Gender Differences in Skin: A Review of the Literature

H a r r y Dao, Jr., MD; a n d R e b e c c a A. Kazin, MD

Johns Hopkins Medical Institutions, Baltimore, Maryland

ABSTRACT

Background: There has been increasing interest in studying gender differences in skin to learn
more about disease pathogenesis and to discover more effective treatments. Recent advances have
been made in our understanding of these differences in skin histology, physiology, and immunol-
ogy, and they have implications for diseases such as acne, eczema, alopecia, skin cancer, w o u n d
healing, and rheumatologic diseases with skin manifestations.
Objective: This article reviews advances in our understanding of gender differences in skin.
Methods: Using the PubMed database, broad searches for topics, with search terms such as gender
differences in skin and sex differences in skin, as well as targeted searches for gender differences in spe-
cific dermatologic diseases, such as gender differences in melanoma, were performed. Additional arti-
cles were identified from cited references. Articles reporting gender differences in the following areas
were reviewed: acne, skin cancer, wound healing, immunology, hair/alopecia, histology and skin
physiology, disease-specific gender differences, and psychological responses to disease burden.
Results: A recurring theme encountered in m a n y of the articles reviewed referred to a delicate
balance between normal and pathogenic conditions. This theme is highlighted by the complex
interplay between estrogens and androgens in m e n and women, and how changes and adaptations
with aging affect the disease process. Sex steroids modulate epidermal and dermal thickness as well
as i m m u n e system function, and changes in these hormonal levels with aging and/or disease pro-
cesses alter skin surface pH, quality of wound healing, and propensity to develop a u t o i m m u n e dis-
ease, thereby significantly influencing potential for infection and other disease states. Gender dif-
ferences in alopecia, acne, and skin cancers also distinguish hormonal interactions as a major target
for which more research is needed to translate current findings to clinically significant diagnostic
and therapeutic applications.
Conclusions: The published findings on gender differences in skin yielded m a n y advances in our
understanding of cancer, immunology, psychology, skin histology, and specific dermatologic dis-
eases. These advances will enable us to learn more about disease pathogenesis, with the goal of offer-
ing better treatments. Although gender differences can help us to individually tailor clinical man-
agement of disease processes, it is important to remember that a patient's sex should not radically
alter diagnostic or therapeutic efforts until clinically significant differences between males and
females arise from these findings. Because many of the results reviewed did not originate from ran-
domized controlled clinical trials, it is difficult to generalize the data to the general population.
However, the pressing need for additional research in these areas becomes exceedingly clear, and
there is already a strong foundation on which to base future investigations. (Gend Med. 2007;4:308-
328) Copyright © 2007 Excerpta Medica, Inc.
Key words: gender differences, skin, sex steroids, i m m u n o l o g y and a u t o i m m u n e diseases, wound
healing, skin cancer.

Accepted for publication August 27, 2007.

Printed in the USA. Reproduction in whole or part is not permitted. 1550-8579/$32.00

308 Copyright © 2007 ExcerptaMedico, Inc.

 H. Dao, Jr. and R.A. Kazin

INTRODUCTION ferences in the following areas were reviewed:

Over the past 25 years, there has been increas- acne, skin cancer, wound healing, immunology,
ing interest in studying gender differences to hair/alopecia, histology and skin physiology,
learn more about disease pathogenesis and to disease-specific gender differences, and psycho-
discover more effective treatments, if not cures. logical responses to disease burden. Published
However, in a MEDLINE search from 1975 to results were considered to be statistically sig-
2004 for publications on gender-specific derma- nificant if P _<0.05.
tologic research, Holm et al I found few perti-
nent articles. In our review of gender-specific HISTOLOGY/SKIN PATHOLOGY
differences in skin, we found statistically sig- As the largest organ in the body, skin is the pri-
nificant results pertinent to gender differences mary protective barrier between an individual
in skin that were not always clearly obvious and his or her environment. Gender differences
from reading the abstracts only. Our search for in skin structure can be used as a strategy for
articles examining gender differences in skin learning about the pathogenesis of certain skin
yielded m a n y advances in our understanding diseases, such as atopic dermatitis, that are
of immunology, skin histology/physiology, spe- characterized by derangements in skin struc-
cific dermatologic diseases, and quality of life. ture and function. Sex steroids influence skin
Skin histology and physiology are frequently thickness, thereby influencing susceptibility to
altered in dermatologic skin conditions, and infection and potential for wound healing. We
gender differences in skin structure can be used also examined other differences, such as skin
as a strategy for learning about the pathogenesis pH, that may alter skin flora and thus vary
of certain skin diseases, such as atopic dermati- thresholds for skin infections in susceptible
tis. Furthermore, gender differences in the patients.
i m m u n e system can offer insight into the
pathogenesis of a multitude of diseases with Differential Effects of Sex Steroids in
cutaneous manifestations as well as the process Murine Skin Layers
of wound healing. Lastly, differences in response Animal studies have noted gender differences
to skin conditions, partly influenced by societal in skin. Male mice have a 190% thicker dermis,
expectations and responses to ideals of attrac- but a thinner epidermis and hypodermis, than
tiveness, can significantly alter the quality of do female mice, resulting in male skin that is
life among individuals coping with similar 40% thicker than female skin. 2 Data collected
severities of identical dermatologic conditions. from performing gonadectomies and testing
The purpose of this article was to highlight the effects of androgen and estrogen treatments
these recent advances in our understanding and on mouse skin suggest that estrogen plays a
consider the implications of this knowledge in major role in regulating epidermal thickness, 2
helping us to better prevent, manage, and pos- and that estrogen's effects in regulating epider-
sibly cure, skin diseases. mal thickness are mainly via estrogen receptor-~
(ERa) and not estrogen receptor-~ (ER~).3 After
METHODS gonadectomy, female murine dermal thickness
A PUBMED search of relevant articles was con- increased, whereas male murine dermal thick-
ducted. General searches for topics, such as ness did not significantly change, suggesting
gender differences in skin and sex differences in that androgens play a major role in regulating
skin, as well as targeted searches for gender dif- dermal thickness. Moreover, treatment with
ferences in specific dermatologic diseases, such the androgens dihydrotestosterone and dehy-
as gender differences in melanoma, were per- droepiandrosterone significantly increased
formed. Additional articles were identified from murine dermal thickness by 22% and 19%,
cited references. Articles reporting gender dif- respectively. 2

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Gender Medicine

Susceptibility to Dermatologic Diseases instructed participants to avoid all cosmetic

Due to Gender Differences in Human products for 7 days before measurement of skin
Skin Physiology pH, but it is still conceivable that cosmetics may
In humans, male skin is thicker t h a n female have longer-lasting effects on skin pH that need
skin, 4 and females have thicker subcutaneous to be considered w h e n analyzing results. A fur-
tissues t h a n do males, s With aging, female skin ther strength of the study is that participants
becomes thinner t h a n male skin, 6 and post- were permitted time to become acclimated to
menopausal w o m e n especially experience a standard room temperature and humidity before
decrease in skin thickness, suggesting that estro- study measurements were taken, 19 which ac-
gens play a role in maintaining skin. 7 Sex ster- counted for the fact that overall sweat rates and
oids can change skin thickness; ovariectomy is total lactate secretion are greater in males t h a n
associated with t h i n n i n g of the skin whereas in females. 23 Williams et a124 found that w o m e n
estrogen therapy thickens skin. 8 have more acidic axillary skin surface pH t h a n
Conflicting results have been published about m e n have, and after washing with tap water, the
gender differences in the physiology of h u m a n axillary skin surface pH decreases significantly
skin. Skin pH is believed to influence the stratum in women, whereas it slightly increases in men.
corneum layer (ie, the skin's barrier function) and In the future, better understanding of the skin's
the flora of organisms living in the skin. 9-n response to cleansing with water and different
Indeed, males may carry more aerobic flora and types of soaps in different regions of the body
biotypes than may females, without any observed will result in gender-specific recommendations
qualitative differences in the flora. 12 Studies of for skin care, especially in relation to specific
skin pH in different areas of the body may offer dermatologic diseases characterized by deranged
valuable insight to the poorly understood patho- skin pH.
genesis of some diseases resistant to current stan- What clinical significance can be attributed to
dards of treatment, such as hidradenitis suppura- gender differences in skin lipid and protein con-
tiva, which tends to affect women in the axillae tent remains to be fully elucidated. In a study of
and m e n in perianal areas. 13 Even small differ- skin friction in 11 anatomical regions, skin sur-
ences in pH may significantly change the struc- face lipid content was found to be statistically
ture of skin, TM and increasingly basic skin surfaces lower on the forehead, dorsal forearm, and post-
may allow for skin colonization of pathologic auricular areas in females, but the dynamic fric-
microorganisms. 9,14 An interesting clinical corre- tion coefficient (p) showed no gender differ-
lation is a study that suggested an association ence. 2s With age, there was a significant change
between elevated intertriginous pH and the in ceramide ratios in females but not in males,
increased incidence of candidal intertrigo in and it was suggested that female hormones
patients with diabetes, is played a possible role in the makeup of stratum
One study found no significant gender differ- corneum sphingolipids. 26 Gender differences in
ences in skin surface pH, transepidermal water cutaneous protein composition have also been
loss, stratum c o r n e u m hydration, or casual observed and are hypothesized to result from
sebum content. 16 However, 4 other studies found different protein makeup between males and
that w o m e n had higher skin surface pH levels females, which is influenced by differing hor-
t h a n did men, 17-2° and yet another study report- m o n e statuses. 19
ed the opposite finding. 21 What may be con-
founding these results is that different areas of GENDER DIFFERENCES IN IMMUNOLOGY
the body were sampled among the studies. Also, The i m m u n e system protects against foreign
the use of cosmetics may have increased pH 22 antigens to prevent disease while m a i n t a i n i n g a
and prevented consistent results. To mitigate the level of self-tolerance to prevent a u t o i m m u n e
effect of cosmetics on skin pH, Jacobi et al ~9 disease. Sex steroids influence m a n y different

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 H. Dao, Jr. and R.A. Kazin

i m m u n e responses, and changing levels of sex to pay for an e n h a n c e d i m m u n e response.

steroids with aging and other disease states Estrogens encourage the development of autore-
have been implicated in a variety of gender dif- active B cells41 and are believed to inhibit apopto-
ferences observed in w o u n d healing, infectious sis to permit the survival of autoreactive T cells.42
and a u t o i m m u n e diseases, and m a n y other der- As a result, autoimmune diseases are found much
matologic conditions. Subsequently, an elabo- more commonly in females.
rate and complex interaction between different Despite m o u n t i n g evidence that sex steroids
sex steroids and their receptors has been un- contribute to gender differences in i m m u n o l o -
covered. The underlying basis for these gender gy, the underlying pathogenesis has yet to be
differences in immunology, however, has not made clear. Defects in the X chromosome,
been clarified. which normally contains genes that influence
sex h o r m o n e levels and i m m u n e tolerance, m a y
Basis for Disease Expression be potential culprits. 43 Evidence in favor of this
A vast a m o u n t of literature explores gender proposition includes the fact that diseases
differences in the i m m u n e system, with sex ster- involving changes to the X chromosome, such
oids c o m m o n l y implicated in causing these dif- as Turner's syndrome, in which an X chromo-
ferences. 27 In general, estrogen stimulates the some is missing, are more c o m m o n l y associated
i m m u n e system whereas testosterone inhibits with the development of a u t o i m m u n e diseas-
it. 28 However, this statement is far too simplistic, es. 44 Another potential contributor to gender
as revealed after the discovery of the novel ER[3 differences in i m m u n o l o g y are Langerhans'
in 1996. 29 The 2 types of estrogen receptors, ERct cells (LCs), which are derived from the bone
and ER[3, are differentially expressed in different marrow and play an important role as antigen
cell lineages and have different functions. For presenting cells in the cutaneous i m m u n e
example, ER{3 signaling mediates the apoptosis response. 4s-47 LC density has been found to cor-
of undifferentiated monocytes via the Fas/Fas relate with T-cell response, lending support to
ligand system, 3° and signaling via ERa decreases the idea that LCs play a role in i m m u n e reac-
proinflammatory cytokine levels in mice models tions in the skin. 48-5° However, gender differ-
of autoimmune diseases. 31 Targeted treatments ences in h u m a n LC density or structure have
with selective ER modulators have great poten- not been described.
tial in treating autoimmune diseases more selec-
tively while decreasing adverse effects. Lyme Borreliosis: Disease Expression
At least before menopause, it is believed that Influenced by Gender Differences
women are better able than m e n to cope with Lyme borreliosis is a vector-borne disease with
infectious diseases because they have higher CD4 a characteristic cutaneous manifestation k n o w n
lymphocyte levels and a higher propensity to as erythema migrans, sl From 1992 to 1998,
develop a Thl response, express more inflamma- males aged 5 to 19 and >60 years had a higher
tory cytokines, develop a more robust antibody incidence of Lyme borreliosis infection t h a n
titer in response to vaccination, and generate did females in the same age range, s2 In a 5-year
higher immunoglobulin levels in response to follow-up study of individuals in Sweden who were
antigenic challenges. 28,32-34 Whereas estrogens diagnosed with erythema migrans and treated
stimulate the humoral i m m u n e response, andro- with antibiotics, 31 of 708 people were reinfect-
gens enhance the cellular i m m u n e response. 34-39 ed, with the overwhelming majority of those (27
As a result, diseases characterized by robust of 31) being w o m e n aged >44 years. 53 W h e n
humoral i m m u n e responses that lead to counter- lymphocytes were collected from reinfected
productive levels of Th2 lymphocytes are highly individuals and stimulated in vitro with a vari-
female dominant compared with diseases due to ety of antigens, w o m e n had substantially more
Thl dysfunction. 4° Unfortunately, there is a price spontaneous production of total cytokines t h a n

311
Gender Medicine

did men; however, w o m e n also had substantially have increased risks of developing SLE, with the
greater Th2 ratios, suggesting that they may have risk being proportional to the duration of treat-
had a Th2 dominant response and a decreased ment. s7 Both males and females with SLE have
inflammatory response even though they had a increased activity of the cytochrome P450 en-
larger absolute secretion of cytokines. 28 Further zyme CYPIB1 that preferentially converts estra-
research needs to focus on how women's i m m u n e diol to more potent serum estrogens such as
systems adapt to decreasing estrogen levels after 16-~-hydroxyestrone, 36,4°,58 resulting in a 20-fold
menopause. increase in the fraction of high- to low-potency
estrogens in patients with SLE versus healthy
AUTOIMMUNE DISEASES individuals. 59 It has been suggested that increased
There is a striking gender difference in the prolactin levels may partly be responsible for de-
prevalence and incidence of a u t o i m m u n e dis- creased androgen levels, which have been associ-
eases. Precipitous changes in some of these ated with SLE. 38'60-62
ratios with aging have directed m u c h research
toward the possible roles of sex hormones and Scleroderma
their receptors, as well as inherent differences Scleroderma, also k n o w n as systemic sclerosis
in sex chromosomes and the i m m u n e system (SSc), is an autoimmune connective tissue dis-
b e t w e e n the sexes. ease that can lead to fibrosis of multiple organ
systems. 63 Involvement in scleroderma may be
Chronic Immune limited to the skin (limited cutaneous or CREST
Thrombocytopenic Purpura syndrome) or include m a n y internal organs (dif-
Chronic i m m u n e thrombocytopenic purpura fuse cutaneous systemic sclerosis or progressive
(ITP) occurs especially in w o m e n in their 30s systemic sclerosis). 63 Overall female-to-male inci-
and 40s, with a female-to-male ratio of 3-4:1 dence ratios of scleroderma have been reported
which suggests that sex hormones may play a to be 2.9:1 and 3:1. 64,6s In the reproductive years,
role in its pathogenesis. 54 It is believed that the female-to-male SSc ratio is as high as
megakaryocyte and platelet generation is con- 15:1 before plummeting to 1.8:1 in those aged
trolled via "thrombopoietic" cytokines, s5 whose _.45 years. 64 The rate of m o n o s o m y X is 2-fold
production m a y be influenced by sex hor- higher in females with SSc than in healthy
mones, s6 Although a study examining gender- women, suggesting that haploinsufficiency of
related differences in the thrombopoietic cyto- X-linked genes may be a contributor to the
kine pattern in patients with ITP failed to find female predominance of SSc and other autoim-
any gender differences in cytokine levels regulat- m u n e diseases. 66 One recent meta-analysis in-
ing thrombopoiesis in these patients, people volving 1291 patients and 3435 controls from
with chronic ITP may have higher levels of estra- 11 case-control studies found SSc to be associated
diol than may patients without chronic ITP, sug- with occupational exposure to solvents (odds
gesting that sex hormones play a role in ITP ratio = 2.4), and m e n had a statistically signifi-
susceptibility, independent of sex. s4 cant higher relative risk of developing SSc w h e n
exposed to solvents than w o m e n did (odds ratio =
Systemic Lupus Erythematosus 3.0 vs 1.8), though the 95% CIs did overlap
Systemic lupus erythematosus (SLE) is an auto- slightly. 67
i m m u n e disease with a female-to-male ratio of A prospective study of 91 patients with SSc
3:1 before puberty, 10-15:1 during the reproduc- found only 2 clinical differences between men
tive years, and 8:1 after menopause. 38 This gen- and women: whereas myositis was 7-fold more
der difference in incidence suggests that sex c o m m o n in m e n than in women, m e n had a
hormones play a key role in the pathogenesis of lower prevalence of arthralgias. 68 One study in a
SLE. Postmenopausal w o m e n taking estrogen cohort of patients found that m e n had shorter

312
 H. Dao, Jr. and R.A. Kazin

m e a n disease duration t h a n did women, 69 HAIR/ALOPECIA

though this finding was not observed in another Complex Interplay Between Estrogen,
study. 68 Gender differences in age at disease Androgen, and Progesterone
onset or diagnosis have not been reported, 6s,e9 ERs have been implicated in modulating hair
and no consensus exists concerning sex as a growth. Very little gender difference has been
prognostic factor in SSc. Some studies have con- found in the expression of the 2 ERs (ie, ER{, and
cluded that m e n have worse survival rates t h a n ER[3) in nonbalding scalp skin, 87 but it is not
do women, 7°,71 yet other studies have found no known whether there is a gender difference in
statistically significant gender differences in ERs in balding skin. ER[3 has widespread localiza-
morbidity or mortality in SSc. 68'72'73 tion in the hair follicle, especially in the dermal
papilla cells and the specialized bulge region of
Rheumatoid Arthritis the outer root sheath, and appears to be the main
Rheumatoid arthritis (RA) is characterized by receptor for estrogen's effect on hair growth, as
a chronic i n f l a m m a t o r y synovitis TMand affects The mechanism behind male pattern hair loss is
more females t h a n males, 7s,76 with an incidence poorly understood because it has been observed
4 to 5 times higher in females t h a n in males to correlate with androgen levels in at-risk in-
younger t h a n age 50 that decreases to a ratio of dividuals, 89,9° a l t h o u g h it has b e e n suggested
-2:1 after 60 to 70 years of age. 77 A significant that scalp hair growth does not require androgen
decline in the incidence of RA has been observed receptors (ARs).91 A complex interplay between
over the past decades 78,79 especially in females, estrogen and ARs may regulate the skin and its
who showed the largest decrease in incidence, s° appendages, as suggested by the antagonistic
It has been suggested that oral contraceptive nature between estrogens and androgens in other
use m a y account for some of this decline, sl tissues, such as ER[~'s inhibition of dihydrotestos-
Smoking in men, but not in women, has been terone in the prostate by decreasing levels of AR. 92
associated with a 2-fold higher risk of develop- Even less understood is the role of progesterone
ing RA. 82 Females usually develop RA earlier in receptor (PR) in hair growth.
life t h a n do males, 83,84 and a study of male and
female patients matched for duration of disease Androgenetic Alopecia
found no differences in disease activity or Androgenetic alopecia occurs most promi-
severity, with the exception that w o m e n had nently in m e n and usually involves the frontal
Sj6gren's syndrome more frequently t h a n did and temporal scalp areas; adult male plasma
men. 8s Another study observed gender differ- androgen levels are believed to be necessary for
ences in the clinical presentation of RA, with this process, which begins after puberty and
m e n developing erosive disease earlier and continues t h r o u g h o u t adult life. In the dermal
more frequently and also more c o m m o n l y papilla of hair follicles, PR has stained positive
developing nodules and rheumatoid lung dis- in the nucleus and cytoplasm in 30% of cases of
ease, whereas w o m e n usually manifested with androgenetic alopecia. 93 However, Pelletier and
sicca syndrome, s6 Ren 88 did not find PRs in hair follicles. Further
It now appears that women have 2 major fac- research is needed to determine what role PRs
tors increasing their susceptibility to autoimmune play in modulating hair growth in skin. Limited
diseases. During their reproductive years, women evidence stems from one study which found
have to cope with the immune-inducing effects that chronic progesterone treatment decreased
of increased estrogen levels, and after menopause, ER concentration in m o n k e y skin. 94
women have to contend with decreases in estro-
gen that may thereby increase autoreactive mono- Female Pattern Hair Loss
cyte survival resulting from decreased activation In contrast to male pattern hair loss, female
of the Fas/Fas ligand system. 3° pattern hair loss usually occurs independently of

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Gender Medicine

androgen levels and begins after 30 years of age, be increased by androgens 1°3 and decreased by
involving the frontal and parietal scalp areas in estrogens. 1°4,1°s Acne is believed to result from
a more diffuse pattern. 9s-97 It has been suggested the hyperresponsive reaction of sebocytes and
that females may be protected from developing keratinocytes to androgens, which lead to fol-
androgenetic alopecia because they have less licular plugging, 1°6-1°9 thus promoting the in-
5~-reductase and AR activity in the frontal and flammatory response to Propionibacterium acnes,
occipital scalp hair follicles. 96 Women also have which flourishes in follicular ducts, 11° especially
more aromatase expression in scalp hairs, espe- in skin with elevated surface pH. 9 It is poorly
cially on the occiput, suggesting that estrogen understood why some sebocytes are hyperre-
formation from testosterone is a protective factor sponsive to androgens; one possibility is that the
against developing androgenetic alopecia. 96,97 ratio of hormones may be more important than
actual hormonal levels.
Potential for Gender-Tailored Though increased levels of androgens have
Treatment of Hair Loss been associated with increased sebum produc-
Currently, topical 17J3--estradiol is used in some tion, this observation has not been reproduced
countries to treat female pattern hair loss,98 pos- in vitro. TM Recently, the synergistic and cata-
sibly by prolonging anagen.99 Conrad et al 1°° lytic effect of increasing sebaceous lipids when
cultured anagen VI follicles from frontotemporal using linoleic acid (which acts as a ligand at
scalp skin in the presence of estrogen and docu- the peroxisome proliferator-activated receptor
mented significant gender differences in the re- [PPAR]) with testosterone has been demonstrat-
sponse of human scalp hair follicles to estrogen ed. TM Whether or not differences in dietary
stimulation. In males, ER~ predominantly stains habits (thereby influencing linoleic acid levels)
in the nuclei of matrix keratinocytes, whereas in or gender differences in these receptors exist re-
females, ER~ stains predominantly in dermal mains unknown. What is exciting is the future
papilla fibroblasts of hair follicles. In response to potential for local PPAR modulation in acne
estrogen treatment, males showed significantly in- treatment.
creased immunoreactivity of ER~ in dermal papil-
la fibroblasts, whereas females failed to show any Gender Differences in
change in ER~ immunoreactivity. Furthermore, Murine Sebaceous Glands
in response to estrogen treatment, transforming Male mice have 45% larger sebaceous glands
growth factor-~2 immunoreactivity increased than do their female counterparts, T M a find-
significantly in the lower outer root sheath in ing that, if true in humans, could account for
females but decreased in males. Other genes were men being more likely to have refractory acne.
found to be regulated differently depending on Sex steroid stimulation may be one cause for
sex, and further advances in our understanding this difference; gonadectomy in male mice
of estrogen-dependent gene regulation will help resulted in a 46% atrophy of sebaceous gland
us develop gender-tailored treatments for male size, whereas gonadectomy in female mice in-
versus female pattern balding. ER modulators that creased sebaceous gland size by 19%. 112 There
promote catagen can also be used to treat hirsut- are significant gender differences in AR and
ism, but gender differences in the response to ERa expression in male versus female sebocytes.
estrogen need to be elucidated.98 AR is expressed almost exclusively in sebocyte
nuclei of male mice but is decreased in sebocyte
ACNE cytoplasm and nuclei of female mouse. ERa is
Hyperresponsive Sebum Production: not found in intact male mouse sebaceous glands,
One Step in Acne Pathogenesis but females have strong ERc~expression in basal
It is believed that sebum production plays a cell nuclei, 112 consistent with the fact that an-
role in the development of acne 1°1,1°2 and may drogens increase sebum production.

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 H. Dao, Jr. and R.A. Kazin

Gender Differences in less frequently t h a n do boys. 12° Indeed, non-

Human Sebaceous Glands atopic eczema has been noted to occur twice as
Sex hormones are produced locally in h u m a n c o m m o n l y in girls (5.9%) t h a n in boys (3.1%),
skin, and their varying levels of expression and this difference accounts for the larger num-
reflect differential expression of sex steroid- bers of girls t h a n of boys with eczema. 12°
producing enzymes in different skin cell types, Compared with 5- to 7-year-old boys, girls in this
of which sebaceous glands are prominent, n3 same age group have been shown to have a
However, it is not k n o w n whether there are higher skin surface pH and decreased stratum
h u m a n gender differences in sebaceous gland corneum hydration, ~2° factors that have been
sex steroid receptor expression, although andro- associated with an increased propensity in chil-
gens may influence cell proliferation and lipo- dren for developing acute atopic eczematous
genesis in the sebaceous gland. 88 Basal cells and lesions. 126 Girls with eczema also have substan-
sebocytes in sebaceous glands have more posi- tially higher transepidermal water loss t h a n do
tive immunostaining for ER~ t h a n for ERc¢88 boys with eczema. 127 Another reason for late-
and ER[~ is the overwhelmingly predominant onset eczema without atopy has also been
ER expressed in the epidermis. 87,88 Moreover, hypothesized to be related to gender differences
melanocortin-1 receptor expression in sebocytes in indoor versus outdoor activity. It has been
and keratinocytes of acne-involved skin was reported that girls play indoors more frequent-
recently found to be increased compared with ly t h a n do boys, 12° and children who play more
normal skin and has been implicated in acne indoors t h a n outdoors have an almost 2-fold
pathogenesis. TM Further studies are needed to greater prevalence of eczema. ~27
detect any potential gender differences in these
receptors in the skin and its appendages, but WOUND HEALING
even if these studies do not yield results, differ- Sex Steroid Influences in the Epidermal
ing hormonal levels between the sexes likely Permeability Barrier in Animals
contribute to the higher rate of sebum produc- Animal studies have demonstrated signifi-
tion in adult m e n versus adult women. 2°,ns,n6 cant roles for sex steroid actions in the develop-
Isotretinoin is a potent systemic treatment for m e n t of the permeability barrier. Barrier devel-
severe acne and serves to decrease sebaceous o p m e n t in fetal rat skin is accelerated by
gland production and size, whereas other acne estrogens and is retarded by testosterone, and
treatments mainly address P acnes and follicular male rat fetuses have slower epidermal barrier
keratinization. formation t h a n do female rat fetuses, 128 sug-
gesting that androgens are responsible for the
Pediatric Eczema observed gender differences in cutaneous bar-
In newborns, no gender differences in the rier function. 129
development of eczema have been found, n7-12° Accelerated cutaneous wound healing, associ-
However, in the first 6 m o n t h s of life, boys have ated with decreased AR stimulation on mac-
a higher propensity to develop eczema t h a n do rophages causing in vivo downregulation of
girls. 121 In contrast, there is a higher prevalence tumor necrosis factor-c~ (TNF-~), occurs after
of eczema in girls t h a n in boys in the preschool castration in male mice or AR blockade with flu-
ages, 12° and this trend continues into adoles- tamide. 13° Not all types of androgens are solely
cence. 1 2 2 - 1 2 4 Eczema without concomitant respi- associated with decreased inflammatory respons-
ratory allergies may be more c o m m o n in girls es and impaired wound healing; androgens have
t h a n in boys (female-to-male ratio of 1.4:1), also been associated with both pro- and anti-
whereas males more c o m m o n l y have eczema inflammatory states. 120 In vitro macrophage
with concomitant respiratory allergies? 2s These production of TNF-(z and interleukin-1 has been
findings suggest that girls have atopic eczema inhibited by androstenediol, TM emphasizing that

315
Gender Medicine

m u c h remains to be understood about the com- accepted in male recipients, 14° providing further
plexity of sex steroid actions. evidence that the H-Y antigen may play a role in
skin graft rejection.
Skin Grafts in Animals: Associations with
Langerhans" Cells and the H-Y Antigen Implications for Sex Steroids in
Skin allografts are rejected more frequently and Human Wound Healing
quickly in females than in males, and orchiectomy Abnormal wound healing in the elderly results
in males results in quicker rejection of skin al- in significant morbidity, mortality, and costs in
lografts. 132 Koyama et a1133 hypothesized that if health care. TM Being male is considered a risk fac-
LCs did play a role in the i m m u n e reaction in the tor for abnormal healing in the elderly, and m e n
skin and were involved in skin graft rejection, they have an altered inflammatory response and take
would be found in differing amounts in males longer t h a n w o m e n to heal acute wounds. 145-147
versus females. Male mice had substantially lower In response to trauma, hemorrhage, and sepsis,
LC density in the hind limb and ear skin than w o m e n have substantial survival advantages
did female mice; castration substantially increased over men. 148-154 For example, w o m e n fare sig-
LC density in male mice whereas ovariectomy had nificantly better t h a n m e n after challenge with
no effect on LC number in female mice. Andro- surgical sepsis, with a mortality rate of 26% ver-
gens made in the testes may suppress LC density sus 70%, respectively,ls5
in males, contributing to more rejection of skin Trauma is associated with alterations in sex
allografts in females than in males. 132-134 steroid concentrations, with higher estrogen con-
However, other studies of epidermal LC density centrations in both sexes and decreased testoste-
in humans, 135,136 mice, 48 and guinea pigs 137 have rone levels in males, ls6-16° Patients with delayed
not found any differences in LC density between wound healing resulting from abnormalities in
males and females. A unique aspect of Koyama's sex steroid levels (eg, patients with decreased tes-
study not found in the previous research was that ticular function leading to androgen deficiency,
age-matched mice were used; it is known that LC patients with renal failure, patients' status post-
density decreases gradually over time, potentially ovariectomy, and those in their elderly years)
confounding data if age-matched subjects are not stand to benefit greatly from increased under-
used. 133,138 Subcutaneous and topical application standing of the role of sex steroids in wound heal-
of testosterone propionate substantially decreases ing. Physiologicallevels of 5-cz-dihydrotestosterone
LC density both in castrated males and normal decrease wound i m m u n e function and impair
female mice, providing further evidence that sex wound healing after trauma and hemorrhage, in
differences in LC density may be a result of high- a milieu of increased proinflammatory cytokines
er androgen levels in males. 139 and decreased tumor growth factor-]3 at the
Recent studies have been undertaken to learn w o u n d site. 129,161Gender differences in the h u m a n
more about a male-specific minor histocompati- epidermal permeability barrier have not been
bility antigen, the histocompatibility Y (H-Y) demonstrated, but understanding such a differ-
antigen, which is located on the long arm of sex ence, if it exists, would help clinicians to recog-
c h r o m o s o m e y.140,141 The H-Y antigen was first nize the poorly understood influence that sex
described in 1968 as a transplantation antigen in plays in the severity of diseases associated with
mice that potentially caused male mice skin abnormal skin barrier function, such as atopic
grafts to be rejected in female mice recipients, dermatitis and severe psoriasis, that occur more
whereas female mice skin grafts were tolerated in frequently in males t h a n in females. 129
male mice recipients. 142,143Another study involv- Decreased estrogen levels, leading to decreased
ing rats had similar results, finding that male stimulation of cutaneous ERs, may lead to sig-
skin grafts were rejected within 6 weeks after nificant downstream effects that can interfere
grafting, whereas all female skin grafts were with wound healing, such as impaired cytokine

316
 H. Dao, Jr. and R.A. Kazin

signal transduction, destructive levels of inflam- ER[3was found to be the predominant ER type in
mation, and an altered protein balance. ~29 melanocytic lesions, suggesting that estrogen
Indeed, estrogen treatment accelerates cutane- and estrogen-like ligands play roles in melano-
ous wound healing, 162 and topical estrogens cyte physiology via ER[~.168 ER[~was most immu-
have been used in elderly patients to promote noreactive in dysplastic nevi with severe atypia
quicker and more effective wound healing. 14s and lentigo malignas, and its immunoreactivity
However, elderly males respond substantially less varied depending on the microenvironment,
to estrogen treatment than do their female coun- with melanocytes in invasive melanomas show-
terparts129; this may be a result of testosterone's ing less reactivity than melanocytes that were
antagonism of wound healing, because increas- stillinproximityto keratinocytes.168 Furthermore,
ing testosterone levels in elderly men are posi- ER~ immunoreactivity decreased with increas-
tively correlated with increased delays in wound ing Breslow depth, suggesting that the loss of
repair. 129 Counterproductively, high proinflam- ER[3 expression in melanomas may be a signifi-
matory responses in the skin inhibit proper cant stage in which melanomas become inde-
wound healing, and the elderly may lack suffi- pendent of estrogen.168 In addition, in nonmela-
cient anti-inflammatory responses. In contrast, noma melanocytic lesions, there was a trend
young adults may have sufficient levels of sys- toward women having more ER[3 immunoreac-
temic and local estrogen that play a role in tivity in lesions than men did, but the trend was
reducing inflammation via influencing cell ad- not statistically significant, possibly because the
hesion molecule expression. 129 study size was not large enough. 168
From birth until death, the probability of devel-
CANCER oping melanoma is 1.72% (1 in 58) in men and
Influence of Sex Steroids: Evidence from 1.22% (1 in 82) in women, and men have an
Animal Studies and Cultures -2-fold higher probability of developing mela-
The bulge region of the hair follicle is believed noma compared with women between 60 and
to be a source of hair follicle stem cells. 163 Skin 79 years of age.169 Sex is also a prognostic factor in
carcinomas may stern from this bulge region and cutaneous melanoma,17°-173 with women tending
be triggered by estradiol, 163 and 1713-estradiol to have better prognoses compared with men? 74A75
has been shown to induce squamous cell carci- Indeed, between 1973 and 1997, the rate of death
noma (SCC) and basal cell carcinoma (BCC) in from melanoma in the United States was 2-fold
mice and rats, an effect that is reversed after greater in males than in females. 176,177
gonadectomy.TM High levels of ER[3, and not Studies searching for relationships between
ERc~, have been discovered in h u m a n SCC tis- sex and melanoma tumor thickness, one of the
sues and cell lines. 165 Treatment with tamoxi- most important factors in predicting outcomes,
fen, an estrogen antagonist, significantly inter- have found conflicting results. One study did not
fered with SCC invasion, in part by decreased find sex to be significantly associated with prog-
intracellular focal adhesion kinase signaling, nosis in intermediate- to-thick melanomas, TM
inhibition of epidermal growth factor receptor, whereas 2 other studies showed that males had
and derangements in actin. 16s 17[~-estradiol also decreased survival compared with women when
stimulates melanocyte division in cultur@ 66 matching for tumor thickness. 172,178Furthermore,
even though a study conducted before the dis- men with positive sentinel lymph node (SLN)
covery of the novel ERJ3 reported that there biopsies may have worse prognoses than women
were no ERs in malignant melanoma. 167 with positive SLNs.174,178
However, sex has not been associated with
Melanoma SLN status? 78-1ss A prospective study, involving
Before 1995, studies failed to find ERc~in mela- 1829 patients aged 18 to 70 years with melano-
nomas, but after the discovery of ER[3 in 1996, 29 mas _1.00 m m Breslow thickness who were

317
Gender Medicine

treated with wide excision and SLN biopsy, (309/100,000 for m e n vs 165.6/100,000 for
found that male sex was associated with thicker w o m e n ) , 193 and Australia (2058/100,000 for m e n
melanomas, an increased tendency to have vs 1194/100,000 for women). 194 It has been
t u m o r ulceration, and a greater likelihood of observed that w o m e n are significantly younger
being older than 60 years of age at melanoma than m e n when receiving a diagnosis of BCC
diagnosis. 178 Even when taking these associa- (aged 63.5 years vs 64.9 years, respectively, with
tions into account, sex was still determined to be a 95% CI o f - 2 . 4 to -0.4). 189
an independent factor affecting survival in cuta- In Sweden, males have been noted to have an
neous melanoma. Future study directions in this -20-fold higher incidence of skin cancer of the
area include investigating whether there is any ear, compared with females. 198 Other studies
delay in seeking or obtaining medical care in have also found striking gender differences in
m e n versus women, because men were more the locations of NMSC, and whereas BCC tumors
likely to present with melanoma at an advanced occur more often on the ears and scalp in males,
age of >60 years. they occur more often on the lips, neck, and legs
Sex steroids may play a role in melanoma. In in females. 189,196 It has been speculated that the
women, malignant melanoma is rare before reason for higher frequency of BCC on the upper
puberty but sharply increases in incidence from lip in w o m e n may be due to the lack of mous-
puberty until about 50 years of age, when the tache hairs protecting the underlying skin from
incidence decreases after menopause. 176,177 Also, sun exposure, as also observed in another study
the risk of females developing cutaneous malig- reporting a female-to-male ratio of 3.5:1 for
nant melanoma is increased by -16% for every upper-lip BCCs that increases to 16:1 in younger
5 years of delayed childbearing, and multiparity w o m e n 30 to 39 years of age. 189,197 Other factors
reduces the risk of developing cutaneous malig- influencing these gender differences in BCC
nant melanoma by - 8 % for each additional include the use of carcinogenic cosmetics, earlier
birth186; a pooled analysis has also demonstrated referral in females, and a more conscientious
similar benefits of an earlier age at first birth and attitude of females toward their skin. 197 It has
of multiparity in decreasing the risk of develop- also been hypothesized that hair follicles play a
ing cutaneous melanoma. 187 However, the m y t h role in the development of BCC. 198 H u m a n pap-
that nevi may grow or change during pregnancy illoma virus DNA has been found in plucked
is not true and should not delay diagnostic hair, 199 implicating gender differences in hair
evaluation by a health professional. 188 Learning follicle density in accounting for the observed
more about gender differences in melanoma can gender differences in BCC location. 189
suggest new treatment modalities, one possibili- A very large series of 10,245 patients with
ty being the use of sex steroids and hormonal BCCs found that these malignancies of the head
therapy. 178 and neck occurred more frequently in w o m e n
(85.2%) than in m e n (81°/o). TM W h e n analyzed
Nonmelanoma Skin Cancer by subtype, superficial BCCs showed the largest
Two studies (n = 1711 and n = 5044) have gender difference in distribution, occurring more
found that BCCs had higher male-to-female ratios predominantly on the head in w o m e n (44.5% in
of 1.17189 and 1.4219°, respectively, but another w o m e n vs 34.7% in men) but more predomi-
study (n = 10,245) reported a male-to-female nantly on the trunk in m e n (49.9% in m e n vs
ratio of 0.92. TM Although incidence rates of non- 42% in women). TM W o m e n more frequently had
melanoma skin cancer (NMSC) vary by location, the morphoeiform type (7.2% in w o m e n vs 5.2%
m e n have consistently been found to have high- in men). Overall male-to-female ratios were 1.02
er incidence rates than do w o m e n in studies in nodular BCCs, 0.96 in superficial BCCs, and
b a s e d in G e r m a n y (100.2/100,000 for m e n 0.73 in morphoeiform BCCs. W o m e n more com-
vs 72.6/100,000 for women), 192 N o r t h America m o n l y were younger than m e n when undergo-

318
 H. Dao, Jr. and R.A. Kazin

ing excision of nodular and superficial BCCs of men, women tend to be treated earlier and have
the trunk, contrasting with the observation that better prognoses for skin cancers.
women tended to be older than men when
undergoing excision of both superficial and CONCLUSIONS
nodular BCCs of the head and neck. Our search for articles examining gender differ-
ences in skin yielded many advances in our un-
QUALITY OF LIFE derstanding of skin histology, immunology, spe-
Engaging the patient in an active discussion of cific dermatologic diseases, and quality of life.
their emotional reaction toward their dermato- These advances will enable us to learn more about
logic condition is crucial in understanding how disease pathogenesis, with the goal of offering
their lives are affected--the number of com- better treatments and compassionate care.
plaints cannot be simply correlated with quality A recurring theme encountered in many of the
of life. Gender differences in psychology are articles referred to a delicate balance between
partly influenced by cultural expectations as normal and pathogenic conditions. One of the
well as by the surrounding environment, and most studied delicate balances is the complex
these differences help determine patients' re- interplay between estrogens and androgens in
sponses to their dermatologic conditions as well men and women, and how changes and adapta-
as the degree to which they may become func- tions with aging affect the disease process. Sex
tionally impaired in society. The response and steroids modulate epidermal and dermal thick-
the degree of impairment do not always corre- ness as well as immune system function, and
late with each other. changes in these hormonal levels with aging
With psoriasis, men may be more afraid than and/or disease processes alter skin surface pH,
women of losing their jobs when taking time off quality of wound healing, and propensity to
from work for medical appointments. 200However, develop autoimmune disease, thereby signifi-
women with psoriasis experience more stigmati- cantly influencing potential for infection and
zation than do men. 2°1 A study of patients aged other disease states. The discussed gender dif-
>15 years with atopic dermatitis found no sig- ferences in alopecia, acne, and skin cancers also
nificant gender differences in age, duration of distinguish hormonal interactions as a major
disease, or disease severity; however, women target for which more research is needed to
more frequently reported their atopic dermatitis translate current findings to clinically signifi-
in all locations of the body except for the feet.1 cant applications.
Similarly, another study in healthy volunteers Although m a n y significant gender differ-
noted that women tended to have more subjec- ences were found that can help us individu-
tive complaints of dry skin than did men (P < ally tailor clinical management of disease
0.001), despite there being no clinical or objec- processes, it is important to remember that a
tive differences in any measurements taken dur- patient's sex should not radically alter diag-
ing the study. 2°2 The largest gender difference nostic or therapeutic efforts until clinically
was in reported location of atopic dermatitis in significant differences between males and fe-
visible areas such as the head, neck, and hands: males arise from these findings. Furthermore,
78.3% of women versus 55.7% of men reported because m a n y of the results reviewed did not
disease activity in these areas, and lesions in vis- originate from randomized controlled clinical
ible areas diminished quality of life more in trials, it is difficult to generalize the data to
women than in men. 1 Although a heightened the general population. However, the pressing
sensitivity for disease may decrease quality of life need for additional research in these areas be-
more in women than in men with skin disease comes exceedingly clear, and there is already
in visible areas, 1 it partly helps to explain the a strong foundation on which to base future
previously mentioned fact that, compared with investigations.

319
Gender Medicine

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Address correspondence to: Rebecca A. Kazin, MD, Johns Hopkins Dermatology & Cosmetic Center
at Green Spring Station, 10755 Falls Road, Suite 350, Luthersville, MD 21093. E-mail: [email protected]

328