PCR analysis.
from telogen to anagen was noticed. The authors speculated Moreover, Asc 2-P repressed DHT-induced DKK-1 protein
that the effects of Asc 2-P were mediated through prolifera- expression as examined by enzyme-linked immunosorbent
tive and anti-apoptotic effects on DPCs since the mRNA assay (ELISA) [67]. The same team investigated whether or
level of insulin-like growth factor-1 (IGF-1) was increased not L-threonate (an ascorbate metabolite) could attenuate
3.8-fold after treatment with Asc 2-P. This finding suggested DHT-induced DKK-1 expression. They observed via
that Asc 2-P induced secretion of growth factor(s), including RT-PCR analysis and enzyme-linked immunosorbent assay
IGF-1, which stimulated the growth of human DPCs, pro- that DHT-induced DKK-1 expression was attenuated in the
moted the elongation of hair shafts, and induced early con- presence of L-threonate. Also, DHT-induced activation of
version from telogen to anagen in mice [57]. DKK-1 promoter activity was significantly repressed by
These data were in line with earlier findings in human hair L-threonate, and that a co-culture system featuring outer root
follicles by Itami [58] and Philpott [59], reporting that IGF-1 sheath (ORS) keratinocytes and DPCs showed that DHT
induced the proliferation of epithelial cells and promoted inhibited the growth of ORS cells, which was then signifi-
hair follicle growth in cultured hair; similar results were cantly reversed by L-threonate [68].
reported in transgenic animals [60]. Kwack et al. investi-
gated whether the promotion of hair growth by Asc 2-P is
mediated by IGF-1 and, if so, what is the exact mechanism of All these in vitro research suggests exciting, favorable
the Asc 2-P-induced IGF-1 expression. DPCs were cultured, effects of Vit C and its derivatives on hair follicles, but
and the level of IGF-1 was measured by reverse transcription- up to date, there is no in vivo evidence, not even in lab
polymerase chain reaction after Asc 2-P treatment. IGF-1 animals, on the actual and specific hair growth poten-
mRNA in DPCs was upregulated, and IGF-1 staining was tial of Vit C.
increased in the DPCs of cultured human hair follicles by
References 333
56.7 Topical Action of Vit C on the features of the product, the challenge lies with devel-
oping a stable formulation and finding the most efficient
Very little is known about Vit C accumulation in the skin, and transepidermal delivery method [82]. Several innovative
there are no studies investigating the relationship between methods have been developed, including nanomolecules
skin Vit C content and nutrient intake or plasma supplies. [83], multilamellar vesicles [84], ascorbyl palmitate vesicles
According to some authors, healthy skin contains high (Aspasomes) [85], and microemulsions [86, 87]. Moreover,
concentrations of Vit C, with levels comparable to other physical methods offering increased skin permeability, such
body tissues and well above plasma concentrations, suggest- as iontophoresis [88], Laser, and microdermabrasion tech-
ing active accumulation from the circulation. Most of the Vit niques, have been tested with positive results [89].
C in the skin appears to be in intracellular compartments, and Vit C has been reported to improve the clinical appearance
it is transported into cells from the blood vessels present in of photoaged skin and enhance the synthesis of composite
the dermal layer [69]. elastin fibers and collagen [90]. Sauermann et al. evaluated
Vit C levels in the skin have not often been reported, and the effects of topical application of Vit C on volar forearms of
there is considerable variation in the published levels, with a 33 women. They reported that topical Vit C resulted in a sig-
tenfold range across various independent studies [70]. nificant increase in dermal papillae density from 4 weeks
However, as already mentioned, both the uptake of ascorbate onward compared to its vehicle. Also, it partially restored the
from the intestinal tract and the renal clearance are very anatomical structure of the epidermal- dermal junction in
tightly controlled and together determine the bioavailability young skin and increased the number of nutritive capillary
and plasma levels of ascorbate. Therefore, regardless of the loops in the papillary dermis close to the epidermal tissue in
amount of the quantity of Vit C administered orally, one the aged skin of postmenopausal women [91].
could not predict or target a “Vit C level” on the scalp and Until today, there are no in vivo studies in humans on the
hair follicles. Despite high doses of oral supplementation, it transdermal absorption of Vit C by the scalp. Nevertheless,
is well-known that only a small fraction of Vit C will be bio- the transfollicullar delivery of Vit C on the scalp will likely
logically available and active in the skin [71]. be sufficient for adequate absorption since other molecules
To overcome this problem, topical epidermal administra- with properties to similar Vit C have been found to use the
tion of Vit C has been tested and thoroughly reviewed, pilosebaceous route efficiently without needing incorpora-
although the efficacy of this method depends on the formu- tion into sophisticated penetration molecules [92, 93].
lation used [72, 73]. Consequently, Vit C is one of the most
commonly used vitamins in the cosmeceutical industry [74] Synopsis
available in several active forms. Among all forms, Vit C plays a vital role in skin health, and there is a strong
L-ascorbic acid is the most biologically active and well- association between Vit C deficiency and the loss of several
studied [71, 75]. essential skin functions, including hair loss. However, oral
administration of Vit C in otherwise healthy individuals has
not shown any positive effects in normal or balding hair folli-
cles, and there are not even anecdotal reports on the hair
Nevertheless, upon epidermal application, transcuta-
growth potential of Vit C. In vitro studies have shown positive
neous penetration of Vit C is very limited [76], with
action of Vit C on both normal and balding hair follicles, and
stratum corneum being the major physical obstacle
probably Vit C will have a role in the future in the management
limiting transcutaneous permeation [77, 78].
of hair disorders. Nevertheless, there are no in vivo studies on
the effects of topical Vit C application on the scalp of patients
with AGA/FPHL. Unfortunately, the inherent minimal trans-
L-ascorbic acid is a water-soluble and unstable molecule, cutaneous permeation of Vit C limits clinical application.
hence the poor penetration into the skin because it is repelled
by the hydrophobic character of the stratum corneum. Even
though it has a low molecular weight (<500 Dalton), which References
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Vit E (α-Tocopherol)
57
became known as the “antisterility vitamin”, but soon scien-

Basic Concepts tists realized that it had this effect only in rats.
• Vit E is a lipid-soluble, chain-breaking radical scav-
enger and potent antioxidant, also involved in a
wide range of physiological processes, ranging 57.1 Actions of Vit Ε
from immune function and control of inflammation,
to the regulation of gene expression. Vit E is the major lipophilic antioxidant in plasma, mem-
• α-tocopherol is the most active form of Vit E in branes, and tissues of all mammals [3]. In humans,
humans, it is minimally absorbed transcutaneously, α-tocopherol is the most abundant Vit E homolog, followed
and tocopherol acetate found in most cosmetics is by γ-tocopherol. Only α-tocopherol meets human Vit E
not converted into α-tocopherol in the human skin. requirements because it is the only form that was demon-
In addition, minimal information exists regarding strated to reverse Vit E deficiency symptoms in humans. It is
the benefits of Vit E supplementation on hair loss. also the only Vit E form maintained in plasma and tissues.
• Even though most (>95%) of adults fail to meet The principal role of Vit E is the arrest of chain propaga-
dietary recommendations for Vit E -without notice- tion by scavenging lipid peroxyl radicals, with one molecule
able ill effects, though-, frank Vit E avitaminosis is of tocopherol having the ability to scavenge 2 peroxyl radical
very rare in developed countries, whereas chronic molecules [4, 5]. As it is a fat-soluble molecule, it is incorpo-
administration of high doses of Vit E can actually rated into cell membranes protecting them from oxidative
increase morbidity and mortality. damage [6]. Lately, new biological activities have been
• Experimental use of tocopheryl polyethylene glycol described for several tocopherols, which are unrelated to
succinate (TPGS) combined with Minoxidil their antioxidant capacity. According to some experts, these
increased the topical absorption of Minoxidil and uniquely essential compounds for the human body cannot be
commercial availability is anticipated. considered simple antioxidants [7]. Other experts, however,
doubt the beneficial cardiovascular and cancer-protective
effects of Vit E and consider it nothing more than an antioxi-
dant [8].
Vit E is a collective term referring a group of 8 naturally Vit E has been demonstrated to inhibit Protein Kinase C
occurring lipid-soluble molecules (homologs), of which 4 are (PKC), and this inhibition causes the inhibition of vascular
tocopherols (α, β, γ, and δ tocopherols) and 4 are tocotrienols smooth muscle cell proliferation, bringing smooth muscle
(α, β, γ and δ tocotrienols) [1]. Vit E was discovered in 1922 growth to a halt [9]. The inhibition of PKC in many cells may
by Evans and Bishop, of the University of California in be relevant in explaining the anti-atherosclerotic [10] and
Berkeley, and the name “tocopherol” they proposed is derived anti-tumor effects [11] of Vit E in vivo. Furthermore, the
from the Greek word “tocos” = offspring and the Greek verb expression of several genes is under the non-antioxidant con-
“phero” = to bear, since the unknown till that time molecule trol of α-tocopherol, suggesting an action of α-tocopherol in
was required to prevent fetal resorption in pregnant rats fed protection against disease [12]. Furthermore, Vit E is consid-
lard-containing diets that were easily oxidizable [2]. The -ol ered essential for normal neurological function [13], for the
ending indicates its alcohol functional group. Tocopherol inhibition of platelet aggregation [14] and the protection of
338 57 Vit E (α-Tocopherol)
the highly unsaturated acyl chains of polyunsaturated fatty acetate as a preventive agent of doxorubicin-induced alope-
acids from oxidation [15]. cia. Initial results demonstrated no protective activity,
whereas a later study on rabbits showed that rabbits fed an
α-tocopherol-supplemented diet showed evidence of protec-
57.2 Topical Action of Vit E tion against doxorubicin-dependent inhibition of new hair
growth [24].
Vit Ε is one of the most frequently used ingredients in cos- Chen et al. evaluated the efficacy of promoting hair
metic and skin care formulations, and products with concen- growth after topical application of 2% Minoxidil Topical
trations of Vit E ranging from 0.1 to 20% have been developed Solution (MTS) supplemented with tocopheryl polyethylene
and used in many countries. However, there is a surprising glycol succinate (TPGS) -an FDA approved water-soluble
lack of published data on dose-response studies defining the Vit E nutritional supplement and drug delivery vehicle- in
optimal dose of Vit E for topical application. co-solvent systems of various compositions, using C57BL/6 J
mice as a model. The results revealed that the addition of
0.5% TPGS into MTS enhanced the proliferation of hair. An
Interestingly, when applied topically, Vit Ε is distrib- increase in the amount of TPGS to 2% led to decreased hair
uted in a gradient fashion in the stratum corneum, with growth, and a tendency for the plasma concentration of
the highest levels in the deeper layers of the epidermis Minoxidil to increase was noted [25]. Sheu et al. also tested
and lowest levels closest to the surface [16]. Still, over- the effect of TPGS on the penetration flux of MTS and its
all absorption is minimal and rarely exceeds 12% of retention in the skin using ten different solvent formulations
the applied dose [17]. reporting similar results [26].
Beoy et al. [27] conducted a 32-week, randomized,
double-blind, placebo-controlled trial in Malaysia on 38 vol-
unteers with varying hair loss levels, ranging from patchy
Another parameter that dictates the efficacy of Vit E on loss of scalp hair to more severe scalp hair loss. Twenty-one
topical products is the homolog contained in the formulation, volunteers were randomly assigned to orally receive 100 mg
since tocopherol acetate, often found in topical products, is of mixed tocotrienols daily, while 17 volunteers were
only very slowly and to a minor extent, converted to the assigned to receive a placebo capsule. Two parameters were
active α-tocopherol in the human skin in vivo, despite ade- chosen to evaluate the efficacy of tocotrienol supplementa-
quate absorption [18]. Moreover, the effect of the delivery tion: hair counts inside a 2 × 2 cm tattoo demarcated area and
system on the permeation and metabolism of Vit Ε in topical weight of hairs, with 20 strands randomly chosen and cut to
products also plays a key role [19], and nanoparticles have 1 cm in length and weighted to calculate the percentage
been reported as the most effective means of topical delivery change from baseline. The number of hairs of the volunteers
of Vit Ε [20]. There is widespread use of Vit E as a topical in the tocotrienol supplementation group increased signifi-
treatment, with claims for improved wound healing and cantly as compared to the placebo group, with the former
reduced scar tissue formation. A review by Sidgwick et al. recording a 34.5% increase at the end of the 8-month supple-
concluded that there is limited clinical evidence to support mentation as compared to a 0.1% decrease for the latter.
these claims. The majority of published articles are ranked as However, there was no statistically significant increase in the
lowest (category 4) LOE (level of evidence), being of limited weight of hair (p > 0.05) between pre- and post-
quality, with individual flaws, including low patient num- supplementation for both groups of volunteers. All volun-
bers, poor randomization, no blinding, and short follow-up teers, except one in the tocotrienol supplementation group,
periods [21]. showed a positive response at the end of the study, recording
In general, though, the topical action of Vit Ε as a com- an increase in the number of hairs evaluation area. Eight vol-
pound with anti-aging properties has been poorly studied, unteers (40.0%) showed hair increases of more than 50%,
with few studies in humans. one volunteer (5.0%) had a 25–50% increase, nine volun-
teers (45.0%) had increases between 10 and 25%, while one
volunteer (5.0%) showed a hair increase of less than 10%.
57.3 Vit E and the Hair Follicle Only one volunteer (5.0%) in the tocotrienol supplementa-
tion group had a slight decrease in the number of hairs. On
Concerning the use of Vit E in hair growth promotion, there the other hand, only eight volunteers in the placebo group
are just a few in vitro, animal, and human studies on the showed an increase in the number of hairs after 8 months,
effects of Vit E on hair follicles. with 1 (6.7%) showing more than 20% increase and the
Studies conducted in the mid-1980s in lab animals [22] remaining 7 (46.7%) showing negligible increases. Seven
and humans [23] evaluated the effectiveness of α-tocopherol volunteers (46.7%) had a decrease in the number of hairs.
According to the authors, this observed effect was attributed reported that Vit E group had fewer incident prostate and col-
to the antioxidant activity of tocotrienols that helped reduce orectum cancers compared with the group not receiving Vit
lipid peroxidation and oxidative stress in the scalp, which E (number of cases 99 compared with 151 and 68 compared
has been associated with alopecia [27]. The authors based with 81, respectively). Hartman et al. concluded that long-
these hypotheses on previous similar observations reported term α-tocopherol supplementation decreases serum andro-
by Akar et al. [28] and Koca et al. [29] on alopecia areata gen concentrations and could have been one of the factors
patients. Koca et al. [29] observed an increase in lipid per- contributing to the observed reduction in incidence and mor-
oxidation and a decrease in superoxide dismutase (SOD) lev- tality of prostate cancer in the α-tocopherol treatment group
els in patients with alopecia areata compared to controls. of an earlier (1995) ATBC Study by Albanes et al. [32]
Unfortunately, the reported results in the Beoy et al. study
were not supported by before-and-after pictures, and the
journal chosen for publication has a very low impact factor However, the results of later meta-analyses strongly
score [27]. disagree with these. Results from the extensive
Ahn et al. [30] conducted an in vitro and in vivo study to “Selenium and Vitamin E Cancer Prevention Trial
investigate the hair growth properties of tocopherol acetate, (SELECT)” trial by Klein et al. [33] showed that Vit E
stevioside, L-menthol, and a mixture of three compounds. supplements (400 IU/day) significantly increased
They demonstrated that separately, tocopherol acetate, prostate cancer risk among healthy men.
L-menthol, and stevioside promote the proliferation of
HaCaT keratinocyte cells and that L-menthol promotes the
proliferation of both dermal papilla cells and HaCaT kerati-
nocytes in a dose- and time-dependent manner. Then, they The report included 54,464 person-years of follow-up,
used 30 C57BL/6 mice divided into six groups (five animals and compared to placebo in which 529 men developed pros-
per group) (group A: the vehicle control; group B: Minoxidil tate cancer, 620 men in the Vit E group developed prostate
3%; group C: tocopherol acetate; group D: stevioside; group cancer (hazard ratio, HR = 1.17; 99% CI: 1.004–1.36,
E: L-menthol; and group F: a mixture of L-menthol, tocoph- p = 0.008) [33]. These findings are in accordance with earlier
erol acetate, and stevioside). The concentrations of these results by Bjelakovic et al. [34] in 2008. Bjelakovic et al.
agents (0.5%) were determined by the half-maximal value of meta-analyzed the literature findings of the Cochrane Library
a standard used to prepare nonmedical cosmetic products. and included all primary and secondary prevention random-
When tocopherol acetate, L-menthol, and stevioside were ized clinical trials on all five major antioxidant supplements
each applied topically to shaven skin of C57BL/6 mice, only (β-carotene, Vit A, Vit C, Vit E, and selenium) vs. placebo or
tocopherol acetate and L-menthol alone were effective in no intervention. In overall 67 randomized trials with 232,550
promoting hair growth. A mixture of tocopherol acetate, participants, researchers found a significantly increased mor-
L-menthol, and stevioside was more effective than tocoph- tality due to Vit E use (relative risk, RR = 1.04, 95% CI:
erol acetate or L-menthol alone in promoting hair growth 1.01–1.07). The same research team updated their review in
in vivo. Tocopherol acetate and L-menthol upregulated genes 2012 by adding literature findings from MEDLINE,
known to promote hair growth, including keratin, keratin- EMBASE, LILACS, the Science Citation Index Expanded,
associated protein, forkhead box, sonic hedgehog (SHh), and Conference Proceedings Citation Index-Science [35].
FGF-10, desmoglein 4, deoxyribonuclease 1-like 2, lim They even scanned citations of relevant publications and
homeobox protein, and cadherin 3. The authors concluded asked pharmaceutical companies for additional trials.
that the synergistic effect of the mixture on mice was almost Overall, 78 randomized trials with 296,707 participants were
the same as that of Minoxidil, and it should be further inves- included, and 56 trials, including 244,056 participants, had a
tigated [30]. low risk of bias. In the 56 trials with a low risk of bias, Vit E
Dietary Vit E has also been hypothesized to induce increased mortality (RR = 1.03, 95% CI: 1.00–1.05).
changes in steroidogenesis and androgen production by
affecting cholesterol homeostasis. Hartman et al. analyzed
the data from the Alpha-Tocopherol Beta-Carotene Cancer 57.4 Food Sources
Prevention (ATBC) study, a placebo-controlled, randomized
intervention trial testing the hypothesis that β-carotene and The human diet contains eight different Vit E-related mole-
α-tocopherol supplements prevent lung and other cancers cules, all synthesized by plants. Vegetable oils, mostly oil
[31]. The results from 29,133 eligible male cigarette smokers from wheat germ, sunflower oil, and high-value, green, leafy
aged 50–69 years old randomly assigned to receive β-carotene vegetables, are all rich in Vit E [36]. Outside of greens, the
(20 mg), α-tocopherol (50 mg), β-carotene and α-tocopherol, foods with the most Vit E tend to be high-fat foods. These
or placebo daily for 5–8 years were published in 1996 and include nuts, seeds, especially sunflower seeds, almonds,
cereals, extracted oils, and fatty fish. Many oil rich-plants inadequacy since all these individuals appear to undergo no
give humans adequate amounts of Vit E, with olives and avo- evident ill effects, and their circulating α-tocopherol concen-
cados being the richest in tocopherols. However, one should trations are not abnormal [42].
keep in mind that Vit E is a relatively difficult nutrient to Frank Vit E deficiency is rare, and overt deficiency symp-
obtain from the diet and to meet dietary recommendations, a toms have not been found in healthy subjects who obtain
fact that the 2010 Dietary Guidelines did not emphasize [37]. little Vit E from their diets. Consequently, in developed
countries, Vit E deficiency is very rare and is more common
in developing counties due to malnutrition [46]. In devel-
57.5 Dietary Recommendations oped countries, Vit E deficiency occurs as a result of genetic
defects in the α-tocopherol transfer protein (α-TTP) [47] and
In adult men, the recommended dietary allowance (RDA) of in fat malabsorption cases, such as cholestatic liver disease,
Vit Ε is 15 mg or 22 IU. This dose refers to α-tocopherol of Crohn’s disease, or cystic fibrosis [48].
natural origin, which is the most potent form of Vit E. In con- Concerning Vit E toxicity, there is not a single published
trast to other vitamins, synthetic Vit E, also found as dl-α- report of systemic adverse effects from dietary Vit E, and the
tocopherol, is less potent, and therefore higher quantities are median lethal dose LD50, required to kill 50% of experimen-
needed to cover Vit E needs [38]. Adequate intake (AI) is set tal rats or mice, is 4000 mg of Vit E per kg of body [49]. The
at 12 mg and tolerable upper intake levels (UL) at 1000 mg current opinion considers Vit E to be one of the least toxic
(1500 IU) since Vit Ε in high doses may interact with the fat-soluble vitamins, and mega-doses of Vit E are consumed
actions of Vit K and can act as an anticoagulant, increasing in the belief that it reduces the level of free radicals in the
the risk of bleeding [39, 40]. body [50]. The risk of Vit E hypervitaminosis is very low,
and Vit E has no mutagenic, teratogenic, or carcinogenic
properties. Reflecting this lack of evidence for harm, the
57.6 Deficiency- Excess of Vit E National Academy of Sciences set the Tolerable Upper
Intake Limit (UL) for Vit E at 1000 mg, more than 60 times
Although α-tocopherol was discovered in 1922, it was not the RDA, and, probably, more than 100 times what an aver-
until the 1980s that α-tocopherol deficiency was described in age American adult eats in a day [45].
humans [41]. Moreover, it took another decade to define the Regular consumption of more than 1000 mg (1500 IU) of
deficiency symptoms in cases that additional nutritional or tocopherols per day may be expected to cause hypervitamin-
metabolic defects did not complicate the α-tocopherol defi- osis E, with an associated risk of Vit K deficiency and, con-
ciency disorder [42]. sequently, bleeding problems [51]. Based on human studies,
Notably, there is a vigorous debate concerning the Vit E a daily dosage of 100-300 mg Vit E can be considered harm-
status in the U.S. and the characterization of Vit E deficiency less from a toxicological perspective. Double-blind studies
or Vit E inadequacy. According to the report by Moshfegh involving a large number of subjects have demonstrated that
et al. (2005), sponsored by the Agricultural Research Service large oral doses of up to 3200 IU/day led to no consistent
of the U.S. Department of Agriculture, the average U.S. adult adverse effects [52]. Vit E (d-α-tocopherol) levels higher
eats no more than half the Dietary Reference Intake (DRI) than 800 mg have been occasionally related to symptoms
for Vit E, 7.5 mg of the recommended 15 mg/day. such as fatigue, nausea, mild gastrointestinal problems, pal-
pitation, and temporary increase of arterial blood pressure.
These symptoms are reversible upon discontinuation of Vit E
In fact, according to the Dietary Recommendation [53]. Additionally, there is evidence for an adverse effect on
standards, Vit E is one of the most common vitamin hair growth following excessive Vit E intake, where a signifi-
deficiencies in the United States, with as many as 92% cant decrease in serum thyroid hormone levels was found in
of men and 98% of women in America not consuming volunteers taking 600 IU of Vit E per day for 28 days [54].
sufficient dietary Vit E to meet the estimated average While this dosage is technically 30 times the RDA, even
requirements [43]. higher levels appear to be well-tolerated, and this kind of
mega-dose can often be found in multivitamin supplements.
Synopsis
In a study assessing a biomarker of Vit E status, Lebold Vit E serves as a peroxyl radical scavenger, and at a molecu-
et al. [44] found that only individuals who are highly moti- lar level, some of its metabolites regulate cell signaling and
vated and interested in their diets consumed nearly the rec- modulate gene transcription. Oral supplementation of Vit E
ommended α-tocopherol amounts [45]. The question has shown to increase the relative risk for cancer but does
remains, however, as to which are the symptoms of Vit E seem to positively affect hair follicles of individuals with
References 341
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Inositol (Vitamin B8)
58
phate underline their great importance [2]. Myo-inositol

Basic Concepts plays a vital role as the structural molecule for many sec-
• Inositol is not an essential nutrient and is consid- ondary messengers, the inositol phosphates. Myo-inositol is
ered a pseudo-vitamin since it can be synthesized in involved in a number of intracellular signal transduction
the human body; however, it has essential structural pathways [3] and serves as an essential component of the
roles and is involved in several intracellular signal structural lipids phosphatidylinositol and its various phos-
transduction pathways. phates, the phosphatidylinositol phosphate lipids [4].
• Inositol hexakisphosphate salt, aka phytic acid, is Inositol is essential for the proper function of the nervous,
considered both an antinutrient (decreases protein immune, and muscular systems [5]. It is involved in the
digestion and bioavailability of Ca2+, Mg2+, Fe2+and metabolism of fatty acids, preventing fatty acid accumula-
Zn2+) and a beneficial food compound with known tion in the liver [6], participating in insulin signal transduc-
anti-oxidant and cancer-protective properties. tion [7] and gene expression [8], cell membrane potential
• Inositol is also considered a safe and effective treat- maintenance [9], and intracellular Ca2+ concentration con-
ment for polycystic ovary syndrome (PCOS) but the trol [10].
correlation of inositol with effects on human hair fol- Inositol has been used therapeutically in managing
licles is very weak, and reports of benefits of inositol hepatic disease, and large doses of inositol have been studied
administration in patients with AGA/FPHL is sparse. for the treatment of depression, obsessive-compulsive disor-
der, and panic attacks [11]. Inositol is also considered a safe
and effective treatment for polycystic ovary syndrome
(PCOS), working by increasing insulin sensitivity. It is capa-
Inositol exists in nature in nine stereoisomers, with cis- ble of restoring spontaneous ovarian activity, and conse-
1,2,3,5trans-4,6-cyclohexanehexol or myo-inositol being the quently, fertility in most patients with PCOS [12].
most widely occurring form. Inositol is a sugar alcohol, d-chiro-inositol has been shown to reduce hyperandrogen-
closely related to glucose and is not considered a real vitamin, ism in women with PCOS [13], probably by lowering plasma
in the strict sense of the word, since it can be synthesized in Testosterone [14].
the human body using glucose-6-phosphate as substrate. Notably, inositol hexakisphosphate, IP6, which is abun-
dant in high-fiber foods, possesses benefits for human health,
such as enhancing the immune system, preventing pathologi-
For this reason, it is not an essential nutrient and is cal calcification and kidney stone formation [15], and lower
considered a “pseudo-vitamin” [1]. elevated serum cholesterol. Most importantly, striking anti-
cancer actions of IP6 were demonstrated in different experi-
mental models since it induces differentiation of malignant
cells, enhances the anticancer effect of conventional chemo-
58.1 Actions of Inositol therapy, controls cancer metastases, and improves the quality
of life [16]. Fibers with high phytate content, the salt of IP6,
Inositol, phosphatidylinositol, and some of their mono- and such as cereals and legumes, show a negative correlation
polyphosphates act synergistically with the Vit B complex with colon cancer, indicating that phytate, and not fiber per
members. Methionine and choline and an extraordinary se, suppresses colon carcinogenesis [17].
range of cellular functions controlled by inositol pyrophos-
344 58 Inositol (Vitamin B8)
58.2 Inositol and the Hair Follicle large amounts of phytic acid, which is not generally bioavail-
able to non-ruminant animals lacking the digestive enzyme
Inositol has been empirically related to effects on hair folli- phytase required to remove the phosphate groups. Moreover,
cles initially by Woolley [18]. He reported that cultures from phytic acid also chelates dietary Ca2+, Mg2+, Fe2+, and Zn2+,
the intestinal tract of animals that exhibited spontaneous cure making them non-absorbable, and contributing to mineral
of alopecia yielded microorganisms that synthesized signifi- deficiencies in populations in developing countries whose
cantly more inositol than organisms isolated from the tracts diets rely highly on bran and seeds for their mineral intake
of mice that had become hairless [18]. [26]. The chemical properties of phytic acid make it both an
Sato-Miyaoka et al. [19] have related the Inositol trispho- antinutrient (decreases protein digestion and bioavailability
sphate receptor (InsP3R), a membrane glycoprotein complex of Ca2+, Mg2+, Fe2+and Zn2+) and a beneficial (potent anti-
acting as a Ca2+ channel activated by inositol trisphosphate oxidant) food compound [27] with known cancer-protective
(InsP3), with the hair follicle physiology. They demonstrated properties [17].
that IP3R3 is expressed explicitly in the hair follicles and is
vital for regulating the hair cycle. They reported that in
IP3R3-deficient mice, deletion of IP3R3 produced cyclic alo- 58.4 Dietary Recommendations
pecia. They proposed the IP3R3/NFAT-dependent signaling
pathway actively controls that hair shedding, possibly There is no official recommended daily allowance (RDA) for
through the regulation of cytokeratin filaments in keratino- inositol, which is not recognized as a true vitamin. It is also
cytes [19]. Inositol-dependent enzymes [20] involved in the challenging to list recommended daily intakes since myo-
activation of the Akt signaling pathway [21] and the media- inositol is synthesized from glucose-6-phosphate in humans,
tion of phenotypic effects of corticotropin-releasing hor- and most inositol is synthesized in the kidneys, typically in
mone on the human skin [22] might also be indirectly related amounts of a few grams per day [28]. As a rough guide,
to Inositol effects on hair follicles since they are all impli- many nutritionists advise a daily consumption of 1000 mg
cated in the hair follicle physiology [23]. for adults.
However, there are no in vivo or clinical studies on the 58.5 Deficiency- Excess of Inositol
direct and specific actions of inositol on hair follicles.
Inositol deficiency may theoretically arise through a plethora
of different mechanisms, including reduced food-dependent
intake, increased catabolism and excretion, decreased bio-
There is only one very small study, authored by Prager synthesis, inhibition of intestinal and cellular uptake [29].
et al. [24], and it is extensively presented and reviewed in However, frank Inositol deficiency in humans remains very
Chap. 71. The authors claimed hair-growth effects of a sup- rare [30] and occurs in inositol-depleted psychiatric patients
plement containing Inositol 100 mg among multiple other on chronic treatment with lithium [31].
ingredients (lecithin 50 mg, phosphatidylcholine 25 mg, There are no reports of toxic action for excess intake ino-
Niacin 15 mg, Biotin 100 mcg, β-sitosterol, and Saw sitol [31], and intake of 12 g/day for 28 days tested in the
Palmetto). That study has significant methodological errors treatment of depression did not cause any serious adverse
and limitations, including a lack of objective measurement effects besides mild gastrointestinal side effects such as nau-
techniques or photographic evidence of positive results. sea, flatus, and diarrhea, with the severity of side effects not
Even if the reported results were accurate and cosmetically increasing with dosage [32].
significant, they could not be attributed to one ingredient,
and it is impossible to identify the impact of each ingredient Synopsis
separately. Inositol and its phosphate derivatives (namely, Inositol-
hexakisphosphate, InsP6, or phytic acid) have been demon-
strated to exert a plethora of valuable health effects. However,
58.3 Food Sources there is no evidence suggesting inositol’s action in the physi-
ology of hair follicles of healthy adults or patients with AGA/
Foods containing the highest concentrations of myo-inositol FPHL. Inositol is included in multivitamin supplements
(including its compounds and salts) are citrus fruits, beans, promising “healthy hair” mostly because it is perfectly safe,
grains, and nuts [25]. However, beans and grains contain and there is no possibility of inositol toxicity.
References 345
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phytate? Cancer. 1985;56(4):717–8.
18. Woolley DW. Synthesis of inositol in mice. J Exp Med.
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2. Saiardi A. Cell signalling by inositol pyrophosphates. Subcell Iwanaga H, Mikoshiba K. Regulation of hair shedding by the type 3
Biochem. 2012;59:413–43. IP3 receptor. J Invest Dermatol. 2012;132(9):2137–47.
3. Berridge MJ. Inositol trisphosphate and diacylglycerol: two inter- 20. Ooms LM, Horan KA, Rahman P, Seaton G, Gurung R,
acting second messengers. Annu Rev Biochem. 1987;56:159–93. Kethesparan DS, Mitchell CA. The role of the inositol polyphos-
4. Michell RH. The multiplying roles of inositol lipids and phosphates phate 5- phosphatases in cellular function and human disease.
in cell control processes. Essays Biochem. 1997;32:31–47. Biochem J. 2009;419(1):29–49.
5. Schell MJ. Inositol trisphosphate 3-kinases: focus on immune and 21. Zhang J, He XC, Tong WG, Johnson T, Wiedemann LM, Mishina Y,
neuronal signaling. Cell Mol Life Sci. 2010;67(11):1755–78. Feng JQ, Li L. Bone morphogenetic protein signaling inhibits hair
6. Holub BJ. The nutritional significance, metabolism, and function follicle anagen induction by restricting epithelial stem/progenitor
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Nutr Res. 1982;4:107–41. 22. Slominski A, Zbytek B, Zmijewski M, Slominski RM, Kauser S,
7. Larner J. D-chiro-inositol--its functional role in insulin action Wortsman J, Tobin DJ. Corticotropin releasing hormone and the
and its deficit in insulin resistance. Int J Exp Diabetes Res. skin. Front Biosci. 2006;11:2230–48.
2002;3(1):47–60. 23. Alexandrescu DT, Kauffman CL, Dasanu CA. The cutaneous epi-
8. Steger DJ, Haswell ES, Miller AL, Wente SR, O'Shea dermal growth factor network: can it be translated clinically to
EK. Regulation of chromatin remodeling by inositol polyphos- stimulate hair growth? Dermatol Online J. 2009;15(3):1.
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9. Kukuljan M, Vergara L, Stojilkovic SS. Modulation of the kinet- double-blind, placebo-controlled trial to determine the effective-
ics of inositol 1,4,5-trisphosphate-induced [Ca2+]i oscillations by ness of botanically derived inhibitors of 5-alpha-reductase in the
calcium entry in pituitary gonadotrophs. Biophys J. 1997;72(2 Pt treatment of androgenetic alopecia. J Altern Complement Med.
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Minerals, Trace Elements, and Hair
Follicles 59
Minerals represent a broad group of chemical elements Table 59.1 Major minerals and trace minerals in human nutrition
required as essential nutrients by organisms to perform func- Directly involved in hair follicle Not directly involved in
tions necessary for life. Minerals are one of the four groups physiology the hair follicle physiology
of essential nutrients, along with vitamins, essential fatty Major minerals (required intake of more than 100 mg/
day) + Recommended Daily Intake (RDA) for an average adult
acids, and essential amino acids. male
Minerals, by definition, originate from the earth and can- Sulfur (S) 900 mg Potassium (K) 3400 mg
not be made by living organisms. Of the 118 elements on the Calcium (Ca) 800 mg Sodium (Na) 2300 mg
periodic table, just 25 are essential to human life. These vary Phosphorus (P) 580 mg Chloride (Cl) 30,000 mg
in amounts in the body, and perform a several essential meta- Magnesium (Mg) 330 mg
bolic functions. Depending on the amount of the individual Trace minerals (required intake of less than 100 mg/day and
recommended daily intake (RDA) for an average adult male
mineral in the body, the minerals have been classified into
Iron (Fe) 6 mg Chromium (Cr)
the “major minerals” with a recommended intake of more Zinc (Zn) 9.4 mg Manganese (Mn)
than 100 mg/day, and the “trace minerals” with a recom- Silicon (Si)a 24-33 mg Molybdenum (Mo)
mended intake of less than 100 mg/day (Table 59.1). Boron (B) 1 mg Nickel (Ni)
In a human diet, all minerals come from eating plants and Iodine (I) 95 μg Fluoride (Fl)
animals or from drinking water. There are five major miner- Selenium (Se) 45 μg Vanadium (V)
als in the human body: Calcium, Phosphorus, Potassium, Copper (Cu) 700 μg Cobalt (Co)
Sodium, and Magnesium. All remaining elements found in Cadmium (Cd)a
Arsenic (As)a
the human body, namely Sulfur, Iron, Chlorine, Cobalt,
Aluminum (Al)a
Copper, Zinc, Manganese, Boron, Molybdenum, Iodine, Tin (Sn)a
Silicon, and Selenium, are trace elements. All are thought on a
Essentiality not yet established
the basis of good evidence to be necessary for life, and all of
the mass of trace elements put together is less than 10 gr for
an average adult human body and do not add up to the body and regulate fluid balance in the human body and take part in
mass of Magnesium, the least common of the five major numerous metabolic processes.
minerals. Apart from their enzymic or catalytic role, minerals exert
Many of the functions of minerals and trace elements a structural role in all tissues and consequently to the hair
were known long before vitamins were discovered. In the follicle and its product, the hair. One perfect example is Ca+2,
early twentieth century, when vitamins were continually which participates in the synthesis of keratin and the differ-
identified, minerals and trace elements were overshadowed entiation and proliferation of keratinocytes. It is also the
since most scientific research on nutrition was directed most abundant mineral in the human body and accounts for
towards the newly-found vitamins. 1–2% of the total body weight in adult humans. Trace metals
Minerals are typically found in high quantities in the are found in much smaller quantities and exert mostly cata-
human body, and after being absorbed, they remain lytic roles, participate in hundreds of enzymes (e.g., zinc),
unchanged. The same applies to trace elements. Minerals are and are involved in metabolism’s most critical functions.
essential for the metabolism of nutrients, i.e., proteins, car- Iron, for example, is the main component of hemoglobin,
bohydrates, and fats; they also add rigidity and strength to transferring oxygen to tissues. Elements such as Boron or
the skeleton. They are incorporated into organic compounds Zinc are involved in androgen metabolism, while Iodine is
348 59 Minerals, Trace Elements, and Hair Follicles
essential for producing thyroid hormones. Finally, they serve strong correlations, mostly due to methodological limitations.
as charged ions for myriad other cellular functions and elec- Since minerals and trace elements are extensively stored in
tron transport reactions. the human body, they are not likely to be eliminated and are
In general, deficiency of metals or trace elements in the not chemically converted, unlike organic compounds (e.g.,
average adult in developed countries is extremely rare, with vitamins). Therefore, the risk of toxicity from excessive con-
the marked exception of Iron deficiency, which is the most sumption is much higher than that of deficiency. The only
prevalent dietary deficiency in both developed and develop- notable exception is Iron since Iron overload is extremely rare
ing countries. Indeed, Iron is the only trace element that has compared to the prevalence of iron deficiency.
been directly correlated with hair loss by some experts, even Only those minerals and trace elements related to hair fol-
though views are still controversial. The same correlation licle physiology or hair loss in the literature will be reviewed
exists between ferritin levels and hair loss, but as will be fur- in the following chapters.
ther explained, studies cannot substantiate etiologically
Calcium (Ca+2)
60
60.1 Actions of Ca+2

Basic Concepts
• Ca+2 plays a crucial role in skeletal mineralization The four basic functions of calcium in the body are bone and
along with a wide range of biologic functions, while tooth formation, blood clotting, muscle and nerve action, and
it is also involved in keratin synthesis, differentia- metabolic reactions.
tion and proliferation of keratinocytes. The vast majority of total body Ca+2 (>99%) is present in
• Serum Ca+2 levels are very tightly regulated and do the skeleton as Ca+2-phosphate complexes, primarily as
not fluctuate with changes in dietary intakes; the hydroxyapatite, which is responsible for much of the mate-
body uses bone tissue as a source and reservoir for rial properties of bone. Besides providing skeletal strength,
Ca+2 in order to maintain constant levels of Ca+2 in bone Ca+2 provides a dynamic store to maintain the intra- and
blood, muscle, and intercellular fluids. extracellular Ca+2 pools [3]. Ca+2 also acts as an electrolyte
• There are no demonstrated in vitro or in vivo posi- and has several additional essential roles in all human body
tive effects of Ca+2 on the hair follicles of animals or systems: it is vital for muscle function, nerve conduction,
humans despite its fundamental physiological role vessel contraction and vasodilatation, intracellular signaling,
in hair growth. hormonal secretion, and function of blood cells. Still, less
• More than 60% of postmenopausal women in the than 1% of total body Ca+2 is needed to support all these criti-
U.S. use Ca+2 supplements to prevent and treat cal metabolic functions [4].
osteoporosis, and even though these products can
rarely lead to actual hypercalcemia, chronic use can
lead to renal insufficiency, vascular and soft tissue 60.2 Ca+2 and the Hair Follicle
calcification.
The skin and the hair follicles have long been known as a
target organ for Vit D (1,25(OH)2 D3, calcitriol) and Ca+2 [5].
Ca+2 has a fundamental structural role in all body tissues,
Calcium (Ca+2) is the most abundant major mineral in the including hair, since it is involved in the synthesis of keratins
human body and accounts for 1–2% of adult human body and the keratinization of outer root sheath cells [6]. The
weight [1]. No less than 99% of Ca+2 is found in bones and activities of peptidylarginine and deiminase enzymes
teeth where it supports their structure and function, while 1% involved in the incorporation of arginine into inner root
is found in plasma and soft tissues. Despite the large amount sheath cells are Ca+2-dependent [7, 8] and in the differentia-
of Ca+2 in the human body, intra- and extracellular Ca+2 lev- tion and proliferation of keratinocytes [9, 10]. Although cal-
els are very tightly regulated in order to exert cellular func- citriol and Ca+2 promote the differentiation of keratinocytes,
tions efficiently [2]. This balance is regulated by the actions until recently, available studies did not suggest a direct role
of parathyroid hormone (PTH), that in combination with Vit for calcitriol or Ca+2 in hair follicle cycling, unlike that of the
D, regulate Ca+2 homeostasis. Vit D receptor (VDR), which is extensively reviewed in
350 60 Calcium (Ca+2)
Chap. 19, Vol. 1. Mady et al. were the first to suggest such a turnover. These, in turn, are regulated by a set of interacting
role for Ca+2 in hair growth since deprivation of Vit D com- hormones, including PTH, calcitriol, ionized Ca+2 itself, and
bined with low dietary Ca+2 intake resulted in non-cicatricial their corresponding receptors in the gut, kidney, and bone.
alopecia in nursing mice [11]. Serum Ca+2 homeostasis is dependent on negative feedback
mechanisms (the complex details of which go beyond the
scope of this chapter), helping to maintain total serum Ca+2
60.3 Dietary Recommendations levels in healthy individuals within a relatively narrow physi-
ologic range of ∼10% [16].
The amounts of Ca+2 required for bone health and mainte-
nance of adequate rates of Ca+2 retention in healthy adult
men and women between ages of 19–50 years are established Ca+2 levels in serum are under tight homeostatic con-
as Recommended Dietary Allowance (RDAs) and set at trol, and Ca+2 intake is not normally correlated with
1000 mg [4, 12]. Ca+2 serum levels. However, diets that are low or very
According to older references, pregnant women and lac- high in Ca+2 can override normal homeostatic control,
tating women were required to intake 1200 mg of Ca+2 daily, causing changes in blood levels of Ca+2 or calciotropic
and the same RDAs were applied to postmenopausal women hormones [17].
under Hormone Replacement Therapy [1]. Recent RDAs do
not make these distinctions and only require higher intake
(1200 mg) for postmenopausal women (>50 years old) and
the same amount for men after the age of 70 years old [4]. Accordingly, hypocalcemia and hypercalcemia indicate
Adequate intake (AI) is set at 800 mg and tolerable upper serious disruption of Ca+2 homeostasis but do not, on their
intake level (UL) at 2500 mg. In some individuals, particu- own, reflect Ca+2 balance. Both can be classified by the main
larly the elderly, Ca+2 supplements may be needed to achieve organ responsible for the disruption of Ca+2 homeostasis,
an RDA of Ca+2 since a typical diet might fail in this aspect although, clinically, more than one mechanism is invariably
[13]. involved [16].
60.4 Food Sources 60.5.1 Hypocalcemia
Milk, yogurt, and cheese, especially cheddar cheese, are rich Hypocalcemia is defined as an ionized serum Ca2+ concen-
natural sources of Ca+2 and are the major food contributors of tration that falls below the lower limit of the normal range
this nutrient to individuals in developed countries. Fish, and results primarily from medical conditions or treat-
especially small ones, such as sardines, are an excellent ments, including hypoparathyroidism, chronic kidney dis-
source [14]. Most grains do not contain high amounts of Ca+2 ease, surgical removal of the stomach, achlorhydria, and
unless they are fortified. Foods fortified with Ca+2 include chronic use of certain diuretics. In hypoparathyroidism,
many fruit juices, drinks, and cereals [15]. Non-dairy sources hypocalcemia can even occur acutely and become a real
include vegetables, such as red cabbage, broccoli, kale, tofu, life-threatening medical emergency [18]. Symptoms of
dried figs, and beans. Spinach provides Ca+2, but its bioavail- hypocalcemia include numbness and tingling in the fingers,
ability is poor and this is also true for most plant sources of muscle cramps, convulsions, lethargy, poor appetite, and
Ca+2. In general, vegan diets can be poor in Ca+2 and caution abnormal heart rhythms. If left untreated, hypocalcemia
is advised. due to Ca+2 deficiency leads to death [19]. Absorptive hypo-
The small intestine absorbs approximately 30% of dietary calcemia -caused solely by a low dietary Ca+2 intake- is very
Ca+2 ingested by a healthy adult. Notably, this can be signifi- rare because the homeostatic mechanisms are highly effi-
cantly diminished if the bioavailability of dietary Ca+2 is low- cient and maintain serum Ca+2 in the low physiologic range
ered by Ca+2-binding agents such as cellulose, phosphate, at the expense of Ca+2 bone stores. However, absorptive
and oxalate found in foods. hypocalcemia is common in chronic Vit D deficiency, osteo-
malacia, rickets, and impaired calcitriol production, as in
chronic kidney disease [20].
60.5 Deficiency- Excess of Ca+2 Deficient dietary intake of Ca+2 results in a continuous
need to absorb Ca+2 from the bones, which gradually leads to
Ca+2 requirements are dependent on the state of Ca+2 metabo- reduced Ca+2 levels in the bones, low bone density, and
lism, which is regulated by three main mechanisms: intesti- osteoporosis [21]. Although osteoporosis is more prevalent
nal absorption, renal reabsorption/excretion, and bone in white postmenopausal females, it often goes unrecognized
References 351
in other populations, and also older men are at high risk of this effect is not well established [4]. Some studies also link
suffering from this disorder [22]. high supplemental Ca+2 intake with increased risk of cardio-
vascular disease [17, 30].
Individuals who take excessive Ca+2 supplements might
60.5.2 Hypercalcemia experience mild gastrointestinal side effects including
gas, bloating, constipation, abdominal pain, thirst, nausea,
Excess intake of Ca+2 may cause hypercalcemia, but the inef- and frequent urination or a combination of these symp-
ficient absorption of Ca+2 by the intestine, excessive Vit D toms [31].
intake, or excessive secretion of PTH are more likely causes.
Excessive dietary intake of Vit D (hypervitaminosis D) can Synopsis
be toxic, resulting in fragile bones, kidney stones, calcifica- There are no reports on the selective action of Ca+2 on the
tion of soft tissues, and elevated blood calcium concentra- human hair follicle, and there is no indication for Ca+2 sup-
tions with Ca+2 deposits in the kidney nephrons interfering plementation in patients with AGA/FPHL or other hair loss
with kidney function [23]. conditions.
Hypercalcemia caused solely by excessive dietary

References
intake of Ca+2 has never been reported and occurs
either by extreme (or chronic, or both) Ca+2 supple- 1. Food and Nutrition Board, Institute of Medicine. Calcium. Dietary
mentation [24] or due to failure of Ca+2 regulation reference intakes: calcium, phosphorus, magnesium, Vitamin
mechanisms. D & Fluoride. Washington, DC: National Academy Press; 1997.
p. 71–145.
2. Weaver CM, Heaney RP. Calcium. In: Shils M, Olson JA, Shike M,
Ross AC, editors. Nutrition in health and disease. 9th ed. Baltimore:
Williams & Wilkins; 1999. p. 141–55.
These are most commonly associated with primary hyper- 3. Rizzoli R, Bonjour JP. Physiology of calcium and phosphate homeo-
parathyroidism or malignancy due to the bone destruction stasis. In: Seibel MJ, Robins SP, Bilezikian JP, editors. Dynamics of
that occurs when tumors metastasize to bone [25]. bone and cartilage metabolism. San Diego, CA: Academic; 2006.
Absorptive hypercalcemia caused solely by very high p. 345–60.
4. Committee to Review Dietary Reference Intakes for Vitamin D and
Ca+2 intakes has the potential to cause hypercalcemia, mostly Calcium, Food and Nutrition Board, Institute of Medicine. Dietary
in patients with chronic kidney disease. When these patients Reference Intakes for Calcium and Vitamin D. Washington, DC:
receive amounts of dietary Ca+2 that exceed the ability of National Academy Press; 2010.
their kidneys to filter and excrete the Ca+2 load, they may 5. Bikle DD. Vitamin D and the skin: physiology and pathophysiol-
ogy. Rev Endocr Metab Disord. 2012;13(1):3–19.
suffer from higher death rates from all causes and especially 6. Niderla-Bielinska J, Jankowska-Steifer E, Moskalewski
from cardiovascular disease [17]. S. Keratinization of outer root sheath cells is prevented by con-
Hypercalcemia due to Ca+2 supplementation is the only tact with inner root sheath of rat hair follicles. Arch Derm Res.
condition that applies to otherwise healthy adults. Ca+2 sup- 2009;301(5):337–45.
7. Rogers GE, Harding HW, Llewellyn-Smith IJ. The origin of
plements with or without Vit D have long been used to slow citrulline-containing proteins in the hair follicle and the chemical
down bone loss and osteoporosis development in adults, nature of trichohyalin, an intracellular precursor. Biochim Biophys
making these supplements the first-line treatment of choice. Acta. 1977;495(1):159–75.
Tang et al. conducted a meta-analysis that included 29 ran- 8. Fietz MJ, McLaughlan CJ, Campbell MT, Rogers GE. Analysis
of the sheep trichohyalin gene: potential structural and calci-
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ment of osteoporosis in individuals aged 50 years or older. 1993;121(4):855–65.
They reported that minimum doses of 1200 mg of Ca+2 and 9. Mauro T, Dixon DB, Komuves L, Hanley K, Pappone
800 IU of Vit D are recommended [26]. Consequently, sup- PA. Keratinocyte K+ channels mediate Ca2+−induced differentia-
tion. J Invest Dermatol. 1997;108(6):864–70.
plemental use of Ca+2 has become extremely widespread, 10. Manaves V, Qin W, Bauer AL, Rossie S, Kobayashi M, Rane
and more than 60% of middle-aged and older women in the SG. Calcium and vitamin D increase mRNA levels for the growth
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However, Ca+2 supplementation is controversial, as the tional channels are not observed. BMC Dermatol. 2004;16(4):7.
11. Mady LJ, Ajibade DV, Hsaio C, Teichert A, Fong C, Wang Y,
bioavailability of Ca+2 is strongly dependent on the solubility Christakos S, Bikle DD. The transient role for calcium and vitamin
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Boron (B)
61
other nutrients, and a regulatory role in the metabolism of

Basic Concepts minerals and other trace elements. There is substantial evi-
• Boron is a bioactive element which, in nutritional dence that boron is essential for continuous absorption and
amounts, beneficially affects the absorption and function of calcium, phosphorus, and magnesium, and sub-
function of other trace elements, such as calcium, sequently in bone metabolism [4]. Boron plays a vital role in
phosphorus, and magnesium; it is also involved in osteogenesis, and its deficiency has been shown to impact
central nervous system function and in facilitating bone development and regeneration adversely [2].
hormone action. According to Hakki et al. [5], boron induces mineraliza-
• There are no published studies on specific and tion of osteoblasts by regulating the expression of genes
direct effects of boron on the hair follicle, but boron related to tissue mineralization and the actions of key mole-
supplementation has been found to increase the pro- cules and hormones (17β-estradiol [E2], Testosterone [T], and
duction of 17β-estradiol, testosterone, and free tes- Vit D) involved in bone growth and turnover [5, 6]. According
tosterone, which might have an impact on hair to earlier research by Penland, boron is also essential to the
follicles of patients with AGA/FPHL. brain’s electrical activity, especially in enhancing memory,
cognitive function, and hand-eye coordination [7, 8].
Other functions of boron, extensively presented in a
review article by Pizzorno, titled “Nothing Boring About
Boron is an essential nutrient for specific organisms, notably Boron,” are [6]:
vascular plants and diatoms. It has not been yet characterized
as an essential trace element in humans since it does not 1. Dramatically improves wound healing;
exhibit specific, unique, or exclusive biological function, 2. Boosts magnesium absorption;
unlike its actions in plants [1]. Interestingly, the importance 3. Reduces levels of inflammatory biomarkers, such as
of boron to human health did not even become apparent until high-sensitivity C-reactive protein (hs-CRP) and tumor
the mid-1980s [2]. necrosis factor α (TNF-α);
4. Raises levels of antioxidant enzymes, such as superoxide
dismutase (SOD), catalase, and glutathione peroxidase;
61.1 Actions of Boron 5. Protects against pesticide-induced oxidative stress and
heavy metal toxicity;
Since no specific biochemical function has been defined for 6. Influences the formation and activity of key biomole-
boron, its nutritional essentiality has still not been firmly cules, such as S-adenosyl methionine (SAM-e) and nico-
established. Nevertheless, boron deprivation experiments tinamide adenine dinucleotide (NAD);
with humans have yielded some persuasive findings for the 7. Has demonstrated preventive and therapeutic effects in
hypothesis that boron is an essential nutrient. Evidence from several cancers, such as prostate, cervical, and lung can-
numerous laboratories using a variety of experimental mod- cers, and multiple and non-Hodgkin’s lymphomas; and
els, including humans, showed that boron is a bioactive ben- 8. May help ameliorate the adverse effects of traditional
eficial element [3]. chemotherapeutic agents.
Properties attributed to boron include maintaining the
structure and proper function of cellular membranes, sup- Additionally, boron impacts the production and activity of
porting cellular metabolic processes [3], interaction with steroid hormones, increases the serum levels of E2 in peri-
354 61 Boron (B)
and postmenopausal women, the levels of T in men, and increased, indicating boron had androgen amplifier effects:
those of Vit D in both sexes [9, 10]. (1) free T/T (pg/mL/ng/mL) increased from 3.62 to 4.66; (2)
T/E2 (ng/mL) rose from 91.68 to 148; and (3) free T/E2 (ng/
mL) from 0.31 to 0.67. It is well known that approximately
61.2 Boron and the Hair Follicle 98% of T molecules are bound to proteins in the blood, prin-
cipally to SHBG, and are not bioavailable because bound
There are no published studies on the direct or specific hormones cannot exit capillaries [6, 16].
effects of boron on hair follicles. However, boron’s effect on
steroidogenesis and its mechanism has been initially investi-
gated in two studies conducted on adult male rats [11, 12], Thus, the elevation of unbound free T seen with boron
whereas increased levels of sex steroids have been demon- supplementation may have significant beneficial rami-
strated in both men and women after boron supplementation fications, particularly in aging men in whom, typically,
[6]. These effects in the androgen and estrogen concentration levels of SHBG increase and levels of free T decrease
in plasma might impact scalp hair follicles of individuals [17].
with AGA/FPHL, but there is no research or data on this
hypothesis.
In 1987, Nielsen et al. reported that dietary boron reple-
tion in postmenopausal women (n = 13), who were previously However, the positive effect that increased free T has in
on a low-boron diet, significantly increased their serum E2 the quality of life, depression, and in some aspects of sexual
and T levels, particularly in those women whose dietary function on androgen-deficient middle-aged men [17] could
intake of magnesium was low. In women on a low-magnesium probably turn to be negative on those males already suffering
diet, E2 almost doubled, increasing from an average of from AGA, due to the amplified amount of androgens reach-
21.1 pg/mL to 41.4 pg/mL. Testosterone more than doubled, ing the scalp hair follicles [6]. However, there is no proof for
rising from an average of 0.31 ng/mL to 0.83 ng/mL. Similar this hypothesis.
increases were seen in women on an adequate-magnesium
diet: E2 rose from an average of 15.5 pg/mL to 38.0 pg/mL,
and T increased from 0.38 ng/mL to 0.65 ng/mL [6, 13]. 61.3 Food Sources
In 1997, Naghii et al. [14] published the findings of a
single-blind, cross-over trial, reporting a similar increase in The content of boron in specific foods has been published
serum levels of E2 in healthy males (n = 18) since dietary from several countries, including the U.S. High concentra-
supplementation with 10 mg/day of boron for 4 weeks tions of boron (l.0–4.5 mg/100 g) are found in nuts, dried
resulted in plasma E2 concentrations being significantly fruits, legumes, and avocado. Moderate concentrations (0.1–
increased (51.9 ± 21.4 to 73.9 ± 22.2 pmol/L; p < 0.004) and 0.6 mg/100 g) are found in fresh fruits and vegetables and
there was a trend for plasma T levels to be increased. honey; trace or minimal concentrations of boron (0.01–
In 2011, Naghii et al. [15] published a subsequent study 0.06 mg/100 g) are found in foods from animal sources such
on eight healthy males being administered 1 week of boron as fleshy meat, cheese, and butter [18]. Overall, luxuriant
supplementation of just 6 mg/day, and findings included: (1) natural boron sources include fruits, vegetables, legumes,
a significant increase in free T (fT), which rose from an aver- like tomatoes, broccoli, green peppers, apples, and grapes,
age of 11.83 pg/mL to 15.18 pg/mL; (2) a significant decrease and generally vegetables grown in soil rich or fortified with
in E2, which dropped from 42.33 pg/mL to 25.81 pg/mL; and boron.
(3) significant decrease on sex hormone-binding globulin
(SHBG). All of the inflammatory biomarkers that were mea-
sured also decreased: interleukin IL-6 dropped from 1.55 pg/ 61.4 Dietary Recommendations
mL to 0.87 pg/mL; high-sensitivity C-reactive protein (hs-
CRP) showed a remarkable decrease of 50%, from 1460 ng/ The U.S. Institute of Medicine has not confirmed that boron
mL to 795 ng/mL; and TNF-α decreased by approximately is an essential nutrient for humans, so neither recommended
30%, from 12.32 pg/mL to 9.97 pg/mL. Concomitantly, lev- daily allowance (RDA) nor an adequate intake (AI) have
els of dihydrotestosterone DHT, cortisol, and Vit D slightly been established, whereas the tolerable upper intake level for
increased. According to the authors, the significant decrease adults is 20 mg/day. The average adult dietary intake of
in the men’s plasma E2 after 1 week of boron supplementa- boron is estimated at 0.9–1.4 mg/day, with approximately
tion suggests a higher rate of conversion of total T to free T 90% being absorbed [19].
in the Testosterone metabolic pathway. In support, the ratios According to Forrest H. Nielsen Ph.D., who has done
of free T/T, T/E2, and free T/E2 were all significantly considerable research on the beneficial bioactivity of boron,
References 355
an intake of 1–13 mg/day of boron, received either through viduals. Additionally, since it affects the production and
the diet or by a dietary supplement is “an apparent beneficial activity of steroid hormones, resulting in increases in con-
intake” [20, 21]. Nielsen has been insisting for decades that centrations of testosterone, free testosterone (and conse-
existing dietary guidelines should be formulated, and estab- quently of DHT) in plasma, its supplemental intake may
lishing a dietary reference intake for boron is fully justified have a negative impact on scalp hair follicles in patients with
[20, 21]. Unfortunately, boron still receives limited attention AGA/FPHL and should probably be avoided.
or mention when dietary guidelines or intake recommenda-
tions are formulated.
References
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manifest as abnormal metabolism of calcium and magne- mance. Environ Health Perspect. 1994;102(Suppl. 7):65–72.
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acid, borates, and many organo-boron compounds are rela- distribution of boron in selected tissues and on testosterone synthe-
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copper, iodine, iron, manganese, molybdenum, nickel, silicon,
Boron is ubiquitous in foods, and therefore, there is no indi- vanadium, and copper. National Academy Press; 2001. p. 510–21.
cation whatsoever for boron supplementation in healthy indi-
356 61 Boron (B)
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Sulfur (S)
62
namely methionine, cysteine, cystine, homocysteine, and tau-

Basic Concepts rine. Other important molecules are the two sulfur-containing
• Sulfur is an elemental macronutrient for all living vitamins biotin and thiamine, α-lipoic acid, coenzyme A, glu-
organisms and one of the core elements required for tathione, methylsulfonylmethane (MSM), chondroitin sul-
biochemical functioning. fate, glucosamine sulfate, fibrinogen, and heparin.
• Organosulfur compounds have structural, antioxi- With the exception of thiamin [3] and biotin [4], all of
dant, and anti-inflammatory properties, while these sulfur compounds are synthesized from just one parent
sulfur-containing amino acids cysteine and cysteine compound, namely methionine, an essential amino acid that
are the main amino acid components of keratin must be ingested through the diet [5].
found in the outer skin, hair, and feathers.
• There are only a few, small-size, studies investigat-
ing the effects of oral administration of cysteine in 62.1 Actions of Sulfur
patients with hair loss. Anecdotal reports on the
positive action of cysteine supplements on hair are The role of elemental sulfur in human nutrition has not been
very popular, but effects remain weakly substanti- extensively studied, and sulfur research on humans has
ated in the scientific literature. focused mostly on the role of SAAs, low-molecular-weight
• The percutaneous absorption of sulfur is extensive, thiols, and disulfides in redox reactions.
and the safest, most bioavailable and absorbable Sulfur operates as a carrier of reducing hydrogen and its
forms in oral supplements are MSM (Methyl- electrons for cellular repair of oxidation [6]. Incorporation of
Sulfonyl-Methane) and DMSO. Sulfur supplemen- sulfur into amino acids, proteins, enzymes, vitamins, and
tation is rarely needed since sulfur deficiency is other biomolecules makes sulfur essential for the entire bio-
extremely rare in humans. logical kingdom [7]. Organosulfur compounds in the human
body, especially thiols, have pro-oxidant or antioxidant prop-
erties, depending on the physiological circumstances, but are
generally considered antioxidants [8]. Some are also involved
Sulfur is a chemical element with the symbol S and atomic in the catabolism of fats, carbohydrates, and proteins as well
number 16. It is a multivalent, nonmetallic element found in as in the production of ATP [9].
large amounts in the human body. It is the third most abun- Taurine, l-cysteine, N-acetylcysteine, α-lipoic acid, and
dant mineral based on the percentage of total body weight, the Glutathione tripeptide (consisting of γ-glutamine-
representing 0.25% of the average body weight, slightly cysteine-glycine) have the most potent antioxidant potential
higher than sodium [1]. Sulfur-containing compounds are of all organosulfur compounds [10, 11].
found in all body cells and are indispensable for life, but sul-
fur in the human body is almost always found in the form of • Taurine is the most abundant intracellular amino acid in
organosulfur compounds or metal sulfides. Most of the 150– humans, even though it is not a canonical amino acid and is
170 g of sulfur in the human body are distributed in sulfite not incorporated in proteins. Taurine is unique, both for its
structural proteins, and a small percentage is found within all high concentrations in animal tissues and the variety of
cells [2]. physiological functions ascribed to it due to its unique
The principal sulfur-containing compounds of interest in chemical structure. Taurine is involved in bile acid conjuga-
humans are the five sulfur-containing amino acids (SAAs), tion and cholestasis prevention, antiarrhythmic/inotropic/
358 62 Sulfur (S)
chronotropic effects, central nervous system neuromodula- 62.2 Sulfur, the Skin, and the Hair Follicle
tion, retinal development and function, endocrine/metabolic
effects, and possesses antioxidant/anti-inflammatory prop- Sulfur is a time-honored therapeutic agent used since antiq-
erties [12]. uity for the treatment of skin diseases. It has a long history of
• N-acetylcysteine (NAC) is a potent antioxidant and a widespread use in a variety of dermatological disorders, such
potential treatment option for conditions characterized by as acne vulgaris, rosacea, seborrheic dermatitis, dandruff,
the generation of free oxygen radicals since it has sulfhy- pityriasis versicolor, scabies, and warts [25]. Sulfur has anti-
dryl groups that can scavenge free radicals [13]. NAC, fungal, antibacterial, and keratolytic activity, and when
besides being the primary antidote for acetaminophen poi- applied topically, it induces various histologic changes,
soning, it is also recommended as a potential treatment including hyperkeratosis, acanthosis, and dilatation of der-
option for different disorders resulting from the generation mal vasculature [26]. Sulfur-containing baths also have a
of free oxygen radicals, such as chronic bronchitis, ulcer- long history of use in the treatment of psoriasis, rheumatic
ative colitis, liver cancer, muscle performance, hemodialy- pain, infections, and sulfur from hydrogen sulfide (H2S) of
sis, asthma, Alzheimer's and Parkinson’s disease [14]. thermal springs has been demonstrated to have therapeutic
• Alpha-lipoic acid plays an essential role in mitochondrial properties [27, 28].
dehydrogenase reactions and works as a cofactor in the mul-
tienzyme complexes that are responsible for the o xidative
decarboxylation of α-ketoacids [15]. Alpha-lipoic acid Consequently, products containing sulfur or SAAs are
administration has been shown to enhance the antioxidant typically recommended for “good hair health” and are
potency of other antioxidants (Vit C and Vit E). It is useful found in numerous cosmetics or cosmeceuticals.
or potentially useful as a therapeutic agent in several oxida-
tive stress models, such as ischemia-reperfusion injury, dia-
betes, cataract formation, immune- activation in HIV,
neurodegeneration, and radiation injury [16]. Cysteine is the SAA most commonly prescribed by physi-
• Glutathione tripeptide is the most abundant endogenous, cians to treat hair loss, and its alleged action on the hair fol-
non-protein thiol, and its functions include regulation of licle is reviewed in Chap. 42.
prostaglandin biosynthesis [17], regulation of cell growth Overall, there are no published studies associating sulfur
and protein function, detoxification of free radicals and with AGA, besides an “interesting” cross-sectional study by
peroxides, and maintenance of immune function [18]. Ansai et al. [29]. They studied 170 elderly Japanese male
Glutathione is a substrate for glutathione transferases and subjects with AGA aged 60–65 years old by measuring oral
peroxidases, enzymes that catalyze the reactions for sulfur-containing gases using a compact-designed device
detoxification of xenobiotics and reactive oxygen species, and found a significant association between CH3SCH3 levels
making glutathione pool a molecule of key importance in (Dimethyl sulfide) in volatile sulfur-containing gases and
the defense against oxygen radical pathology [19]. AGA. The level of CH3SCH3 was found to be much higher in
males with AGA, gastrointestinal diseases, hypertension,
The beneficial actions of organosulfur compounds (isothio- and hypercholesterolemia. Nevertheless, the authors did not
cyanates, diallyl sulfide, allicin) found in garlic, onions, and present any hypothesis and concluded that additional
other allium vegetables are discussed in Chap. 76. Concerning research is needed to corroborate findings and clarify the
details on these therapeutically relevant sulfur-containing biological mechanisms related to the increase in CH3SCH3
compounds and their various properties, Parcell has pub- levels in subjects with severe AGA [29].
lished an excellent and lengthy review that the interested
reader can refer to Ref. [20].
Concerning the structural role of sulfur, SAAs form cova- 62.3 Food Sources
lent disulfide bonds (S-S) between peptide chains, which
confer unique structural properties, as in the case of cystine Inorganic sulfur cannot be utilized by mammalian cells to
and cysteine. These are the main amino acid components of produce methionine because sulfate reduction does not occur
keratin found in the outer skin, hair, and feathers [21], and in mammalian cells, and sulfate ions cannot be absorbed
sulfur in hair keratins was discovered in 1939 by Pillemer directly by the human digestive tract [30, 31]. Consequently,
et al. [22] Disulfide bonds of cystine and cysteine provide dietary sulfur intake is provided indirectly by proteins rich in
mechanical strength and insolubility of keratin. They also SAAs [6, 32]. SAAs are more abundant in animal and cereal
and determine the shape and durability of keratin found in proteins than in legume proteins. The ratio of methionine to
hair, nails, and skin [23], while at the same time, sulfur takes cysteine tends to be higher in animal proteins than in plant
part in epidermal collagen production [24]. sources. SAAs are mainly found in meat, poultry, fish, egg,
62.5 Deficiency- Excess of Sulfur 359
and dairy [33]. Eggs are exceptionally high in sulfur, proba- malnutrition are more likely to be a threat to the health and
bly to nourish feather formation in chicks, and the character- not the sulfur deficiency per se.
istic odor of rotting eggs is due to hydrogen sulfide. However,
not all plant foods are low in SAAs. Several commonly eaten
plant foods high in methionine (in decreasing order) are Since the extracellular sulfate pool in humans is among
corn, sunflower seeds, oats, chocolate, cashews, walnuts, the smallest of animal species [41], sulfur is stored in
almonds, and sesame seeds [34]. all cells of the body in the form of glutathione in the
Allium vegetables, such as garlic, onions, leeks, and chives, liver [42], whereas “hard” keratins [43] of skin, nails,
also contain significant quantities of sulfur, and their “healing” and hair also contain large amounts of sulfur which is
properties are attributed to their high sulfur concentration [35, continuously lost.
36]. Cruciferous vegetables, such as broccoli, cauliflower,
cabbage, kale, and Brussels sprouts, are also rich sources of
sulfur-containing substances known as glucosinolates.
Other factors that can reduce the availability of methio-
nine/cysteine are chronic inflammatory bowel disease [44]
62.4 Dietary Recommendations and chronic administration of drugs metabolized by sulfation
[45].
There are no studies that have measured the sulfur balance Sulfation is a major pathway for hepatic detoxification of
effectively in humans or other animals. All metabolic stud- pharmacological agents, and certain drugs, such as acet-
ies, even those that focus on the requirements for SAAs, aminophen, require sulfate for their excretion [38].
actually studied nitrogen balance and not sulfur balance per Concerning the potential for toxicity of excess sulfur, with
se [20]. very few exceptions, the sulfur compounds discussed in this
Sulfur is found in most foods, and, as a consequence, it is chapter all have very low toxicological profiles [2]. Adverse
considered that practically all diets would meet the minimum toxic effects from topically applied sulfur are uncommon
daily requirements. Accordingly, the U.S. Institute of and are typically limited to the skin [46], but one should note
Medicine has not established an official Recommended that there are rare reports of fatalities in infants after massive
Daily Allowance (RDA), an Adequate Intake (AI), or a epidermal application of sulfur [47].
Tolerable Upper Intake Level for sulfur. In 1989, a subcom- As already mentioned, most organosulfur compounds are
mittee of the U.S. Food and Nutrition Board, National not stored in the body, and any dietary excess is readily oxi-
Research Council, issued its last update RDAs for protein dized to sulfate, excreted in the urine (or reabsorbed depending
and amino acids, relying on nitrogen balance studies per- on dietary levels), or stored in the form of glutathione [38, 42].
formed by Rose et al. back in 1955 [37]. Depending on the organosulfur compound that is administered
The RDA for a combined SAAs intake (methionine and in excess, one can exhibit different signs and symptoms of mild
cysteine) for adults has been set at 14 mg/kg of body weight toxicity or effects indirectly related to the compound. Too
per day, equivalent to approximately 910 mg/day for a 70 kg much NAC may cause glutamine production to be favored over
adult, or 13 mg/kg/day. However, when Rose recommended urea production, eventually to the point that toxic ammonia
these amounts, he suggested that a “safe intake” should be accumulates [20, 48]. Cysteine and its oxidation product cys-
twice the amount of 2.0 g/day, probably acknowledging that tine are well established as being relatively toxic at high levels
his studies had been done on a limited number of individuals, of intake, and relevant information is contained in a excellent
usually 3–6 individuals for each amino acid [38]. and comprehensive review by Harper et al. [49].
Consequently, other experts consider the 13 mg/kg/day fig- Organic sulfur compounds are metabolized by the
ure to be too low and recommend an intake of at least 25 mg/ molybdenum-dependent mitochondrial enzyme sulfite oxi-
kg/day of SAA for adults [39]. dase (sulfoxidation), which metabolizes sulfites to sulfates,
which are excreted in the urine or reused by the body [20,
50]. A deficiency in molybdenum (a very rare nutritional
62.5 Deficiency- Excess of Sulfur deficiency) or of sulfite oxidase may render an individual
more sensitive to sulfur-containing drugs and compounds
Actual sulfur deficiency is very rare in developed countries [51]. The safest, most bioavailable, and absorbable chemical
and may only be related to diets extremely deficient in form of sulfur supplement is MSM (Methyl-Sulfonyl-
protein-content or when dietary intake comes exclusively Methane) [52]. MSM is the oxidized form of dimethyl sulf-
from soils low in sulfur. In the U.S., low-sulfur soils are oxide (DMSO), a by-product of the wood industry, first
found in the Pacific Northwest and the Great Lakes region introduced as a therapy to the scientific community in 1963
[40]. In these cases, though, protein deficiency and overall by the research team of Stanley W. Jacob, MD [53].
360 62 Sulfur (S)
DMSO is an intermediate chemical compound in the nor- Synopsis

mal sulfur cycle in all living organisms. DMSO was initially Although sulfur and its organic compounds have a great sci-
used as an organic solvent, and decades later was credited entific interest and various potential clinical applications,
with potent antioxidant and anti-inflammatory [54] and there is no evidence supporting its supplementary adminis-
cancer-protective properties [55], as well as favorable prop- tration in any form in AGA/FPHL unless there are other
erties in the treatment of peptic ulcer [56] and CNS trauma underlying conditions, such as chronic malabsorption, gen-
[57]. The topical use of DMSO has produced positive results eral malnutrition, or increased losses. Diets that are adequate
in treating systemic sclerosis [58], faster recovery from her- in protein contain adequate sulfur, and supplementation is
pes zoster infection [59], and chronic skin ulcers [60]. very rarely required. Administration of cysteine and cysteine
DMSO also increases skin elasticity [61], enhances healing has not been convincingly related to improvement in hair
of burns [62], improves blood circulation of the skin [63], growth. Although there is a large amount of hype and market
and helps in injuries of muscles and tendons [64]. advertising praising their efficacy for improving hair, effects
Disadvantages of DMSO’s topical use include local changes remain mostly unsubstantiated in the scientific literature.
in skin pigmentation [65] and an unpleasant metallic garlic-
like breath odor, which is the main reason for the limited use
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Iodine (I)
63
sues, including mammary glands, eyes, gastric mucosa,

Basic Concepts cerebrospinal fluid, arterial walls, salivary glands, and the
• Iodine is the major constituent of thyroid hormones, cervix [2].
regulates thyroid gland function, and plays a crucial Every trace of iodine in nutrition is rapidly absorbed by
role in diverse processes related to cellular growth, the intestinal tract, mainly in the form of iodide, and is stored
development, differentiation, and metabolism. in the thyroid gland until used. Inside the thyroid follicular
• Thyroid hormone receptors TR-α and TR-β have cells, thyroid peroxidase oxidizes iodide ions to form iodine
been detected in most parts of the human hair folli- atoms, which will be added onto tyrosine residues on thyro-
cles and directly affect their growth, whereas both globulin to produce T4 or T3. This process is controlled by
hypothyroidism and hyperthyroidism can induce Thyrotropin-Releasing Hormone (TRH), which is produced
changes in the physiology of the skin and the pilo- by the pituitary [3].
sebaceous unit.
• Dietary hypothyroidism and hyperthyroidism
affecting the skin and hair follicles are not common 63.1 Actions of Iodine
in developed countries and are both easily treatable
with common dietary interventions. Actually, the The thyroid hormones act on all human body cells and are
most reliable source of iodine is iodized table salt. essential for their proper development and differentiation.
• Topical or systemic use of iodine or thyroid hor- These hormones are primarily responsible for regulating
mones in AGA/FPHL patients have not been protein, fat, and carbohydrate metabolism, coordinating how
reported in the literature since their side-effects are human cells use energy compounds. They mostly affect pro-
potentially severe, whereas thyromimetic com- tein synthesis, neural maturation [3] and increase the body’s
pounds that act locally but are devoid of any sys- sensitivity to catecholamines, a function mediated through
temic pharmacological actions are currently under coordinated and synergistic interactions with the sympatho-
investigation. adrenal system [4]. Moreover, iodine is involved in the func-
tion of the immune system. The adequate intake of iodine is
necessary for the development of the nervous system in utero
and during neonatal life, with iodine deficiency being the
Iodine is a chemical element with symbol I, atomic number leading -yet easily preventable- dietary cause of intellectual
53. It is an essential element for life and is the heaviest trace disability worldwide [5].
element commonly needed by living organisms. It is required The actions of thyroid hormones in the target cells are
for the synthesis of the growth-regulating thyroid hormones achieved through a series of highly regulated intracellular
triiodothyronine and thyroxine, named T3 and T4, respec- processes that allow them to bind to thyroid hormone recep-
tively, after their number of iodine atoms [1]. tors (TRs) and influence gene transcription. These processes,
The human body contains approximately 100 mg of which go beyond the scope of this chapter, include transport
iodine, 15–20 mg of that is concentrated in thyroid tissue, of thyroid hormones into the cell, activation or inactivation
and inside formed hormone molecules mostly accumu- by the deiodinases, and expression of TR isoforms, nuclear
lated in the thyroid gland. The rest is located in other tis- corepressors, and coactivators [6].
364 63 Iodine (I)
63.2 Thyroid Hormones and the Hair deficiency worldwide, especially in mountainous and upland
Follicle areas. Iodized salt is probably the principal source of iodine
in most developed countries [17].
The thyroid hormone receptors TR-α and TR-β have been
detected in the nuclei of the outer root sheath (ORS) cells,
dermal papilla cells, fibrous sheath cells, arrector pili muscle 63.4 Dietary Recommendations
cells, and sebaceous gland cells [7, 8]. In vitro studies on
ORS cells and the papillary dermis have shown that thyroid Intake recommendations for iodine have been established by
hormones act mostly through subtype TR-β1 and have the Food and Nutrition Board (FNB) at the Institute of
numerous direct positive effects on the growth of hair folli- Medicine of the National Academies [18]. Similar recom-
cles on being enhanced human hair survival in vitro [9]. The mendations have been made by several organizations, includ-
skin is a classic target-tissue for the action of thyroid hor- ing the American Thyroid Association (ATA), the World
mones, and the specific actions of thyroid hormones on Health Organization (WHO), the iodine Global Network and
human hair follicles [9, 10] and sebaceous glands [11] are UNICEF [19].
extensively described in the literature. Both hypothyroidism According to a consensus from these authorities,
and hyperthyroidism can induce changes in the skin’s physi- Recommended Daily Allowance (RDA) of iodine for adults
ology, and the pilosebaceous unit and the causal relationship is set at 150 μg, the adequate intake (AI) at 95 μg, and the
between thyroid gland diseases and hair loss have long been tolerable upper intake level (UL) at 1100 μg. Consequently,
established [8]. However, the precise pathophysiological 1.5 g of iodized table salt is enough to cover the RDA for
mechanisms remain unknown. For more details on the effects adults [20]. A slightly higher iodine intake for pregnant and
of thyroid hormones on human hair follicles, the reader lactating women (250 mcg per day) is recommended.
should refer to Chap. 19, Vol. 1. Concerning the suggested
guideline for thyroid function tests in hair loss patients, the
reader should refer to Chap. 10, Vol. 1. 63.5 Deficiency- Excess of Iodine
Overall, iodine levels cannot be reliably measured in humans,

63.3 Food Sources given the considerable day-to-day variation in iodine intake.
Since humans excrete more than 90% of dietary iodine in the
Absorption of iodine from dietary sources is very efficient urine [21], median urinary iodine concentrations have been
(>90%), and the thyroid gland accumulates the iodine quan- widely used as a biomarker of population iodine intake.
tity it needs from the plasma, reaching iodine concentrations According to the criteria of WHO, population iodine defi-
even 50 times higher inside the gland than in plasma [12]. ciency is defined by median urinary iodine concentrations
Foods of marine origin, such as fish, seaweeds (kelp), and <150 μg/L for pregnant women and <100 μg/L for all other
shellfish, have high iodine content because marine plants and groups [22].
animals concentrate iodine from seawater [13]. Other foods Iodine deficiency leads to hypothyroidism in which the
vary tremendously in iodine content, depending on their thyroid gland reactively hypertrophies to obtain more iodine
source and what may have been added to the soil or animal from the plasma. This results in a concomitant enlargement
food. Because the mammary gland concentrates iodine, milk of the thyroid tissue, causing simple, reactive goiter.
and dairy products are usually a good source of iodine, so Hypothyroidism is associated with skin dryness, telogen
long as the animals received enough iodine in their diet. effluvium, along with dry, brittle, and dull hair shafts [23].
Fruits and vegetables contain iodine, but the amount var-
ies depending on the soil’s iodine content, fertilizer use, and
Confusingly, hyperthyroid states can also lead to telo-
irrigation practices [14]. Iodine concentrations in plant foods
gen effluvium, together with decreased hair diameter
can range from as little as 10 mcg/kg to as high as 1 mg/kg
and brittle, greasy hair [24], despite an apparently
of dry weight. This variability affects the iodine content of
increased hair matrix proliferation [25].
foods that animals consume and—in turn—the iodine con-
tent of meat and animal products [15]. Low iodine content is
generally found in geographic locations with mountains or
frequent flooding. Salt iodization programs have dramatically reduced the
In 1924, the addition of iodine to table salt was estab- prevalence of iodine deficiency in developed nations, but it
lished to address the health problem of endemic goiter, which remains a significant public health problem in the developing
was then prevalent in the United States [16]. Salt iodization world. Although about 70% of households worldwide now
programs, which most countries have implemented ever have access to iodized salt [26], mild-to-moderate iodine
since, have dramatically reduced the prevalence of iodine deficiency remains a public health concern in at least 30
References 365
countries, and there are still no iodine excretion data avail- The signs and symptoms of this—iatrogenic by supple-
able for another 42 countries [27]. Symptoms of hypothy- mentation—hyperthyroidism are insomnia, fatigue, diarrhea,
roidism include extreme fatigue, swollen limbs, weight gain, arrhythmia, heart palpitations, weight loss, muscle weakness,
constipation, depression, difficulty in memory and concen- sweating, heat intolerance, tremor, irritability, dizziness
tration, mental slowing, low basal body temperatures, cold exophthalmos, and thinning of hair. Even though the tolerable
intolerance, and, typically, hair loss. Research suggests that upper intake level not related to symptoms is 1100 μg [34],
hypothyroidism results in poor social and economic achieve- toxicity cases have been reported in individuals consuming
ments due to low educability, apathy, and reduced work pro- even up to 5000 mg daily, which is also a very infrequent
ductivity [28]. occurrence. Chronic, excessive iodine intake has been corre-
Most people are not at risk of exhibiting toxic symptoms lated with an increased risk of thyroid cancer [35, 36].
from excessive iodine intake from dietary sources since Elemental iodine (I2) is toxic if orally ingested undiluted, and
iodine’s organic form is less toxic than the inorganic forms the lethal dose for an adult human is 30 mg/kg, which is about
of potassium iodide or sodium iodide found in food supple- 2.1–2.4 g for a human weighing 70–80 kg [37].
ments [29]. From available data, it is contemplated that some
individuals can tolerate very high levels of iodine with no Synopsis
apparent side effects and that iodine intakes up to 1000 μg/ Iodine and thyroid hormones have significant actions on
day are probably safe for the majority of the population [29]. human hair follicles. Iodine deficiency is rare in developed
In iodine-replete adults, elevated serum thyroid-stimulating countries, and thyroid disease that may affect hair growth is
hormone (TSH) has been found at chronic iodine intakes of mostly related to other thyroid conditions. Unless the patient
≥750 μg/day in children and ≥1700 μg/day in adults [30]. with diffuse hair loss or signs of AGA/FPHL is severely mal-
Most reports on the excess intake of dietary iodine come nourished, iodine deficiency is unlikely. However, screening
from Asia, since various edible seaweed species, typical in blood work should always include thyroid-stimulating hor-
traditional Asian meals, contain large amounts of iodine. mone (TSH) and T4 levels since any telogen effluvium
related to thyroid deficiency or excess is imminently treat-
able, and the related hair loss is reversible. A physical thy-
Average Japanese dietary intakes are estimated to roid exam (palpation) and a thyroid ultrasound should also
range between 1000 and 3000 μg of iodine/day, and be ordered, unlike the common practice of saving these tests
iodine-induced goiter or hypothyroidism are not for only the cases of suspected alopecia areata.
uncommon in Japan and can be reversed by restricting
seaweed intake [30, 31].
References
1. Ekholm R. Biosynthesis of thyroid hormones. Int. Rev. Cytol.
1990;120:243–88.
In iodine-sufficient individuals, excess iodine intake is 2. Cavalieri RR. Iodine metabolism and thyroid physiology: current
most commonly associated with elevated blood concentra- concepts. Thyroid. 1997;7(2):177–81.
tions of the TSH that inhibits thyroid hormone production, 3. Dunn JT, Dunn AD. Update on intrathyroidal iodine metabolism.
leading to hypothyroidism and goiter [32]. The thyroid gland Thyroid. 2001;11(5):407–14.
4. Silva JE, Bianco SD. Thyroid-adrenergic interactions: physiologi-
adaptation to excess iodine starts with the acute Wolff- cal and clinical implications. Thyroid. 2008;18(2):157–65.
Chaikoff effect, first described in 1948 by Dr. Jan Wolff and 5. Delange F. Iodine deficiency. In: Braverman LE, Utiger RD, editors.
Dr. Israel Lyon Chaikoff at the University of California Werner and Ingbar’s the thyroid. 8th ed. Philadelphia: Lippincott
Berkeley, USA. This is an autoregulatory phenomenon that Williams & Wilkins; 2000. p. 295–316.
6. Brent GA. Mechanisms of thyroid hormone action. J. Clin. Invest.
inhibits organification in the thyroid gland, forming thyroid 2012;122(9):3035–43.
hormones and release in circulation [33]. In most individu- 7. Billoni N, Buan B, Gautier B, Gaillard O, Mahé YF, Bernard
als, the decreased production of thyroid hormones is only BA. Thyroid hormone receptor beta1 is expressed in the human hair
transient and resumes after adaptation to the acute Wolff- follicle. Br. J. Dermatol. 2000;142(4):645–52.
8. Ahsan MK, Urano Y, Kato S, Oura H, Arase S. Immunohistochemical
Chaikoff effect. Vulnerable patients with specific risk factors localization of thyroid hormone nuclear receptors in human hair
(autoimmune thyroid disease, previous history of thyroid follicles and in vitro effect of L-triiodothyronine on cultured cells
surgery, subacute thyroiditis, etc.) might have an increased of hair follicles and skin. J. Med. Invest. 1998;44(3–4):179–84.
risk of failing to adapt to the acute Wolff-Chaikoff effect and 9. Trüeb RM. Hormones and hair growth. Hautarzt. 2010;61(6):
result in iodine-induced hypothyroidism. In most individu- 10. 487–95.
Alonso LC, Rosenfield RL. Molecular genetic and endocrine mech-
als, an excess iodine load provides a rich substrate for anisms of hair growth. Horm. Res. 2003;60(1):1–13.
increased production of thyroid hormones leading to iodine- 11. Ebling FJ. Hormonal control and methods of measuring sebaceous
induced hyperthyroidism [34]. gland activity. J. Invest. Dermatol. 1974;62(3):161–71.
366 63 Iodine (I)
12. Nath SK, Moinier B, Thuillier F, Rongier M, Desjeux JF. Urinary 23. Messenger AG. Thyroid hormone and hair growth. Br. J. Dermatol.
excretion of iodide and fluoride from supplemented food grade salt. 2000;142(4):633–4.
Int. J. Vitam. Nutr. Res. 1992;62(1):66–72. 24. Leonhardt JM, Heymann WR. Thyroid disease and the skin.
13. Dahl L, Bjorkkjaer T, Graff IE, Malde MK, Klementsen Dermatol. Clin. 2002;20(3):473–81.
B. Fish—more than just omega 3. Tidsskr. Nor. Laegeforen. 25. Schell H, Kiesewetter F, Seidel C, von Hintzenstern J. Cell cycle
2006;126(3):309–11. kinetics of human anagen scalp hair bulbs in thyroid disorders
14. Allaway WH. An overview of distribution patterns of trace elements determined by DNA flow cytometry. Dermatologica. 1991;182(1):
in soils and plants. Ann. N. Y. Acad. Sci. 1972;28(199):17–25. 23–6.
15. Pennington JAT, Schoen SA, Salmon GD, Young B, Johnson RD, 26. United Nations Children’s Fund. The state of the World’s children
Marts RW. Composition of Core foods of the U.S. food supply, 2007. New York: UNICEF; 2006.
1982-1991. III. Copper, Manganese, selenium, and Iodine. J. Food 27. Pearce EN, Andersson M, Zimmermann MB. Global iodine nutri-
Compos. Anal. 1995;8(2):171–217. tion: where do we stand in 2013? Thyroid. 2013;23(5):523–8.
16. Trumbo PR. FDA regulations regarding iodine addition to foods 28. Zimmermann MB. Iodine and iodine deficiency disorders. In:
and labeling of foods containing added iodine. Am. J. Clin. Nutr. Erdman JWJ, Macdonald IA, Zeisel SH, editors. Present knowl-
2016;104(Suppl 3):864S–7S. edge in nutrition. 10th ed. Wiley; 2012. p. 554–67.
17. World Health Organization. United Nations Children’s Fund 29. Pennington JA. A review of iodine toxicity reports. J. Am. Diet.
& International Council for the Control of Iodine Deficiency Assoc. 1990;90(11):1571–81.
Disorders. Assessment of iodine deficiency disorders and monitor- 30. https://lpi.oregonstate.edu/mic/minerals/iodine.
ing their elimination. 3rd ed. Geneva, Switzerland: WHO; 2007. 31. Zava TT, Zava DT. Assessment of Japanese iodine intake based on
18. Institute of Medicine, Food and Nutrition Board. Dietary refer- seaweed consumption in Japan: a literature-based analysis. Thyroid
ence intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Res. 2011;5(4):14.
Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, 32. Wolff J, Chaikoff IL. Plasma inorganic iodide as a homeostatic
Vanadium, and Zinc. Washington, DC: National Academy Press; regulator of thyroid function. J. Biol. Chem. 1948;174(2):555–64.
2001. 33. Leung AM, Braverman LE. Consequences of excess iodine. Nat.
19. http://lpi.oregonstate.edu/mic/minerals/iodine#RDA. Rev. Endocrinol. 2014;10(3):136–42.
20. Zimmermann MB. Iodine deficiency. Endocr. Rev. 34. Paul T, Meyers B, Witorsch RJ, Pino S, Chipkin S, Ingbar SH,
2009;30(4):376–408. Braverman LE. The effect of small increases in dietary iodine on thy-
21. Rasmussen LB, Ovesen L, Christiansen E. Day-to-day and within- roid function in euthyroid subjects. Metabolism. 1988;37(2):121–4.
day variation in urinary iodine excretion. Eur. J. Clin. Nutr. 35. Lind P, Langsteger W, Molnar M, Gallowitsch HJ, Mikosch P,
1999;53(5):401–7. Gomez I. Epidemiology of thyroid diseases in iodine sufficiency.
22. WHO, UNICEF and ICCIDD. Assessment of the iodine deficiency Thyroid. 1998;8(12):1179–83.
disorders and monitoring their elimination. 2007 WHO/NHD/01.1. 36. Franceschi S. Iodine intake and thyroid carcinoma-a potential risk
http://whqlibdoc.who.int/publications/2007/9789241595827eng. factor. Exp. Clin. Endocrinol. Diabetes. 1998;106(Suppl 3):S38–44.
pdf. 37. http://www.sciencelab.com/msds.php?msdsId=9927547.
Magnesium (Mg+2)
64
64.1 Actions of Magnesium

Basic Concepts
• Magnesium (Mg+2) is a cofactor in more than 300 The physiological role of Mg+2 is principally related to enzyme
enzyme systems that regulate diverse biochemical activity. More than 300 enzyme systems are dependent on the
reactions in the human body, including protein syn- presence of this cation, and notably, all enzymes utilizing ATP
thesis, muscle and nerve function, blood glucose require Mg+2 for substrate formation [4]. Mg+2 is critical for
control, and blood pressure regulation. several cellular functions, including oxidative phosphoryla-
• Magnesium deficiency has been reported to elevate tion and glycolysis, while it is also required for a number of
C-reactive protein (CRP) levels, tumor necrosis steps during the synthesis of DNA, RNA, and proteins [5].
factor-alpha (TNF-a), and interleukin-6, which are Magnesium takes part in muscular and nerve function,
implicated in the pathophysiology of AGA/ blood glucose control, blood pressure regulation and contrib-
FPHL. However, Mg+2 status or supplementation utes to bone structural development [6]. Despite the low
has not been reported to contribute to hair follicle amount of Mg+2 in plasma, the clinical complications of
physiology independently. Mg+2 depletion are due to the perturbation of Mg+2-requiring
• Dietary surveys indicate that a substantial propor- enzyme systems. These are associated with common chronic
tion of the population falls short of the estimated diseases such as diabetes [7, 8], arterial hypertension [9, 10],
Mg+2 requirements. However, Mg+2 supplementa- cardiovascular disease [11], sudden death [12], osteoporosis
tion should be cautious since hypermagnesaemia [13], and migraine headaches [14].
due to excessive supplementation can be
life-threatening.
64.2 Mg+2 and the Hair Follicle
Magnesium plays an essential role in nucleotide synthesis, a

Magnesium (Mg+2) is the most common intracellular diva- continual process in the rapidly dividing hair follicle [15].
lent cation and the second most abundant cation in intracel- Magnesium is necessary for Calcium metabolism [16],
lular fluid, essential to every human body cell. The adult which is, in its turn, a structural component of hair. Moreover,
human body contains approximately 24 g (1 mol) of Mg+2; Mg+2 deficiency has been reported to elevate C-reactive pro-
about 60% is found in bone tissue, and the rest 40% in all tein (CRP) [17], tumor necrosis factor-alpha (TNF-a) [18],
other soft tissues [1]. and interleukin-6 levels [19]. In addition, Mg+2 has been
Extracellular Mg+2 accounts for only 1% of total body found to reduce cortisol levels under extreme physical stress
Mg+2 content. In the plasma, 55% of Mg+2 is ionized or [20], and insulin resistance [21].
free, 15% is complexed to anions. The rest 30% is bound
to protein, mostly albumin [2], with these levels being kept
under tight control [2]. Normal plasma Mg+2 concentra- Given that AGA has been correlated with the factors
tions range between 0.75 and 0.95 mmol/L, and even mentioned above and increased cortisol and insulin
though only about 0.3% of the total body Mg+2 is present levels, Mg+2 could indirectly affect hair follicle physi-
in plasma, the majority of analytical data obtained is from ology (see Chap. 14, Vol. 1).
this body fluid [3].
368 64 Magnesium (Mg+2)
However, very few studies in the literature have tested the significantly reduced in hair treated with hard water as com-
independent contribution of Mg+2 in hair follicle physiology. pared to hair treated with de-ionized water (p = 0.001). The
Additionally, just a couple of studies and one meta-analysis authors speculated that when the hair reacts with hard water,
have tried to interpret the statistical association of blood and Calcium, and Mg+2 cations are absorbed from the water by
serum levels of Mg+2 in patients with dermatological disor- the anion sites of hair, resulting in oxidation of hair, similar
ders—including Alopecia Areata (AA)—with varied results, to the oxidative damage in hair dyeing [29]. However, a simi-
which can be explained based on sample size, methodology, lar study by Srinivasan et al. reported that the hardness of
and population variation. water does not interfere with the tensile strength or the elas-
Mussalo-Rauhamaa et al. determined concentrations of ticity of hair [30].
12 trace elements in serum, erythrocytes, hair, and urine of
27 Finnish alopecia patients (19 female, 8 male, mean age
29 ± 11 years). They reported that no differences in element 64.3 Food Sources
concentrations of the samples as compared to those of the
general population could be found [22]. Bruske et al. statisti- Since Mg+2 protoporphyrin is an essential part of the chloro-
cally interpreted blood and serum levels of Zinc, Mg+2, and phyll molecule, the green pigment in plants, all green, leafy
Copper of 380 patients with AA, AGA, psoriasis vulgaris, vegetables, like spinach, kale, and collard greens, are par-
vitiligo, rosacea, venous ulcer, and atopic eczema, compared ticularly rich in Mg+2. Moreover, pumpkin seeds, sunflower
with 31 healthy individuals. Blood and serum levels of Mg+2 seeds, grains, nuts, and milk are valuable Magnesium
were similar in all dermatological diseases; all of them were sources [31].
increased compared to the control group (p = 0.05) [23]. Magnesium is also added to several kinds of breakfast
Bhat et al. concluded that Mg+2 levels are not altered in AA cereal and other fortified foods. Given that Mg+2 is found in
[24], whereas the meta-analysis of Jin et al. reported that natural foods in small quantities, it is necessary to have vari-
there was no significant difference between the AA patients ety in the diet, while some types of food processing, such as
and controls in the levels of serum Mg+2 (p = 0.07) [25]. refining grains in ways that remove the nutrient-rich germ
Overall, the evidence is conflicting or insufficient to sug- and bran, lower Mg+2 content substantially [32].
gest differences in levels of Mg+2 in AA patients [26], and
none of these studies had suggested any kind of etiological
Drinking water can be surprisingly rich in Mg+2, but
correlation between Mg+2 disorders and AA. Tataru et al.
the Mg+2 content of water varies dramatically among
conducted a study to test the hypothesis of a correlation
geographic regions.
between low serum levels of Mg+2 and idiopathic diffuse alo-
pecia in three groups of young women. Group 1 included 26
women with various idiopathic alopecias, group 2 included
14 women with diffuse alopecias of identified cause (sebor-
rheic alopecia, hyperthyroidism, PCOS, etc.), and group 3 64.4 Dietary Recommendations
was the control group of 24 healthy women. This study
revealed that in group 1, the percent of hypomagnesemia was In 1997, the Food and Nutrition Board of the Institute of
significantly higher compared to the control group (46.1% Medicine increased the recommended dietary allowance
vs. 8.3%). The hypomagnesemic status was also significantly (RDA) for Mg+2, based on the results of the latest, tightly
higher in women with diffuse alopecias with an identified controlled balance studies that utilized more accurate meth-
cause vs. the control group (21.4% vs. 8.3%). The supple- ods of measuring Magnesium [33]. Contemporary RDAs of
mentation therapy with Magne B6® (manufactured by Mg+2 for adult men >30 years old is 420 mg (320 mg for
Sanofi-Aventis) alone was beneficial to improve the hair loss women), adequate intake (AI) is 330 mg, and tolerable upper
in young women with apparently idiopathic diffuse alopecia intake level (UL) that applies only to supplemental Mg+2 is
[27]. However, the authors did not suggest a causative cor- 350 mg, while there is no established UL value for intake
relation between hypomagnesemic status and hair loss. from natural sources [34].
An interesting experimental study was authored by
Luqman et al., who collected hair samples from 76 male
individuals in Pakistan and tested the effect of “hard water” 64.5 Deficiency- Excess of Magnesium
in the weakening of hair compared with distilled water.
Calcium Carbonate and Magnesium Sulphate in water have Dietary surveys in the United States consistently indicate
been found in previous studies to result in temporary and that a substantial proportion of the population falls far short
permanent hair hardness, respectively [28]. The results of of the estimated requirements. Analysis of questionnaire data
Luqman et al. showed that the tensile strength of hair was from the National Health and Nutrition Examination Survey
References 369
(NHANES) of 2005–2006 found that most Americans of all absorption of Magnesium from different kinds of Mg+2 sup-
ages ingest less Mg+2 from food than their respective RDAs plements varies [33, 52]. Small studies have found that
[35]. However, no current data on Mg+2 status in the United Mg+2 in the aspartate, citrate, lactate, and chloride forms is
States are available since the NHANES has not determined better absorbed, and forms of Mg+2 that dissolve well in
serum Mg+2 levels in its participants since 1974 [36], and liquid are more readily absorbed in the gut than less soluble
Mg+2 is not evaluated in routine electrolyte testing in hospi- forms [53, 54].
tals and clinics [33, 37]. The frequency of hypomagnesemia Too much Mg+2 from food does not pose a health risk in
has been evaluated in an unselected population group of healthy individuals since the kidneys can eliminate excess
about 16,000 individuals in Germany. The study claimed that amounts in the urine [55]. The initial symptom of excess
14.5% suffered from a subclinical deficiency of Mg+2, and Mg+2 supplementation is diarrhea -a well-known side effect
33.9% had Mg+2 levels below optimal reference range of Mg+2 used therapeutically as a laxative- that can be accom-
(>0.75 mmol/L), with generally higher frequencies in panied by nausea and abdominal cramping. Intravenous
females and outpatients [38]. Mg+2 administration in excess amounts may result in danger-
ous neuromuscular and cardiovascular toxicity [56].
Very massive doses of magnesium-containing laxatives
The low magnesium content of refined foods and the
(Milk of Magnesia®) and antacids are actual health dangers.
lower intake of green leafy vegetables and whole
Reports of cases typically >5000 mg/day Mg+2 have been
grains has probably contributed to a higher prevalence
associated with Mg+2 toxicity [57], including fatal hypermag-
of hypomagnesemia in the general population.
nesemia in children [58] and the elderly [59]. Confusingly,
symptoms of Mg+2 toxicity resemble those of Mg+2 deficiency,
with the sole difference being that severe to lethal hypotension
Symptomatic hypomagnesemia due to low dietary intake occurs in Mg+2 toxicity. Severe Mg+2 toxicity symptoms,
in otherwise-healthy individuals is very uncommon because which usually develop at serum concentrations exceeding
the kidneys limit urinary excretion of this mineral under low- 1.74–2.61 mmol/L, include nausea, lethargy, confusion, dis-
intake conditions [39]. However, habitually low intakes, turbances in normal cardiac rhythm, and deterioration of kid-
excessive losses, or medical conditions that reduce Mg+2 ney function. All these are related to severe hypotension.
absorption can lead to Mg+2 inadequacy. Habitually low These are accompanied by vomiting, facial flushing, retention
intakes of Mg+2 induce changes in biochemical pathways of urine and ileus, before progressing to muscle weakness, dif-
that can increase the risk of illness over time, namely, hyper- ficulty in breathing, and cardiac arrest [55].
tension and cardiovascular disease, type 2 diabetes, osteopo- Several types of medications have the potential to interact
rosis, and migraine headaches [36]. Most severe clinical with Mg+2 supplements or affect Mg+2 status [33]. Magnesium
Mg+2 deficiency cases are hereditary [40] due to inherited supplements may interact with tetracyclines, loop diuretics,
disorders of renal Mg+2 handling. Serum Mg+2 concentration PPIs, and ingestion should be separated by at least 4 h [60].
is subjected to genetic factors in ≈30% of cases [41, 42].
Recently, six genomic loci influencing serum Mg+2 levels Synopsis
were identified [43]. Magnesium is the best supporting actor of the “mineral king-
Mild to severe Mg deficiency occurs in patients with dom”, being necessary for more than 300 chemical reactions
+2
malabsorption disorders [44], in patients under chronic in the human body. Inevitably, some of these actions of Mg+2
diuretic [45] or proton pump inhibitor (PPIs) treatments [46] are—mostly indirectly—involved in hair follicle physiology.
and in alcoholic patients [47]. Magnesium deficiency due to However, neither hypomagnesemia nor hypermagnesemia
selective malabsorption of Mg+2 alone is extremely rare [48], have been reported to cause or even correlate with hair loss.
and hypomagnesemia occurs mostly in conjunction with Since a substantial proportion of the population falls far
hypokalemia, hyponatremia, hypophosphatemia, and hypo- short of the estimated RDAs for Mg+2, monitored supple-
calcemia since overall mineral homeostasis is disrupted [49, mentation can be suggested to even healthy individuals, but
50]. Early signs of Mg+2 deficiency include loss of appetite, it is not expected to affect their hair status.
nausea, vomiting, fatigue, and weakness. As hypomagnese-
mia worsens, neurological symptoms appear, including
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Silicon (Si)
65
Basic Concepts
65.1 Actions of Silicon
• Silicon (Si) is a bioactive beneficial trace element,
not fully acknowledged as an essential nutrient, that Silicon has fewer recognized actions in the human body com-
exhibits vital roles in the structural integrity of pared to other minerals, and most are not entirely clarified.
nails, hair, and skin, in overall collagen synthesis, Nevertheless, it is hypothesized to be an essential trace ele-
bone mineralization, and bone health. ment ever since the studies of King et al. conducted on cats
• The sole source of Si in humans is through the diet, [4]. It is the third most ubiquitous trace element in the human
but the bioavailability of this element is unclear and body and is present in plasma at concentrations similar to
differs significantly among foods and food physiologically fundamental elements such as Iron, Copper,
supplements. and Zinc. Si is excreted in the urine in similar orders of mag-
• Minimal evidence from small studies suggests that nitude to Calcium, one of the most important cell signaling
Si in the form of ortho-silicic acid (OSA) supple- molecules and primary bone mineral, prompting suggestions
mentation can have beneficial effects on skin and that Si may have an important—if not essential—biological
hair follicles and might even have a direct positive role [5].
effect in hair morphology and tensile properties of Silicon is suggested to be integrally bound to connective
hair. tissues and their components and to possess an important
structural role [2, 6]. Silicon deprivation experiments in the
1970s, conducted on growing chicks [7] and rats [8], sug-
gested that it may also be essential for normal growth and
Silicon is a non-metallic element with an atomic weight of development in higher animals, including humans. These
28 and is the second most abundant chemical element in the experiments demonstrated an essential role of Si in bone
Earth’s crust. It accounts for more than 27% percent of the mineralization since Si′s deficiency led to skeletal deformi-
crust’s mass, only following oxygen at 45.5% [1]. ties, including an abnormal skull, long bone structures, and
Silicon is rarely found in its elemental form due to its high malformed joints with poor cartilage content [9]. Most likely,
affinity for oxygen, forming silica and silicates, which at these deformities were due to decreased collagen and glycos-
92%, are the most common Si minerals [2]. When Si atoms aminoglycan synthesis in connective tissue, suggesting a
bind to two atoms of Oxygen (O2), it acquires the form of structural role of Si in the cross-linking of glycosaminogly-
silicon dioxide (SiO2), which most people know as “common cans, polysaccharides, and mucopolysaccharides. All these
sand”, but it can also take the form of quartz and other crys- imply an integral role for Si [7].
talline rocks. Silicon dioxide (or silica) is the most studied
chemical compound following water and the most vital
Si-containing inorganic substance. Occupational exposure to Nevertheless, till today, Si has not been granted the
respirable crystalline silica (RCS) is a serious but prevent- “official title” of an essential element for humans.
able health hazard. Prolonged exposure to RCS causes one of
the oldest known industrial diseases, silicosis, and subse-
quent lung cancer. However, these are not related to the trace Ortho-silicic acid (H4SiO4, OSA), the simplest silicic
element Si and will not be further reviewed [3]. acid, is considered the predominant form of Si in plasma
374 65 Silicon (Si)
[10], is water-soluble, and stable in highly diluted aqueous a significant positive effect on the skin surface, skin mechan-
solutions. It plays a crucial role in delivering Si to cells and ical properties, and reduced fragility of hair and nails accord-
thus represents the primary source of Si for both humans and ing to the assessment of hair brittleness a visual analog scale
animals. The body retains small amounts of absorbed Si in (VAS). According to the authors, these findings suggested a
all tissues [11], and most of the ≈7 g of Si found in the regeneration or de novo synthesis of collagen fibers [23].
human body is located in the connective tissue of bones, tra- Strumia et al. conducted the first SEM (Scanning electron
chea, aorta, tendons, and skin [12]. The study of Si in the microscopy imaging.) microanalysis study of Si in hair loss
human body and respective biochemical changes occurring by evaluating the presence of Si in the hair of 20 female
in Si deficiency led to the conclusion that it is involved in patients with telogen effluvium and 20 healthy female con-
bone mineralization and osteoporosis [2, 13], collagen syn- trol subjects, aged 14–77 years old. Overall, 40 specimens of
thesis, aging of skin [14, 15], condition of hair and nails [16],untreated scalp hair were obtained by pull test and analyzed,
atherosclerosis [17], Alzheimer’s disease [18], maturation of and Si was found in 5% (n = 1) of the patients with hair loss
the immune system [19], and other biological effects and dis- and in 35% (n = 7) of the controls (p < 0.05). According to
orders [20]. the authors, this observation supported the role of Si in hair
trophism [24].
Early animal research has suggested a structural role of Si
65.2 Silicon, the Skin and the Hair Follicle in the cross-linking of glycosaminoglycans in connective tis-
sue [6, 7]. Thus, treatment with ch-OSA was hypothesized to
In the skin, Silicon is vital for optimal collagen synthesis and improve glycosaminoglycan structure in the dermis and the
activation of hydroxylating enzymes, improving skin keratin structure in hair and nails. An interaction of Si with
strength and elasticity since physiological concentrations of keratin was also hypothesized, considering that OSA silanol
OSA have been reported to stimulate fibroblasts to secrete groups are known to form complexes with amino acids [25]
collagen type I [21]. Silicon is a ubiquitous element present and peptides [26]. Wickett et al. investigated the effect of ch-
in most tissues in the human body and is also present at OSA on hair in a randomized, double-blind, placebo-
1–10 ppm in hair [22] and nails [15]. controlled study in 48 women with fine hair who were orally
The scientific studies evaluating the efficacy and safety of given 10 mg Si/day for 9 months, in the form of ch-OSA
using dietary supplements containing Si for beneficial effects beadlets (n = 24) or placebo beadlets (n = 24). Hair morphol-
on hair and nails date back to the early 1990s. One of the first ogy and tensile properties were evaluated before and after
to investigate the effects of Si on the skin and hair was Lassus treatment. The elastic gradient decreased in both groups, but
[16], who conducted an open study on 50 women with bio- the change was significantly smaller in the ch-OSA group
logically aged skin and fragile or thin hair and/or brittle (−4.52%) compared to the placebo group (−11.9%)
nails. These women were treated orally with 10 mL colloidal (p = 0.027). Additionally, the break load decreased signifi-
silicic acid once daily for 90 days and applied colloidal cantly in the placebo group (−10.8%) but not in the ch-OSA
silicic acid to the face for 10 min twice daily. In the 47 sub- supplemented group (−2.20%, p < 0.011). Other parameters
jects who completed the study, there was a statistically sig- (break stress, elastic modulus, and cross-sectional area)
nificant improvement in the skin’s thickness and turgor, changed in the ch-OSA group but not in a statistically signifi-
wrinkles, and condition of the hair and nails. However, cant manner. According to the authors, oral intake of ch-
Lassus was a designated contract author for the company OSA had a positive effect on tensile strength, reduced hair
producing Silicon-based products, the article is published in elasticity and strength, and improved hair thickness. The
“Τhe Journal of International Medical Research” which authors concluded that ch-OSA supplementation seemed to
operates under a page-charge basis (non-peer-reviewed), and partially prevent tensile strength loss and suggested a struc-
all of the -few in number- articles that he has published dur- tural effect of ch-OSA on hair fibers [27]. This study is the
ing his brief career as an author, are hosted in that journal single one in the scientific literature claiming a direct posi-
(see Chap. 46). tive effect in the hair morphology and tensile properties of
Since Si was suggested to be crucial in the formation and hair caused by Si supplementation. Notably, it was funded by
maintenance of connective tissue, Barel et al. investigated Bio Minerals n.v., a Belgium-based company that manufac-
the effect of choline-stabilized OSA (ch-OSA) on the skin, tures and develops dietary supplements utilizing ch-OSA
nails, and hair in a randomized, double-blind, placebo- technology [28]. Therefore, possible conflicts of interest
controlled study. Fifty women with photodamaged facial might apply.
skin were administered orally 10 mg Si/day in the form of Other products that contain Si as an ingredient and claim
ch-OSA pellets (n = 25) or placebo pellets (n = 25) for to possess hair growth properties are marine extract com-
20 weeks. Oral intake of ch-OSA, unlike placebo, resulted in pounds reviewed extensively in Chap. 46.
65.5 Deficiency- Excess of Silicon 375
65.3 Food Sources daily, on the basis of the Si content of foods in the average
U.S. diet [36]. This range was narrowed down by Jugdaohsingh
Natural levels of Si are much higher in plant-derived foods et al., who estimated the daily Si intake to be 24–33 mg/day
than meat or dairy products [2]. Plants absorb OSA from the in the Framingham and Framingham Offspring cohorts [30].
soil, isolate elemental Si, and use it for mechanical and struc- However, no recommended daily intake for Si has been
tural support [29], incorporating it in compounds referred to defined since it has not yet been established as an essential
as phytolithic silica. nutrient [37]. Accordingly, the U.S. Institute of Medicine has
Several reports concerning the Si content of foods have not set an official Recommended Daily Allowance (RDA), an
been published. For decades, bioavailability data were Adequate Intake (AI), or a Tolerable Upper Intake Level for
available only for dietary fluids, and no data were available Si. Therefore, 20 mg/day of Si are assumed to be adequate for
on the bioavailability of Si from solid foods until the study adult needs and considered an amount commonly provided
of Jugdaohsingh et al. in 2002 [30]. High levels of Si are by an average Western diet [35].
found in unrefined (“whole”) grains such as barley, oats,
rice bran, and wheat bran [31]. Overall, the absorption and
bioavailability differ significantly between foods, and the 65.5 Deficiency- Excess of Silicon
mean bioavailability of Si from plant-based foods such as
cereals, grains, and some fruits and vegetables is ≈40%. Considering the abundance of Si in the human body, it seems
Interestingly, bananas, which have the highest concentra- unlikely that Si deficiency could occur in humans. Actually,
tion of Si from all other sources (5.5 mg/100 g), have a neg- neither Silicon deficiency nor any Silicon-responsive condi-
ligible absorption (<2%) compared, to green beans, which tions have yet been identified in humans [36], and dietary Si
are both high in Si (2.5 mg/100 g) and have a high, absorp- excess has not been linked to any disease or condition [37].
tion rate, ≥50% [30]. Other foods with adequate Si content On the contrary, in animal studies, Si deficiency has been
and bioavailability are asparagus, cabbage, cucumber, correlated with reduced bone mass and slow healing of frac-
olives, radishes, brown rice, and cereals, flour, bread, pasta, tures [38].
and bread products [31]. Nevertheless, Si supplements are quite popular and mar-
Silicon in drinking water is derived from the weathering keted with claims that Si (quoting) “encourages the growth
of rocks and soil minerals, and since different types of min- of thick and healthy hair”, “increases the luster and shine of
erals weather at different rates, the concentration of Si in hair”, “prevents the skin from becoming flabby”, and
water depends on the surrounding geology. Drinking water “restores the natural glow of the skin”. Naturally, clinical
and other fluids provide the most readily bioavailable source studies evaluating the efficacy of Si in any of these claims are
of Si in the diet (50–80%) since Si is principally present as still painfully missing [39].
OSA, and fluid ingestion can account for ≥20% of the total Few studies evaluating the safety, efficacy, and bioavail-
dietary intake of Si and could be even higher from mineral ability of the different chemical forms of Si are properly
waters [32]. designed, include a large number of volunteers, and have a
long follow-up period. There are different forms of Si sup-
plements available, and the most important considerations in
Beer, a macerated whole-grain cereal product, contains order to select the best option are safety and bioavailability
the highest level of Si from all beverages [33]. Beer is [39]. According to Van Dyck et al., who were the first to
probably the best source of Si regarding absorption examine the in vivo bioavailability of Si from food and food
and bioavailability, according to Sripanyakorn et al., supplements in a female subject, Si absorption is strongly
who reported that the absorption of Si from beer by influenced by its chemical form, by the matrix and the diet in
nine healthy volunteers was 55% within 6 h after con- which it is present [40]. A more recent study by Sripanyakorn
sumption of 0.6 L of beer containing 22.5 mg Si [34]. et al. confirmed that supplemental Si is likely to vary widely
in intestinal availability (from <1% to >50%) depending on
its chemical form, and different forms of Si supplements are
expected to have varied absorption profiles. Most polymeric
65.4 Dietary Recommendations silicates show negligible-to-low bioavailability, monomeric
silicates are readily absorbed, and overall particulate sili-
Until the 1990s, the human requirement for Si was estimated cates were decreasingly well absorbed with increasing
to be in the range of 5–20 mg/day, based on average estimated polymerization.
daily intakes of Si [35]. More recently, average Si intake in OSA, which is a small, neutrally charged molecule, repre-
the United States was estimated to be in the range of 20–50 mg sents the most bioavailable form of Si [41, 42]. Other supple-
376 65 Silicon (Si)
ments available over the counter include ch-OSA, dry 8. Schwarz K, Milne DB. Growth-promoting effects of silicon in rats.
Nature. 1972;239(5371):333–4.
horsetail extract, silicon dioxide, colloidal silica gel, and
9. Carlisle EM. Biochemical and morphological changes associ-
monomethyl trisilanol in solution. The highest number of ated with long bone abnormalities in silicon deficiency. J Nutr.
studies in the literature evaluates ch-OSA, which has been 1980;110(5):1046–56.
approved for human consumption and is known to be non- 10. Berlyne GM, Adler AJ, Ferran N, Bennett S, Holt J. Silicon metab-
olism. I. some aspects of renal silicon handling in normal man.
toxic, in addition to representing the most bioavailable form
Nephron. 1986;43(1):5–9.
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1977:255–68.
12. Carlisle EM. Silicon. In: Frieden E, editor. Biochemistry of the
Si supplements from bamboo and seaweed are safe but essential Ultratrace elements. New York: Plenum Press; 1984.
have low bioavailability, unlike shellfish products, that p. 257–91.
13. Eisinger J, Clairet D. Effects of silicon, fluoride, etidronate and
contain large Si amounts and are highly bioavailable magnesium on bone mineral density: a retrospective study. Magnes
[43]. Res. 1993;6(3):247–9.
14. Reiser KM, Last JA. Silicosis and fibrogenesis: fact and artifact.
Toxicology. 1979;13(1):51–72.
15. Martin KR. Chapter 14. Silicon: the health benefits of a metalloid.
Very little toxicity data exist regarding aqueous silica In: Sigel A, Sigel H, Sigel RKO, editors. Interrelations between
consumption due, in part, to the lack of anecdotal reports of essential metal ions and human diseases, metal ions in life sciences,
vol. 13. New York: Springer; 2013. p. 451–73.
toxicity and general presumption of safety. However, a few
16. Lassus A. Colloidal silicic acid for oral and topical treatment of
rodent studies have been conducted, which indicate a No aged skin, fragile hair and brittle nails in females. J Int Med Res.
Observed Adverse Effects Level (NOAEL) of 50,000 ppm 1993;21(4):209–15.
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Synopsis
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derives solely from the diet, and the intake, metabolism, and
Thompson RP, Powell JJ, Hampson GN. Orthosilicic acid stimu-
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23. Barel A, Calomme M, Timchenko A, De Paepe K, Demeester N,
reports of the effects of Si in AGA/FPHL. Therefore, even if Rogiers V, Clarys P, Vanden BD. Effect of oral intake of choline-
Si supplements claim impressive benefits for human hair, stabilized orthosilicic acid on skin, nails and hair in women with
there is no solid scientific data to support them. photodamaged skin. Arch Dermatol Res. 2005;297(4):147–53.
24. Strumia R, Lauriola MM. Silicon in hair loss: a preliminary
SEM microanalysis study. J Eur Acad Dermatol Venereol.
2007;21(8):1120–1.
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3. Brown T. Silica exposure, smoking, silicosis and lung cancer— Berghe D, Calomme M. Effect of oral intake of choline-stabilized
complex interactions. Occup Med (Lond). 2009;59(2):89–95. orthosilicic acid on hair tensile strength and morphology in women
4. King EJ, Stantial H, Dolan M. The biochemistry of silicic acid: the with fine hair. Arch Dermatol Res. 2007;299(10):499–505.
presence of silica in tissues. Biochem J. 1933;27(4):1002–6. 28. https://www.food.be/companies/bio-minerals-nv.
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Selenium (Se)
66
a component of selenoproteins, some of which have essential

Basic Concepts enzymic functions [2]. Studies have identified 25 selenopro-
• Selenium is an essential trace mineral and a con- tein genes in humans that play critical roles in reproduction,
stituent of selenoproteins. It has structural and thyroid hormone metabolism, DNA synthesis, protection
enzymic roles, being best-known as an antioxidant from oxidative damage, and infection [3], though many have
and a catalyst for the production of active thyroid roles that have not yet been fully elucidated [4]. Se exists in
hormones. two forms: inorganic, as selenate and selenite, and organic,
• In humans, both the deficiency and excess of Se as selenomethionine and selenocysteine [5]. Soils contain
have been reported to cause hair loss, and Selenium inorganic selenites and selenates that plants accumulate and
Sulfide topical products have been used for decades convert to organic forms, namely selenocysteine, selenome-
for the treatment of moderate to severe seborrheic thionine, and their methylated derivatives. The Se content in
dermatitis. However, only anecdotal reports of posi- the human body is estimated to be in the 13–20 mg range,
tive effects on patients with AGA/FPHL exist. and skeletal muscle is the primary site of Se storage, account-
• Se dietary intakes range from high to very low ing for approximately 28–46% of the total Se pool [5, 6].
according to geography, and Se deficiency—even
though rare—is endemic in areas of the planet with
very low soil levels of Se. Fortunately, in most devel- 66.1 Actions of Selenium
oped countries, the population is Selenium-replete.
• The therapeutic window of Se is very narrow, main- The multifaceted aspects of Se have attracted worldwide
taining a very thin line between a level of necessity clinical and research interest in the last few decades.
and harmfulness, and Se toxicity from supplemen- Selenium is currently the focus of intense scientific debate
tation, which is mostly unnecessary, can result in and investigation on the possible involvement of selenopro-
massive hair loss in addition to nail and skin teins in health, most notably concerning cancer [7]. The most
disorders. abundant selenoproteins in the human serum are selenopro-
tein P, corresponding to 50% of the total amount of Se in the
human body [8, 9], and glutathione peroxidase, correspond-
ing to another 10–30%.
Selenium is a non-metal essential trace element with the Selenium is a component of selenocysteine, an unusual
symbol Se and atomic number 34. It was first described in amino acid, aka the 21st amino acid. It resides at the active
1818 by the Swedish chemist Jöns Jacob Berzelius (1779– site of Se-dependent enzymes, which are mostly cofactors
1848), who began his career as a physician. He named this for the reduction of antioxidant enzymes [10].
element after the Greek moon goddess Selene (Greek Selenocysteine-containing enzymes that have been identi-
“σελήνη” (Selene) meaning Moon). Selenium seldom occurs fied in mammals include the glutathione peroxidase family
in its elemental state or as a pure core compound in the (GPX1, GPX2, GPX3, and GPX4), three iodothyronine
Earth's crust and resembles sulfur in many of its chemical deiodinases, and two thioredoxin reductases [11].
properties [1]. Concerning the glutathione peroxidase family, Se functions
Trace amounts of Se are necessary for cellular function in as a redox center and controls the intracellular redox state.
most organisms, including all animals and, of course, The best-known example of this redox function is reducing
humans. In contrast, Se salts are toxic in large amounts. Se is hydrogen peroxide and damaging lipid and phospholipid
380 66 Selenium (Se)
hydroperoxides to harmless products, namely water, and tein deficiency to abnormalities in skin and hair and provided
various alcohols [12, 13]. This function helps maintain genetic evidence for the role of these proteins in keratinocyte
membrane integrity, conserves prostacyclin production, and function and cutaneous development [24]. Hwang et al. [25]
reduces the likelihood of propagation of further oxidative were the first to evaluate the hair changes in a C57BL/6
damage to biomolecules such as lipids, lipoproteins, and mouse model associated with Se excess and deficit and tried
DNA, with the associated increased risk of conditions such to determine the pathogenic mechanism [25]. They observed
as atherosclerosis and cancer [12, 14]. a significant decrease of the Bcl-2/Bax ratio in both the
The thyroid gland and every cell that physiologically Se-excess and Se-deficient groups, and since the progression
needs thyroid hormone to function uses Se indirectly. Se is a to telogen due to apoptosis in hair follicles is caused by a
cofactor for three of the four known thyroid hormone deio- reduction of the Bcl-2/Bax ratio [26–28], they hypothesized
dinases, which activate—and then deactivate—thyroid hor- that this is the underlying mechanism in Se-induced hair
mones and their metabolites [15, 16]. Selenium also disorders.
possesses plenty of interesting biological effects in the In humans, both deficiency and excess of Se have been
human body that go beyond this chapter's scope: it evinces reported to cause hair loss. Concerning Se deficiency, alope-
antioxidant activity, anti-inflammatory, antimutagenic, anti- cia in infants on total parenteral nutrition has been relieved in
carcinogenic, or chemopreventive, antiviral, antibacterial, a few weeks by Se supplementation in the form of selenite
antifungal, and antiparasitic effects in humans and animals [29, 30]. Kanekura et al. [31] published an interesting case-
[14, 17]. There are dozens of systematic reviews and report of Selenium deficiency in an 18-month-old boy that
meta-analyses on the effects of Se in practically every sys- led to dry skin along with sparse, short, thin, light-colored
tem in the human body, and the reader can refer to a vast hair. The skin lesions disappeared upon dietary supplementa-
number of excellent articles. tion of Se [31]. Selenium deficiency probably causes telogen
effluvium by disruption of structural proteins network in
keratin and amalgamate. The resulting disulfide bridges
However, the associations between Se exposure and
make the hair shaft more fragile, with eventual generalized
multiple positive effects that were found in some
hair loss [32, 33].
observational studies should not be taken as evidence
of a causal relation, and results should be interpreted
with caution. Confusingly, the clinical manifestations of Se toxicity
also include alopecia, in addition to nail dystrophy,
skin rashes, gastrointestinal upset, and neurologic dys-
function, such as disorientation.
66.2 Selenium and the Hair Follicle
Selenium is vital for the proper function of many organs, Massive hair loss associated with elevated Se concentra-
including the skin. It is known, mostly from experiments in tions in plasma has been reported in Selenium toxicity as
animals, that an excess or deficiency of Se causes abnormali- well, associated either with excessive Se supplementation
ties in hair, such as hair loss, change of hair texture, and hair [34] or consumption of foods containing toxic amounts of
hypopigmentation [18]. Se, either wheat [35] or Brazilian nuts.[33, 36].
Selenium-deficient rats display a slower growth rate and A group of plants have been classified as seleniferous
sparse hair growth [19, 20], and similar effects of Se disor- plants by virtue of their content in selenocystathionine, a
ders have also been demonstrated in dogs [21] and pigs [22, selenium-containing analogue of the sulfur amino acid cys-
23]. These findings imply that Se plays a role in hair follicle tathionine. They include Lecythis ollaria (coco de mono),
morphogenesis and that the impaired antioxidant function of Astragalus pectinatus (narrowleaf milkvetch), and Stanleya
glutathione peroxidase might damage hair follicles. However, pinnata (desert prince's plume). The plants are toxic by vir-
the exact role of Se in hair growth is still mostly unknown tue of their high content in selenium resulting in selenium
since there are no rodent models to investigate the underly- intoxication with inhibition of anagen. While human intoxi-
ing mechanism. cation with seleniferous plants is rare, there have been reports
Sengupta et al. [24] generated mice with targeted removal from South America and the United States, where selenium
of selenoproteins in keratin 14 (K14) expressing cells and poisoning has been associated with hair loss in Native
their differentiated descendants. Lack of selenoproteins in Americans [37, 38]. The cytotoxic effect can be reversed by
epidermal cells led to hyperplastic epidermis and aberrant administration of l-cystine [39].
hair follicle morphogenesis, accompanied by progressive Selenium in the form of Se sulfide is found in several skin
alopecia after birth. These findings linked severe selenopro- products, lotions, shampoos. There is a large volume of lit-
66.4 Dietary Recommendations 381
erature concerning the specific effects of topical Se sulfide 66.3 Food Sources
products on human skin and hair follicles. The efficacy of Se
disulfide suspension in the treatment of dandruff and sebor- Selenium enters the food chain through plants, which take it
rheic dermatitis of the scalp has been known since the 1950s up from the soil. However, since Se is not uniformly distrib-
[40]. Even Orentreich, the "father" of Hair Follicle uted on the Earth's crust, the amount of Se in a given type of
Transplantation (see Chap. 84, Vol. 3), has published in 1964 plant-based food depends on the amount of Se in the soil.
a review on the influence of Se disulfide shampoo on human Several other factors contribute, such as soil pH, amount of
hair growth and the hair cycle [41]. organic matter in the soil, and whether Se is in a form that is
Selenium sulfide shampoos are generally considered safe, amenable to plant uptake [61].
well tolerated [42], and more effective in dandruff treatment
than ordinary commercial shampoos [43, 44]. Head &
Shoulders® and Selsun® are the most popular medicated As a result, Se concentrations in plant-based foods
shampoo brands containing Se sulfide. However, several vary widely by geographic location [62, 63]., and in
studies have also investigated the adverse effects of Se on several areas of countries such as China or Finland,
hair follicles. Archer et al. [45] reported that the 2.5% Se selenium salts are added to chemical fertilizers to
sulfide suspension produced human hair roots changes when increase selenium in soils [64].
applied topically for just 9 h. More specifically, 39.0% of the
hairs in the treated area broke in the shaft without pulling out
the hair root, whereas only 10.6% in the sample pulled from According to the U.S. Department of Agriculture Food
the untreated area broke in this way. The authors considered Composition Database, an example of soil-dependent high
that these changes might represent a toxic effect of the Se content are Brazil nuts. They are the most abundant
Selenium ion on the hair papillae [45]. Grover has reported dietary source of Se with 544 μg selenium/ounce, though this
partial loss of hair in six cases following the repeated use of is soil-dependent since the Brazil nut does not require high
a Se sulfide shampoo [46], and hair loss has been reported in levels of the element for its own needs [65].
guinea pigs in which the detergent was not washed away to The Se content of soil affects its amounts in the plants that
provide an intense exposure to the active substance [47]. animals eat, so the quantities of Se in animal products also
These findings probably represent local Se toxicity and are vary [62, 63]. However, Se soil concentration has a smaller
not relevant in everyday use, provided the shampoo is used effect on Se levels in animal products since animals manage
according to the directions of the manufacturer. In support of to maintain predictable tissue concentrations of Se through
this argument is the early finding of Slinger et al. [48], who homeostatic mechanisms, and formulated livestock feeds
were unable to demonstrate any Se sulfide absorption as generally contain the same element levels [66].
indicated by urinary excretion, even when the Se sulfide Proteins selenomethionine and selenocysteine are the
shampoo was used daily for 19 days on eczematous areas of organic forms of Se found in natural foods [67], while inor-
atopic dermatitis [48]. ganic Se, such as selenite, is not found in the food chain and
There is a clear indication for the use of Se sulfide sham- metabolizes differently [68]. The richest sources of seleno-
poos to treat moderate to severe seborrheic dermatitis of the methionine and selenocysteine are seafood (especially tuna
scalp [49], and their efficacy is comparable to that of and shrimps) and organ meats, whereas muscle meats, dairy
Ketoconazole or Miconazole-containing shampoos [50]. products, cereals, and other grains also have high Se content.
However, Se sulfide shampoos appear to be less well-tolerated The primary food sources of Se in the American diet are
[51]. Selenium sulfide is effective against tinea capitis and has breads, grains, meat, poultry, fish, and eggs [69]. The amount
a potent sporicidal effect against Malassezia spp [52]. A com- of Se in drinking water is not nutritionally significant in most
parative study of 1% commercially available Selenium sulfide geographic regions [70].
shampoo and 2.5% Se sulfide prescription lotion in the adjunc-
tive treatment of tinea capitis infection demonstrated equal
efficacy [53]. Rarely, the use of Se sulfide shampoos may 66.4 Dietary Recommendations
cause hair shaft discoloration, a rare condition called xan-
thotrichia [54], while Se-containing lotions may cause green Intake recommendations for Se and other nutrients are pro-
hair [55] or orange to red-brown scalp discoloration [56, 57]. vided in the Dietary Reference Intakes (DRIs) developed by
There have been no scientific reports on topical Se lotions the Food and Nutrition Board (FNB) at the Institute of
or shampoos having a positive effect in AGA/FPHL, in con- Medicine of the National Academies [70]. Se needs are esti-
trast to Ketoconazole shampoo, which has been reported to mated based on the amount of Se required for the ideal func-
have a mild to moderate hair growth potential both in lab tion of glutathione peroxidase. Recommended dietary
animals and humans [58–60] (see Chap. 31). allowance (RDA) for adults is 55 μgay, adequate intake (AI)
is set at 45 μg, and tolerable upper intake level (UL) is with Se inadequacy or deficiency. Early indicators of excess
400 μg. After intake, Se is distributed extensively to all tis- intake are a typical garlic breath odor and a metallic mouth
sues and skin [71]. taste [70, 81]. Selenosis in humans is a rare event evident
The plasma Se concentration is often used to assess the only in very high Se areas, and according to the World Health
nutritional status of Se. A plasma Se concentration of ≥8 μg/ Organization, Se toxicity is endemic in South Dakota (USA),
dL in a healthy subject indicates that plasma selenoproteins Venezuela, and China [82, 83]. However, most known cases
are optimized, and the subject is Selenium replete. According result from industrial accidents and episodes involving the
to the analysis of data from the 2009–10 National Health and ingestion of "super-potent" Selenium supplements [34]. In
Nutrition Examination Survey (NHANES) that determined 2010, over 200 patients suffered acute selenosis due to a mis-
plasma Se levels in 17,630 subjects in the U.S., more than formulated liquid dietary supplement containing more than
99% of the subjects were Selenium replete [70, 72]. Since 200 times the labeled concentration of Se and a higher than
most estimates of Se intake in the United States are 80 μg/ the labeled concentration of chromium [36]. The most com-
day or higher, routine Se supplementation is not recom- mon clinical signs of selenosis are diarrhea (78%), fatigue
mended in the United States [73]. (75%), hair loss (72%), joint pain (70%), nail discoloration
or brittleness (61%), and nausea (58%), in addition to skin
rashes, mottled teeth, irritability, and nervous system abnor-
66.5 Deficiency- Excess of Selenium malities [84].
In selenosis, the hairs break at the scalp's level with
The therapeutic window of Se is extremely narrow [25], and slight trauma, such as scratching, while the follicles remain
Se maintains a very thin line between a level of necessity and intact [35]. Scalp rash is frequent, and severe itching has
harmfulness. Toxicity appears when the level of Se is higher also been reported, leading to lost/broken hairs from any
than 1 μg/g, and deficiency appears when it is lower than site of the body. Nails become brittle and are shed, and the
0.1 μg/g [25, 74]. Overall, human Se dietary intakes range new nail is also dystrophic. Skin lesions have been reported,
from high to very low according to geography, and human mainly on the limbs, i.e., dorsum of hands and feet, the
Selenium-deficiency diseases have been recognized in outer side of the legs and thighs, the forearms, and the back
regions of the world notable for their low soil content of Se, of the neck [35].
such as volcanic regions. Diseases attributed to Se deficiency Supplemental Se is available in many forms, including
are Keshan disease, endemic cardiomyopathy, and Kashin- multivitamin/multimineral supplements and stand-alone
Beck disease, deforming arthritis, first identified in an area in products. Most often, Se is in the forms of selenomethionine
China with the lowest recorded Se levels on Earth [75]. or of selenium-enriched yeast, grown in a high-selenium
Naturally, both these conditions are believed to have other medium, or as sodium selenite or sodium selenate [70]. Most
additional causative cofactors. multivitamin/multimineral supplements typically contain
Besides insufficient Se intake in low soil-selenium areas, 55–70 μg of Se per serving. Selenium-specific supplements
the main conditions associated with Se deficiency fall into typically contain either 100–200 μg/serving, and the human
two categories: body absorbs more than 90% of selenomethionine but only
about 50% of Se from selenite [85].
1. parenteral/enteral nutrition, malabsorption, or long-
Synopsis
term hemodialysis,
The Selenium research field has grown dramatically in the
2. chronic conditions associated with oxidative stress,
last few decades, and studies on Se biology provide exten-
such as chronic alcohol or drug abuse and human
sive new information regarding its importance for human
immunodeficiency virus (HIV) infection [76].
health. Selenium is an essential micronutrient in mammals
but is also recognized as toxic in excess. Both Se deficiency
and toxicity from excess intake are very rare, and both will—
Moreover, vegans [77], elderly people [78], pregnant- strangely—result in hair loss. However, given the lack of
lactating women [79], and heavy smokers [80] have higher human research, it is surprising that "hair growth supple-
Se needs and may develop deficiency according to the rele- ments" are marketed as containing Selenium. Considering
vant literature. Signs and symptoms reported are similar to that no less than 99% of the population in developed coun-
Zn deficiency, i.e., fragile hair, hair loss, brittle nails, and tries is Selenium replete and that there are no scientific
cardiomyopathy [31]. reports of Se supplements or topical lotion/shampoos having
Chronically high intakes of the organic and inorganic a positive effect in AGA/FPHL, there is no indication for
forms of Se may lead to selenosis and has similar effects their use in AGA/FPHL.
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Iron (Fe+2)
67
Iron is a chemical element with the symbol Fe and atomic

Basic Concepts number 26. It is the most common element on Earth by mass,
• Iron is an essential co-factor for a host of metabolic forming most of Earth’s outer and inner core. Iron is an
reactions necessary for the function of the oxygen- essential trace element and the most important transition
carrying protein hemoglobin and proteins of the metal found in all living organisms (archaeans, bacteria, and
electron transport chain. eukaryotes), including humans [1]. Iron is the primary inor-
• Iron deficiency (ID) is ranked by WHO as the ganic component of hemoglobin and various other Iron-
world’s most common nutritional deficiency, and containing proteins and enzymes, some of which contain
ID is frequently cited as a possible cause of diffuse heme prosthetic groups, such as cytochrome and catalase [2].
hair loss, making it standard practice for The average total elemental Iron quantity in the human
Dermatologists to prescribe iron supplementation body is approximately 0.005% of body weight or about 3.8 g
in women under the assumption that low iron stores for men and 2.3 g for women. No less than 70% of this
may cause hair loss. However, this practice is not amount is found in hemoglobin present in circulating eryth-
evidence-based per se. rocytes. This amount remains constant despite only 1 mg of
• The required iron levels and their significance for iron being absorbed daily (under normal conditions) since
hair loss are still objects of scientific debate, with the human body efficiently recycles its hemoglobin for the
several observational studies evaluating the associa- iron content [3]. Much of the remaining Iron in the human
tion between decreased ferritin levels and hair loss body is found in serum storage proteins [4] ferritin and
having resulted in conflicting results. hemosiderin, the latter being a ferritin degradation product.
• Although a causal link has not been proven, several A smaller amount lies in myoglobin that transfers oxygen to
studies have found higher rates of iron depletion or muscles, and the remaining is stored for future use in the
lower iron stores (as assessed by serum ferritin liver, spleen, bone marrow, or intracellular proteins [5].
which acts as a buffer against both iron deficiency Humans cannot excrete iron actively, so its concentration
and iron overload) in patients, particularly women, in the body must be controlled at the site of iron absorption,
presenting with otherwise unexplained hair loss. which is the proximal small intestine [6]. After uptake in
• However, low iron and low ferritin levels are not per cells, iron storage is delicately regulated; Iron ions are never
se a hair loss causative factor, nor a prerequisite for “free” since they have a high potential for biological toxicity.
hair loss, and low ferritin levels are a potential risk A significant component of this regulation is the protein
factor for hair loss in some women; most women with transferrin, which binds iron ions absorbed from the duode-
CTE will respond positively to iron treatment when num and carries them to cells.
they reach a certain ferritin target value. However, at
this time, the exact mechanisms by which reduced
iron stores may affect hair follicles remain elusive. 67.1 Actions of Iron
• There are no definitive answers, and evidence is
insufficient to recommend iron supplementation to Iron can exist in oxidation states ranging from −2 to +6, but in
all hair loss patients with ID in the absence of ane- biological systems, standard occurring oxidation states are the
mia. Consequently, patients must be approached on ferrous (+2), ferric (+3), and ferryl (+4) states [7]. The rapid
a case-by-case basis. interconversion of Iron oxidation states is a mechanism
through which iron participates in electron transfer and a
386 67 Iron (Fe+2)
mechanism whereby iron can reversibly bind ligands. The 67.3 Iron Deficiency (ID)
common biological ligands for iron are oxygen, nitrogen, and
sulfur atoms [7, 8]. Thus, iron is suited to participate in numer- Since the correlation of iron and hair follicle physiology are
ous essential biochemical reactions, generally classified as quite complex and elusive, a detailed review of iron inade-
oxygen transport and storage, electron transfer, and substrate quacy and iron deficiency (ID) is useful before proceeding.
oxidation-reduction reactions. Four major classes of iron-con- Iron deficiency (ID) may be considered as a continuum:
taining proteins exist in the mammalian system: iron-contain-
ing heme proteins (hemoglobin, myoglobin, and cytochromes), 1. Initially Iron Depletion,
iron-sulfur enzymes (flavoproteins, hemeflavoproteins), pro- 2. Then Iron Deficiency Erythropoiesis (IDE),
teins for iron storage and transport (transferrin, lactoferrin, fer- 3. Finally, Iron Deficiency Anemia (IDA).
ritin, hemosiderin), and other iron-containing or activated • In Iron Depletion, body iron stores are diminished,
enzymes (sulfur, non-heme enzymes) [8]. leaving little to no reserves, but functional and trans-
In the principal oxygen transport nonenzymatic proteins, port iron remains normal, and there is no limitation in
hemoglobin and myoglobin, iron functions as a critical ligand the supply of iron to the functional compartment, the
for dioxygen binding. In iron-sulfur enzymes, iron partici- erythrocytes.
pates in single-electron transfer reactions primarily in energy • In IDE, both iron stores and transport iron are dimin-
metabolism. In the third category, iron is bound to various ished, and the supply of iron to the functional compart-
forms of heme and participates again in electron transfer reac- ment is suboptimal but not reduced sufficiently to
tions when associated with various co-factors (e.g., cyto- cause measurable anemia.
chrome P450 complexes). The final group of iron-containing • Finally, in IDA, storage, transport, and functional iron
enzymes is a catch-all grouping in which iron is not bound to are all severely decreased. There is a measurable defi-
a porphyrin ring structure or in iron-sulfur complexes [8]. cit in the most accessible functional compartment -the
Since the intricate details of iron biology go beyond the erythrocyte-, that can lead to impaired function of mul-
scope of this chapter, the interested reader can refer to the tiple organ sites and systems [9].
excellent review by Beard [8].
Iron deficiency (ID) is ranked as the most common
nutritional deficiency globally, with substantial health
67.2 Iron Distribution and economic costs, according to the World Health
Organization, which estimates that approximately
Total body iron is classically viewed as being distributed
50% of the 1.6 billion cases of anemia worldwide are
among three compartments, storage iron, transport iron, and
due to ID [11].
functional iron:
• Functional iron consists of iron bound to hemoglobin,

myoglobin, and numerous, diverse heme enzymes, such In the USA, the prevalence of ID is 12–16% in adolescent
as cytochromes, and non-heme enzymes, such as ribonu- girls and women of reproductive age (16–49 years old) and
cleotide reductase. Functional iron is calculated indirectly 6–9% in women 50 years of age and older [12, 13]. In other-
through the concentration of hemoglobulin and hemato- wise healthy men aged 16–69, ID is much more rare [9], just
crit [9, 10]. 2%, and is more frequent in those actively engaged in sports
• Transport iron represents iron transported to the tissues, [14].
and it is bound mainly to transferrin. It is measured by the “Making and breaking” of erythrocytes is at the heart of
concentration of erythrocyte zinc protoporphyrin, the iron physiology: more than 2.4 million erythrocytes are pro-
concentration of transferrin/total iron-binding capacity duced every second, each containing more than 280 million
(TIBC), and serum iron and transferrin saturation. hemoglobin molecules, all together requiring more than
• Storage iron represents the body’s iron reserves bound to 1 × 1015 iron atoms every single second to maintain adequate
ferritin and hemosiderin and is best measured by serum erythropoiesis. These numbers translate into 20 mL of blood
ferritin concentration [4]. being produced daily, containing 6 g of hemoglobin and
20 mg of iron [15]. These requirements are mostly met by
iron recycling of senescent red blood cells by macrophages.
Serum ferritin is an indirect marker of the total amount
In the absence of bleeding (including menstruation) or preg-
of iron stores in the body, and is used as a diagnostic
nancy, only a small quantity of iron is lost daily, and body
test for Iron-Deficiency Anemia.
iron is highly conserved [7, 15]. Daily basal iron losses,
67.5 Iron and Hair loss in General 387
which refer to the obligatory loss of iron in the feces, urine prevent the proper functioning of the enzyme, resulting in
sweat, and skin exfoliation, are limited to between 0.9 and inhibition of cell proliferation [28]. Hair follicle matrix
1.02 mg/day in men and non-menstruating women and may cells are probably the most rapidly dividing cells in the
drop to 0.5 mg/day in ID [16]. Dietary iron absorption com- human body. They may be particularly sensitive even to a
pensates for iron losses (bleeding) or increased needs (preg- minor decrease in iron availability, resulting in reduced
nancy, childhood, hypoxia) and hepatic iron stores serve as a hair growth under ID conditions [27, 29]. Inhibition of
buffer [15]. other iron-dependent enzymes, such as stearyl CoA
The most common causes of ID in healthy premenopausal desaturase, which, when mutated, causes hair loss in mice
women are menstrual blood loss, pregnancy, and lactation. [30] and is present in the human hair follicle [31], could
Αdditional risk factors include menorrhagia (>80 mL), intra- contribute to hair loss, as well.
uterine devices, history of IDA, and inadequate iron intake 2. Hair follicle matrix cells and dermal papilla cells, due to
[13]. In postmenopausal women and men of all ages, reduced their rapid proliferation, show lower ferritin levels and
intestinal absorption or gastrointestinal and genitourinary higher levels of free iron [32, 33], while they have propor-
blood loss are the most frequent causes, which must be tionally higher energy requirements than other cells. Iron
excluded by lab work and history taking. Other groups most and hemoglobin reduction possibly could cause a reduc-
likely to have ID are infants and young children, regular tion of tissue vascularization and tissue hypoxia.
blood donors, cancer patients, gastrointestinal surgery 3. Vanderford et al. [34] demonstrated that maternal iron-
patients, heart failure patients, and strict vegans. restricted diets enhanced the incidence of c-kit-dependent
The bulk of experimental and epidemiological evidence alopecia in IL-10-deficient mouse pups. They suggested
in humans suggests that functional consequences of ID mast cells as potential effector cells [34], allowing them
(related both to anemia and tissue iron concentration) occur to speculate an iron-dependent inflammatory process in
only when ID is severe enough to cause a measurable the hair follicle.
decrease in hemoglobin concentration [7]. Typical symp- 4. The role of iron during the hair cycle had not been exten-
toms of ID are similar to those of anemia and include fatigue sively studied until lately. St. Pierre et al. [35], in their
and reduced exercise tolerance [17]. Signs of severe anemia seminal review (2010), hypothesized that ID might alter
include skin and conjunctival pallor, tachycardia, and low the hair cycle’s normal progression. They argued that
blood pressure [18]. Consequences of ID are partially attrib- CDC2, NDRG1, ALAD, and RRM2 genes are upregu-
uted to the reduced supply of oxygen to tissues and the lated in the bulge region and can be regulated by Iron,
depletion of non-heme iron-containing molecules [19]. whereas Decorin and DCT genes are downregulated, also
Clinical manifestations of ID include anxiety and irritability regulated by iron. However, whether these six genes play
[20], impaired physical work performance, low mental per- a role in iron-dependent processes in the hair follicle
formance, cognitive impairment in young girls [21, 22], and remains to be elucidated.
fatigue in non-anemic women [23]. Probably the most severe 5. Du et al. [36] published their findings in Science (2008)
consequences are abnormalities of immune response and and provided evidence for understanding the relation-
T-cell proliferation [24]. ship between Iron metabolism and hair growth. The
Prolonged ID leads to IDE and eventually to IDA, charac- authors reported the loss of body hair in “mask mice”
terized by fatigue and weakness, shortness of breath, dizzi- that were iron-deficient due to a mutation in the Tmprss6
ness, and difficulty concentrating, while mouth ulcers and protein. This finding was associated with high levels of
hair loss might also occur [25]. It is, however, important to the hepcidin protein, resulting in poor iron absorption in
note that young patients with ID or even IDA may be com- the gut. Hepcidin, a liver-derived circulating peptide
pletely asymptomatic [26]. hormone, is the critical regulator of both iron absorption
and release from macrophages and other cell types and
the distribution of iron throughout the body, including
67.4 How Can Iron Deficiency Affect Hair plasma [37]. Remarkably, iron supplementation in these
Follicles? mice not only reversed the ID but also restored hair
growth.
The exact mechanisms by which reduced iron stores may
affect hair follicles are not fully known. Nevertheless, five
mechanisms are possibly related, as summarized by Kantor 67.5 Iron and Hair loss in General
et al. [27] and other researchers:
Iron deficiency has been implicated in hair, nail, and skin
1. Enzyme mechanisms seem to be the most relevant since disorders, and it has even been associated with generalized
iron is a co-factor for ribonucleotide reductase, the rate- pruritus, including documentation of improvement with iron
limiting enzyme in DNA synthesis. Iron depletion could replacement [38, 39]. Coilonichia, glossitis, and angular
388 67 Iron (Fe+2)
stomatitis, either alone or as part of the Plummer-Vinson

syndrome, have also been associated with ID [40]. In contrast, only ID can cause very low serum ferritin
The association of ID and hair loss was first noted by concentrations; therefore, a low serum ferritin value is
Cunningham (1932) in iron-deficient rats [41]. Hård [42] very specific for ID.
first postulated non-anemic ID as an etiologic factor for dif-
fuse hair loss in women [42]. Since then, most classic text-
books of clinical Dermatology consider ID as a causative Since serum ferritin measurement is the most sensitive
factor of chronic telogen effluvium (CTE) [43–47]. However, and powerful screening tool for estimating the iron status in
it was not until the early 1990s that the significance of iron adults, therefore, many authors have tried to correlate low
stores as assessed by serum ferritin levels in women with ferritin levels with hair loss.
hair loss has been systematically studied by Rushton et al. The controversy over serum ferritin levels in women
[48, 49] complaining of hair loss starts with a scientific debate
over what is the normal serum ferritin level for women
[51]. According to Schrier (2017), a cut-off point of
Since then, various observational studies have evalu- 10–15 μg/L is considered to yield a sensitivity of 59%
ated the relationship between ID, decreased ferritin and specificity of 99% for diagnosing ID and is, there-
levels and hair loss and resulted in surprisingly oppos- fore, used by many laboratories as the lower limit of nor-
ing conclusions. Almost all of these studies have mal, based on reference sample groups [26]. Ferritin
focused exclusively on women, with some suggesting 15 μg/L is the highest value of ferritin found in patients
that ID, even in the absence of IDA, may cause hair with IDA, and iron supplementation in women with
loss. serum ferritin of >16 μg/L increases serum concentra-
tions of ferritin, but not of hemoglobin [52]. In women of
childbearing age, using a cut-off point of 30 μg/L yields
a sensitivity of 92% and specificity of 98%, whereas a
The controversy starts with a debate over the normal cut-off of 41 μg/L has a sensitivity and specificity of 98%
serum ferritin level for women and gets even further compli- [26].
cated by using different reference ranges based on individ- Rushton et al. [53], however, have repeatedly ques-
ual interpretations of the literature on the subject. Another tioned the validity of the “normal” cut-off point of
factor making consensus even harder to reach is that the 10–15 μg/L of serum ferritin in women. They argue that
non-scarring alopecias that have been related with iron sta- the “normal” values for red blood cell count, hemoglo-
tus, namely Alopecia Areata (AA), AGA/FPHL, and CTE bin, and serum ferritin concentration cited by laborato-
have different etiologies and should be separately evaluated ries were obtained from sampling populations of
and not as a “group”, with ID being their common feature. genuinely iron-deficient women! Nevertheless, Waalen
However, since more than one, or even all three of these et al. [51], in a large-scale, cross- sectional study on
conditions, can simultaneously coexist in the same patient, 25,559 participants, 12,731 men and 12,828 women
this makes interpretation of results exceedingly complex. opposed the views of Rushton et al. [51] In their answer-
Moreover, this is just one of the parameters complicating ing counter-comment, Rushton et al. [54] eventually
the understanding of iron and hair loss interrelatedness. demonstrated that 38% of the women in the study of
There are more! Ferritin and hair loss in general. Waalen et al. actually had ID, despite the “accepted” fer-
Ferritin is a secretory form of a glycosylated protein that ritin value [54]. Rushton argued validly that women
normally declines with depletion of tissue iron stores and should not have lower reference limits for hemoglobin
increases with iron loading. Ferritin can be artificially elevated and ferritin concentrations than men of the same age and
in the face of anemia of chronic disease, inflammation, cancer, that in many women with inadequate iron stores, the only
or liver disease in its capacity as an inflammatory acute-phase evident sign is CTE [53, 55].
reactant and not as a marker for iron overload [50]. Therefore,
ferritin levels need to be interpreted with caution in patients
with chronic inflammation, rheumatoid arthritis, infection, According to Rushton, there is no objective evidence
neoplasia, or chronic kidney disease. Ultimately, a normal to support a sexual dimorphism for Hb or ferritin con-
serum ferritin may not always exclude iron deficiency, and the centrations in humans, and this approach makes per-
utility is improved by taking a concurrent C-reactive protein fect sense to the present author [56].
(CRP) and an erythrocyte sedimentation rate.
67.7 Iron and AGA/FPHL 389
67.6 Association Between Iron Deficiency, 2. Individuals with a mild hereditary predisposition, or with
Ferritin and Hair Loss the presence of other triggering factors, that low iron
stores may lower their threshold to the point where they
As already mentioned, the association between ID and non- develop alopecia; these patients would be the most likely
scarring scalp hair loss in women has been investigated in to benefit from iron therapy,
several studies but with conflicting results. 3. Individuals without a hereditary predisposition or other
Trost et al. published an excellent review in 2006 sum- triggering factors, that low body iron would not cause any
marizing the results of relevant publications up to that year type of alopecia.
(10 articles) that have addressed the relationship of iron
stores to various non-scarring scalp hair loss (AA, CTE, and According to this theory, the same ferritin levels may trigger
AGA/FPHL) and commented on the essential methodologi- hair loss in predisposed patients but not affect others. More
cal differences that hindered reaching a scientific consensus particularly, ferritin levels <40 μg/L are strongly correlated
[57]. with the increase of hair follicles’ number in telogen in pre-
In 2013, St. Pierre et al. [35] summarized 13 studies in disposed individuals. When ferritin levels are between 40
chronological order that have addressed the relationship of and 70 μg/L, hair loss continues, and only at levels > 70 μg/L
iron stores to hair loss until that year. They noted that almost will hair follicles return to normal circularity and re-enter
all had focused on women exclusively and had considerable anagen. This finding has been earlier demonstrated clinically
variations in study design, controls, definitions of ID and by Rushton et al. (1992), who reported that women with
IDA, as well as clinical conditions defining hair loss. These FPHL treated with Cyproterone acetate (CPA) and ethinyl
studies included between 12 and 5110 subjects; 5 were cross- estradiol responded better when serum ferritin was above
sectional studies, 4 were case-control studies, 3 were pro- 70 μg/L [58].
spective cohort studies, and one was a double-blind, According to Rushton et al., when ID develops, the syn-
placebo-controlled study. Overall, 8 of those studies sup- thesis of ferritin by the liver ceases. Ferritin that was located
ported the association between ID and hair loss, five studies in growing follicles is released in the serum to support other
did not support the relationship, and some suggested that ID, organ functions, such as the bone marrow. As a consequence
even in the absence of IDA, may cause hair loss. Since the of this loss of ferritin, the follicles go into telogen [58].
scope of this chapter is to determine the relationship between Ferritin levels less than 40 μg/L (90 pmol/L) are associated
Iron and AGA/FPHL, the reader who is interested in the very with an increase of telogen. When the levels are between 40
engaging yet pretty confusing debate between experts, such and 70 μg/L (90 and 156 pmol/L), an excess of telogen hair
as Olsen, Sinclair, and Rushton, on whether serum ferritin is loss is also observed. Only when serum levels are >70 μg/L,
associated with hair loss, can refer to these two excellent will hair re-enter in anagen.
reviews [35, 57].
However, the confusing and often contradicting results

67.7 Iron and AGA/FPHL
of all these otherwise well-designed studies could be
Many respected researchers have attempted since the early
possibly explained by a hypothesis of Kantor et al. [27]
1990s to understand the effect of ID in AGA and FPHL,
This research team proposed the “threshold theory” for
reaching, unfortunately, contradicting results.
the action of Iron in hair follicles.
Rushton et al. (1990) studied 100 premenopausal women
with FPHL, aged 14–54, and compared them with 20 control
subjects, aged 17–49 years. Of the 100 FPHL subjects, 50
They hypothesized that decreased iron stores lower the were chosen for biochemical and hematologic investigation,
threshold for developing different types of alopecia, and this and results were compared to those of controls. Overall, 72%
theory seems to explain the ecumenical effect of diminished (n = 36) had serum ferritin concentration <40 μg/L, lower
iron stores on a variety of etiologically distinct forms of hair that of the lowest control with healthy hair (40 μg/L) [48].
loss [27]. The authors gave examples of three hypothetical In a subsequent, prospective, controlled study, Rushton
patient scenarios: et al. [58] studied 40 premenopausal women with FPHL,
aged 18–47. Twenty of these women received CPA for
1. Individuals with a powerful genetic predisposition to 12 months, and another 20 women served as the control
develop AA or AGA that low body iron stores are not group. In both groups, 10 of the 20 women had ferritin
important for triggering these disorders; these patients >40 μg/L, and all had a hemoglobin concentration >11.0 g/
will lose hair regardless of their iron store levels, dL. Researchers reported a significant increase in the mean
390 67 Iron (Fe+2)
total hair density and the meaningful hair density in patients (defined as hemoglobin <12 g/dL) was seen in 19.6% of pre-
in the CPA-treatment group who also had serum ferritin con- menopausal women with serum ferritin <15 μg/L, 3.4% of
centrations >40 μg/L. In contrast, treated patients with ferri- those with serum ferritin 15–40 μg/L, but only 1% of those
tin <40 μg/L did not have a significant change in mean total with serum ferritin >70 μg/L. [62]
and meaningful hair densities. The control group underwent
a remarkable reduction in the average total (p < 0.05) and
meaningful hair density (p < 0.05), while there was no cor- According to these results, the authors concluded that
relation between serum ferritin concentration and hair loss in a decrease in ferritin levels might be considered as a
the control group [58]. potential risk factor for excessive hair loss since a
A study by Aydingöz et al. compared 10 women (mean age decrease in 30 units of serum ferritin level in premeno-
32 years) with FPHL, 33 women with CTE, and 46 healthy pausal women presenting an initial serum ferritin con-
controls. The study did not detect any statistically significant centration of 70 μg/L would lead to a 28% increase in
difference in the prevalence of depleted iron stores (<15 μg/L) the odds of excessive hair loss.
or prevalence of IDA in subjects with hair loss compared to
controls (33.3% vs 45.6%, respectively) [59].
A prospective cohort study by Sinclair (2002) on 194 Their conclusions were in accord with those of Rushton
women, aged 11–72 years, with hair loss for ≥6 months, et al. [63], who considered that ferritin reduction is a poten-
showed that 12 subjects (6%) had ferritin concentrations tial risk factor for CTE [63]. This conclusion was also con-
<20 μg/L, with normal, however, hemoglobin concentration, firmed by a later study by Moeinvaziri et al. [64] on 30
while 7 out of these 12 women had histologically confirmed women with CTE, reporting that females with ferritin
FPHL. These FPHL patients were treated with Spironolactone <30 μg/L had >2000% higher odds (OR = 21.0) to develop
200 mg/day and iron supplementation for 3–6 months until CTE [64].
ferritin concentration climbed to >20 μg/L. Four of these Bregy and Trüeb [59] conducted a cross-sectional study
seven women with FPHL had reduced hair shedding and on 418 women and, after excluding all those who had any
increased hair volume, while three women showed no other factor responsible for hair except for the variations of
improvement. The response rate of patients with FPHL and ferritin levels in question. They ended-up analyzing 181—
ferritin concentration <20 μg/L was similar to the response otherwise healthy—women with FPHL and/or CTE. The
rate of the 108 women with FPHL and normal iron stores total number of women with FPHL was 159 (87.8%), CTE
that were treated with Spironolactone alone [60]. (with or without clinical FPHL) was 135 (75.6%), and with
Kantor et al. [27] compared serum ferritin levels of female combined FPHL and CTE was 113 (62.4%). There were 112
patients with CTE (n = 30), FPHL (n = 52), AA (n = 17), and (61.9%) women with a serum ferritin level >30 μg/L, 55
AA totalis/universalis (n = 7) with a control group of 11 women (30.4%) between 10 and 30 μg/L, and 14 women
healthy patients. Mean serum ferritin levels were lower in (7.7%) <10 μg/L. There was a significant correlation between
subjects with FPHL (37.3 μg/L) and AA (24.9 μg/L) vs the age of women and serum ferritin levels, with younger
healthy control subjects (59.5 μg/L), but not lower when (menstruating) women having significantly lower ferritin
compared with those with CTE (50.1 μg/L) or AA totalis/ levels (p < 0.001). However, no correlation was found
universalis (52.3 μg/L). From the results of this study, Kantor between ferritin levels >10 μg/L and telogen rates, whether
et al. formulated their “threshold hypothesis” presented ear- in total subjects, patients with FPHL, or patients with CTE.
lier [27]. Olsen et al. [61] conducted a controlled study on 381
Deloche et al. (2007) of L’Oréal Recherche, using the Caucasian pre- and postmenopausal women with FPHL
data from a large, French epidemiological study “SU. (n = 285) or CTE (n = 96) and 76 women who had no history
VI.MAX” (“Supplementation en VItamines et Minéraux or physical findings of hair loss (control subjects) to investi-
AntioXydants”), evaluated a cohort of 5110 women for a gate whether ID was indeed more prevalent in women with
possible link between ferritin levels and FPHL [61]. This hair loss. When ferritin level of ≥15 μg/L was used as the
was the first study conducted in such a large cohort of women cut-off point, ID occurred in 12.4%, 12.1%, and 29.8% of
and provided strong arguments in favor of the relationship premenopausal women with FPHL (n = 170), CTE (n = 58),
between iron stores and hair loss, especially in premeno- and control subjects (n = 47), respectively, and in 1.7%,
pausal women. Among the women affected by excessive hair 10.5%, and 6.9% of postmenopausal women with FPHL
loss, a larger proportion (59%) had low iron stores (<40 μg/L) (n = 115), CTE (n = 38), and control subjects (n = 29),
compared to the remainder of the population (48%). In all, respectively. When ferritin ≥40 μg/L was used as the cut-off,
10.2% of the women with serum ferritin <15 μg/L and 12.3% ID occurred in 58.8%, 63.8%, and 72.3% of premenopausal
of women with serum ferritin 15–40 μg/L believed they had women with FPHL, CTE, and control subjects, respectively,
excessive hair loss, compared with only 6.8% of women with and in 26.1%, 36.8%, and 20.7% of postmenopausal women
serum ferritin >70 μg/L. In premenopausal women, anemia with FPHL, CTE, and control subjects, respectively. Using a
67.8 Topical Iron 391
ferritin level of ≥70 μg/L, ID occurred in 87.1%, 86.2%, and that providing daily nearly 100 mg iron may not be an innoc-
91.4% of premenopausal women with FPHL, CTE, and con- uous regimen for correcting iron depletion [66].
trol subjects, respectively, and in 58.3%, 57.9%, and 65.5% Rushton and van Neste [67] commented on the article with
of postmenopausal women with FPHL, CTE, and control the title “Autistic-Undisciplined - Practice What You Preach!”,
subjects, respectively. According to these results, there was by Trüeb et al. [63] rejecting that approach and explaining
no statistically significant increase in the incidence of ID in that (quoting) “There is no objective evidence to support a
premenopausal or postmenopausal women with FPHL or sexual dimorphism for Hb or ferritin in humans.” [56]
CTE vs control subjects regardless of the ferritin levels. The
sole exception in results was when a ferritin cut-off point of
Olsen has probably best summarized the situation in an
15 μg/L was used, in which case there was a significant dif-
older commentary (2005) titled: “Iron deficiency and
ference between premenopausal women with FPHL
hair loss: the jury is still out.” [68] Truly, data so far are
(p = 0.004), CTE (p = 0.024), and control subjects [61].
conflicting, there are no definitive answers, and a
Park et al. [65] conducted a retrospective chart review on
causal link between Iron, ferritin levels, and AGA/
female patients with FPHL (n = 113), male patients with
FPHL has not been yet proven.
AGA (n = 97), and 210 healthy controls, screening serum
ferritin, Iron, and total iron-binding capacity. Their study
demonstrated the first direct comparison between hair loss
patients and the same number of healthy controls matched by 67.8 Topical Iron
age and sex. No less than 82.3% of FPHL patients had serum
ferritin <70 μg/L (vs 15.23% in controls), and 46.9% of Regarding the topical use of Iron on the scalp, reports are
FPHL patients had serum ferritin <30 μg/L (vs 0% in con- limited yet very interesting, and all studies have tested the
trols). Mean serum ferritin concentration was lower in hair growth effects of Ferrous Ferric Chloride (FFC). FFC is
patients with FPHL (49.27 ± 55.8 μg/L), compared with a distinct form of aqueous Iron composed of a complex of
normal healthy women (77.89 ± 48.32 μg/L) (p < 0.001) and ferrous chloride that participates in both oxidation and reduc-
male AGA patients showed considerably lower serum ferri- tion reactions.
tin on the average (132.31 ± 72.1 μg/L) than age-sex matched The earliest study was published by Hirobe [69] and
healthy controls (210.92 ± 53.22 μg/L), although the serum showed that FFC stimulated the proliferation and differentia-
level of FC is within the normal range [65]. tion of cultured keratinocytes, melanoblasts, and melano-
More recently, Trüeb et al. [66] published an article titled cytes derived from newborn mice [69]. In subsequent studies,
“Autistic-Undisciplined Thinking in the Practice of Medical Hirobe added different commercial drinks comprising of
Trichology”. They argued that the practice of uncritical iron FFC, vinegar, vitamins, herbal medicines, and low molecular
supplementation in women complaining of hair loss is to be weight collagen (Pairogen® Akatsuka Co., Tsu, Japan) to
rejected both as unnecessary and as potentially detrimental culture media and tested for their proliferation-stimulating
[66]. They also presented the findings of King et al. to support activity on skin cells. Results suggested that FFC markedly
that there is the possibility that increased iron storage could stimulated (two- to threefold increase) the proliferation of
enhance oxidative injury by inducing the Fenton reaction, human skin fibroblasts, keratinocytes, and melanocytes, syn-
with the perspective of increasing the risk of cardiovascular ergistically with low molecular weight collagen [70, 71].
disease and cancer. In an attempt to demonstrate the pro-oxi- In subsequent in vivo studies, FFC-containing skin lotions
dative capacity of oral iron supplementation, King et al. had (FFC Super Essence Plain Type® and FFC Super Essence
performed a study on women with low iron stores (plasma Moisture Type®, Akatsuka Co.) were painted on the dorsal
ferritin ≤20 μg/L) receiving a daily iron supplement for skin of newborn C57BL/10JHir (B10) mice and resulted in
8 weeks at a level commonly used to treat poor iron status. stimulation of proliferation and differentiation of keratino-
They measured increased lipid peroxidation by ethane exha- cytes, fibroblasts, and melanocytes in the skin. In addition,
lation rates and plasma malondialdehyde. The women served hair loss these mice normally exhibit from 2 to 3 weeks after
as their own controls as pre- and postsupplementation periods birth was inhibited, and hair growth was stimulated [72].
were compared. After 6 weeks of iron supplementation, However, no safe conclusions may be drawn by this publica-
serum ferritin almost doubled, and body iron more than dou- tion, because both FFC solutions contained numerous ingre-
bled, hemoglobin levels increased slightly, and other indica- dients of botanical origin, such as rosemary oil, grape seed
tors of Iron status developed into normal. However, plasma oil, and jojoba oil, which might also have affected hair growth.
malondialdehyde and breath ethane exhalation rates increased As an example of extreme “scientific originality”, the
by >40% between baseline and 6 weeks of supplementation. same researcher has studied whether FFC can stimulate their
These increases correlated significantly with plasma iron and proliferation and differentiation “from a distance”, without
ferritin levels. The authors concluded that the increased indi- being added into culture media or painted on the skin. FFC-
cators of lipid peroxidation as iron status improved suggest containing skin lotions were painted under the culture dishes
392 67 Iron (Fe+2)
(1 mm away from cells) or on the top of the covers of 1–5 whereas tannins (found in tea and coffee), phytates (found in
polystyrene culture dishes (1–5 cm away) and tested for their bran, cereal grains, flour, legumes, nuts, and seeds), and cal-
proliferation- and differentiation-stimulating effects. Hirobe cium (found in dairy products and many over-the-counter ant-
reported that the lotions stimulated the proliferation and dif- acids) will inhibit iron absorption [7, 84]. Interestingly, unlike
ferentiation of human keratinocytes, melanocytes, and fibro- other iron absorption inhibitors, calcium might reduce the
blasts from a distance of 1 mm to 1 cm through physical bioavailability of both non-heme and heme iron.
factors rather than chemical factors [73].
Moreover, topical use of Iron has been reported to promote
However, the effects of enhancers and inhibitors of
hair follicle growth when combined with 5-aminolevulinic
iron absorption are attenuated by a typical mixed west-
acid (5-ALA), a compound widely used in photodynamic
ern diet, so they have little impact on most people’s
therapy. Ishino et al. [74] have demonstrated that 5-ALA
Iron status [7].
alone restores hair growth and prevents hair loss. However,
the phototoxic effect of 5-ALA may lead to the loss of hair
shafts if patients are exposed to sunlight daily [74]. In order to
deal with this problem, 5-ALA has been combined with iron In the United States, Canada, and many other countries,
salts and urea, and the admixture was applied to the scalps of wheat and other flours are fortified with Iron [85].
20 male patients with AGA every night for 1 month. The Fortification of foods with Iron is more challenging than
application time was limited to 2–5 h at night, patients were with other nutrients, such as iodine in salt and Vit A in cook-
instructed to wash their scalp afterward, and results were pub- ing oil. The most bioavailable iron compounds are soluble in
lished by Tanaka et al. [75] in a non-indexed paper. The water or diluted acid but often react with other food compo-
authors reported accelerated hair growth without providing nents to cause off-flavors and color changes, fat oxidation, or
any further data [75] and even decided to patent the com- both [86]. Thus, less soluble forms of Iron, although less
pound [76]. Morokuma et al. [77] tested the hair growth effect well absorbed, are often chosen for fortification to avoid
of a 5-ALA and iron ion admixture on mice. They reported unwanted sensory changes [6].
that it produced a significant impact on hair growth compa-
rable to the hair growth effect of 5% Minoxidil Topical
Solution (MTS). They noted that the hair growth in vivo was 67.10 Dietary Recommendations
not caused by any direct effect on the keratinocytes of the
outer root sheath or dermal papilla cells [77]. Intake recommendations for Iron and other nutrients are pro-
vided in the Dietary Reference Intakes (DRIs) developed by
the Food and Nutrition Board (FNB) at the Institute of
67.9 Food Sources Medicine (IOM) of the National Academies [7].
Recommended daily allowance (RDA) for an adult male is
Dietary Iron has two primary forms: heme and non-heme. 8 mg, for teenage girls is 15 mg, for premenopausal women
Plants and iron-fortified foods contain solely non-heme Iron, 18 mg and for pregnant or breastfeeding women 27 mg. A
whereas meat, seafood, and poultry contain both heme and balanced diet can easily provide the necessary daily Iron
non-heme iron [78]. since the human body efficiently recycles hemoglobin for the
The richest sources of heme iron in the diet include lean iron content [3]. Adequate intake (AI) is 6 mg, and the toler-
meat and seafood [7, 79], from which Iron is also highly bio- able upper intake level (UL) is 45 mg for all ages and both
available. Heme iron, found in meat, poultry, and fish, has a sexes. Vegans and vegetarians are at higher risk for ID, as
bioavailability of approximately 30%, meaning that 30% of their requirements for dietary Iron are considered to be 1.8
ingested heme iron is absorbed [80]. Non-heme iron, found times higher than for omnivores [7].
in plants and iron-fortified foods, has a bioavailability of less
than 10% [81]. Dietary sources of non-heme Iron include
beans, nuts, dark-colored vegetables (e.g., parsley and spin- 67.11 Deficiency- Excess of Iron
ach) dried figs, and fortified grain products [7].
About half of dietary Iron comes from bread, cereal, and Approximately 1.5 mg of elemental Iron is absorbed from
other grain products in the United States [7, 82, 83]. The aver- the average diet daily, but in patients with ID, the body com-
age bioavailability of Iron is 14–18% from mixed diets pensates by further increasing absorption. Although
(including substantial amounts of meat, seafood, and Vit C) improved diet and overall nutrition are preferable to isolated
and 5–12% from vegetarian diets [82, 84]. Vit C (found in replacement of any micronutrient, iron absorption from
large amounts in citrus fruits, broccoli, and cauliflower) foods may be inadequate to restore iron stores, and targeted
enhances Iron’s bioavailability by up to 50%, especially if supplementation is usually necessary. Once the presence of
ingested Iron is of plant origin [80]. In addition to Vit C, meat, ID has been established, iron supplementation should be
poultry, and seafood can enhance non-heme iron absorption, prescribed.
67.11 Deficiency- Excess of Iron 393
Iron has been used to treat anemia for more than 300 years. and constipation. These can occur in 15–20% of patients with
However, it was not until the nineteenth century when Pierre oral iron therapy and may render oral therapy intolerable for
Blaud introduced ferrous sulfate that eventually became the some individuals [17]. Alternatives include using extended-
standard treatment for IDA [87]. In order to maximize release iron preparations, liquid iron preparations, ferrous
absorption, for the treatment of IDA, the Centers for Disease salts with lower elemental iron contents, and taking iron tab-
Control and Prevention recommend 50–60 mg of oral ele- lets with meals [17, 81, 91]. Also, gradually increasing the
mental Iron daily. dose or intaking with food may minimize gastrointestinal side
effects. Other forms of supplemental Iron, such as heme iron
polypeptides, carbonyl iron, iron amino-acid chelates, and
Since the amount of Iron absorbed from a dose increases
polysaccharide-iron complexes, might cause fewer gastroin-
with increasing doses, the overall daily dose should be
testinal side effects than ferrous or ferric salts [7, 92].
divided, when possible, into 2–3 doses daily since
Iron can also be given parenterally, as intramuscular (IM)
absorption is lower in higher doses [9, 12]. Notably,
and intravenous (IV) preparations. Both may be necessary
Iron in doses higher than 100 mg will accumulate in the
for patients who cannot tolerate oral Iron and those with
liver and other organs, with toxic effects [88].
continued ID, despite adequate oral therapy, such as patients
with gastrointestinal or genitourinary bleeding, malabsorp-
tion conditions, or both. It is best to avoid IM Iron because
Iron prescribed for medical reasons should be obtained of the local pain at the injection site and the risks of scar-
from a known source that adheres to good manufacturing pro- ring, and the potential relationship to sarcoma development
cesses (GMP). Because of its higher solubility, ferrous Iron in [93].
dietary supplements is more bioavailable than ferric Iron [7,
83]. The ferrous salts, including ferrous sulfate, ferrous fuma-
Although very few clinicians will prescribe IV iron
rate, and ferrous gluconate, are all equally tolerated and effec-
with trepidation, newer compounds for IV use, includ-
tive, according to studies [89, 90]. Of these, ferrous sulfate is
ing ferric gluconate, iron sucrose, and low-molecular-
the most economical and is widely recommended as a first-
weight iron dextran, are very safe. They are associated
line treatment [81, 89–91]. Since only approx. 10–30% of the
with a very low rate of adverse events when compared
oral dose of Iron is absorbed, the recommended dosage of
with older products, such as high-molecular-weight
50–60 mg of oral elemental Iron corresponds to 325 mg fer-
iron dextran [94].
rous sulfate and should be usually administered for
3–6 months until iron stores are replenished. This is a simple
and inexpensive scheme to help rebuild iron stores.
Other authors recommend higher starting dosages, usu- Monitoring iron status and duration of therapy is impera-
ally prescribing ferrous sulfate 300 mg (60 mg of elemental tive, mostly to avoid iron overload. The hemoglobin concen-
Iron) 3–4 times daily [17, 81, 91], generally resulting in iron tration should be checked at a minimum of 4 weeks after
absorption of ≥150 mg/day in an iron deplete patient [17]. starting oral iron supplementation therapy. If a patient with
Some experts advise taking 250 mg of Vit C along with fer- IDA is administered ferrous sulfate 300 mg (60 mg elemen-
rous salts to enhance absorption instead of increasing tal iron) 3–4 times daily, the hemoglobin concentration
ingested iron amount [81]. All these regimens can be modi- should rise by 2 g/dL after 4 weeks [81, 89]. If the rise in
fied as appropriate. Other strategies to enhance iron absorp- hemoglobin concentration is less, this may be attributed to
tion include drinking tea and coffee 1–2 h after a meal rather poor compliance, malabsorption, a coexisting cause of ane-
than during, eating foods with high Vit C content during mia in addition to IDA, or continued blood loss. If there is an
meals, and consuming dairy products as snacks rather than appropriate response in hemoglobin concentration after
during meals. 4 weeks, oral iron supplementation should be continued until
Iron in food is mostly ferric Iron and is most soluble and the repletion of normal hemoglobin levels, usually evident
best absorbed below a pH of 3. Accordingly, ferrous salts by 3 months. Therapy should be continued for 6 months to
should be given on an empty stomach and should not within replace iron stores fully [17, 81]. If iron stores, hemoglobin,
2 h of any of the inhibitors of iron absorption mentioned ear- or both have not normalized within 3–6 months, new or con-
lier [17, 81]. Fortunately, ferrous Iron found in oral iron sup- tinued blood loss should be considered.
plements is soluble even at a pH of 7 or 8 and is more readily Iron is available in many dietary supplements. Multivitamin/
absorbed than diet ferric ions [81]. This may be important in multimineral supplements with Iron, especially those “designed
patients with an altered gastric environment, such as in for women”, typically provide 18 mg/d of Iron (100% of the
Helicobacter Pylori infection, gastric atrophy, or achlorhy- RDA) [7]. Multivitamin/multimineral supplements for men or
dria, commonly affecting the elderly [91]. The most common seniors frequently contain less or no iron. Iron-only supple-
complication of oral ferrous salt therapy is gastrointestinal ments usually deliver more than the RDA, with some providing
upset, including abdominal pain, bloating, nausea, vomiting, as much as 65 mg of Iron (360% of the RDA). In 1997, the
394 67 Iron (Fe+2)
FDA began requiring oral supplements containing more than 1. A uniform definition of ID, which may be diagnosed by
30 mg of elemental Iron per dose to be sold in single-dose blood tests done in the absence of iron supplementation,
packaging with strong warning labels [7, 95]. 2. A reliable screening test and a scientific consensus for the
Typically, iron homeostasis is achieved through gastroin- use of this test to prove deficiency/insufficiency of Iron,
testinal absorption changes, and Iron is notably lost through 3. Evaluation of ID in women, with clearly defined types of
sweat, shed epidermal cells, gastrointestinal and menstrual hair loss, with the recording of multiple necessary vari-
blood loss. However, the human body cannot regulate iron ables for sorting-out of related diseases or interpretations
excretion [96], and long-term unnecessary iron supplementa- for iron insufficiency,
tion in healthy individuals can lead to acquired hemochroma- 4. Larger tested groups and respectively larger control
tosis [46]. groups that take into account all these variables,
One of the most significant potential side effects of iron 5. Well-controlled therapeutic studies, which include objec-
supplementation is iron overload, which can cause tissue tive measuring tools for hair growth, such as target area
damage or fibrosis, and should be avoided. According to the hair counts or phototrichogram in women with docu-
Institute of Medicine, the upper limit of iron intake for men, mented ID and hair loss, both before and after the correc-
pregnant and non-pregnant women 18 years of age or older tion of the deficiency,
is 45 mg/d [7]. Adults with normal intestinal function have a 6. Generous funding.
minimal risk of iron overload from dietary sources of Iron
[82]. However, acute intakes of more than 20 mg/kg iron All of the above are necessary to demonstrate any relat-
from supplements or drugs can lead to iron overload and tox- edness, let alone causality, between ID and hair loss. We
icity. These may present with gastric upset, constipation, should also consider all these factors that may affect the
nausea, abdominal pain, vomiting, and faintness, especially result, both in the control group and the disease in ques-
if food is not taken simultaneously [7, 82]. The mechanism tion, independently [45]. For instance, in the case of
of iron toxicity involves the production of free radical spe- women with hair loss and ID, it is wise to evaluate their
cies that can oxidize a wide array of lipids and proteins. This nutritional status, while one should consider the following
eventually leads to tissue damage and fibrosis [97]. There is variables, in both groups, that could affect iron status [
also some evidence that high dietary iron intake in normal 100–104]:
individuals may lead to an increased risk of colorectal can-
cer, especially in the proximal colon [96, 98]. In case the • Age,
physician suspects iron overload, the definitive test is a liver • Menses: quantity, frequency, etc.,
biopsy. • Recent pregnancy or abortion,
• Diet: except for Iron and the essential amino acid l-lysine,
in healthy individuals, nutrition plays a minor role in
67.12 Future Challenges patients with unexplained CTE. However, those who
selectively avoid certain foods or fail to eat well may
The effort to correlate Iron with hair loss in both sexes is develop ID post-facto, like in the case of hair-loss induced
exceptionally complicated, and it remains unclear whether depression,
isolated ID causes hair loss or whether iron supplementation • Iron supplements, including “hidden” Iron in contracep-
is helpful in hair loss. tive pills,
• Concurrent medical conditions or drugs that may lead to
blood loss, such as systemically administered steroids,
What we do know, however, is that low Iron or low fer-
anticoagulants, NSAIDs, etc.,
ritin levels are neither a cause of hair loss per se nor a
• High zinc intake in supplements, consumption of large
prerequisite for hair loss.
amounts of tannins from tea or coffee, Mg+2 or Ca+2 sup-
plementation, together with iron supplements, may all
result in iron insufficiency.
This is evident because no more than 30–35% of women
in the United Kingdom, USA, and Japan who complain of Each of these variables may alter lab test results and
increased hair shedding actually have low iron levels, while explain the partially increased risk for ID in the hair loss
most women, even the ones suffering from IDA, do not lose group. All these variables should be compared to those of
their hair [99]. properly matched control subjects.
According to Olsen [68], to fully determine the interrelat- Nevertheless, proving whether replenishing iron stores is
edness of ID and hair loss, the following would be necessary: beneficial in these patients or not will depend on the results
67.14 Author’s Notes 395
for iron administration in patients with hair loss and low fer-
Observational studies conducted until 2021 are exten- ritin, who do not have established IDA [106].
sive and well-designed, but the number of the require- Nevertheless, since the “threshold theory” seems to have
ments mentioned above have not been met in any a valid point, it is probably wise to have a target-value of fer-
study, precluding a cause-effect relationship between ritin set at 70 μg/L for women who present with hair loss.
hair loss and ID. This does not mean that one should attribute the hair loss to
low iron stores per se, but ensuring that iron levels are ade-
quate will probably give the best chances for higher efficacy
of iron supplementation therapy performed in a double-blind of the prescribed medical treatment, oral or topical [58, 63].
controlled manner in otherwise healthy women with hair loss
due to FPHL or TE and serum ferritin levels >10 μg/L. This
type of study is still painfully missing. 67.14 Author’s Notes
67.13 Conclusions So Far • The only lab work the author requests when a female
patient visits his practice is blood count, ferritin, and sedi-
Physicians should remember that humans, either by evolu- mentation rate. Most women do not have thyroid or any
tionary pressure or “intelligent design”, are built to make other hormonal imbalances, and one can avoid unneces-
blood at the expense of hair when nutrients are scarce [105]. sary expensive tests. Measurement of the erythrocyte
sedimentation rate and CRP may indicate when ferritin is
likely to be elevated as an acute phase reactant.
Although not yet proven, there is a prevailing view that
• The author has yet to encounter a premenopausal woman
hepcidin upregulation diverts Iron from nonessential
with hair loss of any etiology who has a ferritin >70 ng/
tissues, such as the hair follicle, to support the essential
mL, so practically all his premenopausal patients with
iron requirements of vital tissues in some women.
hair loss will get a prescription for supplemental Iron
combined with Vit C for enhanced absorption.
• The author will not prescribe treatment with MTS, Low-
Consequently, when presented with a woman with hair Level Laser or other unless ferritin is >40 ng/mL; results
loss, simple blood count, including serum ferritin concentra- are usually disappointing when ferritin levels are too low,
tion, CRP and erythrocyte sedimentation rate, should be rou- and it is hard to convince patients to remain on treatment
tinely requested. Naturally, the decision for this should be if their initial experience is negative.
based on the doctor’s medical judgment. Until today, there is • Many women will have impressive results by replenish-
still not enough proof to fully justify general screening for ing their iron stores alone, even without any hair growth
iron levels in patients with hair loss, and data is insufficient treatment (Fig. 67.1)
Fig. 67.1 40-year-old female patient with extensive FPHL and and 3 intravenous injections of a total of 2.5 g of Iron, she has already
depleted iron stores—Ferritin 6 ng/mL—who was treated 5 years ago regained enough hair not to want further topical treatment
with a bad hair transplant by a “hair transplant clinic”. After 6 months
396 67 Iron (Fe+2)
• Intravenous iron loading is hugely efficient, saves months Vanadium, and Zinc : a report of the Panel on Micronutrients.
Washington, DC: National Academy Press; 2001.
of oral treatment, and, when administered by a
8. Beard JL. Iron biology in immune function, muscle metabolism
Hematologist under supervised conditions, is very toler- and neuronal functioning. J Nutr. 2001;131(2S-2):568S–79S.
able and safe. It can be a bit more costly, but some patients 9. No authors. Recommendations to prevent and control iron defi-
are willing to pay a small price to avoid several months of ciency in the United States. Centers for Disease Control and
Prevention. MMWR Recomm Rep. 1998;47(RR-3):1–29.
oral iron supplementation.
10. Brittenham GM. Disorders of iron metabolism: iron deficiency
and overload. In: Hoffman R, editor. Hematology: basic principles
and practice. 3rd ed. New York: Churchill-Livingstone; 2000.
Synopsis p. 397–428.
11. World Health Organization. Worldwide prevalence of anemia
So far, having low iron stores has been considered a possible
1993–2005: WHO global database on anemia. World Health
contributing factor in hair loss in women. However, a direct Organization; 2008.
relationship between ferritin levels and hair loss has not been 12. Centers for Disease Control and Prevention (CDC). Iron defi-
confirmed. It remains a matter of debate since it is very ciency— United States, 1999-2000. MMWR Morb Mortal Wkly
Rep. 2002;51(40):897–9.
complicated to clarify a cause-effect relationship between
13. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson
hair loss and iron deficiency (ID). Another difficulty in deter- CL. Prevalence of iron deficiency in the United States. JAMA.
mining the interrelatedness of ID and hair loss is the variable 1997;277(12):973–6.
definition of ID used in published studies. The lack of con- 14. Fogelholm M. Inadequate iron status in athletes: an exaggerated
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sensus on the threshold level for ID and lack of proof that
erals and electrolytes. Boca Raton: CRC Press. p. 81–95.
reversing the deficiency reverses the hair loss precludes the 15. Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpet
statement that ID is a causative factor in adults with AGA/ for iron metabolism. Cell. 2017;168(3):344–61.
FPHL, chronic telogen effluvium, or diffuse alopecia. So, it 16. Green R, Charlton R, Seftel H, Bothwell T, Mayet F, Adams B,
Finch C, Layrisse M. Body iron excretion in man: a collaborative
remains unclear whether isolated ID causes hair loss or
study. Am J Med. 1968;45(3):336–53.
whether iron supplementation helps hair loss patients. 17. Adamson JW. Iron deficiency and other hypoproliferative ane-
Therefore, even though assessment of serum ferritin levels is mias. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo
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matologists commonly prescribe iron supplementation in
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Copper (Cu)
68
metal ion to its specific targets [5]. Consequently, Cu remains

Basic Concepts firmly bound to proteins ceruloplasmin and metallothionein
• Copper (Cu) is essential to all living organisms [6, 7], with these carriers binding 90–95% of Cu.
because it is a key constituent of essential enzymes. Free Cu is not exchangeable in vivo, prohibiting Cu ions
It is involved in numerous electron transfer pro- from being involved in chemical reactions unless needs are
teins, including superoxide dismutase and the cyto- markedly increased, as in the case of local or systemic
chrome-C oxidase respiratory enzyme complex. inflammation [8]. The remaining 5–10% of the Cu amount in
• Cu has been reported to effectively inhibit both the body is associated with albumin and low-molecular-
5α-R isotypes in vitro, to amplify the actions of weight components, such as l-histidine, being chemically
prostaglandin PGE2, and it is involved in the tyrosi- active [9].
nase enzyme, which plays a crucial role in melanin
production and hair pigmentation.
• Copper concentration in hair and serum differ 68.1 Actions of Copper
between hair loss patients and healthy controls, but
a causative correlation has not been reported, and Copper proteins have various and diverse roles in biological
since Cu deficiency is very rare, there indication for electron transport and oxygen transportation processes.
Cu supplementation in hair loss patients is These proteins exploit the straightforward interconversion of
debatable. Cu(I) and Cu(II). As a result, Cu plays a vital role in many
proteins that react with oxygen and in numerous electron
transfer proteins.
The biochemical role of Cu is mostly catalytic, being a
Copper is a transition metal with the symbol Cu and atomic cofactor in numerous metalloenzymes, acting as oxidases to
number 29. It is an essential trace element in all known reduce molecular oxygen [10]. Many Cu metalloenzymes
organisms and is found in all human body tissues, with the have been identified in humans using the dual redox states of
highest concentrations measured in the liver and brain [1]. Cu(I) and Cu(II) and their relatively facile interconversion,
Cu is mostly present in biological systems as cupric form under physiological conditions, in oxidation-reduction
(Cu++), although several distinct types of the bound cation cycles. Examples of cellular processes that depend on Cu
can be found in Cu-containing enzymes, often in combina- include the mitochondrial aerobic metabolism. Cu is the cen-
tion within a single protein. Nearly two-thirds of the body Cu tral metal ion of cytochrome C oxidase, catalyzing the reduc-
content (80–120 mg) are located in muscle and skeleton, but tion of oxygen to water, which is the essential step in cellular
studies with isotopes have shown that the liver is a principal respiration [11]. Another Cu enzyme, lysyl oxidase, is vital
site in maintaining plasma cu concentrations [2]. in cross-linking collagen and elastin, both required for the
Free, ionic Cu is toxic and maintained to minimum formation of connective tissue [12].
required levels for the normal function of cells. It is mostly Cu is also necessary for iron metabolism and hemoglobin
undetectable and estimated at concentrations <10−18 M inside synthesis, the formation and maintenance of myelin and is
cells [3]. In order to minimize the probability of unbound involved in the formation of melanin pigment in the skin,
(free) Cu from participating in redox reactions and to ensure hair, and eyes [13], while it is the catalyst of superoxide dis-
delivery of Cu ions to specific target, proteins intermediaries, mutase (SOD) [14]. Copper notably plays an indispensable
the Cu chaperones, tightly bind Cu ions [4] and deliver the role in the physiology of the human central nervous system.
400 68 Copper (Cu)
Cu is also a cofactor of dopamine-β-hydroxylase, peptidyl- Mussalo-Rauhamaa et al. found statistically significant

α-monooxygenase, superoxide dismutases, and many other differences between the serum Cu content in AA, Alopecia
enzymes. It is a critical contributor to catecholamine biosyn- Totalis, and Alopecia Universalis patients [32]. Jin et al.
thesis, activation of neuropeptides and hormones, protection (1998) determined the contents of Zinc, Cu, Iron, and
against reactive oxygen species (ROS), respiration, and other Manganese in the hair of AGA patients and 38 hair-healthy
processes essential for normal CNS function [15]. men. The results showed that the hair zinc and manganese
Acute and chronic inflammation will alter Cu metabo- levels in AGA patients were significantly lower than in hair-
lism. Cu and ceruloplasmin concentrations increase signifi- healthy men, whereas the hair Cu level in AGA patients was
cantly in inflammatory diseases, and Cu-based products are substantially higher than in hair-healthy men (p < 0.05) [33].
particularly useful in acute and chronic inflammatory dis- Naginiene et al. (2004) found increased levels of Cu and
eases [16, 17], although their mode of action remains unclear chromium in the hair of 80 children with (undefined) alope-
[18, 19]. cia compared to healthy individuals [34]. Bhat et al. (2009)
assessed the levels of Zinc, Cu, and Magnesium in the serum
of 50 AA patients (34 men and 16 women) and 50 controls
68.2 Copper and the Hair Follicle and reported that serum Cu levels are not altered in AA com-
pared to controls [35].
Copper is crucial for the enzymes required for oxidation of Skalnaya et al. (2011) conducted a clinical and laboratory
thiol groups to dithiol- cross-links, which are essential for study on 153 women with FPHL and 32 female controls and
keratin fiber strength [20]. Consequently, Cu deficiency has demonstrated that the level of Cu in the frontal areas was
been linked to hair disorders in certain rare conditions: in similar in both FPHL and control groups (12.7 μg/g and
children with a rare autosomal-recessive malabsorption dis- 12.6 μg/g, respectively) and that it was higher in the occipital
order, Menkes kinky hair syndrome, hypopigmented hair, area of the FPHL group compared to the control group. The
and pili torti are typical [21]. Acquired Cu deficiency result- occipital level of Cu positively correlated with the concentra-
ing in hypopigmented hair can also be seen in premature tion of free Testosterone in the serum in the FPHL group.
babies, in inadequate cow milk intake, or total parental nutri- The authors hypothesized a crucial role of Cu metabolism
tion and after a long-term Zinc therapy [22]. Other actions of disturbances in the onset, development, and potential phar-
Cu on the hair follicle involve the tyrosinase enzyme [23], maceutical targets for the treatment of FPHL [36]. Amirnia
which plays a crucial role in melanin production and hair et al. (2013) conducted a small study in Iran, measuring the
pigmentation [24, 25]. Fatemi et al. have hypothesized that Cu and Zinc in the serum and hair on 27 patients with AA, 27
because copper plays an important role in melanin forma- patients with AGA, and their findings were compared with
tion, a low serum copper concentration may play a role in 27 controls. The mean Cu contents of hair and serum were
premature graying of hairs [26]. significantly lower among patients with AA (7.91 ± 2.72 μg/
Interestingly, other properties that have also been attributed dL) and AGA (7.25 ± 2.5 μg/dL), compared to controls
to Cu might have indirect effects on hair follicles. Sugimoto (10.34 ± 2.3 μg/dL) (p < 0.05) [37].
et al. reported that 5α-Reductase isotype I was strongly inhib- Dastgheib et al. (2014) investigated the relationship
ited by Cd, Cu, and Zn with IC50 values of 0.9, 1.9, and 2.0 μM, between AA and levels of iron, zinc, and Cu in the serum and
respectively. In contrast, 5α-R isotype II activity was inhibited hair of 16 female patients with AA and 27 healthy controls
only by Cu, with an IC50 value of 19.2 μM [27]. Cu has been and reported no statistically significant difference [38]. Kil
reported to reduce DHT production in homogenates of the et al. (2013) evaluated zinc and Cu serum concentrations
human prostate with benign hyperplasia [28]. Moreover, Cu between 30 health controls and 312 patients who were diag-
has been proposed to amplify the action [29] of prostaglandin nosed with AA (n = 94), AGA (n = 84), FPHL (n = 77), and
PGE2, which, according to early studies, has cytoprotective telogen effluvium (n = 47). In all hair loss patients, the mean
effects and induces follicular stem cell activation, follicular serum zinc was significantly lower than in the control group
cell proliferation, and hair growth [30]. More recently (2012), (84.33 ± 22.88 vs. 97.94 ± 21.05 μg/dL, p = 0.002), whereas
low levels of PGE2 and high levels of PGD2 in balding hair the serum Cu was not significantly different between groups
follicles have been strongly correlated with AGA pathophysi- (96.44 ± 22.62, p = 0.975). The analysis of each group
ology [31] (see Chap. 11, Vol. 1). showed that all groups of hair loss had statistically lower
zinc concentration, but not Cu concentrations [39].
Many researchers have correlated Cu and diffuse hair Ozturk et al. (2014) evaluated the levels of zinc and Cu in
loss, alopecia areata (AA), and AGA/FPHL for decades. hair, serum, and urine samples of 116 Turkish males with
Laboratory or clinical studies offered conflicting AGA and compared them to those of 100 healthy controls.
results, which can probably be explained based on sam- Both zinc and Cu hair levels were reduced significantly in
ple size, methodology, and population variation. AGA patients (p < 0.05), although zinc and Cu levels of
serum and urine did not differ between groups (p > 0.05)
68.2 Copper and the Hair Follicle 401
[40]. Overall, a meta-analysis by Jin et al. investigating the

association between serum level of Zinc, Cu, Iron/Ferritin,
Selenium or Magnesium, and AA on 10 eligible articles
involving 764 subjects concluded that there was no signifi-
cant difference between the AA patients and controls in the
levels of serum Cu (p = 0.81) [41].
However, none of these studies correlates Cu with hair

loss of any kind in a causative manner, nor does any
study claim that Cu supplementation would have any
positive effect on hair loss.
The topical use of Cu products in the form of Cu-tripeptides

allegedly having hair growth potential is reviewed in Chap. 44.
Copper readily penetrates intact human skin in vivo [42]. In
contact with skin, Cu will oxidize and may penetrate the stra-
tum corneum after forming an ion pair with skin exudates
[43]. Other effects of Cu on human hair include the occasional
occurrence of “green hair” (chlorotrichosis) after swimming
in pools containing high levels of Cu [44], more frequent in
individuals with preexisting structural hair damage [45]
(Fig. 68.1). The source of exogenous copper in chlorotrichosis
commonly is water flowing through copper pipes or swim-
ming pools rich in chlorine and copper-containing algaecides
[47]. The acidity of tap water, usually caused by decalcifica-
tion systems, is thought to cause the release of copper from the
pipes. The low pH of the water facilitates copper solubility,
while the high pH within the hair facilitates copper precipita-
tion, which is quickly followed by adhesion to anionic mole- Fig. 68.1 Green hair (chlorotrichosis) is a very rare and unusual hair
disorder occurring after exposition to a pool containing a very low con-
cules within hair shafts. Therefore, it is postulated that
centration of copper (0.9 ppm). Greening of the hair does not occur
chlorotrichosis may persist in insufficiently rinsed hair with after systemic absorption of copper. (From Trüeb [46])
residual alkaline shampoo [48].
402 68 Copper (Cu)
68.3 Food Sources inhibits copper absorption, resulting in zinc-induced copper

deficiency [54]. A significant 20% of Cu deficiency cases
The best sources of Cu include several types of legumes, have unknown causes.
whole grains, nuts, and seeds. Sesame seeds, cashews, and Copper deficiency is accompanied by anemia-like symp-
soybeans are considered excellent vegetable sources of Cu, toms and abnormalities in glucose and cholesterol metabo-
together with leafy greens, including turnip greens, spinach, lism. Normocytic, hypochromic anemia, leukopenia, and
kale, asparagus, and mustard greens. Other natural sources neutropenia are typical [53], whereas neurological symp-
of Cu are cereals, mushrooms, coffee, chocolate, and nuts, toms of Cu deficiency are similar to those of Vit B12 defi-
while water from copper pipes may contain large amounts of ciency (fatigue, anorexia, mood disorders) and are not easily
the element. reversible [55]. Typical skin signs include premature hair
Cu content in foodstuff varies according to local condi- graying, hair loss, and dermatitis with skin hypopigmenta-
tions. Soil Cu concentration, slurry/manure spreading, use of tion [56].
Cu compounds as bactericides or fungicides on crops, and The long-term toxicity of Cu is not well studied in
Cu emissions from smelting and casting industries may humans, but it is rare in general populations not having some
affect the Cu content in cereals, fruit and vegetables, and, to hereditary defect in Cu homeostasis [10, 50]. Familial rela-
a lesser extent, meat and animal products [49]. However, tionships and genetic factors are required for the expression
despite those variations, food groups such as offal and nuts, of liver toxicity from high levels of Cu intake, and Cu is only
and to a lesser extent, cereals and fruit, are regarded as excel- one factor needed for the expression of these diseases [10,
lent sources of Cu, while milk and dairy products contain 57]. Cu homeostasis is generally well-maintained with effec-
low amounts. tive regulatory mechanisms, and Cu toxicity resulting from a
disruption in the homeostasis of Cu, which is affected by the
interaction among zinc, Cu, iron, and molybdenum, is asso-
68.4 Dietary Recommendations ciated with tissue damage and a number of diseases which go
beyond the scope of this chapter [58]. Also, the level of
The recommended dietary allowance (RDA) for adult men dietary protein, interacting cations, and sulfate all can influ-
and women is 900 μg/day. The median intake of Cu from ence the absorption and utilization of Cu [59]. These disease
food in the United States is approximately 1.0–1.6 mg/day states are most often linked to the role of Cu as a redox-
for adult men and women [10]. Adequate intake (AI) is set at active transition metal that may initiate oxidative damage
220 mcg, and the tolerable upper intake level (UL) for adults [60].
is 10,000 μg/day (10 mg/day), a value based on protection Chronic Cu toxicity does not commonly occur in humans
from liver damage as the critical adverse effect [50]. because of efficient transport systems that regulate absorp-
tion and excretion. Excess copper in the body may result
from eating acidic foods cooked in uncoated copper cook-
68.5 Deficiency- Excess of Copper ware intended to be used for specific culinary tasks, such as
preparing preserves or meringues. Otherwise, copper cook-
Cu is involved in a myriad of biological processes. As a con- ware is lined with a nonreactive metal to prevent contact
sequence, the full range of clinical features resulting from between acidic foods and structural copper element of the
perturbations in the activities of cuproenzymes means that cookware [46].
although severe Cu deficiency is relatively straightforward to Another source of chronic excess Cu is drinking water
diagnose, identifying marginal deficiency is problematic containing a high concentration of copper salts from copper
[49]. water pipes. This can result from low water pH, presence of
Most diets contain enough Cu (1–5 mg/day) to prevent a chelating agents, or connection of electrical ground wires to
deficiency and not enough to cause toxicity. Frank Cu defi- copper water pipes, which causes sufficient flow of electrical
ciency in humans is rare but has been found in several excep- current to ionize the metal [46]. Excessive intake of Cu is
tional conditions [10]. It has been observed in premature associated with nausea, fatigue, behavioral disorders,
infants fed with milk formulas, in infants recovering from decreased immunity, joint pain, liver damage that can even
malnutrition associated with chronic diarrhea and fed cow’s lead to cirrhosis [61].
milk [51], and in patients with prolonged total parenteral Copper transport proteins can be disabled by autosomal
nutrition [10, 52]. Other predisposing conditions are gastric recessive mutations, and when the amount of copper in the
bypass surgery and bariatric surgery [53] and long-term or liver overwhelms the proteins that bind it, it causes oxidative
excess zinc supplementation since excessive zinc intake damage through a process known as the Fenton reaction.
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Zinc (Zn)
69
Zinke (prong, tooth), and it is meant “toothlike, pointed or

Basic Concepts jagged,” since metallic zinc crystals have a needle-like
• Zinc is a structural component of more than 1000 appearance.
zinc-associated transcription factors and serves as In 1869, Raulin et al. [2] were the first to report that Zn
the active center for approximately 300 metalloen- was essential for the growth of the fungus Aspergillus niger.
zymes in the human body, contributing to cellular Later, it was shown to be an essential nutrient for microor-
growth and development, wound healing, immune ganisms, plants, and animals; for rats and mice in the 1930s
function, and collagen synthesis, among many other and pigs in 1955 [3]. However, the history of our recognition
functions. of the significance of zinc in human nutrition and, even more
• Zn is found in enzymes with significant actions in so, in clinical medicine and public health is remarkably brief,
hair follicles; it is a structural molecule of the especially given the pervasiveness of this mineral in biology
androgen receptor, is involved in androgen produc- [4]. Actually, the essentiality of zinc for humans was only
tion, is a potent in vitro inhibitor of caspases and Zn recognized in 1961 by Prasad et al. [5]
deficiency affects the actions of ERK, Akt, Bcl-2 Between 2–4 g of zinc are distributed throughout the
and Bax pathways which are involved in follicular human body, and 85% of Zn is stored in the brain, muscle,
physiology. bones, kidney, and liver. The highest concentrations are
• There are numerous studies correlating zinc levels located in the prostate and the choroids of the eye [6]. In the
with Alopecia Areata, telogen effluvium, and AGA/ serum, Zn is bound mostly to albumin and in lower amounts
FPHL, but none has claimed causality, while only into at least another 12 proteins, such as α-microglobulin and
patients with hair loss attributed to Zn deficiency or transferrin [7]. The serum zinc concentration is tightly regu-
with low serum Zn levels might benefit from zinc lated through homeostatic mechanisms, and the amount of
supplementation. free Zn found in the serum is less than 1/1000 of the total
• The direct or indirect actions of Zn supplementation amount stored in the human body. Zinc concentration in cir-
on hair follicles in Zn replete individuals can be culation is maintained in a narrow range (10–15 μg/L),
contradicting since oral Zn administration might despite widely diverse dietary intakes of this metal and dif-
increase serum Testosterone and DHT levels and ferences in bioavailability of intake sources [8].
even exacerbate hair loss in AGA/FPHL due to the
biphasic mode of action of Zn; therefore supple-
mentation must be cautious and precise. 69.1 Actions of Zinc
Zinc is involved in multiple aspects of cellular metabolism,

and since no specific receptors for zinc ions have been identi-
Zinc is a chemical element with the symbol Zn and atomic fied so far, it is reasonable to assume that zinc interacts with
number 30. In the periodic table, Zn belongs in group IIb, numerous proteins and signal transduction pathways. The
along with toxic heavy metals such as Cadmium and zinc atom has an impressive ability to participate in strong
Mercury. Yet, zinc is relatively non-toxic for humans and liv- but easily exchangeable ligand binding. The remarkable flex-
ing creatures in general [1]. ibility of zinc’s coordination geometry allows proteins to use
The element was probably named by the alchemist Swiss- it to shift conformations rapidly to perform biological reac-
born German alchemist Paracelsus after the German word tions. Both these properties have proved to be extraordinarily
406 69 Zinc (Zn)
useful in biological systems [9] and enzymes with a zinc

atom in the reactive center are widespread in biochemistry. Zn is also necessary for the production of androgens
The incorporation of zinc into mammalian biological sys- from the adrenals and testicles, as well as for steroid
tems has been further facilitated by the lack of redox proper- metabolism in general [21]. Additionally, it is essential
ties of the zinc atom, which, in contrast to copper and iron, for male fertility, spermatogenesis, and male pheno-
allows its utilization without the risk of oxidant damage [10]. type [22] since Zn is a structural molecule of the
Zinc is so ubiquitous in subcellular metabolism that it is an androgen receptor, which has two zinc finger domains
essential component of the catalytic site or sites of at least [23, 24].
one enzyme in all six enzyme classes [11]. Overall, zinc is a
structural component of more than 1000 zinc-associated
transcription factors, including DNA-binding zinc finger Notably, zinc’s role in the development and progression
proteins, and serves as the active center for approximately of prostate malignancy and its potential application in the
300 metalloenzymes in the human body [12]. prevention and treatment of prostate cancer are issues that
The biological functions of zinc can be divided into three have not been answered fully [25, 26], but the details go
categories [13], namely catalytic, structural, and regulatory: beyond the scope of this chapter.
1. Catalytic: Zn is an efficient Lewis acid, making it a use-

ful catalytic agent in hydroxylation and numerous other 69.2 Zinc and the Hair Follicle
enzymatic reactions, acting as an electron recipient in
cellular reactions (e.g., RNA polymerase). Along with Of all tissues, the skin has the third-highest abundance of
copper, they are integral parts of SOD enzymes [14], zinc in the body, after the choroid of the eye and the prostate.
2. Structural: Zn serves a purely structural role in “zinc The epidermis has a higher zinc concentration than in the
motif fingers”, forming parts of transcription factors, dermis, probably due to a zinc requirement for the active pro-
which are three-dimensional proteins that recognize DNA liferation and differentiation of epidermal keratinocytes [27].
base sequences during the replication and transcription of Some of the enzymes for which zinc serves as the active
DNA [15], center, such as carbonic anhydrase, superoxide dismutase,
3. Regulatory: Zn acts as a regulatory molecule during the dopachrome tautomerase, metallothionein, and various
replication of DNA and the expression of genes [16]. It is metalloproteases, exert significant actions in the hair follicle
also an essential element for the activation and matura- [28–30]. One typical example is alkaline phosphatase, a
tion of T-lymphocytes [17] and a crucial regulator of cel- zinc-dependent enzyme with elevated activity in highly pro-
lular apoptosis. liferative tissues, such as the hair follicle [31]. However, the
exact mechanism of zinc’s effect on the hair follicle is mostly
Consequently, zinc contributes to cellular development and unknown, and Plonka et al. in their seminal study, described
growth, immune functions, wound healing, skin metabolism several biological considerations that render it quite likely
(especially collagen synthesis), the functional regulation of that zinc has indeed hair growth-modulatory properties [32]:
the central nervous system, maintenance of retinal functions
(through participation in Vit A metabolism), in taste and 1. Zn is a potent inhibitor of endonucleases, critical constit-
olfaction, saliva production and secretion, production, and uents of the apoptotic process [33]. Given the crucial role
viability of sperm, prevention of carcinogenesis and aging of keratinocyte apoptosis in the hair follicle regression
(participation in scavenging superoxides), maintenance of during catagen [34], Zn-mediated inhibition of endonu-
gonadal functions and pregnancy (involvement in the synthe- clease activity is a leading candidate for an inhibitor of
sis and secretion of sex hormones), glucose metabolism (par- hair follicle regression.
ticipation in the synthesis and action of insulin) and lipid 2. The effect of Zn on cellular apoptosis seems to be ambig-
metabolism [18]. uous and to have pro- and anti-apoptotic properties,
Interestingly, the most characteristic biochemical func- depending on its concentration, even along the same cel-
tion of Zn in humans is in the male reproductive system. The lular line [35, 36]. Zinc is a potent in vitro inhibitor of
normal human (and other mammalian) prostate gland’s pri- caspase-3, caspase-6, caspase-7, and caspase-8 [37, 38].
mary functional and metabolic activity is its unique accumu- Zn deficiency may, on the contrary, stimulate cellular
lation of high zinc levels. These are required for the apoptosis, disturbing the action of chemical molecules
production and secretion of extremely high zinc citrate levels ERK and Akt [39] or may act anti-apoptotically, activat-
as a major prostatic fluid component [19, 20]. ing Bcl-2 and Bax mitochondrial proteins, increasing the
69.2 Zinc and the Hair Follicle 407
fraction of Bcl-2/Bax and consequently enhancing cellu- ship may explain the known increased DHT content in pros-
lar resistance to apoptosis [40]. tatic tissues with high zinc concentrations [60]. Leake et al.
3. Zn cations are essential components of zinc finger motifs [61] suggested a possible physiological role for regulating
for numerous transcription factors and steroid hormone Testosterone (T) metabolism by zinc in the human prostate
receptors [41] that have long been considered as funda- gland.
mental hair growth regulators, such as androgens [42],
ΑP-2 [43], and the product of the hairless gene [44, 45].
The role of Zn in the “zinc finger domain” of transcrip- Interestingly, their results showed that Zn exhibits a
tional factors of Gli transcription factors superfamily has biphasic effect on the activity of the 5α-R enzyme fam-
been proved to play a vital role in the Sonic hedgehog ily. At low concentrations of zinc (300 nM), it signifi-
(Shh) cellular signaling pathway responsible for cellular cantly increased DHT formation compared to
proliferation, differentiation, and survival [46]. The experiments performed in the absence of added zinc,
expression of Gli1 and Gli2 has been found in the human while, at high concentrations, 3, and 300 mM, the con-
epidermis and the outer root sheath [47], while the version of T to DHT was significantly inhibited [61].
involvement of Shh transcription factors in the morpho-
genesis and growth of the hair follicle has been shown in
numerous individual studies [48–50]. This decrease was mediated by both a non-competitive
4. Zn inhibits the expression or activity of numerous inhibition of T’s binding to 5α-R and a reduction in the
enzymes crucial for the hair follicle, such as tyrosinase NADPH cofactor formation. The data also suggested that the
(the rate-limiting enzyme of melanogenesis in the hair increase in T metabolism observed at low zinc concentra-
follicles [51]) and iNOS [52]. tions does not produce any changes in Testisterone’s binding
5. Additionally, Zn is essential for the stability [53] and to the 5α-R enzyme.
repair of DNA [54, 55], parameters of obvious impor- Arreola et al. [62] reported that plasma concentrations of
tance in hair biology, since the epithelial hair matrix is zinc, prolactin, T, and DHT were lower in nine young males
one of the most rapidly proliferating and most damage- aged 14–19 years suffering from insulin-dependent diabetes
prone tissues in humans [56]. than in controls. In contrast, the ratios of androstenedione to
6. In view of the increasing insight into immunological con- T and DHT were higher, suggesting a diminished conversion
trols of hair growth [57], Zn may also affect the human of androstenedione to T and relating Zn to the
hair follicle through its known, dose-dependent, immuno- 17-β-hydroxysteroid dehydrogenase enzyme activity [62]. In
modulatory effects [6, 58]. their study on foreskin samples, Stamatiadis et al. [63] tested
the effects of Azelaic acid (AzA), zinc sulfate (ZnSO4), and
Additionally, zinc has been implicated in steroid endocrinol- Vit Β6 on the inhibition of 5α-R. At a concentration as low
ogy, and during the 1980s and 1990s, numerous researchers as 3 mmol/L, AzA inhibited 5α-R by 98%, while ZnSO4
published their findings on the relation of zinc and the required a concentration of 15 mmol/L to achieve a 98%
metabolism of androgens. Since the human prostate and the inhibition. When both compounds were combined, just
hair follicle share a common, double, embryonic background 0.5 mmol/L of AzA and 3 mmol/L of ZnSO4 were enough to
and share common biochemical pathways on how androgens achieve a 95% inhibition. Adding Vit Β6 (0.025%) to ZnSO4
affect them, some of the findings on prostate cells might be resulted in a twofold increase in the inhibition of the 5α-R
relevant for human hair follicles, as well. enzyme activity, whereas Vit Β6 alone or combined with
Wallace et al. [59] were the first to demonstrated that the AzA had no inhibitory effect. The additive effect of all three
increased Dihydrotestosterone (DHT) content in prostatic compounds, in concentrations that had no inhibitory activity
tissues treated with zinc eventually resulted in inhibition of when used alone (Vit Β6 0.025%, 0.1 mmol/L of AzA, and
the NADPH-dependent 5α-Reductase (5α-R) enzyme at high 0.5 mmol/L of ZnSO4) resulted in 90% inhibition of 5α-R
zinc concentrations. Later, many researchers focused their activity [63]. Notably, others have not replicated these inter-
efforts on understanding the biochemical roles of zinc in esting findings (see Chap. 33).
androgen metabolism [59]. Sinquin et al. [60] were the first Fahim et al. [64] reported a significant reduction of pros-
to note that a significantly increased quantity of 5α-reduced tate weight, of 5α-R activity, and total protein and DNA con-
steroids was measured when 0.1–2.0 mM zinc chloride was centrations in prostate tissue (p < 0.05) treated with
added in homogenates of human hyperplastic prostates. neutralized zinc (zinc arginine), without affecting spermato-
Additionally, the activities of 3α- and 3β-hydroxysteroid genesis [64]. Sugimoto et al. [65] assessed the possible dif-
dehydrogenases were inversely related to the concentration ferential effects of various cations on the two types of 5α-R
of zinc in the prostate preparations, and this inverse relation- in a human adrenal carcinoma cell line. Results showed that
408 69 Zinc (Zn)
5α-R type I was strongly inhibited by Cd, Cu, and Zn and 69.3 Zinc and Alopecias
moderately inhibited by Ni and Fe, with IC50 values of 0.9,
1.9, 2.0, 169.2, and 174.3 μM, respectively [65]. Hair loss in both rats [71] and mice [72] has been reported
Om et al. [66] reported that the hepatic conversion of T to due to zinc deficiency since the 1940s. Concerning effects in
DHT was significantly reduced and that the formation of humans, there is a widespread perception that zinc deficiency
estradiol from T was increased considerably in rats fed a may cause alopecia since hair loss is often a presenting sign
zinc-deficient diet compared with freely fed and pair-fed of zinc deficiency, along with a distinctive vesiculobullous
control rats. Rats fed the zinc-deficient diet had significantly dermatosis, mucosal findings, and diarrhea [73]. This can be
lower serum concentrations of luteinizing hormone (LH), true in specific conditions, such as in gastric by-pass surgery
estradiol, and T. These results indicated that zinc deficiency [74], severely malnourished children [75], and the extremely
reduced circulating LH and T concentrations, altered hepatic rare congenital skin disease acrodermatitis enteropathica.
steroid metabolism, and modified the levels of receptors of The latter, despite being well known among Dermatologists,
sex steroid hormones [66]. Prasad et al. [67] reported that few will have ever seen an actual case in their clinical carreer
dietary zinc restriction in healthy young men was associated [76].
with a significant decrease in serum T concentrations after Arguments that zinc deficiency can be a disturbing factor
20 weeks of zinc restriction. Also, zinc supplementation for for the growth of hair have been emerging since the 1980s,
6 months on marginally zinc-deficient normal older men and in the scientific literature, there are studies correlating
increased serum T, concluding that zinc may play an essen- zinc levels with Alopecia Areata (AA), telogen effluvium,
tial role in modulating serum T levels [67]. Jalali et al. [68] and AGA/FPHL.
investigated the effect of 250 mg/day of zinc sulfate supple- As early as 1976, Wolowa et al. reported the results of
ment therapy for 6 weeks, on the serum levels of T, follicle- treating 284 patients [42 with AA, 106 with Alopecia Totalis
stimulating hormone (FSH), LH, and prolactin, in 100 (AT), and 136 with Alopecia Universalis (AU)] for up to
hemodialysis male patients. Serum levels of T, LH, and zinc 6 years, with Solvezink®, a formula containing zinc sulfate.
increased significantly but did not have a definite effect on In patients with AA, a state without relapse of 1–4 years was
hemodialysis patients with sexual dysfunction [68]. achieved in 42.8% of cases, and in AT and AU, maintenance
However, these effects of zinc on plasma T have not been therapy was necessary to ensure a permanent regrowth of the
confirmed in zinc-replete men. Koehler et al. [69] investi- hair [77, 78]. However, no objective hair growth measure-
gated whether the administration of a zinc-containing nutri- ment techniques were used, there are no before-and-after
tional supplement caused an increase of serum T levels on photos of patients in the article, and no independent or
fourteen healthy, regularly exercising men, aged 22–33 years, blinded researchers were employed to evaluate the claimed
eating a zinc-sufficient diet. According to the authors, no sig- results. A double-blind study was conducted by Ead [79] on
nificant changes regarding serum total and free T or the 42 subjects with AA, AT, and AU (38 completed it). There
metabolism of T were observed [69]. was no improvement in the extent or the activity of the dis-
Tsai et al. [70] reported that zinc chloride at a 200– ease in those individuals on the active drug compared with
500 nmol dose significantly increased the proliferation of placebo either by an objective or subjective assessment;
human follicle dermal papilla cells (HFDPCs) and the however, serum zinc levels and the zinc levels in hair were
expression of cell cycle regulatory proteins. The proliferative increased in the group on the active drug at the end of
activity in HFDPCs treated with 100–1000 nM zinc chloride 3 months [79].
was significantly enhanced, ranging from 20 to 175.6% com- Since those early reports, numerous studies on the effects
pared with the control cells. A dose-dependent decrease in of zinc in AA have been published and are splendidly sum-
anti-apoptotic Bcl-2 production was observed in HFDPCs marized in a recent (2017) review by Thomson et al. [80]
treated with zinc chloride. In contrast, the production of pro- According to this review, four out of six case-control studies
teins associated with the cell cycle decreased when the cells [81–86] have identified lower serum zinc levels in patients
were treated with 1000 nmol zinc chloride, and HFDPC with AA as compared to controls and serum levels also
death was induced. Increased levels of cell cycle regulators appear to be inversely associated with severity of the disease.
and the activated AKT and ERK decreased when HFDPCs However, oral zinc studies as a treatment for AA have yielded
were treated with a higher dose of zinc chloride, suggesting inconsistent results [79, 87–89], and the only double-blind,
that zinc can induce cell proliferation in a narrow dose range. placebo-controlled trial by Ead did not support supplementa-
Both the apoptotic Bax protein and caspase-3 increased in tion for patients with AA [79].
zinc chloride-treated HFDPCs. Moreover, the cell viability Currently, there is a paucity of evidence surrounding zinc
of HFDPCs decreased with higher doses of zinc chloride supplementation and AA, highlighting the need for addi-
even though cell proliferation increased with an equivalent tional, double-blinded trials with this essential trace element
concentration of zinc chloride [70]. as monotherapy in AA. Whether serum zinc levels should be
69.4 Zinc and AGA/FPHL 409
routinely assessed clinically is a question better answered and compared it with 100 healthy controls. They reported
with further investigation. Jin et al. [90], who investigated that zinc and copper levels in hair were significantly
the alterations of serum level of trace elements and AA using decreased in AGA patients (p < 0.05), although serum and
a meta-analysis approach, indicated that patients with AA urine levels were not different between AGA patients and
had a lower serum level of zinc (p < 0.0001) compared to controls (p > 0.05) [96]. In contrast, Siah et al. [97], who
healthy controls, suggesting that low serum levels of zinc conducted a retrospective chart review on 210 females with
seem to be important risk factors for AA [90]. FPHL and a mean age of 45.5 years, did not support the asso-
Concerning telogen effluvium, a study by Arnaud et al. ciation of low serum zinc and FPHL, as demonstrated in pre-
[91] showed no link with telogen effluvium and zinc [91] vious studies. According to their findings, the mean serum
whereas, Karashima et al. [92] published a series of five zinc level of their patient group was within the normal range,
patients with zinc deficiency-related telogen effluvium who and only 15% (23/149) of patients had low zinc levels on
were treated with oral zinc, and in all cases, hair loss their first visit [97].
improved [92]. Cheung et al. [93] performed a retrospective Aiempanakit et al. [98] conducted a cross-sectional case-
cross-sectional study of patients with telogen effluvium in control study on 114 participants, 27 males with AGA, 30
the greater Pittsburgh, Pennsylvania area. They demonstrated females with FPHL, and 57 age- and gender-matched con-
that the prevalence of Vit D, ferritin, and zinc deficiencies trols. Patients with AGA and FPHL had mean plasma zinc
were non-trivial, and therefore they justified including these levels lower than those in the control group, the difference
laboratory studies in initial clinical evaluation [93]. However, being statistically significant (56.63 ± 11.44 vs.
none of these studies reported a causative correlation between 63.47 ± 11.10 μg/dL, respectively, p = 0.002). When ana-
zinc and telogen effluvium. lyzed by gender, both males and females in the case group
had mean plasma zinc levels lower than the control group
(males: 59.40 ± 12.73, 64.81 ± 10.19 μg/dL, p = 0.09;
69.4 Zinc and AGA/FPHL females: 54.13 ± 9.69, 62.27 ± 11.89 μg/dL, p = 0.005) [98].
Siavash et al. [99] conducted a prospective, randomized con-
Concerning AGA/FPHL and zinc, minimal data is available, trolled trial in a total of 73 females with hair loss, aged
and all studies were published after 2011. Despite the incon- 15–45 years old, who participated in that 4-month study. The
clusive data, some authors claim that there is scientific evi- participants were randomized into four groups to receive co-
dence underlying the efficacy of an alternative approach in administration of zinc sulfate and calcium pantothenate (1
these conditions, including zinc [94]. zinc sulfate capsule and 1 calcium pantothenate tablet twice
Skalnaya et al. [95] conducted a clinical and laboratory a week), zinc sulfate (1 capsule/day), calcium pantothenate
study on 153 women with FPHL and 32 control women. (1 capsule/day), and 2% Minoxidil Topical Solution (MTS,
FPHL patients presented an increased copper content and 1 mL, b.i.d). Hair density increments were lowest for the
decreased magnesium, selenium, and zinc contents in the zinc group alone, then for calcium pantothenate, after that
occipital area of the scalp. A negative correlation between for the co-administration group, and was highest in the 2%
the zinc content in the occipital region and the dehydroepian- MTS group. In the co-administration group, hair count
drosterone level in the blood was found. In addition, the changes increased from 118.6 ± 9.9 hairs/cm2 to 121.9 ± 11.1
authors showed a regional variation in scalp hair zinc level hairs/cm2 (p = 0.042) whereas for the MTS 2% group they
with lower zinc content in the hair of the frontal area in com- increased from 120.1 ± 9.7 hairs/cm2 to 132.3 ± 10.5 hairs/
parison to the occipital region in women with FPHL [95]. cm2 (p = 0.001). Even though changes in the zinc plus cal-
Kil et al. [82] evaluated zinc and copper serum concentra- cium pantothenate group were clinically insignificant
tions between 30 health controls and 312 patients who were (3.3 ± 2.2 hairs/cm2), authors considered them “significant”
diagnosed with AA (n = 94), AGA (n = 84), FPHL (n = 77) and acknowledged as only limitations the short duration of
and telogen effluvium (n = 47). The analysis of each group the study and that the participants were not blinded to treat-
showed that all groups of hair loss had statistically lower ment [99]. Notably, there are no before-and-after photos of
zinc concentration, and in all patients, the mean serum zinc patients in the article, and no independent or blinded
levels were significantly lower than in the control group researchers were employed to evaluate the claimed results.
(84.33 ± 22.88 vs. 97.94 ± 21.05 μg/dL, p = 0.002). However, Dhaher et al. [100] conducted a case-control study on 55
this value was within the range of the reference value of the women aged 20–45 years, separated into a group of 27
measuring equipment in the study (70–130 μg/dL) and was women with FPHL and an age-matched control group of 28
higher than the concentration of 70 μg/dL, at which zinc healthy women group. The serum and hair zinc, and iron
supplementation usually is commenced. assays were done for all participants. Both hair and serum
Ozturk et al. [96] evaluated zinc and copper levels in hair, zinc levels in the FPHL group were significantly lower than
serum, and urine samples of 116 Turkish males with AGA that in the control group (103.4 ± 25.5 ppm vs.
410 69 Zinc (Zn)
143.5 ± 33.1 ppm for hair and 65.6 ± 14.2 μg/dL vs. cance of zinc levels in assessing the susceptibility of AGA
128.4 ± 41.4 μg/dL for serum, p > 0.05). The hair iron level patients to conservative therapy. Using a ≤ 10 μmol/L thresh-
in FPHL was significantly lower than in controls old concentration for the absence of an effect and > 10 μmol/L
(17.9 ± 3.8 ppm vs. 26.9 ± 7.4 ppm, p > 0.05). Serum iron for the positive effect, the positive predictive values, negative
level in the FPHL group was lower than in the control group, predictive values, and the integral indicator of the signifi-
but it was not significant statistically (88.9 ± 22.3 μg/dL vs. cance of Zn in relation to the ongoing conservative therapy
100.9 ± 18.9 μg/dL). The authors concluded that serum and were 88%, 55%, and 72.3%, respectively [104].
hair levels of zinc and iron were lower in FPHL patients Interestingly, despite results being inconclusive and
compared to that individuals, and except for hair iron, levels largely contradictory, Zn remains—after centuries of use—a
were not correlated with the severity of alopecia. They con- classic, adjunctive treatment for hair loss, possibly because it
sidered that their findings indicate that trace elements might is considered as an essential antioxidant of the skin, through
play an essential role in the etiopathogenesis of FPHL, but the production of SOD that might exert positive actions on
they did not produce any hypothesis to support a causative the hair follicles [105]. This rationale could probably date
link [100]. back to misinterpretation of in vivo results in mice, in which
El-Esawy et al. [101] conducted a case-control study on high-dose (but non-toxic) oral zinc is a powerful yet ambiva-
60 AGA patients and on 60 healthy volunteers who were age, lent hair growth modulator.
sex, and body mass index (BMI) matched. The serum zinc
level (μg/dL) was lower significantly in patients compared to
However, as Plonka et al. demonstrated in their semi-
controls (mean ± SD = 60.267 ± 10.817, 80.8 ± 6.47 respec-
nal study, the ultimate effects of oral zinc supplemen-
tively; p = 0.01), suboptimal biotin levels (μg/dL) were found
tation on the hair follicle mostly depend on the timing
in AGA patients while it was within normal values in con-
and duration of zinc administration as well as on the
trols (Mean ± SD = 339.4 ± 12.125, 532.82 ± 35.224, respec-
hair follicle status. Oral administration of Zn sulfate in
tively; p = 0.01). There was also a significant positive
mice led to the inhibition of normal or chemotherapy-
correlation between serum zinc and serum biotin (p = 0.001)
induced catagen, the acceleration of subsequent ana-
but nonsignificant correlations as regards the AGA clinical
gen, and inhibition of hair growth by retardation of
grades, BMI, disease duration, or between serum zinc and
anagen initiation [32]. So, most probably, not only
patients’ age [101].
under physiological conditions but also during patho-
logical hair follicle cycling—the effects of zinc likely
Another speculated mechanism that Zn could affect depend strictly on the dose and duration of zinc action
hair growth in AGA/FPHL patients is through its role and are highly unpredictable.
in collagenase and matrix metalloprotease enzymes
[18] that could prevent perifollicular fibrosis in AGA
[102]. This mechanism of action has also been reported
69.4.1 Topical Use of Zinc
for Minoxidil [103] but has not been demonstrated for
zinc in vivo.
Zinc is routinely applied on the skin and scalp in the form of
zinc pyrithione, a coordination complex of zinc with fungi-
static and bacteriostatic properties [106], used in the treat-
Kondrakhina et al. [104] studied 48 patients with AGA, ment of seborrhoeic dermatitis. Zinc pyrithione shampoos
aged 18–55 years (range 26.2 ± 5.3) with early-stage AGA administered in patients with seborrheic dermatitis and tinea
(stages I–IV according to the Norwood–Hamilton scale). versicolor are effective and safe since the percutaneous
Patients were treated for 4 months, with 5% MTS, while absorption of pyrithione is minimal [107]. Zinc pyrithione
trace element and vitamin imbalances were corrected with also possesses keratolytic, and normalization properties on
oral supplements. Among the studied nutrient parameters the ultrastructure of stratum corneum [108], is not subject to
(Zn, Cu, Mg, Ca, Fe, and Se, as well as vitamins B12, E, D, tachyphylaxis, and maintains long-term efficacy [109].
and folic acid), differences between these groups were shown There is only one published study on the combined use of
in zinc content only. Baseline serum biochemical and micro- 5% MTS and 1% pyrithione zinc shampoo (PZS) in AGA
nutrient parameters in patients showed a different response treatment, authored by Berger et al. [110]. The study was a
to conservative therapy. The absence of a positive effect 6-month, 200-patient, randomized, investigator-blinded,
group comparison revealed a significant 25% decrease in Zn parallel-group, clinical study to assess the efficacy of a 1%
levels. At the same time, there was no difference in any other PZS (used daily), compared with 5% MTS (applied twice
biochemical parameters analyzed. The authors claimed that daily), a placebo shampoo, and a combination of 1% PZS
the results might indicate the possible prognostic signifi- and 5% MTS. Hair count results showed a significant
69.7 Deficiency- Excess of Zinc 411
(p < 0.05) net increase in total visible hair counts for the 1% 69.5 Food Sources
PZS, the 5% MTS, and the combination treatment groups
relative to the placebo shampoo after 9 weeks of treatment, Zinc is widely distributed in foods, and it is rarely present as
which later turned in favor of the 5% MTS group. The rela- a free ion. Rich sources of zinc are certain types of seafood,
tive increase in hair count for the 1% PZS was slightly less such as crab and lobster, with oysters containing many times
than half that for the 5% MTS and was essentially main- more zinc per serving than any other food. Red meat, poul-
tained throughout the 26-week treatment period, whereas no try, milk, and cheddar cheese provide most of the zinc in the
advantage was seen in using both the 5% MTS and the 1% American diet [118]. Other reliable food sources include
PZS. Assessments of global improvements by the patients beans, nuts, whole grains, fortified breakfast cereals, lentils,
and investigators generally showed the benefit of 5% MTS soy, spinach, fortified cereals, baked beans, and broccoli
whereas the benefit of the 1% PZS used alone was apparent [119].
only to the investigator. The lack of an additive benefit from Phytates present in whole-grain breads, cereals, legumes,
the combined use of MTS and 1% PZS was surprising, as the and other foods, chelate zinc and inhibit its absorption [120,
mechanisms of action would appear independent, and the 121]. Thus, the bioavailability of zinc from grains and plant
authors hypothesized that some shared benefit pathway pre- foods is lower than that from animal foods, although many
vented a combined benefit [110]. Only one pair of before- grain- and plant-based foods are still adequate zinc sources
and-after dermatoscopic photos at ×25 magnification are [119].
presented from a patient at baseline and after 17 weeks of
treatment.
Due to a lower bioavailability of zinc from plant-based
Baek et al. [111] investigated on 22 subjects (5 men and
foods, the dietary need for zinc in vegan populations is
17 women) the effects of the application of a commercially
50% greater than their respective dietary requirements
available shampoo containing 0.6% zinc pyrithione, 0.5%
in the general population [122, 123].
dexpanthenol, 0.1% nicotinamide, 0.5% triaminodil, and
0.17% Thujae Occidentalis semen extract vs. a placebo
shampoo. After 16 weeks, a mean change from baseline total
hair count of 3.4 hairs/cm2 (3.9%) was found in the 20
patients of the shampoo group, whereas a mean change from 69.6 Dietary Recommendations
baseline hair count of −0.8 hairs/cm2 (−0.9%) was found in
the 20 patients of the placebo group (p > 0.05 between the Intake recommendations for zinc and other nutrients are pro-
two groups) [111]. vided in the Dietary Reference Intakes (DRIs) developed by
Concerning other (indirectly) potentially beneficial the Food and Nutrition Board (FNB) at the Institute of
actions of topical zinc on AGA/FPHL patients, Pierard- Medicine of the National Academies [119].
Franchimont et al. have reported that the erythromycin-zinc Recommended dietary allowance (RDA) of zinc for an
complex significantly reduced sebum output [112, 113]. adult male has been set at 11–14 mg and for an adult female
Since the sebum contains high amounts of DHT, which can at 8–11 mg. The adequate intake (AI) is set at 9 mg, and the
be re-absorbed by the hair follicle and perpetuate the nega- tolerable upper intake level (UL) at 40 mg, a value based on
tive androgen effect on balding hair follicles, reducing sebum the reduction in erythrocyte copper-zinc superoxide dis-
output of scalp hair follicles with topical zinc compounds mutase activity.
could be beneficial (see Chap. 15, Vol. 1). Percutaneous
absorption of zinc varies depending on skin pH, zinc concen-
tration in the compound, and type of formulation [114, 115]. 69.7 Deficiency- Excess of Zinc
Zinc chloride can be irritative, unlike zinc oxide, which is
tolerable and results in more constant concentration on the Most adults in the United States consume the recommended
skin than other formulations [116]. The mean concentration daily amounts of zinc according to two national surveys, the
of zinc in human skin after application determined by dry third National Health and Nutrition Examination Survey
weight, atomic absorption spectrophotometry is 60 μg/g in (NHANES III) [124] and the 1994 Continuing Survey of Food
the epidermis, 40 μg/g in the upper dermis and reduces even Intakes of Individuals (CSFII) [125]. However, some evidence
further towards deeper layers [27]. suggests that zinc intakes among older adults might be marginal
Kanti et al., in their recent systematic review (Evidence- and that 20–25% of older adults have inadequate zinc intakes
based (S3) guideline for the treatment of androgenetic alope- [119, 126]. These results are not conclusive since zinc nutri-
cia in women and in men [117]), included two studies [110, tional status is difficult to measure adequately using ordinary
111] on zinc pyrithione which obtained level of evidence 2 laboratory tests [127] due to its distribution throughout the body
and grade of evidence B and A2 respectively [117]. as a component of various proteins and nucleic acids [128].
412 69 Zinc (Zn)
Even though plasma or serum zinc levels are the most

commonly used indices of zinc status, these levels do not
necessarily reflect cellular zinc status due to tight homeo-
static control mechanisms [119, 129]. Additionally, they may
be impacted by several variables, and clinical effects of zinc
deficiency may be observed in the absence of abnormal labo-
ratory indices [130]. Nevertheless, a systematic review by
Lowe et al. [131] confirmed that in healthy individuals,
plasma, urinary, and hair zinc are reliable biomarkers of zinc
status [131]. Most often, a presumptive diagnosis of zinc
deficiency can be made in the context of zinc-deficiency
symptoms, signs of malnutrition (e.g., underweight,
hypoalbuminemia), or conditions commonly associated with
zinc deficiency.
Fig. 69.1 Zinc deficiency (acquired acrodermatitis enteropathica):
Zinc deficiency may be either acquired or inherited, and
peculiar acral and periorificial dermatitis and alopecia with positive pull
since the deficiency conditions relevant in this chapter are test. (From Trüeb [142])
the acquired ones, details on these conditions will only be
presented.
The most common cause of acquired zinc deficiency is a dequate zinc to the infusates [138], and in women with high
insufficient uptake from food since no more than 20%–30% calcium intake for osteoporosis [139].
of dietary zinc is actually absorbed [132]. Dietary risk fac- Both deficiency and excess intake of zinc give delayed
tors include vegetarianism, as bioavailability of zinc is lower signs, and symptoms since zinc’s tight homeostatic mecha-
in vegetables than meat [122]. Vegetarians typically consume nisms prevent wide serum zinc concentration variations for
more legumes and whole grains containing phytates that weeks [140]. In zinc deficiency, the spectrum of clinical
bind to zinc and inhibit absorption from the intestinal tract signs and symptoms is broad, and nonspecific [130] and clin-
[122]. High phytate content in diet is the leading cause of ical manifestations associated with zinc deficiency arise pri-
zinc deficiency worldwide and was first identified in an marily from the cutaneous changes similar to those found in
Iranian population by Prasad et al. [5], with Prasad being acrodermatitis enteropathica [141]. Clinical manifestations
probably the most prolific researcher on the effects of zinc in of mild to moderate zinc deficiency in adults include male
human physiology. hypogonadism, diarrhea, glossitis, nail dystrophy, skin
In the last six decades, it has been found by Prasad (and a roughness, reduced appetite, lethargy, decreased immunity,
few other researchers) that minor zinc deficiencies are actu- sensory disorders, and diffuse hair loss presented as telogen
ally widespread in the developing world and affect more than effluvium. The extreme form of zinc deficiency (acroderma-
2 billion people worldwide [133]. Zinc deficiency caused by titis enteropathica) occurs only in end-stage alcoholics, in
malnutrition is the 11th major risk factor in the global distri- patients chronically treated with penicillamine (which che-
bution of disease burden and is associated with 1.8 million lates zinc and removes it from the circulation), or on long-
deaths annually [134]. Most of the affected individuals are term parenteral nutrition (Fig. 69.1). Also, in those who
poverty-stricken and rarely consume foods rich in highly suffer from the rare recessive hereditary disease acroderma-
bioavailable zinc while subsisting on foods rich in zinc titis enteropathica [143] due to mutations in the SLC39A4
absorption inhibitors and/or containing relatively small gene, which codes for a zinc-specific transporter [144].
amounts of bioavailable zinc [129]. Although the consequences of zinc deficiency have been
Other causes of zinc deficiency include sickle cell anemia recognized for decades, it is only recently that attention has
[135], malabsorption syndromes (sprue or inflammatory been directed to the potential consequences of excessive zinc
bowel disease), increased gastrointestinal losses (as in gas- intake. No data indicate adverse interactions between zinc
tric by-pass surgery [136]), increased urinary excretion [73] and other nutrients when zinc is found in food; however,
(as in liver cirrhosis, diabetes, nephrosis, renal failure, and adverse nutrient interactions are present after feeding zinc in
malignant tumors), and certain medications (drugs with che- the form of dietary supplements [119].
lating activity are >170 compounds, but most common are Chronic ingestion of zinc supplements up to the UI levels
diuretics [137], valproic acid, and penicillamine). Other con- (40 mg elemental zinc/day) is generally considered safe.
ditions of increased zinc metabolism include alcoholism, Manifestations of overt toxicity symptoms include head-
burns, infections, pregnancy, collagen vascular disease, and aches, metallic taste, nausea, vomiting, abdominal cramping,
anorexia nervosa. Also, zinc deficiency may present in and diarrhea [1, 119] and will occur only with extremely
patients on parenteral nutrition without the addition of high zinc intakes. Prolonged exposure to amounts greater
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“Alternative Medicine”, Herbs,
and Hair Loss 70
“There is no alternative medicine. There is only medicine that more than just to “treat” actual disease or symptoms, either
works and medicine that does not.”
Richard Dawkins together with prescription drugs (a strategy later named
“complementary medicine)” or on their own (simple “alter-
Alternative medicine is a misnomer because it suggests that native medicine”). More commonly, herbals were -and still
there are two kinds of medicine, alternative to each other. are- used to improve “quality of life and Well-being,” “sup-
However, the author trusts there is no such thing as conven- port natural healing,” “boost the immune system”, lose
tional/orthodox, alternative or complementary, integrative, weight, or even to enhance muscle growth in weight training.
or holistic medicine. There is one medicine, the one we have These commercial products generally consist of multiple
discovered through centuries of trial and error of saving lives herbal constituents bundled together, sometimes tied to an
and of increasing our evidence-based knowledge one step at assumption that if an individual product is thought useful, a
a time. combination will be even more so [2].
When someone wants to sell an idea, an opponent is
handy, especially if what he/she is selling cannot stand on its
The “hidden” truth is that the “alternative movement”
merit. This is how the term “allopathic” was coined by
is, actually, part of a societal trend towards the rejec-
Samuel Hahnemann, the creator of “homeopathy” and is still
tion of science as a method of determining facts.
in use as a derogatory sleight against mainstream medicine.
His followers are still only shadowboxing an invisible enemy.
Having said that, it is interesting to elaborate on the termi-
nology and “mindset” of complementary-alternative medi- Within the movement, it is also often asserted that “scien-
cine (CAM). tific medicine” is only one of a vast array of options in
healthcare [3]. Probably a more precise, actual “definition”
of the term “alternative medicine” is probably just this:
CAM is an umbrella term for multiple diagnostic and
Unsubstantiated attempt of therapeutic intervention.
therapeutic methods that lie outside “orthodox,” “con-
Furthermore, whether a given “method” exists for 5000
ventional,” or -correctly named- evidence-based medi-
years, whether it is believed, followed, or practiced by three
cine. Initially, the term “alternative medicine” was
billion people, all is irrelevant since it does not make it less
coined in the early 1970s when it came into general
or more likely to be valid, useful, or safe. It just means it is
use as part of the alternative lifestyle movement that
more resilient and fashionable. Popularity is no proof of effi-
originated in the U.S.
cacy. Far from it!
Alternative medicine is an excellent example of a “buzz- 70.1 Herbals and Botanicals in General
word,” which, according to the Merriam-Webster dictionary,
is “an important-sounding, usually technical word or phrase, Plants have been used since the dawn of humanity for medi-
often of little meaning, used chiefly to impress laymen” [1]. cal purposes, and fossil records date the use of plants as
In the mid-twentieth century, with the increasing appeal medicines at least to the Middle Paleolithic age, almost
of a holistic way of life, along with “alternative medicine”, 60,000 years ago [4]. Written records of the use of herbal
herbal products began to enter the field, namely those pro- medicine date back more than 5000 years, and in fact, for
duced by commercial entities. The public used herbals for most of history, herbal medicine was the only available med-
418 70 “Alternative Medicine”, Herbs, and Hair Loss
icine [5]. Even as recently as 1891, 59% of the

U.S. Pharmacopeia listings comprised of herbal products [6]. Even though there is no complete and official defini-
Moreover, plant and herbs or their derivatives formed the ori- tion of what exactly CAM is, the U.S. nation library of
gin of much of modern pharmacotherapy and continue to be medicine defines it as “…a group of diverse medical
a rich source for creating new pharmaceutical compounds. and health care practices and products that are not
Some estimate that as many as one-third to one-half of cur- presently considered to be part of conventional medi-
rently used drugs were derived initially from plants [7]. cine.” [14]
Fabricant et al. [8] identified 122 compounds of defined
structure, obtained from 94 species of plants, that are used
globally as drugs and demonstrated that 80% of these had According to other definitions (quoting) “alternative
had an ethnomedical use, identical or related to the current treatment means health-related treatment as practiced out-
usage of the active elements of the plant [8]. side the health service and is not performed by a licensed
Dozens of essential drugs have derived from herbals/ health care professional” [15]. Additionally, “when patients
botanicals in the past, including acetylsalicylic acid, quinine, use alternative therapies in addition to the treatment they
morphine, and other opioids, reserpine, colchicine, digitalis, receive at the hospital, it is also called complementary or
atropine, vinblastine, vincristine, ephedrine. There is cur- integrated treatment” [15].
rently an ongoing and vigorous effort to identify herbals that No matter what the exact definition is -if there can be
might yield chemicals with medicinal properties, especially one-, the use and acceptance of CAM have been steadily
for the treatment of various cancers [9]. Plant extracts or rising in Western countries [16]. Popular CAM approaches
their derivatives are used even today in traditional therapeu- include acupuncture; Ayurveda; biofeedback; chelation
tic systems, such as Chinese botanical medicine, Indian therapy; chiropractic care; energy healing therapy; special
medicine (Ayurvedic), or Japanese medicine (Kampo), while diets (including vegetarian and vegan, macrobiotic,
often enough, their use is integrated into “conventional med- Atkins, Pritikin, and Ornish); folk medicine or traditional
icine” in western countries [10, 11]. According to the World healers; guided imagery; homeopathic treatment; hypno-
Health Organization, as many as 90% of the African popula- sis; naturopathy; non-vitamin, non-mineral dietary sup-
tion, 70% of the Indian population, and 40% of the Chinese plements; massage; meditation; progressive relaxation; qi
population continue to depend on these traditional therapeu- gong; tai chi; or yoga [17]. There is something for every
tic systems and utilize herbals/botanicals for their primary “palate”!
health care needs and general healthcare [2, 12]. Eisenberg et al. [18] were the first to document the trends
These traditional therapeutic systems have flourished as and costs of CAM in nationally representative random
systems of medicine in use for thousands of years and are household telephone surveys in 1990 and 1997. They
still in place today because of their organizational strengths, reported a 47.3% increase in total visits to alternative medi-
and they focus primarily on multi-component mixtures. An cine practitioners, from 427 million in 1990 to 629 million
abundance of ethnomedical information on plant uses can in 1997, thereby exceeding total visits to all U.S. primary
be found in the scientific literature but has not yet been care physicians [18]. Alternative therapies were used most
compiled into a usable form. Undoubtedly, with the rapid frequently for chronic conditions, including back problems,
industrialization of the planet and the loss of ethnic cultures anxiety, depression, and headaches. Out-of-pocket expendi-
and customs, some of this information will disappear. tures relating to alternative therapies in 1997 were conserva-
Sadly, ethnomedical information collection remains an aca- tively estimated at $27.0 billion, which was comparable
demic endeavor of little interest to most industrial groups with the projected out-of-pocket expenditures for all U.S.
primarily [8]. physician services that same year [18]. The comparative
analysis of data from the 2002 and 2007 National Health
Interview Survey (NHIS) also revealed that approx. 38% of
70.2 Medicine and “Alternative Medicine” adults and 12% of children were using some form of CAM
for an array of diseases and conditions. Most alarmingly,
The progress and efficacy of modern, evidence-based medi- 72% of users did not inform their physicians about using
cine are impressive and undeniable in all fields. Additionally, CAM [19]. In Europe, according to the World Health
a growing number of essential discoveries offer a better qual- Organization, there are an estimated 100 million users of
ity of life and, most importantly, global life expectancy at CAM, and patients suffering from severe or chronic disease
birth has increased by 10.2 years since 1980 [13]. favor the use of CAM therapies [20]. Even in countries with
Nevertheless, for decades now, CAM has managed to get a universally accessible healthcare system such as Norway,
established in the collective conscience, and its popularity is more than a third of all patients with cancer use some form
steadily rising. of CAM [15].
70.4 Why Do Patients Prefer Herbs Over Drugs? 419
70.3 Medicine and Herbal …“Medicine” Astin, in his highly cited study (>3700 citations), investi-
gated the possible predictors of CAM use and tested three
Herbal medicine, phytotherapy, phytomedicine, ethnomedi- theories to explain their use [26]:
cine, herbal medicinal product, and dietary supplements are
all terms used interchangeably to denote the use of botani- 1. Dissatisfaction: Patients are not satisfied with conven-
cals in healthcare and fall under the large umbrella-term of tional treatment because it has been ineffective, has pro-
CAM [21]. Although many herbs are of historical interest duced adverse effects, is seen as impersonal, too
only, more than 20,000 herbal products are currently technologically oriented, and/or too costly [26].
available over the counter and commonly used by patients in 2. Need for personal control: Patients seek alternative thera-
the U.S. [22] According to a study by Barnes et al. [23] based pies because they see them as less authoritarian, more
on 31,044 interviews of U.S. adults >18 years of age, botani- empowering, and as offering them more personal auton-
cal dietary supplements had been used by 20% of the general omy and control over their health care decisions [26].
population in the preceding 12 months. Healthy individuals 3. Philosophical congruence: Alternative therapies are
used these products primarily for health maintenance, and an attractive because they are considered more compatible
even higher number of patients suffering from various dis- with patients’ values, worldview, spiritual/religious phi-
eases to treat their condition [23]. Adults >18 years of age losophy, or beliefs regarding the nature and meaning of
who used herbals were more likely to do so because they health and illness [26].
believed that CAM products “combined with conventional
medical treatments would help” (54.9%) and/or they thought Surprisingly, results showed that negative attitudes toward or
“it would be interesting to try” (50.1%) [24]. Unfortunately, experiences with conventional medicine were not predictive
in this survey, it was evident that patient-physician discus- of CAM use. Among those who reported being highly satis-
sion about the use of herbs and other CAM means was the fied with their conventional practitioners (54%), an impres-
exception rather than the norm. Less than 1/3 of adults sive 39% used alternative therapies, while 40% of those
(regardless of age, sex, ethnicity, education, or income) using reporting high levels of dissatisfaction (just 9% of respon-
herbs disclosed this practice to their licensed healthcare pro- dents) were users of alternative medicine [26]. Although
vider [24]. there was a trend in the direction of those desiring to keep
control in their own hands as more likely to use CAM, this
variable was also not a significant predictor.
70.4 Why Do Patients Prefer Herbs Over However, the results did provide strong support for the
Drugs? philosophical/value congruence theory in several ways.
Having a holistic philosophy of health (“…the health of my
According to Eisenberg et al. [25], who conducted telephone body, mind, and spirit are related, and whoever cares for my
interviews in a national sample of 1539 adults, educated, health should take that into account…”) was predictive of
middle-class, Caucasians, and between 25–49 years of age CAM use, suggesting that, in part, it may reflect shifting cul-
were the ones most likely to use CAM. Even though the fre- tural paradigms, particularly concerning recognizing the
quency of use of CAM varied among socio-demographic importance of spiritual factors in health [26]. Second, the
groups, it was not confined to any particular segment of the statement, “I had a transformational experience that causes
population, and the majority used CAM for chronic, as me to see the world differently than before,” also emerged as
opposed to life-threatening, medical conditions [25]. a significant predictor. The fact that only 4.4% (n = 45) of the
What makes CAM products so popular and attractive is sample was categorized as relying primarily on CAM sug-
still unknown. According to surveys, there is a general lay- gested that most individuals appear to use CAM in conjunc-
man perception that natural products/herbs/botanicals are tion with, rather than instead of, more “conventional
safer and cause less adverse effects than “synthetic treatment” [26].
pharmaceuticals.” Unfortunately, this holistic health philosophy is growing
even more popular. Is this correct?
Well, there is a lack of evidence for the efficacy and safety
Moreover, even though individuals using CAM treat- of most types of alternative methods for treatment and symp-
ments or products do not expect to be cured of any tom relief. For some of the alternative treatment methods,
severe condition or disease with CAM, they are still there is mostly evidence of adverse events [15]. Nevertheless,
more willing to use herbs than pharmaceuticals. the global botanical supplements market size was valued at
17.74 billion $ in 2017 [27].
70.5 Just How Effective Are Herbs Clinical efficacy may be overestimated if an intention to treat
Actually? analysis is not done.
The efficacy of herbal products could theoretically be tested

And this is precisely what happens with most of the
in clinical trials with protocols similar to those used when
RCTs who have reported positive results since finding
synthetic drugs are tested. However, many methodological
a CAM RCT with intention-to-treat analysis is still
and practical challenges cannot be surmounted.
impossible [34].
Unlike modern drugs, a herbal product is not supposed to
exert its physiological action through a single mechanism,
but its action is -allegedly- multifaceted, reflecting “compo-
sitional plurality”. Another important aspect is that the majority of CAM
RCTs reporting positive effects for treatments are usually
published in “specialist” CAM publications that exist to pub-
The so-called “art of herbal medicine” (supposedly)
lish scientific evidence for -and rarely against- a particular
involves a complex therapeutic intervention in which
therapy. While these “positive” results from systematic
the mild effects of single natural interventions or sev-
reviews may reflect the specific efficacy of the respective
eral plant ingredients are built into an efficacious, indi-
treatments, other factors may also be involved.
vidualized therapeutic regimen [28].
One of these factors is the tendency of the authors to sub-
mit and editors to publish “positive studies”, working on the
strength and direction of the results, a phenomenon recog-
Clinical experience shows that this approach is applicable nized in mainstream medicine and coined “publication bias”.
for a wide range of conditions but remains to be proven Pittler et al. [30] systematically investigated publication bias
through scientific inquiry. Although a growing science-based in the literature on CAM by assessing the direction of RCTs’
literature supports the efficacy of individual herbs and outcome, their methodological quality, and sample size in
defined herbal combinations, evidence for the efficacy of relation to the type and impact factor of the journals of pub-
individually-prescribed herbal combinations is scarce. lication [30]. They confirmed that publication bias was evi-
Experts are justifiably skeptical; yet, laypeople are convinced dent in no-impact or low-impact factor CAM journals, even
of the therapeutic value of herbs and botanicals. at the pre-submission stage. Most likely, this resulted from
the author’s self-censorship of negative findings, or bias at
the review stage, resulting from editorial and commercial
70.6 Challenges in Studying the Efficacy pressures to show positive treatment effects. They reported
of Herbs that no- or low-impact factor CAM journals preferentially
accepted positive trials even when they were methodologi-
The frequent use of CAM by the general population is paral- cally poor. This phenomenon is less apparent in the main-
leled by the expanding scientific information published in stream literature, which is not CAM specific and accepts
specialized journals. Several herbs have proven to be effec- reports of trials on a wide range of therapies. High-impact
tive when tested in vitro on lab animals and have even given factor mainstream medical (MM) journals publish equal
positive results in small-scale clinical trials [29], but a much numbers of positive and negative trials of CAM therapies.
higher number of studies have reported negative results [30]. Interestingly, Pittler et al. found that positive trials were of
Moreover, the methodological quality of randomized con- lower quality than negative trials in the CAM journals, sig-
trolled trials (RCTs) in most areas of CAM is highly vari- nificantly so in non-impact factor journals and even in high-
able. The majority has significant shortcomings in reporting impact factor MM-journals. A significant difference in
and/or methodology, while the intention to treat approach is quality was observed between positive and negative trials,
inadequately described and ineptly applied [31]. which suggests that bias in favor of positive treatment out-
Intention-to-treat analysis is a strategy for analyzing ran- comes at the expense of quality exists even among respected
domized controlled trials that compare patients in the groups scientific journals [35, 36].
to which they were initially randomly assigned. This is gen-
erally interpreted as including all patients, regardless of
whether they actually satisfied the entry criteria, the treat- 70.7 Are Herbal Supplements Actually
ment actually received, and subsequent withdrawal or devia- Safe?
tion from the protocol [32]. The intention-to-treat analysis is
a principle espoused by U.S. FDA regulatory and scientists Many consumers believe that since herbal and botanical
at the National Institutes of Health (NIH) as the most appro- products are of natural origin, they are automatically safe or
priate criteria for assessing the utility of a new therapy [33]. safer than synthetic pharmaceuticals. However, this is a false
70.8 The Legal Status of Herbals and Botanicals 421
assumption and a dangerous oversimplification. In reality, authentication and quality control are at least required in
there are many instances and several different reasons that most markets, regulation varies considerably.
the exact opposite can be true. In the U.S., the FDA regulates drugs, food additives,
The sad truth is that botanical products are related to dietary supplements, and dietary ingredients. The pre-market
severe adverse effects. approval process for food additives and pharmaceuticals is
tedious and expensive, requiring rigorous testing of the prod-
uct’s safety. The FDA carefully reviews all evidence before
Inherent toxicity, inconsistent levels of active ingredi-
any new product is introduced into the market.
ents leading to accidental overdose, contamination
Unlike pharmaceuticals and food additives, botanical
with pesticide or herbicide residues, heavy metals, or
dietary supplements are not characterized as pharmaceutical
microbes, use of the incorrect part of the plant, mis-
substances but as food supplements. Therefore, they are not
identification of the plant species incorporated into the
subject to the current legislation applicable to pharmaceuti-
product, and interactions with prescribed medication
cals. These products are not subject to the quality or toxicity
the patient is already taking, are just a few of the things
controls within the strict framework applicable to pharma-
that can go wrong with herbal manufacturing and con-
ceutical products but based on the status applicable to food.
sumer intake [37].
They do not require premarketing approval by the FDA
unless drug-like efficacy is claimed, and the manufacturers
of botanical supplements are not required to provide rigorous
Given that herbal products are heterogeneous mixtures of scientific evidence of safety or efficacy. They are only
active substances, their use can result in side effects or required to provide information to support their labeling
severe adverse reactions. Unfortunately, the actual fre- claims. Furthermore, the safety of botanical dietary supple-
quency of these effects for most herbs is unknown because ments remains the manufacturer’s responsibility, determined
nearly none has been tested in large clinical trials and primarily through “self-regulation”. Until December 2006,
because surveillance systems are much less extensive than when the President of the USA signed the Dietary Supplement
those in place for pharmaceutical products. A review con- and Nonprescription Drug Consumer Protection Act. S.
ducted by the U.S. Office of the Inspector General con- 3546, manufacturers were not even obliged to inform the
cluded that surveillance systems designed to detect adverse FDA on reports or complaints about adverse effects related
reactions to herbs are inadequate and probably detect less to their products [43]. Overall, when it comes to herbs and
than 1% of all events [22, 38]. Additionally, since conven- botanicals, the FDA’s role in safety assurance is limited to
tional drugs and herbals are often used concomitantly by post-marketing monitoring of adverse effects [44].
patients, this can lead to clinically relevant herb-drug inter- In the E.U., botanical dietary supplements are regulated
actions. To date, several clinically important drugs have either as drugs or as food supplements. If therapeutic claims
been identified to interact with commonly used herbs [39]. are made, then evidence of safety and efficacy for these
These include warfarin, midazolam, digoxin, amitriptyline, botanical dietary supplements is required. If a product is a
cyclosporine, omeprazole, and verapamil, most of which mixture of botanicals with a long history of human use, in
have narrow therapeutic indices substrates for cytochrome that case, it is termed as a “traditional herbal medicinal
P450s (CYPs) [40]. For further information, the interested product” and is subject only to safety and quality require-
reader can refer to the review of the available literature by ments, as in the U.S. [44, 45] when botanical dietary supple-
Hu et al. (2005) on herb-drug interactions with clinical sig- ments are marketed for health maintenance or promotion, or
nificance [41]. To appreciate how common this problem is, when health claims are made, then the E.U. regulates them
a clinical survey by Bush et al. [42] found that 15% of as food supplements, and evidence of efficacy must be pro-
patients receiving conventional pharmacotherapy also take vided [44, 46].
herbal products and, among these, potential adverse herb- In response to concerns regarding botanical integrity and
drug interactions were observed in 40% of patients [42]. quality assurance, the FDA recently instituted the require-
The main inherent reason is the low quality of botanicals, ment that botanical dietary supplements under its jurisdic-
which are insufficiently regulated. tion be prepared using “good manufacturing practice”
(GMP) [44, 47, 48]. These guidelines complement the adver-
tising and labeling regulations required by the U.S. Federal
70.8 The Legal Status of Herbals Trade Commission [49] and are similar to those in effect in
and Botanicals the E.U.. Enforcement of these regulations is helping to
ensure that consumers can purchase accurately labeled
Inadequate quality control of herbal products is not surpris- botanical dietary supplements that are not contaminated with
ing. The use of botanical dietary supplements worldwide has heavy metals, pesticides, herbicides, or microbes. However,
increased rapidly since the 1980s. Even though botanical these regulations do not require testing botanical dietary
supplements for potential adverse interactions with prescrip- macological efficacy [50]. The U.S. Pharmacopeial
tion drugs, nor do they require evidence of efficacy [44]. The Convention (USP) has, since its inception in 1820, provided
possibility of overdose is also an issue since studies to estab- guidance on standardization of botanical dietary supple-
lish maximum tolerated dosages and safe long-term chronic ments and USP monographs on many botanicals are avail-
dosages are not required and are rarely carried out. Therefore, able, including procedures to facilitate standardization and
the safety and efficacy of most botanical dietary supplements botanical authentication [51].
lack documentation, which concerns many health care However, herbals vitally differ from pharmaceutical
providers. drugs; whereas prescription drugs are manufactured in a con-
According to van Breemen (quoting), “to ensure a safe sistent and chemically standardized fashion, the production
and effective product, botanical dietary supplements should of herbals, whether traditional crude or commercial, cannot
be developed in a manner similar to that of pharmaceuticals. duplicate the same manufacturing procedures to ensure con-
This involves identifying mechanisms of action and active tent identity [2]. In many instances, commercial herbal prod-
constituents, chemical standardization based on the active ucts do not even contain the labeled species; other times,
compounds, biological standardization based on pharmaco- they have significant variations in total content or contain no
logical activity, preclinical evaluation of toxicity and poten- measurable active ingredient, with labeled milligrams being
tial for drug-botanical interactions, metabolism of active weakly associated with the measured constituent [52, 53].
compounds, and finally, clinical studies of safety and effi- The concentrations of ingredients are incredibly inconsis-
cacy. Completing these steps will enable the translation of tent, with lot-to-lot variations in the content of active ingre-
botanicals from the field to safe human use as dietary supple- dients exceeding 1000%. In reality, spotting herbal products
ments” [44]. with concentrations within 10% of their label claim is a rare
However, meeting these requirements is utterly impossi- exception, according to multiple studies [54–58].
ble. Consumers use these products through a leap of faith. Notably, in published CAM RCTs, poor quality control
and high content variability is an important issue that can
detract from the value of otherwise well-designed studies.
70.9 Standardization of Herbs Wolsko et al. (2005) reported that the documented character-
ization of herbal supplements in published RCTs is inade-
When the package of a pharmaceutical product lists its fea- quate; from the 81 RCTs that met the inclusion criteria, only
tures, it is taken for granted that it is reliable and applicable 12 (15%) reported performing tests to quantify actual con-
for the entire content. This is called standardization. tents, and just 3 (4%) provided adequate data to compare real
Moreover, we know which is the product’s active sub- with expected content values of at least one chemical con-
stance -only rarely will it be more than two- and which are stituent [59].
the inert excipients since they are all listed in detail. Scientists
count on this “convention”, i.e., what is listed on the package
is true and accurate, so that one may predict the benefits of a 70.10 Why is Herbal Standardization
treatment and therefore accept the responsibility of Impossible?
prescription.
Although generally considered and used as a single product,
herbals consist of a variable number of chemical constitu-
In other words, every pill, of every package, of every
ents, a fact obviously not appreciated until the advent of
lot number, in every manufacturing site, of every coun-
modern chemistry. The bioactive components of plants, cul-
try producing that same pharmaceutical product, con-
tivated or growing in the wild, remain unknown. Even the
tains precisely the same active ingredients, at the exact
ones we know of have been shown to vary both with cultivar
same concentration.
and with growing conditions, among other parameters [60]:
• Age of the plant,

To ensure that a safe and effective herbal product is mar- • Geographic location and elevation,
keted to the consumers, botanical supplements should also • Horticultural practices,
be standardized. The goal of standardization is to provide • Amount of sun, water, and fertilizer uptake while
consumers with a product that contains consistent levels of growing,
active ingredients (chemical standardization) and predictable • Time of the year of growth,
pharmacological and physiological effects (biological stan- • Time of the day of harvest,
dardization), using the appropriate bioassays. Reproducibility • Part of the plant used,
of the dietary supplement helps ensure safety by preventing • Active constituent levels at harvest,
accidental overdose due to lot to lot variation and by provid- • Type of extract (aqueous, alcoholic, glycerin),
ing the consumer with predictable physiological and phar- • Final delivery form.
70.12 Herbs for BPH = Herbs for AGA? 423
Even if one could calculate, predict, or standardize all these “complement” prescribed drugs for LUTS [64]. In the United
parameters, every capsule, dried extract, or other delivery States, about 40% of men opting for non-surgical therapy of
forms will contain parts of hundreds of different plants. BPH are self-treated with herbal supplements alone or in
Actually, when using a herb or botanical product, no one conjunction with drugs. That number continues to grow
really knows: since one clear advantage of those herbal medicines over
pharmaceutical drugs is the absence of side-effects in most
• Where it comes from, patients, except placebo side-effects, of course [65].
• Which and how much of each active ingredient it There have been more than 30 phytotherapeutic com-
contains, pounds described for BPH management, and initially (back
• How efficient it is, in the 1970s), the urologic community was encouraged by
• Whether it is contaminated with pesticides, heavy metals, trial results that suggested phytotherapy could effectively
microbial agents, and mycotoxins, treat symptomatic BPH and LUTS. Since that time, several
• How dangerous each pill of a package may eventually be! well-constructed studies have consistently demonstrated that
these agents are mostly safe for ingestion but no more effica-
It is wise to keep these parameters in mind while reading the cious than placebo [62]. Nevertheless, with the expansion of
following chapters and before considering prescribing CAM health food stores, vitamin shops, and internet companies
products for hair growth. selling these agents, the use of botanicals for the treatment of
symptomatic BPH has become a lucrative business in the
USA, with revenues reaching close to US$6.4 billion in sales
70.11 Herbs and Benign Prostate for the 2014 fiscal year [66]. Furthermore, a substantial
Hypertrophy (BPH) amount of these sales is directed to younger males who do
not suffer from BPH, but AGA!
The male prostate and the hair follicles in humans share a
common embryological background. The growth and devel-
opment of both organs depend on the interaction between 70.12 Herbs for BPH = Herbs for AGA?
mesoderm (hair dermal papilla vs. prostatic stroma) and
ectoderm (outer root sheath keratinocytes vs. prostatic epi- Some of the herbs reviewed in the following chapters have
thelium) [61]. However, these two organs share another been reported to effectively relieve LUTS. Moreover, these
essential similarity when it comes to pathological conditions. same herbs are marketed as hair growth agents, as well. What
Benign prostatic hyperplasia (BPH) and AGA are both is the idea behind this, one might ask?
androgen-dependent disorders, displaying in situ high levels LUTS is caused by BPH. BPH is caused by DHT. Since
of DHT, and both demonstrate a favorable therapeutic DHT is the cause of AGA, though creative, associative think-
response to finasteride. Interestingly, DHT has the exact ing, botanicals initially targeting older males, in the last two
reverse effects on androgen-sensitive hair follicles, which decades have a new market segment to target: Younger males
miniaturize under DHT’s influence, compared to the epithe- with AGA. The clinical result of intake of these herbs sup-
lial and stromal cells of the prostate, which undergo hyper- posedly resembles that of finasteride, symptomatic relief of
plasia. Based on similar androgen-responding tissue growth urinary tract symptoms. Even though the exact mechanism
and disease pathogenesis, as well as therapeutic experience, of action of any of these dozens of herbs is not clearly defined
speculation has arisen as to the association between AGA or merely unknown, through “associative speculation”, they
and BPH (see Chap. 22, Vol. 1). Men opting for non-surgical are considered as having a similar mechanism of action with
therapy for BPH can either use 5α-Reductase inhibitors finasteride, i.e., inhibiting 5α-reductase and preventing the
(Finasteride, Dutasteride), α1A receptor blocking agents conversion of Testosterone to DHT. So, through these cre-
(e.g., prazosin, Tamsulosin) or, lately, phosphodiesterase ative assumptions and given that finasteride is FDA-approved
type 5 inhibitors (5PDEI, e.g., sildenafil, aka Viagra®). for the treatment of AGA, there has been a massive market-
However, even though these drugs are “established values” ing effort to correlate these herbs as hair growth agents, as
among medicines against BPH, many patients seek and well.
resort to “natural” remedies, mostly botanicals [62].
Plant extracts were already and extensively prescribed
From the marketeer’s perspective, it is pretty straight-
many years before the arrival of these modern drugs for
forward, even elementary: Why not sell the same prod-
BPH. In Austria, France, and Germany, phytotherapeutic
uct to two distinct target groups, BPH and AGA
agents were considered first-line treatment for moderate
patients? After all, this is precisely what the original
lower urinary tract symptoms (LUTS) and comprised
producers of finasteride did with their compound.
roughly 90% of all prescriptions filled for BPH management
[63]. Many urologists in these countries still use herbals to
Of course, the critical difference is that finasteride had to Unfortunately, no matter how absurd the claim, individu-
undergo a formal FDA approval process for safety and effi- als suffering from hair loss are willing to believe it. Often,
cacy before being marketed to any target group. In contrast, separating fact from fiction is impossible in the minds of
herbals or botanicals initially used in the treatment of LUTS young men desperate to get their hair back [71]. These men,
(with unproven efficacy, since premarketing approval by the as most clinicians already can confirm, are willing to try any-
FDA is not required) were “honored by association” as being thing on their head just to grow some hairs. Reports of the
efficient hair growth agents! For years already, these herbal lifetime prevalence CAM use by dermatologic patients is
products claiming to “improve prostate health and function” very high, ranging from 35% to 69% [72]. An interesting
are widely marketed also as hair growth agents and are read- study by Kim et al. [73] quantified the use of CAM in Korean
ily available without a prescription in pharmacies, drug- patients with AGA, atopic dermatitis (AD), or psoriasis and
stores, and other retail outlets. Most importantly, they are was the first study reporting on the attitudes of individuals
available for purchase online via internet retailers, most of with AGA regarding botanicals [73]. Of the 678 patients
them making even specific health (or hair growth claims), recruited from the dermatologic clinic of three tertiary hospi-
according to studies [67]. tals in Korea who were included in the survey, 235 had AGA,
254 had AD, 189 had psoriasis, and were all investigated
independently by constructed and self-directed
70.13 Herbal Products and ΑGΑ/FPHL questionnaire:
The use of specific plants for the treatment and prevention of • 158/235 of AGA patients (67.2%) reported current or past
AGA is a topic of recent scientific interest since 1993. use of CAM for their condition, a higher percentage than
However, no clinical trials or other studies had been carried patients with AD or psoriasis,
out on the subject. Since the early 1990s, the topic has grown • 69 (29.4%) used CAM products for 1–6 years, 18 (7.7%)
steadily, and the search for suitable plants to promote growth for 5–10 years, significantly more than patients with AD
and regrowth of hair is on the rise [68]. or psoriasis,
There are several common misconceptions and “myths” • 118/235 were using some topical product (mostly sham-
on hair loss in general and on AGA specifically, enhanced by poo, n = 116) and 46 used oral products, and on average,
skepticism on the efficacy and safety of the FDA-approved 3.6 different products was used by each of the 158 indi-
hair growth medications. This has offered to manufacturers viduals with AGA,
and marketers of herbal hair growth products a very recep- • 63 individuals decided to try CAM after recommenda-
tive and easy-to-manipulate market, eager to believe that tions from family members and friends, 50 through infor-
herbs and botanicals will safely and permanently grow their mation from the media, 43 because they desired to try all
hair back. Natural products are unequivocally advocated in potential treatments, and only 16 (10.1%) after physician
the cosmetic and hair care industry, and more than 1000 dif- recommendation,
ferent plant extracts have been examined concerning hair • 115/235 had negative concerns about conventional medi-
growth activity. Since these substances are regarded as foods, cine, 23/115 considered the effect of conventional drugs
regulation and scrutiny of nutritional labeling practices are would be temporal or would not cure, and 29/115 due to
minimal. These “natural” botanical hair products are avail- (supposedly) frequent adverse events,
able in the form of capsules, pills, infusions, teas, tinctures, • Only 6/235 (2.6%) reported excellent results with CAM,
extracts, essential oils used as tonics, lotions, cleansers, anti- 31 (13.5%) reported good results, while 192 (83.9%)
dandruff shampoos, and conditioners [69]. reported fair, disappointing, or very disappointing
The field is steadily growing, with new herbs and new results.
“active” ingredients regularly added, while numerous pat-
ents on allegedly effective natural treatments for hair loss
appear [70]. Most of these herbs come from the “exotic Far
East,” the “mystical China,” and the “sensual India.” 70.14 “Instructions for Use” of the Following
Chapters
Claims on these herbs are not limited to their “exotic”
• In the following chapters, the most popular botanical
origin, and notably, some manufacturers of herbal hair
products reported in the scientific literature to promote
tonics even claim that Asian men suffer less often from
hair growth will be reviewed. Those with human trials
AGA and usually have black and thick hair because the
will be reviewed separately and more extensively.
herb they are selling is popular in Asia.
70.15 Final Note 425
• Potential biochemical mechanisms through which the In this most scientific of ages, “orthodox medicine” is com-
ingredients of each herb might act on the hair follicle, mitted to embracing an ever more evidence-based approach
both unconfirmed (traditional) and scientifically con- to clinical practice and still has a long way to go.
firmed, will be presented to the best of the author’s knowl- Unfortunately, consumers of health care are increasingly
edge and understanding. exposed to a plethora of nonsense (non-science) claims that
• Numerous properties are reported for each herb, but prac- waste their money, distance them from effective care strate-
tically all are in vitro properties of the herbal extract’s gies, and, not infrequently, even cause harm [77]. In situa-
separate ingredients and are mostly of academic interest. tions where there is little risk of harm and the possibility of
• Under no circumstances should the in vitro properties be benefit, supporting a patient in their interest in complemen-
considered applicable in vivo. After oral administration, tary therapies can strengthen the patient-physician relation-
most herbal ingredients will undergo phase I and/or phase II ship. However, when a patient’s desire to utilize alternative
metabolism in vivo (cytochrome P450 or extensive catabo- therapies poses a health risk, physicians have the ethical
lism by colonic microbiota) and will not be present as their obligation to skillfully counsel the patient toward those ther-
parent forms in the circulation. Additionally, for most herbal apies that are medically appropriate [78].
remedies used in folk medicines, data on their disposition
and biological fate in humans are entirely lacking.
• It is important to critically evaluate the scientific and eth- 70.15 Final Note
nomedical literature related to the botanicals or natural
products in each chapter and treat those published in In the following chapters, hundreds of articles on herbal
CAM journals with healthy skepticism, especially if products reporting hair growth in vitro or on lab animals will
reporting positive properties or results. Articles in these be cited. One cannot help but wonder about the zeal, and
journals are “easier to publish,” will enrich the curriculum considerable research effort on the hair growth properties of
of the authors without, however, necessarily enhancing herbal and botanical products, especially when approved,
overall scientific/medical knowledge. safe, and quite efficient pharmaceutical molecules do exist
• Very limited human clinical data is available on herbal for decades.
hair-growth treatments. Essential parameters, such as
long-term safety, proper dosage regimens, optimal ingre-
The answer is probably simple: Young researchers who
dient concentration, appropriate vehicle, and others are
want to enrich their “resume” with scientific publica-
unknown in all studies.
tions and, at the same time, get trained in laboratory
• Most herbal hair-growth treatments are mixtures of mul-
study conditions choose a “low-level” hair follicle
tiple compounds. Even if the reported results were objec-
research.
tive and cosmetically significant (which are most often
neither), they could not be attributed to one ingredient
alone, and there is no way of identifying the impact of
each ingredient separately. There are many reasons for making such a choice: Results
(or lack of them) are easy to demonstrate and measure,
Finally, one should consider that the high level of acceptance expensive equipment is rarely necessary, research cost can
of herbals among the general population represents a chal- be kept low, and the required “know-how” is usually poor. In
lenge to healthcare professionals of all disciplines and raises addition, results on hair growth are interesting for the public,
a host of ethical issues. Since the whole ethos of evidence- can be quickly published in specialized CAM journals, peer-
based medicine crucially depends on reproducible, quantifi- review is limited –if any- and results cannot even be chal-
able outcomes, the physician should first answer to him- or lenged since discrepancies in reproducibility can be attributed
herself the following questions before recommending any to lack of standardization of the tested herbal product.
herbal product to his/her patients [74–76]: Additionally, materials are easy to find and cheap, the results
can be safely presented in conferences, posters, or work-
1. Is there any actual evidence on the efficacy, safety, dos- shops, while at the same time, small-size cosmeceutical
age, interactions, and potential toxicity in humans of this companies “lurk” for findings to launch the next “hip” herbal
herbal product? product. This product will contain a promising, natural
2. What is the expected result from this herbal product com- ingredient that acts “like Minoxidil” or “like finasteride” but,
pared to that of an FDA-approved hair growth treatment, as always, “without side-effects” and “is suitable for both
i.e., what is the “opportunity cost” on the patient’s head? sexes”. Manufacturers who will produce this new product
3. Would I recommend this product to a member of my will have excellent chances to make money, fast and safely:
close family under similar circumstances? New AGA/FPHL patients continuously add-up in the mar-
ketplace, they are often desperate to get their hair back, the United States, 1990–1997: results of a follow-up national survey.
JAMA. 1998;280(18):1569–75.
likelihood of severe adverse effect by the use of a topical
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21. Obodozie OO. Pharmacokinetics and drug interactions of herbal
Except for hair loss patients who will be wasting time,
medicines: a missing critical step in the phytomedicine/drug devel-
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macokinetics—theory, methods, and applications. Croatia: InTech;
2012. p. 127–56.
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Saw Palmetto (Serenoa repens Sabal
serrulatum) 71
across; the berries are fleshy, about 2 cm in diameter, and

Basic Concepts blue-black in color [1].
• Saw Palmetto extract (SPE) is popularly used for Saw palmetto extract (SPE) derives from the processing
the symptomatic relief of Benign Prostatic of the plant’s fruit and seeds, is generally easy to isolate, and
Hyperplasia (BPH), and the presumed mechanism has been used in several forms of traditional herbal and folk
of action is through the inhibition of androgen- medicine [2]. Historically, Saw Palmetto berries had been
sensitive pathways, but according to meta-analyses, used as a staple food to treat stomach pain and diarrhea, an
its actual clinical efficacy is not considered higher expectorant, an antiseptic, a metabolic stimulant, to treat goi-
than placebo. ter, anorexia, and polycystic ovaries, even as a diuretic and a
• The Saw Palmetto liposterolic extract contains high sexual tonic [3]. American Indians used the fruit for food and
amounts of free fatty acids with in-vitro anti- to treat a variety of urinary and reproductive system prob-
androgenic and 5α-Reductase inhibitory properties; lems. SPE as a remedy for the symptomatic relief of Benign
it also inhibits cyclooxygenase and 5-lipoxygenase Prostatic Hyperplasia (BPH) has been reported in the medi-
pathways in vitro, thereby preventing the biosyn- cal literature since 1800 [4].
thesis of inflammation-producing prostaglandins In the U.S., the plant gained recognition as an official rem-
and leukotrienes. However, its other primary active edy in 1906, being first mentioned in the U.S. Pharmacopoeia
ingredient, β-sitosterol, has been proven to increase [5], followed by the inclusion in the U.S. National Formulary
the expression of TGF-β1 and PKC-α that could (1906–1950) [6]. Human exposure to Saw Palmetto occurs
exert apoptotic effects on balding hair follicles. when the extract is taken for medicinal purposes: orally as a
• The mild anti-androgenic actions of Saw Palmetto capsule or tea and topically as a hair lotion or an acne lotion/
have been documented only in vitro, and there is no ointment.
convincing evidence that any of these mechanisms
are relevant in vivo.
• Significant evidence for advocating the use of SPE 71.1 Saw Palmetto Mechanism of Action
in AGA is lacking since those few available publi-
cations are of low quality. However, physicians Even though SPE’s mechanism has been investigated in sev-
need to be aware of this herb as patients are com- eral in vitro or indirect in vivo studies, it has still not been
monly using it, and opinions will be sought about fully defined, and the number of components identified in the
its efficacy. SPE is continually increasing. Saw Palmetto is considered to
possess anti-androgenic properties, although the exact com-
pound (or compounds) responsible have not been identified.
The n-hexane lipidosterolic extract of Serenoa repens
Saw Palmetto or Serenoa repens (also known by its botanical (LSESr) is, supposedly, the most “active” and widely
name, Sabal serrulatum) is a plant of the Arecaceae’s family, studied Saw Palmetto product. It usually contains 70–95%
and it is an American bushy dwarf palm tree and cabbage free fatty acids (FFAs), such as capric, caproic, caprylic,
palm. It is endemic to the subtropical Southeastern United lauric, myristic, oleic, linoleic, linolenic, stearic, and pal-
States, most commonly along the south Atlantic and Gulf mitic acids with their ethyl esters and glycerides that
Coastal plains and sandhills, and in the West Indies islands. occur most likely during the extraction process [7, 8].
The plant may grow to a height of 6 m, with leaves up to 1 m Other ingredients of LSESr in smaller quantities are phy-
430 71 Saw Palmetto (Serenoa repens Sabal serrulatum)
tosterols, namely β-sitosterol, stigmasterol, cycloartenol, have only been documented in vitro, and there is no convinc-
lupeol, lupenon, and methylcloartenol [9]. Most experts ing evidence that any of these mechanisms are relevant
consider that FFAs in the LSESr are the major pharmaco- in vivo.
logically active components, while earlier studies assumed
that the steroidal compounds and β-sitosterol were most
active [10]. 71.2 Saw Palmetto and Lower Urinary
The effects of LSESr have been tested on a diverse array Tract Symptoms
of in vitro cultures, providing exciting findings. In the
baculovirus-directed insect cell expression system, the The use of plants and herbs (phytotherapy) to treat lower uri-
LSESr has displayed a non-competitive inhibition of the nary tract symptoms (LUTS) attributable to BPH is common
5α-Reductase (5α-R) type I isotype and uncompetitive inhi- and has been growing steadily in the last decades in many
bition of the 5α-R type II isotype [11, 12]. Western countries. As already mentioned, SPE has been used
for a myriad of indications, as a diuretic, an aphrodisiac,
even as a breast augmenter [21]. However, its primary clini-
This suggests that the mode of action is rather a modu-
cal usage is in the treatment of BPH and LUTS, and it is by
lation of the activity by modification of the lipid envi-
far the most popular of the several phytotherapeutic agents
ronment of the enzyme than an interaction at its
commercially available with these indications. Since the
catalytic site [12].
1990s, Saw Palmetto has been one of the top ten top-selling
herbal medicines in the United States, and the worldwide
year turnover of Saw Palmetto preparations was estimated to
Both 5α-R isotypes seem to be very sensitive to the com- be in excess of 700 million dollars [22]. In a US national
position of their molecular environment. The accessibility of survey conducted in 2002, 1.1% of the adult population in
the enzyme to its cofactor depends on the protein’s confor- the US, or approximately 2.5 million adults, reported using
mational state, the latter depending on the membrane’s com- Saw Palmetto [23]. However, in a more recent based on data
position [20]. Consequently, LSESr cannot be directly collected from a combined sample of 88,962 adults as part of
compared to Finasteride for its ability to inhibit both 5α-R 2002, 2007, and 2012 Adult Alternative Medicine (ALT)
isoenzymes and that it belongs to a “new class” of 5α-R supplements to NHIS, the estimated use of Saw Palmetto
inhibitors [12]. LSESr has been reported to inhibit competi- reportedly dropped to 0.4% of adults in the US [24].
tively the binding of [3H]methyltrienolone to the cytosolic Interestingly, the situation in Europe is quite different
androgen receptor of the rat prostate [13] and human fore- concerning the popularity of this herb, since it is steadily still
skin fibroblasts [14]. It can also act as a weak surrogate 5α-R increasing. In Germany, 90% of patients with BPH are self-
inhibitor, affecting the proliferative response of prostate cells treated with Saw Palmetto or other plant extracts, and half of
to b-FGF more than their basal proliferation at high concen- the German urologists prefer to treat BPH and LUTS by pre-
trations [15]. It has also been reported that LSESr acts as an scribing plant-based extracts instead of synthetic drugs [4]. It
indirect α-blocker [16] by occupying α1-receptors of the is remarkable how can the use of Saw palmetto be so wide-
periurethral prostate cells, causing smooth muscle relaxation spread in some countries, even though concrete scientific
via the α1-adrenergic receptors. Moreover, it has even been evidence on the actual effects of the extract on the prostate’s
attributed with anti-inflammatory properties by inhibiting size is painfully lacking, despite the large number of clinical
cyclooxygenase and 5-lipoxygenase pathways, thereby pre- trials published during the last three decades. In many of
venting the biosynthesis of inflammation-producing prosta- these studies, Permixon® (Pierre Fabre Medicament, Paris,
glandins and leukotrienes [17, 18]. Other mechanisms of France), a supposedly standardized LSESr, has been admin-
action that have been reported include alteration of choles- istered and is the most extensively prescribed and studied
terol metabolism, anti-estrogenic, anti-estrogenic, pro- phytotherapeutic agent used in the treatment of symptomatic
apoptotic, and a decrease in available sex hormone-binding BPH. Permixon® is essentially composed of fatty acids (a
globulin [19]. mean from 15 different batches of 94 gr/100 gr of extract), of
Even though the exact -and optimal- composition of SPE which FFAs account for a mean of 83.5 gr/100 gr of extract.
has not yet been established, the clinical benefits are gener- The mean values of the FFAs fraction percentage are 35%
ally related to the free fatty acid content [15]. Raynaud et al. oleic, 30% lauric, 11% myristic, and 5% linoleic acids.
(2000) have conducted extensive research on the high anti- Phytosterol, aliphatic alcohols, and polypyrenic compounds
androgenic potency of FFAs, and researchers concluded that are only present in minute quantities (<2%). According to
several FFAs, namely γ-linolenic, myristoleic, lauric, and some early studies in the 1980s and 1990s, the clinical effi-
oleic acids are moderate inhibitors of both 5α-R isotypes cacy of Permixon® in the medical management of BPH has
in vitro [20] (see Chap. 43). However, these mechanisms been positively demonstrated, regarding the reported symp-
71.3 The Saw Palmetto Controversy 431
tomatology and peak urinary flow rate [25–28]. Studies pub- ineffective to treat BPH and LUTS [19, 36]. In response to
lished after 2000 also reported the efficacy of SPE and these unfavorable results, Novara et al. (2016) published the
Permixon®. Debruyne et al. (2004) reported that Permixon® findings of their own meta-analysis, including only studies in
320 mg/day was slightly superior to Tamsulosin 0.4 mg/day which Permixon® was tested and not just any SPE. The
in reducing LUTS in severe BPH patients after 3 months and authors claimed that Permixon® has the highest activity and
up to 12 months of treatment in a double-blind study on 59 the most strict standards of drug preparation and extraction
and 65 patients randomized to Tamsulosin and Permixon® and that the negative results of previous Cochrane database
groups, respectively. Notably, this study has been criticized meta-analyses [19, 36] included studies in which lower qual-
for the lack of a placebo arm [29]. ity extracts were used. They claimed that the conclusions of
Carraro et al. (1996) conducted a 6-month long, double- the recent Cochrane meta-analysis on Saw Palmetto in the
blind, randomized equivalence study comparing the effects treatment of LUTS/BPH apparently do not apply to
of 320 mg Permixon® with 5 mg Finasteride in 1098 men Permixon® studies since their meta-analysis showed that
with moderate BPH using the International Prostate Permixon® was more effective than placebo. Additionally,
Symptom Score (IPSS) as the primary endpoint. Both they claimed that Permixon® had efficacy similar to that of
Permixon® and Finasteride decreased the IPSS (−37% and Tamsulosin and short-term Finasteride in relieving LUTS
−39%, respectively), improved the quality of life (38% and while having a favorable safety profile, with a minimal
41% respectively), and increased peak urinary flow rate impact on sexual function, which is significantly affected by
(+25% and +30%, p = 0.035). Finasteride markedly all other drugs used to treat LUTS/BPH [37].
decreased prostate volume (−18%) and serum PSA levels
(−41%); Permixon® improved symptoms with little effect on
volume (−6%) and no change in PSA levels [30]. However, 71.3 The Saw Palmetto Controversy
the absence of a placebo control group makes interpretation
of these results problematic. Boyle et al. published two meta- A great deal of controversy concerning the clinical effects of
analyses in 2000 and 2004 and reported that all available SPE is evident in the literature, as the above-mentioned con-
published trials of Permixon® for treating men with BPH tradicting results of studies and meta-analyses prove. Patients
showed a significant improvement in peak flow rate and seem to report mild to modest improvements in urinary
reduction in nocturia above placebo [31, 32]. symptoms, flow measures, and reduced nocturia, while
researchers cannot explain the improved symptomology
since no actual reduction in prostate volume has ever been
The major issue of these -and all- meta-analyses is that
reported.
they strongly depend on the quality of the studies
To test the histologic effects of long-term use of SPE on
entering the meta-analysis (“garbage in – Garbage
the human prostate, Di Silverio et al. (1998) were the first
out”) [33]. Dozens of other studies have addressed saw
who sectioned BPH samples of patients treated with
Palmetto’s effectiveness in BPH patients and have
Permixon® 320 mg/day for 3 months. They analyzed speci-
reported positive results. Notably, most of these stud-
mens from the periurethral, subcapsular, and intermediate
ies were small-sized, uncontrolled, short-term trials,
regions and determined concentrations Testosterone (T),
the extracts used were not standardized [5], and very
DHT, and EGF by radioimmunoassay in each region. They
few met the WHO BPH consensus conference quality
reported that a statistically significant reduction of DHT
criteria [33, 34].
(p < 0.001) and EGF (p < 0.01) was observed exclusively in
the periurethral region, with increased T values (p < 0.001).
According to the authors, these results confirmed the capac-
Of all published studies, only one, 12-month long, double- ity of Permixon® to inhibit in vivo the 5α-R enzyme but
blind study, published in the “New England Journal of noted that these results are applicable only in human patho-
Medicine” by Bent et al. (2006), had a well-designed proto- logical prostate and significant only in the periurethral
col. In this highly published, industry-independent, and region. They also speculated that the preferential reduction
probably best-designed phytotherapy trial, 225 patients were of DHT and EGF content in the periurethral region is
followed for 12 months, and the authors reported that the involved in the clinical improvement of the obstructive
efficacy of SPE was comparable to placebo and did not symptoms in BPH during LSESr treatment [38].
improve symptoms or objective measures of BPH [35]. Most However, as already mentioned, the results of studies on
importantly, both meta-analyses (2009 and 2012) conducted SPE’s actual efficacy in BPH and LUTS treatment are con-
by the National Center for Complementary and Alternative tradicting. The hypothesis of Novara et al. concerning differ-
Medicine, authored by Tacklind et al. and published by the ences in quality of SPEs used in trials seems to have a solid
Cochrane Library database, found that SPE products are point since commercially available herbal medicinal prod-
ucts may vary in contents and concentration of their active also explain the controversy between the results of the stud-
ingredients. This largely depends on the plant’s geographical ies. Interestingly, the German Federal Health Agency
source, the time of harvest, plant parts used, type of extract requires Saw Palmetto labels to state that “This medication
(aqueous, alcoholic, glycerine), and delivery forms [39] (See relieves only the difficulties (pain and frequent urination)
Chap. 70). Therefore, considerable differences may be associated with an enlarged prostate without reducing the
observed in the results of clinical trials of heterogeneous enlargement” [45].
products even when the same botanical species are used [40],
and this has been demonstrated in several studies.
Habib et al. (2004) reported significant differences in the 71.4 Saw Palmetto and ΑGΑ
ingredients of 14 different Saw Palmetto extracts that were
analyzed. Concentrations of fatty acids, methyl- and ethyl- 71.4.1 Is SPE a True 5α-R Inhibitor?
esters, long-chain esters, and glycerides differed signifi-
cantly and possibly impacted the clinical effectiveness and Saw Palmetto is the most advertised phytotherapeutic agent
safety of extracts [41]. Booker et al. (2014) conducted the for the management of AGA. This popularity is based on the
most comprehensive phytochemical analysis of 57 commer- assumption that since it has been reported to relieve LUTS
cial SPE preparations, all claiming to contain 320 mg of symptoms due to BPH, which is DHT-related, it must reduce
LSESr and 70–95% of FFAs. Products from nine different DHT, which miniaturizes hair follicles in patients with AGA.
countries were analyzed, and the authors reported a high
level of heterogeneity of the various products in the total
Bluntly, since Finasteride is effective in treating BPH
amount, including nine fatty acids. Products containing only
and AGA by reducing DHT, SPE is assumed to be able
Saw Palmetto had an average daily dose of 230.5 ± 127.2 mg
to treat AGA!
of FFAs per day (mean ± SD) with values ranging from
30.89 to 1473.2 mg, whereas the combination products con-
tained 261.0 ± 247.5 mg with values ranging from 8.34 to
1173.02 mg daily. Setting aside the logical fallacy of the assumption, one
should remember that SPE’s inhibitory effects on 5α-R
enzymes have been intensely debated and doubted. LSESr
The differences ranged from one-tenth FFAs up to 4.6
has never been proven to inhibit the 5α-R enzymic system
more FFAs than the declaration given on the package
in vivo.
for the mono-preparations [42].
The whole issue started initially with two studies pub-
lished in 1984 in the same issue of the “Journal of Steroid
Biochemistry”. Both articles reported SP’s in vitro inhibitory
Feifer et al. (2002) determined the analytical accuracy properties on the 5α-R enzymic system of the rat prostate
and reliability of commonly used nutritional supplements for cells and human foreskin fibroblasts [13, 14]. Yet, these two
prostate disease by comparing the amounts of active ingredi- studies used extremely high SPE concentrations, not feasible
ents of several brands of Vit E, Vit D, selenium, lycopene, in vivo, and used potent solvents to achieve these concentra-
and Saw Palmetto and published their results in the peer- tions. Since 5α-R enzymes are located in cellular mem-
reviewed journal “The Journal of Urology”, in 2002. Saw branes, concentration-dependent solubilization of 5α-R
Palmetto (6 samples) demonstrated tremendous variability enzymes has been demonstrated at even low concentrations
with some samples containing no active ingredients, other of detergents [46], let alone the extreme ones used in these
samples within a range of −97% to +140% of the declaration studies. Therefore, the reported inhibitory action on the cul-
given on the package, and with 3 containing less than 20% of tured cells was due to the non-chemical reactions of the
the claimed dosage [43]. Scaglione et al. (2008) tested the enzymes with the solvents that transferred this very high
potency of 7 lipid/sterol extracts of Saw Palmetto on the SPE concentration [47].
inhibition of 5α-R type I and II isoenzymes, and results have In 1999, Bayne et al. reported that Permixon® at a concen-
clearly shown that brands and batches are significantly dif- tration of 10 μgr/mL (similar to the calculated plasma con-
ferent [44]. centration in patients receiving recommended Permixon®
Unfortunately, since SPEs are regarded as foods, regula- therapeutic dosage) was shown to be an effective inhibitor of
tion and scrutiny of these nutritional supplement labeling both 5α-R I and II, without influencing the secretion of PSA
practices are minimal. The trend toward the widespread use by the epithelial cells, even after stimulation with
of dietary supplements among patients with prostatic disor- Testosterone. However, the morphology of Permixon®-
ders coupled with the lack of rigorous quality control results treated cells was found to be markedly different from that of
in many men using substandard products. This fact might untreated controls. Cells that had been treated with Permixon®
71.4 Saw Palmetto and ΑGΑ 433
demonstrated extensive accumulation of lipids in the cyto- between Finasteride and placebo concerning serum T,
plasm and widespread damage of intracellular membranes, except on days 3 and 6, respectively (p ≤ 0.05) [51]. The
including mitochondrial and nuclear membranes [48]. Habib table lists the IC50 for each botanical extract compared to
also reported in 2004 that Permixon® is an effective dual Finasteride [47] (Table 71.1).
inhibitor of 5α-R isoenzyme activity in the LNCaP prostate These conclusions were confirmed by Marks et al. (2001),
cancer cell line, and they also reported that it does not inter- who investigated the effects of SPE on human prostatic tis-
fere in any way with the transcription of the PSA gene and sue and measured serum androgens [52]. They demonstrated
the capacity of epithelial cells to secrete PSA [49] that SPE:
Nevertheless, in these studies, there was neither a reduc-
tion in the secretion of PSA by the epithelial cells nor favor- • did not reduce DHT serum levels,
able changes in the volume of the prostate, suggesting that • did not increase T serum levels (that would actually be a
5α-R inhibition or other anti-androgenic activity was not proof of 5α-R inhibition and DHT reduction in favor of T),
demonstrable in vivo, as Madersbacher et al. (2008) very • did not affect PSA levels,
reasonably argue in their review titled “Plant extracts: sense • the prostatic tissue DHT levels were reduced by 32%
or nonsense?” [33]. from 6.49 to 4.40 ng/g in the SPE group (p < 0.005), with
Interestingly, earlier, well-designed, in-vitro studies have no significant change in the placebo group.
demonstrated quite the opposite results than those claiming
inhibitory effects of LSESr on the 5α-R enzymic system. So, SPE was found to reduce DHT by 32–50% only locally
Rhodes et al. (1994) used human prostate cells as a source of in the prostatic tissue, which has already been demonstrated
5α-R, and compounds were incubated with an enzyme prep- in previous studies [50, 53]. The summarized actions of SPE
aration and [3H]-T. in serum and prostatic tissue compared to those of Finasteride
are listed in Table 71.2.
Interestingly, there have never been any in vitro studies
The researchers measured the production of [3H]-DHT
concerning the effects of LSESr on human hair follicles.
to calculate the activity of 5α-R. IC50 values (ng/mL)
were Finasteride = 1 and Permixon® = 5600. This
translates into 5600 mg of Permixon® as necessary to Table 71.1 Inhibition of Human Prostatic 5α-Reductase by Finasteride
inhibit the 5α-R enzymic system comparably to just and Various Commercially Available Plant Extracts. (Adapted with per-
1 mg of Finasteride, making Permixon® an extremely mission from Rhodes et al. [50])
weak inhibitor of the enzyme [49]. Ingredient IC50 (ng/mL)
Finasteride 1
Permixon® (Serenoa Repens) 5600
Talso (Sabalis Serrulatae) 7000
In castrated rats stimulated with T or DHT, Finasteride Strogen forte (Sabalis Serrulatae) 31,000
inhibited the T-stimulated prostate growth, while Permixon® Prostagutt (Sabalis Serrulatae) 40,000
did not inhibit DHT stimulated growth, demonstrating that Tadenan (Pygeum Africanum) 63,000
Remigeron (Sabalis Serrulatae) 300,000
Permixon® had neither anti-androgen nor 5α-R inhibitory
Bazoton (radix Urticae) >500,000
activity. In addition, in a 7-day human clinical trial, Harzol (Hypoxis rooperi) >500,000
Finasteride, but not Permixon® or placebo, decreased serum
DHT in men, further confirming the lack of 5α-R inhibition
by Permixon® [50]. Table 71.2 In vivo effects of Finasteride vs. SPE
Strauch et al. [51] compared the effect of single and Finasteride Saw Palmetto
multiple doses of Finasteride and Permixon® on the inhibi- Serum
tion of 5α-R as assessed by serum DHT level determina- PSA 50% decrease No change
tion. Thirty-two healthy male volunteers (age range DHT 70% decrease No change
20–30 years) were administered Finasteride 5 mg (n = 10), Testosterone Slight increase No change
Prostatic tissue
Permixon® 80 mg × 2 twice a day (n = 11), or placebo
Volume 20% decrease No change
(n = 11) once a day during a 1-week open, randomized, Epithelium (%) 55% decrease 40% decrease
placebo-controlled study. After 12 h, a single dose of DHT 80% decrease 32%–50% decrease
Finasteride 5 mg reduced serum DHT level by 65% Testosterone 5–10 X increase No change,125% increase
(p < 0.01). There was no effect of Permixon® or placebo Apoptosis Increase No change
group on the serum DHT levels. No significant difference Cellular proliferation No change No change
was detected between Finasteride and Permixon® or Androgen receptors Unknown No change
71.4.2 Can Saw Palmetto Be Useful in AGA/ • Also, the article does not contain any before-and-after
FPHL? photos or any objective method of efficacy to support the
claims of the authors.
Concerning studies testing the efficacy of orally adminis-
tered or topical products containing SPE in AGA/FPHL, the The compound that was investigated and considered by
literature is minimal. the authors having a positive effect on AGA was β-sitosterol.
Morganti et al. (1998) were the first to test the efficacy of However, β-sitosterol had already been demonstrated to have
a topical SP-containing lotion twice daily, alone and in com- no effect whatsoever in 5α-R inhibition, in contrast to other
bination with an oral tablet containing gelatin-cystine 4 SPE compounds such as myristic acid, lauric acid, and oleic
times a day. They -allegedly- conducted a double-blind, acid, which have been identified as pharmacologically active
placebo-controlled trial which included 60 volunteers (30 compounds, and moderate to potent inhibitors of both types
men with ΑGΑ and 30 women with FPHL, aged 21–38), of 5α-R in vitro [20, 28, 54].
randomized in 5 groups of 12 subjects each over a period of
50 weeks. The study is not indexed in Pubmed, is very poor
β-sitosterol does not possess anti-inflammatory prop-
in methodology, and suffers from severe conflicts of interest
erties, as was initially (1992) claimed by Breu et al.
(see Chap. 42, Ref. [46]).
[55] In contrast, Kassen et al. (2000) reported that
Prager et al. (2002) tested a compound with SPE 200 mg
β-sitosterol increases the expression of TGF-β1 and
and β-sitosterol 50 mg in AGA treatment on 26 men,
PKC-α [56], both been inducers of follicular apoptosis
23–64 years of age, in good health, with mild to moderate
(see Chap. 11, Vol. 1).
AGA, randomized in an active and a control group. The
authors reported that from the 19 patients who completed the
study, 60% of patients in the active group (n = 6/10) were
rated as “improved” at the final visit as compared to baseline, There are, however, favorable data on the actions of
compared to 11% of patients in the control group (n = 1/9) β-sitosterol on AGA/FPHL from a small-scale trial presented
[53]. However, the results of this small study are very ques- during the 4th Intercontinental Meeting of Hair Research
tionable for multiple reasons: Societies, in 2004 in Berlin, on 34 men with AGA and 28
women with FPHL (aged 18–48), who were treated with a
• The study is supposedly randomized and double-blind. β-sitosterol topical lotion for 3 months. The authors reported
However, the sample was very small, with only 10 patients a 36% increase in hair density using a phototrichogram and a
in the active group and 9 in the control group. Notably, reduction of 67% to the secretion of sebum with the use of
even the authors admitted that statistical significance was sebometry [57]. Notably, there was no control group, and the
not achieved with such small groups, but, strangely, they study was too short in duration.
claimed that it was not an end-point goal of the study. Prof. Tosti (2008) presented at the 13th Annual meeting
• The extract used by the active group did not contain only of the European Hair Research Society, Genoa, Italy, the
SPE 200 mg and β-sitosterol 50 mg but numerous other results of a clinical trial comparing the addition of 0.5% SPE
compounds with potentially positive effects on hair folli- and taurine to ketoconazole shampoo vs. ketoconazole sham-
cles, namely lecithin 50 mg, inositol 100 mg, phosphatidyl poo alone. Results were reported as improved for the combo
choline 25 mg, niacin 15 mg, and biotin 100 μg. Even if shampoo [58].
the reported results were objective and cosmetically sig- Rossi et al. (2012) conducted a 24-month long open-label
nificant, they could not be attributed to one ingredient study to determine SPE’s efficacy in treating AGA by com-
alone, and there is no way of identifying each ingredient’s paring its results on hair growth with those of Finasteride
impact separately. 1 mg on 100 patients with mild to moderate AGA randomly
• The duration of patient evaluation varied. Some patients divided into two groups of equal size. One group (n = 50)
were evaluated at 18 weeks and others at 24 weeks, yet received SPE 320 mg every day for 24 months, while the
again both time frames were too short to reach a safe con- other group (n = 50) received Finasteride 1 mg every day for
clusion since studies on hair growth need to be at least the same period and global photographs were taken at base-
8–12 months long to compensate for seasonal variations line (T0), during (Τ3, 6, 9, 12, 15, 18, 21) and after the com-
in hair growth. pletion of the study (Τ24). The efficacy of the treatments was
• The essential methodological flaw of this study is that the evaluated with a score for each patient, comparing photo-
evaluation of both patients and researchers was subjec- graphs taken at baseline and at T24, then rated the paired
tive, and no objective hair counting techniques were used. photographs separately based on a 7-point scale (ranging
Reported data consisted only of patient satisfaction and from −3 = greatly decreased to +3 = greatly increased). All
patient perception details of how much their hair photos were examined by the same three experts, two derma-
improved. tologists experienced in assessing changes in scalp hair
71.4 Saw Palmetto and ΑGΑ 435
growth, and one junior dermatologist. Upon completion of cacy of a food supplement containing L-cystine, 100 mg
the study, in the SPE group, 5 patients (10%) scored −1 SPE, Equisetum extract, zinc, zinc, vitamins: B3, B5, B6,
(mild decrease), 26 patients (52%) scored 0 (no change), 19 D-biotin L-cystine and taurine (Lambdapil® Anti Hair Loss
patients (38%) scored +1 (mild increase), and no patients capsules, Isdin SA, Provençals, Barcelona, Spain). A total of
scored higher than +1. In the Finasteride group, 5 patients 70 subjects, 35 men with AGA (mean age 40.6 ± 2.5) and 35
(10%) scored −1, 11 patients (22%) scored 0, 30 (60%) women with FPHL (mean age 46.5 ± 2.6), were randomized,
scored +1, 3 patients (6%) scored +2 and 1 patient scored +3 and 23 men and 23 women received the active treatment
(p < 0.005). Moreover, Finasteride was significantly while 12 men and 12 women received the placebo. The
(p < 0.001) more effective in patients with stage ΑGΑ II-III authors reported that the number of hairs removed in the pull
of the Norwood-Hamilton scale, and Finasteride improved test decreased steadily for both treated and placebo groups
the image of both the frontal and vertex areas of the scalp, over the 6-month period but was significantly greater for the
while SPE seemed to -hardly- stabilize the disorder and only treated group compared to the placebo group (p < 0.05). In
on the vertex. This study had some important limitations men, the authors reported a statistically significant increase
since there was no control group, no hair weighing was used, (23.4% increase) in the anagen/telogen ratio in the active
and groups were not crossed-over. No before-and-after pho- treatment group at month 6 as compared with baseline. Also,
tos are included in the full-text paper. Yet, according to the there was a statistically significant difference (p < 0.05) with
authors, the study still managed to confirm the efficacy of a +3.7% increase in the total percent of anagen hair in the
Finasteride and showed that SPE might have a mild hair active treatment group from baseline to month 6 vs. -0.8%
growth potential but significantly inferior to that of decrease in the placebo group, and a −3.7% decrease in the
Finasteride [59]. total percent telogen hair in the active treatment group vs. a
Wessagowit et al. (2016) conducted a pilot, prospective, +0.8% increase in the placebo group. However, the results
open-label, within-subject comparison study at the Institute of presented on the table in the full-text version seem false,
Dermatology in Bangkok. Fifty male volunteers aged counting for only 9% increase instead of the claimed 23,4%.
20–50 years applied topical SPE lotion for 24 weeks, and stan- For both women and men, a majority of subjects described
dardized macrophotographic hair analyses were conducted on an increase in hair volume (slight or moderate) in the active
all subjects using the Canfield photography system. This was treatment group as compared with the placebo group from
the first study on SPE employing an objective measuring tech- month 6 (p < 0.01). However, this subjective experience is
nique. The study design was too complicated, and volunteers probably wrong, since during 6 months, hair will not have
used one 3.3 mL vial of concentrated SPE daily by applying it grown more than 4-5 cm, and already growing hair shafts
to the thinning areas on the scalp for the first 4 weeks, and will not change their caliber unless entering a new hair cycle.
2 mL of SPE lotion was applied daily to the whole scalp Patients reported improved quality of life (QOL), and
throughout the study period of 24 weeks. Overall, after the enhanced self-perceived efficacy using the SPE-containing
photographic assessments, investigators reported a slight tablet. The full-text article contains 2 sets of minuscule
increase of the hair at the anterior and vertex scalp, statistically before-and-after photos of one female and one male, both
significant at 0 vs. 12th, 12th vs. 24th, and 0 vs. 24th-week with a full-head of hair at baseline, showing negligible hair
time-points. Hair count and size improved at week 12, but the growth at 3 and 6 months. In addition, serious conflicts of
beneficial effects waned at week 24. This study’s main limita- interest apply. Isdin SA funded the study, also was involved
tions included the unreasonably complicated design (since in the design of the study protocol, and was permitted to
they tested the efficacy of an SPE serum and lotion simultane- review the manuscript and suggest changes, whereas Narda
ously), the short duration, and that it was an open-label, M. and Aladren S. work for Isdin SA. The study was pub-
within-subject comparison pilot trial without controls. lished in a journal not indexed in Pubmed [61].
Additionally, the ingredients of the products were multiple Bassino et al. (2019) reported that SPE enhanced the vas-
(serum: SP, Green tea extract, Peony root extract, Piroctone- cular endothelial growth factor (VEGF) production and
olamine, and unspecified Oligopeptides; lotion: same as the β-catenin expression and prevents 5-α R II activity induced
serum but less concentrated), and results could not be safely by T. However, once again, these in vitro effects required
attributed to SPE or to any other ingredient. Interestingly, in concentrations hundreds of times higher than those feasible
the three example pictures of a typical patient with corre- in vivo, something that the authors did not mention [62].
sponding macrophotographs of the vertex scalp that are Evron et al. (2020) published a systematic review on the
included in the published article, showing baseline, week 12, effects of SPE in alopecia in general. They included five ran-
and week 24, one can hardly see any difference at all in cover- domized clinical trials and 2 prospective cohort studies that
age of the vertex of this allegedly “typical patient” [60]. demonstrated positive effects of topical and oral supplements
Narda et al. (2017) conducted a monocentric, prospective, containing SP (100–320 mg) among patients with androge-
randomized, parallel-group, double-blind, placebo-netic alopecia (AGA) and telogen effluvium. Sixty percent
controlled study to investigate the safety of use and the effi- improvement in overall hair quality, 27% improvement in
total hair count, increased hair density in 83.3% of patients, include minor gastrointestinal complaints, such as mild
and stabilized disease progression among 52% were noted abdominal epigastric pain, which can be alleviated by taking
with the use of various topical and oral SP-containing sup- SPE supplements after food. Other common, mild com-
plements. SP was well tolerated and not associated with seri- plaints include diarrhea, nausea, fatigue, headache, insom-
ous adverse events in alopecia patients. However, the authors nia, muscular pain, tachycardia, angina pectoris, palpitations,
did not consider the details and limitations of some of the angiopathy, breathlessness, urinary infection, dry mouth, tes-
studies as mentioned above or the conflicts of interest. They ticular pain, decreased libido, and rhinitis, which are all gen-
only acknowledged that the exclusive impact of SP could not erally reversible upon treatment discontinuation [39, 71].
be adequately assessed, as many supplements were com- Despite careful assessments, no clinical evidence for seri-
prised of multiple active ingredients, and several studies ous toxicity with SPE has been clinically observed [39, 71].
failed to adequately specify the precise amount of SP or the There is also no evidence of SP-drug interactions, and over-
exact formula content used [63]. all, SPE seems to pose no risk for drug interactions in humans
[39, 72]. Using alprazolam, midazolam, caffeine, chlorzoxa-
zone, debrisoquine, and dextromethorphan as probe sub-
In conclusion, even though scientific evidence is pain-
strates, two clinical studies found that SPE had no significant
fully lacking concerning the effects of SPE on AGA/
effects on CYP1A2, CYP2D6, CYP2E1, or CYP3A4 in
FPHL, commercial preparations containing SPE have
healthy volunteers [73–75].
even been patented as hair lotions for the treatment of
At dosages 2 and 5 times the maximum recommended
seborrhea and hair loss [64], as capsules for the treat-
daily human dosages, SPE did not significantly affect the
ment of hair loss [65] and lotions and ointments for the
normal biological markers of liver toxicity in rats [76].
treatment of acne [66].
SP-induced emergencies or serious adverse effects, such as
pancreatitis, cholecystitis, bleeding diathesis, have only spo-
radically appeared in the literature [77, 78]. Moreover, the
In the recent (2018) systematic review (Evidence-based fact that it does not decrease PSA levels allows no room for
(S3) guideline for the treatment of androgenetic alopecia in concerns that long-term use of SPEs might mask a prostatic
women and in men) issued for the European Dermatology malignancy [48].
Forum, Kanti et al. included only the trial of Rossi et al. [58], Studies indicate that SPE at 50-300 mg/kg/day inhibits
which was considered as level of evidence 2 and grade B, the androgen-stimulated prostatic hyperplasia in what
commenting that they “cannot make a recommendation for appears to be a dose-dependent manner within studies. The
or against treatment with Serenoa repens per os at the present 50 mg/kg/day is tenfold higher than the ~5 mg/kg/day
time” [67]. ingested by humans (assuming 320 mg/day of LSESr and
70-kg weight), but not high enough to mitigate concern for
such serious effects such as mutagenicity [79]. Studies con-
71.5 Dosage- Adverse Effects—Safety ducted at the University of Pavia in Italy found no indication
of teratogenic effects at doses up to 600 mg/kg in rats and
Concerning BPH management, SPE is usually administered rabbits. Further, when both male and female rats were given
at daily doses of 320 mg/day, divided into two or three doses doses up to 600 mg/kg per day for 10 weeks prior to mating
[68]. Daily doses of 480 mg/d or higher and different dose and during gestation, no effects on fertility or offsprings
regimens have not shown to be more effective [69]. At the were noted [80]. No clinical studies in pregnant humans have
usual daily dose of 320 mg, SPE seems to have a mild estro- been reported. The use of SPE in pregnancy has not been
genic and anti-progesterone effect, while in all comparative tested scientifically and is not recommended [81], and since
studies, the occurrence of adverse effects leading BPH it is allegedly a 5α-R inhibitor, it is classified as pregnancy
patients to treatment discontinuation was 7% for placebo, category X, the category indicating the greatest concern for
9% for SP, and 11% for Finasteride [70]. pregnant women [82]. These supplements are required by the
Amidst conflicting data on its utility as a treatment for FDA to be labeled as pregnancy category X but no such
BPH, current evidence suggests that SPE is well-tolerated by requirement is in place for most marketed SPE products.
patients and is not associated with severe adverse events.
Concomitantly, most adverse events reported are mild, infre- Synopsis
quent, and reversible. A systematic review by Agbabiaka The liposterolic extract of Saw Palmetto (SPE) has been con-
et al. (2009) on the adverse events of SPE mono-preparations sidered to possess in vitro anti-androgenic properties, inhibit
suggests that they are generally rare, mild, and similar to the binding of DHT to the androgen receptor, and prevent the
those occurring in the placebo groups [39]. The most fre- conversion of Testosterone into DHT by inhibiting the activ-
quently reported adverse events in clinical trials with SPE ity of 5α-R enzymes. Additionally, it is reported to inhibit
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Pygeum Africanum (Prunus Africana)
72
International Trade in Endangered Species (CITES) at the

Basic Concepts Ninth Conference of the Parties [2, 3].
Pygeum Africanum (PygA) extract is a popular phyto- After processing the bark of PygA with chloroform, fat-
therapy agent that has been used in Europe since the soluble molecules are isolated, and the extract is filtrated,
early 1970s to treat mild to moderate lower urinary purified, dried, and manufactured into various herbal prod-
tract symptoms (LUTS) attributable to Benign Prostatic ucts, the most popular product being the capsular form. The
Hyperplasia (BPH), but with unconfirmed efficacy. species has a very long history of traditional uses. In tradi-
In animal models, PygA modulates bladder con- tional African folk medicine, the extract from PygA’s bark
tractility, has anti-inflammatory activity, decreases the powder is used to prepare a beverage for fever, malaria,
production of leukotrienes and other 5-lipoxygenase wound dressings, and stomach aches. It is also used as a pur-
metabolites, inhibits fibroblast production, and restores gative, for kidney diseases, as an appetite stimulant, for gon-
the secretory activity of prostate epithelium. However, orrhea, as a tonic, and to treat urological symptoms in men,
direct anti-androgenic actions are not verifiable. as reviewed by Steward [4]. In Europe, mainly in Germany,
Even though it contains free fatty acids, the PygA is a popular alternative phytotherapeutic agent since
5α-Reductase inhibitory properties of the extract are 1969. It has been mostly used to treat men with mild-to-
extremely weak, and since it inhibits -in vitro- the moderate lower urinary tract symptoms (LUTS) attributable
effects of EGF, IGF-I, and FGF on fibroblasts, it a neg- to Benign Prostatic Hyperplasia (BPH), and its use has been
ative impact on balding hair follicles can not be steadily increasing since then [5, 6].
excluded. Moreover, recent studies suggest that PygA extracts
exhibit anti-androgenic and antiangiogenic properties, can
kill tumor cells via apoptotic pathways, prevent the prolifera-
tion of prostate cancer cells, and alter the signaling pathways
Pygeum africanum, PygA (scientific name Prunus required for the maintenance of prostate cancer [7, 8].
Africana) is also known as “the African cherry”. It is an ever- Therefore, in the future, some suggest that it could prove to
green canopy tree, 30-40 m in height, widely distributed in be a useful supplement for individuals at high risk for devel-
central and southern Africa’s montane habitats, particularly oping prostate cancer.
in Kenya and Cameroon [1]. Prior to the discovery (1966)
that its bark extract is a potentially effective herbal remedy,
PygA was a relatively common, but never abundant, mon- 72.1 Pygeum Africanum’s Mechanism
tane species. Notably, it is still entirely wild-collected [2]. of Action
The bark of PygA is black to brown, corrugated or fissured,
and scaly, fissuring in a characteristic rectangular pattern. Similar to other botanicals for the prostate, PygA has a
The discovery of the medicinal properties of the PygA poorly defined mechanism of action, which still remains elu-
bark for a myriad of health conditions initiated a massive sive. Currently, the proposed primary mechanisms originate
harvest of its stem bark for international market needs. It has from the results of in vitro studies and animal models. They
the rare ability to regenerate its bark -as long as the vascular include growth factor inhibition, anti-inflammatory, and
cambium is not destroyed. Because of the growing global immunomodulatory properties, effects on bladder contractil-
demand for the bark, by 1995, it was already included as an ity, modulation of androgen production, and direct effects on
endangered species in Appendix II of the Convention of the function of prostate epithelium [9–13].
442 72 Pygeum Africanum (Prunus Africana)
already reviewed the same 18 RCTs and reached similar

Its clinical effects are most probably due to the conclusions.
improvement of obstruction-induced contractile dys- However, the major problem of all meta-analyses is that
function of the detrusor smooth muscle of the bladder they strongly depend on the quality of the studies entering
[14, 15] by antagonizing the 5-lipoxygenase metabo- the meta-analysis (“garbage in - garbage out”). Most clinical
lite production [11]. trials investigating the efficacy of botanicals suffer from
common flaws, such as short duration of studies, variability
in study design, using non-standardized phytotherapeutic
PygA has also been reported to be a potent inhibitor of rat preparations, and the types of reported outcomes. Later,
prostatic fibroblast proliferation in response to direct activa- multi-center clinical studies on the role of PygA in the pre-
tors of protein kinase C, the defined growth factors bFGF, vention and therapy of BPH also had quite a few limitations,
EGF, and IGF-1 [16]. The extract from PygA bark contains and results did not withstand scrutiny [28, 29]. Therefore,
several pharmacologically active compounds, and Kadu patients should be informed that none of the BPH manage-
et al. sampled 20 tree populations throughout the species’ ment guidelines currently recommends PygA as a treatment
natural range in Africa and reported that the average option [30].
concentration (mg/kgw/w) in increasing order was: lauric The utilization of the extract for the chemoprevention and
acid (18), myristic acid (22), n-docosanol (25), ferulic acid chemotherapy of prostate cancer has been suggested in the
(49), β-sitostenone (198), β-sitosterol (490), and ursolic acid review of Komakech et al., who claimed that phytochemicals
(743) [17]. from PygA have the ability to affect numerous targets associ-
Phytochemical research aiming to identify and isolate all ated with the degradation of the prostate cancer cells [8].
active ingredients of PygA described numerous other sub-
stances, such as campesterol and pentacyclic triterpenoids
[18]. Some experts believe that the main actions of PygA 72.3 Pygeum Africanum and AGA
extract can be attributed to β-sitosterol, which is found in
high concentrations in the extract [19, 20]. Other reported Since PygA supposedly alleviates LUTS attributable to
essential constituents in the PygA extract are BPH, which is caused by DHT, it is hypothesized to act by
N-butylbenzenesulfonamide (NBBS) [21, 22] and atraric reducing the levels of DHT, which miniaturizes the hair fol-
acid. Both are considered two novel androgen receptor (AR) licles in patients with AGA. Since Finasteride is effective in
antagonists and the first known natural, complete, and spe- treating BPH and AGA by reducing DHT, PygA is wishfully
cific AR antagonists. In vitro, both can inhibit AR transloca- assumed to treat AGA. Setting aside the logical fallacy of all
tion to the cell nucleus by binding to it, thereby downregulating these assumptions, one should remember that the inhibitory
the androgens levels [23]. effects of PygA extract on 5α-Reductase (5α-R) enzymes
have not been demonstrated in vivo. PygA extract contains
several free fatty acids (FFAs), which have been demon-
72.2 Pygeum Africanum, BPH, strated to possess moderate in vitro 5α-R inhibitory proper-
and Prostate Cancer ties (see Chap. 43). However, no in vivo results have ever
been published [31].
The effectiveness of PygA in the relief of obstructive urinary Choo et al. demonstrated that pretreatment with PygA
symptoms was initially reported in rabbits, which are the significantly reduced the “obstructive” effects of DHT on
ideal experimental models of bladder obstruction since their micturition in rats, counteracted the hormone-induced
cystometry pressure curve is similar to that of humans [24]. enlargement of the prostate, and reduced the prostate weight
Several animal studies and human trials have thereafter dem- in the ventral but not the dorsal lobe [12]. However, this can-
onstrated the effects of Pigeum africanum. However, the not be interpreted as PygA extract having direct anti-
quality of literature on PygA for BPH treatment is severely androgenic properties.
limited by well-documented methodological flaws [25]. Rhodes et al. used the human prostate as a source of 5α-R,
The results of the effectiveness of PygA in the treatment and compounds were incubated with an enzyme preparation,
of LUTS and BPH have been reported in meta-analyses by and [3H] T and [3H]-DHT production was measured to cal-
Andro et al. [26] Ishani et al. [5], and Witl et al. [27] Wilt culate 5α-R activity. IC50 values (ng/mL) were for
et al. [27], who meta-analyzed [18] randomized controlled Finasteride = 1 and Tadenan® = 63,000, meaning that
trials involving 1562 men and published their findings in the 63,000 mg of Permixon® would be necessary to result in
Cochrane Library database, concluded that a standardized inhibition of 5α-R enzymic system comparable to just 1 mg
preparation of PygA may be a useful treatment option for of Finasteride, making Tadenan® an extremely weak inhibi-
men with LUTS consistent with BPH. Ishani et al. [5] had tor of 5α-R enzymes [32].
References 443
Currently, there are no studies of any kind concerning the sia: a systematic review and quantitative meta-analysis. Am J Med.
2000;109(8):654–64.
effects of PygA extract on human hair follicles. Nevertheless,
6. Barlet A, Albrecht J, Aubert A, et al. Efficacy of Pygeum africanum
numerous topical preparations and oral supplements contain- extract in the medical therapy of urination disorders due to benign
ing PygA are marketed to treat hair loss, claiming to have prostatic hyperplasia: evaluation of objective and subjective param-
“surrogate” Finasteride effects, with the “…bonus of “no eters. A placebo-controlled double-blind multi-center study. Wien
Klin Wochenschr. 1990;102(22):667–73.
adverse effects”. At the moment, there is no evidence for
7. Shenouda NS, Sakla MS, Newton LG, Besch-Williford C,
advocating the use of PygA extract in AGA/FPHL. Physicians Greenberg NM, MacDonald RS, Lubahn DB. Phytosterol Pygeum
need to be aware of the herb as many patients use it, and africanum regulates prostate cancer in vitro and in vivo. Endocrine.
opinions will be sought about its efficacy. 2007;31(1):72–81.
8. Komakech R, Kang Y, Lee JH, Omujal F. A review of the potential
of phytochemicals from Prunus africana (hook f.) Kalkman stem
bark for chemoprevention and chemotherapy of prostate cancer.
72.4 Dosage- Adverse Effects—Safety Evid Based Complement Alternat Med. 2017;2017:3014019.
9. Boulbès D, Soustelle L, Costa P, Haddoum M, Bali JP, Hollande
F, Magous R. Pygeum africanum extract inhibits proliferation of
Pygeum africanum is generally safe at the usual daily dose of
human cultured prostatic fibroblasts and myofibroblasts. BJU Int.
100 mg, and there have been no reports on interactions with 2006;98(5):1106–13.
pharmaceutical compounds [30], while reported adverse 10. Lawson RK. Role of growth factors in benign prostatic hyperplasia.
effects are rare and mainly mild gastrointestinal disorders. Eur Urol. 1997;32(Suppl 1):22–7.
11. Paubert-Braquet M, Cave A, Hocquemiller R, et al. Effect of
The dose range for PygA is between 75 mg and 200 mg, with
Pygeum africanum extract on A23187-stimulated production of
100 mg serving as the mode dose. Though relatively few lipoxygenase metabolites from human polymorphonuclear cells. J
investigations have targeted dose schemes, Chatelain et al. Lipid Mediat Cell Signal. 1994;9(3):285–90.
compared the efficacy and safety of Tadenan® 50 mg b.i.d. 12. Choo MS, Bellamy F, Constantinou CE. Functional evaluation of
Tadenan on micturition and experimental prostate growth induced
vs. 100 mg o.d. and claimed that both regimens proved
with exogenous dihydrotestosterone. Urology. 2000;55(2):292–8.
equally effective and safe at 2 months [25]. As reported in 13. Yoshimura Y, Yamaguchi O, Bellamy F, Constantinou CE. Effect of
the meta-analysis by Ishani et al. [5], 13 of the analyzed 18 Pygeum africanum tadenan on micturition and prostate growth of
studies provided information on adverse events, which the rat secondary to coadministered treatment and post-treatment
with dihydrotestosterone. Urology. 2003;61(2):474–8.
tended to be infrequent and mild in nature. The mean percent
14. Levin RM, Riffaud JP, Bellamy F, Rohrmann D, Habib M,
of participants who dropped out was 12% (179 men) and did Krasnopolsky L, Zhao Y, Wein AJ. Protective effect of Tadenan
not differ among PygA (13%), placebo (11%, p < 0.4), and on bladder function secondary to partial outlet obstruction. J Urol.
other controls (8%, p < 0.5). The most common complaint 1996;155(4):1466–70.
15. Gomes CM, Disanto ME, Horan P, Levin RM, Wein AJ, Chacko
was mild gastrointestinal upset.
S. Improved contractility of obstructed bladders after Tadenan
treatment is associated with reversal of altered myosin isoform
Synopsis expression. J Urol. 2000;163(6):2008–13.
Pygeum africanum might alleviate LUTS attributable to 16. Yablonsky F, Nicolas V, Riffaud JP, Bellamy F. Antiproliferative
effect of Pygeum africanum extract on rat prostatic fibroblasts. J
BPH but does not have any anti-androgenic properties.
Urol. 1997;157(6):2381–7.
Although many topical or orally administered products con- 17. Kadu CA, Parich A, Schueler S, et al. Bioactive constituents
taining Pygeum africanum claim to possess hair growth in Prunus africana: geographical variation throughout Africa
properties, there is no evidence whatsoever, and individuals and associations with environmental and genetic parameters.
Phytochemistry. 2012;83:70–8.
with AGA/FPHL should not waste time and resources in this
18. Gathumbi PK, Mwangi JW, Mugera GM, Njiro SM. Toxicity of
direction. chloroform extract of prunus africana stem bark in rats: gross and
histological lesions. Phytother Res. 2002;16(3):244–7.
19. Dreikorn K. The role of phytotherapy in treating lower urinary
tract symptoms and benign prostatic hyperplasia. World J Urol.
References 2002;19(6):426–35.
20. Dreikorn K, Berges R, Pientka L, Jonas U. Phytotherapy of benign
1. Nyamai DW, Mawia AM, Wanbua FK, Njoroge A, Matheri prostatic hyperplasia. Current evidence-based evaluation. Urologe
F. Phytochemical profile of Prunus africana stem bark from Kenya. A. 2002;41(5):447–51.
J Pharmacogn Nat Prod. 2015;1:110. 21. Schleich S, Papaioannou M, Baniahmad A, Matusch R. Extracts
2. Stewart KM. The African cherry (Prunus africana): can lessons be from Pygeum africanum and other ethnobotanical species with
learned from an over-exploited medicinal tree? J Ethnopharmacol. anti-androgenic activity. Planta Med. 2006;72(9):807–13.
2003;89(1):3–13. 22. Papaioannou M, Schleich S, Roell D, et al. NBBS isolated from
3. Bodeker G, van 't Klooster C, Weisbord E. Prunus africana (Hook.F.) Pygeum africanum bark exhibits androgen antagonistic activity,
Kalkman: the overexploitation of a medicinal plant species and its inhibits AR nuclear translocation and prostate cancer cell growth.
legal context. J Altern Complement Med. 2014;20(11):810–22. Investig New Drugs. 2010;28(6):729–43.
4. Stewart KM. The African cherry (Prunus africana): from hoe han- 23. Roell D, Baniahmad A. The natural compounds atraric acid and
dles to the international herb trade. Econ Bot. 2003;57(4):559–69. N-butylbenzene-sulfonamide as antagonists of the human andro-
5. Ishani A, MacDonald R, Nelson D, Rutks I, Wilt TJ. Pygeum afri- gen receptor and inhibitors of prostate cancer cell growth. Mol Cell
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24. Levin R, Brading AF, Mills IW, Longhust PA. Experimental mod- study of phytotherapy for benign prostatic hyperplasia. Clin Trials.
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Philadelphia: WB Saunders; 2000. p. 169–96. 29. Hutchison A, Farmer R, Verhamme K, Berges R, Navarrete RV. The
25. Chatelain C, Autet W, Brackman F. Comparison of once and twice efficacy of drugs for the treatment of LUTS/BPH, a study in 6
daily dosage forms of Pygeum africanum extract in patients with European countries. Eur Urol. 2007;51(1):207–15.
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with long-term open label extension. Urology. 1999;54(3):473–8. extracts: sense or nonsense? Curr Opin Urol. 2008;18(1):16–20.
26. Andro MC, Riffaud JP. Pygeum africanum extract for the treatment 31. Raynaud JP, Cousse H, Martin PM. Inhibition of type 1 and type
of patients with benign prostatic hyperplasia: a review of 25 years 2 5alpha-reductase activity by free fatty acids, active ingredients
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27. Wilt T, Ishani A, Mac Donald R, Rutks I, Stark G. Pygeum africa- 32. Rhodes L, Primka RL, Berman C, Vergult G, Gabriel M, Pierre-
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Proanthocyanidins
73
epigallocatechin-3-gallate (EGCG), which is the most abun-

Basic Concepts dant catechin in green tea (see Chap. 74).
• Proanthocyanidins are a group of natural com- Each proanthocyanidin’s properties depend on their struc-
pounds widely distributed in plants, and research ture variability, which in turn depends upon the nature of the
has shown that they have diverse properties that are flavan-3-ol extension and end units (stereochemistry at the
useful in treating several conditions. chiral centers and the hydroxylation pattern), the location
• Extensive research spanning over a decade under- and stereochemistry of the interflavan linkage between the
taken by a Japanese research team has demonstrated monomeric units and the degree of polymerization [5]. The
that procyanidins Β-2, B-3, and C-1 possess signifi- physiological and pharmacological properties of proantho-
cant hair growth properties in vitro, in animal mod- cyanidins are numerous and go beyond the scope of this
els, and humans, according to 3 small clinical chapter, therefore will just be mentioned: radical scavenger
studies. [5, 6], antioxidant [7], anti-mutagenic [8], antitumor-
• The assumed mechanism of action is through the promoting [9], antifungal [10], anti-viral [11], anti-
inhibition of PKC (Protein kinase C), the neutral- hypertensive [12] and capillary-protective [13].
ization of the catagen-inducing effects of TGF-β1, Proanthocyanidins probably exert their roles by three dis-
TGF-β2, and through the activation of mitogen- tinctive mechanisms, which they all possess to a greater or
activated protein kinase, MAK 1 and 2 to the hair lesser degree and derive in essence from the properties of the
follicle. simple phenolic nucleus itself. These properties are: (a) their
• According to available data, procyanidins with hair complexation with metal ions (iron, manganese, vanadium,
growth potential are found in apple and barley copper, aluminum, calcium, etc.), (b) their antioxidant and
extracts and their isolation is complicated and radical scavenging activities, (c) their ability to complex
costly. with other molecules, including macromolecules such as
proteins and polysaccharides [14].
Proanthocyanidins, also known as condensed tannins, are a 73.1 Proanthocyanidins and the Hair
group of polyphenolic secondary metabolites synthesized in Follicle.
plants as oligomers (or polymers) of flavan-3-ol units (also
known as epicatechin) via the flavonoid pathway [1, 2]. Takahashi and Kamimura, both working at the Japanese
Proanthocyanidins are widely distributed in fruits, legume research laboratory “Tsukuba Research Laboratories”, have
seeds, cereal grains and can be found in the respective bever- been working on proanthocyanidins since 1992, and they are
ages, such as juice, wine, cider, tea, and cocoa. They contrib- credited with every significant discovery related to clinical
ute to the bitter flavor and astringency, having a significant effects of proanthocyanidins.
influence on the mouthfeel [2, 3]. Proanthocyanidins serve In 1998, Takahashi et al. conducted an impressively
diverse biological and biochemical activities, including pro- extensive research effort to discover natural products that
tection against predation (herbivorous animals) and patho- possess hair-growing activity. They assembled more than
gen attack (both bacteria and fungal), as well as restricting 130 pharmaceutically usable and edible plants and divided
the growth of neighboring plants [4]. Epicatechin, upon each plant into several sections, such as roots, leaves, seeds,
addition of gallic acid, will form the structural molecule of and fruit. Then, they applied solvent extraction to all sam-
446 73 Proanthocyanidins
ples, first by chloroform, then by methanol, and finally by the mechanism of action might be. One of the proposed theo-
hot water. In all, they prepared more than 1000 plant extracts ries was that the growth-promoting effects of procyanidins
and examined the growth-promoting activity of each extract on the outer root sheath cells would switch the bulb into ana-
on hair epithelial cells isolated from C3H mouse dorsal skin. gen by some elusive mechanism, reportedly through the
immigration of sheath cells towards the bulb [18, 19].
Findings from earlier studies reported that procyanidins pos-
They discovered that proanthocyanidins extracted
sess PKC (Protein kinase C) inhibitory activity [20, 21].
from grape seeds promoted proliferation of hair folli-
Therefore, Kamimura and Takakashi investigated the rela-
cle cells by about 230% relative to controls (100%)
tionship between the PKC-inhibiting activity of procyani-
and that these compounds demonstrated remarkable
dins and their hair-growing activity. They demonstrated that
hair-cycle-converting activity from telogen to anagen
procyanidin B-2 and procyanidin C-1 selectively inhibited
in the C3H mice in vivo test system [15].
PKC, intensively promoted hair epithelial cell proliferation
in vitro, and stimulated anagen induction in vivo. The PKC
IC50 of procyanidin B-2 was 28 μΜ, and that of procyanidin
In a subsequent article (1999), Takahashi et al. reported C-2 was just 9 μΜ. The authors speculated that the hair-
that procyanidin Β-2 (an epicatechin dimer) and procyanidin growing activity of these molecules was related to their
C-1 (an epicatechin trimer) had the highest hair growth poten- PKC-inhibiting activity [22] since PKC has been reported
tial [16]. The maximum growth-promoting activity on mouse earlier to induce telogen transition and preservation [7].
hair epithelial cells with procyanidin B-2 reached 300% Another theory was presented by Kamimura et al., who
(30 μM) relative to controls (100%) in a 5-day culture. The examined the relationship of procyanidin Β-3 to the TGF-β
optimum concentration of procyanidin C−1 was lower than signaling pathway, a well-known regulator of catagen induc-
that of procyanidin B-2, and the maximum growth-promoting tion [17]. The addition of TGF-β1 to hair epithelial cell cul-
activity of procyanidin C-1 was 220% (3 μM). Minoxidil tures decreased the cell growth dose-dependently, and the
was less effective in the same cell culture system, demon- addition of procyanidin B-3 to the culture neutralized the
strating 160% proliferative activity at 400μΜ concentration. growth-inhibiting effect of TGF-β1. From these results, it
Topical application of 1% procyanidin oligomers on shaven was concluded that procyanidin B-3 could directly promote
C3H mice in the telogen phase led to significant hair regen- hair epithelial cell growth, counteract the growth-inhibiting
eration (procyanidin B-2, 69.6% ± 21.8%; procyanidin B-3, effect caused by TGF-β1 in vitro, and stimulate anagen
80.9% ± 13.0%; procyanidin C-1, 78.3% ± 7.6%) based on induction in vivo. Additionally, proanthocyanidins exhibit
the shaven area; application of vehicle only led to the regen- potent anti-inflammatory properties through elastase inhibi-
eration of 41.7% (SD = 16.3%) whereas Minoxidil 1% led to tion [23] and general radical scavenging activity [14].
the regeneration of 81.2% ± 10.5%. Kim conducted an analysis of bleached hair using electro-
In a similarly designed study, the same research team dis- phoresis, transmission electron microscope, and fluores-
covered that procyanidin B-3 deriving from barley extract cence dye. They reported that procyanidin oligomers strongly
induced significant growth-promoting activity of 140% rela- bind to the keratin in hair and inhibit hair breakdown caused
tive to controls [17]. A subsequent study (2002) of the same by oxidative damage [24]. A subsequent study by Kamimura
research team demonstrated that procyanidin Β-3 possesses et al. presented a theory of procyanidin B-2 upregulating the
similar hair growth properties with procyanidin Β-2 and pro- expression of MEK-1 and 2 (Mitogen-activated protein
cyanidin C-1. These two molecules were found to increase kinases) in cultured murine hair epithelial cells [25]. They
the proliferation of epithelial cells, keratinocytes, and skin speculated that the hair-growing effects of procyanidin
fibroblasts. The in vivo extension of the study, in a mice oligomers are associated with their growth-promoting effects
model, proved that their effectiveness in inducing transition on hair epithelial cells that follow MEK activation and their
of telogen hair follicles to anagen was higher than that of protective properties against TGF-β1- or TGF-β2-induced
Minoxidil 1% [16]. apoptosis that triggers catagen induction [26].
73.2 Mechanism of Action 73.3 Proanthocyanidins and AGA

of Proanthocyanidins on the Hair
Follicle Kamimura et al. conducted the first small clinical trial inves-
tigating the effects of a 1% procyanidin B-2 scalp tonic on
The exact mechanism of action of proanthocyanidins to epi- human hair growth. It was a double-blind, 6-month long
dermal cells and hair follicles is unknown, and in all the pub- clinical test involving a total of 29 subjects aged 30–50 years
lications mentioned above, the authors only assumed what with mild to moderate AGA. Nineteen men in the procyani-
73.4 Dosage- Adverse Effects—Safety 447
din B-2 group and 10 men in the placebo control group were hairs in a designated scalp area (a circle of 0.8 cm in diame-
analyzed, and the hair-growing effect was evaluated using a ter = 0.5 cm2) of the procyanidin group subjects after the
macro-photography technique combined with measure- 6-month trial was 3.3 ± 13.0, vs. -3.6 ± 8.1 (p < 0.001) in the
ments of the hair diameter of clipped hairs. The authors control group. The total number of hairs in the designated
measured the increase in the number of total hairs on the scalp area after 12 months of procyanidin treatment signifi-
0.25 cm2 designated scalp area of all subjects after 6 months cantly increased over the baseline value measured at the start
of treatment. The increase was significantly greater in the of the trial (11.5 ± 16.5; p < 0.005). Notably, 2 sets of clinical
procyanidin B-2 group vs. the placebo group (procyanidin photographs of two subjects before and after a 12-month
B-2, 6.68 ± 5.53 vs. placebo, 0.08 ± 4.56; p < 0.005). The treatment are included in the published article and actually
increase in the number of terminal hairs, defined as hairs show moderate efficacy of the specific procyanidin agent in
>60 μm in diameter, was significantly greater in the procy- the vertex area [31].
anidin B-2 group (1.99 ± 2.58 vs. placebo 0.82 ± 3.40;
p < 0.02). According to the authors, these results showed
that the 1% procyanidin B-2 lotion had and evident potential 73.4 Dosage- Adverse Effects—Safety
as a safe and promising future AGA treatment option. The
article does not contain any before-and-after photos or any Proanthocyanidins were discovered back in 1947 by Jacques
objective method of efficacy to support the claims of the Masquelier, who developed and patented techniques for their
authors [27]. The authors even considered that their results extraction from pine bark and grape seeds. The research on
compared favorably to those of oral Finasteride 1 mg/day, their properties is still ongoing, and the dermatological
citing for comparison the results of Kaufman et al., in which applications of these compounds are increasing [32].
an increase of 86 total hairs/5.1 cm2 (calculated as 4.22 total Unfortunately, there is no detailed information on the con-
hairs/0.25 cm2) after 12-month therapy was reported [28]. tent of foods in specific proanthocyanidins oligomers [33].
However, this comparison is not applicable since the stan- Notably, apples contain eight times on average per serving
dard deviation in the presented results is very high the amount of proanthocyanidins found in wine, with signifi-
(6.68 ± 5.53) and the Phase III clinical trials of Finasteride cant content differences between varieties, with some of the
measured terminal hairs and not total hairs. Additionally, highest amounts found in the Red Delicious and Granny
other studies (unpublished at the time), such as the one of Smith varieties [34].
Saraswat et al., would report a significantly higher number Specific proanthocyanidins are not commercially avail-
of terminal hair (36.1 hairs/cm2) for Finasteride 1 mg after able as isolated compounds, and their isolation from natural
12 months, which is closer to empirical findings of everyday sources is a very complex and costly industrial process [35,
clinical practice [29]. Kamimura et al. published in 2001 the 36]. Notably, in the initial study of Takakashi et al., 20 tons
4-month results of the same trial and reported that in the of apple juice were used to isolate just 107 g of procyanidin
procyanidin B-2 group, 78.9% of patients showed an Β-1 of purity >95% (wt/wt) pure in dry weight [16]. In the
increased mean value of hair diameter, whereas only 30.0% subsequent studies, from 5.86 kg of apples, 412 mg of procy-
in the placebo group showed an increase (p < 0.02). The anidin C-1 of purity >94 (wt/wt)% pure in dry weight was
diameters of the bases of the collected hairs were measured isolated [18], whereas, 30 kg of seed husks of barley were
using a micrograph-equipped microscope (BH-2, Olympus necessary to produce approximately 159 mg of procyanidin
Optical Co., Tokyo, Japan) at a magnification of ×300. Β-3 of purity >94 (wt/wt)% pure in dry weight [17].
However, the article does not contain any before-and-after Nevertheless, commercially available grape seed extracts
photos to support the findings of the authors [30]. (GSE) are easy and cheap to produce, claiming to be rich
The same research team published the results of their lat- sources of proanthocyanidins that can be used locally on the
est clinical trial in 2005, which was a 12-month long, double- scalp or taken orally for hair growth benefits.
blind study on 43 patients with ΑGΑ (27–58 years old)
randomized to 21 males in the procyanidin group and 22
The author personally contacted Prof. Takahashi, and
males in the placebo group. The test agent was a 0.7% (w/w)
he explained that proanthocyanidins in commercial
procyanidin lotion, and 2 mL per dose was applied to the
GSE do not have a hair growth potential since they
affected scalp area twice daily, giving a daily dose of 18.7 mg
contain gallic acid, which has been found to exert
of procyanidin oligomers. Subjects in the placebo group
apoptogenic effects and to increase the expression of
received the vehicle alone. In the first 6 months, the procy-
caspases [37]. According to Prof. Takahashi, the only
anidin and the placebo groups were compared to assess the
proanthocyanidins that can be useful as a treatment
medicinal effects of procyanidin oligomers, and the applica-
option in AGA/FPHL are found in apple and barley
tion time of the procyanidin group was subsequently
extracts.
extended to 12 months. The increase in the total number of
448 73 Proanthocyanidins
A evaluated the safety of topical procyanidin B-2 as a 4. Bais HP, Vepachedu R, Gilroy S, Callaway RM, Vivanco
JM. Allelopathy and exotic plant invasion: from molecules and
hair-growing agent. They examined the mutagenicity, acute
genes to species interactions. Science. 2003;301(5638):1377–80.
subcutaneous injection effects, primary irritation, skin sensi- 5. Haslam E. Vegetable tannins - lessons of a phytochemical lifetime.
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procyanidin B-2 was found to be safe and acceptable from 6. Bagchi D, Garg A, Krohn RL, Bagchi M, Tran MX, Stohs
SJ. Oxygen free radical scavenging abilities of vitamins C and E,
the series of irritation and toxicological tests. In more detail,
and a grape seed proanthocyanidin extract in vitro. Res Commun
mutagenicity tests using bacteria showed procyanidin B-2 to Mol Pathol Pharmacol. 1997;95(2):179–89.
be non-mutagenic. Chromosomal aberration tests using CHL 7. Kamimura A, Takahashi T. Procyanidin B-2, extracted from
cells indicated that it caused polyploidy, but no structural apples, promotes hair growth: a laboratory study. Br J Dermatol.
2002;146(1):41–51.
aberrations. Also, micronucleus tests for mutagenicity using
8. Liviero L, Puglisi PP, Morazzoni P, Bombardelli E. Antimutagenic
mice were negative. Acute subcutaneous injection studies activity of procyanidins from Vitis vinifera. Fitoterapia.
using rats revealed no significant injury symptoms; the lethal 1994;65(2):203–9.
dose (LD50) of procyanidin B-2 is higher than 2000 mg/kg 9. Gali HU, Perchellet EM, Gao XM, Karchesy JJ, Perchellet
JP. Comparison of the inhibitory effects of monomeric, dimeric,
(subcutaneous injection)
and trimeric procyanidins on the biochemical markers of skin
Primary irritation tests using rabbits indicated that a pro- tumor promotion in mouse epidermis in vivo. Planta Med.
cyanidin B-2 containing preparation showed no primary 1994;60(3):235–9.
irritation. In the guinea pig maximization test, there was no 10. Eberhardt TL, Young RA. Conifer seed cone proanthocyani-
dins polymers: characterization by 13C NMR spectroscopy
evidence of sensitization to procyanidin B-2. In primary ocu-
and determination of antifungal activities. J Agric Food Chem.
lar irritation tests using rabbits, procyanidin B-2 containing 1994;42(8):1704–8.
preparation and vehicle showed slight irritation of conjuncti- 11. Barnard DL, Smee DF, Huffman JH, Meyerson LR, Sidwell
vae, which was assumed to be caused by ethanol [38]. RW. Antiherpesvirus activity and mode of action of SP-303, a novel
plant flavonoid. Chemotherapy. 1993;39(3):203–11.
Additionally, in all the small yet well-designed clinical trials
12. Cheng JT, Hsu FL, Chen HF. Antihypertensive principles from the
mentioned earlier, procyanidin lotions were well tolerated, leaves of Melastoma candidum. Planta Med. 1993;59(5):405–7.
there were no adverse effects reported or drop-outs from the 13. Maffei Facino R, Carini M, Aldini G, et al. Free radicals scav-
study. enging action and anti-enzyme activities of procyanidines from
Vitis vinifera. A mechanism for their capillary protective action.
Arzneimittelforschung. 1994;44(5):592–601.
Synopsis 14. Haslam E. Natural polyphenols (vegetable tannins) as drugs: pos-
Topical procyanidins from apple and barley have been dem- sible modes of action. J Nat Prod. 1996;59(2):205–15.
onstrated in a few in vitro, in vivo, and clinical studies con- 15. Takahashi T, Kamiya T, Yokoo Y. Proanthocyanidins from grape
seeds promote proliferation of mouse hair follicle cells in vitro and
ducted by Takakashi et al. to have significant hair growth
convert hair cycle in vivo. Acta Derm Venereol. 1998;78(6):428–32.
properties, to be tolerable and safe. However, no other 16. Takahashi T, Kamiya T, Hasegawa A, Yokoo Y. Procyanidin oligo-
research teams have replicated these studies, and further evi- mers selectively and intensively promote proliferation of mouse
dence of these products being a potential treatment option hair epithelial cells in vitro and activate hair follicle growth in vivo.
J Invest Dermatol. 1999;112(3):310–6.
for AGA/FPHL is not available. Although procyanidins
17. Kamimura A, Takahashi T. Procyanidin B-3, isolated from bar-
extracted from various plants, especially grapes, have been ley and identified as a hair-growth stimulant, has the potential to
widely used as nutritional supplements, their safety and counteract inhibitory regulation by TGF-beta1. Exp Dermatol.
potential long-term toxicity still need to be further investi- 2002;11(6):532–41.
18. Takahashi T. Biological actions of oligomeric procyanidins: pro-
gated to allow a systematic evaluation. The isolation of pro-
liferation of epithelial cells and hair follicle growth. Methods
cyanidins with hair-growth properties from natural sources is Enzymol. 2001;335:361–8.
a very complex and costly industrial process, and these com- 19. Oshima H, Rochat A, Kedzia C, Kobayashi K, Barrandon
pounds are not commercially available as isolated Y. Morphogenesis and renewal of hair follicles from adult multipo-
tent stem cells. Cell. 2001;104(2):233–45.
compounds.
20. Polya GM, Wang BH, Foo LY. Inhibition of signal-regulated pro-
tein kinases by plant-derived hydrolysable tannins. Phytochemistry.
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M. Investigation of the topical application of procyanidin oligomers
Green Tea (Camellia sinensis)
74
water. However, most of the tea consumed in the world is

Basic Concepts black tea (78%), whereas green tea consumption comprises
• Green tea polyphenols (GTPs) inhibit a variety of only 20% [3].
enzymes in vitro, are potent antioxidants, and can The unique feature of green tea production is that the pro-
alter specific properties of cancer cells in culture. cessing of the tea leaves does not involve any form of fer-
Whether any of these effects is responsible for their mentation. Freshly harvested tea leaves are briefly heated in
in vivo effects is unclear. a pan or steamed without any additives. The brief heating
• The most prevalent and potent GTP is inactivates polyphenol oxidase, thereby preserving the anti-
epigallocatechin-3-gallate (EGCG), to which sev- oxidant activities of the polyphenols, prevents fermentation,
eral beneficial effects have been attributed, includ- producing a dry, stable product. The average total polyphe-
ing the in vitro inhibition of both 5α-reductase nol contents of green and black teas are similar, but with dif-
enzymes and the repression of the expression of ferent flavonoids present due to the degree of oxidation
androgen receptor genes. However, whether EGCG during processing [3, 4]. However, the exact polyphenolic
modulates androgenic activity in vivo in humans and other volatile organic contents of green tea vary and are
has not been demonstrated yet. influenced by climate, season, horticultural practices (e.g.,
• In vitro and animal studies have demonstrated that grown in the sun vs. grown under the shade), variety, and
EGCG has anti-apoptotic properties through the especially the age of the leaves, as well as the production
activation of Erk and Akt signaling pathways and method. Besides being directly consumed as an extract,
the increase of the Bcl-2/Bax ratio and that it pos- green tea is mostly used as an additive to alcoholic bever-
sessed an overall protective effect against follicular ages, desserts, and ice cream. Green tea oil is also used in the
effects of DHT. However, clinical studies are sparse, food industry for cooking and flavor-enhancing properties
and the potential for systemic or topical toxicity and in the textile industry as a fabric pigment [5].
remains an issue.
74.1 General Properties of Green Tea
Tea is the most popular beverage globally, with areas of Asia According to Chinese mythology, the first who supposedly
reporting the highest consumption per capita. In 2013, the discovered green tea and its therapeutic properties was the
global production of green tea was approx. 1.7 million tons, Chinese emperor Shen Nung, as early as the twenty-eighth
with a forecast to double in volume by 2023 [1]. Green tea, century B.C. [6] he was—most probably—a mythical figure
just like all types of tea, is made from the processed leaves of and not an actual emperor, and he has been thought to have
evergreen shrub Camellia sinensis. The leaves of Camellia taught the ancient Chinese not only their practices of agricul-
sinensis undergo different withering and oxidation processes ture but also the use of herbal drugs. The modern tea industry
to attain varying levels of oxidation, resulting in different tea has its origins in the spread of tea cultivation into India
colors, namely green tea, white tea, yellow tea, oolong, pu- between 1818 and 1834, derived through importing the tea
erh tea, and black tea [2]. Drinking tea has been considered a plant from China [7].
health-promoting habit since antiquity, and more than two- Green tea contains characteristic polyphenolic com-
thirds of the world’s population consumes this beloved bev- pounds, such as (−)-epigallocatechin-3-gallate (EGCG),
erage, making it the second-most popular beverage next to (−)-epigallocatechin (EGC), (−)-epicatechin-3-gallate
452 74 Green Tea (Camellia sinensis)
(ECG), and (−)-epicatechin (EC). Flavonols, including quer- Overall, well-designed epidemiological studies and inter-
cetin, kaempferol, myricitin, and their glycosides, are also vention trials are needed to evaluate further the cancer-
present in tea, and a typical cup of green tea usually contains preventive activities of tea and green tea polyphenols (GTPs)
250–350 mg tea solids, of which 30–42% are catechins, and in humans.
3–6% is caffeine [8]. The most abundant catechins in green
tea are EGCG (5–12%) and ECG (1–5%) [9, 10] with EGCG
having been intensively investigated for its biological activi- 74.2 Green Tea and the Skin
ties and properties.
EGCG is the most potent catechin in green tea, and Concerning the properties of GTPs on the skin, there are
in vitro research has attributed EGCG with antioxidant [11], hundreds of in vitro studies and a few in vivo studies on lab
antibacterial, antiviral [12], anti-inflammatory [13], antiath- animals [17, 27, 28] suggesting a beneficial effect of GTPs
erogenic [14], and even anticarcinogenic properties [15, 16]. on several dermatological diseases. GTPs in small-size trials
Much of the suggested anticarcinogenic effect of green tea is have been reported to block the damaging effects of UVB
predominantly credited to EGCG. In cell culture models, [29] and UVA radiation [30], thus reducing sunburn response
EGCG has been shown to decrease cell viability and pro- [31], UV-induced immunosuppression [32], skin cancer risk,
mote apoptosis in multiple cancer cell lines, including pros- and photoaging [33]. They have also been shown to have
tate cancer, with no effect on non-cancerous cell lines [17]. antiviral (on HPV and genital warts) [34] and anti-
Some authors have even reported tumor regression both inflammatory effects by targeting cells or cellular interac-
in vitro [18] and in vivo in lab animals [19, 20]. These actions tions in the skin, as well as the skin microbiome [35].
are attributed to the property of EGCG to bind directly to Studies on the transdermal absorption of EGCG have been
several receptors and signaling molecules, inhibiting the performed in vitro [36, 37], while in vivo investigations have
functions of key receptors, kinases, proteinases, and other been restricted to animals [38, 39], and under experimental
enzymes [21]. conditions, EGCG seems to be adequately absorbed. However,
evaluation of the effects of GTPs in human skin is minimal.
EGCG effectively penetrates the dermal barrier in mice
However, epidemiological studies have not yielded
[40], but since animal skin exhibits different permeability
conclusive results on the cancer-preventive effect of
properties compared to human skin, results are not directly
green tea consumption in humans, possibly due to dif-
applicable to humans [41]. Scalia et al. [42] were the first to
ferent confounding factors and results of inverse asso-
examine the effect of topical vehicles on the in vivo human
ciation, positive association, or no association
stratum corneum penetration by a tape-stripping technique.
depending on the organ or the type of cancer under
They reported that GTPs in hydrophilic ointment led to high
examination [22].
concentrations in the stratum corneum but negligible sys-
temic availability of GTPs, without mentioning, though,
whether GTPs could reach the dermis [42]. Studies on the
Lu et al. [23] reported that tea consumption is associated use of GTPs with a double-blind, randomized approach and
with an increased risk of bladder cancer (Odds Ratio, OR: large patient numbers are painfully missing. Another chal-
3.29, 95% CI: 1.34–8.05) [23]. Bianchi et al. [24] reported lenge is that standard delivery systems for topical application
that individuals who consumed >5 cups/day (>90th percen- of GTPs have not been established. This is partially due to
tile) had a suggestive decreased risk (OR: 0.7, 95% CI: 0.5– the nature of these highly reactive compounds since they are
1.0) of bladder and kidney cancers [24], whereas Johnson easily oxidized and gradually lose their activity if not used
et al. [25], in their review, suggest that green tea may have a immediately after preparation [43, 44].
distinct role as a chemopreventive agent for prostate cancer Still, the topical application of GTPs is assumed to result
[25]. Boehm et al. [26], who meta-analyzed 51 studies with in sufficient penetration of active substances through the skin
more than 1.6 million participants and published their results [45], and GTPs are popularly used in skincare and anti-aging
in the Cochrane Database of Systematic Reviews, concluded products without, though, any concrete evidence on the effi-
there is insufficient and conflicting evidence to give any firm cacy [46].
recommendations regarding green tea consumption for can-
cer prevention. According to their results, the desirable green
tea intake is 3–5 cups per day (up to 1200 mL/day), provid- 74.3 Green Tea as an Antiandrogen
ing a minimum of 250 mg/day catechins. As long as the daily
recommended allowance is not exceeded, those who enjoy An interesting property of EGCG is the in vitro inhibition of
“a cup of green tea” should continue its consumption since it both 5α-Reductase (5α-R) enzymes. Interestingly, very lim-
is safe at moderate, regular, and habitual use [26]. ited research has been done on the issue. Liao et al. [9]
74.4 Green Tea and the Hair Follicle 453
reported that EGCG is a potent inhibitor of 5α-R isotype Ι rodent diets. The results showed that 33% of the mice in
but not isotype ΙΙ, having an IC50 = 12 μΜ for 5α-R isotype Ι experimental Group A had significant hair regrowth during 6
[9]. According to later (2002) studies by Hiipakka et al. [47], months of treatment (p = 0.014). No hair growth was
EGCG was reported as a competitive inhibitor of NADPH observed among mice in the control group, and 8% of con-
and showed potent inhibition of type 1 (IC50 = 12 μΜ) and trols even showed progressive hair loss during the study
less of type 2 5α-R (IC50 = 73 μΜ) in cell-free but not in period vs. none in the active group [51].
whole-cell assays of 5α-R. The authors speculated that the Kwon et al. [52] were the first to evaluate the effect of
lack of activity in whole cells might have been due to an EGCG on hair growth using human scalp anagen hair folli-
inability of these catechins to cross the cell membrane or to cles of five healthy male volunteers (20–31 years). EGCG at
enzymatic or non-enzymatic changes in the structure of these 0.1 μM or 1 μM induced hair follicle elongation by
catechins in assays using whole-cell cultures. When they 123.0% ± 9.0% and 121.6% ± 7.1% compared with the
replaced the gallate ester in EGCG with long-chain fatty vehicle-treated controls, respectively. EGCG significantly
acids, they produced potent 5α-R inhibitors which were enhanced hair growth at 5 μM by 181.2% ± 15.8% (p < 0.05),
active in both cell-free and whole-cell assay systems. Lin and in a wide concentration range 0.01–0.5 μM, EGCG
et al. [48] also demonstrated that when they synthesized sev- enhanced the proliferation of human dermal papilla cells
eral 3-O-acylated (e)-epigallocatechins, and especially when (DPCs) in vitro in a dose-dependent manner (p < 0.05), pos-
palmitic acid was coupled with EGCG, the inhibitory activ- sibly through the activation of Erk and Akt signaling path-
ity was impressively increased to IC50 = 0.53μΜ [48]. ways. Moreover, EGCG treatment for 24 h increased Bcl-2
However, in vivo activity is ultimately dependent upon expression but decreased Bax expression in a dose-dependent
attaining pharmacologically active agents in target tissues, manner (p < 0.05). This is a positive action since Bcl-2 has
which will depend on absorption, distribution, metabolism, an anti-apoptotic effect, whereas Bax induces apoptosis.
and excretion of the agents. Liao et al. [27] tested the in vivo Finally, the authors applied 10% EGCG or ethanol vehicle
effects of EGCG on the hamster flank organ growth, a typical daily to two regions of the occipital scalp of three normal
androgen-dependent tissue, the growth of which is promoted human volunteers for four successive days to determine
by Testosterone (T) and DHT and inhibited by 5α-R inhibi- whether the changes observed in vitro also occurred in vivo.
tors. EGCG actually inhibited the DHT-dependent growth of DPCs excised from in vivo scalp hair follicles after treatment
the hamster flank organ. The authors speculated that it might with 10% EGCG showed almost threefold P-Erk expres-
act by a mechanism other than inhibition of 5α-R [27]. Ren sional increases versus vehicle-treated controls. Akt phos-
et al. [49] might have solved this “mystery” since they con- phorylation increased 2.5-fold in response to 10% EGCG
ducted a study to determine whether GTPs have inhibitory treated regions compared to vehicle-treated regions, Bcl-2
effects on androgen action in an androgen-responsive, pros- expression increased over twofold, whereas Bax expression
tate cancer cell line, LNCaP. By using immunoblotting, reduced by 50% after topically treating 10% EGCG, thus,
northern blot analysis, and transient transfections, they dem- confirming that the events initially observed in vitro actually
onstrated that EGCG could repress the transcriptional activi- occurred also in vivo [52].
ties of the androgen receptor promoter region and inhibit Kim et al. [53] conducted the first in vivo experiment,
androgen action by repressing the transcription of the andro- examining the effect of topical EGCG on hair loss caused by
gen receptor gene [49]. However, it is not known whether intra-dermal Testosterone injection on 60 B6CBACF1/J
GTPs can modulate in vivo the androgenic activity in humans female mice. Their results suggested that EGCG prevented
[50]. hair loss by reducing T-induced apoptosis of follicular epi-
thelial cells and provoked hair regrowth after epilation, with-
out interfering with the expression of enzymes
74.4 Green Tea and the Hair Follicle 7β-hydroxysteroid dehydrogenase (HSD) και β-HSD [53].
Shin et al. [54] investigated whether EGCG reduced
There are very few studies associating green tea with hair DHT-mediated cellular damage in human DPCs. The results
growth properties. Only one study examined the in vivo suggested that EGCG inhibited DHT-induced cell death and
effects in humans, testing a herbal multi-formula product but growth arrest, intracellular ROS levels, and senescence.
had severe methodological flaws. Additionally, EGCG improved the DHT-mediated elevation
Esfandiari et al. [51] conducted an experimental study in of intracellular ROS levels and thus protected human DPCs.
randomly assigned 60 female Balb/black mice into two equal EGCG significantly upregulated or downregulated overall 53
groups; A (experimental) and B (control). Group A received miRNAs. Furthermore, the authors predicted the targets of a
a 50% fraction of polyphenol extract from dehydrated green number of the EGCG-regulated miRNAs. Many of the pre-
tea in their drinking water for 6 months, Group B received dicted target genes were associated with pathways regulating
regular drinking water, and both groups were fed regular anti-oxidation, apoptosis and cell death, proliferation and
cell growth, aging, and the cell cycle. Their results showed isoflavones). The reported results were positive. However,
that the EGCG-mediated regulation of those regulatory path- the study had severe limitations and conflicts of interest (see
ways was related to alterations of miRNA expression in Chap. 45, Ref. [55]).
DHT-exposed human DPCs and that EGCG provided an
overall protective effect against DHT [54].
Chung et al. [55] used 6-week-old male C57BL/6 mice to 74.5 Dosage- Adverse Effects—Safety
examine the effect of a traditional topical herbal complex
(Houttuynia cordata) widely used in Asia for the treatment The route of administration mostly determines the potential
of patients with hair loss, usually in combination with toxicity of GTEs. Products containing green tea or GTPs are
GTE. The mice were randomly divided into four groups mostly cosmetics, shampoos, and vitamin supplements,
(negative control, Finasteride 1 mg/kg as a positive control, whereas hair tonics containing green tea are used for hair
and two concentrations of the herbal complex, 200 mg/kg loss and reduction of seborrhea [58]. Concerning the topical
and 400 mg/kg, as experimental groups), and all were fed route, standard delivery systems for topical application of
corresponding medications orally for 25 days. Hair growth GTPs have not been established, partially because these
was evaluated visually and microscopically, and Western highly reactive compounds are readily oxidized in the envi-
blot analysis for Insulin-like growth factor IGF-1 and ronment and gradually lose their activity if not used immedi-
transforming growth factor TGF-β1 was performed. They ately after preparation.
reported that the area of hair regrowth was 55.1% (± 3.8), Another challenge is the epidermal penetration, which is
70.2% (± 6.3), 83.5% (± 5.7), and 86 (± 6.9) in the negative negligible in humans unless high concentrations of GTPs or
control, herbal complex 200 mg/kg, 400 mg/kg and EGCG in a formulation are used, significantly increasing the
Finasteride group, respectively. In the histologic examina- cost. Additionally, it is not certain that the action of EGCG in
tion, the hair follicle count in deep subcutis was 2.6 (± 0.7), high concentrations is positive for skin and hair follicles. A
5.8 (± 0.7), 8.6 (± 1.2), and 7.9 (± 0.9), whereas the diameter study by Trompezinski et al. [59] reported that EGCG
of hair follicles was 11.9 μm (± 5.0), 17.4 μm (± 3.9), decreases VEGF production by activated keratinocytes,
22.8 μm (± 5.2) and 18.1 μm (± 2.1) in the negative control, which could have adverse effects on hair follicles [59].
herbal complex 200 mg/kg, 400 mg/kg group and Finasteride Oral consumption of green tea is generally safe since the
group, respectively. The expression of IGF-1 was 0.14 (± bioavailability of catechins is low after oral administration.
0.01), 0.23 (± 0.02), 0.24 (± 0.01) and 0.21 (± 0.01) the However, under specific conditions, such as fasting or after
expression of TGF-β1 was 0.26 (± 0.01), 0.19 (± 0.02), 0.15 repeated high dose-administration, catechin plasma levels
(± 0.01) and 0.18 (± 0.02) in negative control, the 200 mg/kg can reach toxic levels. Prolonged oral intake of green tea
400 mg/kg and Finasteride group, respectively (all p < 0.05 products is potentially harmful because GTE catechins at
to p < 0.001) [55]. high doses have induced goiter in rats [60]. The dietary
Zhang et al. [56] evaluated the effect of EGCG on the administration of 500 mg/kg/day EGCG for 13 weeks
growth of mink hair follicles and investigated the possible increased bilirubin and decreased fibrinogen, while a single
molecular mechanisms. Data from ex vivo culture showed oral dose of 2000 mg/kg EGCG was lethal in rats [61].
that, in the presence of 0.5–2.5 μM EGCG, the growth of
mink hair follicles was promoted. In vitro, the proliferation
There have been several reports of hepatotoxicity
of DPCs was enhanced by 0.5–4 μM EGCG treatment. More
related to GTPs supplements in humans. Verhelst et al.
cells entered S phase upon treatment of EGCG, accompanied
[62] even reported a patient with acute hepatitis,
by upregulation of cyclin D1 and cyclin E1. Furthermore,
resembling drug-induced hepatitis, induced by intake
when exposed to EGCG, the sonic hedgehog (Shh) and AKT
of an oral green tea derivative that claimed protection
signaling pathways were activated in both hair follicles and
against hair loss [62].
primary DPCs and outer root sheath cells (ORSCs). Inhibiting
either of these two pathways partly reversed the effect of
EGCG on the proliferation and cell cycle of DPCs and
ORSCs. The authors concluded that EGCG promotes the Although most of the potential health benefits of green tea
growth of mink hair follicles at concentrations of 0.5–2.5 μM and GTPs have been attributed to their antioxidant properties,
through activating Shh and AKT signaling pathways [56]. an increasing body of evidence suggests that GTPs can even
In 2017, Nichols et al. [57] conducted an open-label, pro- behave as pro-oxidative compounds. Experiments performed
spective, proof-of-concept 24-week long study on the effi- in rat liver cells showed that high concentrations of GTEs and
cacy and safety of an oral supplement, Forti5®, containing of single tea phenolics are toxic. This cytotoxicity appears to
GTE, among several other ingredients (omega-3 and -6 fatty be related to the gallic acid unit, and the most toxic compound
acids, cholecalciferol, melatonin, beta-sitosterol, and soy was EGCG, while the least cytotoxic was epicatechin [63].
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drugs—I. A novel method based on the conclusions of international
Ginkgo Biloba (Maidenhair Tree)
75
traditionally used to treat several medical conditions, while

Basic Concepts the flowers are not edible [2]. The German surgeon Englbert
• The standardized Gingko Biloba Extract (GBE) Kaempfer was the first to use the term “Ginkgo” in 1712, but
named EGb761® is the most extensively researched Carl Linnaeus was the one who named it Ginkgo biloba in
herb; it contains potent flavonoids, diterpines, gink- 1771 [3].
golide-B, and bilobalide, which seem to act
synergistically.
• GBE has vasodilatory, antioxidant, free-radical 75.1 General Properties of Ginkgo Biloba
scavenger, and anti-inflammatory properties, and is
an inhibitor of platelet-activating factor. Even Ginkgo biloba is the most ancient and valued among medici-
though it reduces Nitric Oxide radicals and improves nal plants, its use dating back to 1505 A.D. Ginkgo biloba
skin microcirculation, it can reduce the activity of seeds have been used in the belief that they can treat pulmo-
fibroblasts and inhibit collagen production. nary disease, chronic cough, bladder inflammation, and
• GBE seems to have contradicting properties con- enuresis, while the leaves have been used to treat cardiovas-
cerning hair growth; there are no direct in vitro cular disease and skin infections [4, 5].
studies in hair follicle cultures and only a single The therapeutic effects and pharmacological actions of
in vivo study published in a Japanese journal is Ginkgo biloba are attributed to the joint effect of multiple
available. components, and no individual component is regarded to
exert a significant effect solely. Novel phytochemical con-
stituents in Ginkgo biloba have been investigated, with many
compounds isolated and described, including terpenes and
Ginkgo Biloba is a dioecious tree that can live for more than trilactones (ginkgolides and bilobalides). More than 20 fla-
800 years and is the only living species in the division vonoid glycosides, along with glucosides, biflavones, vita-
Ginkgophyta, all others being extinct. It is regarded as a “liv- mins, and essential amino acids, are known to occur in GBE
ing fossil“because of the species’ uninterrupted existence for [6, 7]. However, the constituent components of the leaves of
270 million years and is the oldest tree in the world, with no Ginkgo biloba undergoes fluctuating changes with respect to
living relative in existence. Mature trees have massive trunks many parameters:
with a girth of >7 m, and they reach a height of 30–40 m.
• the season, since higher amounts of flavonoids are
extracted in autumn than in spring [8],
The extreme tenacity of this species was witnessed in
• the country of origin of the tree,
Hiroshima, Japan, where six trees growing between 1
• the age of the tree,
and 2 km from the 1945 atom bomb explosion were
• the time of harvest during the day.
among the few living things in the area to survive the
blast [1].
Therefore, it has been considered essential to standardize the
GBE to obtain consistent bioactivities [9].
GBE has been developed for pharmaceutical purposes in
Ginkgo biloba extract (GBE) is produced from the fan- Germany since 1965, but the first commercially available
shaped leaves, and together with the white-yellow seeds, are extract registered for human use was produced in France in
460 75 Ginkgo Biloba (Maidenhair Tree)
1974 under the name EGb761® and is among the bestselling and whole animal models have revealed that GBE may have
herbal medications worldwide [10]. EGb761® is a (suppos- anticancer properties related to antioxidant, anti-angiogenic,
edly) standardized extract containing flavone glycosides and gene-regulatory actions [21].
(kaempferol, quercetin, isohamnetine) at 22–27%, and ter- Mechanisms to explain GBE’s potential procognitive and
penlactones at 5–7%, of which 2.6–3.2% bilobalide and neuroprotective effects are mostly attributed to increased
2.8–3.4% ginkgolides A, B, C which are unique in this plant. cerebral blood flow [22]. Indeed, GBE inhibits platelet-
Notably, the most pharmacologically potent are ginkgolide-Β activating factor (PAF) and enhances nitric oxide (NO) pro-
and bilobalide [9]. Despite the reported standardization, duction in vessels, with subsequent beneficial effects in
when Kressmann et al. [11] studied a variety of products peripheral and cerebral blood flow [23]. Other experts con-
concerning the pharmaceutical quality, such as the number sider that GBE’s mechanisms of action warranting neuropro-
of constituents and in vitro dissolution, results were incon- tective, antioxidant, free-radical scavenger, membrane
sistent with label information. In terms of the content of stabilizer, and PAF inhibiting properties are due to gink-
active substances, flavone glycosides ranged from 24 to 36% golide-B [24]. Other pharmacologic effects of GBE include
and terpene lactones from 4% to 11%. Concerning ginkgolic the following: endothelium relaxation mediated by inhibi-
acids, contents ranged from <500 to ≥90,000 ppm. Most of tion of 3′,5′-cyclic GMP (guanosine monophosphate) phos-
the investigated products released more than the required phodiesterase [25]; inhibition of age-related loss of
75% of the content of both components within 30 min. muscarinergic cholinoceptors and α-adrenoceptors; stimula-
However, several products showed clear and relevant differ- tion of choline uptake in the hippocampus [26], and inhibi-
ences in dissolution rates to the rest, indicating much poorer tion of beta-amyloid deposition in the brain [27].
pharmaceutical quality than expected [11]. To assess GBE’s efficacy and safety, Birks et al. reviewed
all relevant, randomized, double-blind controlled studies, in
which GBEs at any strength and over any period were com-
75.2 Ginkgo Biloba, Scientific Research pared with placebo for their effects on people with acquired
and Applications cognitive impairment, including dementia, of any degree of
severity. They published their results in the Cochrane
Ginkgo biloba is one of the most extensively studied herbs, Database of Systematic Reviews, initially [15] in 2002, fol-
and numerous clinical studies have been conducted to evalu- lowed by an update [28] in 2007 and another in 2009 [29]. In
ate its therapeutic value for various conditions. GBE is all three reports, they disclosed that GBEs appear to be safe
widely prescribed in Germany and France to treat a range of with no excess side effects compared with placebo.
conditions, including memory and concentration problems,
confusion, depression, anxiety, dizziness, tinnitus, and head-
However, evidence that GBEs have predictable and
ache. The worldwide sales of Ginkgo biloba products are dif-
clinically significant benefits for patients with demen-
ficult to estimate but are believed to be worth around 500
tia or cognitive impairment is inconsistent and
million USD, and this has resulted in overharvesting of
unreliable.
Gingko biloba leaves. The International Union for
Conservation of Nature (IUCN) listed the species under the
threatened category of “endangered” due to the rapid decline
in the numbers of individual trees worldwide, for which con- This was due to limitations, such as poor methodological
servation measures are required [12]. quality and unsatisfactory methods, limited sample size,
GBE has been reported to improve cognitive functions, short duration of most trials, and publication bias, resulting
particularly memory loss, attention, alertness, vigilance, in inconsistent findings of included trials. These same find-
arousal, and mental fluidity [13, 14], to be useful in the early ings have been reported by other authors who conducted sys-
stages of cognitive impairment and dementia [15] and in tematic reviews on GBEs [30].
mild to moderate Alzheimer’s disease [16]. Early studies
reported that GBE was helpful to patients with peripheral
arteriopathy [17], with circulatory problems of venous or 75.3 Ginkgo Biloba, the Skin, and the Hair
arterial etiology [14], and even to have a potential role in Follicle
cardiovascular disease [18]. Recent studies have indicated
that GBE, as an add-on to antipsychotic medication, amelio- GBE exhibits in vivo free-radical-scavenger activity [31],
rates the symptoms of chronic schizophrenia [19] and inhibits prostaglandin PGE2, downregulates COX-2 both
improves selective attention, some executive processes, and in vitro and in male ICR mice, without affecting COX-1/
long-term memory for verbal and non-verbal material [20]. COX-2 activity, and inhibits skin inflammation after topical
Recent studies conducted with various molecular, cellular, application [32]. GBE locally induces superoxide dismutase
References 461
(SOD) and catalase enzyme activity in the epidermis after events has not been established according to the systematic
topical application, and it also systemically increases the review by Savović et al. [48] They included eight random-
activity of both enzymes in the liver, heart, and kidney of ized controlled trials and concluded that the “available evi-
Sprague Dawley rats [33]. GBE has been reported to have dence does not demonstrate that extract of Ginkgo biloba
potent in vivo vasodilatory properties [34], to improve skin causes significant changes in blood coagulation parameters”
microcirculation [35], to have enhancing effects on the pro- [48]. A more recent meta-analysis of 18 randomized con-
liferation of normal human skin fibroblast in vitro increase trolled trials by Kellermann et al. [49], designed to determine
[36], and to have the ability to inhibit NO-stimulated PKC the effect of GBE on outcome parameters of hemostasis
activity [37]. associated with risk of bleeding, reported that GBE intake
All these in vitro and experimental in vivo properties did not indicate a higher bleeding risk [49].
could be interesting concerning hair growth, mostly the NO Concerning the potential for herb–drug interactions, GBE
suppression [38]. Wolf et al. [39] reported that the basal NO constituents, namely, ginkgolic acids I and II, have been
level was enhanced threefold by stimulating dermal papilla found to significantly inhibit one or more of the cDNA
cells (DPCs) with DHT (but not with Testosterone) and that human P450 isoforms at concentrations of <10 μM [50].
NO is a signaling molecule in human DPCs, implicated in Furthermore, GBE should not be taken concomitantly with
basal and androgen-mediated hair follicle activity [39]. CYP2C19 substrates (e.g., omeprazole) [47]. The topical
However, there is only one experimental study on the effects application of GBE has not been related to any adverse
of GBE on hair growth on C3H strain mice, published in a effects on lab animals [51] or humans [52], while it has been
Japanese scientific journal by Kobayashi et al. [40], demon- reported to get transcutaneously absorbed at a satisfactory
strating the promoting effect on the hair regrowth of a 70% rate under experimental conditions [53].
ethanolic GBE [40]. GBE is generally well tolerated, and side effects are rare,
Ever since, no other studies have claimed hair-growth usually mild, and related to excessive consumption of GBEs.
effects for GBE. A more recent study by Trompezinski et al. Symptoms include gastrointestinal disturbances (nausea,
[41] reported that GBE exerted a potent inhibition on VEGF vomiting, diarrhea), headaches, dizziness, palpitations, rest-
and CXCL8/IL-8 levels in activated keratinocytes, a property lessness, weakness, and allergic skin reactions. Anaphylaxis-
which could—theoretically—have a negative effect on hair like reactions occur only with intravenous administration
follicles [41]. [54]. The unprocessed Ginkgo biloba leaf contains ginkgolic
acids that are toxic, and leaves should not be consumed [51,
55]. Although no studies have been performed to support any
75.4 Dosage- Adverse Effects—Safety restrictions on the use of Ginkgo during pregnancy or lacta-
tion, it seems prudent not to administer it in the absence of
Ginkgo biloba products are commonly available as oral tab- data [56].
lets, extracts, capsules, or teas. No adequate studies are
determining the dose of GBE needed to achieve beneficial Synopsis
effects, although the recommended dose of EGb761® is Ginkgo biloba is a very popular (actually overhyped) herb,
40–60 mg, 3–4 times daily, based on clinical trials [9]. attributed with impressive cognitive-enhancing properties
Studies show that relatively low risk is associated with the that have not been reliably documented. The properties of
consumption of GBE products. However, the most severe some ingredients in the Gingko biloba Extract (GBE) could
potential clinical problem with GBE is the inhibition of the have hair growth potential, but other ingredients could
PAF [42]. equally exert adverse effects on the hair follicle. There is no
data on the in vivo hair growth efficacy of topically used
GBE, whereas oral administration requires caution and is not
This makes GBE use in conjunction with warfarin
justified under any circumstances in the treatment of AGA/
[43], aspirin [44], or other antiplatelet agents a matter
FPHL.
of clinical judgment. GBE has been related to sponta-
neous bleeding, postoperative bleeding, and prolonga-
tion of clotting time [45, 46].
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Allium Cepa (Red Onion)
76
quercetin chemical species, namely isoquercetin, quercetin

Basic Concepts diglucoside, quercetin monoglucoside-1, quercetin monoglu-
• Allium cepa has been used since antiquity as a coside-2, free quercetin, and kaempferol. Quercetin mono-
medicinal and food source. It contains high amounts glucoside-1 and quercetin diglucoside are the major flavonoids
of important members of quercetin chemical spe- accounting for 80% of the total quercetin content [5].
cies such as sulfides (ACSOs) and anthocyanins
that possess favorable properties on hair follicles
in vitro. 76.1 General Properties of Allium Cepa
• Red onion juice is a folk remedy for hair loss that
lacks concrete scientific support besides a small Red onions are good sources of a variety of nutrients and
study on Alopecia Areata patients and several phytochemicals, including organosulfur compounds and fla-
manufacturer-sponsored small studies with contro- vonoids. Onion plants synthesize flavonoids as protective
versial results. compounds against damage by UV radiation and by intracel-
• There are significant practical difficulties for the lular hydrogen peroxide. Allium cepa makes the most gener-
use of red onion juice as a “home remedy”, such as ous contribution of antioxidant flavonoids to the Western
the unpleasant smell and rapid neutralization. European diet by virtue of their content and their frequency
of consumption [7].
Bioactive phenolic compounds found in onions are widely
recognized as beneficial to health, with the potential to pro-
Allium cepa is one of the oldest domesticated and cultivated tect the body from certain degenerative diseases [8]. Many
vegetables in human history. It has been grown and selec- reports have indicated that red onions have a wide range of
tively bred in cultivation for at least 7000 years, but the beneficial human health properties, such as anticholesterol-
onion’s geographic origin is uncertain because the wild emic [9], antimutagenic [10], and antioxidant capacity [11].
onion is nowadays extinct [1]. According to archaeologists, There is an increasing attention on the antioxidant content of
botanists, and food historians, the first cultivated, farmed onions since their regular consumption is associated with a
onions probably appeared in central Asia or Persia. In ancient reduced risk of neurodegenerative disorders and cataract for-
Egypt, it was the only vegetable depicted with gold flakes, mation [12]. A meta-analysis by Zhou et al. [13] evaluating
and its spherical, concentric shape symbolized eternity [2]. the relationship between Allium vegetable intake and risk of
In ancient Greece and Rome, athletes used it as food for the prostate cancer reported that Allium vegetables, and particu-
“balance of blood” and as an extract for soothing sore mus- larly garlic intake, relate to a decreased risk [13]. Other prop-
cles [3]. erties that have been attributed to Allium cepa are antiplatelet/
Allium family members (onion, garlic, etc.) contain two anticoagulant [14], antibiotic, anti-asthmatic [15], and even
classes of biochemically active ingredients, mainly in the androgenic properties that can positively affect sperm health
form of cysteine derivatives such as flavonoids and sulfur parameters [16].
oxides, namely S-alk(en)yl-L-cysteine sulphoxides (ACSOs)
[4]. Other organosulfur compounds and nonvolatile sulfur-
However, most of these belong to popular medical or
containing peptides and proteins found in Allium family
“mixed” (popular and medical) myths, with varying
members are isothiocyanates, diallyl sulfide, and allicin [6].
degrees of “popular” and scientific support [17].
Allium cepa has also been found to contain five important
466 76 Allium Cepa (Red Onion)
Concerning the topical use of Allium cepa products, tive smell (absent in the tap-water group) which canceled the
recently, several studies have addressed the positive effects blind methodology. Finally, there are no before-and-after
of Allium cepa in the treatment of hypertrophic scars and photos of the results in the article to support the claimed find-
keloids. Allium cepa products both as a monotherapy [18], ings [22].
combined with pentaglycan and allantoin [19], or triamcino- Cucé et al. [23] conducted an open, monocentric, pro-
lone acetonide [20] lead to clinical improvement of scars and spective 12-week study on 20 male volunteers with AGA
reduced erythema, pigmentation, lesion induration, itching, (average age 32.5 years, range: 23–40 years) to test the effi-
and discomfort of hypertrophic and post-operative scars cacy of a novel formula Cellium® GC 210 mg/mL through
[21]. self-assessment and scalp biopsies [23]. The participants
applied 1 mL of the topical solution on either dry or wet
scalp twice a day (total daily dose: 2 mL), at 12 h intervals
76.2 Allium Cepa, Hair Follicles over a period of 12 weeks. They attended two clinical exami-
and AGA/ FPHL nations for data collection and vertex scalp biopsies; one
before the start of treatment (W0 phase) and the second
The use of Allium cepa juice is a traditional folk remedy for 12 weeks after treatment (W12 phase). The volunteers’ satis-
hair loss, credited with potent hair-growth properties. faction with the product reached an average of 8.3/10; 90%
Scientific evidence counts for one study on Alopecia Areata of participants observed new hair growth, 63–73% observed
patients and several small studies on a specific commercial faster hair growth, 84% observed more hair, 68% experi-
product, initially named Cellium® GC 210 mg/mL (Legacy enced a pleasant sensation following application, 65% clas-
Healthcare, Epalinges, Switzerland) and later named sified the product as good or very good, and none reported
CG210®. The botanical blend is based on Allium Cepa Bulb adverse reactions to the product. Concerning biopsies, before
Extract, Citrus Medica Limonum Fruit Extract, Theobroma and after treatment with topical solution, there was a statisti-
Cacao Seed Extract, and Paullinia Cupana Seed Extract. cally significant increase of 73.9% in the fraction of CD1A+
The first report is a single-blind, small study published by Langerhans cells in the epidermis (p = 0.003), an increase of
Sharquie et al. [22], who tested the effectiveness of topical 41.7% in the fraction of Ki-67+ cells in the epidermis
crude onion juice in treating patchy Alopecia Areata com- (p = 0.012), and an 89% increase in the fraction of
pared to tap water. The first group (crude onion juice treated BCL2 + cells in the epidermis (p = 0.001). In addition, a two-
group) consisted of 45 patients, 30 males (66.6%) and 15 fold increase in the expression of BCL2 in the epidermis was
females (33.4%). Their ages ranged between 5 and 50 years, observed, which has an anti-apoptotic role in hair follicles
with a mean of 23 years. The second group (control) con- (see Chap. 11, Vol. 1) The authors claimed that the product
sisted of 17 patients, 10 males (58.8%) and 7 females increases the proliferation and anti-apoptotic action of kera-
(41.2%). Their ages ranged between 3 and 35 years, with a tinocytes in the dermis and epidermis and reduces scalp
mean of 19 years. Both groups applied the treatment twice micro-inflammation. The full-text article does not contain
daily on the scalp for 2 months. During follow-up, 22 patients any before-and-after pictures of patients, and only histology
dropped out of the study for unknown reasons, while the photos are included. In the bibliography, several in-house
remaining 23 patients completed the follow-up for 2 months. studies of the manufacturer are cited [24–26].
The authors reported that regrowth of coarse terminal hairs Takeda et al. [27] conducted a randomized, double-blind,
started after just 2 weeks of treatment with crude onion juice. placebo-controlled, single-center, prospective, efficacy pilot
At 4 weeks, hair regrowth was noticed in 17 patients (73.9%), study to investigate the potential synergic effect when com-
and, at 6 weeks, hair regrowth was observed in 20 patients bining oral Finasteride 1 mg treatment with CG210®. They
(86.9%) and was significantly higher among males (93.7%) aimed to evaluate the hair diameter improvement following
compared to females (71.4%) (p < 0.0001). In the tap-water topical application of CG210® in AGA subjects already using
treated-control group, hair regrowth was seen in only two Finasteride 1 mg for at least 3 years. Twenty healthy male
patients (13%) at 8 weeks of treatment, with no difference volunteers between 31 and 67 years old, suffering from AGA
between sexes. According to the authors, crude onion juice corresponding to the stages ranging from IIV to IV of the
was an effective topical therapy for patchy alopecia areata, Hamilton classification enrolled in the study. The random-
but many severe limitations of this study practically cancel ization process resulted in 10 AGA volunteers receiving the
its clinical validity. Some of the severe methodological flaws topical placebo (Group A), 10 AGA volunteers receiving the
include: groups were too small and not comparable; pediat- topical CG210 (Group B). All subjects applied the topical
ric patients were investigated together with adults; the dura- lotion once a day, with a total dose between 1.3 and 2 mL. The
tion of the study was too short at 2 months; there was no results were evaluated by hair diameter improvement, scored
control group on which no intervention was carried out to in micrometers. A dozen hairs at the parietal region midline
exclude spontaneous recovery; the onion juice has a distinc- part were collected and cut at the bottom end 1 cm before the
trial and 12 months. The hair samples were then measured of life evaluation, and trichogram (anagen to telogen ratio).
using the Keyence Corporation IM6020 device. As the cross- The authors reported that the clinical evaluation demonstrated
section of a hair is oval, the minimum range was chosen for an increased hair density in 25 of 26 patients receiving the
the statistical analysis. After 12 months of topical application active lotion (great improvement in 2, moderate improvement
of the CG210®, the product was well accepted by the sub- in 23, and stable condition in 1 patient), while all the patients
jects, and there was no complaint for adverse effects. In receiving the control lotion were evaluated as stable (p < 0.001
Group A (oral Finasteride 1 mg + topical placebo), an aver- for any improvement). The self-assessment score signifi-
age increase of 2.12 μm in hair diameter was observed, cantly increased from baseline to 6 months in the intervention
which corresponded to +4.17% increase. In Group B (oral group (p < 0.001) but not in the control group (p = 0.56).
Finasteride 1 mg + topical CG210®), the average increase of Accordingly, the change from baseline was significantly
hair diameter was 2.98 μm, representing an increase of higher in the intervention group (p < 0.001). No topical or
+5.74%. In terms of “between group” difference, the out- systemic adverse reactions were reported during the study
come from Group A differed significantly from that of Group period. The full-text article contains 6 small pairs of low-
B (p = 0.002). Compared to Group A, an additional 37.7% quality before-and-after photos depicting mild improvement.
increase in hair diameter was observed in Group B. The The article has several limitations, such as the small sample
authors concluded that the product should set a new standard size, the single-blind methodology, the lack of an indepen-
in the management of excessive hair loss addressing the two dent examiner, the use of trichogram to measure anagen hairs
key issues that currently have not yet been simultaneously instead of a more precise technique, such as hair counts, and
tackled, i.e., premature cell apoptosis in the hair follicles and the use of subjective self-assessment method [28].
micro-inflammation in the scalp. However, reading the num- Everything else that can be found in the scientific litera-
bers correctly, a less “impressive” picture becomes evident. ture is in vitro or studies in lab animals on the hair growth
properties of isolated ingredients that can be found in Allium
• Finasteride + topical placebo users had a mean hair diam- cepa extract (among several other plant extracts), namely fla-
eter of 50.88 μm before treatment and 53.00 after vonoids, quercetin, and proanthocyanidins [29–32].
12 months (2.12 μm).
• Finasteride + topical CG210® users had a mean hair diam-
These in vitro findings are academically interesting but
eter of 51.93 μm before treatment and 54.91 after
do not translate into clinical efficacy in any way.
12 months (2.98 μm).
Τhese increases are both equally insignificant in clini-

cal terms concerning coverage and patient 76.3 Dosage- Adverse Effects—Safety
satisfaction.
Patients who want to try a hair-growth “home remedy” made
out of Allium cepa juice will face considerable technical dif-
The full-text article includes a case study of a 43 years old ficulties concerning storage, choice of onion type and size,
Japanese volunteer who had been using Finasteride 1 mg for and processing details.
3 years and started the application of topical botanical blend According to Gennaro et al. [33], the storage of onions for
CG210® for 12 months in combination with oral Finasteride 6 weeks in different conditions, all of them mimicking home
1 mg. The pictures, showing a comparison of “before” (hair storage habits, decreased the amount of total anthocyanins
diameter measurement: 47.1 ± 3.92 μm) and “after” 12 months’ by 64–73%, whereas the total antioxidant activity was
of combined use of oral Finasteride 1 mg and the topical CG210® reduced to 29–36% [33]. Loss of onion flavonoids subjected
(hair diameter measurement: 51.9 ± 10.8 μm) even though of to “cooking” ranges as follows: frying, 33%; sauteing, 21%;
small size and low quality, depict significant improvement [27]. boiling, 14–20%; steaming, 14%; microwaving, 4%.
Katoulis et al. [28] conducted a randomized, single- Commercial, dehydrated onion products contained minimal
blinded, vehicle-controlled study on 39 women with amounts or no flavonoids [34]. Small onions have higher fla-
FPHL. The 39 participants were randomized (2:1) in a single- vonoid content per kilogram than larger ones, whereas the
blinded manner using simple randomization and were distribution of the flavonoids across an onion bulb from the
assigned to apply either CG210® (intervention group, n = 26, first (outside) to the seventh (innermost) scale decreases
mean age 57.5 (range 35–67 years) or the vehicle (control gradually. An essential drawback of the topical use of Allium
group, n = 13, mean age 47 (range 38–65 years), twice daily, cepa solution is the intense, characteristic onion odor that
for 24 weeks. Subjects were evaluated at 0, 12, and 24 weeks anyone using (and those around him/her) will have to with-
by clinical examination, photographic documentation, quality stand, making it an even less ideal treatment option.
468 76 Allium Cepa (Red Onion)
Synopsis 15. Griffiths G, Trueman L, Crowther T, Thomas B, Smith B. Onions-a

global benefit to health. Phytother Res. 2002;16(7):603–15.
Flavonoids, sulfides, and quercetin are found in large
16. Khaki A, Fathiazad F, Nouri M, Khaki AA, Khamenehi HJ,
amounts in Allium cepa and have been credited with in vitro Hamadeh M. Evaluation of androgenic activity of allium cepa on
hair growth properties. However, there is no evidence on the spermatogenesis in the rat. Folia Morphol. 2009;68(1):45–51.
efficacy of Allium cepa as a topical in the treatment of AGA/ 17. Martínez-Gimeno A. Onions, myths, beliefs, fashion and reality in
asthma. Allergol Immunopathol (Madr). 2009;37(6):309–13.
FPHL, while its oral administration has no practical use.
18. Draelos ZD. The ability of onion extract gel to improve the cos-
Moreover, necessary parameters, such as the adequate con- metic appearance of postsurgical scars. J Cosmet Dermatol.
centration, a suitable solvent to maximize absorption, the 2008;7(2):101–4.
optimal dosage, and long-term safety of its use on the scalp, 19. Campanati A, Savelli A, Sandroni L, Marconi B, Giuliano
A, Giuliodori K, Ganzetti G, Offidani A. Effect of allium
are unknown. Most importantly, the disturbing odor of the
CepaAllantoinPentaglycan gel on skin hypertrophic scars: clini-
Allium cepa juice makes it a suboptimal choice. cal and video-capillaroscopic results of an open-label, controlled,
nonrandomized clinical trial. Dermatol Surg. 2010;36(9):1439–44.
20. Koc E, Arca E, Surucu B, Kurumlu Z. An open, randomized, con-
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4. Augusti KT. Therapeutic values of onion (Allium cepa L.) and gar- of a new natural active ingredient in 210 mg/mL topical solution,
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constituents for the treatment of hair loss. J Ethnopharmacol. 34. Lee SU, Lee JH, Choi SH, Lee JS, Ohnisi-Kameyama M, Kozukue
2015;4(175):470–80. N, Levin CE, Friedman M. Flavonoid content in fresh, homepro-
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Sophora Flavescens
77
flavescens extract (SFE) is produced. Traditionally, the SFE

Basic Concepts has been used in the belief it can treat fever, dysentery, viral
• Sophora flavescens root extract contains more than hepatitis, jaundice, skin and mucosal diseases (e.g., vagini-
200 distinct compounds; the primary components tis, psoriasis, eczema), enteritis, pyogenic infections of the
are flavonoids and alkaloids, to which a broad spec- skin (e.g., abscesses, carbuncles), arrhythmias, viral myocar-
trum of biological activities has been credited. ditis, allergic reactions, and pain [3, 4].
• Sophora flavescens extract has been reported to
increase IGF-1 and KGF in vitro, inhibit enzyme
5α-Reductase isotype II, accelerate entry to anagen, 77.1 General Properties of Sophora
and increase hair growth rate. Kurarinone and kura- Flavescens
ridin constituents decrease Νitric Oxide production
and inflammatory cytokines CCL2, tumor necrosis Sophora flavescens produces a broad range of secondary
factor TNF-α, interleukin (IL)-1β and inducible metabolites, some of which have received considerable
nitric oxide synthase. attention due to their wide-reaching biological activities and
• There is limited data on the hair growth properties novel structures.
of Sophora flavescens extract in humans, and the More than 200 compounds have been isolated and identi-
strong potential for adverse effects limits oral fied from SFE, and the constituents are classified into four
administration or even chronic topical. groups: 124 flavonoids, 47 alkaloids, 9 terpenoids, and 26
are other components.
Among all these compounds, alkaloids and flavonoids
are considered to be the primary active components. The
Sophora flavescens is a deciduous, slow-growing shrub, major flavonoids in the roots of Sophora flavescens are
growing to 1.5 m high by 1 m wide, with deltoid-sword-like quercetin, rutin, and 20 individual kushenols named A to X
leaves, 3–5 cm long and 1–2 cm wide. It belongs to the genus [5]. The major alkaloids can be classified by structure into
of the Fabaceae family, in which more than 15 members have groups including matrine-type alkaloids (e.g., oxymatrine,
a long history of use in traditional Chinese medicine. It is matrine), cytisine-type alkaloids (e.g., N-methylcytosine),
endemic in Asia, Oceanica, and the Pacific islands, prefers anagyrine- type alkaloids and lupinine-type alkaloids.
light (sandy) or medium (loamy), moist neutral or alkaline According to some authors, oxymatrine and matrine consti-
soils, and requires ample sunlight to grow [1]. The active tute 2% of the dry weight of the roots and are the major
parts of the plant are its roots, which are harvested in autumn bioactive components that contribute to a variety of pharma-
or spring, have a white to yellow color, with a very character- cological effects [6].
istic bitter taste and strong odor. Scientific research on Modern pharmacological studies have shown that matrine,
Sophora flavescens was initially conducted in Russia in the the most active of these two components, has multi-
early nineteenth century, although “therapeutic” applications pharmacological effects, including significant antitumor,
have been reported in China as early as 100 B.C. antiviral, anti-inflammatory, hepatoprotective, antiarrhyth-
It has been widely used in Chinese traditional and popular mic, analgesic, antipyretic, antianaphylactic, and anti-
medicine in which it is referred to as Kushen or Ku-Shen [2]. asthmatic activities [5, 7–9]. Furthermore, oxymatrine has
The traditional use of Sophora flavescens includes the decoc- been found to be useful as an antihypertensive, antioxidant,
tion or powder of dried plant roots from which the Sophora antiapoptotic, immunomodulator, at protecting hepatocytes
472 77 Sophora Flavescens
and reducing hepatic fibrosis [10, 11]. The SFE has also been at a concentration of 0.1 ng/mL. At a much higher concentra-
demonstrated to possess antipruritic [12], vasodilative [13], tion (100 ng/mL), it significantly increased hair shaft elonga-
mild antiandrogenic [14], mild estrogenic [15], antimicrobial tion over a period of 6 days and slowed the reduction in
[16], anti-inflammatory, and significant antioxidant [17] growth rate by suppressing the transition to catagen-like
properties in lab animals. morphology (p < 0.01). They also isolated ingredients
L-maackiain and medicarpin as the major bioactive com-
pounds present in SFE, both of which are Leguminosae-
77.2 Sophora Flavescens and ΑGΑ specific pterocarpan derivatives that belong to the
isoflavonoid family. Then, they conducted a small-size, ran-
The SFE has been demonstrated to possess vasodilatory and domized, double-blind, placebo-controlled clinical study for
antiandrogen properties. Kuroyanagi et al. [14] reported that 6 months on 36 patients with AGA (age range 29–54 yo)
100 μg/mL of SFE showed antiandrogen activity on who received the active extract and 37 patients with AGA
5α-Reductase (5α-R) and 5α-DHT-receptor binding with an (age range 25–53 yo) who received a placebo lotion. Overall,
inhibitory rate of 40.5% and 89.2%, respectively [14]. improvements were noted in the inspected alopecia scores
Additionally, recent studies have demonstrated other poten- for 22/36 subjects (61%) in the active group, but only in
tially useful properties that—in theory—could render SFE a 16/37 subjects (43%) in the placebo group. According to the
potential treatment for hair loss. Indeed, two lavandulyl fla- authors, the inter-group comparison showed that the improve-
vonoid ingredients of SFE, kurarinone, and kuraridin inhib- ment in the inspected alopecia scores in the active group was
ited inducible nitric oxide synthase (iNOS)-dependent NO significant (p < 0.01). However, no further details on the
production and ROS generation, and suppressed the expres- results or before-and-after photos were disclosed in the pub-
sion of inflammatory cytokines potently, CCL2, tumor lication. One table, including the intra- and intergroup com-
necrosis factor (TNF)-α, interleukin (IL)-1β, and iNOS in parisons of hair loss improvement after 6 months, is totally
lipopolysaccharide (LPS)-stimulated RAW264.7 macro- unconvincing (and unsubstantiated) concerning of the effi-
phages [18]. ciency of SFE on inducing hair growth in vivo [22].
However, there is very little experimental evidence sug-
gesting that SFE could stimulate hair growth in vivo.
Regarding the action of Sophora flavescens on hair follicles, 77.3 Dosage- Adverse Effects—Safety
there have been two conference abstracts and one publica-
tion addressing its effects in vitro and in lab animals. Despite the long use of Sophora flavescens root in traditional
Τakahashi et al. reported that SFE can elongate anagen medicine to treat numerous diseases, it has also been known
hair follicles and stimulate the growth of outer root sheath to be harmful when used chronically or in excessive dosages.
cells cultured in vitro [19, 20]. Roh et al. [21] showed that Although daily clinical administration of SFE usually does
the topical application of SFE onto the backs of C57BL/6 not result in any significant adverse effects in humans and
mice daily for 30 days induced an earlier telogen-to-anagen related systematic toxicity and safety evaluations have been
initiation. However, the growth of dermal papilla cells rare, systemic toxicity and safety issues are in urgent need of
(DPCs) cultured in vitro was not affected. PT-PCR analysis further attention and study.
showed that SFE induced mRNA levels of growth factors
such as IGF-1 and KGF dose-dependently (p < 0.05) in
Toxic effects from the use of the root may include nau-
DPCs, suggesting that its effects on hair growth may be
sea, dizziness, vomiting, constipation, spasms, distur-
mediated through the regulation of growth factors in DPCs.
bance of speech, irregular breathing, respiratory
In addition, the authors evaluated the effect of SFE on the
failure, and even death [23].
5α-R enzyme system, using the rat prostate as a source for
5α-R isotype II. They reported that SFE inhibited dose-
dependently the activity of 5α-R type II, with 0.001% con-
centration inhibiting approximately 60% of the enzyme Compared to the crude extract, the alkaloids from SFE
activity, 0.01% inducing 85% inhibition, and 0.1% inducing can cause spasms and palsies of the respiratory center in both
>99% inhibition of 5α-R type II enzyme [21]. cold- and warm-blooded animals. The injection of matrine
Takahashi et al. [22] published the only in vivo trial on the into rabbits was found to induce central nervous paralysis
effects of SFE in AGA. Initially, they used a human hair and spasms, and the minimum lethal dose of LD50 is 0.4 g/
keratinocyte proliferation assay and ex vivo organ cultures of kg. The LD50 values of matrine administered orally or by
human hair follicles to examine the potential of SFE to stim- subcutaneous injection in mice were found to be 1.18 g/
ulate hair growth via anagen prolongation. SFE induced a kg ± 0.1 and 571.2 mg/kg ± 48.8, respectively [24]. An intra-
significant increase in human hair keratinocyte proliferation muscular injection of oxymatrine in mice was found to be
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Concerning the topical use of SFE, it has been shown to 12. Yamaguchi-Miyamoto T, Kawasuji T, Kuraishi Y, Suzuki
have potent inhibitory properties on tyrosinase, involved in H. Antipruritic effects of Sophora flavescens on acute and chronic
hair and skin melanogenesis [25]. According to Shin et al. itchrelated responses in mice. Biol Pharm Bull. 2003;26(5):722–4.
13. Yamahara J, Kobayashi G, Iwamoto M, Chisaka T, Fujimura H,
[26], who investigated the mechanism DNA of action of SFE
Takaishi Y, Yoshida M, Tomimatsu T, Tamai Y. Vasodilatory
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formation and transport of melanosomes [26]. It is, there- 14. Kuroyanagi M, Arakawa T, Hirayama Y, Hayashi T. Antibacterial
and antiandrogen flavonoids from Sophora flavescens. J Nat Prod.
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1999;62(12):1595–9.
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G, De Keukeleire D. Estrogenic and anticarcinogenic properties of
Synopsis kurarinone, a lavandulyl flavanone from the roots of Sophora flave-
scens. J Nat Prod. 2004;67(11):1829–32.
Sophora flavescens extract (SFE) has been reported to pos-
16. Cha JD, Moon SE, Kim JY, Jung EK, Lee YS. Antibacterial activity
sess in vitro and experimental hair growth properties; how- of sophoraflavanone G isolated from the roots of Sophora flaves-
ever, in a single, small-size human trial, positive effects were cens against methicillin-resistant Staphylococcus aureus. Phytother
minimal and dubious. Chronic ingestion of the SFE carries Res. 2009;23(9):1326–31.
17. Jung HA, Jeong DM, Chung HY, Lim HA, Kim JY, Yoon NY, Choi
the likelihood of neurological events, and considering the
JS. Re-evaluation of the antioxidant prenylated flavonoids from the
minimal clinical effects, it is not justified under any roots of Sophora flavescens. Biol Pharm Bull. 2008;31(5):908–15.
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application might also have unwanted depigmenting effects Sophora flavescens suppress lipopolysaccharide-induced activation
of nuclear factor-kappaB and mitogen-activated protein kinases in
on scalp skin and hair follicles.
RAW264.7 cells. Biol Pharm Bull. 2010;33(6):1019–23.
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Oryza Sativa Bran (Rice Bran)
78
bran is usually not consumed as part of an ordinary diet

Basic Concepts because it does not masticate well and because of possible
• Rice bran being a byproduct of the rice milling pro- hull contamination. Therefore, most rice bran is discarded or
cess, is rich in phytochemicals, antioxidants, and used as livestock feed and for oil production [3].
minerals. Rice bran oil contains high amounts of
free fatty acids (≈38% oleic acid and ≈34% lin-
oleic) with recognized in vitro anti-androgenic 78.1 General Properties of Oryza
properties. Sativa Bran
• In vitro studies have shown that Rice bran extract
potently inhibits 5α-Reductase, has hair growth- Nutrient analysis of rice bran and its derivatives indicate that
promoting activity, increases the expression of hair oils (20–29%), carbohydrates (20–27%), and proteins (10–
growth factors VEGF, IGF-1, and KGF, decreases 15%) are the three major components in addition to several
TGF-β2, and induces anagen. In a clinical trial, the valuable phytonutrients, antioxidants, and minerals [4]. Rice
increase in hair density, hair shaft diameter, and bran is also rich in B-complex vitamins [5]. In addition, it
patient satisfaction were comparable to 2% has been reported that rice bran contains high levels of phy-
Minoxidil Topical Solution. tochemicals, such as γ-oryzanol, γ-aminobutyric acid, tocot-
• Rice bran oil functions in cosmetics as a condition- rienols, tocopherols, carotenoids, phytic acid, phenolic
ing agent across a wide range of product types and compounds, octacosanol, and squalene [6]. Overall, pig-
is generally very safe for human use, both topically mented brans contain more bioactive compounds than white
and orally. brans.
Rice bran contains 12–13% oil and highly unsaponifi-
able components (4.3%). The composition of rice bran oil
is similar to that of peanut oil, containing large amounts
Oryza Sativa, commonly known as Asian rice, is the mono- of oleic acid (≈38%) and linoleic acid (≈34%), both with
cotyledonous plant species most commonly referred to in known in-vitro anti-androgenic activity (see Chap. 43).
English as rice. It is one of the most important crops world- Rice bran oil is extracted from rice bran using supercriti-
wide, available in over 5000 varieties, and is a staple food for cal carbon dioxide (scCO2) by both pilot [7] and lab scale
over half of the world’s population [1]. [8]. The raw rice bran oil contains both saturated and
Before consumption, almost all rice is milled, a process unsaturated fatty acids, in which palmitic acid is a major
that leads to the conversion of brown rice to white rice. This acid (12–26% w/w, typically 18% w/w). The unsaturated
crucial step in rice post-production results in approximately fatty acids are mainly oleic acid (35–46% w/w, typically
7% of rice bran as a byproduct during the rice milling pro- 42% w/w) and linoleic acid (25–38% w/w, typically 37%
cess. The global rice production in 2014 was 741 million w/w) [9]. The antioxidant γ-oryzanol, found at around 2%
tons, and this massive amount of production resulted in more of crude rice bran oil content, was thought to be a single
than 70 million tons of rice bran in 2014 [2]. compound when initially isolated; it is now known to be a
Rice bran serves as a source of numerous individual bio- mixture of steryl and other triterpenyl esters of ferulic
active compounds such as oils, fibers, proteins, and minerals, acids [10].
many of which have been widely studied and shown to Rice bran ash, the end-product of rice bran incineration,
exhibit beneficial effects in vitro and in vivo. However, rice is rich in silicon (Si, 65% w/w) but also contains other min-
476 78 Oryza Sativa Bran (Rice Bran)
erals, such as potassium, phosphorous, K2O, CaO, Na2O, days after the DPCs were administered the various treat-
MgO, Al2O3, ZnO, MnO2, and Fe2O3, as well as soluble ments, western blot analysis showed that type I collagen
silicic acids [11]. expression was increased 2.5-fold in the OSA group and
Bioactive rice brans and hulls have been reported to have fourfold in the RBM group. ALP expression (a marker of
numerous health-promoting effects in cells, animals, and DPCs in vivo correlated with hair regeneration) was increased
humans. These include antioxidative, anti-inflammatory, 1.5-fold in the OSA and RBM group, while the expression of
immunostimulating, antibiotic, antiallergic, anticarcino- fibronectin was increased ≈3-fold in the OSA group and 2.5-
genic, antidiabetic, and anti-cholesterogenic properties [12]. fold in the RBM group. Also, the expression of Wnt-3α and
β-catenin protein was increased in OSA and RBM group
compared to the control group. Furthermore, the expression
78.2 Oryza Sativa Bran and Hair Follicles of IL-1a was decreased by more than 50% in the OSA and
RBM groups compared to the negative control. Analysis of
Ruksiriwanich et al. [13] first reported the inhibition of mRNA expression by RT-qPCR showed that type I collagen
5α-Reductase (5α-R) isotype I by Oryza sativa bran extract increased 1.2-fold in the OSA- and RBM-treated DPCs,
(OSBE) prepared by supercritical CO2 fluid. One fraction of whereas type IV collagen increased 2.7-fold in the OSA
the OSBE gave the highest content of unsaturated fatty acids group and 3.5-fold in the RBM group. However, TGF-β2
(linolenic acid 7.52 ± 1.12%, w/w; linoleic acid mRNA decreased by 80% in the OSA and RBM groups,
49.25 ± 3.67%, w/w; oleic acid 42.17 ± 4.12%, w/w), high compared to the negative control. Immunohistochemical
antioxidative activities with high stimulation index on human staining of the DPCs for versican protein showed a signifi-
normal skin fibroblast (stimulation index = 1.01 ± 0.34) and cant increase in the OSA- and RBM-treated groups com-
the highest 5α-R type I inhibition (93.33 ± 10.93% of c ontrol) pared to the negative control. The authors commented that
on DU-145 prostate cancer cell line. The same fraction of RBM could recover of DPCs activity and decreased
OSBE at 0.1 mg/mL showed the highest 5α-R type I inhibi- inflammatory-related markers. Additionally, RBM may pro-
tion activity on the DU-145 cell line at 93.33 ± 10.93% of the long anagen by increasing type I collagen, fibronectin, ALP,
control, which was higher than the standard Finasteride type IV collagen, and versican through the activation of the
(57.07 ± 6.52%) and Dutasteride (76.56 ± 4.76%) of about β-catenin/Wnt signaling pathway [15].
1.64 and 1.22 times, respectively [13].
Choi et al. [14] evaluated the hair growth-promoting
activity of rice bran supercritical CO2 extract (RB-SCE) by 78.3 Oryza Sativa Bran and AGA
applying a 3% RB-SCE solution on the dorsal skin of
C57BL/6 mice once per day for 4 weeks. As a negative con-
trol (NC) 10% ethanol and positive control (PC) 3% Oryza sativa bran extract is one of the very few plant-
Minoxidil Topical Solution (MTS) were both topically based hair growth products supported by an actual
applied, respectively. The authors evaluated the histological clinical trial.
morphology and mRNA expression levels of cell growth fac-
tors using real-time reverse transcriptase-polymerase chain
reaction. RB-SCE demonstrated a hair growth-promoting Choi et al. [16] conducted a 16-week, double-blind, ran-
potential similar to 3% MTS, showing that the hair follicles domized, controlled, single-center trial to evaluate the
were induced to enter anagen. The number of hair follicles in safety and efficacy of RB-SCE in the treatment of AGA/
the PC and RB-SCE groups were 24 and 18/mm2, respec- FPHL. Twenty-two women with FPHL and 28 men with
tively, vs 4/mm2 in the NC group (p = 0.0001). In addition, AGA were randomly assigned to the experimental and pla-
mRNA expression levels of vascular endothelial growth fac- cebo groups, and 43 subjects (22 men and 21 women) com-
tor (VEGF, p = 0.004), insulin-like growth factor-1 (IGF-1, pleted the study, ages ranged from 28 to 68 years (mean,
p = 0.0001), and keratinocyte growth factor (KGF, 43.3 ± 11.6 years). The experimental group received a scalp
p = 0.0001) were also significantly increased, and that of application of 0.5% RB-SCE (8 mL/day) for 16 weeks,
transforming growth factor-β (TGF-β, p = 0.001) decreased while the control group received a scalp application of pla-
in RB-SCE-treated groups. The authors claimed that among cebo. Changes in hair count, diameter, and density were
the major components of RB-SCE, linoleic acid, and evaluated with a Folliscope®. Patient satisfaction was eval-
γ-oryzanol induced the formation of hair follicles according uated by a questionnaire, and clinical global photographs
to the examination of histological morphology and mRNA were reviewed in a blinded manner by expert panels com-
expression levels of cell growth factors [14]. posed of three independent dermatologists using a 7-point
Kim et al. [15] researched the effect of rice bran mineral scale [16]. The increase in hair density in males did not
extract (RBM) and ortho-silicic acid (OSA) on DPCs. Three significantly differ between the RB-SCE and placebo
groups at 8 weeks but significantly differed at 16 weeks. deemed very safe [17]. In the skin sensitivity test in rabbits,
The average increase in the number of hairs was 3.06 and RB-SCE was classified as a very weak irritant, with no evi-
9.72 hairs/cm2 in the RB-SCE group and −0.19 and 2.69 dence of erythema, eschar, or edema [18]. The dermal toxic-
hairs/cm2 in the placebo group at 8 and 16 weeks, respec- ity of topically administered RB-SCE in male and female
tively (p = 0.410 and p = 0.034). In females, the increase in rats in a 4-week repeated-dose fashion resulted in no abnor-
hair density did not significantly differ between the RB-SCE mal RB-SCE-associated changes with respect to external
and placebo groups at any time (p = 0.25). The change in signs, urine, and blood, or organs. The no-observed-adverse-
diameter did not differ significantly between the RB-SCE effect level (NOAEL) of RB-SCE was considered to be
and placebo groups at 8 weeks (8.6 vs 6.8, p = 0.711). After 2000 mg/kg/day for both sexes. Therefore, RB-SCE can be
16 weeks of treatment, the experts observed improved hair regarded as a very safe agent for topical dermal administra-
growth in the RB-SCE group (0.89 ± 0.601, p = 0.002), tion at a moderate dose [19]. Finally, RB-SCE showed no
while no improvement in hair growth was observed in male genotoxicity in the bacterial reverse mutation assay up to
subjects in the placebo group (0.08 ± 0.862, p = 0.753). 5000 mg/plate and in the in vivo micronucleus test up to
After 16 weeks of treatment, the dermatologists observed 600 mg/kg body weight. Therefore, it is regarded as a non-
improved hair growth in female subjects in both the genotoxic material.
RB-SCE group (1.25 ± 0.452, p = 0.000) and the placebo Rice bran oil is used in cosmetics as a conditioning agent
group (1.11 ± 0.601, p = 0.013). The combined overall sat- across a wide range of product types, formulations, and
isfaction of all male and female subjects in the RB-SCE product categories. According to the amended final report on
treatment group was significantly higher than that of the Oryza Sativa bran oil’s safety assessment, it had an oral LD50
placebo group at 16 weeks (p = 0.005). Nevertheless, the of >5 g/kg in white rats. A three-generation oral dosing study
increase in hair density and diameter, as well as patient sat-reported no toxic or teratologic effects in albino rats fed 10%
isfaction with 0.5% RB-SCE after 16 weeks, were similar rice bran oil compared to a control group fed peanut oil.
to or slightly lower than those reported for 2% MTS after Undiluted rice bran oil is not an irritant or sensitizer in ani-
48 weeks [16]. mal skin tests. Rice bran oil and rice germ oil were negative
in ocular toxicity assays, were negative in an Ames assay,
and γ-oryzanol was negative in bacterial and mammalian
Notably, the amount of 0.5% RB-SCE used in the
mutagenicity assays. Oral carcinogenicity studies done on
study (8 mL/day) was relatively high, and considering
components of rice bran (phytic acid and gamma-oryzanol)
that the formulation is oily in nature, that would make
were negative [21].
it quite difficult for patients to comply for extended
Concerning the physicochemical characteristics and the
periods of time due to social and cosmetic issues.
transfollicular penetration of rice bran oils, those were inves-
tigated by Manosroi et al. [22] They used porcine skin by
Franz diffusion cells of gel RB oil niosomes, RB oil nio-
The full-text article contains 3 very low-quality before- somes, gel RB oil, and RB oil solution [22]. The ex vivo skin
and-after photographs of only a part of the vertex of an permeability of the porcine and human skin do not differ sig-
RB-SCE-treated male subject at baseline, weeks 2 and 4 nificantly [23]. Also, the porcine skin is structurally closest
showing minimal hair growth. Strangely, there are no photos to that of humans [24]. Results suggested that a gel contain-
of patients at 16 weeks. Another severe limitation of the ing RB oil loaded in niosomes was the suitable system for
study includes the short duration that cannot compensate for topical anti-androgenic effects in AGA/FPHL because of the
seasonal variations in hair growth. convenient use and high transfollicular penetration in the
skin, but not in the receiving compartment due to low sys-
temic effect [22].
78.4 Dosage- Adverse Effects—Safety
Synopsis
Choi et al. have thoroughly investigated the toxicological Oryza Sativa bran extract and oil have been recently investi-
safety of RB-SCE. Initially, it was evaluated in vitro [16], gated for their hair growth properties. In vitro studies report
and further safety evaluations included single oral dose tox- that the free fatty acid content of the oil inhibits 5α-R and has
icity in rats [17], an acute dermal and ocular irritation test hair growth-promoting properties. A single clinical study
[18], a single dose, and 4-week repeated dose dermal toxicity also reported positive results in both males and females with
study [19] and a genotoxicity assessment [20]. AGA/FPHL. Oryza sativa bran is generally very safe for
In the single oral dose toxicity study in rats, the approxi- human use, both topically and orally, and future products
mate lethal dose (ALD) of RB-SCE was estimated at containing this extract could be useful in hair loss
>10,000 mg/kg, and orally administered RB-SCE was treatment.
478 78 Oryza Sativa Bran (Rice Bran)
References 15. Kim YM, Kwon SJ, Jang HJ, Seo YK. Rice bran mineral extract
increases the expression of anagen-related molecules in human
dermal papilla through wnt/catenin pathway. Food Nutr Res.
1. Gross BL, Zhao Z. Archaeological and genetic insights into 2017;61(1):1412792.
the origins of domesticated rice. Proc Natl Acad Sci U S A. 16. Choi JS, Park JB, Moon WS, Moon JN, Son SW, Kim MR. Safety
2014;111(17):6190–7. and efficacy of rice bran supercritical CO2 extract for hair growth
2. FAO. FAO rice market monitor. Rome, Italy: Food and Agriculture in androgenic alopecia: a 16-week double-blind randomized con-
Organization (FAO); 2015. trolled trial. Biol Pharm Bull. 2015;38(12):1856–63.
3. Park HY, Lee KW, Choi HD. Rice bran constituents: immunomod- 17. Choi JS, Moon WS, Moon JN, et al. Cytotoxicity and single-dose
ulatory and therapeutic activities. Food Funct. 2017;8(3):935–43. oral toxicity testing for rice bran supercritical CO2 extract. Toxicol
4. Taha FS, Mourad RM, Mohamed SS, Hashem AI. Enzymatic pre- Environ Health Sci. 2013;5(4):215–20.
treatment of stabilized rice bran with mixed enzymes: evaluation of 18. Choi JS, Moon JN, Moon WS, Cheon EJ, Kim JW, Kim M-R. Acute
oil. Am J Food Technol. 2012;7(8):452–69. dermal and ocular irritation testing of rice bran supercritical
5. Saunders RM. Rice bran: composition and potential food uses. CO2extract (RB-SCE) and 0.5% RB-SCE essence product. Toxicol
Food Rev Int. 1985;1(3):465–95. Environ Health Sci. 2015;7(1):65–72.
6. Jariwalla RJ. Rice-bran products: phytonutrients with potential 19. Choi JS, Cheon EJ, Kim TU, Moon WS, Kim JW, Kim MR. Dermal
applications in preventive and clinical medicine. Drugs Exp Clin toxicity study of rice bran supercritical CO2 extract in Sprague-
Res. 2001;27(1):17–26. Dawley rats. Food Sci Biotechnol. 2015;24(3):1167–76.
7. Shen Z, Palmer MV, Ting SST, Fairclough RJ. Pilot scale extraction 20. Choi JS, Cheon EJ, Kim TU, Moon WS, Kim JW, Kim
and fractionation of rice bran oil using supercritical carbon dioxide. MR. Genotoxicity of rice bran oil extracted by supercritical CO2
J Agric Food Chem. 1997;45(12):4540–4. extraction. Biol Pharm Bull. 2014;37(12):1963–70.
8. Chen X, Ahn D. Antioxidant activities of six natural phenolics 21. Anon. Amended final report on the safety assessment of Oryza
against lipid oxidation induced by Fe2+ or ultraviolet light. Journal Sativa (rice) bran oil, Oryza Sativa (rice) germ oil, Rice bran
of the American oil Chemist's. Society. 1998;75:1717–21. Acid,Oryza Sativa (rice) bran wax, hydrogenated Rice bran wax,
9. Orthoefer FT. Chapter 10: Rice bran oil. In: Shahidi F, editor. Oryza Sativa (rice)bran extract, Oryza Sativa (rice) extract, Oryza
Bailey’s, Industrial oil and fat products. 6th ed. Wiley; 2005. p. 465. Sativa (rice) germ powder, Oryza Sativa (rice) starch, Oryza Sativa
10. Sayre RN, Saunders RM. Lipid technologies and applications: rice (rice) bran, hydrolyzed Rice bran extract, hydrolyzed Rice bran
bran and Rice bran oil. New York: Marcel Dekker; 1990. protein, hydrolyzed rice extract, and hydrolyzed rice protein. Int J
11. Jang HJ, Seo YK. Pigmentation effect of rice bran extracted min- Toxicol. 2006;25(Suppl 2):91–120.
erals comprising soluble silicic acids. Evid Based Complement 22. Manosroi A, Ruksiriwanich W, Abe M, Manosroi W, Manosroi
Alternat Med. 2016;2016:3137486. J. Transfollicular enhancement of gel containing cationic niosomes
12. Friedman M. Rice brans, rice bran oils, and rice hulls: composition, loaded with unsaturated fatty acids in rice (Oryza sativa) bran semi-
food and industrial uses, and bioactivities in humans, animals, and purified fraction. Eur J Pharm Biopharm. 2012;81(2):303–13.
cells. J Agric Food Chem. 2013;61(45):10626–41. 23. Simon GA, Maibach HI. The pig as an experimental animal model
13. Ruksiriwanich W, Manosroi J, Abe M, et al. 5α-reductase type 1 of percutaneous permeation in man: qualitative and quantitative
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Biol Pharm Bull. 2014;37(1):44–53.
Polygonum Multiflorum (Ho-Shou-Wu)
79
79.1 General Properties of Polygonum

Basic Concepts
Multiflorum
• Polygonum multiflorum is one of the most impor-
tant and frequently used traditional Chinese herbs
With a broad spectrum of biological and pharmacological
with allegedly anti-aging, immunologic, anti-
effects, Polygonum multiflorum has been used as a tradi-
hyperlipidaemic, neuroprotective, anti-cancer, and
tional medicine for several centuries in China. Laboratory
anti-inflammatory properties.
studies and clinical practice have demonstrated that even
• It contains several bioactive constituents, including
though Polygonum multiflorum has a lower antioxidant
flavones, quinones, and stilbenes that might posi-
capacity and phenolic content compared to other members of
tively affect hair follicles in vitro, and is frequently
the Polygonum family [4], some ingredients isolated from
prescribed as a hair growth herb in certain
the extract could have valuable biological and therapeutic
countries.
actions. Some of these include anti-tumor [5], anti-
• Experimental and in vitro data show moderate hair
inflammatory [6], antioxidant [7], radical scavenging [8],
growth properties. However, caution is advised
antibacterial [9], anti-HIV [10], antifungal [11], hepatopro-
since oral administration can be dangerous due to
tective [12], nephroprotective [13], antidiabetic [14], and
the severe hepatotoxic potential.
anti-atherosclerotic properties [15]. Additionally, it exerts
protective effects against neurodegenerative diseases [16–
18] and cardiovascular diseases [19, 20], affects lipid metab-
Polygonum multiflorum, also known as “He-shou-wu” in olism [21], and has been used to treat male infertility and
China and “Fo-ti” in North America. It is one of the most menopausal symptoms [22, 23].
popular perennial, medicinal, vine-like herbs officially listed There are numerous chemical constituents in the
in the Chinese Pharmacopoeia [1, 2]. The root is tuberous, Polygonum multiflorum extract (PME), including flavones,
hypertrophic, oblong, dark brown in color, and is used after quinones, and stilbenes. Stilbenes are the main characteristic
processing by steaming with black bean. components in PME, whereas quinones and their derivatives
Polygonum multiflorum has a rich and mystical history have been isolated and identified, and most of them are
that illustrates precisely why it grew to such stature and fame anthraquinones. The predominant anthraquinones are
and hints at some of its more exotic -and highly sought after- emodin-type anthraquinones [24], which are similar to res-
benefits and effects. Its Chinese name, “Ho-shou-wu”, trans- veratrol but have -supposedly- superior antioxidant activity.
lates into “Mr. Ho’s hair is black”, and legend has it that back
in 800 A.D., an old, impotent, sterile man was the first to
experiment on ingesting the roots of the plant. 79.2 Polygonum Multiflorum and the Hair
Follicle
Eventually, his hair color shifted from gray to a rich,
lustrous black. The legend has it that he also became Polygonum multiflorum extract is traditionally valued and
virile, and over the following years, he managed to reported for hair-blacking and hair loss in traditional Chinese
father at least five children and lived well into his hun- medicine. However, several vital problems in its clinic usage
dreds, with some “sources” recording his final age as and mechanisms are still unsolved or lack scientific evi-
160 years old [3]. dence. Some studies suggest that the hair growth properties
of PME can be attributed to estrogenic properties, but the
480 79 Polygonum Multiflorum (Ho-Shou-Wu)
results are contradicting [25]. Other studies speculate that it (p < 0.001) in the number of hair follicles in CZ-treated mice
strongly inhibits the elimination of Superoxide dismutase (58.66 ± 3.72) and Minoxidil-treated mice (40 ± 2.71),
(SOD) on the skin and maintains the natural anti- whereas PME effects (28 ± 2.72) were similar to those of the
inflammatory activity of SOD [26]. Concerning the antian- vehicle (25 ± 2.83) [30].
drogenic activity of PME, Cho et al. reported that a 500 μg/ Li et al. [31] investigated the hair growth promotion prop-
mL solution of the dried 50% ethanol PME resulted in 80.7% erties of two different extractions, Polygonum multiflorum
inhibition of the 5α-Reductase enzyme and that emodin Radix (PMR, raw crude drug) and Polygonum multiflorum
inhibited the enzyme activity in a dose-dependent manner, Radix Preparata (PMRP, processed crude drug), adminis-
having an IC50 of 40 μM [27]. tered orally and/or topically on 88 C57BL/6 J male mice.
The PME is a popular folk hair loss treatment in Chinese Hair growth promotion activities were investigated by hair
traditional medicine, and since the early 2000s, it has gained length, follicles numbers, hair-covered skin ratio, and hair
popularity in many Western countries. Therefore, a few color. Several cytokines involved in the hair growth proce-
researchers decide to investigate the effects of PME on hair dure were tested, such as fibroblast growth factor 7 (FGF-7),
follicles. Park et al. [28] examined the effect of PME in Shh, β-catenin, insulin-like growth factor-7 (IGF-7), and
inducing telogen to anagen transition on 7-week-old telo- hepatocyte growth factor (HGF). Mice were randomly
genic C57BL6/N mice and additionally determined the assigned to 11 groups (each with n = 8) and received differ-
expression of β-catenin and Sonic hedgehog (Shh) by immu- ent topical, oral, or combination treatments. According to the
nohistochemistry analysis. Topical application of PME for 1, authors, oral administration of both PMR and topically given
2, 3, and 4 weeks increased the number of hair follicles on PMRP showed hair growth promotion activities. They
experimental animals and extended follicle length signifi- reported that oral PMR groups had a higher hair-covered
cantly compared to the control group. Immunohistochemical skin ratio (allegedly 100 ± 0.00% after 6 weeks) than oral
analysis results showed that Shh protein and β-catenin PMRP groups (48%–88%). The authors speculated that the
expression levels were significantly upregulated in mice hair growth promotion effect of oral PMR was most proba-
after the topical application of PME compared to the control bly mediated by the expression of FGF-7, while topical
group at 2 weeks. PMRP promoted hair growth by the stimulation of SHH
expression. However, careful interpretation of the only multi-
photograph included in the article showing the hair-covered
However, the photos included in the full-text article
skin ratio (%) from first to sixth week in the oral groups
show negligible difference in hair coverage between
reveals that none of the oral extracts was more efficient than
the active and control groups, and reported differences
saline at any point during the study (saline also scored
between groups were statistically significant only at
100 ± 0.00% at 6 weeks). This means that the effect of some
2 weeks and not later [28].
of the treatments was inferior to saline [31].
Shin et al. [32] investigated the effects of PME on cultured
human DPCs were investigated. They found that treatment of
Since it was unknown which compounds of PME—if PME extract to cultured DPCs showed hair growth support-
any—contribute to hair growth, Sun et al. [29] carried out a ing activities by stimulating cell proliferation and mitochon-
study to evaluate the effects of ten isolated compounds from drial activity, decreasing the gene expression of catagen
PME using dermal papilla cells (DPCs). Compounds 1, 2, 3, inducing protein DKK-1, and modulating the expression of
6, and 10 increased the proliferation of DPCs compared with Bcl-2 and BAD. In addition, PME stimulated the secretion of
the control and specifically, compound 2 at a concentration growth factors essential for hair growth (IGFBP2, PDGF and
of 10 and 20 μM induced a greater increase in the prolifera- VEGF), prominently abrogating the DHT-induced stimula-
tion of DPCs than Minoxidil 10 μM, which was used as a tion of androgen receptor (AR) expression, and inhibiting the
positive control (p < 0.001). Additionally, treatment of increment of DP 3D spheroids size by DHT treatment. The
vibrissa follicles with compound 2 for 21 days increased PME prolonged the anagen stage in the human hair follicle
hair-fiber length significantly (35%), and results were com- organ culture model, that supports the possible therapeutic
parable to Minoxidil [29]. potential of PME for anti-hair loss treatment [32].
Begum et al. [30] investigated the hair growth-promoting There are no published clinical trials in the scientific lit-
effects of topical application of PME, Chrysanthemum erature concerning patients with hair loss using
zawadskii (CZ), Minoxidil 2%, and vehicle, applied daily for PME. However, there are two unpublished trials, and they
40 consecutive days on athymic nude mice skin. The maxi- are both cited in a publication by Han et al. on the effects of
mum hair score (2.5 ± 0.29) was obtained in the CZ—treated Polygonum multiflorum for treating hair graying in
group, while PME scored similarly to the vehicle. C57BL/6 mice [33]. The results of both trials are untrace-
Histological observation revealed a significant increase able, and they were sponsored by a manufacturer of hair
References 481
loss products containing Polygonum multiflorum (NuHair, researchers have found that PME also interacts with warfarin
Natrol LLC). and can even induce severe bone marrow suppression [24].
Additionally, the long-term use of Polygonum multiflorum
• One study is an allegedly double-blind, 6-months-long, may lead to kidney toxicity [49].
placebo-controlled study by Blum [34], on pre- and post- Other, less severe side effects of oral PME include gastro-
menopausal women. After taking PME for 3–6 months, intestinal upset and diarrhea due to anthraquinones, which
the subjects were administered surveys, and results are known irritants of the intestinal mucosa and can have a
revealed a significant improvement of hair loss (25 in 26 potent laxative effect [50]. PME, and especially emodin, has
participants, 97%) and perceived hair appearance (20 in been reported to induce embryonic toxicity and mutagenic-
26 participants, 80%). Additionally, 77% of women in the ity. Consequently, women should avoid it during their repro-
PME group reported “thicker hair,” which was rated as ductive years [51].
“significant” and “dramatic” improvement [34].
• In the second study, 48 subjects aged 30- to 60-years-old Synopsis
(n = 24 men, n = 24 women) with various hair loss condi- Polygonum multiflorum is a very popular herb in traditional
tions (age-related, stress-induced, medication-induced, Chinese medicine, credited with a plethora of positive
and postpartum) received a standardized extract of NuHair effects, one of which being hair growth. In vitro and lab ani-
twice daily. After 1 month of treatment, 91% of men and mal studies have shown that the Polygonum multiflorum
87% of women reported improvement. Additionally, none extract (PME) might actually have positive effects on hair
of the study participants reported any side effects during follicles through unknown mechanisms. However, no clini-
the treatment period [35]. cal data are associating a potential efficacy of PME in AGA/
FPHL, while the hepatotoxic potential of the orally adminis-
tered PME does not justify its use under no cisrcumastance.
Both these “reports” should be reviewed with healthy
The topical application of PME is probably safe, but there is
skepticism, though, due to conflicts of interest and
no clinical evidence on its transdermal absorption or
severe methodological shortcomings that strongly
efficacy.
remind of “contract-studies”.
References
Other in vitro or ex vivo studies have suggested that PME
could be used as a potential agent for the treatment of early 1. Bensky D, Gamble A. Chinese herbal medicine: materia medica.
Seattle, WA: Eastland Press; 1993.
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However, this exciting application goes beyond the scope of Pharmacopoeia of the People's Republic of China (PPRC). Beijing:
this chapter [36–38]. China Chemical Industry Press; 2010. p. 22–3.
3. Unschuld PU. Medicine in China: history of pharmaceutics.
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4. Huang WY, Cai YZ, Xing J, Corke H, Sun M. Comparative
79.3 Dosage- Adverse Effects—Safety analysis of bioactivities of four polygonum species. Planta Med.
2008;74(1):43–9.
The PME is a very popular commercial treatment for hair 5. Choi SG, Kim J, Sung ND, Son KH, Cheon HG, Kim KR, Kwon
BM. Anthraquinones, Cdc25B phosphatase inhibitors, isolated
loss, both as a topical and an orally administered extract, from the roots of Polygonum multiflorum Thunb. Nat Prod Res.
alone and in combination with other herbs. However, the 2007;21(6):487–93.
clinical efficacy and the safety of PME and its bioactive 6. Li RW, David Lin G, Myers SP, Leach DN. Anti-inflammatory
products have attracted much attention lately due to the activity of Chinese medicinal vine plants. J Ethnopharmacol.
2003;85(1):61–7.
increasing number of published reports of hepatotoxicity. 7. Chiu PY, Mak DH, Poon MK, Ko KM. In vivo antioxidant action of
Notably, PME is ranked in the top 5 of herbs in traditional a lignan-enriched extract of schisandra fruit and an anthraquinone-
Chinese medicine inducing hepatotoxicity [39, 40]. PME has containing extract of polygonum root in comparison with schisan-
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Panax Ginseng (Korean or Asian
Ginseng) 80
affiliated with the genus Panax, and just five of them are used
Basic Concepts therapeutically, namely Korean ginseng (Panax ginseng
• Panax ginseng is the most popular herb globally, C.A. Meyer, named by the Russian scientist Carl Anton
native to Korea and China, and has been used for Meyer in 1843), South China ginseng, American ginseng,
health-related purposes for at least 5000 years in Japanese ginseng, and Pseudoginseng [1].
both traditional Korean and Chinese medicinal sys- The history of the use of Panax ginseng (PG) began prob-
tems. Lately, it is used worldwide for a broad range ably more than 2,500 years ago, and the first written record
of indications, including diabetes, cardiovascular, is >2,000 years old. The herbal root is so named as "Ginseng"
and chronic liver disease. (man-root), referring to the root's characteristic forked shape,
• It displays restorative, tonic, revitalizing properties which resembles a human's shape, with trunk, arms, and
and contains numerous bioactive constituents, legs. The genus name Panax (Pan = all + akos = medicine)
including the steroid-like saponins Ginsenosides, means "cure-all" in Greek and shares the same origin as
which are unique to ginseng species. "panacea" -who was the Goddess of universal remedy- illus-
• Panax ginseng is frequently prescribed as a hair trating the high stature of this herb, which is also known as
growth herb, and increasing evidence suggests that the "lord" or "king of herbs" [2]. Due to this shape, it has
several of the dozens of ginsenosides found in the been believed to benefit all aspects of human being, body,
root extract are potent regulators of hair growth, mind and soul. In the Bancao Gangmu (Chinese Encyclopedia
preventing apoptosis of hair follicles in irradiated of Herbs) written by Li Shizhen in China, in 1596 A.D., it
mice, promoting hair growth in C57BL/6 mice and was included as an ingredient for curing 23 diseases, and it is
promoting human and murine vibrissae hair growth also included in 653 (16.6%) of the total 3,944 prescriptions
in organ cultures. in Dongeui Bogam (Korean Clinical Pharmacopoeia), writ-
• Ginsenosides enhance the proliferation of DPCs ten by the Korean herbalist, Huh Joon, in 1610 A.D. [2, 3]
and Bcl-2 expression, increase VEGF levels, and Panax ginseng is cultivated and aged for 4–6 years and
activate ERK and AKT signaling pathways, resem- goes through extensive cleaning, steaming, and drying pro-
bling Minoxidil effects. They also inhibit DKK-1 cesses to enhance its pharmacological activity and stability.
expression and TGF-β signaling pathway, resem- The root is harvested after 4–6 years of cultivation and is
bling Finasteride effects on hair follicles. consumed and distributed in 4 types: fresh ginseng (≤4 year
• Clinical data on hair growth effects of Panax ginseng old, right out of the field), white ginseng (≥4-6 year old,
are positive but still inconclusive and evident only in peeled and dried), fresh Taekuksam ginseng (≥4-6 year old,
very high oral doses or highly concentrated topicals. blanched in water), and red ginseng (harvested >6 year old,
The Korea Ginseng Corporation has exclusively steamed and then dried). Each type of PG is further subcat-
funded all published research, and even though it is egorized as ginseng products: fresh sliced, juice, extract
assumed that Panax ginseng is safe and non-toxic, (tincture or boiled extract), powder, tea, tablet, capsule, etc.
safety issues still remain to be elucidated. Approximately 95% of white ginseng is consumed as gin-
seng root, and red ginseng is mostly ingested in various pro-
cessed forms (67%) than as ginseng root (33%). The
representative PG of South Korea is red ginseng, and its
Ginseng is a deciduous perennial plant belonging to the related products are widely consumed as health supple-
genus Panax of the family Araliaceae. Thirteen plants are ments, general food (culinary uses), and medicine. The
486 80 Panax Ginseng (Korean or Asian Ginseng)
majority (estimated >90%) is ingested as health foods, reported in clinical trials to relieve various health problems
namely agricultural products, health supplements, food, and and show effects against a variety of conditions, including
beverages [4]. cardiovascular disorders, diabetes, fatigue, aging, inflamma-
tion, nausea, tumors, respiratory disorders, dyspepsia, vomit-
ing, ulcers, nervousness, anxiety, depression, erectile
Commercial PG is probably the most expensive herb
dysfunction, and menopausal hot flashes [10]. Research
worldwide, it is sold in over 35 countries, and China
reviews postulate that extracts of PG affect the hypothalamus-
has historically been the plant’s largest consumer.
pituitary-adrenal axis and the immune system, which could
account for many of the documented effects [11].
The pharmacological effects of PG are derived from mul-
Panax ginseng is the most commercially popular ginseng tiple active ingredients, including ginsenosides, ginsengo-
species, native to the Korean peninsula, northeast China, and sides, polysaccharides, peptides, phytosterols,
Russian far east, with global sales of PG in 2013 exceeding polyacetylenes, polyacetylenic alcohols, and fatty acids
$2 billion; half was produced by South Korea [4]. [12]. However, most published research on PG’s medicinal
activity has focused on ginsenosides since PG’s pharmaco-
logical activities have been mainly attributed to these com-
80.1 General Properties of Ginseng ponents exerting various effects on diverse tissues and cells
[13]. Ginsenosides, also known as steroid-like saponins, are
Panax ginseng has been used for thousands of years in east- unique to ginseng species and are the PG’s primary active
ern countries, mainly as a tonic to “invigorate weak bodies”, pharmacological components. Since the first isolation of six
but only rarely as a curative medicine for treating or prevent- ginsenosides from PG in the 1960s [14], more than 100 gin-
ing diseases. Over the last decades, it has gained popularity senosides have been isolated and identified from the spe-
in the Americas, Canada, and Europe. cies. They are classified into four groups based on their
Ginseng has a broad spectrum of biological and pharma- backbone types and according to their structural features
cological effects and, in general, displays restorative, tonic, and polarity [15].
and revitalizing properties [5]. There is very extensive litera-
ture on the beneficial effects of PG and its constituents. Thus
far, more than 8000 articles regarding the traditional uses, 80.2 Ginseng and the Hair Follicle
biological and pharmacological effects, and chemical con-
stituents of PG have been published since Petkov initially Panax ginseng has been initially reported to possess hair
reported the pharmacological properties of PG. [6] growth activity in traditional Korean and Chinese medicine
[16]. The literature of in vitro studies from animal and human
cells describing the hair growth-promoting effects of red gin-
Notably, PG is the only herb that even has a devoted
seng and its ginsenosides is quite rich. Studies date back to
medical journal, “the journal of ginseng research”,
the late 1980s, but since 2010, a sudden growing interest in
publishing exclusively in the diverse fields of PG
the hair growth potential of PG developed. However, human
research. The journal of ginseng research is funded by
trials are still very limited, almost exclusively funded by the
the “the Korean Society of Ginseng (KSG)”, founded
Korea Ginseng Corporation, and results, even though favor-
in 1975, aiming to advance the basic and applied sci-
able, do not constitute definitive evidence.
ences related to PG [7].
80.2.1 PG Effects In Vitro and Ex Vivo

Indicative of the extent of research effort and interest in
PG is that a total of 134 clinical studies on PG were regis- Initially, Kubo et al. reported that the 50% ethanol PG extract
tered from 2002 to 2017 in the WHO International Clinical exhibited significant hair growth activity in the ddY strain
Trials Registry Platform (ICTRP). Dozens of systematic mouse model [17]. Kim et al. studied the effect of PG’s water
reviews and meta-analyses of randomized controlled trials fraction on irradiated adult N:GP(s) mice. They reported that
evaluating the efficacy and safety of PG have been pub- PG administration before irradiation resulted in a suppres-
lished [8]. sion of apoptosis and an increase in the number of medullary
Today, PG is used as a dietary supplement to promote cells/unit length compared with the vehicle-treated mice
vitality, improve general well-being, slow the aging process, (p < 0.001), indicating an effect of PG on the recovery of the
prolong life, increase physical stamina and mental concen- hair follicles [18]. Chan et al. reported that ginsenoside
tration, and stimulate immune function [9]. It has been Rg1(G-Rg1), one of the primary ginsenosides, possesses
80.2 Ginseng and the Hair Follicle 487
estrogen-like activity [19]. Matsuda et al. investigated the cytotoxic to human DPCs at concentrations up to 500 μg/
hair growth-promoting effect of two kinds of PG (red and mL. Concerning the effects of topical PGE on hair regenera-
white) using the organ culture of B6C3F1 mice vibrissal hair tion in C57BL/6 mice and according to photographic and
follicles. Red PG extract (rPGE) promoted hair growth in a histologic observations, the high dose (10 mg/mL) group had
dose-dependent manner; the effect was most significant at a more pronounced results than the low dose (1 mg/mL) at day
dosage of 50 μg/mL, after both 48 h (559.3 ± 21.8 μm vs. 7 after depilation. Also, more hair shafts were observed in
control 476.1 ± 34.8, p < 0.05) and 72 h (746.3 ± 29.5 vs. both PGE groups than in the Minoxidil group, according to
control 625.9 ± 48.7, p < 0.05) of culture. Of the major con- the comparing photos provided in the article [22].
stituents of the extract, ginsenoside-Rb1 (G-Rb1) exhibited To determine the importance of ginsenosides in hair
hair growth activity (p < 0.05), but ginsenoside-Rg1 (G-Rg1) regeneration, Li et al. topically applied ginsenosides Rb1 and
and ginsenoside-Ro (G-Ro) were ineffective. Additionally, Rd over the shaved skin of 8 weeks-old C57BL/6 mice, then
20(S)-ginsenoside-Rg3 (20(S)-G-Rg3) showed hair growth- monitored and assessed them for 35 days. Results indicated
promoting activity (p < 0.01) [20]. that treatment with ginsenosides Rb1 and Rd increased cell
Murata et al. investigated the inhibitory activities of PGE proliferation and cell genesis in both anagen and telogen hair
and purified ginsenosides, against 5α-Reductase (5α-R), on follicles by approximately 35%, promoted the premature
testosterone-treated C57BL/6 mice [21]. The rhizome entry of resting hair follicles into anagen, prolonged anagen,
extracts of red PG showed 44.2% inhibition at 1000 μg/mL, and increased hair follicle size. Investigation of p63 demon-
white PG showed the most potent activity among the sam- strated that upregulation of p63 expression in the matrix and
ples tested (68.9% inhibition at the same concentration), and outer root sheath could have been one of the mechanisms by
cultivated PG was the lowest among the samples tested (35% which ginsenosides Rb1 and Rd promoted cell proliferation
inhibition at 1000 μg/mL). G-Ro, the main ginsenoside pres- in hair follicles (HFs) [23].
ent in rhizomes, showed inhibitory activity with an IC50 Shin et al. used gene expression profiling in human DPCs
value of 259.4 μM, ginsenoside Rd. had an IC50 of 285.9 μM, to identify the mechanism and molecules by which ginsen-
and ginsenoside Rg3 showed the highest inhibitory activity, oside Rg3 induces hair growth. Treatment with 1 μM, 5 μM
with an IC50 value of 86.1 μM. However, these results should and 10 μM ginsenoside Rg3 increased the proliferation of
be compared to Finasteride (positive control), which resulted DPCs by 125.4%, 133.5% and 145.8% respectively, com-
in 66.6% inhibition at a concentration of just 250 nM, which pared with untreated control DPCs (p < 0.01). Reverse
is 4000 times less than the tested 1000 μg/mL for extracts transcription-polymerase chain reaction showed dose-
and has an IC50 value of 9.4 nM for 5α-R type II. Hair re- dependent increases in VEGF mRNA levels on treatment
growth using Testosterone-treated C57BL/6 mice was evalu- with Rg3 comparable to that of Minoxidil, which also
ated, and according to the authors, “…the efficacy of tested resulted in increased VEGF levels, but the increase was dose-
samples was relatively low, but the curves for the samples independent. Immunohistochemical analysis showed that
could be distinguished from those of Testosterone”. So, even VEGF expression was significantly upregulated by ginsen-
though in vivo results were statistically insignificant, the oside Rg3 in a dose-dependent manner in human DPCs and
authors still considered the red PG rhizome to be a promising in mouse hair follicles. In addition, the stemness markers
candidate for future hair growth treatments [20]. CD8, CD34, and Ki-67 were also upregulated by ginsen-
Park et al. investigated the effects of PGE on the prolifera- oside Rg3 in the mouse hair follicles. The authors concluded
tion of human hair dermal papilla cells (DPCs) on the pro- that ginsenoside Rg3 promoted hair growth by upregulating
motion of hair regeneration in C57BL/6 mice and measured VEGF expression -a mechanism similar to that of Minoxidil-
the expressions of Bcl-2 and Bax by an immunoblot assay. and also by stimulating hair follicle stem cells [24].
They also compared the effects of different PGE concentra- Shin et al., during the same year, conducted a study to
tions (1 mg/mL and 10 mg/mL) with the effects of Minoxidil confirm the possibility of oral administration of ginsenoside
topical solution (MTS) as a positive control (5%, 100 μL/ F2, a minor saponin of PGE, on hair anagen induction. The
day) or vehicle control (30% ethanol) on the depilation- signaling pathway and anagen induction effect of ginsen-
induced hair cycling in 7-week-old-C57BL/6 mice. PGE sig- oside F2 were investigated in the C57BL/6 hair cell model.
nificantly increased (128–135%) the proliferation of DPCs They also studied the mechanism, including the expression
in a dose and time-dependent manner, at concentrations of of β-catenin Lef-1 and DKK-1, and compared with
0.8, 4, 20, and 100 μg/mL (p < 0.05 to p < 0.001). PGE also Finasteride on the effect of hair growth induction. The prolif-
enhanced Bcl-2 expression and decreased Bax expression eration rates of DPC and HaCaT cell lines treated with
compared to control in a dose-dependent manner at lower 0.1and 1 μM ginsenoside F2 significantly increased by 30%
concentrations (1 μg/mL and 10 μg/mL, p < 0.01, p < 0.001, compared with the 0.2 μM Finasteride-treated group. Also,
respectively). These effects disappeared at high PGE con- the expression of β-catenin Lef-1 and DKK-1 increased by
centrations (100-500 μg/mL), even though PGE was not 140%, 200%, and decreased by 40% in the 0.1 μM and
1 μM F2-treated group, respectively, compared to that of the was inferred through the inhibition of DHT-induced upregu-
Finasteride-treated group (p < 0.05 to p < 0.001). C57BL/6 lation of androgen receptor in DPCs [26].
mice were subjected to the same treatments, orally adminis- Kim et al. prepared a highly concentrated PGE containing
tered with ginsenoside F2 and Finasteride for 56 days, and 194.8 mg/g (19.48% w/w) of ginsenosides, with a ginsen-
the hair growth promotion rates were compared with groups oside content ~3 times higher than that of commercial PGE
treated with Finasteride, which was 20% higher in the gin- for oral supplements in Korea and 14 times higher than that
senoside F2-treated group. The mouse’s hair density on the of conventional root PGE. They hypothesized that this newly
56th day showed an increase of 65% in 0.5 mg/kg of ginsen- prepared PGE and its 6 principal ginsenosides (Rg1, Re,
oside F2 administered group, 98% in the 2.5 mg/kg of gin- Rb1, Rc, Rb2, and Rd) might have a significant hair growth
senoside F2-administered group, and 37% in the effect, comparable to MTS in humans. The tested PGE solu-
Finasteride-administrated group. Hair thickness increased by tion significantly increased VEGF expression, greatest at a
8% in the Finasteride-administered group, 13% in 0.5 mg/kg concentration of 5 mg/mL, and ginsenosides Rb1, Re, and
in the F2-administered group, and 25% in the 2.5 mg/kg of Rg1 also increased VEGF expressions in a dose-dependent
the F2-administered group compared to the vehicle group. manner in cultured human DPCs. In particular, Rg1 showed
The ratio of anagen to telogen in the skin tissue showed the most significant effect, which was significantly higher
1.05 ± 0.16 in the group of 0.5 mg/kg of the F2-administrated than that of Minoxidil (p = 0.00105 vs. Minoxidil treated
group, 1.56 ± 0.45 in the group of 2.5 mg/kg of the group). Other results showed that 2 mg/mL, 5 mg/mL, and
F2-administrated group, and 0.65 ± 0.22 in the Finasteride- 10 mg/mL of PGE and 1 mM of the Rb1, Re, and Rg1 sig-
administrated group. The principal controller in Wnt- nificantly enhanced hair growth of dissected human HFs, at
signaling, β-catenin, was strongly expressed in a concentration of 5 mg/mL, compared to control
F2-administrated hair tissue when compared to the vehicle (p = 0.000086) and this was a similar effect to that of 50 mM
and the Finasteride-administered group in IRS and dermal of Minoxidil. These three ginsenosides enhanced the hair
papilla, whereas DKK-1 expression was inhibited in the gin- elongation by 150–170% compared to the control group for
senoside F2-administrated hair tissue than the vehicle and 5 days, much higher than Minoxidil (+120%, p < 0.001)
the Finasteride-administrated group in hair follicular kerati- [27].
nocyte. Overall, the authors reported that the effects of gin- Li et al. investigated the molecular and cellular mecha-
senoside F2 on hair anagen induction and hair growth were nisms responsible for the hair growth-promoting effect of
through altering the Wnt signal pathway via comparison ginsenoside Re (GRe) in vitro and in vivo by topically apply-
with Finasteride. They concluded that ginsenoside F2 has the ing different doses of Minoxidil and GRe to the backs of
potential of promoting hair growth and hair anagen induction nude mice for 45 days and determining hair shaft length and
[25]. hair cycles. The topical treatment of GRe significantly
Park et al. also evaluated the in vivo efficacy of red PGE increased the hair shaft length and hair existent time, which
on hair growth in C57BL/6 mice and the effects of red PGE, was similar to Minoxidil’s effect. They also demonstrated
ginsenoside-Rb1, and ginsenoside-Rg3 on cultured human that the hair-promotion action of GRe might be mediated by
hair follicles. Experiments on C57BL/6 mice revealed that repression of the TGF-β signaling pathway, confirmed by
the subcutaneous injection of 3% red PGE resulted in more selective suppression of ERK phosphorylation by TGF-β
rapid hair growth than the negative control and showed com- stimulation in the HeLa immortal cell line [28].
parable hair growth to that of the positive control, 0.5% Keum et al. assessed the ability of PGE to protect against
MTS. Furthermore, red PGE and ginsenoside-Rb1 treat- chemotherapy-induced alopecia (CIA) in a well-established,
ments increased the proliferation of hair matrix keratino- in vitro human hair follicle organ culture model. Hair folli-
cytes, as shown by the Ki-67 immunofluorescent activity of cles were incubated with a Cyclophosphamide metabolite
the cultured human hair follicles. Red PGE and ginsenoside- (4-HC), resulting in hair growth inhibition, premature cata-
Rb1 increased the proliferation of human DPCs in a dose- gen induction, and inhibition of cellular proliferation and
dependent manner up to concentrations of 300 μg/mL and apoptosis of hair matrix keratinocytes. In addition, 4-HC
15 μg/mL, respectively. In addition, western blot analyses increased p53 and Bax protein expression and decreased
demonstrated that the effects of red PGE and ginsenoside- Bcl-2 protein expression. Pretreatment with KRG protected
Rb1 were associated with activated ERK and AKT signaling against 4-HC-induced hair growth inhibition and premature
pathways. The authors concluded that the possible hair- catagen development (p < 0.01). PGE also suppressed
growth mechanism of red PGE and its components include 4-HC-induced inhibition of matrix keratinocyte proliferation
the indirect stimulation to hair follicular keratinocytes and and stimulation of matrix keratinocyte apoptosis. Moreover,
that DPCs possibly mediate these through the ERK and AKT PGE restored 4-HC-induced p53 and Bax/Bcl-2 expression.
signaling pathways. Also, the protection against the DHT- Overall, results indicated that PGE might protect against
induced suppression of hair matrix keratinocyte proliferation
80.2 Ginseng and the Hair Follicle 489
4-HC-induced premature catagen development through with control animals on days 8 and 12. There were no effects
modulation of p53 and Bax/Bcl-2 expression [29]. on the expression of insulin-like growth factor IGF-1 [33].
Lee et al. used a highly concentrated PGE (similar to Kim In contrast to all these positive in vitro and experimental
et al. [28]) and reported that it significantly stimulated prolif- in vivo results, Begum et al., who tested the topical applica-
eration and inhibited apoptosis, respectively, in ORS kerati- tion of Eclipta alba, Asiasari radix, and PG on the back of
nocytes. It also affected the expression of apoptosis-related nude mice, reported that there was no difference in hair den-
genes, Bcl-2, and Bax. DKK-1, is a well-known Wnt antago- sity between the PG and control groups, unlike the two other
nist involved in DHT-mediated balding in AGA and was used tested extracts that were effective (see Chap. 83, Eclipta
to inhibit hair growth. PGE dramatically reversed the effect Alba).
of DKK-1 on ex vivo human hair organ culture and enhanced
the growth of hair follicles, an effect similar to that of
Minoxidil. PGE antagonized DKK-1-induced catagen-like 80.2.2 PG Effects in Clinical Trials
changes, in part, through the regulation of apoptosis-related
gene expression in HFs with the mRNA level of Bcl-2 Concerning human clinical trials, data is much more limited.
expression increase, and it also inhibited Bax gene expres- Choi et al., using a hair-tonic mixture of 8 herbal extracts
sion [30]. (one being white PGE) named SPELA 707®, investigated its
Truong et al. investigated the hair regenerative effects of effects and reported that it possessed significant hair cycle
Red ginseng oil (RGO) and its three major components converting activity from the telogen-to-anagen phase in C3H
(occupying 71% of RGO according to earlier research [31]), mice. Furthermore, they reported that SPELA 707® enhanced
including linoleic acid (LA), β-sitosterol (SITOS), or 1% the hair density in subjects with hair loss and promoted the
bicycle (10.1.0) tridec-1-ene (BICYCLO) once a day for conversion of hair into anagen in subjects with AGA -some
28 days in a C57BL/6 mouse model with testosterone- of them treated for up to 2 years with the extract-, through
induced AGA. Among all treatments, RGO produced the inhibition of steroid 5α-R activity.
greatest effect on hair regeneration, and its effect was even
higher than Finasteride. Histological analysis showed that
However, in the full-text publication, serious method-
RGO, along with LA and SITOS -but not BICYCLO- pro-
ological errors are evident, and even before-and-after
moted hair growth through early telogen-to-anagen transi-
photographs of patients reported as AGA patients are
tion and increased the anagen/telogen ratio. Treatment of
Alopecia Areata or diffuse alopecia patients, instead
mice with RGO, LA, or SITOS upregulated Wnt/β-catenin
[34].
and Shh/Gli pathways-mediated expression of genes, such as
β-catenin, Lef-1, Sonic hedgehog (Shh), Smoothened, Gli-1,
Cyclin D1, and Cyclin E in the TES-treated mice. Also, RGO
and its major components reduced the protein level of TGF-β Kim et al. conducted a study to evaluate the efficacy of
but enhanced the expression of anti-apoptotic protein Bcl-2. Korean red ginseng extract (KRGE) in the treatment of
Furthermore, the inhibition of Wnt/β-catenin and Shh/Gli AGA. Twenty-eight male AGA patients (mean age 42.8yo,
signaling pathways was restored in the presence of RGO, Norwood-Hamilton stage III-V) and 12 females suffering
LA, or SITOS. The authors considered that these results sug- from FPHL (mean age 37.8yo, Ludwig stage I & II) were
gest that RGO could be a potential novel therapeutic natural recruited. They were randomly divided into an experimental
product for the treatment of AGA, and major components group (20 patients) who took KRGE (3000 mg/day) orally
such as LA and SITOS synergistically produce the hair re- for 24 weeks and a control group (20 patients) who took a
growth activity of RGO [32]. placebo capsule orally. Changes in hair counts, hair thick-
Lee et al. evaluated the promotion of hair growth by ness, and density were evaluated by Folliscope®. Patient sat-
BeauTop (BT), a mixture of various Chinese herbs, includ- isfaction was evaluated through a questionnaire, and clinical
ing Ginseng radix, Astragali radix, Radix angelicae sinensis, photographs were rated by blinded dermatologists. Hair den-
Ligustri fructus, Rehmannia glutinosa, and Eclipta prostrata, sity significantly increased in the active group from baseline
in 8-week-old C57BL/6 mice. A total of 36 mice were (139.29 ± 27.27) to 24 weeks (155.76 ± 28.81) but not in the
divided into control and BT groups (18 mice/group), and placebo group (136.11 ± 27.91 at baseline, 134.53 ± 29.14 at
subsequent to oral administration of BT at 0.6 g/kg/day to 24 weeks, p < 0.0001). Hair thickness measured in the active
wax/rosin-induced alopecia in C57BL/6 mice, BT signifi- group significantly increased until the 12th week (baseline
cantly induced hair growth at day 8 compared with control 0.0525 ± 0.015 to 0.0623 ± 0.016, p < 0.001) but not at
treatment (p < 0.05). The expression levels of epidermal 24 weeks (0.0607 ± 0.019, p < 0.09) vs. placebo that remained
growth factor (EGF) and fibroblast growth factor (FGF)-7 unchanged (0.0554 ± 0.019 at baseline vs. 0.0556 ± 0.010 at
were increased, and levels of FGF-5 were reduced compared 12 weeks, p < 0.8). Expert panel assessment of global photo-
graphs at 24 weeks was +0.90 ± 0.55 for the active group vs. treatment MTS and oral KRGE might be a more effective
-0.07 ± 0.46 for the placebo group (p < 0.0003). The overall treatment than MTS treatment alone. Notably, this work was
satisfaction of patients was 64.7% for the active group vs. also supported by a 2011 grant from the Korean Society of
46.7% for the placebo group. Concerning possible conflicts Ginseng funded by the Korea Ginseng Corporation [37]. In
of interest, the authors disclosed that their work was sup- the full-text paper, there are tiny in size before-and-after
ported by a 2011 grant from the Korean Society of Ginseng, clinical and phototrichogram photos of one patient from the
which is funded by the Korea Ginseng Corporation [35]. In combination treatment group at baseline, 12, and 24 weeks,
the full-text paper, there are no before-and-after photographs depicting minimal hair growth.
of patients. Lee et al. evaluated the treatment effects of BeauTop [33]
Oh et al. studied the hair growth efficacy and safety of (BT) in AGA and FPHL patients for 6 months by using der-
KRGE in 50 Alopecia Areata (AA) patients (22 female matoscope and clinical photos, scored by three dermatolo-
patients and 28 male patients). They were divided into two gists on 32 participants; 26 males and 6 females. Four tablets
groups, each with 25 patients: group 1 was treated with cor- of BT or placebo were administered daily before breakfast
ticosteroid intralesional injection (named ILI, but the and lunch (8 tablets, 4.8 g of BT daily) for 6 months. The
authors did not determine the exact compound, dose, con- results revealed that 9/17 participants (52.9%) showed
centration, etc.) while taking KRGE, and group 2 was increased hair growth in the BT treatment group. Changes in
treated with the corticosteroid ILI alone. Results were eval- hair growth were as follows: no change, 47.1% patients;
uated by using scalp photography and phototricogram at minimally improved, 5.9% patients; moderately improved,
baseline (0 week) and 12 week. The average hair number of 29.4% patients; and significantly improved, 17.6% patients.
group 1 was 44.27/cm2 at baseline and increased to 101.39/ In the placebo group, 2/15 participants (13%) showed
cm2 at 12 wk. In group 2, the hair density also increased increased hair growth. The authors claimed that BT was even
from 40.21/cm2 at baseline to 91.17/cm2 at week 12, but superior to Finasteride (for both 1-year and 5-year treat-
there were no statistically significant differences between ments) in producing a significant improvement in
the two groups (p > 0.05). The average hair thickness in AGA. However, the study’s duration was too small to com-
group 1 was 0.062 mm, and it increased to 0.085 mm after pensate for seasonal changes (>6 months), all 3 sets of before
12 weeks of combination therapy. In group 2, the hair thick- and after photographs of patients in the publication are of
ness also increased from 0.058 mm to 0.078 mm, still not poor quality, and even the one set of photos that supposedly
significant (p > 0.05). Statistically significant differences shows significant improvement, actually depicted minimal
between data in the two groups (p < 0.05) were only efficacy [38].
reported. The global photographs were reviewed in a blinded
manner by an expert panel of three dermatologists at the end
of the trial using a 4-point scale, with an average score of 80.3 Dosage- Adverse Effects—Safety
3.6 for group 1 and 3.1 for group 2 (p > 0.05). Concerning
conflicts of interest, the authors disclosed that their work In humans, PG is associated with mild toxicity, and few
was supported by the 2010 grant from the Korean Society of adverse events have been reported. Although safety issues
Ginseng, funded by the Korea Ginseng Corporation [36]. In remain to be clarified regarding specific preparations, PG is
the full-text paper, there are no before-and-after photo- presumed to be a nontoxic herb, and data from clinical trials
graphs of patients. suggest that the incidence of adverse events with PG mono-
Ryu et al. comparatively analyzed the efficacy of 3% preparations is comparable to placebo [39].
MTS vs. combined 3% MTS and oral KRGE in treating Most published research studies have used a standardized
FPHL. Forty-one patients with FPHL were split into two PGE in a 200 mg/day dosage, while other sources consider
groups, one using only 3% MTS (group 1, n = 21) and that the recommended daily dose is 0.5–2 g of dried root in
another using 3% MTS with oral KRGE (group 2, n = 20). tea form or chewed, ingested in the morning [40].
Of the 35 patients who finished the treatment (16 from group Standardization is to the ginsenoside content, which is rec-
1 and 19 from group 2), hair density and thickness were sig- ommended to be 1.5–7% for oral preparations [41].
nificantly increased in both groups compared to baseline
(p < 0.05). Hair density in group 2 increased from
101.68 ± 3.07 at baseline to 115.05 ± 3.03 at 24 weeks, while However, this can be an important issue since huge
in group 1, hair density increased from 95.50 ± 4.65 at base- variability in concentrations of market compounds has
line to 107.38 ± 4.24 at 24 weeks. Group 2 showed a greater been reported by Harkey et al., who found concentra-
improvement in hair density and hair thickness over group 1, tions of ginsenosides varying by 15- and 36-fold in
although not statistically significant (p > 0.05). Based on this capsules and liquids, respectively [42].
study’s results, the authors concluded that the combination
References 491
In clinical practice, PGE is commonly prescribed or self- hepatotoxicity, hypertension, reproductive toxicity, and anti-
administered for long periods [43], capsule formulas are coagulant–ginseng interactions, were reviewed and summa-
generally given at a dosage of 100–600 mg/day, usually in rized by Paik et al. [53].
divided doses, whereas physicians should be aware that addi- Concerning the topical use of PG products, Becker et al.
tional “hidden” PG is often an ingredient in energy drinks reported on the safety of PG root-derived ingredients as used
[44]. Nevertheless, PG amounts in energy drinks are far in cosmetics. The total number of uses of PGE they located
below those expected to deliver therapeutic benefits or cause was 277 (196 leave-on products, 77 rinse-off products, and 4
adverse events, unless over-consumed [45]. diluted products) at maximum concentrations of 0.000002%
In general, PG is well-tolerated, its adverse effects are to 0.5% (maximum of 0.5% in leave-on products, 0.3% in
mild and reversible, and according to the literature, PGE rinse-off products, and 0.0004% in diluted products). They
monopreparations are rarely associated with adverse events reported that no data on the dermal/percutaneous or inhala-
or drug interactions. However, the interpretation of docu- tion absorption of PG root-derived ingredients were discov-
mented adverse effects and drug interactions can be difficult ered in the literature, and PGE was not cytotoxic to human
due to the variety of available PG formulations. Since the dermal fibroblasts at concentrations up to 1000 mg/
exact amount of PG in these products may not be identified, mL. Concerning the acute toxicity of PGE, the acute oral
causality is often difficult to determine from the evidence LD50 for rats was 750 mg/kg and 200 mg/kg for mice, oral
provided [46]. Additionally, combination products contain- administration of PGE was nontoxic to rats up to 5000 mg/
ing PG as one of several constituents have been associated kg/day for 105 weeks, up to 5000 mg/kg for life for mice,
with severe adverse events and even fatalities, but the inter- and 15 mg/kg/day for 90 days for dogs [54].
pretation of these cases is also burdensome, as ingredients
other than PG may have caused the problems. Associated Synopsis
adverse effects attributed to PGE include nausea, vertigo, Panax ginseng (PG) is probably the most popular medicinal
gastrointestinal disorders, occasionally appetite suppres- herb globally and is used in more than 35 countries as a food,
sion, and diarrhea. Patients of both genders have reported health supplement, and natural remedy. A plethora of health
mastalgia and female patients have reported vaginal bleed- claims is attributed to PG, one of which is hair growth.
ing due to the estrogen effect of PG. In patients taking high Various ginsenosides, which are steroid-like saponins unique
doses of PG (more than 2.5 g/day), CNS and cardiovascular to the PG family, have demonstrated hair growth properties
effects have been reported, such as euphoria, nervousness, through mechanisms that resemble those of Minoxidil and
insomnia, headaches, hypertension, hypotension, palpita- Finasteride. In vivo, human trials are still rare and very small,
tions, and tachyarrhythmias [47]. PG may interact with caf- with methodological errors and potentially biased, whereas
feine to cause hypertension, and it may lower blood alcohol oral or topical extracts that were used contained large
concentrations. Subjects treated with warfarin or other anti- amounts of active ingredients that are not available outside a
coagulants or antiplatelet drugs should avoid taking gin- clinical setting. The toxicity assessment of PG preparations
seng-based supplements since they have the potential to in human studies suggests that a relatively low frequency of
diminish warfarin anticoagulation by inducing CYP2C9 toxic incidence has been associated with ginseng applica-
activity [48]. Concomitant use of PG and the monoamine tion, although PG is not without capabilities of toxicity.
oxidase inhibitor Phenelzine (Nardil®) may result in manic- Accordingly, the use of PG products on AGA/FPHL patients
like symptoms [49]. must be judicious.
Panax ginseng also possesses hypoglycemic properties,
and caution should be exercised in using PG products in
patients with diabetes because of possible interactions with References
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Rosemary (Rosmarinus Officinalis)
81
In folk medicine, extracts and essential oil from the flow-

Basic Concepts ers and leaves of Rosemarinus officinalis (ROE) are used in
• Rosemarinus officinalis extract (REO) has various the belief they may be useful to treat a variety of disorders.
pharmacologically validated medicinal uses and
owes its properties to polyphenolic compounds,
such as rosmarinic acid, and the phenolic diter- 81.1 General Properties of Rosmarinus
pines, carnosic acid and carnosol. Officinalis
• REO has a long history of use in Dermatology and
has been used for its hydration, soothing, or vasodi- The culinary, medicinal, and fragrance uses of ROE are
latory properties, and traditionally as a hair growth attributed to the vast arrays of chemical constituents collec-
agent. tively known as plant secondary metabolites. ROE contains
• Available scientific evidence on the in vitro, experi- several active ingredients, including polyphenolic com-
mental, and in vivo hair growth properties of REO pounds such as rosmarinic acid and its metabolite, caffeic
is conflicting, and conclusions from available stud- acid [4], together with camphor, ursolic acid, betulinic acid,
ies are positively suggestive. and the phenolic diterpines carnosic acid and carnosol [5].
The antioxidant activity of ROE depends on the phenolic
composition [6], with carnosic acid and carnosol being the
most potent antioxidants that can efficiently protect lipids
Rosemarinus officinalis, commonly known as rosemary, is from oxidation, both in vitro (lipid solutions) and in vivo
one of the most popular perennial culinary herbs cultivated (biomembranes) [7].
worldwide. The name comes from Latin “ros marinus”, liter- REO has been used in traditional folk medicine for prob-
ally meaning “dew of the sea” since originally the plant was lems involved in the central nervous, cardiovascular, genito-
native along the eastern Mediterranean coastline. It is a urinary, reproductive, and respiratory systems, mostly due to
woody, perennial herb with evergreen, fragrant, needle-like its antispasmodic properties [8]. The plant’s volatile essen-
leaves and aromatic blue, pink, white, or purple flowers. It is tial oil is used in oils and lotions for the treatment of various
a common household plant that can stretch to 2 m height, ailments, such as arthritis, gout, muscular pain, and it is also
prefers full sun and well-drained neutral soil, with a pH of used in cosmetology as a fragrance [9]. According to the
6–7 [1]. European Medicines Agency (EMA) recommendation since
Rosemarinus officinalis has many culinary and medicinal 2010, REO can be used for treating dyspepsia and mild spas-
uses, with the most popular former ones being the use of modic disorders of the gastrointestinal tract. It can also serve
fresh and dried leaves to flavor foods with their characteristic as an adjuvant in the relief of minor muscular and articular
aroma, such as stuffing and roast meats [2], as well as being pain in addition to minor peripheral circulatory disorders
consumed in small amount as herbal tea. Additionally, rose- [10]. Experiments conducted with REO have demonstrated
mary extracts are routinely employed as natural antioxidants several notable pharmacological effects. Among the pharma-
to improve the shelf life of perishable foods, and the cologically validated medicinal uses of REO are the antioxi-
European Union has even approved rosemary extract as a dant [4], analgesic [11], antithrombotic [12], antiulcerogenic
safe and effective natural antioxidant for food preservation [13], antimicrobial [14] -mostly against Gram-positive bac-
(E392) [3]. teria [15]-, anti-inflammatory [16], anti-nociceptive [17],
496 81 Rosemary (Rosmarinus Officinalis)
anti-depressant [18], cognition-enhancing [19], antitumero- and Bax in DPCs. Still, one cannot attribute these effects to
genic [20–22], diuretic [23], hepatoprotective [24], and even one specific extract solely, in this case, of Rosmarinus offici-
neuroprotective properties [25]. nalis [34].
Rosmarinus officinalis also has a long history of use in Rastergar et al. in a previous study (2013) had investi-
cosmetic Dermatology as a topical compound due to its anti- gated the combined effects of the same herbal extract mix-
oxidant [26], hydration, and antiaging properties [27]. ture combined with PRP on human DPCs. DPCs were treated
Recently, various researchers have reported on the wound with various concentrations of herbal extracts (1.5–4.5%) in
healing properties of ROE [28] since it has been found to the presence of PRP (10% v/v) for 48 h, and cell prolifera-
increase flap survival due to its antimicrobial and vasodilation was measured by MTT and BrdU methods. It was found
tory effects [29]. to induce significant proliferation of human DPCs at concen-
trations ranging from 1.5 to 4.5% via the expression of ERK
phosphorylation increased in a dose-dependent manner [35].
81.2 The Action of Rosmarinus Officinalis
on the Hair Follicle
81.3 Rosmarinus Officinalis and AGA/FPHL
ROE has been a popular hair growth promoter for centuries.
The properties of some of the phytochemical compounds in Concerning clinical studies on REO’s effects on human hair
ROE could have a beneficial effect on AGA/FPHL. Carnosol growth, minimal data is available, and studies on the isolated
has been reported to downregulate nuclear factor-kappaB effects of REO are still missing.
(NF-κB) [30] and Bcl-2 [31], both associated with AGA’s Hay et al. (1998) conducted a randomized, double-blind,
apoptotic mechanism [32]. Still, in vitro studies on the hair 7-month-long controlled trial on 86 patients diagnosed with
growth potential of REO did not appear in the literature Alopecia Areata. Patients were randomized into 2 groups,
before 2010. the active group massaged a mixture of essential oils (REO,
Murata et al.33 reported that the topical application of thyme, lavender, and cedarwood) in a mixture of carrier oils
ROE 2 mg/day improved hair regrowth in C57BL/6NCrSlc (jojoba and grapeseed) on their scalp daily, while the control
mice that experienced hair regrowth interruption induced by group massaged daily only the carrier oils. Treatment suc-
Testosterone treatment without mediating the androgenetic cess was evaluated on sequential photographs by 2 indepen-
pathway. ROE showed additional 5α-Reductase (5α-R) inhi- dent dermatologists, and the degree of improvement was
bition of 82.4% and 94.6% at 200 and 500 μg/mL, respec- measured by a 6-point scale and computerized analysis of
tively, compared to Finasteride, which inhibited the enzyme traced areas of alopecia. According to the authors, 19 of the
by 81.95% at 250 nM. As an active constituent of 5α-R inhi- 35 patients in the active group who completed the trial
bition, 12-methoxycarnosic acid was identified, and ROE showed improvement compared with 6 of the 28 patients in
and 12-methoxycarnosic acid inhibited androgen-dependent the control group who completed the trial (p < 0.008). The
proliferation of LNCaP cells as 64.5% and 66.7% at 5 μg/mL degree of improvement in the photographic assessment in
and 5 μM, respectively. the active group was significant (p < 0.05) compared with the
placebo. The measurement of traced areas, which was per-
formed in only 32 patients, showed a mean reduction in the
However, one should note that the concentration levels
area affected by 103.9 ± 140.0 cm2 in the active group com-
at which these compounds demonstrated inhibitory
pared with −1.8 ± 155.0 cm2 in the control group [36].
effects are not feasible in vivo [33].
However, the study had severe limitations that were com-
mented on by other authors [37] (lack of a no-treatment
group to exclude spontaneous remission, the different odor
Rastegar et al. (2015) investigated the effects of a mixture of lotions, faulty randomization procedure, etc.), and no
of several herbal extracts (Persea americana, Althaea offici- other team has replicated these results. In addition, the
nalis, Chamaemelum nobile, Thymus vulgaris, Rosmarinus alleged efficacy in Alopecia Areata does not translate into
officinalis, and Urtica dioica) in human dermal papilla cells efficacy in other hair loss disorders.
(DPCs) proliferation. They also analyzed the molecular Concerning studies on patients with AGA/FPHL, there
mechanisms and pathways involved in the mediation of hair are three studies available in the literature. Bureau et al. 38
proliferation by these herbal extracts. The extracts were conducted a double-blind, randomized study vs. placebo in
found to significantly increase the proliferation of human overall 93 healthy volunteers to demonstrate the positive bio-
DPCs at concentrations ranging from 1.5 to 4.5% in a logic effect on hair loss and hair regrowth of a pulsed electro-
concentration-dependent manner, and mixture affected the magnetic field in combination with essential oils administered
protein expressions of ERK, Akt, cyclin D1, Cdk4, Bcl-2, according to a regular treatment schedule of 26 weeks. The
81.3 Rosmarinus Officinalis and AGA/FPHL 497
active group included 31 men and 9 women who applied a 3 months (122.8 ± 48.9 in the REO group in both baseline
solution containing 10 essential oils (one was REO) three and 3 months and 138.4 ± 34 in MTS 2% group in both the
times per week, and the control group included 21 men and baseline and at 3 months) whereas, at 6 months, there was no
8 women who applied a placebo lotion. The essentials oils actual increase in either group (129.6 ± 51.2 in the REO
mixtures were comprised of the following constituents: group and 140.7 ± 38.5 in the MTS 2% group) [39].
Pimenta racemose, Rosmarinus officinalis, Myrtus commu-
nis, Salvia officinalis, Cedrus atlantica, Salvia sclarea,
Despite the “enthusiasm” of the authors, results from
Laurus nobilis, Thymus satureioides, Pogostemon patchouli,
this study do not show any actual hair growth potential
and Cananga odorata. After application, electromagnetic
of REO in AGA patients, not even in those patients
pulses (12.5 V/m at 1 cm and 10 MHz) were delivered for
with mild AGA.
30 min to both groups by a helmet device. Mean hair count
comparisons within the groups significantly favored the
treatment group, which exhibited decreased hair loss in 83%
of the volunteers and a more than 20% hair count increase The full-text article contains 2 pairs of high-quality
over baseline in 53% of patients. The histologic study com- before-and-after photos, one pair of a stage V patient of the
prised of 60 biopsies on 30 individual patients, and an aver- REO group with minimal hair growth and one pair of a stage
age 75% increase in the proliferation index in the treated IV patient of the MTS group also with minimal hair growth.
subjects was demonstrated vs. 21% for the controls. Even Masoud et al. conducted a randomized, double-blind con-
though the results of this article are interesting, the short trolled trial in Sina Hospital, Tabriz, Iran. They enrolled 24
duration and the high complexity of the protocol does not healthy males (mean age 33.04 ± 5.81 years) with mild to
allow one to attribute hair growth properties to any of the 10 moderate AGA and randomly assigned them into two groups
essential oils or the electromagnetic pulses solely. Strangely, [40]. The first group received 5% MTS at morning and eve-
these impressive results have not been replicated by other ning intervals. The second group received 5% MTS in the
teams [38]. morning and a topical herbal solution (THS) in the evening.
Panahi et al. 39 investigated REO’s clinical efficacy in the The THS contained hydroalcoholic extracts of Rosmarinus
treatment of AGA and compared its effects with 2% officinalis and Olea europaea and lipidosterolic extract of
Minoxidil topical solution (MTS). Patients at AGA stages II Serenoa repens (LSEsr). At week 36, the MTS + THS group’s
and III in the Norwood-Hamilton scale were randomly mean hair diameter significantly increased compared to the
assigned to REO (n = 50) or MTS 2% (n = 50) for 6 months, MTS group (p = 0.001). The mean (SD) hair diameters of the
and a standardized professional microphotographic assess- MTS group at weeks 12, 24, and 36 were 51.58 ± 7.67 μm,
ment of each volunteer was taken at the initial interview and 51.17 ± 7.82 μm, and 50.58 ± 7.38 μm, respectively, which
after 3 and 6 months. According to the authors, both groups was not significant compared to the baseline mean hair diam-
experienced a significant increase in hair counts at the eter (53.92 ± 6.73 μm) (p = 0.192). The mean (SD) hair
6-month endpoint compared with the baseline and the diameters of the MTS + THS group were 57.42 ± 8.88 μm,
3-month endpoint (p < 0.05). Additionally, no significant dif- 60.92 ± 7.35 μm, and 62.67 ± 7.19 μm at weeks 12, 24, and
ference was found between the study groups regarding hair 36, respectively, which was significantly higher than the
count, either at month 3 or 6. Both treatments were equally baseline mean hair diameter (52.75 ± 8.74 μm) (p < 0.001).
tolerable in terms of dry hair, greasy hair, and dandruff, For both groups of the study, the mean hair density
while subjects in the MTS group reported scalp itching more increased during the 36-week treatment period. In the MTS
frequently (p < 0.05). The authors included a table of the group in 36 weeks, it was 94.67 ± 4.29 hairs/cm2, which
self-assessment of patients in which all patients reported slightly increased compared to the baseline mean hair den-
improvement of their image, with n = 0 patients reporting sity (94.08 ± 3.96 hairs/cm2) (p = 0.2) in the MTS + THS
“no change” or “worsening” at 6 months! group in 36 weeks it was 96.92 ± 3.06 hairs/cm2, compared
Even more strangely, in the MTS group, 92% and 8% of to 93.83 ± 4.04 hairs/cm2 at baseline (p = 0.003). In addition,
patients reported mild and moderate hair growth at 6 months, the MTS + THS group was reported as superior to the MTS
whereas in the REO group, 18% and 82% reported mild and group for all questions of the self-assessment questionnaire
moderate hair growth respectively! Notably, this study did in 36 weeks. There were statistically notable variations
not include a control group, only patients with mild AGA between the two groups in terms of increasing hair growth,
were included (according to the reported methodology but reducing hair loss, and improving hair appearance, accord-
not to the published photos, though), and the reported hair ing to the data obtained from the patients’ self-assessment
counts were probably barely significant. Careful reading of questionnaire (p < 0.05). The full-text article contains 2
the data in the full-text article concerning hair counts shows small pairs of low-quality before-and-after photos, one pair
that hair counts in both groups were identical at baseline and from each group showing one patient at stage II in the
498 81 Rosemary (Rosmarinus Officinalis)
Norwood-Hamilton scale (MTS + THS group) and one Synopsis

patient at stage IV (MTS), both showing minimal improve- Rosmarinus officinalis is a popular traditional herb used in
ment. The authors concluded that the topical herbal solution hair loss disorders, which seems to have hair growth poten-
(THS) exerted considerable improvement in AGA with a tial via unknown mechanisms. Clinical data on the possible
high degree of patient compliance. This study has been reg- effects of Rosmarinus officinalis extract (REO) in AGA/
istered in ClinicalTrials.gov (NCT03753113) [41]. FPHL are very limited and unclear, and even though REO is
However, there are several methodological limitations in safe and tolerable, based on available evidence, its use is not
the study. The sample size was small, a control group was not recommended.
included, the enrolled participants do not represent AGA
patients in the general population since most had very mild
AGA (stage II-III). In addition, neither authors nor subjects References
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Capsicum (Red Pepper)
82
Capsicum consists of overall >27 species, five of which

Basic Concepts are domesticated. Capsicum annuum, also known as bell,
• Capsaicin, the main pungent in chili peppers, is one sweet, or chili pepper, is the most popular and extensively
of the most commonly used spices globally, and the cultivated family member [2]. Capsicum annuum is a herba-
analgesic, anti-inflammatory, and vasodilating ceous annual that reaches 1 m in height and has glabrous or
properties of the molecule have made it valuable in pubescent lanceolate leaves, white flowers, and fruits that
various cultures for centuries. vary in length, color, and pungency, depending upon the cul-
• Capsaicin is a lipophilic substance belonging to the tivar [3]. The oily concentrated extract from plants of the
class of vanilloids, is an agonist of the transient genus Capsicum has been long used in traditional medicine
receptor potential vanilloid 1 receptor (TRPV1), and consists of five naturally occurring capsaicinoids, includ-
and its potent vasodilating properties are due to the ing the major pungent component, capsaicin.
secretion of substance-P from the afferent sensory Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is
nerve fibers. an alkylamide, and it is by far the most abundant capsa-
• Activation of TRPV1 increases the secretion of cal- icinoid found in chili peppers (69%). Also present are dihy-
citonin gene-related peptide (CGRP), which subse- drocapsaicin (22%), nordihydrocapsaicin (7%),
quently increases IGF-1 and EGF production in homocapsaicin (1%), and homodihydrocapsaicin (1%) [4].
DPCs, keratinocytes, and sebaceous glands. Also, it Capsaicin is a lipophilic chemical that can produce an intense
has positive effects on hair growth in vitro and on burning mouth sensation, which most mammals find unpleas-
lab animals. ant, but birds are unaffected. The secretion of capsaicin pro-
• Studies in humans have shown that capsaicin has a tects the fruit from consumption by insects and mammals,
moderate hair growth potential, but limited safety while the bright colors attract birds that will disperse the
data are currently available for long-term oral or seeds [5]. Since it is a naturally occurring substance, the
topical use. At higher doses, it has been associated U.S. Environmental Protection Agency (EPA) considers cap-
with hair loss and potential carcinogenesis. saicin to be a biochemical pesticide and animal repellent [6].
The amount of capsaicin in hot peppers varies signifi-
cantly among varieties, and the range of pungency (spicy
heat) of chili peppers is measured in Scoville heat units
Capsicum species, also known as chili peppers, belong to the (SHU), named after the inventor of the scale, American phar-
flowering Solanaceae family, originally native to the macist Wilbur Scoville.
Americas, where they have been cultivated for thousands of
years. Following the Colombian exchange -the widespread
transfer of plants, animals, culture, human populations, tech- The Scoville score can range from 100 or less for sweet
nology, and ideas between the Americas and the Old World peppers, between 2500 to 8000 SHU for hot Jalapeños,
during the 15th and 16th centuries-, chili peppers became a and can reach up to 2,200,000 SHU for the world’s
prominent element in many cuisines. Today, peppers are current hottest known pepper named “Carolina
some of the most popular condiments globally, being con- Reaper”, as confirmed by the Guinness Book of World
sumed daily by almost 25% of the world’s population [1]. Records [7].
502 82 Capsicum (Red Pepper)
82.1 General Properties of Capsaicin 82.3 Action of Capsaicin on the Hair

Follicle
Capsaicin was first isolated in 1816 by Christian Bucholz,
and its chemical composition was first determined in 1919 Studies on the specific effects of capsaicin on hair follicles
[8]. The first reports of its pain-alleviating properties are still very limited, and even these are strongly controver-
appeared in the mid-1850s with the recommendation to use sial. However, there is a large volume of research on capsa-
it for parts of the body that burn or itch. Since those first icin’s effects on molecular pathways that are important in
reports, various capsaicin preparations have been employed hair follicle physiology since VR1/TRPV1 is a predominant
to treat a variety of chronic painful conditions [9]. Systematic
receptor in human skin. Additionally, capsaicin’s vasodila-
reviews have shown that capsaicin is efficacious in treating tory actions could positively impact hair follicle due to
nondiabetic neuropathic pain, postherpetic neuralgia, osteo- increased blood perfusion.
arthritis, chronic musculoskeletal pain, overactive bladder, Denda et al. demonstrated the immunoreactivity of the
and pruritus [8, 10]. Additionally, capsaicin is considered a VR1 receptor proteins and ion channels associated with pain
strong anti-oxidant [11], a potent anesthetic, analgesic, and a
sensation on the human skin [21]. Ständer et al. were the first
vasodilating agent [12] and to possess chemopreventive to report the wide distribution of the VR1/TRPV1 in human
properties [13]. Capsaicin and other capsicum-derived ingre- skin. VR1/TRPV1 can be found in sensory nerve fibers, mast
dients are used as skin-conditioning agents, flavoring agents,cells, epidermal keratinocytes, blood vessels, epithelial cells
or fragrance components in cosmetics [14] and are also of hair follicles, eccrine sweat glands, and sebaceous glands
widely used as research tools to study peripheral pain [15]. [22]. Bodó et al. demonstrated that VR1 is also expressed on
other neuroectodermal and mesenchymal cell types, such as
Langerhans cells, mast cells, sebocytes, sweat glands epithe-
Capsaicin is also the active ingredient in “pepper
lium, endothelial and smooth muscle cells of skin blood ves-
spray” commonly employed by government agencies
sels [23].
or military forces worldwide as a non-lethal criminal
In a subsequent study, Bodó et al. [23] reported that
incapacitating agent against interpersonal violence or
TRPV1 activation by capsaicin in organ culture resulted in a
civil unrest and for law enforcement, personal self-
dose-dependent and TRPV1-specific inhibition of hair shaft
defense, and sometimes control of wild animals [16].
elongation, suppression of proliferation, induction of apop-
tosis, premature catagen, and upregulation of intrafollicular
TGF-β2. Cultured human ORS keratinocytes also expressed
functional TRPV1, whose stimulation inhibited prolifera-
82.2 Mechanism of Action of Capsaicin tion, induced apoptosis, elevated intracellular calcium con-
centration, upregulated known endogenous hair growth
Capsaicin activates the vanilloid receptor subtype 1 (VR1)/ inhibitors (Interleukin-1β, TGF -β2), and down-regulated
(TRPV1), a non-selective calcium-permeable cation channel known hair growth promoters (hepatocyte growth factor,
that binds vanilloids. In humans, VR1 expression has been IGF-1, stem cell factor). These findings strongly supported
detected in the central nervous system, spinal cord, and kid- TRPV1 signaling as a significant novel player in human hair
ney, with increasing evidence that VR1 plays an essential growth control and underscored the physiological impor-
role in cutaneous biology and disease [17]. TRPV1 receptors tance of TRPV1 in human skin as a potent, physiologically
are often found on C- and A-delta fibers in the nociceptive relevant hair growth-inhibitory force beyond nociception
sensory pathway, and when VR1 is activated, it initiates a [24]. TRPV1 signaling is also a significant, previously unre-
depolarization cascade that allows for the influx of sodium ported player in human sebocyte biology. Tóth et al. reported
and calcium ions. that capsaicin selectively inhibited basal and arachidonic
Besides affecting nociceptive sensory transmission, the acid-induced lipid synthesis in a dose-, time-, and extracel-
topical use of capsaicin solution or gel causes vasodilation lular calcium-dependent and a TRPV1-specific manner.
and erythema [18] via the secretion of Substance P (SP), Low-dose capsaicin stimulated cellular proliferation via
which provokes erythema and edema, with both histamine- TRPV1, whereas higher concentrations inhibited sebocyte
dependent and histamine-independent pathways [19]. The growth and induced cell death, independent of TRPV1 [25].
SP secreted by primary afferent C-fibers has strong vasoac- Even though Bodó et al. reported adverse effects of cap-
tive effects, causes vasodilatation and profound hypotension saicin on hair follicles [24], other researchers reported indi-
while being also involved as a mediator in sensory processes rect actions of capsaicin that could positively affect hair
of various types, including nociception and inflammation follicle physiology. Weger et al. reported that stimulation of
[20]. (See Chap. 17, Vol. 1). sensory neurons by capsaicin increased tissue levels of IGF-
82.3 Action of Capsaicin on the Hair Follicle 503
1 and IGF-1 mRNA via increased CGRP release. Since cebo. Subcutaneous capsaicin administration significantly
IGF-1 is known to control the hair growth cycle and the pro- increased dermal IGF-1 levels at 30 min after administration
liferation of keratinocytes and differentiation of hair shafts, in wild-type mice (p < 0.01), but not in CGRP-knockout
the authors suggested that capsaicin could have potent effects mice. This strongly suggested that capsaicin might increase
in hair follicles in vivo, as well [26]. In earlier studies, capsa- IGF-1 production in the skin by increasing both transcription
icin stimulated EGF secretion [27], which is essential for the and release of CGRP in sensory neurons of the wild-type
initiation of anagen [28]. It also and upregulated gene expres- mice.
sions of EGF, EGF-2, and their receptors in granulation In the human study, the active group subjects (n = 31)
fibroblasts during wound healing [29], while it also sup- were orally administered capsaicin (6 mg/day) and isofla-
pressed the NF-κB activation pathway [30]. Magnusson vone (75 mg/day), and according to the authors, serum IGF-1
et al. (1996) applied capsaicin 1% solution on the volar fore- levels were significantly increased from the baseline but not
arm of 7 volunteers and reported that it elicited a statistically in the 17 volunteers who received placebo (p < 0.01). Hair
significant increase in skin blood flow at 50 min (98.8 ± 12.2 growth was significantly higher among volunteers who
perfusion units) compared to control solutions of 50 μL 50% received capsaicin and isoflavone (20/31: 64.5%) vs. placebo
ethanol (35.6 ± 12.6 perfusion units, p < 0.0001) [31]. (2/17: 11.8%) at 5 months (p < 0.01). Overall, hair growth
was observed in 88.0% of the 25 patients with AGA who
were administered capsaicin and isoflavone [33]. The authors
All these diverse biological effects of capsaicin might
included3 before-and-after photos of mice showing very sig-
have a positive effect on hair growth. However, actual
nificant results on both capsaicin and capsaicin and isofla-
scientific data on the clinical effects of capsaicin on
vone groups. Also, 4 good-quality sets of before-and-after
hair growth is very limited.
photos of subjects who were administered capsaicin and iso-
flavone for 5 months showing significant hair growth; one
male volunteer with AGA (54 yo), one male volunteer with
Lee et al. of the Dermatologic Clinic of the Yonsei AT (29 yo), one in a female volunteer with FPHL (39 yo, and
University Wonju College of Medicine of Korea presented in in a female volunteer with AA (40 yo). These results were in
2001, during the meeting of the European Hair Research conflict to those of Bodó et al. [24], who reported that capsa-
Society in Tokyo, the results of their research on the com- icin inhibited hair shaft elongation by inducing premature
bined use of capsaicin and Minoxidil on the hairs of back hair follicle regression in vitro.
skin of ICR mice. They divided the mice into 4 groups (con- In a subsequent study by Harada et al., researchers exam-
trol, capsaicin, Minoxidil, and co-applied group) and examined the possibility that capsaicin and isoflavone administra-
ined the hair growth macroscopically and the percentage of tion could reduce arterial blood pressure by increasing IGF-1
the area of hair regrowth by image analysis using phototri- production. They recruited 42 volunteers (24 males with
chogram at the 0, 5th, 10th, 15th, 20th, 25th, and 30th day. AGA and 18 females with FPHL, aged 16–58 years), of
Capsaicin not only induced anagen quickly but also sus- which 29 were normotensive, and 13 were hypertensive. At
tained a constant effect on linear hair growth. Minoxidil also 5 months of administration of capsaicin and isoflavone,
induced anagen promptly and prolonged anagen, whereas serum levels of IGF-1 significantly increased in both normo-
co-application of capsaicin and Minoxidil acted synergisti- tensive and hypertensive volunteers. Systolic and diastolic
cally and resulted in faster and more steady hair growth than blood pressure levels were significantly reduced in the 13
either compound alone [32]. hypertensive volunteers but not in normotensive patients
Harada et al. (2007) examined the possibility that capsa- [34]. The authors attributed these effects to CGRP, which
icin and isoflavone administration could promote hair growth increased the endothelial production of nitric oxide and pros-
by increasing CGRP release from sensory neurons, leading taglandins (PGI2 and PGE2) by activating endothelial nitric
to an increase in IGF-1 production in hair follicles. The study oxide synthase (eNOS) and cyclooxygenase-1, respectively.
design included aCGRP-knockout mice, male C57BL/6 A similar finding had been previously (2006) also reported
mice, and 48 human volunteers with hair loss (25 males and by Okajima et al. [35] Notably, PGE2 has cytoprotective
23 females, aged 9–58 years). Among the volunteers, 34 suf- effects and induces stem cells activation, follicular cells pro-
fered from AGA/FPHL (19 males and 15 females), 13 from liferation, and hair growth and increased PGE2 production is
alopecia totalis (AT, 6 males and 7 females), and 1 female probably the primary mechanism of action of Minoxidil on
from alopecia areata (AA). The authors randomly assigned hair follicles [36] (see Chap. 23).
the 48 volunteers into two groups: 31 patients (25 AGA, 5 Concerning the effects of capsaicin in other hair loss dis-
AT, and 1 AA) were administered capsaicin and isoflavone, orders, Hordinsky et al. applied a 0.075% capsaicin cream on
and 17 patients (14 AGA and 3 AT) were administered a pla- 2 female patients with scalp AA, and they reported vellus
504 82 Capsicum (Red Pepper)
hair regrowth in both of them [37]. Ehsani et al. conducted

the only clinical trial comparing topical capsaicin’s efficacy Capsaicin is a very potent irritant, and if exposed to the
with other therapies used in AA. In a randomized clinical mucous membranes, it can cause severe irritation,
trial, they compared the efficacy of topical capsaicin with pain, and burning. When it gets in the eyes, capsaicin
that of clobetasol ointment in 50 patients (aged 12–60 years) can cause prolonged burning pain with tearing, photo-
with patchy AA of the scalp, with less than 30% of scalp phobia, and blurry vision.
surface involvement, randomized into two equal groups.
Twenty-five patients used clobetasol ointment 0.05% once
daily for 6 weeks, while the other 25 patients used capsaicin The therapeutic index for topical and oral capsaicin
ointment (0.35–0.65 mg of capsaicin/g) once daily for the has not been thoroughly studied. However, a potential co-
first 2 weeks and then twice daily for the next 4 weeks. The carcinogenic role of capsaicin has aroused the interest of
authors observed statistically significant more vellus hair various researchers. Even though capsaicin itself is not a
growth in the capsaicin group compared to the clobetasol carcinogen, long-term exposure to high doses of capsa-
group (3/21 vs. 0/21, respectively) and non-cosmetic hair icin (>100 mg/kg of body weight) can cause peptic ulcers,
growth (6/21 vs. 0/21, respectively) at the 4th, 6th, and 12th- enhance breast cancer metastasis, and accelerate the
week visits (p < 0.05). However, there were no significant development of prostate, stomach, duodenal, and liver
differences in the growth of cosmetically significant hairs cancer when it is associated with a tumor promoter [44,
between the groups (both 2/21, p > 0.05) [38]. 45].
Synopsis
82.4 Dosage- Adverse Effects—Safety Capsaicin seems to have a mild hair growth potential through
the activation of vanilloid receptor TRPV1, which results in
Capsaicin has been widely consumed orally by humans increased IGF-1 production by dermal papilla cells. IGF-1
throughout the world for centuries, and comprehensive acts on keratinocytes, promoting hair growth through stimu-
reviews of its safety have not identified severe toxicity [14, lation of the proliferation of keratinocytes in hair follicles.
39]. Although the presumed lack of toxicity of capsaicin in However, clinical studies on the effects of capsaicin are very
food does not preclude adverse effects related to its actions limited and have not been replicated by other researchers.
on the skin, topical capsaicin is also generally regarded as Additionally, since the long-term safety of the use of topical
safe, both for medical [40] and cosmetic purposes [41]. or oral capsaicin is elusive and might accelerate the develop-
Capsaicin can be administered in many different forms, ment of certain malignancies, its medical use should be
such as low-concentration creams, lotions, films, microemul- extremely judicious.
sions, liposomes, nanotechnology-derived drug delivery sys-
tems, patches, oral formulations, as well as intradermal,
subcutaneous, or intravenous injections. Capsaicin is a very References
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A Few More and Recently Reported
Herbs 83
The following herbs have also been reported to possess hair- resulted in an increase of nuclear β-catenin level and upregu-
growth properties, and their results are reported in summary lation of the phosphorylation of Akt, of cyclin D1, cyclin E,
and in alphabetical order. The reason these herbs do not and CDK2, whereas the expression of p27(kip1) was down-
“entertain” a dedicated chapter is because there is no avail- regulated in the DPCs, while it scarcely inhibited steroid
able data on use in humans for most of these herbs. Also, 5α-R activity. The authors considered that the in vitro hair
their safety, adequate concentration, required dosage scheme, growth effects of this compound are not antiandrogenic but
the long-term safety of use on the scalp, and other significant directly enhance the proliferation of DPCs.
parameters are completely undetermined. For these reasons, Currently, there are no studies on the actual hair growth
none of these is recommended for the treatment of AGA/ properties of AcK in humans.
FPHL, even though some authors consider the use of specific
herbal solutions permissible.
The author has tried to the best of his knowledge to 83.2 Asiasari Radix (Asiasarum Root)
include almost all remaining herbal extracts in the literature
(in alphabetical order) that have been mentioned in hair Asiasarum root (AsR) (rhizome of Asiasarum sieboldii
growth studies. However, the rate by which authors publish F. MAEKAWA) has been frequently used in traditional
on this field is hard to follow. The reason why this is proba- Chinese medicinal formulas for its alleged anti-inflammatory,
bly happening is tackled in Chap. 70. analgesic, and antibacterial properties [3].
Rho et al. investigated the effects of 45 plant extracts tra-
ditionally used for treating hair loss in oriental medicine to
83.1 Acanthopanax Koreanum identify potential stimulants of hair growth. They measured
the proliferation of the immortalized human keratinocyte cell
Acanthopanax koreanum Nakai (AcK) is an indigenous plant line (HaCaT) and human DPCs evaluated by the MTT assay
prevalent throughout South Korea, which has a ginseng-like (a colorimetric assay for assessing cell metabolic activity)
activity [1]. and thymidine incorporation assay and also used C57BL/6
Kim et al. [2] investigated the hair growth promotion and C3H mice to examine the in vivo effects. Among the
effects and underlying mechanisms of the extract of AcK tested plant extracts, the extract of AsR induced earlier
leaves, as well as the isolated compounds from the AcK telogen-to-anagen conversion than did the vehicle control in
extract on the growth of hair. When immortalized rat vibrissa C57BL/6 and C3H mice experiments. In addition, AsR
dermal papilla cess (DPCs) were treated with 1 μg/mL of extract increased the uptake of radio-labeled cysteine in the
AcK extracts for 4 days, the proliferation increased signifi- mouse vibrissae hair follicles cultured in vitro, resulting in a
cantly (119.0 ± 10.4%) compared to the positive control 129% uptake compared to control. It also increased the pro-
Minoxidil sulfate 1 μM (115.0 ± 5.2%) (p < 0.05). Among liferation of HaCaT and DP cells to 106.5% and 115.6%,
several components, acankoreoside J, a lupane-triterpene respectively, as compared to the control treatment. Moreover,
isolated from AcK leaves, markedly promoted the prolifera- the AsR extract induced the expression of vascular endothe-
tion of DPCs (121.2 ± 7.1% at 1 μM; p < 0.05). When rat lial growth factor (VEGF) in human DPCs that were cultured
vibrissa follicles were treated with acankoreoside J, which in vitro by 125% but had no inhibitory effect on
was isolated due to its high potency, the hair-fiber lengths of 5α-R. Interestingly, the A. radix extract showed cytotoxic
the vibrissa follicles increased significantly, even more than effects for both cells at concentrations higher than 0.0001%
with the positive control. Treatment with acankoreoside J [4]. Begum et al. investigated the synergistic hair growth
508 83 A Few More and Recently Reported Herbs
effect of the methanol extracts of 4 herbs (including AsR, see (p < 0.05), respectively, as compared to the control group.
Ref. [5]) and reported that although the hair length of AsR For IGF-1 mRNA expression in the skin tissue, at week 4,
extract-treated mice increased significantly longer compared the MTS and ChO oil groups showed a significantly higher
to the control group in the previous hair cycle, it became expression by 204% (p < 0.05) and 426% (p < 0.01), respec-
similar with that of the control group afterward. tively. At week 4, VEGF expression in the MTS and ChO oil
At the moment, there are no reports on the actual hair groups showed a significantly higher expression by 74% and
growth properties of AcK in humans. 96% (p < 0.05), respectively. However, the expression of
EGF (a catagen inducer) in the MTS and ChO oil groups was
significantly decreased by 66% and 61% (p < 0.05), respec-
83.3 Chaemacyparis Obtuse (Japanese tively, as compared to the saline group [9].
Cypress, Hinoki) Despite the interesting in vivo results in lab animals and
the popularity of products containing ChO oil extracts, there
Chamaecyparis obtuse (ChO) is a slow-developing tree that are no studies on the actual hair growth properties in humans.
grows to 35 m tall and has a trunk of 1 m in diameter.
Although the ChO essential oil’s biological activity is not
fully known, the oil contains several types of terpenes such 83.4 Citrullus Colocynthis (Bitter
as sabinene, limonene, bornyl acetate, borne a-terpineol, and Cucumber) (9-
elemol. All these have been shown to possess antimicrobial
and antifungal properties [6] in addition to antioxidative and The fruit of Citrullus colocynthis (CiC) is rich in α-sitosterol,
anti-inflammatory effects [7]. campesterol, stigmasterol, α-spinasterol [10], and at least 6
Hair tonics based on ChO are popular in Japan. However, different cucurbitacin glycosides [11]. The seeds of the plant
studies on the hair growth effects of this plant are very lim- are rich in fat and protein, and the oil content of the CiC
ited. Lee et al. investigated the hair growth-promoting effect seeds is 23%, with the primary constituent fatty acids being
of the ChO oils in vitro and in vivo in mice. They reported linoleic acid (66.73%), oleic acid (14.78%), palmitic acid
that ChO oils promoted the early phase of hair growth in (9.74%), and stearic acid (7.37%) [12]. The seeds of CiC are
shaved mice. Using the human keratinocyte cell line HaCaT, usually administered orally, or the seed extract has been used
they discovered that certain sub-fractions of the ChO essen- topically in Ayurveda medicine for the management of
tial oils affected hair morphogenesis and hair growth regula- “Indralupta” (“hair loss” in Indian) [13].
tion. Subfractions E and D significantly increased VEGF‘s There are only a couple of lab studies addressing the
gene expression (150%–220%) and KGF (20%) without potential hair growth effects of CiC. One study was pub-
upregulating the hair growth inhibition factor, TGF-β1. lished by Roy et al. [14], who tested a mixture of herbal
Cuminol, eucarvone, and calamenene were present in both extracts containing CiC. Dhanotia et al. evaluated the hair
subfractions [8]. The authors reported that certain ingredi- growth activity of topically applied petroleum ether extracts
ents of the ChO oil resulted in the upregulation of VEGF (PEEs) of CiC in androgen-induced alopecia on Swiss albino
transcription, promoting angiogenesis. This effect could mice who were injected intramuscularly with Testosterone
contribute to the hair growth-promoting effect in animal for 21 days. As reflected from the follicular density, the
models [8]. results of the treatment with 2% (2.29 ± 0.32) and 5%
Park et al. examined the action mechanism of the ChO oil (2.44 ± 0.31) PEEs of CiC were comparable to the positive
on hair growth in C57BL/6 mice by determining enzyme control Finasteride (2.19 ± 0.37) and significantly higher
activities and cytokine expressions related to hair growth in than the control group (1.38 ± 0.21), (p < 0.001). The authors
the skin tissue. The animals were divided randomly into hypothesized that the mechanism of the extract is antiandro-
three groups (15 mice each), which consisted of a saline con- genic and that since oleic and linoleic acids are abundant in
trol group, a 3% Minoxidil (MTS) positive control group, the CiC extract, this property may be attributed to the free
and a 3% ChO oil treatment group. The researchers mea- fatty acid content (see Chap. 41) [15].
sured: (a) the ALP activity, a zinc-metalloenzyme widely At the moment, there are no studies on the actual hair
expressed in actively proliferating tissues and in cells with a growth properties of CiC in humans.
high metabolic rate, (b) γ-GT, a membrane-bound enzyme
essential in glutathione metabolism, used for keratin synthe-
sis in the hair follicle, (c) the expression of Insulin-like 83.5 Curcuma Aeruginosa
growth factor-1 (IGF-1), VEGF, and SCF, prevent apoptosis
of hair matrix cells and promote hair growth. At week 4, the Curcuma aeruginosa (CuA) is a perennial plant producing
3% MTS and 3% ChO oil treatment groups showed an ALP unbranched leafy stems up to 2 m tall from a large under-
activity increased by 85% (p < 0.001) and 48% (p < 0.05). ground rhizome that can be 16 cm long and 3 cm wide. CuA
The γ-GT activity increased by 294% (p < 0.01) and 254% is one of the most prominently used medicinal plants in
83.6 Cuscuta Reflexa 509
Bangladesh, India, Myanmar, Indonesia, Malaysia, and moderate or significant improvements compared with pla-
Thailand. The following pharmacological activities have cebo (p = 0.008). Subjects’ overall assessments of hair
been reported for CuA: antinociceptive [16], antipyretic, regrowth between the 5% CuA extract and 5% MTS did not
anti-inflammatory [17], antimicrobial [18], antioxidant [19], differ. The full-text article includes high quality and accurate
and antiandrogenic properties [20].Germacrone, furanodi- baseline and month-6 vertex photographs of two subjects
ene, curcumenol, zedoarol, zedoarondiol, zedoalactone A, treated with the combination formulation rated as having
zedoalactone B, isocurcumenol, and isofuranodiene are the moderate and minimal improvement from baseline by expert
major chemical constituents isolated from the rhizomes of panel review.
CuA [21, 22]. Zedoarol, curzerenone, furangermenone, fura-
nodienone, curcumenol, 1, 8-cineol, and camphorare are the
However, a very interesting finding was that all hair
major volatile compounds of CuA [23].
tonic formulations, even placebo, stimulated hair
Suphrom et al. isolated six sesquiterpenes from the rhi-
growth, resulting in gradual increases in the number of
zomes of CuA Roxb. and investigated their antiandrogenic
hairs each month. When the percent changes between
properties. All 6 inhibited the 5α-Reductase enzymic system
baseline and month 6 of the four groups were com-
(5α-R), with germacrone being the most potent compound
pared, these differences did not reach significance.
(IC50 = 0.42 ± 0.05 mg/mL). Germacrone had an antiandro-
genic effect in LNCaP cells when proliferation was
Testosterone-induced and also inhibited the growth of the
flank organ gland of male Syrian hamsters in all tested con- So, overall, the target area hair count did not reach signifi-
centrations (3, 30, and 100 μg) but was ineffective against cance between groups. The authors concluded that the syner-
DHT. A similar activity profile was observed on the gistic effects of CuA extract and 5% MTS were statistically
Finasteride (100 μg) treatment group, with germacrone being significant in tree assessments and should enhance the thera-
more potent than Finasteride. Interestingly, the androgen peutic effects when combined. The study’s limitations include
receptor binding assay showed that germacrone did not bind the relatively small sample size per group, that hair weight
to the androgen receptor. Overall, germacrone showed antian- and diameter were not evaluated, and the inclusion of patients
drogenic effects on both the in vitro and in vivo assays [20]. at high Hamilton-Norwood stages (>IV), who do not gener-
Suphrom et al. assessed the chemical stability to pH, tem- ally respond favorably to topical hair growth treatments [25].
perature, oxygen, and light of antiandrogenic compounds in Srivilai et al. aimed to show that Minoxidil and CuA
the CuA Roxb. extract. They reported that germacrone, both extract’s apparent synergism arises from the improved cuta-
as the solubilized pure compound or a constituent in an neous penetration of Minoxidil by the most bioactive com-
extract of CuA, was stable at pH 2.0–9.0 for at least 14 days. pound germacrone. Skin penetration was measured ex vivo
Stability was unaffected by pH (2.0–9.0) as a dried extract, on Franz diffusion cells using full-thickness human foreskin
but it was slightly degraded by light. The degradation was as membranes. The skin penetration of Minoxidil with 0.2
considerably hindered when in a PEG-40 suspension or and 2% extract increased ~four-fold (accumulated amount in
methanol. In contrast, the less potent antiandrogenic sesqui- receiver + skin viable layer after 8 h). Furthermore, ger-
terpenes were far more stable [24]. macrone enhanced the flux of Minoxidil ten-fold and CuA
Concerning the clinical efficacy of the CuA Roxb. extract, essential oil’s 20-fold. The authors concluded that the addi-
Pumthong et al. [25] conducted a multicenter, double-blind, tion of germacrone promotes Minoxidil’s efficacy, that lower
placebo-controlled study to assess the efficacy and safety of doses of Minoxidil suffice since penetration is enhanced, and
5% CuA extract, compared with 5% MTS, as well as the that the CuA extract/essential oil or germacrone can supple-
synergism of the two actives in promoting hair growths in ment treatment outcomes by acting as antiandrogens [26].
men with AGA. Eighty-seven men aged 20–55 years old The antiandrogen effect of the essential oil of CuA Roxb.
with Hamilton-Norwood types II-VII AGA were randomized has been demonstrated in a couple of other studies, both
to receive 5% CuA extract, 5% MTS, a combination formu- reporting that the CuA Roxb. lotion effectively inhibited
lation (5% CuA hexane extract +5% MTS) or placebo, twice axillary hair growth, a typical androgen-induced hair growth
daily for 6 months. The efficacy was assessed by target area [27, 28].
hair count, global photographic review, patients’ subjective
assessments of hair regrowth, and hair shedding. There were
statistically significant improvements in global photographic 83.6 Cuscuta Reflexa
review; 77% of subjects in the combination group were rated
as minimally or moderately improved, and none of them was Cuscuta reflexa (CuR) is a parasitic plant species common in
judged as being worse (p < 0.001 compared with placebo). the Indian Subcontinent. Many chemical constituents have
Subjects’ overall assessments of hair regrowth were statisti- been isolated from the plant, such as cuscutin, amarbelin,
cally significant for the combination group, and 54% reported β-sitosterol, stigmasterol, kaempferol, dulcitol, myricetin,
quercetin, coumarin, and oleanolic acid. Interestingly, anti- nins, marine plant polyphenols, peptides, carotenoids, and
steroidogenic properties have been attributed to the CuR fucoidans [34]. Eckol and dieckol, the major phlorotannins
methanolic extract [29]. isolated from EcC, have anti-inflammatory activity and
Roy et al. were the first to report on the hair growth prop- increase fibroblast survival by reducing reactive oxygen spe-
erties of a CuR extract on albino rats [30] and summarized cies [35].
the effects of a polyherbal formulation of CuR combined Kang et al. conducted a study to evaluate the effect of EcC
with Citrullus colocynthis and Eclipta alba extracts [31]. on hair growth promotion. When vibrissa follicles were cul-
Pandit et al. evaluated the hair growth activity of the CuR tured in the presence of EcC enzymatic extract (which con-
petroleum ether extract (PEE) in androgen-induced alopecia tains more than 35% of dieckol) for 21 days, it resulted in the
in male Swiss albino mice by subcutaneous Testosterone (T) proliferation of immortalized vibrissa DPCs and increased
injection. After T injection, mice were divided into four hair-fiber length comparable to Minoxidil sulfate 1 μM. The
groups of six mice each, and animals of groups II, III, and IV treatment with the EcC extract resulted in the proliferation of
were given topical application of 0.2 mL of vehicle, 2% immortalized vibrissa DPCs and significantly inhibited 5α-R
Finasteride solution, and 2% CuR PEE, respectively, for activity, but only at a very high concentration (100 μg/mL),
20 days. The extract prevented T-induced hair loss in animals which was toxic to the hair follicles. Topical application of
of the CuR PEE group, similarly to the animals in the the 0.5% EcC enzymatic extract onto the backs of C57BL/6
Finasteride group. Anagen/telogen ratio was significantly mice induced anagen progression sooner (day 26) than the
affected, measured as 1.6:1 in the CuR-treated group vs. 0.1:1 control group but much later than the positive control group
for the T-treated control and 0.91:1 for the Finasteride-treated Minoxidil 5% (13 days). Even though the authors suggested
animals. The follicular density observed in the CuR-treated that dieckol from the EcC extract can stimulate hair growth
group was 2.5 ± 1, 1.33 ± 0.77 in the T-treated control group, by the proliferation of DPCs and/or by the inhibition of 5α-R
and 2.83 ± 1.02 in the Finasteride-treated standard group. activity, in vivo results on mice were not significant, and
However, even though the authors attributed the extract’s hair in vitro results were not relevant in vivo [36].
growth effects to 5α-R inhibition, the IC50 values calculated In a similar study, Bak et al. investigated the hair growth-
for CuR PEE and Finasteride were 1.78 mg and 0.77 μg, promoting effects of acetate-soluble fraction of Ecklonia
respectively, making the extract approximately 2000 times cava (EAFE) and one of its components, dioxinodehy-
less potent than Finasteride in 5α-R inhibition [32]. droeckol. They investigated the proliferation in the outer root
Patel et al. investigated the efficacy of PEE and ethanolic sheath (ORS) cells and DPCs, measured the hair-shaft elon-
extracts (EE) of CuR in promoting hair growth in gation in cultured human scalp hair follicles, and the induc-
cyclophosphamide-induced (CYP) hair loss in 24 male Swiss tion of anagen in C57BL/6 mice. At concentrations of 0.01
albino rats. The animals were randomly divided into 4 groups and 0.1 μg/mL of EAFE, proliferation in the organ culture
of 6 rats each and were treated as follows: group I: vehicle only was increased in the DPCs by 130.6% and 138.6%, respec-
(distilled water, control); group II: CYP solution only, negative tively, and in ORS by 121.8% and 118.7%, respectively
control; group III: CYP solution + CuR PEE solution orally; compared with the vehicle-treated control (100%). Moreover,
group IV: CYP solution + EE solution, orally. The histological 0.1 μg/mL EAFE resulted in a significant increase of IGF-1
study showed that the hair density was maximum (3.75 ± 0.62) mRNA expression, which was 2.17-fold higher than in the
in the vehicle-treated group, 2.5 ± 0.79 in the PE-treated, vehicle-treated control (p < 0.01). Treating human scalp hair
2.33 ± 0.88 in the EE-treated and minimum (2.08 ± 0.79) in the follicles with EAFE at concentrations of 0.01 and 0.1 μg/mL,
control-treated animals. The anagen/telogen ratio was maxi- increased hair shaft elongation was noted (1.26 mm and
mum (3.20:1) in the vehicle-treated group, 1.70:1 in the 1.52 mm, respectively) compared to 0.93 mm in the vehicle-
PE-treated, 1.43:1 in the EE-treated, and minimum (1:2.83) in treated control group. In the C57BL/6 mouse model, the
the control-treated animals. Both CuR PEE and EE showed the newly growing hair shafts were visible on the dorsal skin of
ability to prevent damage to the hair follicles, hair loss, and mice in the groups treated with EAFE or Minoxidil 3% (pos-
damage to the skin structure caused by CYP and to enhance itive control), whereas hair growth was rare in the control
hair regrowth in CYP induced alopecia [33]. group. The authors concluded that the EAFE component,
Despite the interesting in vivo results in lab animals, there dioxinodehydroeckol, promotes hair growth by increasing
are no studies on the actual hair growth properties of CuR in the proliferation activity and expression of IGF-1 in DPCs
humans. [37].
Shin et al. investigated the effect of three E. cava poly-
phenols, dieckol, phlorofurofucoeckol A, and EcC purified
83.7 Ecklonia Cava polyphenols (PPE), and EcC purified polyphenols enriched
with eckol (PPEE), on human hair growth enhancement
Ecklonia cava (EcC) is an edible marine brown alga species in vitro and ex vivo. Treatment with 10 μg/mL PPE enhanced
found in Japan and Korea’s marine areas. It contains various the proliferation of human DPCs by 30.3% more than the
bioactive compounds and derivatives, including phlorotan- negative control, DMSO (p < 0.001). Furthermore, 0.1 μg/
83.9 Erica Multiflora 511
mL PPE extended the human hair shaft 30.8% longer than the PEE treated group was superior as the hairs were soft and
the negative control over 9 days (p < 0.05). IGF-1 mRNA silky akin to the 2% MTS treated group. Since β-sitosterol
expression increased 3.2-fold in human DPCs following was not present in the ethanol extract was present only in the
treatment with 6 μg/mL PPE (p < 0.05), and VEGF mRNA more efficient PEE, the authors attributed the hair growth
expression was also increased two-fold following treatment effects on this ingredient [50].
with 3 μg/mL PPE (p < 0.05). Treatment with 10 μg/mL Datta et al. investigated the efficacy of the methanol
PPE reduced the oxidative stress in human DPCs (p < 0.05). extract of EcA (MEE) as a hair growth promoter on pig-
Ηowever, the effect of the polyphenols seemed to vary mented C57/BL6 mice and reported a dose-dependent activ-
depending on the cell type and test conditions (in vitro, ity. With an extract dose of 3.2 mg/15 cm2, 87.5% of animals
ex vivo, or in vivo). In ex vivo human hair follicle cultures, showed anagen growth, while with an extract dose of
other tested ingredients -when tested alone-, i.e., dieckol, 1.6 mg/15 cm2, 50% of the animals showed the transition
phlorofurofucoeckol A, and PPEE, failed to show signifi- from telogen to anagen (vs. 87% for MTS). Since the degree
cant hair shaft elongation results. These results demon- of anagen induction among MEE and MTS was comparable,
strated a narrow optimal concentration range for cell the authors expected that MEE will have similar hair growth-
proliferation and that a mixture of several antioxidants is promoting activity with MTS in humans [51]. Nevertheless,
more stable and synergistic than single antioxidants [38]. a comparative study with the 5% MTS was not performed.
Despite the exciting results in lab animals, there are no Begum et al. investigated the synergistic hair growth
studies on this herb’s actual hair growth properties in humans. effect of the methanol extracts of 4 herbs (including EcA)
traditionally acclaimed for therapeutic properties of various
human ailments on the back skin of nude mice. Among all
83.8 Eclipta Alba (False Daisy) the plant extracts, EcA was the one that showed allegedly
“outstanding” hair growth promotion compared to other
Eclipta alba (EcA) is known in Ayurveda with the name treatment groups (p > 0.001). The authors reported that
“Kesharaja” which means in Sanscritic “the king of herbs results were cosmetically superior to those of 2% MTS since
that rejuvenates hair” [39]. Various phytochemical scientific irregular and deformed hairs were found in MTS-treated
reports have validated most of the claims of the ethnomedici- mice, while on the EcA-treated mice, hairs were straight,
nal uses, and many compounds have been isolated and iden- thicker, and smother [5].
tified from this plant. These compounds include sterols, Begum et al. investigated the effects of EcA PEE on nude
flavonoids, saponins, phenolic acids, alkaloids, wedelolac- mouse skin with inherited hair follicular abnormalities. EcA
tone, eclalbasaponins, α-amyrin, ursolic acid, oleanolic acid, PEE was applied for 20 consecutive days on the backs of
luteolin, apigenin, coumestan, luteolin-7-glucoside, luteolin, athymic male nude (nu/nu) mice of BALB/c origin. The his-
apigenin, and orobol (isoluteolin) [40]. tological assessments revealed that the PEE-treated skin
EcA has been administered orally or topically in Ayurveda specimens exhibited prominent follicular hypertrophy, a sig-
to treat hair loss, promote hair growth, increase hair luster nificant increase (p < 0.001) in the number of follicular
[41] and pigmentation [42, 43]. EcA is included in numerous keratinocytes in basal epidermal and matrix cells, and a sig-
multi-herbal products against hair loss and is cited in several nificant downregulation (p < 0.001) of TGF-β1 expression
patents on hair growth products in India and the Far East during early anagen and anagen-catagen transition [52].
countries [31, 44–49]. The biological mechanisms and underlying effects of
In the relevant literature, 3 lab studies regarding the hair EcA extracts on hair growth seem to be potently stimulatory
growth potential of EcA can be traced. in vitro and in lab animals. At the moment, there are no stud-
Roy et al. published in 2007 a study using formulations of ies on the actual hair growth properties of EcA in humans.
3 herbs, namely Cuscuta reflexa, Citrullus colocynthis, and Notably, oral administration of the alcoholic extract of EcA
EcA, at different percentages each. These were applied on did not show any adverse effect on hematological parameters
the denuded back of Wistar strain albino rats and compared in lab animals [53].
with the local application of 2% MTS as a positive control.
The highest concentration formulation scored better than 2%
MTS since hair growth appeared sooner, and more hairs 83.9 Erica Multiflora
were in anagen after 30 days of treatment [14]. However,
since the formulations were mixtures, results cannot be Erica multiflora (ErM) is a flowering plant in the heather
attributed to any individual extract. A subsequent study by family, native to the Mediterranean basin. Kawano et al. [54]
the same team was published in 2008 evaluating the petro- evaluated the hair growth promotion activity of the ErM
leum ether (PEE) and the ethanol extract of EcA to promote extract by using the MTT (3-(4,5-dimethyl-2-thiazolyl)-
hair growth in albino rats. The topical application of PEE 2,5-diphenyl-2H-tetrazolium bromide) assay and cell cycle
reduced the time required for hair growth initiation, and the assay on human DPCs in vitro and an administration assay
effects were comparable to 2% MTS. The hair’s quality in on mouse dorsal skin in vivo. Even though the authors
reported that the ErM extract promoted DPC growth and the The only available data on the hair growth properties of
cell cycle with high activity, the growth promotion activity HrS was published by Adhirajan et al., who studied the
and effects on the cell cycle of the ErM extract on human in vivo (on lab animals) and in vitro hair growth potential of
follicular DPCs were statistically significant only at essential oils of HrS from leaves and flowers vs. control and
extremely high concentrations (500 and 5000 μg/mL). When placebo (liquid paraffin) [75]. The authors reported that the
the 500μlg/ml Erica multiflora extract was injected subcuta- leaf extract-treated groups produced a greater effect on the
neously on the trimmed backs of C3H/He mice, the next ana- length of hair on the denuded back of female Wistar albino
gen stage was actually delayed. Strangely, the authors rats when compared to other groups. After 30 days, the
reported that hair growth’s delayed stimulation was the indi- length of hair was 17 ± 1.2 mm in the leave extract group,
rect stimulation of anagen from telogen. 15.8 ± 1.2 mm in the flower extract group, 13.6 ± 1.5 mm in
There are no studies on the hair growth properties of this the control group, and 14.5 ± 1.5 mm in the placebo group.
herb in humans. At the moment, there are no studies on the actual hair
growth properties of this herb in humans.
83.10 Equisetum Arvense (Horsetail)

83.12 Illicium Anisatum (Japanese Star
Horsetail is a renowned ingredient in mainstream products Anise)
against hair loss (see Chap. 46). It contains flavonoids with a
potent free radical scavenging capacity, such as isoquercitrin Illicium anisatum (ILA) is a highly toxic plant, the fruit of
[55], in addition to high amounts of di-E-caffeoyl-meso- which is not edible; instead, the dried and powdered leaves
tartaric acid and phenolic acids [56]. are burned as incense in Japan. The genus Illicium is a rich
Horsetail is extremely rich in silicon [57], sterols (60% of source of prenylated C6-C3 compounds, neolignans, and
which is β-sitosterol) [58], flavonoids [59], and caffeic acid secoprezizaane- type sesquiterpenes, which occur exclu-
[60, 61]. It is one of the best natural sources of silicon, and sively in the Illicium species, and they are considered to be
probably this is why it is so highly used in commercial hair characteristic chemical markers of the species [76].
lotions. The only report associating this herb with hair loss is Sakaguchi et al. used a culture system of B6C3HF1
that of Chaiyana et al. (2017), who reported that all tested mouse vibrissae follicles to examine whether ILA’s extract
Horsetail extracts (chlorophyll-free, hexane, ethyl acetate, promoted hair follicle elongation. Follicles treated with
and ethanolic extracts) could inhibit 5α-R and decrease the water-soluble (WS) extracts of the leaves, fruits, and roots of
secretion of IL-6 in lipopolysaccharide-stimulated macro- ILA or shikimic acid grew significantly longer than controls.
phages [62]. Individual fractions of the extracts (numbers 1 and 2) con-
At the moment, there are no studies on the actual hair taining shikimic acid possessed potent hair follicle elongation
growth properties of this herb, while its use has been reported activity. Reverse transcription-polymerase chain reaction
to induce contact and seborrheic dermatitis, both in lab ani- analysis demonstrated that shikimic acid-induced mRNA
mals [63]and humans [64]. expression of IGF-1, KGF, and VEGF in the hair follicles but
did not affect HGF/SF mRNA expression in these cells [77].
There are no studies on the actual hair growth properties
83.11 Hibiscus Rosa-Sinensis (China Rose) of this herb in humans.
Hibiscus rosa-Sinensis (HrS) is Malaysia’s national flower

and possesses potent pharmacological properties, mostly 83.13 Lygodii Spora
antioxidant [65–67], and antiphlogistic [68]. The extract of
HrS is rich in bioactive components, including quercetin, Lygodii Spora (spore of Lygodium japonicum) has been tra-
carotene, niacin, riboflavin, malvalic acid, gentisic acid, mar- ditionally prescribed for the treatment of lower urinary tract
garine acid, lauric acid, anthocyanin, and anthocyanidin [69, symptoms (LUTS) resulting from benign prostatic hyperpla-
70]. sia (BPH). Therefore, contemporary researchers attributed
According to the texts of “traditional Indian Medicine” antiandrogenic effects to this herb [78].
(Ayurveda), the leaves and flowers of HrS improve the Matsuda et al. investigated the in vitro and in vivo anti-
“image of hair and prevent hair greying” [69–71], and HrS is androgenic activity and the hair growth promotion effect
the most popular constituent in Indian hair tonics [72, 73]. It and underlying mechanisms of the aqueous ethanol extract
has also been reported as being a very efficient natural herbal of Lygodii Spora. The researchers showed the in vitro 5α-R
hair colorant [74]. inhibitory activity and in vivo antiandrogenic activity (of
83.17 Sanguisorba Officinalis 513
the 50% ethanol extract), measuring the flank organ’s 83.16 Salvia Officinalis (Sage)
growth of castrated Syrian hamsters and hair regrowth after
shaving in T-treated C57Black/6CrSlc mice. From the lipo- The name Salvia derives from the Latin salvere (“to feel well
philic constituents of Lygodii Spora, oleic, linoleic, and and healthy”), referring to the herb’s healing properties.
palmitic acids were identified as the main active principles Salvia officinalis (SaO) contains large amounts of caffeic
inhibiting 5α-R [79]. acid and its derivatives, carnosic acid, diterpines [84], flavo-
There are no reports on the hair growth properties of this noids, ursolic acid [85], and more than 75 other compounds,
herb in humans. many of which have potent free radical scavenging proper-
ties [86]. SaO is a rich source of polyphenols, with >160
polyphenols identified in SaO, some of which are unique to
83.14 Piper Nigrum (Black Pepper) the genus, besides rosmarinic acid and lithospermic acid,
which are found in numerous other plants [87].
Piper nigrum is a flowering vine in the family Piperaceae, The extract of SaO has been reported to possess anti-
cultivated for its fruit, usually dried and used as a spice and inflammatory properties and inhibit the mRNA expres-
seasoning. Vietnam is the world’s largest producer and sion of TNF-α and IL-6 in lipopolysaccharide stimulated
exporter of pepper, producing 34% of the world’s P. nigrum RAW 264.7 macrophages at a concentration of 100 μg/
crop as of 2018 [80]. mL [88]. Interestingly, the anti-inflammatory effect of
Hirata et al. [81] examined the 5α-R inhibitory activity of ursolic acid (ID50 = 0.14 μM/cm2) has been reported to be
aqueous ethanolic extracts obtained from several different two-fold more potent than that of indomethacin
parts of six Piper species and found that piperine, a major (ID50 = 0.26 μM/cm2) when evaluated for their ability to
alkaloid amide in the Piper nigrum fruit, showed a potent inhibit the Croton oil-induced ear edema in mice after
5α-R inhibitory activity (IC50 = 0.48 mM). In addition, the topical application [85].
5% methanolic extract of Piper nigrum leaf showed in vivo The topical use of SaO essential oil on the scalp is a very
antiandrogenic activity using the hair regrowth assay in popular folk remedy against hair loss in some countries. It is
T-sensitive male C57Black/6CrSlc strain mice, in which it also used to darken grey hair and deepen the color of brown
scored similarly to oxendolone, a positive reference antian- or black hair. However, there are no studies on this herb’s
drogen, and progestin. hair growth properties, in-vitro, in-vivo, or clinical, in the
There are no reports on the hair growth properties of this scientific literature. The only scientific report of an effect of
herb in humans. SaO on the human scalp is the alleged pediculicidal activities
against the head louse Pediculus capitis [89].
Jin et al. [90] investigated the hair growth potential of
83.15 Puerariae Flos another member of the “Salvia” family, (Salvia plebeia).
They reported that it significantly increased the proliferation
Pueraria is a genus of 15–20 species of plants native to Asia of cultured hDPCs, it decreased the expression of hepatocyte
[82]. Murata et al. [83] reported that the 50% ethanolic growth factor increased, the level of TGF-β1 and SMAD2/3,
extract of Puerariae Flos (PF-ext) showed inhibitory activity and it activated Wnt/β-catenin signaling by raising β-catenin
of 60.2% at 500 μg/mL against the 5α-R enzymic system. In and phospho-GSK3β expression. Also, it increased the
addition, they demonstrated in vivo antiandrogenic activity Bcl-2/Bax ratio and activated cell proliferation-related pro-
using a hair growth assay in T-sensitive male teins, ERK and Akt. Finally, the extract caused an induction
C57Black/6NCrSlc strain mice. The authors argued that of the anagen phase leading to significantly enhanced hair
saponins, including soyasaponin I and kaikasaponin III, growth in treated male mice.
were the active components in the PF-ext. However, inhibi-
tion of 5α-R at concentrations of 20 and 50 μg/mL did not
exceed 45% and only reached 79% at concentrations 83.17 Sanguisorba Officinalis
>500 μg/mL, which was 2000 times higher than the tested
concentration of Finasteride (250 nM), which was still more Sanguisorba officinalis (SaOf) belongs in the family
effective at 82.1% inhibition. In addition, the hair growth Rosaceae. It is a herbaceous perennial plant growing to 1 m
promotion activity in C3H/He mice at 2 mg/mouse/day of tall, which occurs in grasslands, and it is native throughout
the topical administration of PF-ext was demonstrated, but the cooler regions of the Northern Hemisphere in Europe,
significantly lower than that of 1% Minoxidil. northern Asia, and North America.
There are no reports on the hair growth properties of this According to preliminary reports, SaOf has been reported
herb in humans. to exhibit a diverse array of promising properties, such as
anti-oxidant, anti-inflammatory, antiviral, antibacterial, the expression of TGF-β2 in the bulb matrix region was lower
hemostatic, and anticancer [91]. than that of the control follicles that were expected to be in
According to research, FGF-5 has been reported to be a the anagen-catagen transition phase. Thus, the authors spec-
crucial regulator of hair length in humans [92]. Burg et al. ulated that the ScN extract could promote hair growth by
[93] identified a SaOf extract as an effective FGF-5 inhibitor downregulating TGF-β2 and inducing the proliferation of
and demonstrated that the SaOf extract (Maruzen DPCs [95].
Pharmaceuticals, Onomichi, Japan) enhanced the multiplica- At the moment, there are no other studies on the actual
tion of outer root sheath cells in vitro. Additional in vivo hair growth properties of this herb in humans.
analyses indicated that while the SaOf extract did not
enhance the onset of growth, it significantly reduced the
number of telogen follicles and increased hair length. The 83.19 T-Flavanone
authors subsequently tested a topical solution containing a
SaOf extract (named MTP3) in a cohort of human partici- Flavanones are aromatic, colorless flavonoid ketones, and
pants vs. a placebo group in a single-blind study over a they often occur in plants as glycosides deriving from the
4-month period with 3 treatment arms: placebo treatment compound flavone [97].
with the tonic base with no active ingredients (n = 10), treat- t-Flavanone is synthesized as a derivative of astilbin, a
ment group 1 (tonic formulation with 0.095% MTP3, n = 11), flavonoid component of the hypericum extract. It has been
and treatment group 2 (tonic formulation with 0.5% MTP3, hypothesized by Sasajima et al. that it actively stimulates
n = 11). They observed a significantly reduced number of hair growth in AGA by acting as a blood circulation accel-
shed hairs (~70% less shed hairs, p > 0.008) and a decreased erator while focusing on the anchoring strength (tenacity) of
number of vellus hairs, while hair growth rate and anagen: hair [98].
telogen (AT) ratio were increased from baseline in both male One randomized controlled trial (RCT) and two non-
(p = 0.007) and female (p = 0.003) subjects. Subjective RCTs have been conducted on the efficacy of t-flavanone on
assessments of effectiveness indicated that the extract was AGA, but no clinical trial has been conducted on FPHL
rated as “somewhat effective”, “effective”, or “very effec- according to the excellent 2018 review by Manabe et al. [99]
tive” for 74% of the treated group vs. 25% of the control. In an unpublished, non-peer-reviewed, non-RCT, Hotta
A product containing the SaOf extract under the brand et al. recruited 14 male subjects and applied a hair growth
name Évolis® is already commercially available. A small agent containing t-flavanone during an observation period of
subset of 3 females and 3 males from treatment group 1 was 6 months. The mean diameter of newly grown hairs increased
chosen, at baseline, to participate in the photogrammetric by 20% compared to baseline. The number of shed hairs was
investigation at days 0 (baseline), 56, and 112. Photographs also significantly decreased (≤20%) at 4 and 6 months of
were evaluated using the PhotoGrammetrix® Image analysis topical application, whereas no change was found in the pla-
(AMA Laboratories Inc.), quantifying hair density, release, cebo group [100].
and recovery. However, the full-text article does not contain In another unpublished, non-peer-reviewed, non-RCT,
before-and-after photos to support the claims of the authors. Hotta et al. recruited 197 male subjects and separated them
In addition, two of the authors, Maria Halasz and Koichiro into an active and a placebo group. During an observation
Koike, are shareholders in the parent company, Cellmid. period of 30 weeks, the subjects used a hair growth agent
containing t-flavanone, a commercially available hair growth
agent (unknown constituents), and a placebo lotion. The rate
83.18 Schisandra Nigra of moderate or better improvement was 53.1%, 34.8%, and
17.9% in the t-flavanone-containing hair agent group, the
The pharmacological actions of Schisandra Nigra (ScN) are commercially available hair agent group, and the placebo
not yet clear. It has been found to contain schizandronic acid, group, respectively. The t-flavanone-containing and com-
β-sitosterol, schisandrolic acid, oplodiol, schizandronol, mercially available hair agent groups showed a significantly
(+)-catechin-7-β-, D-glycopyranoside, β-sitosteryl gluco- better improvement than the placebo group. The number of
side, androsin and schizandriside [94, 95]. terminal hairs with a diameter of 40 μm or thicker was
Kang et al. [96] investigated the in vitro hair growth increased in the t-flavanone-containing and commercially
potential of the ethanol extract of ScN in the rat vibrissa fol- available hair agent groups, whereas it decreased in the pla-
licles and onto the back of C57BL/6 mice. Anagen progres- cebo group [101]. No more details are available for these
sion was induced, and 20 μg/mL of ScN extract induced a studies besides the abstracts.
greater increase in hair-fiber length (210%) than the positive The only RCT published in a peer-reviewed journal was
control, Minoxidil sulfate 10 μM (150%). When the vibrissa authored by Nagasawa et al. [102] and involved 77 male
follicles in anagen were treated with ScN extract for 7 days, subjects during an observation period of 30 weeks. Subjects
83.21 Trigonella Foenum-Graecum (Fenugreek) 515
used hair growth agents containing 0.1% and 0.5% 83.21 Trigonella Foenum-Graecum
t-
flavanone or placebo. The rate of moderate or better (Fenugreek)
improvement was 40% in the placebo group, 75%, and 70%
for the 0.1% and 0.3% t-flavanone-containing hair growth Fenugreek is found in abundance in western Asia and Greece,
agent group, respectively. Additionally, t-flavanone from which it got its Latin name “graecum”. It reaches 1 m
enhanced the hair-anchoring strength in a hair diameter- high, has open-colored leaves, white flowers, and brown-
independent manner. The culture of human hair follicles yellow seeds with an intense, typical smell of maple or burnt
in vitro with t-flavanone resulted in the upregulation of des- sugar.106 A large variety of phytoconstituents have been iso-
moglein protein expression. The full-text article contains lated from the seeds of fenugreek in phytochemical research,
only one set of low-quality, small size before-and-after including steroids, alkaloids, saponins, coumarins, polyphe-
photos of a stage VII male with minimal improvement at nols, flavonoids, lipids, alkaloids, carbohydrates, amino
30 weeks. acids, and hydrocarbons [105].
Meanwhile, no reliable studies have suggested the effi- Fenugreek allegedly possesses a variety of pharmacologi-
cacy of t-flavanone on FPHL. According to Manabe et al., cal properties attributed to this diverse array of phytocon-
there is very weak evidence that suggests the efficacy of stituents. Fenugreek is rich in phosphorus, iron, biotin,
t-flavanone on AGA, and topical application is permissible: inositol, and several flavonoids, namely vitexin, tricin, narin-
grade of recommendation: C1. In contrast, although there is genin, quercetin, and diosgenin [106]. These flavonoids are
insufficient evidence that suggests its efficacy on FPHL, in potent antioxidants [107] and may increase the bioavailabil-
light of its mild adverse reactions, the topical application was ity of iron and copper in vivo [108]. Diosgenin is a steroidal
considered permissible by the authors [99]. sapogenin belonging to the family of phytoestrogens, and in
fact, it is a precursor for several hormones. Most therapeuti-
cally useful steroidal drugs, including sex hormones and cor-
83.20 Tectona Grandis (Teak Tree) ticosteroids, were initially produced from diosgenin, starting
with the Marker degradation process, which includes proges-
Teak (Tectona grandis, TeG) is a large, tropical, deciduous terone synthesis [109]. This process was also used in the
hardwood tree species placed in the flowering plant family early manufacturing of combined oral contraceptive pills
Lamiaceae that occurs in mixed hardwood forests. [110, 111].
The extract from the seeds of TeG is traditionally Fenugreek contains very high amounts of diosgenin, esti-
acclaimed as a hair tonic in Indian folk medicine. There is mated at 28–92 μg/10 mg of ethanolic extract [112].
a single study by Jaybhaye et al. [103], who investigated Therefore, its action is strongly estrogenic, while it can
the hair growth initiation and promotion effects of the inhibit melanogenesis and act as a skin bleaching agent [113,
petroleum ether extract (PEE) of TeG. The authors incorpo- 114]. The topical use of fenugreek seeds in the form of a
rated the extract into a simple ointment base at 5% and 10% paste or aqueous extract is a popular folk remedy against hair
concentrations and compared it with 2% MTS (positive loss, while oral intake of fenugreek seeds is becoming
control) on the shaved denuded skin of albino mice. The increasingly popular [115].
extract was successful in reducing the time for hair growth The only publication relevant to AGA is that of Moers-
initiation and completion in 5 ± 0.28 days and Carpi et al. [116], who investigated the effect of an oral sup-
18 ± 0.56 days, respectively compared to control (12 ± 0.82 plement containing fenugreek and several micronutrients
and 25 ± 1.02 days, p < 0.001). The results were compara- (Vitamins C, E, B1, B3, B6, B7, B12, copper, zinc, folic
ble to Minoxidil (6 ± 0.41 and 18 ± 1.08 days). The treat- acid, iodine, selenium) compared to placebo in 56 male and
ment successfully brought a higher number of hair follicles female patients with AGA and FPHL. After 6 months of
in anagen (64% and 51%) than standard 2% MTS (49%) treatment, the supplement group showed a mean increase of
and significantly affected the length of hair follicles. In the anagen hair count from the baseline of 5.9% vs. 0.62% for
control group, only 34 ± 0.4% had an average length of the placebo (p < 0.0001).118 However, since the formulation
0.5 mm, whereas, in the extract-treated groups, 46 ± 0.3% was a mixture, results cannot be attributed to any individual
and 48 ± 0.1% hairs longer than 0.5 mm were observed compound.
with 5% and 10% extract treatment, respectively. The treat-
ment results were comparable with those of 2% MTS, in
Oral intake of fenugreek by males is potentially dan-
which case a 49 ± 0.1% hair population had a length of
gerous since it has been found to reduce the size of the
0.5 mm and above [104].
testicles and induce evident damage to the seminifer-
Despite the interesting findings of this single study, there
ous tubules and interstitial tissues in the testicles of
are no studies on this herb’s actual hair growth properties in
rats [117].
humans.
In humans, it exerts potent antifertility activity in both herbal medicine. ZiJ extract contains procyanidin B2, epicat-
males and females and can also increase the risk of bleeding echin, quercetin-3-O-rutinoside (Q-3-R), quercetin-3-O-
in patients under warfarin118, whereas topical use of fenu- galactoside (Q-3-G), kaempferol-glucosyl-rhamnoside
greek extract can cause intense skin allergic reactions [118, (K-G-R), saponarin, spinosin, vitexin, swertish betulinic
119]. acid, jujuboside B, and other bioactive phenolic compounds
with neuroprotective and sedative properties [132, 133].
Yoon et al. investigated the efficacy of an essential oil
83.22 Urtica Dioica (Stinging Nettle) from ZiJ seeds for its potential role in hair growth. Fifteen
BALB/c mice were divided into five groups of three mice
Urtica Dioica (UrD) is an evergreen bush, 60-90 cm high, each, and ZiJ essential oils at different concentrations (0.1%,
found in Italy and Greece. It grows mostly in lowlands and 1%, and 10%) or hydrocortisone were applied over the
hills up to 1800 m and prefers soils rich in nitrogen [120]. It shaved back skin for 7 days. The mice were monitored for
blooms from May to September, and the name “dioca” 21 days, while the control group remained untreated. After
derives from the fact it is a dicot, i.e., bears both female and 21 days, mice treated with 1% and 10% of the ZiJ oil pro-
male flowers to the same plant [121]. duced a greater effect on the length of hair, measured at
The aqueous extract of the dark-green leaves of 9.96 mm and 10.02 mm, respectively, as compared to the
UrD -named IDS23− has been found to possess intriguing control (8.94 mm). Hydrocortisone did not show any effect
antiphlogistic properties due to the high amounts of its major on hair growth. The weight of hair was measured to be 53,
phenolic ingredient, caffeic malic acid [122]. It has been 57, and 54 mg/cm2 area of dorsal skin for 0.1%, 1%, and
reported to offer symptomatic relief in patients with benign 10% of ZiJ oil-treated mice, respectively, vs. 50 mg/cm2 for
prostatic hyperplasia [123] and to possess diuretic properties the control group. However, none of these results were statis-
[124]. tically significant [132, 133], and there are no studies on the
In guinea-pigs, the aqueous and methanolic extracts of actual hair growth properties of this herb in humans [134].
UrD produced hypotensive responses through a vasorelaxing
effect mediated by the release of endothelial nitric oxide and
its opening potassium channels [125]. It has also been References
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Index
A in AGA/FPHL, 144–145
Acanthopanax koreanum, 507 microspheres, 146
Accidental overdose, 422 Alopecia, 322, 344
Acne, 106, 193 Alopecia areata, 368, 400, 408
Acrodermatitis enteropathica, 408 Alpecin® Liquid, 208
ACTH production, 259 Alpha-lipoic acid, 358
Actions of biotin, 321–322 α-tocopherol, 337
Actions of boron, 353–354 Alternative medicine, 417–426
Actions of copper, 399–400 Alternative vehicle, 25
Actions of corticosteroids, 122–123 Ambiguous, 285
Actions of iodine, 363 Amino acids, 315
Actions of iron, 385–386 Anagen, 14, 44, 410, 503
Actions of magnesium, 367 Anagen duration, 142
Actions of silicon, 373–374 Anagen inducer, 110
Actions of Vit A, 297–298 Anagen to telogen ratio, 48
Actions of Vit B3, 303–304 Androgen, 309, 316, 339, 407
Actions of Vit B5, 309–310 Androgen-AR complex, 193
Actions of Vit B6, 315 Androgen index, 180, 187, 190
Actions of Vit C, 329–330 Androgen levels, 255
Actions of Vit Ε, 337–338 Androgen levels in AGA/FPHL, 256
Actions of zinc, 405–406 Androgen metabolism, 170
Activities, 451 Androgen production, 169
Adapalene, 146 Androgen receptor (AR), 14, 115, 134, 180, 193, 406, 430, 453,
Adenosine, 199–200 480, 509
Adrenal glands, 256 Androgen-sensitive, 233
Adrenal seborrhea, acne, and hirsutism syndrome (SAHA), 194 Androstenedione, 255, 407
Adrenarche, 179 Angiogenesis, 142
Adrenocorticotropic hormone (ACTH), 256 Anthraquinones, 479, 481
Adverse effects, 101, 112, 137–138, 158–159, 196, 436–437, 490–491 Anti-androgen, 97, 105, 115, 116, 174, 195, 433, 472
Adverse effects of TCs, 123 Antiandrogenic, 97, 219, 220, 509, 512
Adverse event profile, 84 Anti-androgenic activity, 97, 475
Adverse reactions, 504 Antiandrogenic potential, 220
AGA, 221, 332 Antiandrogenic properties, 105, 429
AGA/FPHL, 135, 365, 408 Anti-apoptotic properties, 14, 406
AGA-miniaturized hair follicles, 14 Antifungal, 133
Akt, 14, 143, 344, 496 Anti-inflammatory, 109, 151, 219, 225, 380, 441, 452, 476, 495
Akt signaling pathways, 453, 488 Anti-inflammatory effects, 142
Albumin, 399 Anti-inflammatory properties, 122, 446
Alcohol abuse and androgens, 259–260 Antimicrobial, 219
Alcohol intake, 258 Antioxidant, 225, 231, 297, 329, 337, 358, 445, 451, 452, 475,
Alcohol on HPG axis, 259 479, 495
Alcoholics, 305 Antioxidant activity, 339
Aldactone®, 97 Antioxidant properties, 151
Aldosterone, 98 Antioxidative, 476
Alfatradiol, 172, 173 Antispasmodic, 495
Alga, 510 Apoptosis, 44
Alkaline phosphatase, 406 Application of MTS, 22
Alkaloids, 471 Arachidonic acid, 220
Allantoin, 466 Aromatase, 170, 171, 516
Allium cepa juice, 466 Aromatization, 257
Allopregnanolone, 56, 60 Ascorbate, 329
All-trans-retinoic acid (ATRA), 127, 141, 298 Ascorbic acid, 329
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 521
K. Anastassakis, Androgenetic Alopecia From A to Z, https://doi.org/10.1007/978-3-031-08057-9
522 Index
Ascorbic acid 2-phosphate (Asc 2-P), 332 C

Asiasari radix (Asiasarum root), 507–508 Ca+2 and hair follicle, 349–350
Aspirin, 305 Ca+2-binding agents, 350
Atrophogenic potential, 125 Caffeic acid, 495, 513
Attention, 460 Caffeine, 152, 221, 304, 310
Avidin, 324 Caffeine and AGA/FPHL, 207–209
Avodart®, 77 Caffeine lotion, 207
Ayurveda, 512 Calcineurin, 110
Azelaic acid, 151, 214, 221, 316, 407 Calcitonin gene-related peptide (CGRP), 503
Azelaic acid and AGA/FPHL, 152–153 Calcitriol, 350
Calcium, 311, 347, 367, 409, 412
Camphor, 495
B Cancer-preventive effect, 452
Bacteriostatic, 151, 410 Canrenone, 97, 100
Balanced healthy diet, 287 Capsaicin, 501
Bark extract, 441 Capsaicinoids, 501
Barley extract, 446 Capsicum, 501
Bax, 143, 406, 408, 487, 489, 496 Cardiovascular, 116
Bax expression, 453 Cardiovascular adverse events, 30
Bax/Bcl-2, 489 Cardiovascular disease, 24, 369
Bcl-2, 143, 406, 408, 480, 487, 489, 496 Carnosic acid, 495
Bcl-2 expression, 453 Carotenoids, 141
Bcl-2/Bax, 14, 143, 227, 407 Caspase, 406
Bcl-2/Bax ratio, 143, 380 Caspase-1, 44
Beer, 375 Caspase-3, 408
Benign prostatic hyperplasia (BPH), 42, 77, 429, 441, 512, 516 Ca+2 supplementation, 351
β-catenin, 480, 488 Catabolism, 303
β-catenin activity, 14 Catagen, 14, 127
β-catenin expression, 435, 480 Cellular response to androgens, 255
β-catenin Lef-1, 487 Ceruloplasmin, 399
Betamethasone, 111, 163 CG210®, 466
Betamethasone valerate, 153 Chaemacyparis obtuse (Japanese cypress, Hinoki), 508
Betamethasone-17 valerate, 146 Chemical standardization, 422
β-sitosterol, 221, 322, 430, 434, 442, 489, 509, 511, 512 Chemopreventive, 502
bFGF, 442 Chemotherapy, 227
Bilobalides, 459, 460 Chili peppers, 501
Bimatoprost, 155 Chloride, 347
Bimatoprost and AGA/FPHL, 157–158 Chlormadinone acetate, 179, 180, 183, 190
Bimatoprost solutions, 158 Chlorotrichosis, 401
Bioavailability, 51, 78, 304, 392 Cholesterol, 248
Bioequivalence, 69 Chronic alcohol intake, 259
Biological model, 90 Cimetidine, 105
Biological standardization, 422 Cimetidine and ΑGΑ/FPHL, 106
Biotin, 89, 295, 310, 357, 515 Circadian rhythm, 231
Biotin and hair follicle, 322–323 Citrullus colocynthis (bitter cucumber), 508
Biotin deficiency, 324 Citrus fruits, 330
Biotinidase, 322 Clinical efficacy of Finasteride, 47–49
Biotinidase deficiency, 325 Clobetasol, 504
Biphasic effect, 407 CNS effects, 87
Body mass index (BMI), 286 CNS stimulant, 205
Bone mineralization, 373 Coenzyme A (CoA), 309
Boron, 347 Coffee, 392, 393
Boron and hair follicle, 354 Cognition-enhancing, 496
Botox®, 201 Cognitive functions, 460
Brain fog, 60 Collagen, 373
Brazilian nuts, 380 Collagen synthesis, 167, 330, 374, 406
Breast cancer, 59 Collagenase, 410
Breast cancer, 59, 85 Colon cancer, 343
Breast enlargement, 81 Combined Oral Contraceptives (COCs), 187
Breast tenderness, 52, 81 Comparison of 5% MTF and 5% MTS, 28
Brittle nails, 323 Compatibility, 286
Broad-band antibiotics, 324 Complementary medicine, 417
Bulge region, 387 Complementary-Alternative Medicine (CAM), 417, 418
Burning, 25 Complete inhibitor of the enzyme 5α-R, 78
Index 523
Compliance, 27 Depressive symptoms, 60

Concentration-dependent, 15, 33 Deprivation (crash) diets and androgens, 258–259
Contamination, 421 Desquamation, 25
Contraceptive measures, 65 Detergent, 248
Contraindications for LDOM, 32 Detoxification, 359
Copper, 515 Dexpanthenol, 89, 309, 311, 411
Copper and hair follicle, 400–402 DHT-induced DKK-1 expression, 332
Copper tripeptides, 225–228 Diabetes, 317, 369
Corticotropin-releasing hormone (CRH), 256 Diane-35®, 115
Corticotropin-releasing hormone (CRH) receptors, 206 Diane-50®, 115
Cortisol, 354, 367 Dickkopf 1 (DKK-1), 332
Cortisol and AGA, 256 Dieckol, 510
Cortisol secretion, 256 Dienogest, 183, 190
Cosmeceuticals, 219 Dietary recommendations, 298, 305, 311, 316, 324, 330–331, 340,
Covalent disulfide bonds, 358 344, 350, 354–355, 359, 364, 368, 375, 381–382, 392,
COX-2, 460 402, 411
C-reactive protein (CRP), 354, 367 Dietary supplement adverse events, 289
Crescina, 202 Dietary Supplement and Nonprescription Drug Consumer Protection
Crohn’s disease, 305 Act, 284
Crown, 18 Differentiation, 349
Crown efficacy, 30 Dihydroprogesterone, 181
Cu+2, 225 Dihydrotestosterone (DHT), 13, 42, 51, 77, 97, 115, 137, 143, 170,
Curcuma aeruginosa, 508–509 180, 190, 206, 255, 260, 354, 400, 407, 411, 423, 431, 453,
Cuscuta reflexa, 509–510 461, 472, 480
Cutaneous vasculature, 261 Dihydrotestosterone suppression, 78
Cyclic AMP (cAMP), 199, 206 Dimethyl sulfoxide (DMSO), 359
Cyclooxygenase-2, 155 Discoloration of urine, 196
Cyclosporin A (CyA), 109 Disease prevention, 287
in AGA/FPHL, 111–112 Diuretic effects, 101
in Alopecia Areata, 110–111 DKK-1, 127, 332, 487, 489
Cynatine, 310 DKK-1 expression, 488
Cynatine HNS, 215, 310 DNA, 407
Cyproterone acetate (CPA), 98, 115, 179, 183, 190, 193, 389
and FPHL, 116–118
in men, 119 D
Cysteine, 211, 357–359, 507 Docosahexaenoic acid (DHA), 221
Cysteine derivatives, 465 Dosage, 436–437, 443, 472–473, 490–491
Cysteine synthesis, 212 Dosage regimen, 22
Cystine, 211, 357, 358 D-pantothenic acid, 309
Cytochrome, 385, 386 Drinking water, 375
Cytochrome c, 110 Drug interactions, 491
Cytochrome P450, 386 Dryness, 25
Duration of action, 50
Duration of anagen, 20
D Duration of telogen, 20
Dandruff, 381 Dutasteride, 77, 80, 85, 87, 222
D-biotin isomer, 321 Dutasteride + Finasteride, 90
Decrease of libido, 51 Dutasteride + Minoxidil, 90
Decreased ejaculate volume, 91 Dutasteride and Fertility, 87
Decreased libido, 81, 91, 101 Dutasteride and FPHL, 83–87
Deficiency, 355, 359–360, 364–365, 368–369, 375–376, 382, Dutasteride and Prostate Cancer (PCa), 84–85
392–394, 402–403, 411–413 Dutasteride and Sexual Adverse Experiences (SAEs), 85–87
excess of biotin, 324–326 Dutasteride and ΑGΑ, 79–83
excess of Ca+2, 350–351
excess of inositol, 344
excess of Vit A, 298–300 E
excess of Vit B3, 305–306 Ecklonia cava, 510–511
excess of Vit B5, 311–312 Eclipta alba (False daisy), 511
excess of Vit B6, 317–318 Ecohair® spray, 208
excess of Vit E, 340–341 Ectopic hypertrichosis, 26
Dehydroepiandrosterone (DHEA), 188, 193, 409 Edema, 24
Dehydroepiandrosterone and its sulfate (DHEA-S), 188, 193, 255, 256 Edible, 365
De-ionized water, 368 Effective dosage of Dutasteride in AGA, 90
Dementia, 460 Effects on PSA, 57
Demodex, 127 Efficacy, 289
Depression, 59–62, 87 Efficacy of Minoxidil, 19
524 Index
EGb761®, 459, 460 Fear, 283

Eicosapentaenoic acid (EPA), 221 Feminization, 65, 118, 196
Ejaculation disorders, 81 Fenton reaction, 391
Ejaculation volume, 83 Ferric iron, 393
Ejaculatory disorders, 51 Ferri-reductase activity, 330
Embryonic development, 297 Ferritin, 385, 386
Emergency department visits, 289 Ferritin and hair loss, 388, 389
Emodin, 481 Ferrous ferric chloride, 391
Emotional stress, 262 Fetal defects, 26
Emulsifier, 247, 248 Fibroblast growth factor (FGF), 339
Endonucleases, 406 Fibroblast growth factor-5 (FGF-5), 514
Εndothelial growth factor (EGF), 13, 431, 442, 503, 508, 516 Fibroblast growth factor-7 (FGF-7), 480
Endurance training, 263 Fibronectin, 476
Enlarged Prostate International Comparator Study (EPICS), 84 Finasteride, 41, 59–62, 84, 137, 144, 163, 233, 239–241, 423, 430,
Epicatechin, 445 431, 454, 485, 487, 490, 508–510, 513
Epigallocatechin-3-gallate (EGCG), 445, 451 Finasteride and FPHL, 65–68
Epitestosterone, 255 Finasteride and prostate cancer (PCa), 57–59
Equisetum arvense (Horsetail), 512 Finasteride effects on Fertility, 56–57
Erectile dysfunction, 51, 54, 81, 91 Finasteride 5mg, 51–52
Erectile function, 85 Finasteride Male Pattern Hair Loss Study Group, 52
Erica multiflora, 511–512 Finasteride topical formulations, 62
Erk, 14, 143, 453, 488, 496 Finasteride vs. Minoxidil, 63–64
Erk-and Akt-dependent pathways, 143 First-pass, 193
Erythema, 25 Fish extract, 242
Erythrocytes, 385, 395 5α-reductase (5α-R), 42, 97, 115, 137, 151, 168, 181, 219, 222, 316,
Erythromycin-zinc complex, 411 322, 400, 407, 423, 431, 442, 452, 472, 476, 480, 487, 509,
ERα, 167, 168 510, 512, 513, 516
ERβ, 167, 168 5α-reductase activity, 257
Essential nutrients, 295, 405 5α-reductase (5α-R) inhibition, 496
Estradiol, 257, 259, 408 5α-reductase (5α-R) inhibitors (5ARIs)
Estrogen effect, 491 5α-R isotype Ι, 42, 220, 430, 432
Estrogen receptors (ERα and ERβ), 167, 168 5α-R isotype ΙΙ, 42, 220, 430, 432
Estrogenic, 436 5α-R type IΙ deficiency, 42
Estrogen-only OC, 189 5-aminolevulinic acid (5-ALA), 392
Ethanol, 25 5% Minoxidil Topical Solution (MTS), 144, 152, 158,
Ethinyl estradiol, 115, 170, 187, 389 162, 410
Ethyl alcohol, 12, 23 5-aminolevulinic acid (5-ALA), 392
Eulexin™, 193 Flavones, 479
Evidence-based medicine, 417 Flavonoids, 465, 467, 471
Evidence Level 1, 19 Flavoproteins, 386
Excess intake of boron, 355 Fluridil, 173
Excessive hair loss, 390 Flushing, 303, 305
Excess of Boron, 355 Flutamide, 117, 193–196
Excess of copper, 402–403 Flutamide Induced Liver Injury (FILI)., 195
Excess of iodine, 364–365 Folic acid, 295
Excess of iron, 392–394 Food additive, 248
Excess of magnesium, 368–369 Food sources, 298, 304, 311, 316–318, 323–324, 330, 339–340,
Excess of selenium, 382 344, 350, 354, 358–359, 364, 368, 375, 381, 392,
Excess of silicon, 375–376 402, 411
Excess of sulfur, 359–360 Food supplements, 281, 283
Excess of zinc, 411–413 Food supplements be dangerous, 288–289
Exercise, 263 Fortification, 392
Exfoliation, 142 FP receptor, 161
Extracellular sulfate pool, 359 FPHL, 12, 116, 221, 400, 409, 490
Eyelash alopecia, 163 FPHL treated with LDOM, 31
Eyelash hypotrichosis, 156 Free estradiol, 259
Eyeliner effect, 157 Free fatty acids (FFAs), 219–223, 429
Free oxygen radicals, 358
Free-radical scavenger, 231
F Fresh ginseng, 485
Facial hypertrichosis, 23 Frontotemporal region, 18
Fat, and carbohydrate metabolism, 363 Fulminant hepatic failure, 305
Fat-soluble vitamin, 297 Fulvestrant, 173
Fat-soluble vitamins, 296 Fulvestrant's, 168
FDA, 116, 282, 394, 420 Functional iron, 386
FDA approval, 12, 15 Fungistatic, 410
Index 525
G Hair texture, 380

Galenic formulation, 32, 127 Hair weight, 45
Gallic acid, 447 Half-life, 78
γ-aminobutyric acid, 475 Hammerstein regimen, 116
γ-INF, 110 Hard water, 368
γ-linolenic acid, 220 H2-blockers, 105
γ-oryzanol, 475, 477 Health claims, 285
Garlic, 358, 359 Heme, 392
Gastrointestinal upset, 393 Hemoglobin, 385, 386
Gelatin, 213 Hemosiderin, 385, 386
General properties of Ginseng, 486 Hepatitis, 481
General properties of green tea, 451–452 Hepatocyte growth factor (HGF), 14, 480, 502, 512
Genotoxicants, 260 Hepatotoxic adverse effects, 116
Germacrone, 509 Hepatotoxicity, 118, 196, 454
GHK-Cu, 225, 226 Hepcidin, 387, 395
Ginkgo biloba extract (GBE), 214, 459 Herbal medicine, 419
Ginkgolides, 459, 460 Herbal root, 485
Ginkgolide-Β, 460 Herbals, 417
Ginseng and hair follicle, 486–490 Herb-drug interactions, 421
Ginseng root, 485 Herbs and benign prostate hypertrophy (BPH), 423
Ginsenoside-Rg1 (G-Rg1), 486, 487 Hibiscus rosa-Sinensis (China rose), 512
Ginsenosides, 485, 486 Higher total T, 260
Glaucoma, 155 High-fat diet, 262
Gleason grade, 85 High-fat diets and androgens, 257–258
Gli1, 407 High-grade PCa, 58
Gli2, 407 Hirsutism, 106, 193
Glucocorticoid, 121 Holistic health, 419
Glucocorticoid receptor (GR), 122, 180 Holistic way of life, 417
Gluconeogenesis, 309 Homeostatic control, 350
Glucose-6-phosphate, 344 Homocysteine, 357
Glutathione, 357, 358 Household expenditures on dietary supplements, 286
Glutathione peroxidase, 379 Human hair, 212
Glutathione peroxidase family, 379 Hydrocortisone, 516
Glycosaminoglycans, 373, 374 Hydroxylation of estradiol, 261
GnRH, 259 Hyperaldosteronism, 97
Goiter, 454 Hyperandrogenic, 194
Gold Standard, 12 Hyperandrogenic women, 117
Gonads, 43 Hyperandrogenism, 257
Good manufacturing, 284 Hypercalcemia, 351
GraftCyte®, 228 Hypercalcemia due to Ca+2 supplementation, 351
Graft-versus-host reactions, 109 Hyperinsulinemia, 257
Grape seed extracts (GSE), 447 Hyperkalemia, 101
Grape seeds, 446 Hypermagnesemia, 369
Graying, 481 Hypertension, 98, 369
Green hair, 381, 401 Hypertrichosis, 30, 32, 109, 155, 161
Green tea and hair follicle, 453–454 Hypertrichosis incidence, 31
Green tea and skin, 452 Hypervitaminosis A, 299
Green tea as antiandrogen, 452–453 Hypocalcemia, 350–351
Green tea polyphenols (GTPs), 451, 452 Hypogonadism, 412
Groups of topical steroids according to potency, 123 Hypomagnesemia, 369
Guilt, 283 Hypoparathyroidism, 350
GULO pseudogene, 329 Hypotension, 24
Gynecomastia, 52, 59, 83, 85, 172 Hypothalamic-pituitary-adrenocortical axis (HPA), 256
Hypothalamic-pituitary-gonadal (HPG) axis, 259
Hypothalamus-pituitary-adrenal axis, 486
H Hypothyroidism, 365
Hair caliber, 31
Hair count, 45
Hair cycle, 344 I
Hair density, 19 Ideal candidates for Minoxidil, 18
Hair diameter, 19 Illicium anisatum (Japanese star anise), 512
Hair gain, 241 Immunosuppressive, 109
Hair loss, 358, 380 Impotence, 52, 81
Hair loss as adverse effect, 189 Incidence of PCa, 58
Hair loss forums, 68 Increased mortality, 289
Hair restoration surgery, 228 Indian medicine (Ayurvedic), 418
526 Index
Indications, 291 Ketoconazole and ΑGΑ/FPHL, 135–137

Induction of anagen, 162 Ketoconazole lotion, 136
Industry-sponsored trials, 309 Ketoconazole shampoo, 134–135
Infertility, 91 Kuraridin, 472
Inflammation, 19 Kurarinone, 472
Inflammatory bowel disease, 324
Infomercials, 249
Inherent toxicity, 421 L
Inhibition of 5α-R ΙΙ, 43 Lamin®, 228
Inositol, 515 Laparoscopic sleeve gastrectomy, 323
Inositol and the hair follicle, 344 Latanoprost, 159
Insulin, 257 Latanoprost and hair follicles, 161–162
Insulin-like growth factor (IGF), 442 Latanoprost lotion, 163
Insulin-like growth factor-1 (IGF-1), 44, 257, 332, 454, 472, 476, Latisse®, 155, 159
501–503, 508, 510, 512 Lauric acid, 219, 220, 429, 430, 434, 512
Insulin-like growth factor-7 (IGF-7), 480 Laxative, 481
Intention-to-treat analysis, 420 L-cystine, 214
Interactions, 289 L-enantiomer, 329
Interleukin IL-1α, 122, 476 Levonorgestrel, 189
Interleukin (IL)-1β, 471, 472, 502, 516 Lifestyle factors, 255
Interleukin (IL)-2 (IL-2), 109 Linoleic acid, 220, 429, 430, 475, 489, 508, 513
Interleukin IL-6, 181, 226, 354, 513 Linolenic, 429
Intermediate metabolism, 321 Lipid-lowering medication, 303
Intestinal availability, 375 Lipidosterolic extract of Serenoa repens (LSESr), 429, 432
Intestinal microflora, 311 Lipid-soluble, 337
Intradermal Dutasteride, 89 Liposomatic CPA, 118
Intralesional, 88, 89 Liposome, 146
Intralesional Dutasteride, 88–89 Liver, 43
Intrauterine devices, 387 Liver damage, 402
Intravenous iron loading, 396 Liver reserves, 299
Iodine, 347 Living fossil, 459
Iodine content, 364 L-methionine, 214
Iron, 347, 515 Loaded nanoparticles, 201
Iron and AGA/FPHL, 389–391 Local absorption, 124
Iron and hair loss, 387–389 Local adverse effects, 25
Iron deficiency (ID), 386–387 Local irritation, 145
Iron deficiency anemia (IDA), 331, 386 Loniten, 11
Iron deficiency erythropoiesis (IDE), 386 Low dose OM (LDOM), 29, 31
Iron depletion, 386 Lower limb edema, 30
Iron-fortified foods, 392 Lower urinary tract symptoms (LUTS), 42, 441, 512
Iron distribution, 386 Low-grade PCa, 58
Iron overload, 394 Low-sulfur soils, 359
Iron recycling, 386 L-tryptophan, 232
Iron:zinc ratio, 413 Lubricating, 310
Irritant, 504 Lung cancer, 290
Irritation, 25 Lung cancer risk, 317
Isoflavonoid, 472 Luteinizing hormone (LH), 259, 408
Isotype I, 400 Lygodii spora, 512–513
Itching, 25, 127 Lysyl hydroxylase, 14
J M
Japanese medicine (Kampo), 418 Macronutrient metabolism, 315
Junk food, 258 Magic pill solution, 283
Magne B6®, 368
Magnesium, 347
K Magnesium deficiency, 367
Kaempferol, 452, 460, 465, 509 Major minerals, 347
KATP channels, 12 Malabsorption syndromes, 212
Kenogen, 14 Malassezia spp, 135
Keratin, 211, 358, 374, 380 Male fertility, 355
Keratin production, 322 Male fetus, 196
Keratin synthesis, 349 Male reproductive system, 406
Keratinocyte growth factor (KGF), 472, 476, 508, 512 Malignancy, 283
Keshan disease, 382 Malondialdehyde, 391
Ketoconazole, 133–138, 144, 381 Manufacturing results, 239
Index 527
Margin of dose safety, 24 National Institutes of Health (NIH), 420

Marine extract compounds, 239 Natural antioxidant, 495
Marine protein extract, 241 Needs, 291
Matrine, 471 Nephrotoxicity, 111
Matrix metalloprotease, 410 Neuroendocrine action, 232
Matrix metalloproteinases, 162, 181 Neurohormone, 231
Medically indicated, 287 Neuromodulator, 231
Medicated shampoo, 381 Neuroprotective effects, 460
Mediterranean diet, 258, 263 New Generation Hair Care, 251
Melanocytes, 162 Niacin, 303, 305, 512
Melanogenesis, 515 Niacin toxicity, 305
Menorrhagia, 387 Niacinamide, 303, 310
Mesotherapy, 33, 88–89 Nicotinamide, 303, 411
Meta-analysis, 83 Nicotinamide adenine dinucleotide (NAD), 303
Metabolic syndrome, 89, 317 Nicotinamide adenine dinucleotide phosphate (NADP), 303
Metabolism, 309 Nicotinic acid, 295, 303
Metabolism of androgens, 407 Night blindness, 297
Metabolism of Finasteride, 50–51 Nitric oxide (NO), 170, 471, 503
Metabolism of minerals, 353 Nitric oxide (NO) production, 206, 460
Metabolism of nutrients, 347 Nocebo effect, 53–54
Metalloenzymes, 399, 405 Nociception, 502
Metalloproteinase, 142 Nongenomic action, 181
Metallothionein, 399 Non-heme, 392
Methicillin-resistant Staphylococcus aureus, 220 Non-HPA-related stress response, 206
Methionine, 211, 212, 215, 357 Norgestimate, 181
Methylsulfonylmethane (MSM), 357 Normal microflora, 324
Mg+2 and hair follicle, 367–368 Normoandrogenic, 66, 195
Micro-inflammation, 227 Nourkrin, 239–241
Microvasculature, 260 Novel Minoxidil formulations, 29
Mineralocorticoid properties, 121 Nuclear factor-kappaB (NF-κB), 110, 122, 496, 516
Mineralocorticoid receptor, 180 NuHair, 481
Miniaturization, 44 Nutritional supplement, 243
Minipulse, 111
Minoxidil, 11, 33, 43, 48, 110, 135, 142–144, 146, 162, 163, 182, 233,
251, 337, 410, 446, 485, 487, 488, 503, 507–510, 513–515 O
Minoxidil reservoir, 18 Obesity, 256–257
Minoxidil and FPHL, 17 Obstructive symptoms, 42
Minoxidil concentration, 15 Ocular hypertension, 155
Minoxidil discontinuation, 21 Off-label, 98
Minoxidil effects, 14 Off-label treatment for FPHL, 65
Minoxidil mesotherapy, 33 Off-label use, 29, 91
Minoxidil plus ATRA, 143 Oleic acid, 219, 220, 247, 429, 430, 434, 475, 508, 513
Μinoxidil's percutaneous absorption, 143 Onion odor, 467
Minoxidil sulfate, 13 Onions, 358, 359
Minoxidil topical foam, 12, 27 Open-angle glaucoma, 161
Minoxidil topical solution (MTS), 12, 62, 144, 146, 194, 207, 239, Oral contraceptives (OCs), 180, 187, 193
240, 311, 392, 409, 476, 477, 490, 509, 511, 515 Oral estrogens, 170–171
Miraculous efficacy, 240 Oral Ketoconazole, 134
Misconceptions, 424 Oral Minoxidil, 29
Monozygotic twins, 45, 80, 259 Organosulfur compounds, 357, 465
Mood disorder, 83 Orphan drug, 115
Mucopolysaccharides, 373 Ortho-silicic acid, 373
Mucous membranes, 297 Osteogenesis, 353
Multivitamin/multimineral supplements (MVM), 282 Outer root sheath (ORS), 364
Multivitamins, 281 Out-of-pocket expenditures, 418
Mutagenicity, 481 Over-the-counter product (OTC), 12
Myoglobin, 385, 386 Oxidation-reduction cycles, 399
Myo-inositol, 343 Oxymatrine, 471
Myricitin, 452
Myristic, 220, 429, 430, 434
P
Pain-alleviating properties, 502
N Palmitic acid, 220, 429, 475, 508, 513
N-acetylcysteine (NAC), 358 Palmitoleic acid, 220
Nanoparticles, 111 Palpitations, 24
National Health and Nutrition Examination Survey (NHANES), 286 Panax ginseng, 485–491
528 Index
Panthenol, 304, 310 Premature hair graying, 402

Pantogar, 213, 215, 310 Premenopausal, 65
Pantothenic acid, 295, 309 Prescription medication use, 286
Para-amino-benzoic acid, 213 Prickling, 25
Parathyroid hormone (PTH), 349, 350 Primary deficiency, 287
Pay-per-page journals, 239, 245 Primary Vit A deficiency, 299
Pay-per-publish journals, 240 Priorin®, 214, 310
PCa chemoprevention, 58 Proanthocyanidins, 445
Peak plasma levels, 51 and AGA, 446–447
Peeling, 142 and hair follicle, 445–446
Pellagra, 305 Processed, 212
Penetration enhancer, 360 Procognitive, 460
Penetration of Vit C, 333 Procyanidin B-2, 446, 448
Penile duplex Doppler ultrasound (PDDU), 56 Procyanidin C-1, 446
Percutaneous absorption, 411 Production, 353
Percutaneous absorption of Minoxidil, 145 Production of androgens, 255, 406
Percutaneous absorption of Spironolactone, 99 Production-conversion of androgens, 255
Pericarditis, 24 Progesterone, 169, 179, 187
Perifollicular fibrosis, 410 Progesterone receptor (PR), 180
Permixon®, 430, 431 Progestin, 187
Pesticide, 205, 501 Progestin-only, 187
P450, 461 Progestin-only hormonal contraceptives, 189
P450 3A4 pathway, 51 Progestins and ΑGΑ/FPHL, 182–183
Pharmacokinetic property, 90 Programs, 364
Pharmacovigilance, 61 Prolactin, 106, 408
Phenelzine, 491 Proliferation, 349
Pheochromocytoma, 32 Propecia®, 43, 79
Philosophy, 419 Propionibacterium, 127
Phosphodiesterase enzyme, 206 Propionibacterium acnes, 151, 220
Phosphorus, 347, 515 Propylene glycol, 12, 23, 25
Photoaged skin, 142 Proscar®, 43
Phototrichogram, 202 Prostaglandin, 460
Phytates, 392, 411 Prostaglandin D2 (PGD2), 13, 127, 303, 304, 306, 400, 503
Phytic acid, 344, 475 Prostaglandin E2 (PGE2), 11, 13, 162, 399, 400, 460, 503
Phytoestrogens, 263 Prostaglandin endoperoxide synthase-1 (PGHS-1), 13, 162
Phytonutrients, 475 Prostaglandin-F2α (PGF2α), 155, 161, 162
Phytosterols, 486 Prostate cancer (PCa), 84, 441, 442, 452
Phytotherapy, 419 Prostate Cancer Prevention Trial (PCPT), 58, 84
Pigmentation, 157 Protein kinase C (PKC), 337, 442, 446
Pigmentation of iris, 163 PSA levels, 436
Pillow contamination, 23 Pseudo-scientific statements, 285
Pineal gland, 231 Pseudo-telogen effluvium, 22
Piper nigrum (Black pepper), 513 Pseudo-vellus, 14, 20
Piperine, 513 Pseudo-vitamin, 343
Pityrosporum ovale, 133, 135, 151 p63 expression, 487
Platelet-activating factor (PAF), 460 Psychoactive compound, 205
PLESS Study Group, 54 Psychological effects, 60
Polycystic ovaries, 187 Puerariae flos, 513
Polycystic ovary syndrome (PCOS), 98, 343 Purity, 288
Polygonum multiflorum, 479 Pygeum africanum, 441–443
Polysaccharide marine product, 243 Pygeum africanum and AGA, 442–443
Polysaccharides, 373 Pyridine derivatives (vitamers), 315
Polysorbate 60, 247 Pyridoxal, 315
Polysorbate 80, 247 Pyridoxamine, 315
Possible interactions, 286 Pyridoxine, 89, 315
Post-Finasteride Syndrome (PFS), 55
Post-Finasteride Syndrome Foundation, 55
Post-marketing monitoring, 421 Q
Postmenopausal, 66, 172 Quercetin, 452, 460, 465, 467, 468, 471, 510, 512, 515
Postpartum hair loss, 170 Quinones, 479
Postpartum telogen effluvium, 170
Potassium, 347
Potassium channels (KATP), 11 R
Potassium-sparing diuretic, 97 Radical scavenger, 337
Potency, 288 RARβ, 142
Predictable risk factors, 55 RARγ, 142
Pregnancy category X, 65 Raw egg white, 321
Index 529
Reactive oxygen species (ROS), 400 Seborrhoeic dermatitis, 128, 135, 317, 381
Real and imaginary conditions, 283 Sebosuppressive effect, 143
Rebound effect, 21 Sebum, 142, 298
Recall bias, 60 Sebum excretion rate, 118
Recalls, 289 Sebum production, 118, 134
Receptor, 349 Secondary deficiency, 287
Receptors, 316 Secondary deficiency of Vit B12, 312
Recommended Dietary Allowance (RDA), 282 Secondary hyperlipidemia management, 305
Recommended doses, 291 Secondary hypogonadism, 256
Red ginseng, 485 Secondary Vit A deficiency, 299
Red onion, 465–468 Sedimentation rate, 395
REDUCE trial (Reduction by Dutasteride of Prostate Cancer Selection bias, 60
Events), 84 Seleniferous plants, 380
Regaine, 12 Selenite, 381
Regulating protein, 363 Selenium, 347
Replication, 406 Selenium and hair follicle, 380–381
Resistance training, 263 Selenium sulfide shampoos, 381
Resveratrol, 479 Selenocysteine, 381
Retin-A®, 146 Selenomethionine, 379, 381
Retinal, 297 Selenoprotein P, 379
Retinoic acid, 141–147, 297 Selenoproteins, 379
Retinoic acid receptor (RAR), 142 Selenosis, 382
Retinoid reaction, 145 Self-regulation, 421
Retinoids, 141 Semen, 78
Retinol, 297 Semen quality, 57
Retinyl-esters, 141 Serenoa repens, 322
Retinοl, 141 Serum cortisol, 256
Revivogen®, 221 Serum DHT reduction, 79
Ribonucleotide reductase, 387 Serum ferritin, 117
Rice bran, 475 Serum Finasteride levels, 65
Rice bran extract, 475 17α-estradiol, 168
Rice bran oil, 475 17β-estradiol, 167, 353
Risk factor for, 390 17β-hydroxysteroid dehydrogenase, 13
Rogaine®, 12 Severe reactions, 289
Rogaine® Extra Strength 5%, 12 Sex drive, 85
Rosemary, 495–498 Sex hormone-binding globulin (SHBG), 133, 180, 188, 255, 260, 516
Rosmarinic acid, 495, 513 production, 257
Rosmarinus officinalis and AGA/FPHL, 496–498 Sexual adverse effects (SAEs), 81
RXRα, 142 Sexual adverse experiences (SAEs), 51–52
Sexual function, 51
Shh/Gli pathways, 489
S Short-bowel syndrome, 324
Safety, 289, 291, 436–437, 443, 472–473, 490–491 Silica, 373
Salt iodization, 364 Silicon, 347, 475, 512
Salvia officinalis (Sage), 513 Silicon dioxide (SiO2), 373
Sanguisorba officinalis, 513–514 Silicon, the skin and the hair follicle, 374
Saponins, 486 Single nucleotide polymorphism (SNP), 90
Saturated FFA, 220 Sitosterol, 508
Saw palmetto, 220, 322 Skin absorption of Finasteride, 62
Saw palmetto and ΑGΑ, 432–436 Skin atrophy, 124
Saw palmetto extract (SPE), 214, 429 Skin care formulations, 338
Saw palmetto liposterolic extract, 429 Skin reservoir, 21
Saw palmetto mechanism of action, 429–430 Smoking, 260–262
Scalp cleanser lotion, 249 Smoking and androgens, 260
Scalp coverage, 19 Smoking, hair follicles, and AGA, 260–262
Scalp massage, 23 Sodium, 347
Scalp's normal flora, 136 Soft tissue calcification, 349
Scandinavian countries, 239 Sonic hedgehog (Shh), 152, 339, 407, 454, 480, 489
Scavenger, 329 Sophora flavescens and ΑGΑ, 472
Schisandra nigra, 514 Sophora flavescens extract (SFE), 471
Scoville heat units, 501 Sophora flavescens root extract, 471
Scurvy, 330, 331 Sorbitan, 247
Seaweeds, 364, 365 Sources of cysteine, 212
Sebaceous glands, 99, 142, 170, 220, 248, 298, 317 Sperm counts, 56
Sebocytes, 248 Spermatogenesis, 56, 406
Seborrhea, 106 Spironolactone, 97, 180, 183, 191, 193, 194, 390
530 Index
Spironolactone and FPHL, 98–99 Thiamine, 303, 357

Standardization of herbs, 422 Thiol group, 211
Staphylococcus, 127 Third-generation progestins, 190
Staphylococcus aureus, 219 3α-HSD, 143
Staphylococcus epidermidis, 151 3β-hydroxysteroid dehydrogenases, 407
Stearic, 429 Thromboembolism, 118, 170
Stearic acid, 508 Thyroid hormone deiodinases, 380
Stem cell factor, 502 Thyroid hormone receptors, 363
Steroid hormone receptors, 407 Thyroid hormones, 348, 363, 379
Steroid hormones, 309, 353 Thyroid hormones and hair follicle, 364
Steroid metabolism, 406 Thyroid peroxidase, 363
Steroidogenesis, 354 Thyroid-stimulating hormone (TSH), 365
Stilbenes, 479 Thyrotropin-releasing hormone (TRH), 363
Storage iron, 386 Thyroxine, 363
Stratum corneum, 23 Tinea capitis, 381
Streptococci, 219 Tissue hypoxia, 387
Stress, 256, 262 Tocopherols, 337
Stress and obesity, 256 Tocopheryl polyethylene glycol succinate (TPGS), 338
Stress response, 256 Tolerability, 29, 63
Stress-response pathways, 259 Tolerance effect, 22
Strict vegans, 387 Tonic, 486
Structural role, 349 Topical action of Vit C, 333
Substance P, 502 Topical action of Vit E, 338
Suicidal antioxidant, 231 Topical adverse effects of TCs, 124–125
Sulfation, 359 Topical cetirizine, 200
Sulfides, 468 Topical corticosteroids (TCs), 122
Sulfotransferase, 13 and AGA/FPHL, 126–128
Sulfoxidation, 359 and Alopecia Areata, 125–126
Sulfur, 347 Topical CPA solution, 118
Sulfur-containing amino acids (SAAs), 213, 357, 358 Topical CyA, 109
Sulfur-containing baths, 358 Topical dexpanthenol preparations, 310
Sulfur, skin, and hair follicle, 358 Topical estrogens, 171–173
Superoxide dismutase (SOD), 225, 226, 353, 399, 406, 410, 480 Topical Finasteride, 62
Surfactant, 248 Topical iron, 391–392
Synthesis of DNA, 367 Topical progestin, 182
Synthetase, 322 Topical roxithromycin (ROX), 201
Synthetic analog of prostamide, 155 Topical solution, 105
Systemic absorption of TCs, 127 Topical Spironolactone, 99–100
Systemic adverse effects, 23 Topical use of Dutasteride, 87–89
Systemic adverse effects of TCs, 123–124 Topical use of Flutamide, 195
Systemic corticosteroids, 111 Topical use of Vit A, 300
Topical use of zinc, 410–411
Total and free T, 260
T Total hair count, 19
Tachycardia, 24 Total parenteral nutrition, 324
Taekuksam ginseng, 485 Toxicity, 133, 490
Tannins, 394 Trace elements, 347
Target area hair counts, 15 Transcription of DNA, 406
Taurine, 357 Transcutaneous absorption, 121
Tea, 392, 393 Transcutaneous permeation of Vit C, 333
Tectona grandis (Teak tree), 515 Transfer of androgens, 255
Telogen, 14 Transferrin, 385, 386
Telogen effluvium, 180, 189, 258, 323, 364, 380, 408, 412 Transforming growth factor (TGF) signaling pathway, 488
Temporary shedding, 20 Transforming growth factor-β1 (TGF-β1), 44, 110, 200, 225, 226, 434,
Tensile strength, 374 446, 454, 508, 511
Teratogen, 91 Transforming growth factor-β2 (TGF-β2), 206, 300, 446, 476,
Terminal hairs, 20 502, 514
Testicles, 515 Transport iron, 386
Testicular atrophy, 101 Tretinoin, 32, 135, 141, 152
Testosterone, 13, 42, 97, 106, 115, 133, 151, 168, 188, 193, 206, 255, Triamcinolone acetonide, 466
353, 354, 400, 407, 423, 431, 432, 453, 461, 487, 508 Trichodynia, 127
T-flavanone, 514–515 TrichoScan®, 214, 233, 245
The action of Rosmarinus officinalis on the hair follicle, 496 Tricomin®, 228
The Helsinki Formula, 249 Triglycerides, 220
The Journal of International Medical Research, 239 Trigonella foenum-graecum (Fenugreek), 515–516
Theories to explain their use, 419 Triiodothyronine, 363
Index 531
Tripeptide, 358 Vit B7, 321

Tripeptide GHK-Cu, 225 Vit B12, 119, 295
True vitamin, 344 Vit C, 295
Tryptophan, 303, 305 Vit C and hair follicles in vitro, 332–333
TR-α, 364 Vit C deficiency, 331
TR-β, 364 Vit C excess, 331–332
TR-β1, 364 Vit D, 295, 349, 353, 354, 409
Tumor necrosis factor-alpha (TNF-α), 354, 367, 472, Vit E, 221, 295
513, 516 Vit E and hair follicle, 338–339
Tyrosinase, 400, 407, 473 Vit E deficiency, 340
2% Ketoconazole cream, 138 Vit E toxicity, 340
2% Minoxidil topical solution, 158, 338 Vit H, 321–326
Vit K, 295
Vitamers, 329
U Vitamins, 295
Uncombable hair syndrome, 322 Vitamins in general, 295–296
Undervirilization, 101 Viviscal, 241–246
Unsaturated FFAs, 221 Volume of distribution, 78
Urinary flow, 42 Vulnerable groups, 287
Urinary flow pressure, 42
Urination, 42
Ursolic acid, 495 W
Urtica Dioica (Stinging nettle), 516 Warfarin, 491, 516
Use of ATRA in AGA/FPHL, 145 Washout period, 50
U.S. food supplement market, 282 Water-soluble, 296, 303, 315
Water-soluble vitamin, 309
Weight stigma, 256
V Weight training, 263
Vanilloid receptor subtype 1 (VR1)/(TRPV1), 502 Westernized diet, 258
Vascular endothelial growth factor (VEGF), 14, 200, 435, 454, 461, White ginseng, 485
476, 480, 487, 508, 512 Wnt/β-catenin signaling pathway, 332, 489
Vasoconstriction, 122 Wnt-3α and β-catenin protein, 476
Vasodilating effects, 304 Wnt-signaling, 488
Vasodilation, 303 Wolff-Chaikoff effect, 365
Vasodilation theory, 13
Vasodilatory, 472
Vegetable consumption, 258 X
VEGF expression, 488 Xandrox®, 153
Versican expression, 332 Xanthotrichia, 381
Vertex, 18–19
Verum-2®, 213
Vit A and hair follicle, 298 Z
Vit A deficiency, 299 Zinc, 153, 221, 311, 323, 347, 394
Vit A paradox, 299 Zinc and AGA/FPHL, 409–411
Vit A synthesis, 298 Zinc and alopecias, 408–409
Vit A toxicity, 299 Zinc and hair follicle, 406–408
Vit B1, 295 Zinc chloride, 408
Vit B2, 295 Zinc deficiency, 408
Vit B3 (niacin), 303 Zinc finger motifs, 407
Vit B3 hypervitaminosis, 305 Zinc finger proteins, 406
Vit B3 and hair follicle, 304 Zinc oxide, 411
Vit B5 and hair follicle, 310–311 Zinc pyrithione, 410
Vit B5 deficiency, 311 Zinc pyrithione shampoos, 136
Vit B6, 152, 153, 221, 295, 407 Zinc sulfate, 152, 316
Vit B6 and hair follicle, 315–316 Zinc supplementation, 402
Vit B6 deficiency, 317 Zizyphus jujube (Chinese date), 516

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Androgenetic Alopecia From A To Z - Vol. 2 Drugs, Herbs, Nutrition and Supplements

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Konstantinos Anastassakis

Androgenetic Alopecia From

Original Greek edition published by G. Zevelekakis and Co., Athens, 2014.

ISBN 978-3-031-08056-2 ISBN 978-3-031-08057-9 (eBook)

NHI Medical William R. Rassman

e­ xperience, without diminishing its clarity or negatively impacting contents or methodology.

Athens, Greece Konstantinos Anastassakis

24.7.9 Finasteride and Prostate Cancer (PCa) ������������������������������������������������� 58

35.3 Effects of Latanoprost on The Scalp����������������������������������������������������������������� 163

Part VI Nutrition, Lifestyle Factors and AGA/FPHL

48 Diet, Lifestyle, and AGA/FPHL��������������������������������������������������������������������������������� 255

Part VII Dietary Supplements and Androgenetic Alopecia

49.6 Can Food Supplements Be Dangerous?������������������������������������������������������������� 288

56.6 Vit C and Hair Follicles In Vitro ����������������������������������������������������������������������� 332

75 Ginkgo Biloba (Maidenhair Tree)����������������������������������������������������������������������������� 459

83.3 Chaemacyparis Obtuse (Japanese Cypress, Hinoki)����������������������������������������� 508

What Hair Loss Patients Expect from a Physician

• a lack of a specific treatment recommendation (66%),

Classification of Hair-Growth Medications

1. FDA-approved compounds with specific indication against ΑGΑ/FPHL (on-label):

What to Expect from Medical Treatment?

1. Delay the onset of catagen,

Medical Treatments and Online Advice

The “Hair Loss Forum Habitat”

Basic Principles of Pharmaceutical Treatment in AGA/FPHL

• It is important to manage AGA/FPHL strategically with the variety of current therapeutic

Mild / Moderate Moderate / Severe Severe

III vertex IV V VI VII

II III IV Medical treatment

IIa IIIa Improvement or satisfied

Medical treatment Continue

5% Minoxidil Topical Solution or Foam

Fig. 1 Algorithmic guideline for the management of AGA

+ topical Minoxidil Cyproterone acetate normal hyperandrogenism

Fig. 2 Algorithmic guideline for the management of FPHL

Beyond Evidence-Based Medicine

Basic Concepts however, with the introduction of Minoxidil Topical

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 11

hair growth agents became more precise and sophisticated,

Fig. 23.1 Comparison of the 60

Mean percent change in interval weight per sq cm

Fig. 23.2 Comparison of the 40

MTS, 2% MTS, placebo, and

Fig. 23.3 Comparison of the 35

Mean percent change in excess cumulative weight

5% minoxidil 2% minoxidil Placebo Untreated

studies, which included 735 females. Since the publication

23.6 Ideal Candidates for Minoxidil

showed that PRP, Finasteride 1 mg (male & female), 5%

that the maximal growth response is attained after 12 months 300

100 Bid application throughout treatment course

Fig. 23.6 Schematic timeline No treatment

23.9.3 Ectopic Hypertrichosis concentration is more frequently related to ectopic hypertri-

23.14 A Final Note by the Author

Basic Concepts and rarely being the reason for discontinuation.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 41

Finasteride is the result of a long-term research program by 24.2 Finasteride in AGA

24.3 Mechanism of Action of Finasteride

Androgen-dependent hair growth and AGA are both depen-

NHI Medical William R. Rassman

e xperience, without diminishing its clarity or negatively impacting contents or methodology.

Athens, Greece Konstantinos Anastassakis

24.7.9 Finasteride and Prostate Cancer (PCa) �� 58

35.3 Effects of Latanoprost on The Scalp�� 163

Part VI Nutrition, Lifestyle Factors and AGA/FPHL

48 Diet, Lifestyle, and AGA/FPHL�� 255

49.6 Can Food Supplements Be Dangerous?�� 288

56.6 Vit C and Hair Follicles In Vitro �� 332

75 Ginkgo Biloba (Maidenhair Tree)�� 459

83.3 Chaemacyparis Obtuse (Japanese Cypress, Hinoki)�� 508

What Hair Loss Patients Expect from a Physician

Classification of Hair-Growth Medications

What to Expect from Medical Treatment?

Medical Treatments and Online Advice

The “Hair Loss Forum Habitat”

Basic Principles of Pharmaceutical Treatment in AGA/FPHL

Beyond Evidence-Based Medicine

23.6 Ideal Candidates for Minoxidil

23.9.3 Ectopic Hypertrichosis concentration is more frequently related to ectopic hypertri-

23.14 A Final Note by the Author

Finasteride is the result of a long-term research program by 24.2 Finasteride in AGA

24.3 Mechanism of Action of Finasteride

24.6 Metabolism of Finasteride saturation of 5α-R isotype II binding of Finasteride50. This

25.7 Dutasteride + Finasteride, 1. The effects of Finasteride on 5α-R II inhibition have a

26.5 Adverse Effects

31.2 Oral Ketoconazole Since Ketoconazole inhibits the production of androgens

36.4.2.1 Topical Estrogens in Men

38.2 Hormonal Effects of OCs in Hair

38.4 How to Avoid OCs-Mediated Hair • Desogen,

Nevertheless, several articles are claiming that cysteine-

43.1 Free Fatty Acids (FFAs)

Basic Concepts 44.1 Mechanism of Action and Properties

References 22. Siméon A, Emonard H, Hornebeck W, Maquart FX. The tripeptide-