Oxford Handbook of Endocrinology and Diabetes 3rd Ed

OXFORD MEDICAL PUBLICATIONS
Oxford Handbook of
Endocrinology and
Diabetes
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Oxford Handbook of
Endocrinology
and Diabetes
Third edition
Edited by
John Wass
Professor of Endocrinology,
Oxford Centre for Diabetes,
Endocrinology and Metabolism (OCDEM),
Oxford, UK
Katharine Owen
Senior Clinical Researcher and Honorary Consultant,
Oxford Centre for Diabetes, Endocrinology and
Metabolism (OCDEM), Oxford, UK
Advisory editor
Helen Turner
Consultant in Endocrinology
Oxford Centre for Diabetes, Endocrinology and
Metabolism (OCDEM), Oxford, UK
1
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First edition published 2002
Second edition published 2009
Third edition published 2014
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v
Foreword
Introduction to the Handbook of Endocrinology

and Diabetes
It is clear that endocrinology is progressing fast and moving far from its
original borders. Originally described as the study of the physiology and
diseases of the endocrine glands, classical endocrinology encompassed the
study of thyroid, hypothalamus, pituitary, adrenals, pancreas, parathyroids
and the reproductive glands. Increasingly diabetes and metabolism are rec-
ognised as overwhelming issues, which are responsible for world epidem-
ics with an enormous human and financial cost. Thus, lately it has become
obvious that the initial definition is too narrow and does not encompass
the breadth of the specialty—it needs to be redefined.
The speciality ‘endocrinology’ should be applied to every area in which
hormones act, extending to brain neurohormones, cognition, oncology,
and also bone diseases, the cardiovascular system and obesity … where
hormones and growth factors interact closely. This new science is closer
to the Hormonology that Starling described, than to Endocrinology as
defined by Laguesse at the end of the 19th century.
This immense amount of knowledge is well summarised in the third
edition of the Oxford Handbook of Endocrinology and Diabetes. Few of
us have the talent of John Wass and Katharine Owen, and Helen Turner
contributed to earlier editions. They have summarised with their col-
leagues, in an extensive though concise manner, our incredible specialty.
This specialty develops every day and continues to rule our behaviours
and diseases.
This Handbook of Endocrinology and Diabetes is a must for all phy-
sicians interested in hormones and related diseases, and in medicine in
general.
Philippe Bouchard
President, European Society of Endocrinology
Member of the National Academy of Medicine
vi
Preface to the
second edition
The first edition of this handbook was well received and sold many copies.
We were told by a number of specialist registrars in training and consult-
ants that it was essential to have it in outpatients. We hope that the same
will be true of the second edition.
Endocrinology remains the most exciting of specialties—enormously
varied in presentation and management and with the ability to affect hugely
and beneficially the quality of life over a long period of time. Our aims with
this second edition remain the same, mainly to have a pocket handbook
which can be easily transported in which all the pieces of information one
so often needs are there as a reminder. We hope it will enable trainees
to enhance their knowledge but also the older and so-called ‘trained’ will
continue to have recourse to its pages when memory lapses occur. We
regard it too as a companion to the Oxford Textbook of Endocrinology and
Diabetes.
We are enormously indebted to our contributors who once again have
provided timely texts full of practical detail. We are also hugely grateful to
our external referees who have looked at all the chapters with great care
and attention. Both have ensured that the text is as up-to-date as possible.
As always we welcome comments for future editions and we hope this
one proves as useful as the first one.
John A.H. Wass
Helen E.Turner
2009
vii
Preface
We remain happy that this handbook has been well received both in its
first and second editions. It has been translated into Chinese, and there
is also an American version which has sold well. We want it to remain
essential for specialist registrars in training and consultants who may have
the occasional memory lapse.
Our subject remains one of the most exciting of the specialties; our aims
with this third edition remain the same—to have, within a small volume,
all the essential information that one needs to look after patients with
endocrine problems and diabetes.
It is also an accompaniment to the Oxford Textbook of Endocrinology
and Diabetes which has recently been published in its second edition
(2011).
For this edition, we have completely revamped the diabetes section,
and we hope and think that this has been made more readily accessible
and assimilable.
We are enormously indebted to our contributors who have pro-
vided expertise and willing collaboration with our project. As always, we
welcome comments which may enhance the next edition.
John Wass and Katharine Owen

2013
ix
Contents
Contributors x
Contributors to the second edition xii
Symbols and Abbreviations xiii
1 Thyroid 1
2 Pituitary 106
3 Adrenal 227
4 Reproductive endocrinology 297
5 Endocrinology in pregnancy 425
6 Calcium and bone metabolism 449
7 Paediatric endocrinology 513
8 Neuroendocrine disorders 553
9 Inherited endocrine syndromes and MEN 575
10 Endocrine surgery 601
11 Endocrinology and ageing 613
12 Endocrinology aspects of other clinical
or physiological situations 627
13 Diabetes 683
14 Lipids and hyperlipidaemia 823
15 Obesity 847
Appendix 1 867
Appendix 2 873
Appendix 3 881
Index 887
x
Contributors
Ramzi Ajjan Ketan Dhatariya

Senior Lecturer and Consultant Consultant in Diabetes,
in Diabetes and Endocrinology, Endocrinology and General
Division of Cardiovascular and Medicine, Elsie Bertram Diabetes
Diabetes Research, The LIGHT Centre, Norfolk and Norwich
Laboratories, University of University Hospitals NHS
Leeds, UK Foundation Trust, Norwich, UK
Asif Ali Julie Edge
Consultant Physician (Diabetes Consultant in Paediatric Diabetes,
and Endocrinology), Department Oxford Children’s Hospital, John
of Medicine, Milton Keynes Radcliffe Hospital, Oxford, UK
Hospital, UK
Nick Finer
Wiebke Arlt Consultant Metabolic Physician,
Professor of Medicine and Head Centre for Weight Loss, Metabolic
of the Centre for Endocrinology, and Endocrine Surgery, University
Diabetes and Metabolism, College London Hospitals, UK
University of Birmingham, UK
Neil Gittoes
Rudy Bilous Consultant Endocrinologist and
Professor of Clinical Medicine, Associate Medical Director,
Academic Centre, James Queen Elizabeth Hospital,
Cook University Hospital, Birmingham, UK
Middlesbrough, UK
Steve Gough
Pratik Choudhary Professor of Diabetes
Senior Lecturer/Consultant, and Consultant Physician,
Department of Diabetes and Oxford Centre for Diabetes,
Nutritional Sciences, The School Endocrinology and Metabolism
of Medicine, Kings College (OCDEM), Churchill Hospital,
London, UK Oxford, UK
Peter Clayton Maggie Hammersley
Professor of Child Health & Consultant Physician and Senior
Paediatric Endocrinology; Clinical Lecturer, John Radcliffe
Director, NIHR Greater Hospital, Oxford, UK
Manchester, Lancashire & South
Cumbria Medicines for Children Niki Karavitaki
Research Network, University of Consultant Endocrinologist,
Manchester, UK Oxford Centre for Diabetes,
Endocrinology and Metabolism
Gerard Conway (OCDEM), Churchill Hospital,
Clinical Lead in Endocrinology Oxford, UK
and Diabetes, Department of
Endocrinology, University College
London Hospitals, UK
CONTRIBUTORS xi
Fredrik Karpe Peter Scanlon

Professor of Metabolic Medicine, Consultant Ophthalmologist,
Honorary Consultant Physician, Gloucestershire and Oxford
Oxford Centre for Diabetes, Eye Units; Medical Tutor and
Endocrinology and Metabolism Senior Research Fellow, Harris
(OCDEM), Churchill Hospital, Manchester College, University
Oxford, UK of Oxford; Visiting Professor
of Medical Ophthalmology,
Kim Lambert University of Bedfordshire, and
Specialist Registrar, Wessex Hertfordshire Postgraduate
Deanery, Winchester, UK Medical School, UK
Alistair Lumb Gary Tan
Locum Consultant Physician, Consultant Diabetologist,
Buckinghamshire Healthcare NHS Oxford Centre for Diabetes,
Trust, Aylesbury, Bucks, UK Endocrinology & Metabolism
(OCDEM), Churchill Hospital, UK
Niki Meston
Consultant Chemical Pathologist, Solomon Tesfaye
Epsom and St Helier University Professor of Diabetic Medicine,
Hospitals NHS Trust, Surrey, UK Royal Hallamshire Hospital,
Sheffield, UK
Helen Murphy
Senior Research Associate Gaya Thanabalasingham
Honorary Consultant, Department Specialist Registrar, Oxford
of Clinical Biochemistry, Centre for Diabetes,
Addenbrooke’s Hospital, Endocrinology and Metabolism
Cambridge, UK (OCDEM), Churchill Hospital,
Oxford, UK
Catherine Nelson-Piercy
Consultant Obstetric Physician, Mark Vanderpump
Department of Obstetrics, Consultant Physician and
Guys and St Thomas’ Hospitals, Honorary Senior Lecturer in
London, UK Diabetes and Endocrinology,
Royal Free Hampstead NHS
Sankalpa Neupane Trust, UK
Wolfson Diabetes and Endocrine
Clinic, Institute of Metabolic
Science, Addenbrooke’s Hospital,
Cambridge, UK
Shwe Zin Chit Pan
Wolfson Diabetes and Endocrine
Clinic, Institute of Metabolic
Science, Addenbrooke’s Hospital,
Cambridge, UK
xii
Contributors to the
second edition
Julian Barth Peter Selby
Consultant in Chemical Pathology Consultant Physician and Senior
and Metabolic Medicine, Leeds Lecturer in Medicine, Manchester
General Infirmary, Leeds, UK Royal Infirmary, Manchester, UK
Karin Bradley Kevin Shotliff
Consultant Physician and Consultant Physician and
Endocrinologist, Bristol Royal Diabetologist, Beta Cell Diabetes
Infirmary and Honorary Senior Centre, Chelsea and Westminster
Clinical Lecturer, University of Hospital, London, UK
Bristol, Bristol, UK
Sara Suliman
Emma Duncan Specialist Registrar in Diabetes,
Consultant Endocrinologist, Endocrinology and Metabolism,
Princess Alexandra Hospital and Diabetes UK; Clinical
Senior Lecturer, University of Research Fellow, Oxford Centre
Queensland, Austalia; for Diabetes, Endocrinology and
Postdoctoral Research Fellow, UQ Metabolism (OCDEM), Churchill
Diamantina Institute for Cancer, Hospital, Oxford, UK
Immunology and Metabolic
Medicine, Australia Janet Sumner
Lead Diabetes Specialist Nurse,
Pam Dyson Churchill Hospital, Oxford, UK
Research Dietician, Oxford
University, Oxford, UK Vivien Thornton-Jones
Lead Endocrine Specialist Nurse,
Mohgah Elsheikh Churchill Hospital, Oxford, UK
Consultant Endocrinologist, Royal
Berkshire Hospital, Reading, UK Helen E. Turner
Consultant Endocrinologist,
Stephen Gardner Department of Endocrinology,
Consultant Physician, Churchill Hospital, Oxford, UK
Buckinghamshire Hospitals NHS
Trust, UK John Wong
Consultant Chemical Pathologist,
John Newell-Price Kingston Hospital, Surrey, UK
Senior Lecturer and Consultant
Endocrinologist, University of
Sheffield, Royal Hallamshire
Hospital, Sheffield, UK
xiii
Symbols and
Abbreviations
b cross-reference
7 approximately
i increased
d decreased
p primary
s secondary
α alpha
β beta
γ gamma
% per cent
♀ female
♂ male
+ve positive
–ve negative
= equal to
≡ equivalent to
< less than
> more than
≤ less than or equal to
≥ greater than or equal to
°C degree Celsius
£ pound Sterling
® registered trademark
2 important
3 don’t dawdle
ACA adrenocortical adenoma
ACC adrenocortical carcinoma
ACE angiotensin-converting enzyme
ACEI angiotensin-converting enzyme inhibitor
ACR albumin:creatinine ratio
ACTH adrenocorticotrophic hormone
AD autosomal dominant
ADA American Diabetes Association
ADH antidiuretic hormone
ADHH autosomal dominant hypocalcaemic hypercalciuria
xiv SYMBOLS AND ABBREVIATIONS
aFP alpha fetoprotein

AGE advanced glycation end-product
AGHDA adult growth hormone deficiency assessment
AHC adrenal hypoplasia congenita
AI adrenal insufficiency
AIDS acquired immunodeficiency syndrome
AIH amiodarone-induced hypothyroidism
AIMAH ACTH-independent macronodular adrenal hyperplasia
AIT amiodarone-induced thyrotoxicosis
AITD autoimmune thyroid disease
alk phos alkaline phosphatase
ALL acute lymphoblastic leukaemia
ALP alkaline phosphatase
ALT alanine transaminase
a.m. ante meridiem (before noon)
AME apparent mineralocorticoid excess
AMH anti-Müllerian hormone
AMN adrenomyeloneuropathy
AMP adenosine monophosphate
AN autonomic neuropathy
ANCA anti-neutrophil cytoplasmic antibody
APS autoimmune polyglandular syndrome
AR autosomal recessive
ARB angiotensin II receptor blocker
ART assisted reproductive technique
AST aspartate transaminase
ATD antithyroid drug
ATP adenosine triphosphate
AVP arginine vasopressin
AVS adrenal vein sampling
bd bis in die (twice daily)
BMD bone mineral density
BMI body mass index
BP blood pressure
bpm beat per minute
Ca calcium
CAH congenital adrenal hyperplasia
CBG cortisol-binding globulin
CCF congestive cardiac failure
CEA carcinoembryonic antigen
SYMBOLS AND ABBREVIATIONS xv
CF cystic fibrosis
CFRD CF-related diabetes
CGM continuous glucose monitoring
cGMP cyclic guanyl monophosphate
cGy centigray
CHD coronary heart disease
CHO carbohydrate
CK creatine kinase
CKD chronic kidney disease
CLAH congenital lipoid adrenal hyperplasia
cm centimetre
CMV cytomegalovirus
CNS central nervous system
COCP combined oral contraceptive pill
COPD chronic obstructive pulmonary disease
CPA cyproterone acetate
CPK creatine phosphokinase
Cr creatinine
CRF chronic renal failure
CRH corticotrophin-releasing hormone
CRP C-reactive protein
CSF cerebrospinal fluid
CSII continuous subcutaneous insulin infusion
CSMO ‘clinically significant’ diabetic macular oedema
CSW cerebral salt wasting
CT computed tomography
CTLA4 cytotoxic T lymphocyte antigen 4
cv coefficient of variation
CV cardiovascular
CVA cerebrovascular accident
CVD cardiovascular disease
CVP central venous pressure
CXR chest X-ray
DCCT Diabetes Control and Complications Trial
DCT distal convoluted tubule
DD disc diameter
DEXA dual-energy X-ray absorptiometry
DHEA dehydroepiandrostenedione
DHEAS dehydroepiandrostenedione sulphate
DHT dihydrotestosterone
xvi SYMBOLS AND ABBREVIATIONS
DI diabetes insipidus
DIT diiodotyrosine
DKA diabetic ketoacidosis
DKD diabetic kidney disease
dL decilitre
DM diabetes mellitus
DME diabetic macular (o)edema
DN diabetic neuropathy
DNA deoxyribonucleic acid
DOC deoxycorticosterone
DR diabetic retinopathy
DRIP/TRAP vitamin D receptor interacting protein/TR-associated
protein
DRS Diabetic Retinopathy Study
DSN diabetes specialist nurse
DSD disorders of sexual differentiation; disorders of sex
development
DTC differentiated thyroid cancer
DVA Driver and Vehicle Agency
DVLA Driver and Vehicle Licensing Agency
DVT deep vein thrombosis
DXA dual-energy absorptiometry
EBRT external beam radiation therapy
ECF extracellular fluid
ECG electrocardiogram
EEG electroencephalogram
eFPGL extra-adrenal functional paraganglioma
e.g. exempli gratia (for example)
eGFR estimated glomerular filtration rate
EM electron microscopy
EMA European Medicines Agency
ENaC epithelial sodium channel
ENETS European Neuroendocrine Tumour Society
ENSAT European Network for the Study of Adrenal Tumours
ENT ear, nose, and throat
EOSS Edmonton Obesity Staging System
ER (o)estrogen receptor
ERT (o)estrogen replacement therapy
ESR erythrocyte sedimentation rate
ESRD end-stage renal disease
ESRF end-stage renal failure
SYMBOLS AND ABBREVIATIONS xvii
ETDRS Early Treatment of Diabetic Retinopathy Study

EUA examination under anaesthesia
FAI free androgen index
FAZ foveal avascular zone
FBC full blood count
FCHL familial combined hyperlipidaemia
FDA Food and Drug Administration
FDG fluorodeoxyglucose
FeSO4 ferrous sulfate
FGD familial glucocorticoid deficiency
FGFR1 fibroblast growth factor receptor 1
FH familial hypercholesterolaemia
FHH familial hypocalciuric hypercalcaemia
FIHP familial isolated hyperparathyroidism
FMTC familial medullary thyroid carcinoma
FNA fine needle aspiration
FNAC fine needle aspiration cytology
FRIII fixed-rate intravenous insulin infusion
FSH follicle-stimulating hormone
FT3 free tri-iodothyronine
FT4 free thyroxine
FTC follicular thyroid carcinoma
5FU 5-fluorouracil
g gram
GAD glutamic acid decarboxylase
GAG glycosaminoglycan
GBM glomerular basement membrane
GBq giga becquerel
GC glucocorticoid
GCK glucokinase
GCS Glasgow coma score
GDM gestational diabetes mellitus
GDP guanosine diphosphate
GEP gastroenteropancreatic
GFR glomerular filtration rate
GGT gamma glutamyl transferase
GH growth hormone
GHD growth hormone deficiency
GHDC growth hormone day curve
GHRH growth hormone-releasing hormone
xviii SYMBOLS AND ABBREVIATIONS
GI gastrointestinal; glycaemic index

GIFT gamete intrafallopian transfer
GIP gastric intestinal polypeptide
GK glycerol kinase
GLP-1 glucagon-like peptide-1
GnRH gonadotrophin-releasing hormone
GO Graves’s orbitopathy
GO-QOL Graves’s Ophthalmopathy Quality of Life
GP general practitioner
GRA glucocorticoid-remediable aldosteronism
GRTH generalized resistance to thyroid hormone
GTF glucose tolerance factor
GTN glyceryl trinitrate
GTP guanyl triphosphate
GTT glucose tolerance test
GWAS genome-wide association studies
Gy Gray
h hour
HA hypothalamic amenorrhoea
HAART highly active antiretroviral therapy
Hb haemoglobin
HbA1c glycosylated haemoglobin
hCG human chorionic gonadotrophin
HCO3– bicarbonate ion
HDL-C high-density lipoprotein cholesterol
HDU high dependency unit
HFEA Human Fertilisation and Embryology Act
hGH human growth hormone
HH hypogonadotrophic hypogonadism
HHS hyperglycaemic hyperosmolar state
HIV human immunodeficiency virus
HLA human leukocyte antigen
hMG human menopausal gonadotrophin
HMG CoA 3-hydroxy-3-methylglutaryl coenzyme A
HNF hepatocyte nuclear factor
HNPGL head and neck paraganglioma
HP hypothalamus/pituitary
HPT hypothalamo–pituitary–thyroid
HPT-JT hyperparathyroidism-jaw tumour (syndrome)
HPV human papillomavirus
SYMBOLS AND ABBREVIATIONS xix
HRT hormone replacement therapy

HSD 11B-hydroxysteroid dehydrogenase
HSG hysterosalpingography
5-HT2B 5-hydroxytryptamine 2B
HTLV-1 human T lymphotropic virus type 1
HU Hounsfield unit
HyCoSy hysterosalpingo-contrast-sonography
Hz hertz
IADPSG International Association of the Diabetes and Pregnancy
Study Groups
ICA islet cell antibodies
ICF intracellular fluid
ICSI intracytoplasmic sperm injection
IDDM insulin-dependent diabetes mellitus
IDL intermediate density lipoprotein
i.e. id est (that is)
IFG impaired fasting glycaemia
Ig immunoglobulin
IGF insulin growth factor
IGT impaired glucose tolerance
IHD ischaemic heart disease
IHH idiopathic hypogonadotropic hypogonadism
IM intramuscular
IPSS inferior petrosal sinus sampling
IQ intelligence quotient
IRMA intraretinal microvascular abnormalities
ITT insulin tolerance test
ITU intensive treatment unit
IU international unit
IUD intrauterine contraceptive device
IUGR intrauterine growth restriction
IUI intrauterine insemination
IV intravenous
IVC inferior vena cava
IVF in vitro fertilization
IVII intravenous insulin infusion
K+ potassium ion
kcal kilocalorie
KCl potassium chloride
kDa kilodalton
xx SYMBOLS AND ABBREVIATIONS
kg kilogram
KPD ketosis-prone diabetes
L litre
LADA latent autoimmune diabetes of adulthood
LCAT lecithin:cholesterol acyltransferase
LDL low-density lipoprotein
LDL-C LDL cholesterol
LFT liver function test
LH luteinizing hormone
LOH loss of heterozygosity
Lpa lipoprotein a
LPL lipoprotein lipase
LVH left ventricular hypertrophy
m metre
MAI Mycobacterium avium intracellulare
MAOI monoamine oxidase inhibitor
MAPK mitogen-activated protein kinase
MBq mega becquerel
MC mineralocorticoid
MCR1 melanocortin 1 receptor
MDI multiple dose injection
MDT multidisciplinary team
MEN multiple endocrine neoplasia
mg milligram
Mg magnesium
MGMT O-6-methylguanine DNA methyltransferase
mGy milligray
MHC major histocompatibility complex
MI myocardial infarction
MIBG metaiodobenzylguanidine
min minute
MIS Müllerian inhibitory substance
MIT monoiodotyrosine
mIU milli international unit
MJ megajoule
mm millimetre
mmHg millimetre of mercury
MMI methimazole
mmol millimole
MODY maturity onset diabetes of the young
SYMBOLS AND ABBREVIATIONS xxi
mOsm milliosmole
MPH mid-parental height
MRI magnetic resonance imaging
mRNA messenger ribonucleic acid
MRSA meticillin-resistant Staphylococcus aureus
MSH melanocyte-stimulating hormone
MSU midstream urine
mSv microsievert
MTC medullary thyroid carcinoma
mTOR mammalian target of rapamycin
mU milliunit
Na sodium
NaCl sodium chloride
NAFLD non-alcoholic fatty liver disease
NASH non-alcoholic steatohepatitis
NaU urinary sodium
NB nota bene (take note)
NDST National Diabetes Support Team
NEC neuroendocrine carcinoma
NEN neuroendocrine neoplasia
NET neuroendocrine tumour
NF neurofibromatosis
NFA non-functioning pituitary adenoma
ng nanogram
NG nasogastric
NHS National Health Service
NICE National Institute for Health and Care Excellence
NIDDM non-insulin-dependent diabetes mellitus
NIS sodium/iodide symporter
nmol nanomole
NOGG National Osteoporosis Guideline Group
NR normal range
NSAID non-steroidal anti-inflammatory drug
NSC National Screening Committee
NSF National Service Framework
NVD new vessels on disc
NVE new vessels elsewhere
O2 oxygen
OA osteoarthritis
OCP oral contraceptive pill
xxii SYMBOLS AND ABBREVIATIONS
od omne in die (once daily)

OD overdose
OGTT oral glucose tolerance test
OHA oral hypoglycaemic agent
OHSS ovarian hyperstimulation syndrome
OR odds ratio
PAI plasminogen activator inhibitor
PAK pancreas after kidney
PAL physical activity level
PAR-Q physical activity readiness questionnaire
PBC primary biliary cirrhosis
PCOS polycystic ovary syndrome
PDE phosphodiesterase
PDR proliferative diabetic retinopathy
PE pulmonary embolism
PEG polyethylene glycol
PET positron emission tomography
pg picogram
PHP primary hyperparathyroidism
PI protease inhibitor
PID pelvic inflammatory disease
PIH pregnancy-induced hypertension
PKA protein kinase A
p.m. post meridiem (after noon)
PMC papillary microcarcinoma
pmol picomole
PNDM permanent neonatal diabetes mellitus
PNMT phenylethanolamine-N-methyltransferase
PO per os (orally)
PO4 phosphate
POF premature ovarian failure
POI premature ovarian insufficiency
POMC pro-opiomelanocortin
POP progesterone-only pill
PPI proton pump inhibitor
PPNAD primary pigmented nodular adrenal disease
PRA plasma renin activity
PRH postprandial reactive hypoglycaemia
PRL prolactin
PRRT peptide receptor radioligand therapy
SYMBOLS AND ABBREVIATIONS xxiii
PRTH pituitary resistance to thyroid hormone

PSA prostate-specific antigen
PTA pancreas transplant alone
PTH parathyroid hormone
PTHrP parathyroid hormone-related peptide
PTTG pituitary tumour transforming gene
PTU propylthiouracil
PUD peptic ulcer disease
PVD peripheral vascular disease
QCT quantitative computed tomography
qds quarter die sumendus (four times daily)
QoL quality of life
RAA renin–angiotensin–aldosterone
RAI radioactive iodine
RCAD renal cysts and diabetes (syndrome)
rhGH recombinant human growth hormone
rhTSH recombinant human thyroid-stimulating hormone
RNA ribonucleic acid
RR relative risk
RRT renal replacement therapy
rT3 reverse T3
RTH resistance to thyroid hormone
s second
SC subcutaneous
SD standard deviation
SDH succinate dehydrogenase
SERM selective (o)estrogen receptor modulator
SGA small for gestational age
SH severe hypoglycaemia
SHBG sex hormone-binding globulin
SIADH syndrome of inappropriate ADH
SLE systemic lupus erythematosus
SNP single nucleotide polymorphism
SNRI serotonin noradrenaline reuptake inhibitor
SPK simultaneous pancreas kidney
SSA somatostatin analogue
SSRI selective serotonin reuptake inhibitor
SST short Synacthen® test
SSTR somatostatin receptor
STED sight-threatening diabetic eye disease
xxiv SYMBOLS AND ABBREVIATIONS
SU sulphonylurea
T3 tri-iodothyronine
T4 thyroxine
TART testicular adrenal rest tissue
TB tuberculosis
TBG thyroid-binding globulin
TBI traumatic brain injury
TBPA T4-binding prealbumin
TC total cholesterol
TCA tricyclic antidepressant
TDD total daily dose
T1DM type 1 diabetes mellitus
T2DM type 2 diabetes mellitus
tds ter die sumendus (three times daily)
TENS transcutaneous electrical nerve stimulation
TFT thyroid function test
Tg thyroglobulin
TG triglyceride
TGF transforming growth factor
TgAb thyroglobulin antibody
TK tyrosine kinase
TKI tyrosine kinase inhibitor
TNDM transient neonatal diabetes mellitus
TNF tumour necrosis factor
TPO thyroid peroxidase
TR thyroid hormone receptor
TRE thyroid hormone response element
TRH thyrotropin-releasing hormone
TSA transsphenoidal approach
TSAb TSH-stimulating antibody
TSG tumour suppressor gene
TSH thyroid-stimulating hormone
TSH-RAB thyroid-stimulating hormone receptor antibodies
TTR transthyretin
U unit
U&E urea and electrolytes
UFC urinary free cortisol
UK United Kingdom
UKPDS United Kingdom Prospective Diabetes Study
SYMBOLS AND ABBREVIATIONS xxv
US ultrasound
USA United States of America
V volts
VA visual acuity
VEGF vascular endothelial growth factor
VEGFR vascular endothelial growth factor receptor
VHL von Hippel–Lindau
VIP vasoactive intestinal polypeptide
VLCFA very long chain fatty acid
VLDL very low density lipoprotein
VMA vanillylmandelic acid
VRIII variable-rate intravenous insulin infusion
vs versus
VTE venous thromboembolism
WBS whole body scan
WDHA watery diarrhoea, hypokalaemia, acidosis
WHI Women’s Health Initiative
WHO World Health Organization
w/v weight by volume
ZE Zollinger–Ellison (syndrome)
Chapter 1 1
Thyroid
Anatomy 2
Physiology 4
Molecular action of thyroid hormone 6
Tests of hormone concentration 8
Tests of homeostatic control 10
Rare genetic disorders of thyroid hormone metabolism 14
Antibody screen 15
Scintiscanning 16
Ultrasound (US) scanning 18
Fine needle aspiration cytology (FNAC) 20
Computed tomography (CT) 22
Positron emission tomography (PET) 23
Additional laboratory investigations 24
Non-thyroidal illness 24
Atypical clinical situations 25
Thyrotoxicosis—aetiology 26
Manifestations of hyperthyroidism 28
Medical treatment 30
Radioiodine treatment 34
Surgery 38
Thyroid crisis (storm) 40
Subclinical hyperthyroidism 42
Thyrotoxicosis in pregnancy 44
Hyperthyroidism in children 48
Secondary hyperthyroidism 50
Graves’s ophthalmopathy 54
Medical treatment of Graves’s ophthalmopathy 58
Surgical treatment of Graves’s ophthalmopathy 60
Graves’s dermopathy 62
Thyroid acropachy 63
Multinodular goitre and solitary adenomas 64
Thyroiditis 68
Chronic autoimmune (atrophic or Hashimoto’s) thyroiditis 70
Other types of thyroiditis 72
Hypothyroidism 74
Subclinical hypothyroidism 78
Treatment of hypothyroidism 80
Congenital hypothyroidism 84
Amiodarone and thyroid function 86
Epidemiology of thyroid cancer 91
Aetiology of thyroid cancer 92
Papillary thyroid carcinoma 96
Follicular thyroid carcinoma (FTC) 99
Follow-up of papillary and FTC 100
Medullary thyroid carcinoma (MTC) 103
Anaplastic (undifferentiated) thyroid cancer 104
Lymphoma 105
2 CHAPTER 1 Thyroid
Anatomy
The thyroid gland comprises:
• A midline isthmus lying horizontally just below the cricoid cartilage.
• Two lateral lobes that extend upward over the lower half of the
thyroid cartilage.
The gland lies deep to the strap muscles of the neck, enclosed in the pre-
tracheal fascia, which anchors it to the trachea, so that the thyroid moves
up on swallowing.
Histology
• Fibrous septa divide the gland into pseudolobules.
• Pseudolobules are composed of vesicles called follicles or acini,
surrounded by a capillary network.
• The follicle walls are lined by cuboidal epithelium.
• The lumen is filled with a proteinaceous colloid, which contains the
unique protein thyroglobulin. The peptide sequences of T4 and T3 are
synthesized and stored as a component of thyroglobulin.
Development
• Develops from the endoderm of the floor of the pharynx with some
contribution from the lateral pharyngeal pouches.
• Descent of the midline thyroid precursor gives rise to the thyroglossal
duct, which extends from the foramen caecum near the base of the
tongue to the isthmus of the thyroid.
• During development, the posterior aspect of the thyroid becomes
associated with the parathyroid glands and the parafollicular C cells,
derived from the ultimo-branchial body (fourth pharyngeal pouch),
which become incorporated into its substance.
• The C cells are the source of calcitonin and give rise to medullary
thyroid carcinoma when they undergo malignant transformation.
• The fetal thyroid begins to concentrate and organify iodine at about
10–12 weeks’ gestation.
• Maternal TRH readily crosses the placenta; maternal TSH and T4
do not.
• T4 from the fetal thyroid is the major thyroid hormone available to the
fetus. The fetal pituitary-thyroid axis is a functional unit, distinct from
that of the mother—active at 18–20 weeks.
Thyroid examination
Inspection
• Look at the neck from the front. If a goitre (enlarged thyroid gland of
whatever cause) is present, the patient should be asked to swallow a
mouthful of water. The thyroid moves up with swallowing.
• Assess for scars, asymmetry, or masses.
• Watch for the appearance of any nodule not visible before swallowing;
beware that, in an elderly patient with kyphosis, the thyroid may be
partially retrosternal.
ANATOMY 3
Palpation (usually from behind)

• Is the thyroid gland tender to touch?
• With the index and middle fingers, feel below the thyroid cartilage
where the isthmus of the thyroid gland lies over the trachea.
• Palpate the two lobes of the thyroid, which extend laterally behind the
sternomastoid muscle.
• Ask the patient to swallow again while you continue to palpate the
thyroid.
• Assess size, whether it is soft, firm or hard, whether it is nodular or
diffusely enlarged, and whether it moves readily on swallowing.
• Palpate along the medial edge of the sternomastoid muscle on either
side to look for a pyramidal lobe.
• Palpate for lymph nodes in the neck.
Percussion
Percuss the upper mediastinum for retrosternal goitre.
Auscultation
• Auscultate to identify bruits, consistent with Graves’s disease (treated
or untreated).
• Occasionally, inspiratory stridor can be heard, with a large or
retrosternal goitre causing tracheal compression (b see Pemberton’s
sign, p. 64).
Assess thyroid status
• Observe for signs of thyroid disease—exophthalmos, proptosis,
thyroid acropachy, pretibial myxoedema, hyperactivity, restlessness, or
whether immobile.
• Take pulse; note the presence or absence of tachycardia, bradycardia,
or atrial fibrillation.
• Feel palms—whether warm and sweaty or cold.
• Look for tremor in outstretched hands.
• Examine eyes: exophthalmos (forward protrusion of the eyes—
proptosis); lid retraction (sclera visible above cornea); lid lag;
conjunctival injection or oedema (chemosis); periorbital oedema; loss
of full-range movement.
4 CHAPTER 1 Thyroid
Physiology
• Biosynthesis of thyroid hormones requires iodine as substrate.
Iodine is actively transported via sodium/iodide symporters (NIS)
into follicular thyrocytes where it is organified onto tyrosyl residues
in thyroglobulin first to produce monoiodotyrosine (MIT) and then
diiodotyrosine (DIT). Thyroid peroxidase (TPO) then links two DITs
to form the two-ringed structure T4, and MIT and DIT to form small
amounts of T3 and reverse T3 (rT3).
• The thyroid is the only source of T4.
• The thyroid secretes 20% of circulating T3; the remainder is generated
in extraglandular tissues by the conversion of T4 to T3 by deiodinases
(largely in the liver and kidneys).
Synthesis of the thyroid hormones can be inhibited by a variety of agents
termed goitrogens.
• Perchlorate and thiocyanate inhibit iodide transport.
• Thioureas (e.g. carbimazole and propylthiouracil) and mercaptoimidazole
inhibit the initial oxidation of iodide and coupling of iodothyronines.
• In large doses, iodine itself blocks organic binding and coupling
reactions.
• Lithium has several inhibitory effects on intrathyroidal iodine
metabolism.
In the blood, T4 and T3 are almost entirely bound to plasma proteins. T4 is
bound in d order of affinity to thyroid-binding globulin (TBG), transthyre-
tin (TTR), and albumin. T3 is bound 10–20 times less avidly by TBG and
not significantly by TTR. Only the free or unbound hormone is available to
tissues. The metabolic state correlates more closely with the free than the
total hormone concentration in the plasma. The relatively weak binding of
T3 accounts for its more rapid onset and offset of action. Table 1.1 sum-
marizes those states associated with p alterations in the concentration of
TBG. When there is primarily an alteration in the concentration of thyroid
hormones, the concentration of TBG changes little (Table 1.2).
The concentration of free hormones does not necessarily vary directly
with that of the total hormones, e.g. while the total T4 level rises in preg-
nancy, the free T4 level remains normal (b Endocrinology in pregnancy,
p. 426).
The levels of thyroid hormone in the blood are tightly controlled by
feedback mechanisms involved in the hypothalamo–pituitary–thyroid
(HPT) axis (see Fig. 1.1).
• TSH secreted by the pituitary stimulates the thyroid to secrete principally
T4 and also T3. TRH stimulates the synthesis and secretion of TSH.
• T4 and T3 are bound to TBG, TTR, and albumin. The remaining free
hormones inhibit the synthesis and release of TRH and TSH.
• T4 is converted peripherally to the metabolically active T3 or the
inactive rT3.
• T4 and T3 are metabolized in the liver by conjugation with glucuronate
and sulphate. Enzyme inducers, such as phenobarbital, carbamazepine,
and phenytoin, increase the metabolic clearance of the hormones
without d the proportion of free hormone in the blood.
PHYSIOLOGY 5
Table 1.1 Disordered thyroid hormone–protein interactions

Serum total T4 and T3 Free T4 and T3
Primary abnormality in TBG
i Concentration i Normal
d Concentration d Normal
Primary disorder of thyroid function
Hyperthyroidism i i
Hypothyroidism d d
Table 1.2 Circumstances associated with altered

concentration of TBG
i TBG d TBG
Pregnancy Androgens
Newborn state Large doses of glucocorticoids;
Cushing’s syndrome
OCP and other sources of oestrogens Chronic liver disease
Tamoxifen Severe systemic illness
Hepatitis A; chronic active hepatitis Active acromegaly
Biliary cirrhosis Nephrotic syndrome
Acute intermittent porphyria Genetically determined
Genetically determined Drugs, e.g. phenytoin (see also
Table 1.4, p. 11)
Hypothalamus
TRH
Other tissues
Anterior
pituitary
TSH
I
I T4 and T3 T4 and T3 + TBG TBG˙T4
TBG˙T3
Fig. 1.1 Regulation of thyroid function. Solid arrows indicate stimulation; broken
arrow indicates inhibitory influence. TRH, thyrotropin-releasing hormone; TSH,
thyroid-stimulating hormone; T4, thyroxine; T3, tri-iodothyronine; I, iodine; TBG,
thyroid-binding globulin.
6 CHAPTER 1 Thyroid
Molecular action of thyroid

hormone
• T3 is the active form of thyroid hormone and binds to thyroid
hormone receptors (TRs) in target cell nuclei to initiate a range
of physiological effects, including cellular differentiation, post-natal
development, and metabolic homeostasis. The actions of thyroid
hormone are mediated by two genes (TRα, TRB), which encode
three nuclear receptor subtypes with differing tissue expression
(TRα1: central nervous system, cardiac and skeletal muscle;
TRB1: liver and kidney; TRB2: pituitary and hypothalamus).
• Both T4 and T3 enter the cell via active transport mediated
by monocarboxylate transporter-8 and other proteins. Three
iodothyronine deiodinases (D1–3) regulate T3 availability to target
cells. The D1 enzyme in kidney and liver is generally considered
to be responsible for the production of the majority of circulating
T3. Although serum T3 concentrations are maintained constant by
the negative feedback actions of the HPT axis, intracellular thyroid
status may vary as a result of differential action of deiodinases. In
the hypothalamus and pituitary, 5’-deiodination of T4 by D2 results
in the generation of T3, whereas 5’-deiodination by the D3 enzyme
irreversibly inactivates T4 and T3, resulting in the production of
the metabolites rT3 and T2. Thus, the relative activities of D2 and
D3 enzymes in T3 target cells regulate the availability of the active
hormone T3 to the nucleus and ultimately determine the saturation of
the nuclear TR.
• TRs belong to the nuclear hormone receptor superfamily and function
as ligand-inducible transcription factors. They are expressed in virtually
all tissues and involved in many physiological processes in response
to T3 binding. TRα and TRB receptors bind to specific DNA thyroid
hormone response elements (TREs) located in the promoter regions
of T3-responsive target genes and mediate the actions of T3.
• Unliganded TR (unoccupied TR, ApoTR) inhibits basal transcription
of T3 target genes by interacting preferentially with co-repressor
proteins, leading to repression of gene transcription. Upon T3 binding,
the liganded TR undergoes conformational change and reverses the
histone deacetylation associated with basal repression. Subsequent
recruitment of a large transcription factor complex known as
vitamin D receptor interacting protein/TR-associated protein (DRIP/
TRAP) leads to binding and stabilization of RNA polymerase II and
hormone-dependent activation of transcription.
• The roles of TRα and TRB have been shown to be tissue-specific.
For example, TRα mediates important T3 actions during heart,
bone, and intestinal development and controls basal heart rate and
thermoregulation in adults, whilst TRB mediates T3 action in the liver
and is responsible for the regulation of the HPT axis.
MOLECULAR ACTION OF THYROID HORMONE 7
Abnormalities of development
• Remnants of the thyroglossal duct may be found in any position along
the course of the tract of its descent:
• In the tongue, it is referred to as ‘lingual thyroid’.
• Thyroglossal cysts may be visible as midline swellings in the neck.
• Thyroglossal fistula develops as an opening in the middle of
the neck.
• As thyroglossal nodules or
• The ‘pyramidal lobe’, a structure contiguous with the thyroid
isthmus which extends upwards.
• The gland can descend too far down to reach the anterior
mediastinum.
• Congenital hypothyroidism may result from failure of the thyroid
to develop (agenesis). More commonly, however, congenital
hypothyroidism reflects enzyme defects impairing hormone synthesis.
Further reading
Williams GR, Bassett JH (2011). Deiodinases: the balance of thyroid hormone: local control of
thyroid hormone action: role of type 2 deiodinase. J Endocrinol 209, 261–72.
8 CHAPTER 1 Thyroid
Tests of hormone concentration

• Highly specific and sensitive chemiluminescent and radioimmunoassays
are used to measure serum T4 and T3 concentrations. Free hormone
concentrations usually correlate better with the metabolic state than
do total hormone concentrations because they are unaffected by
changes in binding protein concentration or affinity.
• See UK guidelines for the use of thyroid function tests. Association
for Clinical Biochemistry, British Thyroid Association, British
Thyroid Foundation (M http://www.british-thyroid-association.org/
info-for-patients/Docs/TFT_guideline_final_version_July_2006.pdf).
TESTS OF HORMONE CONCENTRATION 9
10 CHAPTER 1 Thyroid
Tests of homeostatic control

(See Table 1.3.)
• Serum TSH concentration is used as first line in the diagnosis of p
hypothyroidism and hyperthyroidism. The test is misleading in patients
with s thyroid dysfunction due to hypothalamic/pituitary disease
(b p. 127).
• The TRH stimulation test, which can be used to assess the functional
state of the TSH secretory mechanism, is now rarely used to diagnose
p thyroid disease since it has been superseded by sensitive TSH
assays. It is of limited use; its main use is in the differential diagnosis
of elevated TSH in the setting of elevated thyroid hormone levels and
in the differential diagnosis of resistance to thyroid hormone and a
TSH-secreting pituitary adenoma (see Box 1.1).
In interpreting results of TFTs, the effects of drugs that the patient might
be on should be borne in mind. Table 1.4 lists the influence of drugs on
TFTs. Table 1.5 sets out some examples of atypical thyroid function tests.
Box 1.1 Thyroid hormone resistance (RTH) (b see also

p. 50)
• Rare syndrome characterized by reduced responsiveness to elevated
circulating levels of free T4 and free T3, non-suppressed serum TSH,
and intact TSH responsiveness to TRH.
• Clinical features, apart from goitre, are usually absent but may
include short stature, hyperactivity, attention deficits, learning
disability, and goitre.
• Associated with THB gene defects, and identification by gene
sequencing can confirm diagnosis in 85%.
• Differential diagnosis includes TSH-secreting pituitary tumour
(b p. 180).
• Most cases require no treatment. If needed, it is usually B-adrenergic
blockers to ameliorate some of the tissue effects of raised thyroid
hormone levels.
TESTS OF HOMEOSTATIC CONTROL 11
Table 1.3 Thyroid hormone concentrations in various thyroid

abnormalities
Condition TSH Free T4 Free T3
p hyperthyroidism Undetectable ii i
T3 toxicosis Undetectable Normal ii
Subclinical hyperthyroidism d Normal Normal
s hyperthyroidism (TSHoma) i or normal i i
Thyroid hormone resistance i or normal i i
p hypothyroidism i d d or
normal
Subclinical hypothyroidism i Normal Normal
2° hypothyroidism d or normal d d or
normal
Table 1.4 Influence of drugs on thyroid function tests

Metabolic i d
process
TSH secretion Amiodarone (transiently; Glucocorticoids,
becomes normal after dopamine agonists,
2–3 months) phenytoin, dopamine,
Sertraline octreotide, paroxetine
St John’s wort (Hypericum)
T4 synthesis/ Iodide, amiodarone, interferon α, Iodide, amiodarone,
release lithium interferon alfa, lithium,
sunitinib
Binding proteins Oestrogen, clofibrate, heroin Glucocorticoids,
androgens, phenytoin,
carbamazepine
T4 metabolism Anticonvulsants, rifampicin
T4/T3 binding in Heparin Salicylates, furosemide,
serum mefenamic acid
Table 1.5 Atypical thyroid function tests1

Test Possible cause
Suppressed TSH and normal T3 toxicosis (approximately 5% of
free T4 thyrotoxicosis)
Suppressed TSH and normal Subclinical hyperthyroidism
free T4 and free T3 Recovery from thyrotoxicosis
Excess thyroxine replacement
Non-thyroidal illness
Detectable TSH and elevated TSH-secreting pituitary tumour
free T4 and free T3 Thyroid hormone resistance
Heterophile antibodies, leading to spurious
measurements of free T4 and free T3
Thyroxine replacement therapy (including
poor compliance)
Elevated free T4 and low Amiodarone
normal free T3, normal TSH
Suppressed or normal TSH Non-thyroidal illness
and low normal free T4 and Central hypothyroidism
free T3 Isolated TSH deficiency
Reference
1. Gurnell M, Halsall DJ, Chatterjee VK (2011). What should be done when thyroid function tests
do not make sense? Clin Endocrinol (Oxf) 74, 673–8.
TESTS OF HOMEOSTATIC CONTROL 13
Rare genetic disorders of thyroid

hormone metabolism1
• An X-linked disorder of childhood onset with psychomotor
retardation, including speech and developmental delay and spastic
quadriplegia, caused by defects in the MCT8 gene encoding a
membrane transporter. Male patients have elevated FT3, low FT4, and
normal TSH levels.
• The deiodinase enzymes are part of a larger family of 25 human
proteins containing selenocysteine. A multisystem selenoprotein
deficiency disorder has been identified, manifested by growth
retardation in childhood and male infertility, skeletal myopathy,
photosensitivity, and hearing loss in adults. Thyroid function tests show
raised FT4, normal/low FT3, and normal TSH levels due to functional
D2 deficiency.
1
Reviewed by Refetoff and Dumitrescu (2007) Syndromes of reduced sensitivity to thyroid hor-
mone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin
Endocrinol Metab 21, 277–305.
ANTIBODY SCREEN 15
Antibody screen
High titres of antithyroid peroxidase (anti-TPO) antibodies and/or antithy-
roglobulin antibodies are found in patients with autoimmune thyroid dis-
ease (Hashimoto’s thyroiditis, Graves’s disease, and sometimes euthyroid
individuals). See Table 1.6.
Screening for thyroid disease1
The following categories of patients should be screened for thyroid
disease:
• Patients with atrial fibrillation or hyperlipidaemia.
• Periodic (6-monthly) assessments in patients receiving amiodarone and
lithium.
• Annual check of thyroid function in the annual review of diabetic
patients.
• ♀ with type 1 diabetes in the first trimester of pregnancy and
post-delivery (because of the 3-fold increase in incidence of
post-partum thyroid dysfunction in such patients) (b p. 432).
• ♀ with past history of post-partum thyroiditis.
• Annual check of thyroid function in people with Down’s syndrome,
Turner’s syndrome, and autoimmune Addison’s disease, in view of the
high prevalence of hypothyroidism in such patients.
• ♀ with thyroid autoantibodies—8x risk of developing hypothyroidism
over 20 years compared to antibody –ve controls.
• ♀ with thyroid autoantibodies and isolated elevated TSH—38x
risk of developing hypothyroidism, with 4% annual risk of overt
hypothyroidism.
• Maternal thyroid antibodies are associated with miscarriage and
preterm birth2.
Table 1.6 Antithyroid antibodies and thyroid disease

Condition Anti-TPO Antithyroglobulin TSH receptor
antibody
Graves’s disease 70–80% 30–50% 70–100% (stimulating)
Autoimmune 95% 60% 10–20% (blocking)
hypothyroidism
NB TSH receptor antibodies may be stimulatory or inhibitory. Heterophile antibodies present
in patient sera may cause abnormal interference, causing abnormally low or high values of free
T4 and free T3, and can be removed with absorption tubes.
Reference
1. Tunbridge WM, Vanderpump MP (2000). Population screening for autoimmune thyroid disease.
Endocrinol Metab Clin N Am 29, 239–53.
2. Thangaratinam S, et al. (2011). Association between thyroid autoantibodies and miscarriage and
preterm birth: meta-analysis of evidence. BMJ 342, 1065.
Scintiscanning
Permits localization of sites of accumulation of radioiodine or sodium
pertechnetate (99mTc), which gives information about the activity of the
iodine trap (see Table 1.7). This is useful:
• To define areas of i or d function within the thyroid (see Table 1.8)
which occasionally helps in cases of uncertainty as to the cause of the
thyrotoxicosis.
• To distinguish between Graves’s disease and a thyroiditis (autoimmune
or viral—de Quervain’s thyroiditis).
• To detect retrosternal goitre.
• To detect ectopic thyroid tissue.
The scan may be altered by:
• Agents which influence thyroid uptake, including intake of high-iodine
foods and supplements, such as kelp (seaweed).
• Drugs containing iodine, such as amiodarone.
• Recent use of radiographic contrast dyes can potentially interfere with
the interpretation of the scan.
Table 1.7 Radioisotope scans

Iodine
123
Technetium pertechnetate
99
Half-life Short Short

Advantage Low emission of radiation Maximum thyroid uptake
Has higher energy within 30min of administration.
photons. Hence useful for Can be used in breastfeeding
imaging a toxic goitre with women (discontinue feeding
a substernal component for 24h)
Disadvantage Technetium is only trapped
by the thyroid without being
organified
Use Functional assessment of Rapid scanning
the thyroid
SCINTISCANNING 17
Table 1.8 Radionuclide scanning (scintigram) in thyroid disease

Condition Scan appearance
Graves’s hyperthyroidism Enlarged gland
Homogeneous radionucleotide uptake
Thyroiditis (e.g. de Quervain’s) Low or absent uptake
Toxic nodule A solitary area of high uptake
Thyrotoxicosis factitia Depressed thyroid uptake
Thyroid cancer Successful 131I uptake by tumour tissue
requires an adequate level of TSH,
achieved by giving recombinant TSH
injection or stopping T3 replacement
10 days before scanning
Ultrasound (US) scanning

Provides an accurate indication of thyroid size and is useful for differen-
tiating cystic nodules from solid ones but cannot be used to distinguish
between benign and malignant disease. There are several ultrasonographic
findings that are suspicious for thyroid cancer (hypoechoic, microcalcifica-
tions, irregular margins, central vascularity, incomplete halo). The predic-
tive value of these characteristics varies widely, and they can be used to
select nodules for fine needle aspiration (FNA) biopsy.
• Microcalcification within nodules favours the diagnosis of malignancy;
microcalcifications <2mm in diameter are observed in 760% of
malignant nodules but in <2% of benign lesions.
• Calcification is a prominent feature of medullary carcinoma of the
thyroid.
• It can detect whether a nodule is solitary or part of a multinodular
process.
• Sequential scanning can be employed to assess changes in size of
thyroid over time.
NB Neither scintigraphy nor US is routinely indicated in a patient with
goitre.
ULTRASOUND (US) SCANNING 19
Fine needle aspiration

cytology (FNAC)
• FNAC is now considered the most accurate test for the diagnosis
of thyroid nodules. It is performed in an outpatient setting. One to
two aspirations are carried out at different sites for each nodule.
Cytologic findings are satisfactory or diagnostic in approximately 85% of
specimens and non-diagnostic in the remainder.
• In experienced hands, FNAC is an excellent diagnostic technique, as
shown in Table 1.9.
• Non-palpable nodules (discovered incidentally during other imaging
procedures) have the same risk of malignancy as palpable nodules
of similar size. US-guided FNAC can be performed for non-palpable
nodules and for nodules that are technically difficult to aspirate using
palpation methods alone, such as predominantly cystic or posteriorly
located nodules. In patients with large nodules (>4cm), US-guided
FNAC directed at several areas within the nodule may reduce the risk
of a false –ve biopsy.
• Repeat FNAC after 3–6 months further reduces the proportion of
false –ves.
• It is impossible to differentiate between benign and malignant follicular
neoplasm using FNAC. Therefore, surgical excision of a follicular
neoplasm is always indicated (b p. 99).
• See Table 1.10 for diagnostic categories from FNAC.
Table 1.9 Diagnostic features of FNAC

Feature Range (%) Mean value (%)
Accuracy 85–100 95
Specificity 72–100 92
Sensitivity 65–98 83
False –ve 1–11 5
FINE NEEDLE ASPIRATION CYTOLOGY (FNAC) 21
Table 1.10 Diagnostic categories from FNAC

Category Action
Thy 1 Non-diagnostic. Repeat sampling, using US if
Inadequate necessary
Thy 2 Non-neoplastic Two samples, 3–6 months apart,
showing benign appearances are
indicated to exclude neoplasia. If
rapid growth/pressure effects/high
risk, diagnostic lobectomy may be
indicated
Thy 3 (i) Follicular lesions Lobectomy, with completion
thyroidectomy if malignant (up to
20% risk of malignancy)
(ii) Other suspicious Discussion at thyroid cancer MDT
findings
Thy 4 Suspicious of malignancy, Surgical excision for differentiated
e.g. papillary, medullary, tumour (80% risk of malignancy)
or anaplastic carcinoma/
lymphoma
Thy 5 Diagnosis of malignancy Surgical excision for differentiated
thyroid cancer (>95% risk of
malignancy). Radiotherapy/
chemotherapy for anaplastic thyroid
cancer, lymphoma/metastases
Computed tomography (CT)

• CT is useful in the evaluation of retrosternal and retrotracheal
extension of an enlarged thyroid.
• Compression of the trachea and displacement of the major vessels can
be identified with CT of the superior mediastinum.
• It can demonstrate the extent of intrathoracic extension of thyroid
malignancy and infiltration of adjacent structures, such as the carotid
artery, internal jugular vein, trachea, oesophagus, and regional
lymph nodes.
POSITRON EMISSION TOMOGRAPHY (PET) 23
Positron emission tomography (PET)

• Up to 20% of thyroid incidentalomas found on PET scans may be
malignant and thus require US-guided FNAC.
• Recurrent thyroid cancer that is fluorodeoxyglucose (FDG) avid
positive on FDG PET scanning is unlikely to respond to even high-dose
radioiodine therapy.
Additional laboratory investigations

Haematological tests
• Long-standing thyrotoxicosis may be associated with normochromic
anaemia and, occasionally, mild neutropenia and lymphocytosis and,
rarely, thrombocytopenia.
• In hypothyroidism, a macrocytosis is typical, although concurrent
vitamin B12 deficiency should be considered.
• There may also be a microcytic anaemia due to menorrhagia and
impaired iron utilization.
Biochemical tests
• Alkaline phosphatase may be elevated in thyrotoxicosis.
• Mild hypercalcaemia occasionally occurs in thyrotoxicosis and reflects
i bone resorption. Hypercalciuria is more common.
• In a hypothyroid patient, hyponatraemia may be due to reduced renal
tubular water loss or, less commonly, due to coexisting cortisol
deficiency.
• In hypothyroidism, creatinine kinase is often raised and the lipid profile
altered with i LDL cholesterol.
Endocrine tests
• In untreated hypothyroidism, there may be inadequate responses to
provocative testing of the hypothalamo–pituitary–adrenal (HPA) axis.
• In hypothyroidism, serum prolactin may be elevated because i TRH
leads to i prolactin secretion (may be partly responsible for d fertility
in young women with hypothyroidism).
• In thyrotoxicosis, there is an increase in sex hormone-binding globulin
(SHBG) and a complex interaction with sex steroid hormone
metabolism, resulting in changes in the levels of androgens and
oestrogens. The net physiological result is an increase in oestrogenic
activity, with gynaecomastia and a decrease in libido in ♂ presenting
with thyrotoxicosis.
Non-thyroidal illness (sick euthyroid

syndrome)
• Biochemistry:
• Low T4 and T3.
• Inappropriately normal/suppressed TSH.
• Tissue thyroid hormone concentrations are very low.
• Context—starvation.
• Severe illness, e.g. ITU, severe infections, renal failure, cardiac
failure, liver failure, end-stage malignancy.
• Thyroxine replacement is not indicated because there is no evidence
that treatment provides benefit or is safe.
ATYPICAL CLINICAL SITUATIONS 25
Atypical clinical situations

• Thyrotoxicosis factitia (usually unprescribed intake of exogenous thyroid
hormone in non thyroid disease):
• No thyroid enlargement.
• Elevated free T4 and suppressed TSH.
• Depressed thyroid uptake on scintigraphy.
• Low thyroglobulin differentiates from thyroiditis (which shows
depressed uptake on scintigraphy but i thyroglobulin) and all other
causes of elevated thyroid hormones.
• Struma ovarii (ovarian teratoma containing hyperfunctioning thyroid
tissue):
• No thyroid enlargement.
• Depressed thyroid uptake on scintigraphy.
• Body scan after radioiodine confirms diagnosis.
• Trophoblast tumours. hCG has structural homology with TSH and leads
to thyroid gland stimulation and usually mild thyrotoxicosis.
• Hyperemesis gravidarum. Thyroid function tests may be abnormal with
a suppressed TSH (b see p. 44).
• Choriocarcinoma of the testes may be associated with gynaecomastia
and thyrotoxicosis—measure hCG.
Thyrotoxicosis—aetiology
Epidemiology
• 10x more common in ♀ than in ♂ in the UK.
• Prevalence is approximately 2% of the ♀ population.
• Annual incidence is 3 cases per 1,000 ♀.
Definition of thyrotoxicosis and hyperthyroidism
• The term thyrotoxicosis denotes the clinical, physiological, and
biochemical findings that result when the tissues are exposed
to excess thyroid hormone. It can arise in a variety of ways (see
Table 1.11). It is essential to establish a specific diagnosis, as this
determines therapy choices and provides important information for
the patient regarding prognosis.
• The term hyperthyroidism should be used to denote only those
conditions in which hyperfunction of the thyroid leads to
thyrotoxicosis.
Genetics of autoimmune thyroid disease (AITD)
• AITD consists of Graves’s disease, Hashimoto’s thyroiditis,
atrophic autoimmune hypothyroidism, post-partum thyroiditis, and
thyroid-associated ophthalmopathy, that appear to share a common
genetic predisposition.
• There is a ♀ preponderance, and sex steroids appear to play an
important role.
• Twin studies show i concordance for Graves’s disease and
autoimmune hypothyroidism in monozygotic, compared to
dizygotic, twins.
• It is estimated that genetic factors account for approximately 70% of
the susceptibility for Graves’s disease.
• Sib studies indicate that sisters and children of ♀ with Graves’s disease
have a 5–8% risk of developing Graves’s disease or autoimmune
hypothyroidism.
• On the background of a genetic predisposition, environmental factors
are thought to contribute to the development of disease.
• A number of interacting susceptibility genes are thought to play a role
in the development of disease—a complex genetic trait.
• CTLA-4 (cytotoxic T lymphocyte antigen-4) is associated with Graves’s
disease in Caucasian populations. In particular, the CT60 allele has
a prevalence of 60% in the general population but is also the allele
most highly associated with Graves’s disease. These data emphasize
the complex nature of genetic susceptibility and the likely interplay of
environmental factors.
• Association of major histocompatibility complex (MHC) loci with
Graves’s disease has been demonstrated in some populations but
not others. HLA-DR3 is associated with Graves’s disease in whites.
HLA-DQA1*0501 is associated in some populations, especially for
men. However, the overall contribution of MHC genes to Graves’s
disease has been estimated to be only 10–20% of the inherited
susceptibility.
THYROTOXICOSIS—AETIOLOGY 27
Table 1.11 Classification of the aetiology of thyrotoxicosis

Associated with hyperthyroidism
Excessive thyroid stimulation Graves’s disease, Hashitoxicosis
Pituitary thyrotroph adenoma
Pituitary thyroid hormone resistance
syndrome (excess TSH) (b seeep. 50)
Trophoblastic tumours producing hCG
with thyrotrophic activity
Thyroid nodules with autonomous Toxic solitary nodule, toxic multinodular
function goitre
Very rarely, thyroid cancer
Not associated with hyperthyroidism
Thyroid inflammation Silent and post-partum thyroiditis,
subacute (de Quervain’s) thyroiditis
Drug-induced thyroiditis (amiodarone)
Exogenous thyroid hormones Overtreatment with thyroid hormone
Thyrotoxicosis factitia (thyroxine use in
non-thyroidal disease)
Ectopic thyroid tissue Metastatic thyroid carcinoma
Struma ovarii (teratoma containing
functional thyroid tissue)
Manifestations of hyperthyroidism
(See Box 1.2.)
Box 1.2 Manifestations of hyperthyroidism (all forms)

Symptoms
• Hyperactivity, irritability, altered mood, insomnia.
• Heat intolerance, i sweating.
• Palpitations.
• Fatigue, weakness.
• Dyspnoea.
• Weight loss with i appetite (weight gain in 10% of patients).
• Pruritus.
• i stool frequency.
• Thirst and polyuria.
• Oligomenorrhoea or amenorrhoea, loss of libido, erectile
dysfunction (50% of men may have sexual dysfunction).
Signs
• Sinus tachycardia, atrial fibrillation.
• Fine tremor, hyperkinesia, hyperreflexia.
• Warm, moist skin.
• Palmar erythema, onycholysis.
• Hair loss.
• Muscle weakness and wasting.
• Congestive (high output) heart failure, chorea, periodic paralysis
(primarily in Asian ♂), psychosis (rare).
Investigation of thyrotoxicosis
(See Table 1.12.)
• Thyroid function tests—raised free T4 and suppressed TSH (raised free
T3 in T3 toxicosis).
• TSH receptor antibodies—see b Table 1.6, p. 15. Also useful in the
assessment of cessation of carbimazole and in pregnant women to
assess the risk of fetal thyrotoxicosis.
• Radionucleotide thyroid scan if diagnosis uncertain (b see p. 17 but is
seldom required.
Manifestations of Graves’s disease
(in addition to those in Box 1.2)
• Diffuse goitre.
• Ophthalmopathy (b see Graves’s ophthalmopathy, p. 54).
• A feeling of grittiness and discomfort in the eye.
• Retrobulbar pressure or pain, eyelid lag or retraction.
• Periorbital oedema, chemosis,* scleral injection.*
• Exophthalmos (proptosis).*
• Extraocular muscle dysfunction.*
• Exposure keratitis.*
• Optic neuropathy.*
*
Combination of these suggests congestive ophthalmopathy. Urgent action necessary if: corneal
ulceration, congestive ophthalmopathy, or optic neuropathy (b see Graves’s ophthalmopathy, p. 54).
MANIFESTATIONS OF HYPERTHYROIDISM 29
Table 1.12 Tests which help to differentiate different causes of

thyrotoxicosis
Cause Thyroid Thyroid Thyroid- Thyroglobulin
iodine parietal stimulating
uptake antibodies immunoglobulin
Graves’s i Usually + i
disease positive
Toxic nodular i – – i
goitre
TSH-secreting i – – i
pituitary
adenoma
Hyperemesis i – – i
gravidarum
Trophoblastic i – – i
tumour
de Quervain’s d – – i
thyroiditis
Drugs, e.g. d Usually – i
amiodarone negative
Struma ovarii d – – i
Thyrotoxicosis d – – d
factitia
• Localized dermopathy (pretibial myxoedema, b see Graves’s

dermopathy, p. 62).
• Lymphoid hyperplasia.
• Thyroid acropachy (b see Thyroid acropachy, p. 63).
Conditions associated with Graves’s disease1
• Type 1 diabetes mellitus.
• Addison’s disease.
• Vitiligo.
• Pernicious anaemia.
• Alopecia areata.
• Myasthenia gravis.
• Coeliac disease (4.5%).
• Other autoimmune disorders associated with the HLA-DR3 haplotype.
Reference
1. Boelaert K, Newby PR, Simmonds MJ, et al. (2010). Prevalence and relative risk of other autoim-
mune diseases in subjects with autoimmune thyroid disease. Am J Med 123, 183.e1–9.
Medical treatment
In general, the standard policy in Europe is to offer a course of antithyroid
drugs (ATD) first. In the USA, radioiodine is more likely to be offered as
first-line treatment.
Aims and principles of medical treatment
• To induce remission in Graves’s disease.
• Monitor for relapse off treatment, initially 6–8-weekly for 6 months,
then 6-monthly for 2 years, and then annually thereafter or sooner if
symptoms return.
• Use of a computerized thyroid follow-up register greatly facilitates
monitoring and reduces the necessity for outpatient appointments.
• For relapse, consider definitive treatment, such as radioiodine or
surgery. A second course of ATD almost never results in remission.
Choice of drugs—thionamides
• Carbimazole, which can be given as a once-daily dose, is usually the drug
of first choice in the UK. Carbimazole is converted to methimazole by
cleavage of a carboxyl side chain on first liver passage. It has a lower
rate of side effects when compared with PTU (14 vs 52%).
• Propylthiouracil (PTU) should never be used as a first-line agent in
either children or adults, with the possible exceptions of pregnant
women and patients with life-threatening thyrotoxicosis. PTU
use should be restricted to circumstances when neither surgery
nor radioactive iodine is a treatment option in a patient who has
developed a toxic reaction to carbimazole and antithyroid drug
therapy is needed.
• During the first trimester of pregnancy, propylthiouracil is the preferred
drug of choice because of the possible association of carbimazole with
aplasia cutis.
Action of thionamides
• Thyroid hormone synthesis is inhibited by blockade of the action of
thyroid peroxidase.
• Thionamides are especially actively accumulated in thyrotoxic tissue.
• Propylthiouracil also inhibits the deiodinase type 1 activity and
thus may have advantages when given at high doses in severe
thyrotoxicosis.
Dose and effectiveness
• 5mg of carbimazole is roughly equivalent to 50mg of propylthiouracil.
Propylthiouracil has a theoretical advantage of inhibiting the
conversion of T4 to T3, and T3 levels decline more rapidly after starting
the drug.
• 30–40% of patients treated with an ATD remain euthyroid 10 years
after discontinuation of therapy. If hyperthyroidism recurs after
treatment with an ATD, there is little chance that a second course
of treatment will result in permanent remission. Young patients,
smokers, those with large goitres, ophthalmopathy, or high serum
MEDICAL TREATMENT 31
concentrations of thyrotropin receptor antibody at the time of

diagnosis are unlikely to have a permanent remission.
• β-adrenergic antagonists. Propranolol 20–80mg 3× daily. Considerable
relief from symptoms, such as anxiety, tremor, and palpitations, may
be gained in the initial 4–8 weeks of treatment, before euthyroidism is
achieved.
Atrial fibrillation
Should, if present, convert to sinus rhythm if no structural cardiac abnor-
mality on echocardiography—otherwise, cardiovert after 4 months euthy-
roid. Consider use of aspirin or warfarin according to usual guidelines.
Side effects
• ATDs are generally well tolerated. Uncommonly, patients may complain
of GI symptoms or an alteration in their sense of taste and smell.
• Agranulocytosis represents a potentially fatal, but rare, side effect
of ATD, occurring in 0.1–0.5% of patients. It is less frequent with
carbimazole than with propylthiouracil, and, because cross-reactivity of
this reaction has been reported, one drug should never be substituted
for the other after this reaction has been diagnosed. Agranulocytosis
usually occurs within the first 3 months after initiation of therapy
(97% within the first 6 months, especially on higher doses), but it is
important to be aware of the documented cases, which have occurred
(less frequently) a long time after starting treatment.
• As agranulocytosis occurs very suddenly and is potentially fatal,
routine monitoring of FBC is thought to be of little use. Patients
typically present with fever and evidence of infection, usually in the
oropharynx, and each patient should therefore receive written instructions
to discontinue the medication and contact their doctor for a blood count
should this situation arise.
• Neutrophil dyscrasias occur more frequently in ♂ and are more often
fatal in the elderly.
• Much more common are the allergic type reactions of rash, urticaria,
and arthralgia, which occur in 1–5% of patients taking these drugs.
These side effects are often mild and do not usually necessitate drug
withdrawal, although one ATD may be substituted for another in the
expectation that the second agent may be taken without side effects.
• Thionamides may cause cholestatic jaundice, and elevated serum
aminotransaminases have been reported as has fulminant hepatic failure.
• The frequency of PTU-related severe liver damage is approximately
0.1% in adults, of whom 10% will develop liver failure resulting in liver
transplantation or death (1:10,000 incidence). Data for children suggest
that the risk of drug-induced liver failure may be greater for children
than for adults (1:1,000 incidence).
• All patients should be given written and verbal warnings about the
potential side effects of thionamides.
• Rarely, anti-neutrophil cytoplasmic antibody (ANCA) –ve vasculitis
develops with propylthiouracil therapy. It may cause arthralgia, skin
lesions, glomerulonephritis, fever, and alveolar haemorrhage. Skin
lesions include ulcers. Biopsy reveals vasculitis. Propylthiouracil should
be stopped, and steroids may be needed.
Treatment regimen
Two alternative regimens are practised for Graves’s disease: dose titration
and block and replace.
Dose titration regime
• The p aim is to achieve a euthyroid state with relatively high drug
doses and then to maintain euthyroidism with a low stable dose. The
dose of carbimazole or propylthiouracil is titrated according to the
thyroid function tests performed every 4–8 weeks, aiming for a serum
free T4 in the normal range and a detectable TSH. High serum TSH
indicates the need for a dose reduction. TSH may remain suppressed
for some weeks after normalization of thyroid hormone levels.
• The typical starting dose of carbimazole is 20–30mg/day. Higher doses
(40–60mg) may be indicated in severe cases, with very high levels
of FT4.
• This regimen has a lower rate of side effects than the block and
replace regimen.
The treatment is continued for 18 months, as this appears to represent
the length of therapy which is generally optimal in producing the remission
rate of up to 40% at 5 years after discontinuing therapy.
• Relapses are most likely to occur within the first year and may be
more likely in the presence of a large goitre, ophthalmic Graves’s
disease, current smokers, and high T4 level at the time of diagnosis,
or the presence of TSH receptor antibodies at the end of treatment.
Men have a higher recurrence rate than women.
• Patients with multinodular goitres and thyrotoxicosis always relapse
on cessation of antithyroid medication, and definitive treatment
with radioiodine or surgery is usually advised. Long-term thionamide
therapy at low dose is also an option, particularly for the elderly.
Block and replace regimen
• After achieving a euthyroid state on carbimazole alone, carbimazole
at a dose of 40mg daily, together with T4 at a dose of 100 micrograms,
can be prescribed. This is usually continued for 6 months.
• The main advantages are fewer hospital visits for checks of thyroid
function and shorter duration of treatment.
• Most patients achieve a euthyroid state within 4–6 weeks of
carbimazole therapy.
• During treatment, FT4 values are measured 4 weeks after starting
levothyroxine and the dose of levothyroxine altered, if necessary, in
25 micrograms increments to maintain FT4 in the normal range.
Most patients do not require any dose adjustment.
• The originally reported higher remission rate was not confirmed in
a large prospective multicentre European trial when combination
treatment was compared to carbimazole alone, but side effects were
more common.1
• Relapses are most likely to occur within the first year.
MEDICAL TREATMENT 33
Reference
1. Reinwein D, Benker G, Lazarus JH, et al. (1993). A prospective randomized trial of antithyroid
drug dose in Graves’s disease therapy. European Multicenter Study Group on Antithyroid Drug
Treatment. J Clin Endocrinol Metab 76, 1516–21.
Radioiodine treatment
(See Table 1.13.)
Indications
• Definitive treatment of multinodular goitre or adenoma.
• Relapsed Graves’s disease.
Contraindications
• Young children because of the potential risk of thyroid carcinogenesis.
• Pregnant and lactating ♀.
• Situations where it is clear that the safety of other people cannot be
guaranteed.
• Graves’s ophthalmopathy. There is some evidence that Graves’s
ophthalmopathy may worsen after the administration of radioactive
iodine, especially in smokers. In cases of moderate-to-severe
ophthalmopathy, radioiodine may be avoided. Alternatively, steroid
cover in a dose of 40mg prednisolone should be administered on
the day of administering radioiodine, 30mg daily for the next
2 weeks, 20mg daily for the following 2 weeks, reducing to zero over
subsequent 3 weeks. Lower steroid doses, e.g. starting with 20mg,
may be effective. It is essential that euthyroidism is closely maintained
following radioiodine to avoid worsening of ophthalmopathy.
Caveats
• The control of disease may not occur for a period of weeks or a few
months.
• More than one treatment may be needed in some patients, depending
on the dose given; 15% require a second dose, and a few patients
require a third dose. The second dose should be considered only at
least 6 months after the first dose.
• Compounds that contain iodine, such as amiodarone, block iodine
uptake for a period of several months following cessation of therapy;
iodine uptake measurements may be helpful in this instance in
determining the activity required and the timing of radioiodine therapy.
• ♀ of childbearing age should avoid pregnancy for a minimum of
6 months following radioactive iodine ablation.
• Men should avoid fathering children for 4 months after radiation.
• The prevalence of hypothyroidism is about 50% at 10 years and
continues to increase thereafter.
Side effects are rare
• Anterior neck pain caused by radiation-induced thyroiditis (1%).
• Transient rise (72h) in thyroid hormone levels which may exacerbate
heart failure, if present. This aspect needs consideration in elderly
patients.
RADIOIODINE TREATMENT 35
Table 1.13 Recommended activity of radioiodine

Aetiology Comments Guide dose
(MBq)
Graves’s disease First presentation; no significant eye 400–600
disease
Moderate goitre (40–50g)
Toxic multinodular Mild heart failure; atrial fibrillation or 500–800
goitre in older other concomitant disease, e.g. cancer
person
Toxic adenoma Usually mild hyperthyroidism 500
Severe Graves’s Postpone radioiodine till eye disease 500–800
disease with stable
thyroid eye Prednisolone 40mg to be administered at
disease same time as radioiodine and for further
4–6 weeks (see b Contraindications,
p. 34)
Ablation therapy Severe accompanying medical condition, 500–800
such as heart failure; atrial fibrillation or
other concurrent medical disorders (e.g.
psychosis)
Data taken from The Use of Radioiodine in Benign Thyroid Disease. Royal College of
Physicians, 2007.
Hypothyroidism after radioiodine

• After radioiodine administration, ATDs may be recommenced. The
ATDs should be withdrawn gradually, guided by a 6–8-weekly thyroid
function test. Early post-radioiodine hypothyroidism may be transient.
TSH should be monitored initially, then annually after radioiodine to
determine late hypothyroidism.
• In patients treated for autonomous toxic nodules, the incidence
of hypothyroidism is lower since the toxic nodule takes up the
radioactive iodine while the surrounding tissue will recover normal
function once the hyperthyroidism is controlled.
• Mortality is not increased.
Cancer risk after radioiodine therapy
Radioiodine therapy for hyperthyroidism does not increase the overall risk
of malignancy or thyroid cancer.
Clinical guidelines
The recommendation is to administer enough radioiodine to achieve
euthyroidism, with the acceptance of a moderate rate of hypothyroidism,
e.g. 15–20% at 2 years.
Instructions to patients before treatment

Discontinue ATDs 2–7 days before radioiodine administration since
their effects last for 24h or more, although propylthiouracil has a pro-
longed radioprotective effect. ATDs may be recommenced 3–7 days after
radioiodine administration without significantly affecting the delivered
radiation dose.
Administration of radioiodine (see Table 1.13)
• Radioactive iodine-131 is administered orally as a capsule or a drink.
• There is no universal agreement regarding the optimal dose.
• A dose of 400–800MBq should be sufficient to cure hyperthyroidism
in 90%.
• Most patients are treated with 400–600MBq as the first dose, and
600–800MBq if thyrotoxicosis persists 6–12 months after the
first dose.
Outcomes of radioiodine treatment1
• In general, 50–70% of patients have restored normal thyroid function
within 6–8 weeks of receiving radioiodine. Shrinkage of goitre occurs
but is slower.
Instructions to patients after treatment
Precautions for patients following treatment with radioiodine are sum-
marized in Table 1.14.
RADIOIODINE TREATMENT 37
Table 1.14 Number of days to apply caution after radioiodine

Precaution Administered activity of 131I MBq
≤200 ≤400 ≤600 ≤800
Avoid journeys on public transport >1h 0 0 0 6
Avoid places of entertainment or close 1 5 8 11
contact with other people (duration 3h)
Stay off work when travel alone by 0 0 0 0
private transport and work does not
involve close contact with other people
Stay off work which involves prolonged 8 13 16 18
contact with other people at a distance
of 1m, e.g. bank cashier
Stay off work which involves close 11 17 20 22
contact with other people, including
pregnant ♀ or children, work of a
radiosensitive nature, or commercial
food production
Avoid non-essential close contact (<1m) 16* 22* 25* 27*
with children, teenagers, pregnant
women within the family
Avoid non-essential close contact and 4 9 13 15
sleeping with another person
* These times need to be extended if the child concerned is young and needs a lot of close
contact.
NB These apply only in the UK; they are less stringent in the USA.
Reference
1. Royal College of Physicians of London (2007). The use of radioiodine in benign thyroid disease.
Royal College of Physicians, London.
Surgery
(Aspects of thyroid surgery are also covered b see p. 606.)
Total thyroidectomy is now considered the operation of choice because
of the risk of relapse with partial thyroidectomy. All such patients go home
on T4. See Box 1.3.
Indications
• Documented suspicious or malignant thyroid nodule by FNAC.
• Pregnant women who are not adequately controlled by ATDs or in
whom serious allergic reactions develop while being treated medically.
Thyroidectomy is usually performed in the second trimester.
• Patients:
• Who reject or fear exposure to radiation.
• With poor compliance to medical treatment.
• In whom a rapid control of symptoms is desired.
• With severe manifestations of Graves’s ophthalmopathy, as total or
near total thyroidectomy does not worsen eye manifestations (but
carefully avoid post-operative hypothyroidism).
• With relapsed Graves’s disease.
• With local compressive symptoms which may not improve rapidly
with radioiodine whereas operation removes these symptoms in
most patients.
• With large thyroid glands and relatively low radioiodine uptake.
Preparation of patients for surgery
• ATDs should be used preoperatively to achieve euthyroidism.
• Propranolol may be added to achieve B-blockade, especially in those
patients where surgery must be performed sooner than achieving
euthyroid state.
• Potassium iodide, 60mg 3x daily, can be used during the preoperative
period to prevent an unwanted liberation of thyroid hormones during
surgery. Preoperatively, it should be given for 10 days. Operating later
than this can be associated with exacerbation of thyrotoxicosis, as the
thyroid escapes from the inhibitory effect of the iodide. In practice, it is
rarely needed, as good control of thyrotoxicosis can be achieved with
ATDs in the majority of patients.
• In the patient who appears to be non-compliant with ATDs and
remains thyrotoxic prior to surgery, it may be necessary to admit
them as an inpatient for supervised administration of high-dose ATDs,
together with B-blockade, and measurement of FT4 and FT3 twice
weekly. There is a risk of thyroid crisis or storm if a patient undergoes
operation when thyrotoxic. Most patients can be rendered euthyroid
within 2–4 weeks, and potassium iodide can be administered as above
in this section to coincide with the timing of surgery.
• Additional measures are as for thyroid storm.
SURGERY 39
Box 1.3 Complications of thyroidectomy

Immediate Late
• Recurrent laryngeal nerve damage. • Hypothyroidism.
• Hypoparathyroidism. • Keloid formation.
• Thyroid crisis.
• Local haemorrhage, causing laryngeal oedema.
• Wound infection.
Thyroid crisis (storm)

Thyroid crisis represents a rare, but life-threatening, exacerbation of the
manifestations of thyrotoxicosis. It should be promptly recognized since
the condition is associated with a significant mortality (30–50%, depend-
ing on series); see Box 1.4. Thyroid crisis develops in hyperthyroid
patients who:
• Have an acute infection.
• Undergo thyroidal or non-thyroidal surgery or (rarely) radioiodine
treatment.
Thyroid crisis should be considered in a very sick patient if there is:
• Recent history suggestive of thyrotoxicosis.
• Acute stressful precipitating factor, such as surgery.
• History of previous thyroid treatment.
Laboratory investigations
• Routine haematology may indicate a leukocytosis, which is well
recognized in thyrotoxicosis, even in the absence of infection.
• The biochemical screen may reveal a raised alkaline phosphatase and
mild hypercalcaemia.
• Thyroid function tests and thyroid antibodies should be requested,
although treatment should not be delayed while awaiting the results.
• The levels of thyroid hormones will be raised, but may not be
grossly elevated, and are usually within the range of uncomplicated
thyrotoxicosis.
Treatment
General supportive therapy
• The patient is best managed in an intensive care unit where close
attention can be paid to the cardiorespiratory status, fluid balance, and
cooling.
• Standard anti-arrhythmic drugs can be used, including digoxin (usually
in higher than normal dose) after correction for hypokalaemia.
If anticoagulation is indicated because of atrial fibrillation, then it must be
remembered that thyrotoxic patients are very sensitive to warfarin.
• Chlorpromazine (50–100mg IM) can be used to treat agitation and,
because of its effect in inhibiting central thermoregulation, it may be
useful in treating the hyperpyrexia.
• Broad-spectrum antibiotics should be given if infection is suspected.
Box 1.4 Clinical signs suggestive of a thyroid storm

• Alteration in mental status.
• High fever.
• Tachycardia or tachyarrhythmias.
• Severe clinical hyperthyroid signs.
• Vomiting, jaundice, and diarrhoea.
• Multisystem decompensation: cardiac failure, respiratory distress,
congestive hepatomegaly, dehydration, and prerenal failure.
THYROID CRISIS (STORM) 41
Specific treatment
• Aim: to inhibit thyroid hormone synthesis completely.
• Propylthiouracil 200–300mg 6-hourly via NG tube. Propylthiouracil
is preferred because of its ability to block T4 to T3 conversion
in peripheral tissues. There are no clinical data comparing
propylthiouracil and carbimazole in this situation. ATDs should be
commenced first.
• Potassium iodide, 60mg via NG tube 6-hourly, 6h after starting
propylthiouracil, will inhibit thyroid hormone release.
• B-adrenergic blocking agents are essential in the management to
control tachycardia, tremor, and other adrenergic manifestations:
• Propranolol 160–480mg/day in divided doses or as an infusion at a
rate of 2–5mg/h.
• Calcium channel blockers can be tried in patients with known
bronchospastic disease where B-blockade is contraindicated.
• High doses of glucocorticoids are capable of blocking T4 to T3
conversion: prednisolone 60mg daily or hydrocortisone 400mg IM,
4x daily.
• Plasmapheresis and peritoneal dialysis may be effective in cases
resistant to the usual pharmacological measures.
• Colestyramine (3g tds) reduces the enterohepatic circulation of
thyroid hormones and may help improve thyrotoxicosis.
Subclinical hyperthyroidism
(See Box 1.5.)
• Values of thyroid hormones should be repeated to exclude
non-thyroidal illness.
• Subclinical hyperthyroidism is defined as low serum thyrotropin (TSH)
concentration in patients with normal levels of T4 and T3. Subtle
symptoms and signs of thyrotoxicosis may be present.
• May be classified as endogenous in patients with thyroid hormone
production associated with nodular thyroid disease or underlying
Graves’s disease; and as exogenous in those with low or undetectable
serum thyrotropin concentrations as a result of treatment with
levothyroxine.
There is epidemiological evidence that subclinical hyperthyroidism is
a risk factor for the development of atrial fibrillation or osteoporosis.1
Meta-analyses suggest a 41% increase in all-cause mortality.2
Box 1.5 Indications to treat subclinical hyperthyroidism

Consider treatment with:
• TSH <0.1 (undetectable).
• Atrial fibrillation.
• Osteoporosis.
• The i risk of fracture reported in older ♀ taking thyroid hormone

disappears when those with a history of hyperthyroidism are excluded.
• In many patients with endogenous subclinical hyperthyroidism who do
not have nodular thyroid disease or complications of excess thyroid
hormone, treatment is unnecessary, but thyroid function tests should
be performed every 6 months. In older patients with atrial fibrillation
or osteoporosis that could have been caused or exacerbated by the
mild excess of thyroid hormone, options include long-term, low-dose
antithyroid drug therapy or ablative therapy with 131I.
• In patients with exogenous subclinical hyperthyroidism, the dose
of levothyroxine should be reduced, if possible, excluding those
with prior thyroid cancer in whom thyrotropin suppression may be
required. The dose of levothyroxine used for treating hypothyroidism
may be reduced if the patient develops:
• New atrial fibrillation, angina, or cardiac failure.
• Accelerated bone loss.
• Borderline high serum T3 concentration.
SUBCLINICAL HYPERTHYROIDISM 43
Thyrotoxic hypokalaemic periodic paralysis

• More common in Asians (5–10% of all with thyrotoxicosis due to
Graves’s disease or multinodular goitre) (0.1–0.2% of non-Asian
Europeans/North Americans).
• Thyrotoxic patients with periodic paralysis have been found to have
higher sodium pump activity than those without paralytic episodes.
• Most common form of acquired periodic paralysis which is a muscle
disease in the family of diseases called channelopathies.
• Usual age of onset 20–40 years, mostly ♂.
• Recurrent episodes of painless muscle weakness.
• Duration from minutes to days.
• Flaccid paralysis, usually spreading from legs proximally.
• Clinical manifestations of thyrotoxicosis may be few, and thus TSH
should be checked in anyone presenting with periodic paralysis.
• Improves as thyrotoxicosis treated.
• Low serum potassium during attacks.
• CPK i during recovery phase.
• Precipitated by carbohydrates, insulin, cold, vigorous exercise.
• Treatment with potassium replacement, usually by oral route, and
treatment of thyrotoxicosis.
• Symptoms usually improve within 2–4h; full resolution in 24–48h.
• Non-selective B-blockers, such as propranolol (3mg/kg), help to
prevent attacks until a euthyroid state is achieved.
References
1. Parle JV, Maisonneuve P, Sheppard MC, et al. (2001). Prediction of all-cause and cardiovascular
mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study.
Lancet 358, 861–5.
2. Vadiveloo T, et al. (2011). The Thyroid Epidemiology, Audit, and Research Study (TEARS): mor-
bidity in patients with endogenous subclinical hyperthyroidism. J Clin Endocrinol Metab 96, 1344.
Further reading
Rhee EP, et al. (2012). Case 4-2012—A 37-year-old man with muscle pain, weakness, and weight
loss. New Engl J Med 366, 553.
Thyrotoxicosis in pregnancy
(b also see p. 428 and Box 1.6.)
• Thyrotoxicosis occurs in about 0.2% of pregnancies.
• Graves’s disease accounts for 90% of cases.
• Less common causes include toxic adenoma and multinodular goitre.
• Other causes are gestational hyperthyroidism (hyperemesis
gravidarum) and trophoblastic neoplasia.
• Diagnosis of thyrotoxicosis during pregnancy may be difficult or
delayed.
• Physiological changes of pregnancy are similar to those of
hyperthyroidism.
• Total T4 and T3 are elevated in pregnancy because of an elevated level
of TBG, but, with free hormone assays available, this is no longer a
problem.
• Physiological features of normal pregnancy include an increase in
basal metabolic rate, cardiac stroke volume, palpitations, and heat
intolerance.
• Serum free T3 concentrations remain within the normal range in most
pregnant ♀; serum TSH concentration decreases during the first
trimester.
Symptoms
• Hyperemesis gravidarum is the classic presentation (one-third is toxic).
Tiredness, palpitations, insomnia, heat intolerance, proximal muscle
weakness, shortness of breath, and irritability may be other presenting
symptoms.
• Thyrotoxicosis may occasionally be diagnosed when the patient
presents with pregnancy-induced hypertension or congestive heart
failure.
Signs
• Failure to gain weight despite a good appetite.
• Persistent tachycardia with a pulse rate >90 beats/min at rest.
• Other signs of thyrotoxicosis as described previously.
Natural history of Graves’s disease in pregnancy
There is aggravation of symptoms in the first half of the pregnancy; amelio-
ration of symptoms in the second half of the pregnancy, and often recur-
rence of symptoms in the post-partum period.
Transient hyperthyroidism of gestational
hyperthyroidism (hyperemesis gravidarum)
• The likely mechanism is a raised B-hCG level.
• B-hCG, LH, FSH, and TSH are glycoprotein hormones that contain
a common α subunit and a hormone-specific B subunit. There is an
inverse relationship between the serum levels of TSH and hCG, best
seen in early pregnancy. There is also structural homology of the TSH
and hCG receptors.
THYROTOXICOSIS IN PREGNANCY 45
• Serum free T4 concentration may be i and the TSH levels suppressed

in ♀ with hyperemesis gravidarum.
• Thyroid function tests recover after the resolution of hyperemesis.
• Pregnant ♀ with gestational hyperthyroidism (hyperemesis
gravidarum) (which only accounts for two-thirds of hyperemesis) are
not usually given ATD treatment but managed supportively with fluids,
antiemetics, and nutritional support.
• There is no i risk of thyrotoxicosis in subsequent pregnancies.
• Can be differentiated from Graves’s disease by the absence of a
goitre, antithyroid antibodies, or family history of Graves’s disease, a
history of other autoimmune phenomena, and a previous history of
ophthalmic Graves’s.
Management of Graves’s disease in the mother
• Aim of treatment is alleviation of thyroid symptoms and normalization
of tests in the shortest time. Patients should be seen every 4–8 weeks
and TFTs performed. Serum free T4 is the best test to follow the
response to ATDs. Block and replace regimen should not be used, as
this will result in fetal hypothyroidism.
• Both propylthiouracil (150mg bd) and carbimazole (10–20mg once
daily) are effective in controlling the disease in pregnancy. Historically,
propylthiouracil has been preferred in pregnancy because it is not
associated with aplasia cutis and omphalocele, which may be the case
for carbimazole. However, recent concern regarding hepatotoxicity
of PTU, particularly in children, has led to recommendations that it
should only be prescribed in the first trimester (check liver function
monthly). A B-blocker (propranolol 20–40mg 6–8-hourly) is effective
in controlling the hypermetabolic symptoms but should be used only
for a few weeks until symptoms abate.
• The dosage of ATDs is frequently adjusted during the course of
the pregnancy; therefore, thyroid tests should be done at 2–4 week
intervals, with the goal of keeping free thyroid hormone levels in the
upper third of the reference range.
• Thyroid tests may normalize spontaneously, with the progression of a
normal pregnancy as a result of immunological changes.
• The use of iodides and radioiodine is contraindicated in pregnancy.
• Surgery is rarely performed in pregnancy. It is reserved for patients not
responding to ATDs. If necessary, it is preferable to perform surgery in
the second trimester.
• Breastfeeding mothers should be treated with the lowest possible
dose of carbimazole rather than propylthiouracil in view of the
concern regarding hepatotoxicity.
Pre-pregnancy counselling
• Hyperthyroid ♀ who want to conceive should attain euthyroidism
before conception since uncontrolled hyperthyroidism is associated
with an i risk of congenital abnormalities (stillbirth and cranial
synostosis are the most serious complications). See Box 1.6.
• There is no evidence that radioactive iodine treatment given to the
mother (or father) 6 months or more before pregnancy has an adverse
effect on the fetus or on an offspring in later life.
• Antithyroid medication requirements usually decrease during gestation;

in about 50–60% of patients, the dose may be discontinued in the last
few weeks of gestation.
• The risk of recurrent hyperthyroidism should be discussed with the
patient.
• The rare occurrence of fetal and neonatal hyperthyroidism should
be included during counselling sessions and the diagnosis of Graves’s
hyperthyroidism conveyed to the obstetrician and neonatologist.
Management of the fetus
• The hypothalamo–pituitary–thyroid axis is well developed at 12 weeks’
gestation but remains inactive until 18–20 weeks. Circulating TSH
receptor antibodies (TSH-RAB) in the mother can cross the placenta,
and it is these, rather than the thyroid status of the mother, that cause
neonatal thyrotoxicosis. The risk of hyperthyroidism to the neonate can
be assessed by measuring TSH-RAB in the maternal circulation at the
beginning of the third trimester. Antithyroglobulin antibody and thyroid
peroxidase antibodies have no effect on the fetus.
• Long-term follow-up studies of children whose mothers received
either carbimazole or propylthiouracil have not shown an i incidence
of any physical or psychological defects. The block and replace
regimen using relatively high doses of carbimazole is contraindicated
because the ATDs cross the placenta, but replacement T4 does not,
thus potentially rendering the fetus hypothyroid.
• Monitoring the fetal heart rate and growth rates are the standard
means whereby fetal thyrotoxicosis may be detected. A rate >160
beats/min is suspicious of fetal thyrotoxicosis in the third trimester.
Fetal thyrotoxicosis may complicate the latter part of the pregnancy
of ♀ with Graves’s disease, even if they have previously been treated
with radioiodine or surgery, since TSH receptor antibodies may
persist. If there is evidence of fetal thyrotoxicosis, the dose of the
ATD should be i. If this causes maternal hypothyroidism, a small dose
of T4 can be added since, unlike carbimazole, T4 crosses the placenta
less. A paediatrician should be involved to monitor neonatal thyroid
function and detect thyrotoxicosis.
• Hypothyroidism in the mother should be avoided because of the
potential adverse effect on subsequent cognitive function of the
neonate (see Box 1.6).
• If the mother has been treated with carbimazole, the post-delivery levels
of T4 may be low, and neonatal levels of T4 may only rise to the thyrotoxic
range after a few days. In addition, TSH is usually absent in neonates
who subsequently develop thyrotoxicosis. Clinical indicators of neonatal
thyrotoxicosis include low birthweight, poor weight gain, tachycardia, and
irritability. Carbimazole can be given at a dose of 0.5mg/kg per day and
withdrawn after a few weeks after the level of TSH-RAB declines.
Post-partum thyroiditis
• Defined as a syndrome of post-partum thyrotoxicosis or
hypothyroidism in ♀ who were euthyroid during pregnancy.
• Post-partum thyroid dysfunction, which occurs in ♀ with autoimmune
thyroid disease, is characterized in one-third by a thyrotoxic phase
THYROTOXICOSIS IN PREGNANCY 47
Box 1.6 Potential maternal and fetal complications in

uncontrolled hyperthyroidism in pregnancy
Maternal Fetal
• Pregnancy-induced hypertension • Hyperthyroidism
• Preterm delivery • Neonatal hyperthyroidism
• Congestive heart failure • Intrauterine growth retardation
• Thyroid storm • Small-for-gestation age
• Miscarriage • Prematurity
• Abruptio placentae • Stillbirth
• Accidental haemorrhage • Cranial synostosis
occurring in the first 3 months post-partum, followed by a hypothyroid

phase that occurs 3–6 months after delivery, followed by spontaneous
recovery. In the remaining two-thirds, a single-phase pattern or the
reverse occurs.
• 5–7% of ♀ develop biochemical evidence of thyroid dysfunction after
delivery. An i incidence is seen in patients with type I diabetes mellitus
(25%), other autoimmune diseases, in the presence of anti-TPO
antibodies, and in the presence of a family history of thyroid disease.
• Hyperthyroidism due to Graves’s disease accounts for 10–15% of all cases
of post-partum thyrotoxicosis. In the majority of cases, hyperthyroidism
occurs later in the post-partum period (>3–6 months) and persists.
• Providing the patient is not breastfeeding, a radioiodine uptake
scan can differentiate the two principal causes of autoimmune
thyrotoxicosis by demonstrating i uptake in Graves’s disease and low
uptake in post-partum thyroiditis.
• Graves’s hyperthyroidism should be treated with carbimazole.
Thyrotoxic symptoms due to post-partum thyrotoxicosis are managed
symptomatically using propranolol.
• One-third of affected ♀ with post-partum thyroiditis develop
symptoms of hypothyroidism and may require T4 for 6–12 months.
There is a suggestion of an i risk of post-partum depression in those
with hypothyroidism.
• Histology of the thyroid in the case of post-partum thyroiditis shows
lymphocytic infiltration with destructive thyroiditis and predominantly
occurs at 16 weeks in ♀ with +ve antimicrosomal antibodies.
• There is an i chance of subsequent permanent hypothyroidism in
25–30%. Patients with a history of post-partum thyroiditis should be
followed up with annual TSH measurements.
Further reading
Lazarus JH (2012). Antithyroid drug treatment in pregnancy. J Clin Endocrinol Metab 97, 2289–91.
Hyperthyroidism in children
Epidemiology
Thyrotoxicosis is rare before the age of 5 years. Although there is a pro-
gressive increase in incidence throughout childhood, it is still rare and
accounts for <5% of all cases of Graves’s disease.
Clinical features
• Behavioural abnormalities, hyperactivity, declining school performance
may bring the child to medical attention. Features of hyperthyroidism
are as described previously.
• Acceleration of linear growth is common in patients increasing in
height percentiles on the growth charts. The disease may be part of
McCune–Albright syndrome, and café-au-lait pigmentation, precocious
puberty, and bony abnormalities should be considered during clinical
examination.
Investigations
The cause of thyrotoxicosis in children is nearly always Graves’s disease
(with +ve TSH receptor antibodies), although thyroiditis and toxic nod-
ules have been described, and a radioiodine scan may be useful if the
diagnosis is not clear. Hereditary syndromes of thyroid hormone resist-
ance, often misdiagnosed as Graves’s disease, are now being increasingly
recognized in children.
Treatment
ATDs represent the initial treatment of choice for thyrotoxic children.
Therapy is generally started with carbimazole 250 micrograms/kg (ini-
tial dose 10mg/day). Since relapse after withdrawal of ATDs is com-
mon, definitive treatment with surgery or radioiodine should be offered.
Hepatotoxicity with propylthiouracil can also occur in children.
HYPERTHYROIDISM IN CHILDREN 49
Secondary hyperthyroidism
An elevated serum free T4 and non-suppressed serum TSH are character-
istic of TSH-secreting adenomas or resistance to thyroid hormone.
These conditions must be differentiated (see Table 1.15).
TSH-secreting pituitary tumours
• Estimated incidence 1 per million and <1% of all pituitary tumours.
• There are characteristically elevated serum free T4 and T3
concentrations and non-suppressed (inappropriately normal or frankly
elevated) serum TSH levels.
• Approximately 25% of TSHomas co-secrete one or more other
pituitary hormones; about 15% secrete growth hormone, 10%
prolactin, and rarely gonadotrophins. Approximately 90% are
macroadenomas (>1cm in diameter), and over two-thirds exhibit
suprasellar extension, invasion, or both into adjacent tissues (b see
p. 180).
• Patients with pure TSHomas present with typical symptoms and signs
of thyrotoxicosis and the presence of a diffuse goitre. Patients may
exhibit features of oversecretion of the other pituitary hormones,
e.g. prolactin or growth hormone. Headaches, visual field defects,
menstrual irregularities, amenorrhoea, delayed puberty, and
hypogonadotrophic hypogonadism have also been reported. Careful
establishment of the diagnosis is the key to treatment. Inappropriate
treatment of such patients with subtotal thyroidectomy or radioiodine
administration not only fails to cure the underlying disorder, but may
be associated with subsequent pituitary tumour enlargement and an i
risk of invasiveness into adjacent tissues.
• Treatment options are:
• Transphenoidal surgery.
• Pituitary radiotherapy if surgical results are unsatisfactory or surgery
is contraindicated or not desired.
• Medical therapy with somatostatin analogues, such as octreotide
or lanreotide, may be useful preoperatively and suppresses TSH
secretion in 80% of the cases.
Resistance to thyroid hormones
• Patients with generalized resistance to thyroid hormone (GRTH)
may present with mild hyperthyroidism, deaf mutism, delayed bone
maturation, raised circulating thyroid hormone concentrations,
non-suppressed TSH, and failure of TSH to decrease normally upon
administration of supraphysiological doses of thyroid hormones. Most
patients present with goitre or incidentally found abnormal TFTs.
Treatment is determined by thyroid status.
• The estimated incidence is 1:50,000 live births.
• In selective pituitary resistance to thyroid hormones (PRTH), the
thyroid hormone resistance is more pronounced in the pituitary; thus,
the patient exhibits definite clinical manifestations of thyrotoxicosis.
SECONDARY HYPERTHYROIDISM 51
• About 85% of thyroid hormone resistance syndromes result from

mutations in the gene encoding TRB, and their identification by
gene sequencing can confirm the diagnosis. Mutant receptors have
a reduced affinity for T3 and are functionally deficient. It is usually
inherited in an autosomal dominant pattern, with the affected
individuals being heterozygous for the mutation.
• A subset of RTH receptors has been identified that are capable of
inhibiting wild type receptor action. When co-expressed, the mutant
proteins are able to inhibit the function of their wild type counterparts
in a dominant –ve manner.
• Common features of patients with the thyroid hormone resistance
syndromes include goitre (most commonly) and, less so, tachycardia,
hyperkinetic behaviour, emotional disturbances, ear, nose, and throat
infections, language disabilities, auditory disorders, low body weight,
cardiac abnormalities, and subnormal intelligence quotients.
Treatment in RTH is not usually necessary. In PRTH, treatment may be
needed, but this is uncommon. Chronic suppression of TSH secretion is
with D T4, tri-iodothyroacetic acid, octreotide, or bromocriptine. If this is
ineffective, thyroid ablation with radioiodine or surgery, with subsequent
close monitoring of thyroid hormone status and pituitary gland size.
Table 1.15 Tests useful in the differential diagnosis of TSHomas,

PRTH, and GRTH
Test TSHomas PRTH GRTH
Clinical thyrotoxicosis Present Present Absent
Family history Absent Present Present
TSH response to TRH No change Increase Increase
TSH response to T3 No change Decrease Decrease
(100 micrograms/day +
B-blockers)
SHBG Elevated–92%a Normalb Normal
α subunit Elevated–65% 2% elevated
Pituitary MRI Tumour–30% Normal Normal
microadenomac
Fall in TSH on octreotide 95% No change No change
LAR 20mg/month for
2 months
a
Not usually raised in mixed GH/TSH tumour.
b
Peripheral markers of toxicosis sometimes affected (8% SHBG elevated).
c
The best biochemical test is an elevated α subunit.
Further reading
Abalovich M, Amino N, Barbour LA, et al. (2007). Management of thyroid dysfunction during preg-
nancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab
92(8 Suppl), S1–47.
Abraham P, Avenell A, McGeoch SC, et al. (2010). Antithyroid drug regimen for treating Graves’s
hyperthyroidism. Cochrane Database Syst Rev CD003420.
Bahn RS, Burch HB, Cooper DS, et al. (2011). Hyperthyroidism and other causes of thyrotoxico-
sis: management guidelines of the American Thyroid Association and American Association of
Clinical Endocrinologists. Thyroid 21, 593–646.
Bauer AJ (2011). Approach to the pediatric patient with Graves’s disease: when is definitive therapy
warranted? J Clin Endocrinol Metab 96, 580–8.
Bonnema SJ, Hegedüs L (2012). Radioiodine therapy in benign thyroid diseases. Endocr Rev 33,
920–80.
Brand OJ, Gough SC (2010). Genetics of thyroid autoimmunity and the role of the TSHR. Mol Cell
Endocrinol 322, 135–43.
Brent GP (2008). Graves’s disease. N Engl J Med 358, 2594–605.
Brent GA (2010). Environmental exposures and autoimmune thyroid disease. Thyroid 20, 755–61.
Brix TH, Hegedüs L (2011). Twins as a tool for evaluating the influence of genetic susceptibility in
thyroid autoimmunity. Ann Endocrinol (Paris) 72, 103–7.
Cesur M, Bayram F, Temel MA, et al. (2008). Thyrotoxic hypokalaemic periodic paralysis in a
Turkish population: three new case reports and analysis of the case series. Clin Endocrinol (Oxf)
68, 143–152.
Clementi M, Di Gianantonio E, Cassina M, et al. (2010). Treatment of hyperthyroidism in pregnancy
and birth defects. J Clin Endocrinol Metab 95, E337–41.
Cooper DS, Rivkees SA (2009). Putting propylthiouracil in perspective. J Clin Endocrinol Metab
94, 1881–2.
Franklyn JA (2009). Thyroid gland: Antithyroid therapy--best choice of drug and dose. Nat Rev
Franklyn JA (2010). What is the role of radioiodine uptake measurement and thyroid scintigraphy in
the diagnosis and management of hyperthyroidism? Clin Endocrinol (Oxf) 72, 11–12
Metso S, Jaatinen P, Huhtala H, et al. (2007). Increased cardiovascular and cancer mortality after
radioiodine treatment for hyperthyroidism. J Clin Endocrinol Metab 92, 2190–6.
Pearce SH (2004). Spontaneous reporting of adverse reactions to carbimazole and propylthiouracil
in the UK. Clin Endocrinol 61, 589–94.
Ross DS (2011). Radioiodine therapy for hyperthyroidism. N Engl J Med 364, 542–50.
Vanderpump MP (2011). Should we treat mild subclinical/mild hyperthyroidism? No. Eur J Intern
Med 22, 330–3.
Wiersinga WM (2011). Should we treat mild subclinical/mild hyperthyroidism? Yes. Eur J Intern
Med 22, 324–9.
SECONDARY HYPERTHYROIDISM 53
Graves’s ophthalmopathy
(See European Working Group on Graves’s Ophthalmopathy,
M http://www.EUGOGO.org.)
• An organ-specific autoimmune disorder characterized by swelling of
the extraocular muscles, lymphocytic infiltration, late fibrosis, muscle
tethering, and proliferation of orbital fat and connective tissue.
• The volume of both the extraocular muscles and retroorbital
connective and adipose tissue is increased due to inflammation and
the accumulation of hydrophilic glycosaminoglycans (GAG), principally
hyaluronic acid, in these tissues. GAG secretion by fibroblasts is
increased by activated T-cell cytokines, such as tumour necrosis factor
(TNF) alpha and interferon gamma, implying that T-cell activation is an
important part of this immunopathology. The accumulation of GAG
causes a change in osmotic pressure, which, in turn, leads to a fluid
accumulation and an increase in pressure within the orbit. These changes
displace the eyeball forward and can also interfere with the function of
the extraocular muscles and the venous drainage of the orbits.
• Clinically evident in 720% of patients, but a further 730% may have
evidence on imaging. Most bilateral, but often asymmetrical, and 15%
have unilateral disease.
• Most have mild self-limiting disease, but 75% (more ♂ and the
elderly) have severe disease that threatens sight. The natural history is
variable, with spontaneous amelioration in 66%, no change in 20%, and
worsening in 14%.
• Incidence higher in ♀ (except for severe disease where equal sex
incidence). Prevalence decreasing (? associated with decreased
smoking).
• Bimodal age distribution in ♀, with peak onsets between 40–44 years
and 60–64 years. In ♂, a single peak incidence occurs at 65–69 years.
• There are two stages in the development of the disease, which can be
recognized as an active inflammatory (dynamic) stage and a relatively
quiescent static stage.
• The appearance of eye disease follows a different time course to
thyroid dysfunction, and, in a minority, there is a lag period between
the presentation of hyperthyroidism and the appearance of eye signs.
85% of patients develop Graves’s disease within 18 months of Graves’s
ophthalmopathy developing (20% precede, 40% following).
• 5% of patients with Graves’s ophthalmopathy have hypothyroidism,
and 5% are euthyroid.
• High levels of TSH receptor antibodies identify high-risk patients.
• Current smokers (>20/day) are more likely to develop ophthalmopathy.
• Continuing smoking and uncontrolled hyperthyroidism or
hypothyroidism moderately worsen Graves’s ophthalmopathy.
• The role of an endocrinologist during a routine review of Graves’s
patients is to record accurately the clinical features of Graves’s
eye disease and to identify ocular emergencies, such as corneal
ulceration, congestive ophthalmopathy, and optic neuropathy, which
should be referred urgently to an ophthalmologist, preferably in a
multidisciplinary clinic setting.
GRAVES’S OPHTHALMOPATHY 55
Clinical features
(See Box 1.7.)
• Retraction of eyelids is extremely common in thyroid eye disease.
The margin of the upper eyelid normally rests about 2mm below the
limbus, and retraction can be suspected if the lid margin is either level
with or above the superior limbus, allowing the sclera to be visible.
The lower lid normally rests at the inferior limbus, and retraction is
suspected when the sclera shows above the lid.
• Proptosis or exophthalmos can result in failure of lid closure,
increasing the likelihood of exposure keratitis and the common
symptom of gritty eyes. This can be confirmed with fluorescein or
Rose Bengal stain. As papilloedema can occur, fundoscopy should be
performed. Proptosis may result in periorbital oedema and chemosis
because the displaced orbit results in less efficient orbital drainage.
• Persistent visual blurring may indicate an optic neuropathy and
requires urgent treatment.
• Severe conjunctival pain may indicate corneal ulceration, requiring
urgent referral.
Investigation of proptosis
For details of the ‘NOSPECS’ classification, see M http://www.EUGOGO.
org and The European Group on Graves’s Orbitopathy. However,
NOSPECS is not always satisfactory for prospective objective assessment
of orbital changes, and determining an overall activity score is sometimes
more helpful. This is done by assigning one point for the presence of
each of the following findings: spontaneous retrobulbar pain, pain on eye
movement, eyelid erythema, conjunctival injection, chemosis, swelling of
the carbuncle, and eyelid oedema.
Box 1.7 Assessment of severity of Graves’s

orbitopathy (GO)
Ocular involvement Features
Mild GO Minor lid retraction (<2mm)
Mild soft tissue involvement
Exophthalmos <3mm
No or transient diplopia
Mild corneal exposure
Moderate GO Lid retraction (≥2mm)
Moderate to severe soft tissue
involvement
Exophthalmos ≥3mm
Diplopia
Sight-threatening GO Optic neuropathy
Corneal breakdown
Congestive ophthalmopathy
• Documentation using a Hertel exophthalmometer. The feet of the

apparatus are placed against the lateral orbital margin as defined by the
zygomatic bones. The marker on the body of the exophthalmometer
is then superimposed on the reflection of the contralateral one by
adjusting the scale. The position of each cornea can be read off against
the reflections on a millimetre scale as seen on the mirror of the
apparatus. A normal result is generally taken as being <20mm (<18mm
in Asians, <22mm in Afro-Caribbeans). A reading of 21mm or more is
abnormal, and a difference of 2mm between the eyes is suspicious.
• Soft tissue involvement. Soft tissue signs and symptoms include
conjunctival hyperaemia, chemosis, and foreign body sensation. The
soft tissue changes can be s to exposure but are often seen in the
absence of these aetiological factors.
• CT or MRI scan of the orbit demonstrates enlargement of the
extraocular muscles, and this can be useful in cases of diagnostic
difficulty. This is also more accurate for demonstration of proptosis.
Ophthalmoplegia
• Patients may complain of diplopia due to ocular muscle dysfunction
caused by either oedema during the early active phase or fibrosis
during the later phase. Assessment using a Hess chart may be helpful.
Intraoptic pressure may increase on upgaze and result in compression
of the globe by a fibrotic inferior rectus muscle. Ocular mobility may
be restricted by oedema during the active inflammatory phase or by
fibrosis during the fibrotic stage.
• The two most common findings are defective elevation caused by
fibrotic contraction of the inferior rectus muscle and a convergence
defect caused by fibrotic contraction of the medial rectus. Disorders of
the medial rectus, superior rectus, and lateral rectus muscle produce
typical signs of defective adduction, depression, and abduction,
respectively.
Examining for possible optic neuropathy
• History of poor vision, a recent or rapid change in vision, or poor colour
vision are reasons for prompt referral.
• A visual acuity of <6/18 warrants referral to an ophthalmologist. For
colour vision, each eye should be evaluated by using a simple 15-plate
Ishihara colour vision test. Colour vision is a subtle indicator of optic
nerve function. Failure to identify >2 of the plates with either eye is
an indication for referral. This is unhelpful in the 8% of ♂ who may be
colour-blind.
• Marcus Gunn pupil. The ‘swinging flashlight’ test detects the presence
of an afferent pupillary defect associated with optic nerve compression.
GRAVES’S OPHTHALMOPATHY 57
Medical treatment of Graves’s

ophthalmopathy
(See Box 1.8.)
Simple treatment for lid retraction
• Most patients do not require any treatment since clinical signs usually
improve with treatment of hyperthyroidism or spontaneously with
time (40%).
• Sunglasses help with photophobia and excess tears.
• In patients with significant lid retraction and exposure keratopathy,
topical lubricants improve symptoms (surgery to reduce the vertical lid
fissures can be considered when euthyroid).
• Botulinum toxin injection may reduce persistent upper lid retraction.
• Head elevation during sleep and diuretics may help congestion.
Acute treatment for active ophthalmopathy
threatening sight
• Effectiveness is more likely in those with diplopia at neutral gaze and
an inflammatory component to ophthalmoplegia.
• Glucocorticoids at high dose (60–80mg/day) improve ophthalmopathy
in 60–75% of cases.
• Intravenous glucocorticoid pulse therapy has also been used and
may have the advantage of fewer side effects than high oral doses
of prednisolone (e.g. 0.5g methylprednisolone weekly for 6 weeks,
followed by 0.25g weekly for 6 weeks, with monitoring of liver function
tests 9 PPIs and a bisphosphonate).
• The advantage of intravenous over oral glucocorticoid therapy was
also demonstrated in a meta-analysis of four trials. Intravenous
glucocorticoids were significantly better in reducing clinical activity
scores; the advantage was mostly due to improvements in patients
with severe ophthalmopathy. Adverse events were more common
in patients receiving oral therapy, and high doses have been seen to
induce liver failure.
• If high-dose oral prednisolone treatment—give for 2 weeks and then
tapered gradually.
• Methylprednisolone intravenously is given at a maximum dose of 8g,
as the risk of hepatic necrosis is seen at higher doses.
• Steroid-sparing agents used in long-term therapy include
mycophenolate mofetil, azathioprine, and ciclosporin, but there are
little data suggesting which is more effective.
• Urgent referral to an ophthalmologist is indicated for any suspicion
of optic neuropathy or corneal ulceration. Multidisciplinary clinics are
strongly advised.
MEDICAL TREATMENT OF GRAVES’S OPHTHALMOPATHY 59
Orbital radiotherapy
• Indications for lens-sparing orbital radiotherapy are similar to those for
high-dose glucocorticoids.
• Radiotherapy works by killing retroorbital T cells.
• 20 Gray delivered over ten fractions is the standard regimen.
• Treatment with both radiotherapy and glucocorticoids is more
effective than either alone.
• Effectiveness in 60% of cases <40 years.
Other medical therapies
• Selenium1 may improve symptoms in patients with mild Graves’s
ophthalmopathy, as illustrated by the results of a randomized trial of
selenium (100 micrograms bd), pentoxifylline (600mg bd), or placebo
in 159 patients. After 6 months of treatment, eyelid aperture (37%
vs 12%) and soft tissue signs (43% vs 32%) significantly improved in
patients taking selenium vs placebo. Compared with placebo, selenium
also significantly improved quality of life (both visual functioning and
appearance scores), as assessed by the Graves’s Ophthalmopathy
Quality of Life Questionnaire (GO-QOL). Evaluation at 12 months
confirmed the findings at 6 months.
• A number of reports have indicated that some patients with severe
Graves’s ophthalmopathy may respond to B cell depletion induced by
rituximab, which is a monoclonal antibody directed against the B cell
CD20 molecule. Rituximab induces a fall in TSH receptor antibody
levels and depletion of B cells in the retroorbital tissues, not just the
periphery. Although high doses of this antibody may be associated with
severe side effects from profound immunosuppression, it is possible
that much lower doses may be effective in Graves’s ophthalmopathy
to avoid such effects. This approach to the treatment of severe eye
disease is currently undergoing larger trials; preliminary results from
these trials suggest efficacy in some, but not all, patients.
• Other immunosuppressive regimens have no proven place in the
general management of Graves’s ophthalmopathy.
• Use of depot octreotide has been shown to be of no benefit in
management.
Reference
1. Marcocci C, et al. (2011). Selenium and the course of mild Graves’ orbitopathy. N Engl J Med
364, 1920.
Surgical treatment of Graves’s

ophthalmopathy
(See Box 1.8.)
Surgery for decompression
• Orbital decompression may be indicated for urgent treatment of optic
neuropathy.
• Posteromedial wall of orbit usually removed.
• Complications include dysmotility of the eye, blindness, orbital
cellulitis, CSF leak, cerebral haematoma, obstruction to nasolacrimal
flow, and anosmia.
Surgery for strabismus
• Should be performed after any necessary orbital decompression.
• Aims to allow correct binocular vision.
• Is performed when eyes are in a quiescent phase for at least 6 months
after active disease.
• Involves alteration, loosening, or tightening of eye muscles, often over
several operations, to improve binocular vision.
Eyelid surgery
Is the final stage of any surgical approach and aims to adjust upper and
lower eyelid position to improve comfort and appearance.
SURGICAL TREATMENT OF GRAVES’S OPHTHALMOPATHY 61
Box 1.8 Treatment of Graves’s ophthalmopathy

General measures
• Stop smoking.
• Dark glasses, with eye protection.
• Control thyroid function to maintain strict euthyroidism.
• Prisms for diplopia.
• Consider selenium supplements.
Specific measures
Problem Treatment
Grittiness Artificial tears and simple eye ointment
Eyelid retraction Tape eyelids at night to avoid corneal damage
Surgery if risk of exposure keratopathy
Proptosis Head elevation during sleep
Diuretics
Systemic steroids
Radiotherapy
Orbital decompression
Ophthalmoplegia Prisms in the acute phase
Orbital muscle surgery
Optic neuropathy Systemic steroids
Radiotherapy
Graves’s dermopathy
• This is a rare complication of Graves’s thyrotoxicosis (0.5%). It
is usually pretibial in location (99%) and hence called pretibial
myxoedema.
• Associated with ophthalmopathy (97%) and acropachy (18%).
• It typically appears as raised, discoloured, and indurated lesions on
the front or back of the legs or on the dorsum of the feet and has
occasionally been described in other areas, including the hands and
the face.
• The lesions are due to localized accumulation of glycosaminoglycans.
It is now recognized that there is a lymphocytic infiltrate. Lesions
are characteristically asymptomatic, but they can also be pruritic and
tender. They can be very disfiguring.
• Treatment. Usually not treated. Potent topical fluorinated steroids,
such as fluocinolone acetonide, may be effective (4–8 weeks), not only
in the treatment of localized pain and tenderness, but also in some
resolution of the visible skin signs. Surgery may worsen the condition.
• 25% remit completely; 50% are chronic on no therapy. A beneficial
effect of topical steroids on remission rates is unproven.
THYROID ACROPACHY 63
Thyroid acropachy
• This is the rarest manifestation of Graves’s disease.
• It presents as clubbing of the digits and subperiosteal new bone
formation. The soft tissue swelling is similar to that seen in localized
myxoedema and consists of glycosaminoglycan accumulation.
• Patients almost inevitably have Graves’s ophthalmopathy or pretibial
myxoedema. If not, an alternative cause of clubbing should be
looked for.
• It is typically painless, and there is no effective treatment.
Further reading
Bahn RS (2010). Graves’s ophthalmopathy. N Engl J Med. 362, 726–38.
Banga JP, Nielsen CH, Gilbert JA, et al. (2008). Application of new therapies in Graves’s disease
and thyroid-associated ophthalmopathy: animal models and translation to human clinical trials.
Thyroid 18, 973–81.
Bartalena L (2010). What to do for moderate-to-severe and active Graves’s orbitopathy if gluco-
corticoids fail? Clin Endocrinol (Oxf). 73, 149–52.
European Group on Graves’s orbitopathy (EUGOGO) (2008). Consensus statement of the
European Group on Graves’s orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol.
158, 273–85.
Hegedüs L, Smith TJ, Douglas RS, et al. (2011). Targeted biological therapies for Graves’s dis-
ease and thyroid-associated ophthalmopathy. Focus on B-cell depletion with Rituximab. Clin
Endocrinol (Oxf). 74, 1–8.
Marcocci C, Kahaly GJ, Krassas GE, et al. (2011). Selenium and the course of mild Graves’s orbit-
opathy. N Engl J Med. 364, 1920–31.
Schwartz KM, Fatourechi V, Ahmed DD, et al. (1992). Dermopathy of Graves’s disease (pretibial
myxedema): long-term outcome. J Clin Endocrinol Metab 87, 438–46.
Stiebel-Kalish H, Robenshtok E, Hasanreisoglu M, et al. (2009). Treatment modalities for Graves’s
ophthalmopathy: systematic review and metaanalysis. J Clin Endocrinol Metab. 94, 2708–16.
Träisk F, Tallstedt L, Abraham-Nordling M, et al. (2009). Thyroid-associated ophthalmopathy after
treatment for Graves’s hyperthyroidism with antithyroid drugs or iodine-131. J Clin Endocrinol
Metab. 94, 3700–7.
The European Group on Graves’s Orbitopathy (2006). Clinical assessment of patients with
Graves’s orbitopathy: recommendations to generalists, specialists and clinical researchers. Eur
J Endocrinol 155, 387–9.
Zang S, Ponto KA, Kahaly GJ (2011). Clinical review: Intravenous glucocorticoids for Graves’s
orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab. 96, 320–32.
Multinodular goitre and solitary

adenomas
Background
Nodular thyroid disease denotes the presence of single or multiple palpa-
ble or non-palpable nodules within the thyroid gland.
• Prevalence rates range from 5–50%, depending on the population
studied and sensitivity of detection methods. Prevalence increases
linearly with age, exposure to ionizing radiation, and iodine deficiency.
• Clinically apparent thyroid nodules are evident in 75% of the UK
population.
• Incidence of thyroid nodules is about 4x more in ♀.
• Thyroid nodules always raise the concern of cancer, but <5% are
cancerous.
Clinical evaluation
• An asymptomatic thyroid mass may be discovered either by a clinician
on routine neck palpation or by the patient during self-examination.
• History should concentrate on:
• An enlarging thyroid mass.
• A previous history of radiation, especially childhood head and neck
irradiation.
• A family history of thyroid cancer.
• The development of hoarseness or dysphagia.
• Nodules are more likely to be malignant in patients <20 or >60 years.
• Thyroid nodules are more common in ♀ but more likely to be
malignant in ♂.
• The risk of malignancy is similar in a patient with a single or multiple
nodules. Thus, a dominant nodule in a multinodular goitre should be
evaluated as if it were a single nodule.
• Physical findings suggestive of malignancy include a firm or hard,
non-tender nodule, a recent history of enlargement, fixation to
adjacent tissue, and the presence of regional lymphadenopathy.
• Pemberton’s sign is facial erythema and jugular venous distension on
raising the arms. It is a sign of superior vena caval obstruction caused
by a substernal mass.
• A hot nodule on a radioisotope scan makes malignancy less likely.
• See Box 1.9 for aetiology of thyroid nodules and Box 1.10 for aetiology
of goitre.
MULTINODULAR GOITRE AND SOLITARY ADENOMAS 65
Box 1.9 Aetiology of thyroid nodules

Common causes Uncommon causes
• Colloid nodule. • Granulomatous thyroiditis.
• Cyst. • Infections.
• Lymphocytic thyroiditis. • Malignancy:
• Benign neoplasms: • Medullary.
• Hürthle cell. • Anaplastic.
• Follicular. • Metastatic.
• Malignancy: • Lymphoma.
• Papillary.
• Follicular.
Clinical features raising the suspicion of thyroid malignancy

• Age (childhood or elderly).
• Short history of enlarging nodule.
• Local symptoms, including dysphagia, stridor, or hoarseness.
• Previous exposure to radiation.
• +ve family history of thyroid cancer or MEN syndrome.
• Gardner’s syndrome (familial large intestinal polyposis).
• Familial polyposis coli.
• Cowden syndrome (autosomal, dominantly inherited multiple
hamartomas and breast, thyroid, and other tumours) b p. 584.
• Lymphadenopathy.
• History of Hashimoto’s disease (i incidence of lymphoma).
• High serum TSH.
Investigations
• FNAC (b see p. 20).
• Serum TSH concentration.
• Respiratory flow loop, especially for a large goitre possibly causing
tracheal obstruction.
• CT scan or MRI if there are concerns about retrosternal goitre or
tracheal compression.
Treatment
Toxic multinodular goitre or nodule
Anti thyroid drugs (ATDs)
ATDs are effective in controlling the hyperthyroidism but are not cura-
tive. As the hot nodules are autonomous, the condition will recur after
stopping the drugs. Carbimazole is useful treatment to gain control of
the disease in preparation for surgery or as long-term treatment in those
patients unwilling to accept radioiodine or surgery.
Radioiodine
• This form of treatment is often considered as first choice for definitive
treatment. 131I is preferentially accumulated in hot nodules but not
in normal thyroid tissue which, because of the thyrotoxic state, is
non-functioning.
• Radioiodine treatment commonly induces a euthyroid state, as
the hot nodules are destroyed and the previously non-functioning
follicles gradually resume normal function. A dose of 500–800MBq for
small-to-medium and 600 or 800MBq for medium-to-large goitres is
recommended.
Surgery
• The aim of surgery is to remove as much of the nodular tissue
as possible and, if the goitre is large, to relieve local symptoms.
Post-operative follow-up should involve checks of thyroid function.
• Goitre recurrence, although rare, does occasionally occur.
Non-toxic multinodular goitre
Surgery
• Is the preferred treatment for patients with:
• Local compression symptoms.
• Cosmetic disfigurement.
• Solitary nodule with FNAC suspicious of malignancy.
Radioiodine
• Radioiodine may be particularly indicated in elderly patients in whom
surgery is not appropriate. It may require admission. Up to 50%
shrinkage of goitre mass has been reported in recent studies.
• Hypothyroidism following radioiodine is relatively infrequent but is
still recognized.
Medical treatment
Use of T4 to suppress TSH is associated with risk of cardiac arrhythmias
and bone loss. T4 is useful only if TSH is detectable but is not generally
indicated.
Box 1.10 Aetiology of goitre

• Autoimmune thyroid disease.
• Sporadic.
• Endemic (iodine deficiency, dietary origins).
• Pregnancy.
• Drug-induced (ATDs, lithium, amiodarone).
• Thyroiditis syndromes.
MULTINODULAR GOITRE AND SOLITARY ADENOMAS 67
Pathology
• Thyroid nodules may be described as adenomas if the follicular cell
differentiation is enclosed within a capsule; adenomatous when the
lesions are circumscribed but not encapsulated.
• The most common benign thyroid tumours are the nodules of
multinodular goitres (colloid nodules) and follicular adenomas. The
oncogene changes accounting for these benign thyroid nodules are
not well delineated. Multinodular goitres are occasionally familial,
which means that the patient has at least one germline mutation. One
familial form of non-toxic multinodular goitre has been linked to DNA
markers on chromosome 14q, but the aetiologic gene is not known.
Follicular adenomas are clonal, and approximately 25% of sporadic
follicular adenomas have a hemizygous deletion of a chromosome
region containing PTEN (MMAC1), the tumour suppressor gene in
which germline defects cause Cowden syndrome (see b p. 584).
• Autonomously functioning thyroid adenomas (or nodules) are benign
tumours that produce thyroid hormone. Clinically, they present as a
single nodule that is hyperfunctioning (‘hot’) on thyroid radionuclide
scan, sometimes causing hyperthyroidism. Many of these tumours are
caused by somatic mutations in genes that code for the TSH receptor
and α subunit of the guanyl nucleotide stimulatory protein (Gs).
• Activating mutations of the TSH receptor produce constitutive
activation of adenylyl cyclase in the absence of TSH. The thyroid
follicular cell with this TSH receptor mutation divides and produces
thyroid hormone without TSH stimulation, eventually becoming
clinically recognized as a hot nodule. Among patients with an
autonomously functioning thyroid adenoma, the frequency of TSH
receptor mutations in the adenoma varies from 75% to 80%. Since
the mutations are scattered throughout the receptor, studies of
the entire receptor are most likely to identify a mutation. In rare
families, germline mutations in the TSH receptor cause hereditary
hyperthyroidism, initially with a diffuse goitre but ultimately with a
nodular goitre with multiple hot nodules.
Thyroid nodules in pregnant women
• Increase in size during gestation.
• Increase in number.
• Need FNA as higher risk of malignancy.
• Can be operated upon in second trimester or post-partum.
Further reading
Bahn RS, Castro MR (2011). Approach to the patient with nontoxic multinodular goiter. J Clin
Boelaert K (2009). The association between serum TSH concentration and thyroid cancer. Endocr
Relat Cancer 16, 1065–72.
Eszlinger M, Jaeschke H, Paschke R (2007). Insights from molecular pathways: potential pharmaco-
logic targets of benign thyroid nodules. Curr Opin Endocrinol Diabetes Obes 14, 393–7.
Fast S, Bonnema SJ, Hegedüs L (2011). Radioiodine therapy of benign non-toxic goitre. Potential
role of recombinant human TSH. Ann Endocrinol (Paris) 72, 129–35.
Lueblinghoff J, Eszlinger M, Jaeschke H, et al. (2011). Shared sporadic and somatic thyrotropin
receptor mutations display more active in vitro activities than familial thyrotropin receptor
mutations. Thyroid 21, 221–9.
Thyroiditis
Background
Inflammation of the thyroid gland often leads to a transient thyrotoxicosis
followed by hypothyroidism. Overt hypothyroidism caused by autoim-
munity has two main forms: Hashimoto’s (goitrous) thyroiditis and atrophic
thyroiditis. See Tables 1.16 and 1.17.
Table 1.16 Causes and characteristics of thyroiditis

Cause Characteristic features
Autoimmune thyroiditis Grossly lymphocytic and fibrotic hypothyroidism
(Hashimoto’s) or thyrotoxicosis
Post-partum thyroiditis Lymphocytic thyroiditis, transient thyrotoxicosis
or hypothyroidism
Drug-induced Amiodarone and interferon alfa
Subacute (de Quervain’s) Thought to be viral in origin, multinuclear giant
cells
Riedel’s thyroiditis Extensive fibrosis of the thyroid
Radiation thyroiditis Radiation injury, transient thyrotoxicosis
Pyogenic (rare) Staphylococcus aureus, streptococci, Escherichia coli,
tuberculosis, fungal
Table 1.17 Clinical presentation of thyroiditis

Form of Clinical presentation Thyroid function
thyroiditis
Suppurative Painful, tender thyroid, fever Usually normal
(acute)
Subacute (de Painful anterior neck, arthralgia, Early thyrotoxicosis,
Quervain’s) antecedent upper respiratory tract occasionally late
infection, generalized malaise hypothyroidism
Autoimmune Hashimoto’s: goitre Usually hypothyroid
Atrophic: no goitre Sometimes euthyroid
Rarely early
thyrotoxicosis
Riedel’s Hard, woody consistency of thyroid Usually normal
THYROIDITIS 69
Chronic autoimmune (atrophic or

Hashimoto’s) thyroiditis
(See Tables 1.16 and 1.17.)
• Hashimoto’s thyroiditis. Characterized by a painless, variably-sized goitre
with rubbery consistency and an irregular surface. The normal follicular
structure of the gland is extensively replaced by lymphocytic and
plasma cell infiltrates, with the formation of lymphoid germinal centres.
The patient may have normal thyroid function or subclinical or overt
hypothyroidism. Occasionally, patients present with thyrotoxicosis in
association with a thyroid gland that is unusually firm and with high
titres of circulating antithyroid antibodies.
• Atrophic thyroiditis. Probably indicates end-stage thyroid disease. These
patients do not have goitre and are antibody +ve. Biochemically, the
picture is that of frank hypothyroidism.
Investigations
Investigations which are useful in establishing a diagnosis of Hashimoto’s
thyroiditis include:
• Testing of thyroid function.
• Thyroid antibodies (antithyroglobulin antibodies +ve in 20–25% and
antithyroperoxidase antibodies in >90%).
• Occasionally, a thyroid biopsy to exclude malignancy in patients who
present with a goitre and dominant nodule.
Prognosis
The long-term prognosis of patients with chronic thyroiditis is good
because hypothyroidism can easily be corrected with T4 and the goitre is
not usually of sufficient size to cause local symptoms. In the atypical situ-
ation where Hashimoto’s thyroiditis presents with rapidly enlarging goitre
and pain, a short course of prednisolone at a dose of 40mg daily may
prove helpful.
Any unusual increase in size of the thyroid in patients known to suffer
from Hashimoto’s thyroiditis should be investigated with an FNA and, pos-
sibly later, a biopsy since there is an association between this condition
and thyroid lymphoma (rare, but risk i by a factor of 70).
CHRONIC AUTOIMMUNE THYROIDITIS 71
Other types of thyroiditis

Silent thyroiditis
Associated with transient thyrotoxicosis or hypothyroidism. A significant
percentage of patients have a personal or family history of autoimmune
thyroid disease. It may progress to permanent hypothyroidism. There is a
depressed radionuclide uptake.
b also see pp. 46, 432. Thyroid dysfunction occurring within the first
6 months post-partum. Prevalence ranges from 5% to 7%. Post-partum
thyroiditis develops in 30–52% of ♀ who have +ve thyroid peroxidase
(TPO) antibodies. Most patients have a complete remission, but some may
progress to permanent hypothyroidism. It is thrice as common in patients
with type 1 diabetes mellitus.
Chronic fibrosing (Riedel’s) thyroiditis
A rare disorder characterized by intense fibrosis of the thyroid gland and
surrounding structures, leading to induration of the tissues of the neck.
May be associated with mediastinal and retroperitoneal fibrosis, salivary
gland fibrosis, sclerosing cholangitis, lacrimal gland fibrosis, and parathy-
roid gland fibrosis leading to hypoparathyroidism. Patients are usually
euthyroid. Main differential diagnosis is thyroid neoplasia.
Management
Corticosteroids are usually ineffective. Surgery may be required to relieve
obstruction and to exclude malignancy. Tamoxifen may be of benefit.
Pyogenic thyroiditis
• Rare. Usually anteceded by a pyogenic infection elsewhere.
Characterized by tenderness and swelling of the thyroid gland, redness
and warmth of the overlying skin, and constitutional signs of infection.
• Piriform sinus infection should be excluded. Excision of tract is
preferable to incision and drainage.
• Treatment consists of antibiotic therapy and incision and drainage if a
fluctuant area within the thyroid should occur.
Subacute thyroiditis (granulomatous, giant cell,
or de Quervain’s thyroiditis)
• Viral in origin. Symptoms include pronounced asthenia, malaise, pain
over the thyroid, or pain referred to lower jaw, ear, or occiput. Less
commonly, the onset is acute, with fever, pain over the thyroid,
and symptoms of thyrotoxicosis. Characteristically, signs include
exquisite tenderness and nodularity of the thyroid gland. There is
characteristically an elevated ESR/CRP and a depressed radionuclide
(99mTc can be used) uptake. Biochemically, the patient may be initially
thyrotoxic, though later the patient may become hypothyroid (15%).
OTHER TYPES OF THYROIDITIS 73
• In mild cases, non-steroidal anti-inflammatory agents and paracetamol

offer symptom relief. In severe cases, glucocorticoids (prednisolone
20–40mg/day) are effective. Propranolol can be used to control
associated thyrotoxicosis. Treatment can be withdrawn when T4
returns to normal. T4 replacement is required if the patient becomes
hypothyroid. Treatment with carbimazole or propylthiouracil is not
indicated.
Drug-induced thyroiditis
Causes include:
• Amiodarone.
• Lithium.
• Interferon alfa (15% develop thyroid peroxidase antibodies and/or
thyroid dysfunction).
• Interleukin 2.
Further reading
Costelloe SJ, Wassef N, Schulz J, et al. (2010). Thyroid dysfunction in a UK hepatitis C population
treated with interferon-alpha and ribavirin combination therapy. Clin Endocrinol (Oxf) 73, 249–56.
Fatourechi MM, Hay ID, McIver B, et al. (2011). Invasive fibrous thyroiditis (Riedel thyroiditis): the
Mayo Clinic experience, 1976-2008. Thyroid 21, 765–72.
Lazarus JH, Hall R, Othman S, et al. (1996). The clinical spectrum of postpartum thyroid disease.
QJM 89, 429–35.
Paes JE, Burman KD, Cohen J, et al. (2010). Acute bacterial suppurative thyroiditis: a clinical review
and expert opinion. Thyroid 20, 247–55.
Pearce EN, Farwell AP, Braverman LE (2003). Thyroiditis. New Engl J Med 348, 2646–55.
Premawardhana LD, Parkes AB, Ammari F, et al. (2000). Postpartum thyroiditis and long-term thy-
roid status: prognostic influence of thyroid peroxidase antibodies and ultrasound echogenicity.
J Clin Endocrinol Metab 85, 71–5.
Weetman AP (2004). Autoimmune thyroid disease. Autoimmunity 37, 337–40.
Weetman AP (2011). Diseases associated with thyroid autoimmunity: explanations for the expand-
ing spectrum. Clin Endocrinol (Oxf) 74, 411–18.
Hypothyroidism
Background
Hypothyroidism results from a variety of abnormalities that cause insuf-
ficient secretion of thyroid hormones (see Table 1.18). The commonest
cause is autoimmune thyroid disease. Myxoedema is severe hypothyroid-
ism in which there is accumulation of hydrophilic mucopolysaccharides in
the ground substance of the dermis and other tissues, leading to thickening
of the facial features and a doughy induration of the skin. See Box 1.11 for
pitfalls with the thyroid function tests in non-thyroidal illness.
Epidemiology
• High TSH (>5.0) in 7.5% of ♀ and 2.5% of ♂ >65 years, 1.7% overt
hypothyroidism, 13.7% subclinical hypothyroidism (Whickham Survey, UK).
• Incidence higher in whites than Hispanics or African-American
populations.
• Incidence higher in areas of high iodine intake.
• An elevated TSH is associated with higher serum lipid concentrations,
which may be an additional reason to initiate therapy.
Clinical picture
Adult
• Insidious, non-specific onset.
• Fatigue, lethargy, constipation, cold intolerance, muscle stiffness, cramps,
carpal tunnel syndrome, menorrhagia, later oligo- or amenorrhoea.
• Slowing of intellectual and motor activities.
• d appetite and weight gain.
• Dry skin; hair loss.
• Deep hoarse voice, d visual acuity.
• Obstructive sleep apnoea.
Myxoedema
• Dull expressionless face, sparse hair, periorbital puffiness, macroglossia.
• Pale, cool skin that feels rough and doughy.
• Enlarged heart (dilation and pericardial effusion).
• Megacolon/intestinal obstruction.
• Cerebellar ataxia.
• Prolonged relaxation phase of deep tendon reflexes.
• Peripheral neuropathy.
• Encephalopathy.
• Hyperlipidaemia.
• Hypercarotenaemia (also caused by hyperlipidaemia, diabetes mellitus,
anorexia, and porphyria).
• Psychiatric symptoms, e.g. depression, psychosis.
• Marked respiratory depression with i arterial PCO2.
• Hyponatraemia from impaired water excretion and disordered
regulation of vasopressin secretion.
Myxoedema coma
• Predisposed to by cold exposure, trauma, infection, administration of
central nervous system depressants.
HYPOTHYROIDISM 75
Table 1.18 Classification of the causes of hypothyroidism

TSH Free T4
Non-goitrous i d
Post-ablative (radioiodine, surgery)
Congenital development defect
Atrophic thyroiditis
Post-radiation (e.g. for lymphoma)
Goitrous i d
Chronic thyroiditis (Hashimoto’s thyroiditis)
Transient, 2–8 weeks (de Quervain’s thyroiditis)
Iodine deficiency
Drug-elicited (amiodarone, aminosalicylic acid, iodides,
phenylbutazone, lithium, aminoglutethimide, interferon
alfa, thalidomide, sunitinib, rifampicin, stavudine)
Haemochromatosis
Heritable biosynthetic defects
Maternally transmitted (antithyroid agents, iodides)
Pituitary d d
Panhypopituitarism
Isolated TSH deficiency
Drugs (bexarotene)
Hypothalamic d d
Neoplasm
Infiltrative (sarcoidosis)
Congenital defects
Infection (encephalitis)
Self-limiting i d
Following withdrawal of suppressive thyroid therapy
Subacute thyroiditis and chronic thyroiditis with
transient hypothyroidism
Box 1.11 Pitfalls with the thyroid function tests in

non-thyroidal illness
• TSH suppressed in hospitalized patients with acute illness.
• Dopamine and steroids may suppress TSH, e.g. in critically ill
patients.
• TSH increase during recovery from acute illness.
• TSH may fall during first trimester of pregnancy (hCG).
• TSH inhibited by subcutaneous octreotide.
• Anorexia nervosa is associated with low TSH and FT4.
• Heterophilic antibodies, including rheumatoid factor, may falsely
elevate TSH.
• Adrenal insufficiency may be associated with a raised TSH which
reverses on treatment with glucocorticoids.
HYPOTHYROIDISM 77
Subclinical hypothyroidism
• This term is used to denote raised TSH levels in the presence of
normal concentrations of free thyroid hormones.
• Treatment is indicated if the biochemistry is sustained in patients
with a past history of radioiodine treatment for thyrotoxicosis or
+ve thyroid antibodies as, in these situations, progression to overt
hypothyroidism is almost inevitable (at least 5% per year of those with
+ve antithyroid peroxidase antibodies).
• Two samples should be taken 2–3 months apart to distinguish from
non-thyroidal illness.
• The reference range for serum TSH rises with age.
• There is controversy over the advantages of T4 treatment in patients
with –ve thyroid antibodies and no previous radioiodine treatment.
• If treatment is not given, follow-up with annual thyroid function tests is
important.
• There is no generally accepted consensus of when patients should
receive treatment. Some authorities suggest treatment when
serum TSH is >10mU/L because of i rate of progression to overt
hypothyroidism. Below that, if the TSH is raised, treatment is geared
to the individual patient.
• Increased incidence of cardiovascular risk, probably greater if
<65 years old.
• There is some evidence that women with autoimmune thyroiditis are
more likely to have an increased risk of recurrent miscarriage, although
it is not known whether the risk is related to thyroid autoimmunity or
to subtle thyroid failure. In this situation, there may be an advantage to
giving thyroxine if TSH is between 2.5 and 5mU/L.
• Acceleration of thyroid hormone metabolism during pregnancy can
lead to hypothyroidism in women with a limited thyroid hormone
reserve. If untreated, mild hypothyroidism can lead to subtle
impairment of subsequent childhood neuropsychological development.
Early correction of maternal hypothyroxinaemia is recommended,
aiming to maintain serum TSH in the lower half of the reference range
prior to conception, if possible.
Management
• If serum TSH is >10mU/L, then levothyroxine is indicated.
• If serum TSH is mildly increased between 4–10mU/L and the patient
is TPO antibody +ve, an annual check of serum TSH is recommended,
with commencement of levothyroxine once serum TSH >10mU/L.
• If the patient is thyroid antibody –ve, then ensuring a check of serum
TSH every 3–5 years is all that is required.
• If the patient with a serum TSH 4–10mU/L has symptoms consistent
with hypothyroidism and the TSH elevation persists, then a
3–6 months’ therapeutic trial of levothyroxine appears justified. If
the patient feels improved by therapy, it is reasonable to continue
treatment.
SUBCLINICAL HYPOTHYROIDISM 79
• If the patient with serum TSH 4–10U/L does not have symptoms and
the serum TSH level appears stable with +ve TPO antibodies, the
annual risk of progression to overt hypothyroidism is 4% per year,
and so an annual serum TSH surveillance strategy is warranted. If
the TPO antibodies are –ve, then 3-yearly serum TSH surveillance is
recommended, with a risk of progression to overt hypothyroidism of
3% per year.
• The exception to the above is in neonates and children, pregnancy, or
in someone trying to conceive when a mildly increased serum TSH
should always be treated, as it is associated with adverse outcomes for
both mother and fetus.
• Recent data suggest that levothyroxine treatment for those with serum
TSH 5–10U/L may also now be justified in subjects <65 years and in
those older subjects with documented evidence of heart failure on
echocardiography.
Treatment of hypothyroidism
Note that patients in the UK with hypothyroidism are entitled to a medical
exemption certificate for prescription charges.
• Thyroid hormone replacement with synthetic levothyroxine remains
the treatment of choice in primary hypothyroidism. See Table 1.19 for
excipient content in case of intolerance.
• Levothyroxine with a long half-life enables the patient to take two
doses at once if a dose is omitted.
• Normal metabolic state should be restored gradually, as a rapid
increase in metabolic rate may precipitate cardiac arrhythmias.
• The average replacement dose is 1.6–1.8 micrograms/kg/day.
• To avoid iatrogenic subclinical disease, fasting ingestion of
levothyroxine is best either in the morning or the evening.
• In the younger patients, start levothyroxine at 50–100 micrograms. In
the elderly with a history of ischaemic heart disease, an initial dose of
levothyroxine 25–50 micrograms can be i by 25 micrograms increments
at 4-week intervals until normal metabolic state and TSH is attained.
• Optimum dose is determined by clinical criteria, the objective of
treatment being to restore serum TSH to the normal range.
• TSH should be checked only 6 weeks after any dose change. Once
stabilized, TSH should be checked on an annual basis. Patients should
stay on the same brand of levothyroxine as far as is possible—
otherwise, TSH should be checked at 2 months.
• Muscle problems may take up to 6 months to fully recover.
• It is estimated that 5% of hypothyroid patients remain symptomatic
in spite of levothyroxine replacement and normal serum TSH
concentrations. Possible causes include awareness of a chronic
disease, presence of associated autoimmune diseases, and thyroid
autoimmunity per se (independent of thyroid function).
• In those patients who remain symptomatic and in whom serum TSH
remains towards the upper end of the reference range, it is usual
practice for the dose of levothyroxine to be increased slightly to target
a serum TSH at the lower end of the reference range (≤2.5mU/L).
Whether or not such small changes in serum TSH within the reference
range are associated with symptoms is uncertain.
• Patients with iatrogenic hyperthyroidism (serum TSH <0.03U/L) have a
significantly increased risk of arrhythmia and fractures.
• In most trials, combination levothyroxine-T3 therapy does not appear
to be superior to levothyroxine monotherapy for the management of
hypothyroid symptoms. In three trials, patients preferred combined
therapy to levothyroxine monotherapy; however, in one of those
studies, patients were given doses of thyroid hormone which resulted
in mild hyperthyroidism. In general, clinical trials of combination
levothyroxine-T3 therapy have not successfully replicated physiological
T4-T3 production. Forty micrograms of T3 is approximately equivalent
to 0.125mg of T4.
• One study has suggested that a small group of patients with a
polymorphism in D2 may benefit from levothyroxine-T3 therapy.
Table 1.19 Excipient content of generic levothyroxine tablets
Manufacturer Goldshield Norton/IVAX Cox/Alpharma APS/Berk CP Pharmaceuticals Hillcross
(manufactured (50 + 100 (50 + 100 (only make 25 25 micrograms 50/
by Goldshield) micrograms micrograms micrograms) mic
Excipient only)* only)*
Thyroxine       
Lactose       
Sucrose  
Dextrin 
Maize starch       
Magnesium stearate       
Pre-gelatinized maize  
starch
Stearic acid  
Water  (50 + 100   
micrograms)
Sodium citrate  
Powdered acacia  
* 25 microgram tablets made by Goldshield.
Hillcross: 25 micrograms are manufactured by CP Pharmaceuticals; 50 and 100 micrograms are manufactured by Alpharma.
Norton/IVAX: 25, 50, and 100 micrograms are manufactured by Goldshield.
Data from Drug Information department of each manufacturer, August 2004.
• Dessicated animal thyroid extracts (e.g. thyroid Armour) contain an

excessive amount of T3 and are not consistent with normal physiology.
• In patients with s hypothyroidism, free T4 is the most useful
parameter to follow.
• Dose requirements can increase by 25–50% in pregnancy due to the
increase in thyroid-binding globulin (TBG). Recent data have shown
that mild maternal hypothyroidism in the first trimester is associated
with slightly impaired cognitive function in offspring. Thus, it is now
recommended to routinely i levothyroxine dose by 25 micrograms
in any ♀ on replacement therapy when she learns she is pregnant.
Management of myxoedema coma
• Identify and treat concurrent precipitating illness.
• Antibiotic therapy after blood cultures.
• Management of hypothermia by passive external rewarming.
• Manage in intensive treatment unit if comatose.
• Give warm humidified oxygen by face mask. Mechanical ventilation
needed if hypoventilating.
• Aim for slow rise in core temperature (0.5°C/h).
• Cardiac monitor for supraventricular arrhythmias.
• Correct hyponatraemia (mild fluid restriction), hypotension (cautious
volume expansion with crystalloid or whole blood), and hypoglycaemia
(glucose administration).
• Monitor rectal temperature, oxygen saturation, BP, CVP, and urine
output hourly.
• Take blood samples for thyroid hormones, TSH, and cortisol before
starting treatment. If hypocortisolaemic, administer glucocorticoids.
• Thyroid hormone replacement: no consensus has been reached. The
following is an accepted regimen:
• T4 300–500 micrograms IV or by NG tube as a starting dose, followed
by 50–100 micrograms daily until oral medication can be taken.
• If no improvement within 24–48h, T3 10 micrograms IV 8-hourly or
25 micrograms IV 8-hourly can be given in addition to above.
• Give hydrocortisone 50–100mg 6–8-hourly in case of cortisol deficiency.
Management of persistently elevated TSH despite
thyroxine replacement
(See Fig. 1.2).
• As levothyroxine has a narrow therapeutic index, the margin between
over- and underdosing can be small.
• Elevated TSH despite thyroxine replacement is common, most usually
due to lack of compliance.
• If TSH still elevated when levothyroxine dose at 1.6 micrograms/kg/day
or higher, careful questioning of compliance is needed.
• Consider malabsorption.
• Consider other drugs that may interfere with levothyroxine absorption
(see Box 1.12).
TREATMENT OF HYPOTHYROIDISM 83
TSH rising/not in normal range
Question compliance
Compliance Lack of compliance—encourage

assured compliance and recheck TSH in
–ve antibodies 3 months
? Other ? Malabsorption—check +ve antibodies
malabsorption coeliac antibodies
Confirm
Consider thyroxine absorption test +/– diagnosis and
supervised weekly dose administration treat
(single dose = 7 × 1.6 mcg/kg) with TSH
monitoring monthly.
Fig. 1.2 Suggestions for investigations of elevated TSH despite levothyroxine

replacement therapy to >1.6 micrograms/kg/day.
Box 1.12 Interference with absorption of thyroxine

• Coeliac disease.
• Drugs: i clearance of thyroxine—rifampicin, phenytoin,
phenobarbital, carbamazepine, imatinib; d absorption of thyroxine—
calcium salts, ferrous sulfate, aluminium hydroxide, colestyramine,
omeprazole, sucralfate.
• Atrophic gastritis in Helicobacter pylori infection (d T4 by 30%).
Congenital hypothyroidism
Incidence—about 1 in 3,500–4,000 neonates. All neonates should be
screened. There is an inverse relationship between age at diagnosis and
intelligence quotient (IQ) in later life. In iodine-replete areas, 85% of the
cases are due to sporadic developmental defects of the thyroid gland (thy-
roid dysgenesis), such as the arrested migration of the embryonic thyroid
(ectopic thyroid) or a complete absence of thyroid tissue (athyreosis).
The remaining 15% have thyroid dyshormonogenesis defects transmitted
by an autosomal recessive mode of inheritance. See Box 1.13 for clinical
features.
Thyroid hormone dysgenesis
• Caused by inborn errors of thyroid metabolism. The disorders may be
autosomal recessive, indicating single protein defects.
• Can be caused by inactivation of the TSH receptor, abnormalities
of the thyroid transcription factors TTF1, TTF2, and PAX8, or due
to defects in iodide transport, organification (peroxidase), coupling,
deiodinase, or thyroglobulin synthesis.
• In a large proportion of patients with congenital hypothyroidism, the
molecular background is unknown.
Pendred’s syndrome
Characterized by overt or subclinical hypothyroidism, goitre, and
moderate-to-severe sensorineural hearing impairment. The prevalence
varies between 1 in 15,000 and 1 in 100,000. There is a partial iodide
organification defect detected by i perchlorate discharge. Thyroid hor-
mone synthesis is only mildly impaired and so may not be detected by
neonatal thyroid screening.
Box 1.13 Clinical features and congenital hypothyroidism

The following features are late sequelae of congenital hypothyroid-
ism and, with routine screening now available, should never be seen
nowadays.
• Physiological jaundice.
• Goitre.
• Hoarse cry, feeding problems, constipation, somnolence.
• Delay in reaching normal milestones of development, short stature.
• Coarse features with protruding tongue, broad flat nose, widely
set eyes.
• Sparse hair and dry skin, protuberant abdomen with umbilical hernia.
• Impaired mental development, retarded bone age.
• Epiphyseal dysgenesis, delayed dentition.
CONGENITAL HYPOTHYROIDISM 85
Laboratory tests
• Neonatal screening by measurement of serum TSH.
• Imaging procedure: ultrasonography or 123I scintigraphy.
• Measurement of serum thyroglobulin and low molecular weight
iodopeptides in urine to discriminate between the various types of
defects.
• Measurement of neonatal and maternal autoantibodies as an indication
of possible transient hypothyroidism.
Treatment
Irrespective of the cause of congenital hypothyroidism, early treatment
is essential to prevent cerebral damage. Sufficient T4 should be given to
maintain the TSH in the normal range.
Further reading
Biondi B, Cooper DC (2008). The clinical significance of subclinical thyroid dysfunction. Endocr
Rev 29, 76–131.
Escobar-Morales HF, Botella-Carretero JI, Escobar del Rey F, et al. (2005). Treatment of hypo-
thyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metab 90,
4949–54.
Flynn RW, Bonellie SR, Jung RT, et al. (2010). Serum thyroid-stimulating hormone concentration
and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine
therapy. J Clin Endocrinol Metab 95, 186–93.
Garber JR, Cobin RH, Gharib H, et al. (2012). Clinical practice guidelines for hypothyroidism in
adults. Thyroid 22, 1–32.
Grozinsky-Glasberg S, Fraser A, Nahshoni E, et al. (2006). L. Thyroxine-triiodothyronine com-
bination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of
randomized controlled trials. J Clin Endocrinol Metab 91, 2592–9.
Grüters A, Krude H (2007). Update on the management of congenital hypothyroidism. Horm Res
68(Suppl 5), 107–111.
Hennemann G, Docter R, Visser TJ, et al. (2004). Thyroxine plus low-dose, slow-release triiodothy-
ronine replacement in hypothyroidism: proof of principle. Thyroid 14, 271–5.
Nygaard B, Jensen EW, Kvetny J, et al. (2009). Effect of combination therapy with thyroxine
(T4) and 3,5,3’-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a
double-blind, randomised cross-over study. Eur J Endocrinol 161, 895–902.
Okosieme OE, Belludi G, Spittle K, et al. (2011). Adequacy of thyroid hormone replacement in a
general population. QJM 104, 395–401.
Roberts CG, Ladenson PW (2004). Hypothyroidism. Lancet 363, 793–803.
Rodondi N, den Elzen WP, Bauer DC, et al. (2010). Subclinical hypothyroidism and the risk of
coronary heart disease and mortality. JAMA 304, 1365–74.
Royal College of Physicians (2011). The diagnosis and management of primary hypothyroidism.
Royal College of Physicians, London.
Taylor PN, Panicker V, Sayers A, et al. (2011). A meta-analysis of the associations between com-
mon variation in the PDE8B gene and thyroid hormone parameters, including assessment of
longitudinal stability of associations over time and effect of thyroid hormone replacement. Eur
J Endocrinol 164, 773–80.
Vaidya B, Pearce SH (2008). Management of hypothyroidism. BMJ 337, a801.
Vanderpump MP (2010). How should we manage patients with mildly increased serum thyrotro-
phin concentrations? Clin Endocrinol (Oxf) 72, 436–40.
Amiodarone and thyroid function

Background
• Amiodarone has a high concentration of iodine (39% by weight). It is
a benzofuranic derivative, and its structural formula closely resembles
that of thyroxine. On a dose of amiodarone between 200 and 600mg
daily, 7–21mg iodine is made available each day. The optimal daily
iodine intake is 150–200 micrograms. Amiodarone is distributed in
several tissues from where it is slowly released. In one study, terminal
elimination half-life of amiodarone averaged 52.6 days, with a standard
deviation of 23.7 days.
• Abnormalities of thyroid function occur in up to 50% of patients (see
Table 1.20).
• In the UK and USA, 2% of patients on amiodarone develop
thyrotoxicosis and about 13% develop hypothyroidism.
• Patients residing in areas with high iodine intake develop
amiodarone-induced hypothyroidism (AIH) more often than
amiodarone-induced thyrotoxicosis (AIT), but AIT occurs more
frequently in regions with low iodine intake.
• AIT can present several months after discontinuing the drug because
of its long half-life.
• Hypothyroidism is commoner in ♀ and in patients with thyroid
autoantibodies.
• Thyroid function tests should be monitored initially prior and then
every 6 months in patients taking amiodarone.
• Other side effects and complications occur (see Table 1.22).
• Dronedarone is a non-iodinated benzofuran derivative with
multichannel blocking effects and anti-adrenergic properties. Although
it is an antagonist of TRα1 and TRB1 isoforms, it has little impact on
thyroid hormones.
Pathogenesis
• The high iodine content of amiodarone may inhibit thyroglobulin
iodination and thyroid hormone synthesis and release, causing AIH
(Wolff–Chaikoff effect), or lead to iodine-induced hyperthyroidism in
susceptible individuals (Jod-Basedow phenomenon).
• Amiodarone also inhibits monodeiodination of T4, thus decreasing T3
production, and blocks T3 binding to nuclear receptors.
• Thyrotoxicosis resulting from iodine excess, and therefore i hormone
synthesis, is referred to as AIT type I. Thyrotoxicosis due to a direct
toxic effect of amiodarone (thyroiditis) is referred to as AIT type II (see
Table 1.21).
• Drug-induced destructive thyroiditis results in leakage of thyroid
hormones from damaged follicles into the circulation and, like
subacute thyroiditis, can be followed by a transient hypothyroid state
before euthyroidism is restored.
AMIODARONE AND THYROID FUNCTION 87
Table 1.20 Thyroid function tests in clinically euthyroid patients after

administration of amiodarone
Tests 1–3 months >3 months
Free T3 Decreased Remains slightly decreased but within
normal range
TSH Transient increase Normal
Free T4 Modest increase Slightly increased compared to
pretreatment values, may be in normal
range or slightly increased
Reverse T3 Increased Increased
Table 1.21 Characteristics of AIT (some patients have a mixed form,

and classification is not always possible)
AIT type I (10%) AIT type II (90%)
Aetiology Iodine toxicity Thyroiditis
Signs of clinical thyroid disease Yes No
Goitre Frequent Infrequent
Thyroid antibodies Positive Negative
Radioiodine uptake Normal Decreased
Thyroglobulin Normal or slightly Very elevated
elevated
Late hypothyroidism No Possible
Vascularity (Doppler) Increased/normal Reduced
Diagnosis and treatment

(See Table 1.22.)
• After chronic administration of amiodarone, a steady state is achieved,
typically reflected in mild elevation of free T4 and reduction in free T3.
Thus, in clinically euthyroid patients on amiodarone, a slightly elevated
T4 is neither indicative of hyperthyroidism nor is a low T3 indicative of
hypothyroidism.
• Hyperthyroidism is indicated by significantly i free T4, together with
elevated free T3 and suppressed serum TSH.
• Hypothyroidism is indicated by elevation of TSH, with low serum free
T4. Levothyroxine replacement is almost always considered for those
with serum TSH >20U/L. If serum TSH is between 5 and 20U/L, the
value of levothyroxine replacement can be judged on clinical grounds,
such as abnormality of diastolic function, which can be reversible.
If serum free T4 is below the reference range, then levothyroxine
replacement is usually indicated.
• Discontinuation of amiodarone does not always control the thyrotoxic

state because of its long half-life (particularly in the obese) due to its
very high volume of distribution and fat solubility.
• Numerous complex published algorithms exist for management,
but, since classification into type I and type II is often difficult (see
Table 1.22), in practice, most patients are treated with ATDs ±
glucocorticoids (see Table 1.23).
• There is often reluctance amongst endocrinologists to use relatively
high-dose glucocorticoid therapy, particularly in an elderly patient
group with significant comorbidities who may often present
asymptomatically with a mild, and often self-limiting, disease, but
evidence exists that early use of glucocorticoid therapy is safe and
effective in patients with AIT type II.
• If there is doubt as to whether a patient has AIT type I or type II, a
regimen of 40mg of carbimazole and 40mg of prednisolone daily for 2
weeks, followed by measurement of serum T3 does seem a reasonable
initial strategy. If there is a reduction in serum T3 by >50%, compared
to pretreatment levels, then carbimazole is stopped, as the diagnosis
of AIT type II is suggested. Prednisolone can then be continued in a
tapering dose, reducing course over 2–3 months, according to the
clinical and biochemical response. If there is no change in serum T3
levels following initial treatment, prednisolone can be stopped and
carbimazole is continued, as the assumption is that the predominant
diagnosis is AIT type I.
• Radioiodine is not usually effective because of reduced uptake by the
thyroid gland, reflecting the iodine load associated with the drug.
• Surgery remains a very successful form of treatment, with
euthyroidism being restored within a matter of days. Achieving
preoperative euthyroidism may be difficult, however.
• Cardiac function may be compromised by propranolol used in
combination with amiodarone since this may produce bradycardia and
sinus arrest.
• Potassium perchlorate inhibits iodide uptake by the thyroid gland,
reduces intrathyroidal iodine, and renders thionamides more effective.
It can be given as a 1g daily dose, together with carbimazole, a regimen
shown to restore euthyroidism in a large percentage of patients
with both type I and type II AIT. In small case studies, a combination
of potassium perchlorate and carbimazole has been effective while
treatment with amiodarone was continued.
• See Box 1.14 for treatment of amiodarone-induced hypothyroidism.
AMIODARONE AND THYROID FUNCTION 89
Box 1.14 Treatment of amiodarone-induced

hypothyroidism
Underlying thyroid abnormality (usually Hashimoto’s thyroiditis)
• Amiodarone therapy can be continued.
• Add thyroxine replacement therapy.
Apparently normal thyroid
• Discontinue amiodarone, if possible, and follow up for restoration of
euthyrodism.
• If amiodarone cannot be withdrawn, start thyroxine replacement
therapy.
Table 1.22 Side effects and complications of amiodarone therapy

Side effect Incidence (%)
Corneal microdeposits 100
Anorexia and nausea 80
Photosensitivity, blue/grey skin discoloration 55–75
Ataxia, tremors, peripheral neuropathy 48
Deranged liver function tests 25
Abnormal thyroid function tests 14–18
Interstitial pneumonitis 10–13
Cardiac arrhythmias 2–3
Table 1.23 Treatment of amiodarone-induced thyrotoxicosis

Type I AIT Type II AIT
Step 1: Carbimazole up to 40mg/ Discontinue amiodarone, if
Aim to day or propylthiouracil possible*
restore 400mg/day, in combination, Prednisolone 40mg/day
euthyroidism if necessary, with potassium In mixed forms, add
perchlorate 1g/day for carbimazole or propylthiouracil
16–40 days as in type I AIT
If possible, discontinue
amiodarone*
Step 2: Radioiodine treatment or Follow-up for possible
Definitive thyroidectomy spontaneous progression to
treatment hypothyroidism
* If amiodarone cannot be withdrawn and medical therapy is unsuccessful, consider total
thyroidectomy.
Further reading
Bogazzi F, Bartalena L, Dell’Unto E, et al. (2007). Proportion of type 1 and type 2 amiodarone-induced
thyrotoxicosis has changed over a 27-year period in Italy. Clin Endocrinol (Oxf) 67, 533–7.
Bogazzi F, Bartalena L, Martino E (2010). Approach to the patient with amiodarone-induced thyro-
toxicosis. J Clin Endocrinol Metab 95, 2529–35.
Bogazzi F, Tomisti L, Rossi G, et al. (2009). Glucocorticoids are preferable to thionamides as
first-line treatment for amiodarone-induced thyrotoxicosis due to destructive thyroidi-
tis: A matched retrospective cohort study. J Clin Endocrinol Metab 94, 3757–62.
Franklyn JA, Gammage MD (2007). Treatment of amiodarone-associated thyrotoxicosis. Nat Clin
Pract Endocrinol Metab 3, 662–6.
Han T, Williams GR, Vanderpump MP (2009). Benzofuran derivatives and the thyroid. Clin
Endocrinol (Oxf) 70, 2–13.
Loy M, Perra E, Mellis A, et al. (2007). Color-flow doppler sonography in the differential diagnosis
and management of amiodarone-induced thyrotoxicosis. Acta Radiol 48, 628–34.
Tanda ML, Piantanida E, Lai A, et al. (2008). Diagnosis and management of amiodarone-induced
thyrotoxicosis: similarities and differences between North American and European thyroidolo-
gists. Clin Endocrinol (Oxf) 69, 812–18.
EPIDEMIOLOGY OF THYROID CANCER 91
Epidemiology of thyroid cancer

• Clinical presentation of thyroid cancer is usually as a solitary thyroid
nodule or increasing goitre size (see Tables 1.24 and 1.25).
• Although thyroid nodules are common, clinically detectable thyroid cancer
is rare. It accounts for <1% of all cancer and <0.5% of cancer deaths.
• The incidence of thyroid cancer is increasing, with the majority of the
increase attributable to an increase in incidence of papillary thyroid
cancer measuring ≤2cm.
• Papillary thyroid microcarcinomas (diameter <1cm) are found in up to
one-third of adults at post-mortem in population-based studies.
• Thyroid cancers are commonest in adults aged 40–50 and rare in
children and adolescents.
• ♀ are affected more frequently than ♂.
Table 1.24 Classification of thyroid cancer

Cell of origin Tumour type Frequency (%)
Differentiated:
Papillary >80
Follicular 10
Undifferentiated (anaplastic) 1–5
C cells Medullary 5–10
Lymphocytes Lymphoma 1–5
Table 1.25 Comparison of papillary, follicular and anaplastic

carcinomas (Ca) of the thyroid
Characteristic Papillary Ca Follicular Ca Anaplastic Ca
Age at 30–50 (mean 44) 40–50 60–80
presentation
(years)
Spread Lymphatic Haematogenous Haematogenous
Prognosis Good Good Poor
Treatment Initially: near total Initially: near total Total
thyroidectomy thyroidectomy thyroidectomy
Post-operative TSH Post-operative TSH with lymph node
suppression suppression clearance
High-risk patient:
131
I remnant Chemotherapy
131
I remnant ablation ablation with doxorubicin
Post-operative total Post-operative and cisplatin
body radioiodine total body External beam
scan + thyroglobulin radioiodine scan irradiation
measurement + thyroglobulin
measurement
Aetiology of thyroid cancer

(See Tables 1.26 and 1.27.)
Irradiation
• There does not appear to be a threshold dose of external irradiation
for thyroid carcinogenesis; doses of 200–500cGy seem to produce
thyroid cancer at a rate of about 0.5%/year.
• There is no evidence that therapeutic or diagnostic 131I administration
can induce thyroid cancer, although there is a small increase in death
rates from thyroid cancer after 131I. At present, it is unclear whether
this is due to an effect of 131I or part of the natural history of the
underlying thyroid disease.
• External irradiation at an age <20 years is associated with an i risk
of thyroid nodule development and thyroid cancer (most commonly
papillary). The radioactive fallout from the Chernobyl nuclear
explosion in 1986 resulted in a 4.7-fold increase in thyroid cancer in
the regions of Belarus from 1985 to 1993, including a 34-fold increase
in children. Children aged <10 years were the most sensitive to
radiation-induced carcinogenesis, and the minimal latent period for
thyroid cancer development after exposure is as short as 4 years.
The vast majority of these cancers were papillary carcinomas, many
of which have characteristic solid or solid follicular microscopic
appearance.
• The risk is greater for ♀ and when irradiation occurs at a younger age.
• There is a latency of at least 5 years, with maximum risk at 20 years
following exposure, though this was not seen following the Chernobyl
disaster.
Other environmental factors
Most investigators agree that iodine supplementation has resulted in a
decrease in the incidence of follicular carcinoma.
Genetic syndromes and oncogenes
• Non-overlapping genetic alterations, including BRAF and RAS point
mutations and RET/PTC and PAX8/PPARγ rearrangements, are found in
>70% of papillary and follicular thyroid carcinomas.
• RET/PTC1 proto-oncogene abnormalities in the long arm of
chromosome 10 are associated with some papillary tumours (5–30%),
especially after irradiation (60–80%). It is similar to the abnormality
associated with medullary thyroid carcinoma in MEN2A.
• Post-Chernobyl tumours are characterized by frequent occurrence
of chromosomal rearrangements, such as RET/PTC, whereas point
mutations of BRAF and other genes are much less common in this
population.
• BRAF mutations may be more aggressive, with higher rates of
extrathyroidal extension, lymph node metastases, and clinically
apparent recurrence.
• The tumour suppressor gene p53 has been found to be mutated in
some dedifferentiated cancers.
AETIOLOGY OF THYROID CANCER 93
Table 1.26 TNM staging system for papillary and follicular thyroid
carcinoma
Stage Age <45 years Age >45 years
I Any T, any N, M0 T1, N0, M0
II Any T, any N, M1 T2, N0, M0
III T3, N0, M0 or any T1–3, N1a, M0
IVA T1–3, N1b, M0 or T4a, any N, M0 N, M0
IVB T4b, any N, M0
IVC Any T, any N, M1
Primary tumour (T): T1, tumour ≤ 2cm limited to the thyroid; T2, tumour > 2 to ≤ 4cm
limited to the thyroid; T3, tumour > 4cm limited to the thyroid or any tumour with minimal
extrathyroidal extension (e.g. extension to sternothyroid muscle or perithyroidal soft tissues);
T4a, tumour of any size with extension beyond the thyroid capsule and invading any of the
following: subcutaneous soft tissues, larynx, trachea, oesophagus, recurrent laryngeal nerve;
T4b, tumour invading prevertebral fascia, mediastinal vessels, or encases carotid artery.
Lymph nodes (N): To classify as N0 or N1, at least six lymph nodes should be examined at
histology. Otherwise, the tumour is classified as Nx. N0, no regional lymph node metastasis;
N1a, metastases in pretracheal and paratracheal, including prelaryngeal and Delphian lymph
nodes; N1b, metastases in other unilateral, bilateral, or contralateral cervical or upper
mediastinal lymph nodes.
Distant metastases (M): M0, no distant metastasis; M1, distant metastasis.
Reproduced from Wass, J, Oxford Textbook of Endocrinology and Diabetes, 2011, with
permission from OUP.
Table 1.27 Risk categorization for thyroid cancer follow-up

Very low risk Tumour 1cm N0, M0
Low risk Tumour 2–4cm N0, M0
High risk T3, T4 N0, M0
• Overexpression of the RAS and PTTG oncogenes is also found in

papillary thyroid cancers and have been found to be markers for
adverse prognosis.
• c-myc mRNA expression has been correlated with histological markers
of papillary cancer aggression.
• The use of these and other emerging molecular markers will
likely improve the diagnosis of malignancy in thyroid nodules as
well as facilitate more individualized operative and post-operative
management.
Papillary microcarcinoma of the thyroid (PMC)
• PMC is defined by WHO as a tumour focus of 1.0cm or less in
diameter. It is detected coincidentally on histopathological examination
of the thyroid following resection of multinodular goitre or any thyroid
resected.
• Autopsy studies show:

• Prevalence ranges from 1% to 35.6%.
• No significant difference in the prevalence rates of PMC has been
demonstrated between the sexes.
• PMC rarely progresses to clinically apparent thyroid cancer with
advancing age.
• PMC can be multifocal.
• Cervical lymph node metastasis from PMC ranges from 4.3% to 18.2%.
• Lymph node metastasis was most often associated with multifocal
tumours.
• Although exposure to irradiation increases the likelihood of
developing papillary thyroid cancer, the tumours will usually be >1.0cm
in diameter and thus not PMC.
• Follow-up studies suggest that PMC is a slow-growing lesion which
rarely spreads to distant sites and which carries a good prognosis.
• The recommendations for treatment of PMC vary widely:
• The low morbidity and long survival mean that collection of
randomized prospective data has never been performed, and
comparisons of therapies are based on retrospective studies.
• The treatment of PMC should not cause more morbidity than the
disease process itself.
• Surgical treatment recommendations range from simple excision to
ipsilateral lobectomy.
• With adjuvant therapy, the consensus is routine use of T4, but not
the use of radioiodine, as there is no difference in the recurrence
rate. There is some evidence to keep TSH below the reference
range, but robust data are not available.
AETIOLOGY OF THYROID CANCER 95
Papillary thyroid carcinoma

• Constitutes almost >80% of all thyroid cancers.
• Commoner in ♀ (3:1).
• Rare in childhood; peaks occur in second and third decades and again
in later life (bimodal frequency).
• Incidence: 3–5 per 100,000 population.
Pathology
• Slow-growing, usually non-encapsulated, may spread through the
thyroid capsule to structures in the surrounding neck, especially
regional lymph nodes. Multifocal in 30% of cases.
• Recognized variants are follicular, papillary, dorsal, columnar cell, tall
cell, and diffuse sclerosing.
• Histology. The tumour contains complex branching papillae that have a
fibrovascular core covered by a single layer of tumour cells.
• Nuclear features include:
• Large size with pale-staining, ‘ground glass’ appearance (orphan
Annie-eye nucleus).
• Deep nuclear grooves.
• The characteristic and pathognomonic cytoplasmic feature is the
‘psammoma body’ which is a calcified, laminated, basophilic, stromal
structure.
• It is confined to the neck in over 95% of cases, although 15–20% have
local extrathyroidal invasion. Metastases (1–2% of patients) occur via
lymphatics to local lymph nodes and, more distantly, to lungs.
• Several prognostic scoring systems are in use, none of which permits
definitive decisions to be made for individual patients.
• Low risk—TNM stage I (under 45, no metastases, tumour size <2cm,
who may not need RAI ablation) (See Tables 1.26 and 1.27).
Management
Primary treatment—surgery
• Should be performed by an experienced thyroid surgeon at a centre
with adequate case load to maintain surgical skills.
• In general, as near total thyroidectomy as possible should be performed.
• Clinically evident cervical lymph node metastasis is best treated
with radical modified neck dissection, with preservation of
sternocleidomastoid muscle, spinal accessory nerve, and internal
jugular vein.
Adjuvant therapy—radioiodine therapy
• Post-operative radioiodine therapy is advised in the high-risk patient
with differentiated thyroid cancer. After surgery in a low-risk group,
some thyroidologists argue that 131I is not required. A dose of 3.1GBq
is used for thyroid ablation. A whole body scan done 4–6 months after
administration of 150MBq 131I helps to determine the presence of any
residual disease. In the presence of metastasis, a dose of approximately
5.5–7.4GBq radioiodine is used. Liothyronine should be administered
for 4–6 weeks in place of levothyroxine. It is then omitted for 10 days
PAPILLARY THYROID CARCINOMA 97
prior to the scan, allowing TSH to rise. A low-iodine diet for 2 weeks
increases the effective specific activity of the administered iodine.
Exogenous TSH is an alternative to T3 cessation.
• The patient should be isolated until residual dose meter readings
indicate <30MBq.
• Chronic suppression of serum TSH levels to <0.10mU/L is standard
practice in patients with differentiated thyroid carcinoma. Inhibition of
TSH secretion reduces recurrence rate, as TSH stimulates growth of
the majority of thyroid cancer cells.
Patients are followed up with thyroglobulin levels. After effective treat-
ment, thyroglobulin levels are undetectable. A trend of i thyroglobulin
values should be investigated with a radioiodine uptake scan. Liothyronine
(T3) is substituted for T4 4–6 weeks before the scan and omitted for 10 days
immediately beforehand. As above exogenous TSH can also be used.
Thyroglobulin
• A very sensitive marker of recurrence of thyroid cancer.
• Secreted by the thyroid tissue.
• After total thyroidectomy and radioactive iodine ablation, the levels of
thyroglobulin should be <0.27 micrograms/L.
• Measurement of thyroglobulin levels could be made difficult in the
presence of antithyroglobulin antibodies, which should be checked.
• Coming off thyroid hormones or giving recombinant TSH increases
the sensitivity of thyroglobulin to detect recurrence, but this may not
affect survival rates.
Recurrent disease/distant metastases
• In the case of recurrence, treatment employs all methods used in p
and adjuvant therapy.
• Surgery for local metastases.
• Radioactive iodine for those tumours with uptake.
• External radiotherapy is indicated in non-resectable tumours that do
not take up 131I.
• Bony and pulmonary metastases (usually osteolytic) may be treated
with 131I.
• Unfortunately, only 50% of metastases concentrate 131I.
• External beam radiation is given to patients who have gross residual
disease after attempted surgery and radioiodine. Radiation therapy
may be of value in controlling local disease. If thyroidectomy is not
possible, it is given alone for palliation.
• Due to the low efficacy of traditional cytotoxic chemotherapies,
consensus guidelines now recommend consideration of clinical trials
of novel agents when patients require therapy for progressive, locally
advanced, or metastatic differentiated thyroid cancer.
• Tyrosine kinase inhibitors (TKIs) (e.g. sorafenib, sunitinib, pazopanib,
gefitinib) have been of interest for the treatment of advanced
differentiated thyroid cancer, given the oncogenic roles of mutations
in the serine kinase BRAF and tyrosine kinases RET (in the mutated
fusion protein RET/PTC) and RAS and the contributory roles of tyrosine
kinases in growth factor receptors, such as the vascular endothelial

growth factor receptor (VEGFR).
• Partial responses are reported in approximately 15–30% of patients.
Complete responses are absent, and no study has evaluated survival.
• Side effects that are common to all of the VEGF-targeted TKIs include
hypertension, renal toxicity, bleeding, myelosuppression, arterial
thromboembolism, cardiotoxicity, thyroid dysfunction (typically
hypothyroidism), cutaneous toxicity, including hand-foot skin reaction,
delayed wound healing, hepatotoxicity, and muscle wasting.
• Selumetinib, a selective mitogen-activated protein kinase (MAPK)
pathway antagonist, increases iodine uptake in a subgroup of patients
refractive to radioiodine.
Recombinant TSH
• Avoids morbidity of hypothyroidism during T3 /T4 withdrawal.
• Necessary for patients with TSH deficiency (hypopituitarism) and
thyroid carcinoma.
• Comparable thyroglobulin rise but slightly reduced 131I scan sensitivity
compared to thyroid hormone withdrawal.
• Give 0.9mg of recombinant TSH on day 1 and 2, and measure
thyroglobulin on day 5.
• For serum thyroglobulin testing, serum thyroglobulin should be
obtained 72h after final injection of recombinant TSH.
FOLLICULAR THYROID CARCINOMA (FTC) 99
Follicular thyroid carcinoma (FTC)

• Constitutes 10% of all thyroid cancers.
• Mean patient age in most studies is 50 years.
• Commoner in ♀ (2:1).
• Relatively more common in endemic goitre areas.
Pathology
• Follicular carcinoma is a neoplasm of the thyroid epithelium that
exhibits follicular differentiation and shows capsular or vascular
invasion.
• Differentiation of benign follicular adenoma from encapsulated
low-grade or minimally invasive tumours can be impossible to
diagnose, particularly for the cytopathologist, and surgery is usually
necessary for a follicular adenoma.
• FTC may be minimally invasive or widely invasive.
• Metastases (15–20% cases) are more likely to be spread by
haematogenesis to the lung and bones and less likely to local
lymph nodes.
• Hürthle cell carcinoma is an aggressive type of follicular tumour with a
poor prognosis because it fails to concentrate 131I.
Treatment
As for papillary thyroid carcinoma, b see p. 96.
Follow-up of papillary and FTC

• This should be lifelong—recurrences occur, at least, to 25 years (see
Fig. 1.3).
• Follow-up usually involves an annual clinical review, with clinical
examination for the presence of suspicious lymph nodes and
measurements of serum TSH (to ensure adequate TSH suppression to
<0.1mU/L) and thyroglobulin.
• Serum thyroglobulin should be undetectable in patients with total
thyroid ablation. However, detectable levels may be seen for up to
6 months after thyroid ablation. A trend of i thyroglobulin level
requires investigations with 131I uptake scan (off thyroid hormones or
with TSH stimulation) and other imaging modalities, such as US of the
neck, CT scan of the lungs, or bone scans. Thyroglobulin antibodies
must be checked, as there may be interactions with thyroglobulin
assays.
• TSH-stimulated thyroglobulin levels can be avoided in patients with
thyroglobulin levels <0.27 micrograms/L.
• Isolated lymph node metastases can occasionally be associated with
normal thyroglobulin. Stopping thyroid hormone replacement, or
using recombinant TSH, before the measurement of thyroglobulin can
increase sensitivity of detecting persistent recurrent disease.
• Detectable thyroglobulin and absent uptake on radioiodine uptake
scan may be due to dedifferentiation of the tumour and failure to
take up iodine. In patients with serum thyroglobulin >10ng/mL and
a negative radioiodine scan, (18F)-2-fluoro-2-deoxy-D-glucose PET
may be useful. Metastatic lesions with high avidity for glucose in PET
imaging, measured by elevated standard uptake values, are associated
with resistance to radioiodine therapy and worse prognosis.
For patients with differentiated thyroid cancer (DTC) who undergo subto-
tal thyroidectomy or total thyroidectomy without RAI:
• Follow periodic thyroglobulin (Tg) and perform US.
• Rising Tg over time is suspicious.
For DTC patients after undergoing total thyroidectomy and remnant abla-
tion, the following schedule is recommended:
6–12 months
• Clinical examination, serum TSH, free thyroxine, neck US, Tg, and
thyroglobulin antibodies while on T4.
• If the neck US is suspicious for lymph nodes or nodules >5–8mm, send
for biopsy for cytology and Tg wash.
• If biopsy +ve, send for compartment dissection.
• If biopsy –ve, monitor size of lymph nodes or nodules.
• If the US is –ve and TgAb are –ve, send for rhTSH or thyroxine
withdrawal (THW) Tg stimulation and diagnostic RAI WBS.
• If –ve WBS but stimulated Tg >5–10, send for neck/check CT or
PET/CT.
• If imaging –ve, consider repeat 131I therapy.
FOLLOW-UP OF PAPILLARY AND FTC 101
• If imaging +ve, consider surgery, 131I therapy, EBRT, clinical trial, or

tyrosine kinase inhibitor therapy.
• If –ve WBS and stimulated Tg <5–10, monitor Tg and neck US. If Tg
rising, consider repeat 131I therapy.
• If +ve WBS, consider repeat 131I therapy.
• If the US is –ve but TgAb is +ve, follow TgAb and neck US.
Years 2–10
• Clinical examination, measurements of serum free thyroxine, TSH, and
thyroglobulin annually.
• Neck ultrasonography every 1–2 years or less frequently in low-risk
patients with no evidence of disease.
• Thyrogen-stimulated Tg and WBS if serum Tg increases or there is
other evidence of recurrence.
Years 11–20
• Clinical examination and measurements of serum free thyroxine, TSH,
and thyroglobulin annually.
• Thyrogen-stimulated Tg and WBS if serum Tg increases or there is
other evidence of recurrence.
Years 21+
• Clinical examination and measurements of serum free thyroxine, TSH,
and thyroglobulin annually.
• Thyrogen-stimulated Tg and radioiodine imaging if serum Tg increases
or there is other evidence of recurrence.
See Box 1.15 for thyroid cancer in children.
Thyroid cancer and pregnancy
• The natural course of thyroid cancer developing during pregnancy may
be different from that in non-pregnant ♀.
• Any ♀ presenting with a thyroid nodule in pregnancy appears to have
an i risk for thyroid cancer.
• Evaluation should be undertaken with FNAC. Radioiodine scan is
contraindicated.
• Lesions <2cm diameter or any lesion appearing after 24 weeks’
gestation should be treated with TSH suppression and further
evaluations carried out post-partum.
• If FNAC is suspicious or diagnostic, operation should be performed
at the earliest safe opportunity—generally, the second trimester or
immediately post-partum.
• 131I ablation should be scheduled for the post-partum period and the
mother advised to stop breastfeeding.
• Avoid pregnancy for 6 months after any 131I ablation.
Disease-free 6–12 months after surgery + 131I therapy
Thyroglobulin (Tg) or thyroid hormone therapy
Tg undetectable Tg detectable
rhTSH-stimulated Tg Neck US + CXR
Tg <2 Tg >2 Consider 131I or surgery

(see Fig.1.2)
Post-treatment body scan → negative
Positive
CT
Further imaging
PET
Fig. 1.3 Algorithm for follow-up of low-risk cases of papillary thyroid cancer.
Box 1.15 Thyroid cancer in children

• Uncommon, with an incidence of 0.2–5 per million per year.
• >85% are papillary but with more aggressive behaviour than in adults
(local invasion and distant metastases are commoner).
• Recently, an i incidence in children in Belarus and Ukraine has been
reported following the Chernobyl nuclear accident in 1986. RET
oncogene rearrangements are common in these tumours.
• Management is similar to that in adults.
• Various studies report an overall recurrence rate of 0–39%;
disease-free survival of 80–93% and disease-specific mortality
of 0–10%.
• Evidence is currently lacking on the independent risks or benefits of
radioactive iodine or extensive surgery.
• Many investigators recommend lifelong follow-up with a combination
of thyroglobulin and radionuclide scanning.
MEDULLARY THYROID CARCINOMA (MTC) 103
Medullary thyroid carcinoma (MTC)

also see MEN type 2, b p. 592.
• Accounts for 5–10% of all thyroid cancers.
• Should be managed by a dedicated regional service.
Presentation
• Lump in neck.
• Systemic effects of calcitonin—flushing/diarrhoea.
Diagnosis
• FNAC.
• Comprehensive family history and screening in search for features of
MEN-2 is needed.
• Pathology specimens show immunostaining for calcitonin and staining
for amyloid.
Management
• Baseline plasma calcitonin.
• Baseline biochemical investigations for phaeochromocytoma and
hyperparathyroidism.
• Genetic screening.
• Staging with thoracoabdominal CT/MRI.
• MIBG and pentavalent 99mTc DMSA scintigraphy may also be used.
Treatment
• Total thyroidectomy and central node dissection is the p treatment
modality.
• Germline RET mutation carriers should ideally undergo thyroidectomy
before 5 years of age.
Adjuvant therapy
• Radioiodine and TSH suppression do not play a role.
• External radiotherapy has been shown to be of little benefit.
• For patients with metastatic tumours at least 2cm in diameter, growing
by at least 20% per year, or for patients with symptoms related to
multiple metastatic foci that cannot be alleviated with surgery or
external beam radiotherapy, systemic chemotherapy with a TKI
(vandetanib), as part of a clinical trial, should be considered.
• Therapeutic MIBG may help in some cases.
Follow-up
All patients should have lifelong follow-up at the dedicated regional
service.
Anaplastic (undifferentiated)
thyroid cancer
• Rare.
• Peak incidence: seventh decade; ♀:♂ = 1:1.5.
• Characterized by rapid growth of a firm/hard, fixed tumour.
• Often infiltrates local tissue, such as larynx and great vessels, and so
does not move on swallowing. Stridor and obstructive respiratory
symptoms are common.
• Aggressive, with poor long-term prognosis—7% 5-year survival rate
and a mean survival of 6 months from diagnosis.
• Optimal results occur, following total thyroidectomy. This is usually
not possible and external irradiation is used, sometimes in association
with chemotherapy.
LYMPHOMA 105
Lymphoma
• Uncommon.
• Almost always associated with autoimmune thyroid disease
(Hashimoto’s thyroiditis). Occurs more commonly in ♀ and in patients
aged >40 years.
• Characterized by rapid enlargement of the thyroid gland.
• May be limited to thyroid gland or part of a more extensive systemic
lymphoma (usually non-Hodgkin’s lymphoma).
• Treatment with radiotherapy alone or chemotherapy, if more
extensive, often produces good results.
Further reading
American Thyroid Association Guidelines Task Force (2009). Medullary thyroid cancer: manage-
ment guidelines of the American Thyroid Association. Thyroid 19, 565–612.
American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated
Thyroid Cancer (2009). Revised American Thyroid Association management guidelines for
patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19, 1167–214.
Aschebrook-Kilfoy B, Ward MH, Sabra MM, et al. (2011). Thyroid cancer incidence patterns in the
United States by histologic type, 1992-2006. Thyroid 21, 125–34.
Bogsrud TV, Hay ID, Karantanis D, et al. (2011). Prognostic value of 18F-fluorodeoxyglucose-positron
emission tomography in patients with differentiated thyroid carcinoma and circulating antithy-
roglobulin autoantibodies. Nucl Med Commun 32, 245–51.
British Thyroid Association and Royal College of Physicians (2007). Guidelines for the management
of thyroid cancer (Perros P, ed). Report of the Thyroid Cancer Guidelines Update Group. Royal
College of Physicians, London. Available at: M http://www.british-thyroid-association.org/news/
Docs/Thyroid_cancer_guidelines_2007.pdf.
Hay ID (2007). Management of patients with low-risk papillary thyroid carcinoma. Endocr Pract
13, 521–33.
Hay I, Wass JAH (2008). Clinical Endocrine Oncology, 2nd edn, pp.109–71. Blackwell-Wiley,
Massachussetts.
Kloos RT, Eng C, Evans D, et al. (2009). Medullary thyroid cancer: management guidelines of the
American Thyroid Association. Thyroid 19, 565–612.
Nikiforov YE (2006). Radiation-induced thyroid cancer: what we have learned from Chernobyl.
Endocr Pathol 17, 307–17.
Nikiforov YE, Nikiforova MN (2011). Molecular genetics and diagnosis of thyroid cancer. Nat Rev
Paschke R, Hegedüs L, Alexander E, et al. (2011). Thyroid nodule guidelines: agreement, disagree-
ment and need for future research. Nat Rev Endocrinol 7, 354–61.
Sherman SI (2011). Targeted therapies for thyroid tumors. Mod Pathol 24(Suppl 2), S44–52.
Smallridge RC (2012). Approach to the patient with anaplastic thyroid carcinoma. J Clin Endocrinol
Metab 97, 2566–72.
Anatomy and physiology of anterior pituitary gland 108
Imaging 112
Pituitary function—dynamic tests: insulin tolerance test
(ITT) 114
Glucagon test 116
ACTH stimulation test 117
Arginine test 118
Clomifene test 119
hCG test 120
TRH test 121
Hypopituitarism 122
Investigations of hypopituitarism 125
Treatment of hypopituitarism 126
Anterior pituitary hormone replacement 127
Glucocorticoids 128
Growth hormone (GH) replacement therapy in adults 130
Investigation of GH deficiency 132
Treatment of GH deficiency 134
Pituitary tumours 136
Molecular mechanisms of pituitary tumour pathogenesis 138
Prolactinomas 140
Investigations of prolactinomas 142
Hyperprolactinaemia and drugs 143
‘Idiopathic’ hyperprolactinaemia 143
Treatment of prolactinomas 144
Definition of acromegaly 148
Epidemiology of acromegaly 148
Causes of acromegaly 149
Associations of acromegaly 150
Clinical features of acromegaly 151
Investigations of acromegaly 152
Management of acromegaly 154
Mortality data of acromegaly 157
Chapter 2 107
Pituitary
Definition of Cushing’s disease 158

Epidemiology of Cushing’s disease 158
Pathophysiology of Cushing’s disease 159
Clinical features of Cushing’s disease 160
Investigations of Cushing’s disease 162
Treatment of Cushing’s disease 168
Follow-up of Cushing’s disease 172
Prognosis of Cushing’s disease 172
Cushing’s syndrome in children 173
Non-functioning pituitary tumours 174
Gonadotrophinomas 178
Thyrotrophinomas 180
Pituitary incidentalomas 182
Pituitary carcinoma 184
Pituitary metastases 186
Craniopharyngiomas and perisellar cysts 188
Parasellar tumours 190
Parasellar inflammatory conditions 192
Lymphocytic hypophysitis 194
Surgical treatment of pituitary tumours 196
Transfrontal craniotomy 199
Pituitary radiotherapy 200
Complications of pituitary radiotherapy 202
Drug treatment of pituitary tumours 204
Posterior pituitary 208
Diabetes insipidus (DI) 210
Investigations of DI 212
Treatment of DI 214
Hyponatraemia 216
Syndrome of inappropriate ADH (SIADH) 220
Eating disorders 222
Hypothalamus 223
Pineal gland 224
108 CHAPTER 2 Pituitary
Anatomy and physiology of anterior

pituitary gland
Anatomy
The pituitary gland is centrally located at the base of the brain in the sella
turcica within the sphenoid bone. It is attached to the hypothalamus by
the pituitary stalk and a fine vascular network. The cavernous sinuses are
on either side of the sella, lateral and superior to the sphenoid sinuses,
and comprise important neurovascular structures, including the cavernous
segments of the internal carotid arteries and the cranial nerves III, IV, V,
and VI. The optic chiasm is located superiorly, separated from the pituitary
by the suprasellar cistern and the diaphragma sellae (see Fig. 2.1). The
pituitary measures around 13mm transversely, 9mm anteroposteriorly,
and 6mm vertically and weighs approximately 100mg. It increases during
pregnancy to almost twice its normal size, and it decreases in the elderly.
The anterior pituitary gland receives most of its blood supply from
the hypothalamo-hypophyseal portal system (primary plexus, long portal
venous system, and secondary plexus), which originates from the capil-
lary plexus of the median eminence and superior stalk derived from the
terminal ramifications of the superior and inferior hypophyseal arteries.
This system carries blood and hypophysiotropic hormones down to the
stalk. The remainder of the blood supply is through the pituitary capsular
vessels originating from the superior hypophyseal arteries. The venous
drainage from the anterior pituitary is through the cavernous sinuses into
the petrosal sinuses and the internal jugular veins.
Physiology
(See Table 2.1.)
Prolactin (PRL) secretion*
Single chain polypeptide. Pulsatile secretion in a circadian rhythm with
around 14 pulses/24h, and a superimposed bimodal 24h pattern of secre-
tion with a nocturnal peak during sleep and a lesser peak in the evening.
Growth hormone (GH) secretion*
Single chain polypeptide. Pulsatile secretion—usually undetectable in the
serum, apart from 5 to 6 90min pulses/24h that occur more commonly at
night. The secretion is modified by age and sex.
LH/FSH secretion
Glycoprotein hormones, with α chain common to LH and FSH (also TSH
and hCG), but B chain specific for each hormone. Pulsatile secretion
determined by the frequency and amplitude of GnRH secretion.
Thyroid-stimulating hormone (TSH) secretion
Glycoprotein with α chain common to LH and FSH (also TSH and hCG),
but B chain specific for each hormone. Pulsatile secretion with 9 ± 3
pulses/24h and i amplitude of pulses at night.
ANATOMY AND PHYSIOLOGY OF ANTERIOR PITUITARY GLAND 109
Supraoptic recess
Suprasellar Hypothalamus
cistern
Optic
Sphenoid chiasm
bone Pituitary stalk
III Temporal
IV lobe
VI Internal
carotid
V2 VI
artery
Pituitary gland Sphenoid sinus
Fig. 2.1 The pituitary gland. Reproduced with permission from Weatherall DJ,
Ledingham JGG, and Warrell DA (eds) (1996). Oxford Textbook of Medicine, 3rd
edn. Oxford University Press: Oxford.
Adrenocorticotrophic hormone (ACTH)*

Single chain polypeptide cleaved from pro-opiomelanocortin (POMC).
Circadian rhythm of secretion, beginning to rise from 3 a.m. to a peak
before waking in the morning and gradually falling thereafter.
Posterior pituitary
b see p. 208.
*
Concentrations i with stress: NB venepuncture.
Table 2.1 Anterior pituitary gland physiology
Cell type (hormone) % pituitary +ve regulation –ve regulation Targets Effects
Somatotropes (growth 45–50 Growth hormone-releasing Insulin-like growth factor Liver, cartilage, Linear and somatic
hormone, GH) hormone (GHRH) (IGF-1) and somatostatin muscle, fat, skin Metabolism (lipids,
carbohydrates)
Lactotropes (prolactin, 15–25 (i in Thyrotropin-releasing Dopamine Breast Lactation
PRL) pregnancy) hormone (TRH) and
oestrogen
Gonadotropes 10–15 Gonadotrophin-releasing Oestrogen Gonads Sex steroid product
(luteinizing hormone hormone (GnRH),
Progesterone Folliculogenesis and
and follicle-stimulating oestrogen—late follicular
ovulation (♀)
hormone, LH/FSH) phase of menstrual cycle Testosterone
Spermatogenesis (♂
Inhibin (FSH only)
Thyrotropes 5–10 TRH T4, T3, somatostatin Thyroid Thyroid hormone
(thyroid-stimulating production
hormone, TSH)
Corticotropes 15–20 Corticotrophin-releasing Cortisol Adrenal gland Glucocorticoid and
(adrenocorticotrophin, hormone (CRH) production
ACTH)
Reproduced from Draznin and Epstein, Oxford American Handbook of Endocrinology and Diabetes (2011), with permission of OUP.
ANATOMY AND PHYSIOLOGY OF ANTERIOR PITUITARY GLAND 111
Imaging
Background
• Magnetic resonance imaging (MRI) currently provides the optimal
imaging of the pituitary gland.
• Computed tomography (CT) scans may still be useful in demonstrating
calcification in tumours (e.g. craniopharyngiomas) and hyperostosis in
association with meningiomas or evidence of bone destruction.
• Plain skull radiography may show evidence of pituitary fossa
enlargement but has been superseded by MRI.
MRI appearances
(See Fig. 2.2.)
• T1-weighted images demonstrate cerebrospinal fluid (CSF) as dark
grey and brain as much whiter. This imaging is useful for demonstrating
anatomy clearly. The normal posterior pituitary gland appears
bright white (due to neurosecretory granules and phospholipids) on
T1-weighted images, in contrast to the anterior gland which is of the
same signal as white matter. The bony landmarks have low signal
intensity on MRI, and air in the sphenoid sinus below the fossa shows
no signal. Fat in the dorsum sellae may shine white. T2-weighted
images may sometimes be used to characterize haemosiderin and fluid
contents of a cyst.
• IV gadolinium compounds are used for contrast enhancement. Because
the pituitary and pituitary stalk have no blood–brain barrier, in contrast
to the rest of the brain, the normal pituitary gland enhances brightly
following gadolinium injection. Contrast enhancement is particularly
useful for the demonstration of cavernous sinus involvement and of
microadenomas.
• The normal pituitary gland has a flat or slightly concave upper surface.
In adolescence or pregnancy, the surface may become slightly convex.
Pituitary adenomas
On T1-weighted images, pituitary adenomas are of lower signal intensity
than the remainder of the normal gland. The size and extent of the pitui-
tary adenomas are noted in addition to the involvement of other struc-
tures, such as invasion of the cavernous sinus, erosion of the fossa, and
relations to the optic chiasm. Larger tumours may show low-intensity
areas compatible with necrosis or cystic change or higher intensity signal
due to haemorrhage. The presence of microadenomas may be difficult
to demonstrate. Contrast enhancement, asymmetry of the gland, or stalk
position can be helpful in such cases.
Neuroradiological classification
b see p. 184.
IMAGING 113
(A) (B)
R L
OC
OC
PS
(C) (D)
OC
PG
CA
Fig. 2.2 Normal and abnormal pituitary MRI images. (A) Normal coronal,
post-contrast T1 image showing optic chiasm (OC). (B) Normal sagittal image
showing pituitary stalk (PS) and OC. (C) Pituitary macroadenoma with evidence of
pituitary gland (PG) compression, left cavernous sinus invasion, and encroachment
of carotid artery (CA). (D) Rathke’s cleft cyst—bright T1 image, consistent with
mucinous, proteinaceous, or blood products. Reproduced from Draznin and
Epstein, Oxford American Handbook of Endocrinology and Diabetes (2011), with
permission of OUP.
Craniopharyngiomas
These appear as intra- and/or suprasellar masses with cystic and/or solid
components. A solid lesion appears as iso- or hypointense relative to the
brain on pre-contrast T1-weighted images, shows enhancement following
gadolinium administration, and is usually of mixed hypo- or hyperinten-
sity on T2-weighted sequences. A cystic element is usually hypointense on
T1- and hyperintense on T2-weighted sequences. Protein, cholesterol, and
methaemoglobin may cause high signal on T1-weighted images. Calcification
is present in 45–57%, better visualized by CT or plain skull X-ray.
Further reading
Naidich MJ, Russell EJ (1999). Current approaches to imaging of the sellar region and pituitary.
Endocrinol Metab Clin N Am 28, 45.
Pituitary function—dynamic
tests: insulin tolerance test (ITT)
Indications
• Assessment of ACTH reserve.
• Assessment of GH reserve.
Physiology
IV insulin is used to induce hypoglycaemia (glucose <2.2mmol/L with signs
of glycopenia), which produces a standard stress causing ACTH and GH
secretion.
Contraindications
• 9 a.m. serum cortisol <100nmol/L.
• Untreated hypothyroidism.
• Abnormal ECG.
• Ischaemic heart disease.
• Seizures.
• Glycogen storage disease.
Note that patients should discontinue oral oestrogen replacement for 6
weeks before the test, as i CBG will make the cortisol results difficult
to interpret. Progesterone and transdermal oestrogen may be continued.
See Box 2.1 for procedure.
Response
• In the presence of inadequate hypoglycaemia (glucose >2.2mmol/L),
the test cannot be interpreted.
• A normal cortisol response (peak cortisol >450nmol/L) demonstrates
the ability to withstand stress (including major surgery) without
requiring glucocorticoid cover. Subnormal cortisol response requires
glucocorticoid replacement treatment (b see Glucocorticoids, p. 128).
• Severe GH deficiency in adults is diagnosed if peak GH <3 micrograms/L,
and, in the appropriate clinical situation (b see p. 130), GH replacement
therapy may be recommended. In children, the secretory capacity of GH
is higher, and a cut-off of 10 micrograms/L is used.
PITUITARY FUNCTION—DYNAMIC TESTS: ITT 115
Box 2.1 Procedure

• Continued medical surveillance is essential throughout.
• Patient is fasted overnight. Weight is checked.
• Insert cannula. Check basal (time 0) glucose, cortisol, and GH.
• Administer IV soluble insulin 0.15U/kg (occasionally, 0.2–0.3U/kg
needed in untreated Cushing’s syndrome and acromegaly because of
i insulin resistance).
• Measure glucose, GH, and cortisol at 30, 45, 60, 90, and 120min.
Repeat insulin dose if a bedside stick test for glucose does not show
hypoglycaemia at 45min.
• During the procedure, pulse rate, blood pressure, and manifestations
of hypoglycaemia should be recorded.
• Test is terminated if prolonged hypoglycaemia—may need to
administer 25mL of 25% glucose and IV 100mg hydrocortisone after
sampling for cortisol and GH.
• Ensure patient eats lunch and has normal glucose before discharge.
Glucagon test
Indications
• Assessment of GH reserve.
Physiology
Glucagon leads to release of insulin, which then leads to GH and ACTH
release. The response may be s to the drop in glucose seen after the
initial rise following glucagon injection or may relate to the nausea induced
by glucagon.
Contraindications
• Phaeochromocytoma or insulinoma, glycogen storage disease, and
severe hypocortisolaemia.
• Often unreliable in patients with diabetes mellitus.
• Note that patients should discontinue oral oestrogen replacement
for 6 weeks before the test, as i CBG will make the cortisol results
difficult to interpret.
Response
• The normal response is a rise in glucose to a maximum at 90min. The
cut-offs for cortisol and GH are those of the ITT.
• This is a less reliable test than the ITT, as 20% of normal individuals
may fail to respond.
Box 2.2 Procedure

The test is performed at 9 a.m. following an overnight fast. Basal GH
and cortisol are measured, then 1mg (1.5mg if the patient weighs >90kg)
glucagon is administered SC. The injection may cause nausea, abdominal
pain, and vomiting. Samples for GH, cortisol, and glucose are checked
from 90min, every 30min, until 240min.
ACTH STIMULATION TEST 117
ACTH stimulation test

Short Synacthen® test (tetracosactide test).
Indication
• Assessment of adrenal cortical function.
Physiology
The rationale of its use is that chronic underexposure of the adrenal
glands to ACTH (following prolonged corticosteroid therapy or due to
hypothalamic–pituitary disease) will result in a blunted cortisol response
to exogenously administered ACTH. Furthermore, a lack of cortisol rise
following administration of ACTH demonstrates adrenal cortical disease.
Prolonged ACTH administration will lead to cortisol secretion in ACTH
deficiency but not in p adrenal disease.
Response
The post-stimulation cortisol should rise to >450nmol/L at 30min. This is
an unreliable test of ACTH reserve within 6 weeks of an insult, e.g. surgery
to the pituitary.
Box 2.3 Procedure

• The test can be done at any time of the day; the response is not
time-dependent.
• Synacthen® is administered 250 micrograms IM, and cortisol is
measured at 0, 30, and 60min. When this test is used to measure
ACTH reserve, only the 0 and 30min values are required. The dose
may also be given IV with identical results.
• Note that patients should discontinue oestrogen replacement for
6 weeks before the test, as i CBG will make the cortisol results
difficult to interpret.
Arginine test1
Indication
Second-line test for assessment of GH reserve.
Physiology
Arginine leads to GH release.
Contraindications
None.
Response
A normal response is a rise in GH to >15–20mU/L.
Box 2.4 Procedure

• Fast from midnight, and administer 0.5g/kg (max 30g) arginine IV in
100mL normal saline over 30min from time 0 (9 a.m.).
• Sample glucose and GH at 0, 30, 60, 90, and 120min.
Reference
1. Corneli G, Di Somma C, Baldelli R, et al. (2005). The cut-off limits of the GH response to
GH-releasing hormone–arginine test related to body mass index. European Journal of
Endocrinology, 153, 257–64.
CLOMIFENE TEST 119
Clomifene test
Indications
Assessment of gonadotrophin deficiency (e.g. Kallmann’s syndrome).
Physiology
Clomiphene has mixed oestrogen and antioestrogenic effects. The basis of
the test is competitive inhibition of oestrogen binding at the hypothalamus
and pituitary gland, leading to i LH and FSH after 3 days.
Contraindications
• Avoid in those with liver disease.
• May transiently worsen depression.
Response
• The normal response is a doubling of gonadotrophins by day 10,
usually rising beyond the normal range.
• In hypothalamic or pituitary disease, no gonadotrophin rise is seen.
Prepubertal patients may show a fall in gonadotrophins.
• Ovulation is presumed if day 21 progesterone is >30nmol/L.
hCG test
Indications
To examine Leydig cell function, b see Clinical assessment, p. 402.
Box 2.5 Procedure

• Advise patient of possible side-effects—visual disturbance
(peripheral flickering of vision)—and also of possible ovulation in ♀
(contraceptive advice).
• Measure LH and FSH on days 0, 4, 7, and 10. In ♀, measure day 21
progesterone to detect whether ovulation has occurred.
• Administer clomifene 3mg/kg (max 200mg/day) in divided doses for
7 days.
TRH TEST 121
TRH test
Indications
• Differentiation of pituitary TSH and hypothalamic TRH deficiency.
• Differentiation of TSH-secreting tumour from thyroid hormone
resistance (b see Table 1.15, p. 51).
Response
• Normal response is a rise in TSH by >2mU/L to >3.4mU/L, with a
maximum at 20min and lower values at 60min.
• A delayed peak (60min rather than 20min) is typically found in
hypothalamic disease.
Box 2.6 Procedure

• Administer TRH 200 micrograms IV to supine patient.
• Measure T4 and TSH at time 0, and TSH at 20 and 60min.
• Note occasional reports of pituitary tumour haemorrhage. TRH
induces a rise in blood pressure.
Hypopituitarism
Definition
Hypopituitarism refers to either partial or complete deficiency of anterior
and/or posterior pituitary hormones and may be due to p pituitary dis-
ease or to hypothalamic pathology which interferes with the hypothalamic
control of the pituitary.
Causes
• Pituitary tumours.
• Parapituitary tumours—craniopharyngiomas, meningiomas, secondary
deposits (e.g. breast, lung), chordomas, gliomas.
• Radiotherapy—pituitary, cranial, nasopharyngeal.
• Pituitary infarction (apoplexy), Sheehan’s syndrome.
• Infiltration of the pituitary gland—sarcoidosis, lymphocytic
hypophysitis, haemochromatosis, Langerhans cell histiocytosis,
Erdheim–Chester disease, Wegener’s (ANCA-positive, 1% pituitary
involvement, diabetes insipidus commonest).
• Empty sella.
• Infection—tuberculosis, pituitary abscess.
• Trauma (including traumatic brain injury).
• Subarachnoid haemorrhage.
• Isolated hypothalamic-releasing hormone deficiency, e.g. Kallmann’s
syndrome due to GnRH deficiency.
• Genetic causes.
• Mutations of genes encoding transcription factors, including HESX1
(homeobox gene expressed in embryonic stem cells 1), LHX3
(Lim-domain homeobox gene 3), LHX4 (Lim-domain homeobox
gene 4), PROP-1 (Prophet of Pit1), POU1F1 (Pou domain, class 1,
transcription factor 1).
• Russell viper envenomation.
Features
(See Table 2.2.)
• The clinical features depend on the type and degree of the hormonal
deficits, and the rate of its development, in addition to whether there
is intercurrent illness. In the majority of cases, the development of
hypopituitarism follows a characteristic order, with secretion of GH,
then gonadotrophins being affected first, followed by TSH and ACTH
secretion at a later stage. PRL deficiency is rare, except in Sheehan’s
syndrome associated with failure of lactation. ADH deficiency is
virtually unheard of with pituitary adenomas but may be seen rarely
with infiltrative disorders and trauma.
• The majority of the clinical features are similar to those occurring
when there is target gland insufficiency. There are important
differences, e.g. lack of pigmentation and normokalaemia in ACTH
deficiency in contrast to i pigmentation and hyperkalaemia (due to
aldosterone deficiency) in Addison’s disease.
• NB Houssay phenomenon. Amelioration of diabetes mellitus in patients
with hypopituitarism due to reduction in counter-regulatory hormones.
HYPOPITUITARISM 123
Apoplexy
Apoplexy refers to infarction of the pituitary gland due to either haemor-
rhage or ischaemia. It occurs most commonly in patients with pituitary
adenomas, usually macroadenomas, but other predisposing conditions
include post-partum (Sheehan’s syndrome), radiation therapy, diabetes
mellitus, anticoagulant treatment, disseminated intravascular coagulopa-
thy, and reduction in intracranial pressure. It is a medical emergency, and
rapid hydrocortisone replacement can be lifesaving.
It may present with a syndrome which is difficult to differentiate from
any other intracranial haemorrhage, with sudden onset headache, vomit-
ing, meningism, visual disturbance, and cranial nerve palsy. The diagnosis is
based on the clinical features and pituitary imaging which shows high signal
on T1- and T2-weighted images (b see p. 112). It should be managed by
a pituitary multidisciplinary team. It has been suggested that early surgery
(within 8 days) provides the optimal chance for neurological recovery.
However, some patients may be managed conservatively if the patient has
no significant visual or other neurological manifestations.
After apoplexy, pituitary tumour regrowth may occur (11% at 7 years),
so follow-up surveillance is necessary.
Empty sella syndrome
An enlarged pituitary fossa, which may be p (due to arachnoid herniation
through a congenital diaphragmatic defect) or s to surgery, radiotherapy,
or pituitary infarction. The majority of patients have normal pituitary func-
tion. Hypopituitarism (and/or hyperprolactinaemia) is found in <10%.
Traumatic brain injury (TBI)
• Associated with subarachnoid haemorrhage and skull base fractures.
• May be seen with moderate-to-severe head trauma.
• Most common deficiencies—GH and gonadotrophins (10–15%).
• Best assessed 6–12 months after trauma.
Table 2.2 Main manifestations of hypopituitarism

Hormone deficiency Clinical features
GH Adult GHD (b see p. 130)
Reduced exercise capacity, reduced lean body mass,
impaired psychological well-being, i cardiovascular risk
LH/FSH Anovulatory cycles, oligo/amenorrhoea, dyspareunia
in ♀
Erectile dysfunction and testicular atrophy, loss of s
sexual hair (often after many years) in ♂
Reduced libido, infertility, osteoporosis in both sexes
ACTH As in Addison’s disease, except lack of hyperpigmentation,
absence of hyperkalaemia (b see p. 128)
TSH As in p hypothyroidism (b see p. 74)
PRL Failure of lactation
ADH Polyuria and polydipsia
Sheehan’s syndrome
Haemorrhagic infarction of the enlarged post-partum pituitary gland caus-
ing hypopituitarism, following severe hypotension usually due to blood
loss, e.g. post-partum haemorrhage. It can be fatal, and survivors require
life replacement therapy. Improvement in obstetric care has made this a
rare occurrence in the developed world.
INVESTIGATIONS OF HYPOPITUITARISM 125
Investigations of hypopituitarism
The aims of investigation of hypopituitarism are to biochemically assess
the extent of pituitary hormone deficiency and also to elucidate the cause.
Basal hormone levels
Basal concentrations of the anterior pituitary hormone, as well as the tar-
get organ hormone, should be measured, as the pituitary hormones may
remain within the normal range despite low levels of target hormone.
Measurement of the pituitary hormone alone does not demonstrate that
the level is inappropriately low, and the diagnosis may be missed.
• LH and FSH, and testosterone (9 a.m.) or oestradiol.
• TSH and thyroxine.
• 9 a.m. cortisol.
• PRL.
• IGF-1 (NB May be normal in up to half of GHD, depending on age).
See Box 2.7 for dynamic tests.
Posterior pituitary function
• It is important to assess and replace corticotroph function before
assessing posterior pituitary hormone production because ACTH
deficiency leads to reduced GFR and the inability to excrete a water
load, which may, therefore, mask diabetes insipidus (DI).
• Plasma and urine osmolality are often adequate as baseline measures.
However, in patients suspected to have DI, a formal fluid deprivation
test should usually be performed (b see Box 2.31, p. 213).
Investigation of the cause
• Pituitary imaging—MRI ± contrast.
• Investigation of hormonal hypersecretion if a pituitary tumour is
demonstrated.
• Investigation of infiltrative disorders, (b see Parasellar inflammatory
conditions, pp. 192–3), e.g. serum and CSF ACE, ferritin, hCG, aFP.
• Occasionally, biopsy of a lesion found on imaging is required.
Box 2.7 Dynamic tests

• Dynamic tests, such as the ITT (b see Insulin tolerance test,
p. 114) or glucagon test (b see Glucagon test, p. 116) if the ITT is
contraindicated, are used to assess cortisol and GH reserve.
• Some centres use the short Synacthen® test to assess ACTH
reserve, using the 0 and 30min values of cortisol (b see ACTH
stimulation test, p. 117). There are few false –ves using this
investigation, and it is simpler to perform than the former tests
but gives no measure of GH reserve. It is important to note that
falsely normal results occur when hypopituitarism is of recent onset
because the test relies on the fact that ACTH deficiency causes
atrophy of the adrenal cortex and, therefore, a delayed response
to Synacthen®. Less than 6 weeks of ACTH deficiency may allow a
‘normal’ adrenal response.
Treatment of hypopituitarism
Treatment involves adequate and appropriate hormone replacement
(b see p. 127, p. 128, and p. 130) and management of the underlying cause.
Isolated defects of pituitary hormone secretion
Rarely, patients have isolated insufficiency of only one anterior pituitary
hormone. The aetiology of these disorders is largely unknown, although
loss of hypothalamic control may play a role; an autoimmune pathology
has been suggested in some and genetic mutations in others. Examples
include:
• GnRH deficiency (Kallman’s syndrome—congenital GnRH deficiency
± anosmia).
• Isolated ACTH deficiency.
• Pit1 gene mutation (leads to isolated GH, PRL, and TSH deficiency).
• Prop1 gene mutation (leads to isolated GH, PRL, TSH, and
gonadotrophin deficiency).
Further reading
De Marinis L, et al. (2005). Primary empty sella. J Clin Endocrinol Metab 90, 5471–7.
Glynn N, Agha A (2013). Which patient requires neuroendocrine assessment following traumatic
brain injury, when and how. Clin Endocrinol 78, 17–20.
Pal A, et al. (2011). Pituitary apoplexy in non-functioning pituitary adenomas: long term follow up
is important because of significant numbers of tumour recurrences. Clin Endocrinol 75, 501.
Rajasekaran S (2011). UK guidelines for the management of pituitary apoplexy.Clini Endocrinol 74, 9.
Toogood AA, Stewart PM (2008). Hypopituitarism: clinical features, diagnosis, and management.
Endocrinol Metab Clin North Am 37, 235–61.
ANTERIOR PITUITARY HORMONE REPLACEMENT 127
Anterior pituitary hormone

replacement
Background
Anterior pituitary hormone replacement therapy is usually performed by
replacing the target hormone rather than the pituitary or hypothalamic
hormone that is actually deficient. The exceptions to this are GH replace-
ment (b see Growth hormone replacement therapy in adults, p. 130) and
when fertility is desired (b see Management, p. 396).
See Table 2.3 for usual doses.
Thyroid hormone replacement
This is discussed in the section on p hypothyroidism (b see p. 80).
Monitoring of therapy
• In contrast to replacement in p hypothyroidism, the measurement
of TSH cannot be used to assess adequacy of replacement
in TSH deficiency due to hypothalamo–pituitary disease.
Therefore, monitoring of treatment in order to avoid under- and
over-replacement should be via both clinical assessment and by
measuring free thyroid hormone concentrations, which should be in
the middle/upper part of the normal range.
• FT4 should be monitored before ingestion of daily thyroxine tablets.
• T4 requirements should be reassessed when additional replacement
with other pituitary hormones becomes necessary. Thus, GH therapy,
when added, can cause a reduction of FT4 or unmask previously
undiagnosed hyperthyroidism.
Sex hormone replacement
b see Hormone replacement therapy, p. 346; Androgen replacement
therapy, p. 378.
Oestrogen/testosterone administration is the usual method of replace-
ment, but gonadotrophin therapy is required if fertility is desired (b see
p. 410).
Table 2.3 Usual doses of hormone replacement therapy

Hydrocortisone 10mg on waking, 5mg at lunchtime, and 5mg
early evening or twice daily regimens with a
usual total dose of 15–20mg/day
or
Prednisolone 3mg on waking and 2mg early evening (usual
total dose 5–7.5mg/day)
Levothyroxine 100–150 micrograms/day
GH 0.2–0.6mg/day for adults (0.4–1.0IU)
Oestrogens/testosterone Depends on formulation
Glucocorticoids
Replacement therapy
Patients with ACTH deficiency usually need glucocorticoid replacement
only and do not require mineralocorticoids, in contrast to patients with
Addison’s disease.
The normal production rate of cortisol is 9.9 ± 2.7mg/day. The gluco-
corticoid most commonly used for replacement therapy is hydrocortisone.
It is rapidly absorbed, with a short half-life (90–120min). Prednisolone and
dexamethasone can occasionally be used for glucocorticoid replacement.
The longer half-lives of these two drugs make them useful where sustained
ACTH suppression is required in, for example, congenital adrenal hyper-
plasia (CAH). Dexamethasone is useful when monitoring endogenous
production, as it is not detected in most cortisol assays. Cortisol acetate
was previously used for glucocorticoid replacement therapy but requires
hepatic conversion to active cortisol.
Monitoring of replacement
This is important to avoid over-replacement which is associated with
i BP, elevated glucose and insulin, and reduced bone mineral density
(BMD). Under-replacement leads to the non-specific symptoms, as seen
in Addison’s disease (b see p. 266). A clinical assessment is important,
but biochemical monitoring, using plasma and urine cortisol (UFC) meas-
urements, is used by many endocrinologists. The aim is to keep the UFC
within the reference range. Many centres use plasma cortisol measure-
ments on a hydrocortisone day curve (see Box 2.8). The aim is to keep the
plasma cortisol between 150 and 300nmol/L, avoiding nadirs of <50nmol/L
predose. Conventional replacement (20mg hydrocortisone/24h) may
overtreat patients with partial ACTH deficiency.
Safety
Patients should be encouraged to wear a MedicAlert, indicating that they
are cortisol-deficient, to carry a steroid card, and to keep a vial of paren-
teral hydrocortisone at home to be administered in emergency situations.
Equivalent oral glucocorticoid doses
1mg hydrocortisone is equivalent to:
• 1.5mg cortisol acetate.
• 0.2mg prednisolone.
• 0.0375mg dexamethasone.
• 4mg prednisolone ≡ 20mg hydrocortisone ≡ 0.075mg dexamethasone.
GLUCOCORTICOIDS 129
Box 2.8 Hydrocortisone day curve

There are various protocols for this test, ranging from a 3-point
curve to detect under-replacement (used with 24h UFC to detect
over-replacement)—serum cortisol checked at 9 a.m., 12.30 p.m.
(before the lunchtime dose), and 5 p.m. (pre-evening dose)—to more
frequent sampling to detect over- and under-replacement. This involves
serum cortisol at time 0, then administration of the morning dose of
hydrocortisone. Plasma cortisol is then checked at 30min, 1, 2, 3, and
5h (pre-lunchtime dose specimen), and 7 and 9h (pre-evening dose),
followed by samples at 10 and 11h.
• Oral oestrogen therapy should be stopped 6 weeks before the
test, as i CBG, leading to higher cortisol values, will make the test
uninterpretable.
• This test is only valid for hydrocortisone replacement. Prednisolone
or dexamethasone replacement can only be monitored clinically.
Acute/severe intercurrent illness

• Mild disease without fever. No change in glucocorticoid replacement.
• Pyrexial illness. Double replacement dose for duration of fever.
• Vomiting or diarrhoea. Parenteral therapy 100mg IM (from GP/trained
relative; useful for patient to have vial of hydrocortisone at home with
instruction sheet for emergency administration by suitable, trained
personnel).
• Severe illness/operation. Parenteral therapy with IM hydrocortisone
50–100mg 6-hourly (e.g. 72h for major surgery, 24h for minor surgery).
An alternative is a continual IV infusion of 1–3mg/h hydrocortisone.
Further reading
Persani L (2012). Central hypothyroidism: pathogenic, diagnostic and therapeutic challenges. J Clin
Growth hormone (GH) replacement

therapy in adults
Background
There is now a considerable amount of evidence that there are signifi-
cant and specific consequences of GH deficiency (GHD) in adults and
that many of these features improve with GH replacement therapy. GH
replacement for adults has now been approved in many countries.
Definition
It is important to differentiate between adult and childhood onset GHD.
• Although childhood onset GHD occurs s to structural lesions, such as
craniopharyngiomas and germinomas, and following treatment, such
as cranial irradiation, the commonest cause in childhood is an isolated
variable deficiency of GH-releasing hormone (GHRH) which may resolve
in adult life because of maturation of the hypothalamo–somatotroph
axis. It is, therefore, important to retest patients with childhood onset
GHD when linear growth is completed (50% recovery of this group).
• Adult onset. GHD usually occurs s to a structural pituitary or
parapituitary condition or due to the effects of surgical treatment or
radiotherapy.
Prevalence
• Adult onset GHD 1/10,000.
• Adult GHD due to adult and childhood onset GHD 3/10,000.
Benefits of GH replacement
• Improved QoL and psychological well-being.
• Improved exercise capacity.
• i lean body mass and reduced fat mass.
• Prolonged GH replacement therapy (>12–24 months) has been shown
to increase BMD, which would be expected to reduce fracture rate.
• There are, as yet, no outcome studies in terms of cardiovascular
mortality. However, GH replacement does lead to a reduction (715%)
in cholesterol. GH replacement also leads to improved ventricular
function and i left ventricular mass.
NICE guidelines for GH replacement
Adult criteria
• Severe GHD—GH <9mU/L.
• Impaired QoL (AGHDA QoL score >/= 11).
• Treatment for other pituitary hormone deficiencies.
Reassessment of treatment after 9 months’ treatment (3-month dose titra-
tion, followed by 6-month therapeutic trial)—GH discontinued if improve-
ment in AGHDA <7.
GROWTH HORMONE (GH) REPLACEMENT THERAPY IN ADULTS 131
Young adults (up to 25 years)

• GH discontinued for 3 months at completion of linear growth (<2cm/
year) and GH status reassessed.
• If severe GH deficiency confirmed, GH continued at adult dose until
age 25 years (peak bone mass).
• Age 25 and above—adult criteria apply.
Diagnosis
The diagnosis of GHD depends on appropriate biochemical testing in
the presence of an appropriate clinical context. The latter is important
because distinguishing ‘partial GHD’ from physiological causes of reduced
GH secretion, such as obesity or ageing and pathological causes, e.g.
hypercortisolaemia in Cushing’s syndrome, can be problematic. In these
situations, GHD can be diagnosed when there is supportive evidence, such
as pituitary disease and other anterior pituitary hormone deficiencies.
Who should be tested?
As the features of GHD may be non-specific and biochemical tests can
be misleading in certain clinical situations, such as obesity, investigation of
GHD should only be performed in the following groups of patients:
• Patients with hypothalamo–pituitary disease (GHD occurs early in
hypopituitarism and is almost invariable in patients with other anterior
pituitary hormone deficiencies).
• Patients who had childhood onset GHD.
• Patients who have received cranial irradiation.
Investigation of GH deficiency
Dynamic tests of GH secretion
• ITT is most widely used test. Peak GH <10mU/L (3 micrograms/L) is
diagnostic of severe GHD (see b p. 114).
• Alternative tests, if the ITT is contraindicated, include a combination
of GHRH (1 microgram/kg) and arginine (0.5g/kg) IV over 30min
(see b p. 118).
• A second confirmatory dynamic biochemical test is recommended,
particularly in patients who have suspected isolated GH deficiency.
A single GH dynamic test is sufficient to diagnose GHD in patients with
two or three pituitary hormonal defects.
IGF-1
IGF-1 concentrations may remain within the age-matched reference range
despite severe GHD in up to 50% of patients and, therefore, do not
exclude the diagnosis, and reduced IGF-1 is seen in a number of conditions.
For causes of lowered IGF-1 levels, see Box 2.9.
Abnormalities in adult GH deficiency
• Stimulated GH <10mU/L (3 micrograms/L).
• Low or low-normal IGF-1 (IGF-1 may be normal in up to 50%,
depending on age).
• d BMD.
• i insulin resistance.
• Dyslipidaemia (i LDL).
• Impaired cardiac function.
Clinical features of GH deficiency
• Impaired well-being.
• Reduced energy and vitality (depressed mood, i social isolation,
i anxiety).
• Reduced muscle mass and impaired exercise capacity.
• i central adiposity (i waist/hip ratio) and i total body fat.
• d sweating and impaired thermogenesis.
• i cardiovascular risk.
• i fracture risk (osteoporosis).
Box 2.9 Causes of lowered IGF-1 levels

• GHD.
• Malnutrition.
• Poorly controlled diabetes mellitus.
• Hepatic disease.
• Renal disease.
• Severe intercurrent illness.
INVESTIGATION OF GH DEFICIENCY 133
Treatment of GH deficiency
All patients with GHD should be considered for GH replacement therapy.
In particular, patients with impaired QoL, reduced mineral density, an
adverse cardiovascular risk profile, and reduced exercise capacity should
be considered for treatment.
Dose
See Box 2.10.
• Unlike paediatric practice, where GH doses are determined by body
weight and surface area, most adult endocrinologists use dose titration,
using serial IGF-1 measurements, to increase the dose of GH until the
IGF-1 level approaches the middle to upper end of the age-matched
IGF-1 reference range. This reduces the likelihood of side effects,
mainly related to fluid retention, which were frequently observed in
the early studies of GH replacement in adults when doses equivalent
to those used in paediatric practice were used.
• The normal production of GH is 200–500 micrograms/day in an adult.
Current recommendations are a starting dose of 150–300 micrograms/
day. The maintenance dose is usually 200–600 micrograms/day. The
dose in ♀ is often higher than for age-matched ♂ (particularly if the
female is on oral oestrogens).
Monitoring of treatment
• A clinical examination, looking for reduction in overall body weight
(a good response is loss of 3–5kg in 12 months) and reduced waist/
hip ratio. BP may fall in hypertensive patients because of reduction in
peripheral systemic vascular resistance.
• IGF-1 is monitored to avoid over-replacement, aiming to keep values
within the age-matched reference range. During dose titration, IGF-1
should be measured every 1–2 months. Once a stable dose is reached,
IGF-1 should be checked at least once a year.
• The adverse effects experienced with GH replacement usually resolve
with dose reduction and tend to be less frequent with the lower
starting doses used in current practice.
• GH treatment may be associated with impairment of insulin sensitivity,
and therefore markers of glycaemia should be monitored.
• Lipids should be monitored annually. BMD should be monitored every
2 years, particularly in those with d BMD.
• It may be helpful to monitor QoL using a questionnaire, such as the
AGHDA (adult GHD assessment) questionnaire.
Box 2.10 GH starting doses, according to age

Age (years) Dose (micrograms/day)
<30 400–500
30–60 300
>60 100–200
TREATMENT OF GH DEFICIENCY 135
• As the long-term safety and efficacy of GH replacement in adults is, as

yet, unknown, it is recommended that patients receiving GH therapy
should remain under the care of an endocrinologist. There are large
databases of patients receiving GH in order to monitor and determine
these questions regarding long-term benefits and safety, particularly
with regard to cardiovascular risk.
GH therapy in special situations
• Pregnancy. There are currently no data on GH replacement in
pregnancy.
• Critical illness. There is no good evidence for a beneficial effect of
GH replacement during critical illness. Patients should continue GH
replacement during non-severe illness, but many endocrinologists
would suggest that GH should be discontinued in patients who are
severely ill, e.g. those receiving major surgery or on ITU.
• Cardiac failure. GH treatment has recently been suggested as a
potential therapy in dilated cardiomyopathy. Longer term data are
required in this group of patients.
Adverse effects of GH replacement
See Box 2.11 for contraindications
• Sodium and water retention.
• Weight gain.
• Carpal tunnel syndrome.
• Hyperinsulinaemia.
• Arthralgia (possibly due to intra-articular cartilage swelling).
• Myalgia.
• Benign intracranial hypertension (resolves on stopping treatment).
• No data suggest that GH therapy affects tumour development (no
evidence from long-term studies in children of i risk of recurrence
with GH treatment; insufficient long-term data in adults). No evidence
of i risk of tumour recurrence in adolescents and adults following
childhood malignancy.
Box 2.11 Contraindications to GH replacement

• Active malignancy.
• Benign intracranial hypertension.
• Pre-proliferative/proliferative retinopathy in diabetes mellitus.
Further reading
Carroll PV, Christ ER, Bengtsson BA, et al. (1998). GH deficiency in adulthood and the effects of
GH replacement: a review. J Clin Endocrinol Metab 83, 382–95.
Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML (2011). Endocrine Society.
Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical
practice guideline. J Clin Endocrinol Metab 96, 1587–609.
Pituitary tumours
Epidemiology
• Pituitary adenomas are the most common pituitary disease in adults
and constitute 10–15% of primary brain tumours.
• Approximately 10% of individuals harbour incidental tumours, most
commonly microadenomas.
• The incidence of clinically apparent pituitary disease is 1 in 10,000.
• Pituitary carcinoma is very rare (<0.1% of all tumours) and is most
commonly ACTH- or prolactin-secreting.
See Table 2.4.
Classification
Size
• Microadenoma <1cm.
• Macroadenoma >1cm.
Functional status (clinical or biochemical)
• Prolactinoma 35–40%.
• Non-functioning 30–35%.
• Growth hormone (acromegaly) 10–15%.
• ACTH adenoma (Cushing’s disease) 5–10%.
• TSH adenoma <5%.
Pathogenesis
The mechanism of pituitary tumourigenesis remains largely unclear.
Pituitary adenomas are monoclonal, supporting the theory that there are
intrinsic molecular events leading to pituitary tumourigenesis. However,
the mutations (e.g. p53) found in other tumour types are only rarely
found. A role for hormonal factors and, in particular, the hypothalamic
hormones in tumour progression is also a suggested hypothesis.
Table 2.4 Approximate relative frequencies of pituitary tumours

Tumour type Mean prevalence1 Annual incidence
(per 100,000)
Clinically overt pituitary 72 1–2/100,000
adenomas
Acromegaly 12% 9 4 cases/million
Cushing’s syndrome 7% 1 2 cases/million
Non-functioning adenoma 22 6 cases/million
25%
Prolactinomas 49% 44 10 cases/million (if hyper-
prolactinaemia is considered,
then higher incidence)
TSHomas <1%.
PITUITARY TUMOURS 137
Mortality
Pituitary disease is associated with an increased mortality, predominantly
due to vascular disease. This may be due to oversecretion of GH or
ACTH, hormone deficiencies or excessive replacement (e.g. of hydrocor-
tisone). Radiotherapy of the pituitary is also associated with an increased
mortality (especially cerebrovascular). Craniopharyngioma patients have a
particularly increased mortality.
Reference
1. Fernandez, et al. (2010). Prevalence of pituitary adenomas: a community-based, cross-sectional
study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf) 72, 377.
Molecular mechanisms of pituitary

tumour pathogenesis
Activation of oncogenes
• Gsα mutation found in up to 40% GH-secreting tumours (less in
non-Caucasians) and also described in a minority of NFAs and
ACTH-secreting tumours.
• Ras mutation found in aggressive tumours and mainly pituitary
carcinomas. ? role in malignant transformation.
• Pituitary tumour transforming gene (PTTG) has recently been described
and found to be overexpressed in pituitary tumours. Its role in tumour
pathogenesis is, as yet, uncertain.
Inactivation of tumour suppressor genes (TSG)
• MEN-1 gene loss of heterozygosity (LOH) at 11q13 had been
previously demonstrated in up to 20% sporadic pituitary tumours;
however, the expression of the MEN-1 gene product menin is not
downregulated in the majority of sporadic pituitary tumours.
• Retinoblastoma gene. Mutations in mice lead to intermediate
lobe corticotroph adenomas; however, no mutations have been
demonstrated in human pituitary adenomas.
Cyclins and modulators of cyclin activity
• Mutations of the cyclin-dependent kinases p27 and p18 are rare
in human pituitary tumours (unlike tumours in mice). p27 may be
translationally downregulated, and p16 may be transcriptionally
silenced by methylation of its gene. Cyclin D1 overexpression may be
an early step in pituitary tumourigenesis, as it is commonly found in
different tumour types.
• Mutations are rare in pituitary tumours.
Alterations in receptor and growth factor expression
(e.g.TGF, activin, bFGF)
No consistent patterns have emerged.
Further reading
Asa SL, Ezzat S (1998). The cytogenesis and pathogenesis of pituitary adenomas. Endocr Rev 19,
798–827.
Sherlock M, et al. (2010). Mortality in patients with pituitary disease. Endocr Rev 31, 301–42.
MOLECULAR MECHANISMS OF PITUITARY TUMOUR PATHOGENESIS 139
Prolactinomas
Epidemiology
• Prolactinomas are the commonest functioning pituitary tumour.
• Post-mortem studies show microadenomas in 10% of the population.
• During life, microprolactinomas are commoner than
macroprolactinomas, and there is a ♀ preponderance of
microprolactinomas.
Pathogenesis
Unknown. Occur in 20% of patients with MEN-1 (prolactinomas are the
commonest pituitary tumour in MEN-1 and may be more aggressive than
sporadic prolactinomas). Malignant prolactinomas are very rare and may
harbour RAS mutations.
Clinical features
Hyperprolactinaemia (microadenomas and macroadenomas)
• Galactorrhoea (up to 90% ♀, <10% ♂).
• Disturbed gonadal function in ♀ presents with menstrual disturbance
(up to 95%)—amenorrhoea, oligomenorrhoea, or with infertility and
reduced libido.
• Disturbed gonadal function in ♂ presents with loss of libido and/
or erectile dysfunction. Presentation with reduced fertility and
oligospermia or gynaecomastia is unusual.
• Hyperprolactinaemia is associated with a long-term risk of d BMD.
• Hyperprolactinaemia inhibits GnRH release, leading to d LH secretion.
There may be a direct action of PRL on the ovary to interfere with LH
and FSH signalling which inhibits oestradiol and progesterone secretion
and also follicle maturation.
Mass effects (macroadenomas only)
• Headaches and visual field defects (uni- or bitemporal field defects).
• Hypopituitarism.
• Invasion of the cavernous sinus may lead to cranial nerve palsies.
• Occasionally, very invasive tumours may erode bone and present with
a CSF leak or s meningitis.
For causes of hyperprolactinaemia, see Box 2.12.
PROLACTINOMAS 141
Box 2.12 Causes of hyperprolactinaemia

• Physiological:
• Pregnancy.
• Sexual intercourse.
• Nipple stimulation/suckling.
• Neonatal.
• Stress.
• Pituitary tumour:
• Prolactinomas.
• Mixed GH/PRL-secreting tumour.
• Macroadenoma compressing stalk.
• Empty sella.
• Hypothalamic disease—mass compressing stalk (craniopharyngioma,
meningioma, neurofibromatosis).
• Infiltration—sarcoidosis, Langerhans cell histiocytosis.
• Stalk section—head injury, surgery.
• Cranial irradiation.
• Drug treatment:
• Dopamine receptor antagonists (metoclopramide, domperidone).
• Neuroleptics* (perphenazine, flupentixol, fluphenazine,
haloperidol, thioridazine, chlorpromazine, trifluoperazine,
risperidone, sulpiride).
• Antidepressants (tricyclics, selective serotonin reuptake inhibitors,
monoamine oxidase inhibitors, sulpiride, amisulpride, imipramine,
clomipramine, amitriptyline, pargyline, clorgiline).
• Cardiovascular drugs—verapamil, methyldopa, reserpine.
• Opiates.
• Cocaine.
• Protease inhibitors—e.g. ritonavir, indinavir, zidovudine.
• Oestrogens.
• Others—bezafibrate, omeprazole, H2 antagonists.
• Metabolic:
• Hypothyroidism—TRH increases PRL.
• Chronic renal failure—reduced PRL clearance.
• Severe liver disease—disordered hypothalamic regulation.
• Other:
• PCOS—can make differential diagnosis of menstrual problems
difficult.
• Chest wall lesions—zoster, burns, trauma (stimulation of suckling
reflex).
• No cause found:
• ‘Idiopathic’ hyperprolactinaemia.
*
Quetiapine, clozapine, aripiprazole, and olanzapine are antipsychotics, with little or no effect on
prolactin (lower binding affinity to D2 receptors).
Investigations of prolactinomas
Serum PRL
• The differential diagnosis of elevated PRL is shown in Box 2.12. Note
that the stress of venepuncture may cause mild hyperprolactinaemia,
so 2–3 levels should be checked, preferably through an indwelling
cannula after 30min.
• Serum PRL <2,000mU/L is suggestive of a tumour—either a
microprolactinoma or a non-functioning macroadenoma compressing
the pituitary stalk, with loss of dopamine inhibitory tone to the
lactotroph and subsequent hyperprolactinaemia.
• Serum PRL >4,000mU/L is diagnostic of a macroprolactinoma.
• Hook effect. This occurs where the assay utilizes antibodies recognizing
two ends of the molecule. One is used to capture the molecule and
one to label it. If PRL levels are very high, it may be bound by one
antibody but not by the other. Thus, above a certain concentration,
the signal will reduce, rather than increase, and very high PRL levels
will be spuriously reported as normal or only slightly raised.
Thyroid function and renal function
Hypothyroidism and chronic renal failure are causes of hyperprolactinaemia.
Imaging
• MRI. Microadenomas usually appear as hypointense lesions within
the pituitary on T1-weighted images. Negative imaging is an indication
for contrast enhancement with gadolinium. Stalk deviation or gland
asymmetry may also suggest microadenoma.
• Macroadenomas are space-occupying tumours, often associated with
bony erosion and/or cavernous sinus invasion.
Macroprolactin (‘big’ PRL)
Occasionally, aggregate forms (150–170kDa) of PRL are detected in the
circulation. Although these are measurable in the prolactin assay, they
do not interfere with reproductive function but may be found in 10% of
patients referred. Typically, there is hyperprolactinaemia with regular ovu-
latory menstrual cycles. Assays for macroprolactin are available, using PEG
(polyethylene glycol) precipitation, where low recovery of PRL demon-
strates the presence of macroprolactin, or gel filtration chromatography
(gold standard).
‘IDIOPATHIC’ HYPERPROLACTINAEMIA 143
Hyperprolactinaemia and drugs

(b see p. 141, Box 2.12)
Antipsychotic agents are the most likely psychotropic agents to cause
hyperprolactinaemia. If dose reduction is not possible or not effective, then
an MRI to exclude a prolactinoma and treatment of hypogonadism may be
indicated. Where dopamine antagonism is the mechanism of action of the
drug, then dopamine agonists may reduce efficacy. Drug-induced increases
in PRL are usually <3,000mU/L.
‘Idiopathic’ hyperprolactinaemia
When no cause is found following evaluation, as described on b p. 141,
the hyperprolactinaemia is designated idiopathic but, in many cases, is
likely to be due to a tiny microprolactinoma which is not demonstrable
on current imaging techniques. In other cases, it may be due to altera-
tions in hypothalamic regulation. Follow-up of these patients shows that,
in one-third, PRL levels return to normal; in 10–15%, there is a further
increase in PRL, and, in the remainder, PRL levels remain stable.
Treatment of prolactinomas
Aims of therapy
• Microprolactinomas. Restoration of gonadal function.
• Macroprolactinomas.
• Reduction in tumour size and prevention of tumour expansion.
• Restoration of gonadal function.
• Although microprolactinomas may expand in size without treatment, the
vast majority do not. Therefore, although restoration of gonadal function
is usually achieved by lowering PRL levels, ensuring adequate sex
hormone replacement is an alternative if the tumour is monitored in size.
• Macroprolactinomas, however, will continue to expand and lead to
pressure effects. Definitive treatment of the tumour is, therefore,
necessary.
Drug therapy—dopamine agonists
• Dopamine agonist treatment (b see Dopamine agonists, p. 204)
leads to suppression of PRL in most patients, with s effects of
normalization of gonadal function and termination of galactorrhoea.
Tumour shrinkage occurs at a variable rate (from 24h to 6–12 months)
and extent and must be carefully monitored. Continued shrinkage
may occur for years. Slow chiasmal decompression will correct
visual field defect in the majority of patients, and immediate surgical
decompression is not necessary. Lack of improvement of visual fields,
despite tumour shrinkage, makes improvement with surgery unlikely.
Restoration of other hormonal axes may occur with tumour shrinkage.
• Cabergoline is more effective in normalization of PRL in
microprolactinoma (83% compared with 59% on bromocriptine), with
fewer side effects than bromocriptine.
• Although cabergoline in higher doses used for Parkinson’s disease can
cause right-sided cardiac fibrosis, there is no evidence for this using the
lower doses necessary for the control of PRL levels (see Box 2.13).
• Dopamine agonist resistance (see Box 2.14) may occur when there are
reduced numbers of D2 receptors.
• Tumour enlargement following initial shrinkage on treatment is usually
due to non-compliance. A rare possibility, however, is carcinoma.
Drug therapy—oestrogens
Oestrogen replacement, rather than dopamine agonist therapy, may be
appropriate in ♀ with idiopathic hyperprolactinaemia or microprolacti-
nomas where fertility and galactorrhoea are not issues. Small short-term
series suggest no evidence of tumour enlargement. However, individual
cases where tumour enlargement has occurred make monitoring of PRL
important.
Surgery
b see Transsphenoidal surgery, p. 196.
• Since the introduction of dopamine agonist treatment, transsphenoidal
surgery is indicated only for patients who are resistant to, or intolerant
of, dopamine agonist treatment. The cure rate for macroprolactinomas
TREATMENT OF PROLACTINOMAS 145
treated with surgery is poor (30%), and, therefore, drug treatment is

first-line in tumours of all size. Occasionally, surgery may be required
for patients with CSF leak s to an invasive macroprolactinoma. Cure
rates for microprolactinomas treated with surgery are >80%, but the
risk of hypopituitarism (GH-deficient in 25%) and recurrence (4% at
5 years) makes this a second-line option.
• Bromocriptine given for more than a month may make the tumour
fibrous.
• The surgical management of a CSF leak can be very difficult in patients
with very invasive tumours. Tumour shrinkage with dopamine agonists
will either precipitate or worsen the leak, with the subsequent risk of
meningitis. There is no evidence for the long-term use of prophylactic
antibiotics in this group, but patients at risk should be informed of the
warning symptoms and advised to seek expert medical attention urgently.
Radiotherapy
b see Technique, p. 200.
• Standard pituitary irradiation leads to slow reduction (over years)
of PRL in the majority of patients. While waiting for radiotherapy to
be effective, dopamine agonist therapy is continued but should be
withdrawn on a biannual basis at least to assess if it is still required.
Box 2.13 Cabergoline and cardiac valvulopathy

• Cabergoline, but not bromocriptine, is a 5-hydroxytryptamine 2B
(5-HT2B) receptor agonist.
• High doses of cabergoline (e.g. 3mg/day for ≥6 months in Parkinson’s
patients) have been associated with valvular heart disease (aortic,
mitral, and tricuspid regurgitations) via a 5-HT2B target effect.
• The risk of cardiac valvulopathy appears to be low in prolactinoma
patients on standard doses of cabergoline (<2mg/week).
• For patients requiring higher cabergoline doses, annual clinical
cardiac exams are warranted, and consideration should be given to
periodic echocardiograms.
Reproduced from Draznin and Epstein, Oxford American Handbook of Endocrinology and
Diabetes (2011), with permission of OUP.
Box 2.14 Dopamine agonist resistance

• Definition. Failure to normalize prolactin. Failure to decrease tumour
size to <50%.
• Occurs with 24% treated with bromocriptine, 13% with pergolide,
and 11% with cabergoline.
• D2 receptors are reduced in number but not efficacy.
• Treatment options include switching dopamine agonist, increasing
dose of dopamine agonist, surgery, fertility treatment, or
oestrogen replacement (± DXR (pituitary radiotherapy) for
macroprolactinomas).
• Radiotherapy is not indicated in the management of patients

with microprolactinomas. It is useful in the treatment of
macroprolactinomas once the tumour has been shrunken away from
the chiasm, only if the tumour is resistant.
Prognosis
(See Box 2.15.)
• The natural history of microprolactinomas is difficult to assess.
However, they are a common post-mortem incidental finding, and
<7% show any increase in tumour size. It has been demonstrated that
hyperprolactinaemia in approximately one-third of ♀ will resolve,
particularly after the menopause or pregnancy. This shows that
patients receiving dopamine agonist treatment for microprolactinoma
should have treatment withdrawn intermittently to assess the
continued requirement for it, and certainly the dose may be titrated
downwards over time.
• There are few data on dopamine agonist withdrawal in
macroprolactinomas in the absence of definitive treatment
(radiotherapy or surgery). There are data suggesting that cautious
attempts at dose reduction could be considered after 5 years if the
PRL is normal and the MRI shows no tumour, but it seems that the
majority have a recurrence of hyperprolactinaemia (60–80%) but to
levels lower than pretreatment values.
• It seems, at present, that there is no increase in the risk of breast
cancer.
Management of prolactinomas in pregnancy
b see Prolactinoma in pregnancy, p. 437.
Box 2.15 Dopamine resistance of prolactinoma

• Definition:
• Failure to normalize prolactin on dopamine agonist therapy.
• Failure to decrease tumour size by 50% or more.
• Frequency:
• Bromocriptine 24%.
• Pergolide 13%.
• Cabergoline 11%.
• Cause:
• D2 receptors on tumour decreased in number: normal affinity.
• Treatment:
• Switch dopamine agonist.
• Increase dose of dopamine agonist.
• Transsphenoidal surgery.
• Clomifene gonadotrophins for fertility.
• Oestrogen replacement therapy 9 DXR for macroadenoma.
TREATMENT OF PROLACTINOMAS 147
Further reading
Barber T, et al. (2011). Recurrence of hyperprolactinaemia following discontinuation of dopamine
agonist therapy in patients with prolactinoma occurs commonly especially in macroprolac-
toinoma. Clin Endocrinol 75, 819–24.
Bevan JS, Webster J, Burke CW, et al. (1992). Dopamine agonists and pituitary tumour shrinkage.
Endocrinol Rev 13, 220–40.
Casaneuva FF, Molitch ME, Schlechte JA, et al. (2006). Guidelines of the Pituitary Society for the
diagnosis and management of prolactinomas. Clin Endocrinol 65, 265–73.
Dekkers OM, Lagro J, Burman P, Jørgensen JO, Romijn JA, Pereira AM (2011). Recurrence of hyper-
prolactinaemia after withdrawal of dopamine agonists: systematic review and meta-analysis. J
Clin Endocrinol Metab 95, 43–51.
Karavitaki N, Thanabalasingham G, Shore HC (2006). Do the limits of serum prolactin in disconnec-
tion hyperprolactinaemia need re-definition? A study of 226 patients with histologically verified
non-functioning pituitary macroadenoma. Clin Endocrinol 65, 524–9.
Melmed S, et al. (2011). Diagnosis and treatment of hyperprolactinaemia: an Endocrine Society
Clinical practice guideline. J Clin Endocrinol Metab 96, 273–88.
Molitch ME (1985). Pregnancy and the hyperprolactinaemic woman. New Engl J Med 312, 1364–70.
Molitch ME (1992). Pathologic hyperprolactinaemia. Endocrinol Metabo Clin N Am 21, 877–910.
Molitch ME (2002). Medical management of prolactinomas. Pituitary 5, 55–65.
Molitch ME (2003). Dopamine resistance of prolactinomas. Pituitary 6, 19–27.
Molitch ME (2008). Drugs and prolactin. Pituitary 11, 209–18.
Suliman SG, Gurlek A, Byrne JV (2007). Non-surgical cerebrospinal fluid rhinorrhoea in invasive
macroprolactinoma: incidence, radiological and clinicopathological features. J Clin Endocrinol
Metab 92, 3829–35.
Definition of acromegaly
Acromegaly is the clinical condition resulting from prolonged excessive
GH and hence IGF-1 secretion in adults. GH secretion is characterized by
blunting of pulsatile secretion and failure of GH to become undetectable
during the 24h day, unlike normal controls.
Epidemiology of acromegaly
• Rare. Equal sex distribution.
• Prevalence 40–86 cases/million population. Annual incidence of new
cases in the UK is 4/million population.
• Onset is insidious, and there is, therefore, often a considerable delay
between onset of clinical features and diagnosis. Most cases are
diagnosed at 40–60 years. Typically, acromegaly occurring in an older
patient is a milder disease, with lower GH levels and a smaller tumour.
Pituitary gigantism
The clinical syndrome resulting from excess GH secretion in children prior
to fusion of the epiphyses.
• Rare.
• i growth velocity without premature pubertal manifestations should
arouse suspicion of pituitary gigantism.
• Differential diagnosis. Marfan’s syndrome, neurofibromatosis,
precocious pubertal disorders, cerebral gigantism (large at birth with
accelerated linear growth and disproportionately large extremities—
associated normal IGF-1 and GH).
• Arm span > standing height is compatible with eunuchoid features and
suggests onset of disease before epiphyseal fusion (pituitary gigantism).
CAUSES OF ACROMEGALY 149
Causes of acromegaly
• Pituitary adenoma (>99% of cases). Macroadenomas 60–80%,
microadenomas 20–40%. Local invasion is common, but frank
carcinomas are very rare.
• GHRH secretion:
• Hypothalamic secretion.
• Ectopic GHRH, e.g. carcinoid tumour (pancreas, lung) or other
neuroendocrine tumours.
• Pituitary shows global enlargement. Somatroph hyperplasia seen on
histology.
• Ectopic GH secretion. Very rare (e.g. pancreatic islet cell tumour,
lymphoreticulosis).
• There has been some progress on the molecular pathogenesis of the
GH-secreting pituitary adenomas—as mutations of the Gsα are found
in up to 40% of tumours. This leads to an abnormality of the G protein
that usually inhibits GTPase activity in the somatotroph.
• Gene mutations have been shown in some young patients with
acromegaly who also have large tumours (familial isolated pituitary
adenoma) in whom a family history should be sought.
Associations of acromegaly
• MEN-1. Less common than prolactinomas (b see MEN type 1,
p. 586).
• Carney complex. AD, spotty cutaneous pigmentation, cardiac and other
myxomas, and endocrine overactivity, particularly Cushing’s syndrome
due to nodular adrenal cortical hyperplasia and GH-secreting pituitary
tumours in <10% of cases. Mainly due to activating mutations of
protein kinase A (b see p. 583).
• McCune–Albright syndrome (b see p. 576). Caused by somatic
mosaicism for the gsp mutation.
• Familial isolated pituitary adenomas:
• Existence of two or more cases of acromegaly or gigantism in a
family that does not exhibit MEN-1 or Carney complex.
• Autosomal dominant.
• Most have acromegaly, but acromegaly and prolactinoma families
exist as rarely as do NFA families.
• 30–50% cases have a mutation in the AIP gene (tumour
suppressor gene).
• Early-onset disease (<30 years).
• Poor response to somatostatin analogues.
• Take a careful family history, especially in acromegalic patients with
a large pituitary tumour presenting below the age of 30 years, and
consider screening for AIP.
• See Box 2.25 for causes of macroglossia.
Box 2.25 Macroglossia—causes

• Acromegaly.
• Hypothyroidism.
• Beckwith–Wiedemann syndrome (macrosomia, visceromegaly)—
associated with hypoglycaemia and malignancies.
• Simpson–Golabi–Behmel syndrome (macrosomia and renal skeletal
abnormalities).
• Tongue amyloidoses (primary or secondary to myeloma).
• Mucopolysaccharidoses/lysosomal storage disease.
• Focal tongue lesions, e.g. haemorrhage.
• Down’s syndrome.
• Hyperinsulinaemia.
CLINICAL FEATURES OF ACROMEGALY 151
Clinical features of acromegaly

The clinical features arise from the effects of excess GH/IGF-1, excess PRL
in some (as there is co-secretion of PRL in a minority (30%) of tumours or,
rarely, stalk compression), and the tumour mass.
Symptoms
• i sweating—>80% of patients.
• Headaches—independent of tumour effect.
• Tiredness and lethargy.
• Joint pains.
• Change in ring or shoe size.
Signs
• Facial appearance. Coarse features, oily skin, frontal bossing, enlarged
nose, deep nasolabial furrows, prognathism, and i interdental
separation.
• Deep voice—laryngeal thickening.
• Tongue enlargement—macroglossia (see b p. 209).
• Musculoskeletal changes. Enlargement of hands and feet, degenerative
changes in joints lead to osteoarthritis. Generalized myopathy.
• Soft tissue swelling. May lead to entrapment neuropathies, such as
carpal tunnel syndrome (40% of patients).
• Goitre and other organomegaly—liver, heart, kidney.
NB Fabry’s disease causes thickening of the lips.
Complications
• Hypertension (40%).
• Insulin resistance and impaired glucose tolerance (40%)/diabetes
mellitus (20%).
• Obstructive sleep apnoea—due to soft tissue swelling in
nasopharyngeal region.
• i risk of colonic polyps and colonic carcinoma—extent currently
considered controversial.
• Ischaemic heart disease and cerebrovascular disease.
• Congestive cardiac failure and possible i prevalence of regurgitant
valvular heart disease.
Effects of tumour
• Visual field defects.
Investigations of acromegaly
Oral glucose tolerance test (OGTT)
• In acromegaly, there is failure to suppress GH to <0.33 micrograms/L
in response to a 75g oral glucose load. In contrast, the normal
response is GH suppression to undetectable levels.
• False +ves. Chronic renal and liver failure, malnutrition, diabetes mellitus,
heroin addiction, adolescence (due to high pubertal GH surges).
Random GH
Not useful in the diagnosis of acromegaly as, although normal healthy sub-
jects have undetectable GH levels throughout the day, there are pulses of
GH which are impossible to differentiate from the levels seen in acromeg-
aly. However, in untreated patients, a random GH <0.33 micrograms/L
practically excludes the diagnosis.
IGF-1
Useful in addition to the OGTT in differentiating patients with acromegaly
from normals, as it is almost invariably elevated in acromegaly, except in
severe intercurrent illness. It has a long half-life, as it is bound to binding
proteins, and reflects the effect of GH on tissues. However, abnormalities
of GH secretion may remain while IGF-1 is normal.
MRI
MRI usually demonstrates the tumour (98%) and whether there is extra-
sellar extension, either suprasellar or into the cavernous sinus.
Pituitary function testing
(b also see Insulin tolerance test (ITT), p. 114.) Serum PRL should be
measured, as some tumours co-secrete both GH and PRL.
Serum calcium
Some patients are hypercalciuric due to i 1,25-DHCC, as GH stimulates
renal 1α-hydroxylase. There may be an i likelihood of renal stones due
to hypercalcaemia as well as hypercalciuria (which occurs in 80%). Rarely,
hypercalcaemia may be due to associated MEN-1 and hyperparathyroidism.
GHRH
Occasionally, it is not possible to demonstrate a pituitary tumour, or the
pituitary gland MRI reveals global enlargement and histology reveals hyper-
plasia. A serum GHRH, in addition to radiology of the chest and abdomen,
may then be indicated to identify the cause, usually a GHRH-secreting
carcinoid of lung or pancreas.
INVESTIGATIONS OF ACROMEGALY 153
GH day curve (GHDC)

• GH taken at 4–5 time points during the day.
• This is used to assess response to treatment following surgery or
radiotherapy and also to assess GH suppression on somatostatin
analogues in order to determine whether an increase in dose is
required.
• It does not have a role in the diagnosis of acromegaly, but, in
acromegaly, GH is detectable in all samples in contrast to normal.
The degree of elevation of GH is relevant to the response to all
forms of treatment; the higher the GH, the less frequent treatment
is effective by surgery, drugs, or radiotherapy. See Box 2.26 for
differential diagnosis.
Note on GH and IGF-I assays
• To improve standardization, it is recommended that the GH reference
preparation should be a recombinant 22kDa hGH; presently, 88/624.
• There is currently no acceptable IGF-1 reference preparation.
Box 2.26 Differential diagnosis of elevated GH

• Pain.
• Pregnancy.
• Puberty.
• Adolescence if tall.
• Stress.
• Chronic renal failure.
• Chronic liver failure.
• Heart failure.
• Diabetes mellitus.
• Malnutrition.
• Prolonged fast.
• Severe illness.
• Heroin addiction.
Management of acromegaly
The management strategy depends on the individual patient and also
on the tumour size. Lowering of GH is essential in all situations (see
Fig. 2.7).
Transsphenoidal surgery
(b also see Transsphenoidal surgery, p. 196.)
• This is usually the first line for treatment in most centres.
• Reported cure rates vary: 40–91% for microadenomas and 10–48% for
macroadenomas, depending on surgical expertise.
• A GHDC should be performed following surgery to assess whether
‘safe’ levels of GH and IGF-1 have been attained. If the mean GH is
<2.5 micrograms/L, then the patient can be followed up with annual
IGF-1 and/or GH assessment. If safe levels of GH have not been
achieved, then medical treatment and/or radiotherapy is indicated.
• Surgical debulking of a large macroadenoma should be undertaken,
even if cure is not expected, because this lowers GH levels and
improves the cure rate with subsequent somatostatin analogues.
Tumour recurrence following surgery
This is defined as tumour regrowth and increase in GH levels, lead-
ing to active acromegaly following post-operative normalization of GH
levels. Using the definition of post-operative cure as mean GH <2.5
micrograms/L, the reported recurrence rate is low (6% at 5 years).
Radiotherapy
(b also see Technique, p. 200.)
• This is usually reserved for patients following unsuccessful
transsphenoidal surgery, only occasionally is it used as p therapy. The
largest fall in GH occurs during the first 2 years, but GH continues to
fall after this. However, normalization of mean GH may take several
years and, during this time, adjunctive medical treatment (usually
with somatostatin analogues) is required. With a starting mean GH
>25 micrograms/L, it takes, on average, 6 years to achieve mean
GH <2.5 micrograms/L, compared with 4 years with a starting mean
GH <25 micrograms/L.
• After radiotherapy, somatostatin analogues should be withdrawn on
an annual basis to perform a GHDC to assess progress and identify
when mean GH <2.5 micrograms/L and, therefore, radiotherapy has
been effective and somatostatin analogue treatment is no longer
required.
• Radiotherapy can induce GH deficiency which may need GH therapy.
Definition of cure
• Controlled disease is, most recently, defined as a random GH <1
micrograms/L or nadir GH <0.4 micrograms/L on GTT + normal
age-related IGF-1.
MANAGEMENT OF ACROMEGALY 155
Microadenoma Macroadenoma
Surgery Surgery
GH <2.5µg/L GH >2.5µg/L GH >2.5µg/L GH >2.5µg/L

or GTT GH IGF-1 high IGF-1 high or GTT GH
nadir <1µg/L (10%) (55%) nadir <1µg/L
IGF-1 normal IGF-1 normal
(90%) (45%)
Medical treatment
Somatostatin analogues
(60% normal IGF-1 and GH <2.5µg/L)
or
Dopamine agonists
(10–20% GH <2.5µg/L) IGF-I normal
or
GH receptor antagonists (IGF-1 normal >90%)
GH <2.5µg/L GH <2.5µg/L
IGF-1 normal IGF-1 high
Consider external External beam

beam radiotherapy radiotherapy
Fig. 2.7 Treatment paradigms in acromegaly. Reproduced with permission from

Wass J (2001). Handbook of Acromegaly, p.81. BioScientifica Ltd.
• In treated patients, there is an approximately 25% discordance of GH

and IGF-1. The management of this situation is unclear, but if there are
symptoms, it should probably be treated.
Colonic polyps and acromegaly
• i incidence of colonic polyps and colonic carcinoma has been reported
by many groups. Both retrospective and prospective studies have
demonstrated that 9–39% of acromegalic patients studied have colonic
polyps and 0–5% have been shown to have colonic carcinoma.
• Mechanism. IGF-1 and/or GH are implicated, as both may stimulate

colonic mucosal turnover. However, some studies have failed to
demonstrate a direct relationship between serum levels and polyps/
carcinoma.
• Importance. Patients with acromegaly are probably at slightly
i risk and, therefore, need screening for polyps. All patients aged
>40 years should have routine colonoscopy, and those with polyps
or persistently active acromegaly should receive 5-yearly repeat
colonoscopy. Agreement has not been reached though on the
frequency of follow-up colonoscopy.
Drug treatment
(b also see Somatostatin analogues, p. 204.)
• Somatostatin analogues lead to suppression of GH secretion in 20–60%
of patients with acromegaly. At least 40% of patients are complete
responders, and somatostatin analogues will lead to normalization of
GH (<2.5 micrograms/L) and IGF-1. However, some patients are partial
responders, and although somatostatin analogues will lead to lowering
of mean GH, they do not suppress to normal despite dose escalation.
• Acute response to these drugs is assessed by measuring GH at
hourly intervals for 6h, following the injection of 50–100 micrograms
octreotide SC. This predicts long-term response.
• Depot preparations lanreotide Autogel® and octreotide LAR® are
available. Octreotide LAR® 20mg IM is administered every 4 weeks,
with dose alterations either down or up to 10–30mg every 3 months.
Lanreotide Autogel® 90mg (deep SC) is administered every 28 days,
with dose alteration either down to 60mg or up to 120mg every
3 months. Patients can be taught to self-administer lanreotide.
• These drugs may be used as p therapy where the tumour does not
cause mass effects or in patients who have received surgery and/or
radiotherapy who have elevated mean GH.
• Pasireotide stimulates somatostatin receptors 2 and 5, and treatment
may increase the response rate in patients with acromegaly, but
glucose tolerance declines and patients may develop diabetes mellitus.
Dopamine agonists
(b also see Dopamine agonists, p. 204.)
These drugs do lead to lowering of GH levels but, very rarely, lead to
normalization of GH or IGF-1 (<30%). They may be helpful, particularly
if there is coexistent secretion of PRL, and, in these cases, there may be
significant tumour shrinkage. Cabergoline has recently been shown to be
more effective than bromocriptine and may lead to IGF-1 normalization in
up to 30%. A lower pretreatment IGF-1 favours a good response.
GH receptor antagonists (pegvisomant) b p. 206
Indicated for somatostatin non-responders. Liver function tests should
be monitored 6-weekly for 6 months. MRI of the pituitary is indicated
6-monthly in case of pituitary enlargement (5%). Therapy may be continued
with octreotide or lanreotide to decrease the frequency of pegvisomant
injections (e.g. pegvisomant 10mg daily and lanreotide). Normalization of
MORTALITY DATA OF ACROMEGALY 157
IGF-1 in >90% of patients is reported. More data on the effect on tumour

size are required, as GH rises during treatment. GH levels cannot, there-
fore, be used to guide treatment, and IGF-1 is used to monitor therapy.
Monitoring of liver biochemistry is necessary for safety.
Mortality data of acromegaly

• Mortality in untreated patients is double that of the normal population.
• Major causes include cardiovascular, cerebrovascular, and respiratory
disease. More effective treatment has now i life expectancy.
Further reading
Alexopoulou O, et al. (2008). Divergence between growth hormone and insulin-like growth
factor-I concentrations in the follow-up of acromegaly. J Clin Endocrinol Metab 93, 1324–30.
Bates AS, Van’t Hoff W, Jones JM, et al. (1993). An audit of outcome of treatment in acromegaly.
QJM 86, 293–9.
Bevan JS, Atkin SL, Atkinson AB, et al. (2002). Primary medical therapy for acromegaly: an open,
prospective, multicenter study of the effects of subcutaneous and intramuscular slow-release
ocreotide on growth hormone, insulin-like growth factor-I, and tumor size. J Clin Endocrinol
Metab 87, 4554–63.
Chahal, AS, et al. (2011). AIP mutation in pituitary adenomas in the 18th century and today. N Engl
J Med 364, 43–50.
Daly AF, et al. (2007). Aryl hydrocarbon receptor-interacting protein gene mutations in familial
isolated pituitary adenomas: analysis in 73 families. J Clin Endocrinol Metab 92, 1891–6.
Dekkers OM, et al. (2008). Mortality in acromegaly: a metaanalysis. J Clin Endocrinol Metab 93, 61–7.
Giustina A, et al. (2010). A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab
95, 3141–8.
Jenkins PJ, Bates P, Carson MN, et al. (2006). Conventional pituitary irradiation is effective in lower-
ing serum growth hormone and insulin-like growth factor-I in patients with acromegaly. J Clin
Karavitaki N, et al. (2008). Surgical debulking of pituitary macroadenomas causing acromegaly
improves control by lanreotide. Clin Endocrinol (Oxf) 68, 970–5.
Melmed S (2006). Medical progress: acromegaly. N Engl J Med 55, 2558–73.
Melmed S, Casanueva FF, Cavagnini F, et al. (2002). Guidelines for acromegaly management. J Clin
Orme SM, McNally RJQ, Cartwright RA, et al. (1998). Mortality and cancer incidence in acro-
megaly: a retrospective cohort study. JCEM 83, 2730–4.
Sandret L, et al. (2011). Place of cabergoline in acromegaly: a meta-analysis. J Clin Endocrinol Metab
96, 1322–5.
Trainer PJ, Drake WM, Katznelso L, et al. (2000). Treatment of acromegaly with the growth
hormone-receptor antagonist pegvisomant. N Engl J Med 342, 1171–7.
Wass JAH (ed.) (2009). Acromegaly. BioScientifica: Bristol.
Definition of Cushing’s disease

Cushing’s syndrome is an illness resulting from excess cortisol secre-
tion, which has a high mortality if left untreated. There are several
causes of hypercortisolaemia which must be differentiated, and the
commonest cause is iatrogenic (oral, inhaled, or topical steroids). It is
important to decide whether the patient has true Cushing’s syndrome
rather than pseudo-Cushing’s associated with depression or alcohol-
ism. Secondly, ACTH-dependent Cushing’s must be differentiated from
ACTH-independent disease (usually due to an adrenal adenoma or,
rarely, carcinoma—b see p. 250). Once a diagnosis of ACTH-dependent
disease has been established, it is important to differentiate between
pituitary-dependent (Cushing’s disease) and ectopic secretion.
Epidemiology of Cushing’s disease

• Rare; annual incidence approximately 2/million.
• Commoner in ♀ (♀:♂, 3–15:1).
• Age—most commonly, 20–40 years.
PATHOPHYSIOLOGY OF CUSHING’S DISEASE 159
Pathophysiology of Cushing’s
disease
• The vast majority of Cushing’s syndrome is due to a pituitary
ACTH-secreting corticotroph microadenoma. The underlying aetiology
is ill understood.
• Occasionally, corticotroph adenomas reach larger sizes
(macroadenomas) and rarely become invasive or malignant. The
tumours typically maintain some responsiveness to the usual feedback
control factors that influence the normal corticotroph (e.g. high doses
of glucocorticoids and CRH). However, this may be lost, and the
tumours become fully autonomous, particularly in Nelson’s syndrome.
• NB Crooke’s hyaline change is a fibrillary appearance seen in the
non-tumourous corticotroph associated with elevated cortisol levels
from any cause.
For causes of Cushing’s syndrome, see Box 2.27.
Box 2.27 Causes of Cushing’s syndrome

• Pseudo-Cushing’s syndrome:
• Alcoholism <1%.
• Severe depression 1%.
• ACTH-dependent:
• Pituitary adenoma 68% (Cushing’s disease).
• Ectopic ACTH syndrome 12%.
• Ectopic CRH secretion <1%.
• ACTH-independent:
• Adrenal adenoma 10%.
• Adrenal carcinoma 8%.
• Nodular (macro- or micro-) hyperplasia 1%.
• Carney complex (b see p. 583).
• Exogenous steroids, including skin creams, e.g. clobetasol.
Clinical features of Cushing’s disease

The features of Cushing’s syndrome are progressive and may be present
for several years prior to diagnosis. A particular difficulty may occur in a
patient with cyclical Cushing’s where the features and biochemical mani-
festations appear and disappear with a variable periodicity. Features may
not always be florid, and clinical suspicion should be high.
• Facial appearance—round plethoric complexion, acne and hirsutism,
thinning of scalp hair.
• Weight gain—truncal obesity, buffalo hump, supraclavicular fat pads.
• Skin—thin and fragile due to loss of SC tissue, purple striae on
abdomen, breasts, thighs, axillae (in contrast to silver, healed
post-partum striae), easy bruising, tinea versicolor, occasionally
pigmentation due to ACTH.
• Proximal muscle weakness.
• Mood disturbance—labile, depression, insomnia, psychosis.
• Menstrual disturbance.
• Low libido and impotence.
• There is a high incidence of venous thromboembolism (careful during
surgery).
• Overall mortality greater than of general population (by a factor of 6).
• Growth arrest in children.
Associated features
• Hypertension (>50%) due to mineralocorticoid effects of cortisol
(cortisol overwhelms the renal 11B-hydroxysteroid dehydrogenase
enzyme protecting the mineralocorticoid receptor from cortisol).
Cortisol may also increase angiotensinogen levels.
• Impaired glucose tolerance/diabetes mellitus (30%).
• Osteopenia and osteoporosis (leading to fractures of spine and ribs).
• Vascular disease due to metabolic syndrome.
• Susceptibility to infections.
CLINICAL FEATURES OF CUSHING’S DISEASE 161
Investigations of Cushing’s disease

Does the patient have Cushing’s syndrome?
Outpatient tests
• 2–3x 24h urinary free cortisol. This test can be useful for outpatient
screening—however, the false –ve rate of 5–10% means that it should
not be used alone. (Fenofibrate, carbamazepine, and digoxin may lead
to false +ves, depending on assay, and reduced GFR <30mL/min may
lead to false –ves.) In children: correct for body surface area. Mild
elevation occurs in pseudo-Cushing’s and normal pregnancy.
• Overnight dexamethasone suppression test. Administration of
1mg dexamethasone at midnight is followed by a serum cortisol
measurement at 9 a.m. Cortisol <50nmol/L makes Cushing’s unlikely.
(NB False +ves with poor dexamethasone absorption or hepatic
enzyme induction). The false –ve value is 2% of normal individuals but
rises to <20% in obese or hospitalized patients.
• If both the above tests are normal, Cushing’s syndrome is unlikely.
Inpatient tests
• Midnight cortisol. Loss of circadian rhythm of cortisol secretion is seen
in Cushing’s syndrome, and this is demonstrated by measuring a serum
cortisol at midnight (patient must be asleep for this test to be valid
and ideally after 48h as an inpatient). In normal subjects, the cortisol
at this time is at a nadir (<50nmol/L), but in patients with Cushing’s
syndrome, it is elevated. Late-night salivary cortisol may be promising,
particularly in those with possible cyclical Cushing’s (see Box 2.28).
• Low-dose dexamethasone suppression test. Administration of 0.5mg
dexamethasone 6-hourly (30 micrograms/kg/day) for 48h at 9 a.m.,
3 p.m., 9 p.m., and 3 a.m. should lead to complete suppression of
cortisol to <50nmol/L in normal subjects (30 micrograms/kg/day).
Serum cortisol is measured at time 0 and 48h (day 2).
• Interfering conditions should be considered with all dexamethasone
testing: d dexamethasone absorption, hepatic enzyme inducers
(e.g. phenytoin, carbamazepine, and rifampicin), and i CBG.
Pseudo-Cushing’s
• Patients with pseudo-Cushing’s syndrome will also show loss of
diurnal rhythm and lack of low-dose suppressibility. However,
alcoholics return to normal cortisol secretory dynamics after a few
days’ abstinence in hospital. Severe depression can be more difficult
to differentiate, particularly since this may be a feature of Cushing’s
syndrome itself.
• Typically, patients with pseudo-Cushing’s show a normal cortisol
rise with hypoglycaemia (tested using ITT) whereas patients with
true Cushing’s syndrome show a blunted rise. However, this is not
100% reliable, as up to 20% of patients with Cushing’s syndrome
(especially those with cyclical disease) show a normal cortisol rise with
hypoglycaemia.
INVESTIGATIONS OF CUSHING’S DISEASE 163
Box 2.28 Cyclical Cushing’s

A small group of patients with Cushing’s syndrome have alternating
normal and abnormal cortisol levels on an irregular basis. All causes of
Cushing’s syndrome may be associated with cyclical secretion of corti-
sol. Clearly, the results of dynamic testing can only be interpreted when
the disease is shown to be active (elevated urinary cortisol secretion and
loss of normal circadian rhythm and suppressibility on dexamethasone).
• The combined dexamethasone suppression test–CRH test (0.5mg

dexamethasone 6-hourly for 48h, starting at 12 p.m., followed
by ovine CRH 1 microgram/kg IV at 8 a.m.) (2h after last dose of
dexamethasone) may be helpful, as patients with pseudo-Cushing’s are
thought to be under chronic CRH stimulation, thus showing a blunted
response to CRH after dexamethasone suppression (cortisol 15min
after CRH >38nmol/L in Cushing’s and <38nmol/L in pseudo-Cushing’s).
• IV desmopressin 10 micrograms increases ACTH in 80–90% with
Cushing’s but rarely in patients with pseudo-Cushing’s.
• No screening tests are fully capable of distinguishing all cases of
Cushing’s syndrome from normal individuals/pseudo-Cushing’s
(see Table 2.8).
What is the underlying cause?
ACTH
(See Table 2.9.)
• Once the presence of Cushing’s syndrome has been confirmed, a
serum basal ACTH should be measured to differentiate between
ACTH-dependent and ACTH-independent aetiologies (see Fig.
2.8). ACTH may not be fully suppressed in some adrenal causes
of Cushing’s; however, ACTH >4pmol/L is suggestive of an
ACTH-dependent aetiology.
• The basal ACTH is, however, of very little value in differentiating
between pituitary-dependent Cushing’s syndrome and ectopic
Cushing’s syndrome, as there is considerable overlap between the
two groups, although patients with ectopic disease tend to have higher
ACTH levels (see Fig. 2.8).
Serum potassium
A rapidly spun potassium is a useful discriminatory test, as hypokalaemia
<3.2mmol/L is found in almost 100% of patients with ectopic secretion of
ACTH but in <10% of patients with pituitary-dependent disease.
High-dose dexamethasone suppression test
The high-dose dexamethasone suppression test is performed in an identi-
cal way to the low-dose test but with 2mg doses of dexamethasone (120
micrograms/kg/day). In Cushing’s disease, the cortisol falls by >50% of the
basal value. In ectopic disease, there is no suppression. However, approxi-
mately 10% of cases of ectopic disease, particularly those due to carcinoid
tumours, show >50% suppression, and 10% of patients with Cushing’s dis-
ease do not suppress.
Table 2.8 Screening tests for Cushing’s syndrome

Test False +ves False –ves Sensitivity
24h urinary free cortisol 1% 5–10% 95%
Overnight 1mg 2% normal 2%
dexamethasone 13% obese
suppression test 23% hospital inpatients
Midnight cortisol ? 0 100%
Low-dose dexamethasone <2% 2% 98%
suppression test
Table 2.9 Investigation of ACTH-dependent Cushing’s syndrome

Test Pituitary-dependent Ectopic disease
disease (% with this (% with this finding)
finding)
Serum potassium <3.2mmol/L 10 100
Suppression of basal cortisol 90 10
to >50% on high-dose
dexamethasone suppression test
Exaggerated rise in cortisol on 95 <1
CRH test
Reproduced from Besser M and Thorner GM (1994). Clinical Endocrinology 2nd edn. Mosby.
Copyright Elsevier, with permission.
Corticotrophin-releasing hormone test (see Fig. 2.9)

The administration of 100 micrograms of CRH IV (side effects: tran-
sient flushing; very rarely, apoplexy reported) leads to an exaggerated
rise in cortisol (14–20%) and ACTH (35–50%) in 95% of patients with
pituitary-dependent Cushing’s syndrome. There are occasional reports of
patients with ectopic disease who show a similar response.
Inferior petrosal sinus sampling (see Fig. 2.10)
• Bilateral simultaneous inferior petrosal sinus sampling with
measurement of ACTH centrally and in the periphery in the basal
state and following stimulation with IV CRH (100 micrograms) allows
differentiation between pituitary-dependent and ectopic disease.
A central to peripheral ratio of >2 prior to CRH is very suggestive of
pituitary-dependent disease, and >3 following CRH gives a diagnostic
accuracy approaching 90–95% for pituitary-dependent disease. The test
should be performed when cortisol levels are elevated.
• The accurate lateralization of a tumour using the results from inferior
petrosal sinus sampling (IPSS) is difficult, as differences in blood flow
and catheter placement, etc. will affect the results.
• Brainstem vascular events and deep vein thrombosis are rare
complications.
Cushing’s Adrenal Ectopic

disease tumour ACTH
4000–12000
2000–4000
1000–2000
900
Plasma immunoreactive ACTH (ng/l)
700
500
300
250
200
150
100
50
70 18 81
Fig. 2.8 Plasma ACTH levels (9 a.m.) in patients with pituitary-dependent
Cushing’s disease, adrenal tumours, and ectopic ACTH secretion. From Besser M
and Thorner GM (1994). Clinical Endocrinology 2nd edn. Mosby.
1500 Cushing’s disease

Serum cortisol (nmol/l)
ectopic ACTH
1000
500
<5
−15 0 30 60 90 120
Time (h)
Fig. 2.9 CRH test in pituitary-dependent and ectopic disease. In the patient with
pituitary-dependent disease, the characteristic marked plasma cortisol rise after an
IV bolus of 100 micrograms of CRH is seen. Serum cortisol levels are unaltered
in the patient with ectopic ACTH secretion. Reproduced from Besser M and
Thorner GM (1994). Clinical Endocrinology, 2nd edn. Mosby. Copyright Elsevier, with
permission.
Pituitary imaging
MRI, following gadolinium enhancement which significantly increases
the pickup rate, localizes corticotroph adenomas in up to 80% of cases.
However, it should be remembered that at least 10% of the normal popu-
lation harbour microadenomas and, therefore, the biochemical investiga-
tion of these patients is essential, as a patient with an ectopic source to
Cushing’s syndrome may have a pituitary ‘incidentaloma’.
Other pituitary function
Hypercortisolism suppresses the thyroidal, gonadal, and GH axes, leading
to lowered levels of TSH and thyroid hormones as well as reduced gon-
adotrophins, gonadal steroids, and GH.
Pituitary
Right Left
Adenoma
Inferior petrosal sinus

High jugular vein
Catheter Low jugular vein
Plasma ACTH (ng/L)

After IV CRH 100mg
0min 5min 10min 15min
Left inferior petrosal sinus 14 477 280 123

Right inferior petrosal sinus 16 23 28 54
Simultaneous peripheral vein 17 19 25 32
Fig. 2.10 Simultaneous bilateral inferior petrosal sinus and peripheral vein
sampling for ACTH. The ratio of >3 between the left central and peripheral
vein confirm a diagnosis of Cushing’s disease. Reproduced from Besser M and
Thorner GM (1994). Clinical Endocrinology, 2nd edn. Mosby. Copyright Elsevier, with
permission.
Treatment of Cushing’s disease

(b also see Transsphenoidal surgery, p. 196.)
• This is the first-line option in most cases. Selective adenomectomy gives
the greatest chance of cure, with a reported remission rate of up to
90%. However, strict criteria of a post-operative cortisol of <50nmol/L
lead to lower cure rates but much lower recurrence rates (<10%
compared with up to 50% in those with detectable post-operative
cortisol). This should be the current definition of successful surgery, as
the long-term outcome is significantly better in this group of patients.
• Delayed normalization (1–2 months) of cortisol after surgery can occur.
• Complications of surgery may be higher in these patients, as their
preoperative general status and the condition of the tissues are poorer
than other patients who are referred for surgery.
• Cushing’s is associated with a hypercoagulable state, with increased
cardiovascular thrombotic risks.
• Risk of relapse lasts for at least 10 years and is higher in Cushing’s
disease than for other secreting adenomas (13% at 5 years).
Pituitary radiotherapy
(b also see p. 200.) This is usually administered as second-line treatment,
following unsuccessful transsphenoidal surgery. As control of cortisol lev-
els may take months to years, medical treatment to control cortisol levels,
while waiting for cortisol levels to fall, is essential. A more rapid response
to radiotherapy is seen in childhood.
Adrenalectomy
• This used to be the favoured form of treatment. It successfully controls
cortisol hypersecretion in the majority of patients. Occasionally, a
remnant is left and leads to recurrent hypercortisolaemia.
• Nelson’s syndrome may occur in up to 30% of patients (see Box 2.29).
The administration of prophylactic radiotherapy d the likelihood of this
complication. Careful follow-up of these patients is, therefore, essential
to allow prompt treatment of the tumour. These tumours are associated
with marked increase in ACTH, and associated pigmentation is common.
Loss of normal responsiveness to glucocorticoids is characteristic and,
therefore, biochemical monitoring should be performed at least 6 months
first and then annually by measuring a basal ACTH and rechecking it
1 and 2h after the morning dose of glucocorticoid (ACTH curve).
• Bilateral adrenalectomy may still be indicated when pituitary surgery,
radiotherapy, and medical treatment have failed to control the disease.
It is also helpful in Cushing’s syndrome due to ectopic disease when
the ectopic source remains elusive or inoperable. Laparoscopic surgery
minimalizes morbidity and complications.
TREATMENT OF CUSHING’S DISEASE 169
Box 2.29 Nelson’s syndrome

• Occurs in patients with Cushing’s disease, following adrenalectomy.
• Hyperpigmentation and an enlarging (often invasive) pituitary
tumour, associated with markedly elevated ACTH levels.
• Usually within 2 years of adrenalectomy.
• Overall incidence is 50% at 10 years. However, if pituitary
adenoma visible at time of adrenalectomy, incidence is 80% at
3 years. MRI and ACTH monitoring are important for at least
6 years post-adrenalectomy and should be initiated 6 months after
adrenalectomy.
Peri- and post-operative management following

transsphenoidal surgery for Cushing’s disease
• Perioperative hydrocortisone replacement is given in the standard way,
as it is assumed that the patient will become cortisol-deficient after
successful removal of the tumour.
• After 3–4 days, the evening steroid replacement is omitted and 9 a.m.
cortisol and ACTH checked the following day and 24h later after
withholding steroids. Undetectable cortisol (<50nmol/L) is suggestive
of cure, and glucocorticoid replacement is commenced. Cortisol
50–300nmol/L is compatible with resolution of symptoms, and a day
curve should be performed. Patients with levels >300nmol/L should be
considered for re-exploration and/or radiotherapy.
• Antithrombotic prophylaxis should be considered, as Cushing’s is
associated with a hypercoagulable state.
Medical treatment
(See Table 2.10.)
• This is indicated during the preoperative preparation of patients
or while awaiting radiotherapy to be effective or if surgery or
radiotherapy are contraindicated.
• Inhibitors of steroidogenesis: metyrapone is usually used first-line,
but ketoconazole should be used as first-line in children, as it is
unassociated with i adrenal metabolites. There is also a suggestion
that ketoconazole may have a direct action on the corticotroph as well
as lowering cortisol secretion.
• Disadvantage of these agents inhibiting steroidogenesis is the need to
increase the dose to maintain control, as ACTH secretion will increase
as cortisol concentrations decrease.
• Steroidogenesis inhibitors may be used with glucocorticoid
replacement regimen to completely inhibit cortisol or with an aim for
partial inhibition of cortisol production.
• The dose of these drugs needs to be titrated against the cortisol
results from a day curve (cortisol taken at 9 a.m., 12 noon, 3 p.m.,
6 p.m.), aiming for a mean cortisol of 150–300nmol/L, as this
approximates the normal production rate.
• Response rates for drugs that reduce ACTH/CRH synthesis/release,
e.g. somatostatin agonists (pasireotide affecting SSTR5 and 2),
bromocriptine, valproate, and cyproheptadine, are variable. Pasireotide
improves urinary cortisol to normal in about 30%, but carbohydrate
tolerance may worsen.
• Successful treatment (surgery or radiotherapy) of Cushing’s disease
leads to cortisol deficiency and, therefore, glucocorticoid replacement
therapy is essential. In addition, patients who have undergone bilateral
adrenalectomy require fludrocortisone. These patients should all
receive instructions for intercurrent illness and carry a MedicAlert
bracelet and steroid card.
TREATMENT OF CUSHING’S DISEASE 171
Table 2.10 Drug treatment of Cushing’s syndrome

Drug Dose Action Side effects
Metyrapone 1–6g/day (usually 11B-hydroxylase Nausea
given in four inhibitor i androgenic and
divided doses) mineralocorticoid
precursors lead
to hirsutism and
hypertension
Ketoconazole 400–1,600mg/ Direct inhibitor of Abnormalities of
day given 6–8h. P450 enzymes at liver function (usually
First-line in several different reversible 1 in 15,000)
children sites Gynaecomastia
NB Avoid if taking Needs gastric acid Testosterone d.
H2 antagonists, as for absorption Irregular menses
acid required to
metabolize active Not effective with
compound proton pump inhibitors
Mitotane 4–12g/day (begin Inhibits Nausea and vomiting
(o-p-DDD) at 0.5–1g/day and steroidogenesis Cerebellar disturbance
gradually increase at the side chain Somnolence
dose) cleavage, 11- and
18-hydroxylase, Hypercholesterolaemia
and NB May increase
3B-hydroxysteroid clearance of steroids—
dehydrogenase replacement dosage may
Adrenolytic need to be i
Half-life i liver enzymes
18–159 days i lipids
NB May be teratogenic.
Avoid if fertility desired
Avoid concurrent
spironolactone—
interferes with action
Aminoglu- 0.5–2.0g/day Inhibits Rash 10%
tethimide steroidogenesis d T4
at b p. 450 side i hepatic enzymes
chain cleavage
enzyme.
Mifepristone 400–1,000mg Glucocorticoid Amenorrhoea
antagonist Hypokalaemia
(progesterone and
androgen receptor
antagonist)
Etomidate 0.3mg/kg/h. Useful Inhibits side chain Need steroid
when parenteral cleavage and replacement with this
treatment is 11B-hydroxylase dose
required
Pasireotide 900mg daily Binds SSTR5 and 2 Nearly 50% need
25% get a normal glucose-lowering
24h urine cortisol medications because of
insulin suppression
Follow-up of Cushing’s disease

Successful treatment for Cushing’s disease leads to a cortisol that is unde-
tectable (<50nmol/L) following surgery. (This is due to the total suppres-
sion of cortisol production from the normal corticotrophs in Cushing’s
disease.) An undetectable post-operative cortisol leads to a significantly
higher chance of long-term cure compared to the patients who have
post-operative cortisol between 50–300nmol/L.
• The aim of follow-up is:
• To detect recurrent Cushing’s.
• After successful surgery, the adrenals are suppressed.
• Therefore, patients need to have regular assessment of cortisol
production off glucocorticoid replacement. When cortisol is
detectable following surgery, recurrent disease must be excluded
(low-dose dexamethasone suppression). If recurrence is excluded, it is
then important to document the adequacy of the stress response once
weaned off glucocorticoid replacement (ITT).
Prognosis of Cushing’s disease

• Untreated disease leads to an approximately 30–50% mortality at
5 years, owing to vascular disease and i susceptibility to infections.
• Treated Cushing’s syndrome has a good prognosis. Patients who
have an undetectable post-operative cortisol are very unlikely to
recur (0–20%) whereas 50–75% recur if the post-operative cortisol is
detectable.
• Although the physical features and severe psychological disorders
associated with Cushing’s improve or resolve within weeks or months
of successful treatment, more subtle mood disturbance may persist for
longer. Adults may also have impaired cognitive function. In addition, it
is likely that there is an i cardiovascular risk.
• Osteoporosis will usually resolve in children but may not improve
significantly in older patients. Bone mineral density, therefore, requires
monitoring and may need specific treatment. Alendronic acid has been
shown to be effective therapy, leading to improved bone mineral
density in patients with Cushing’s syndrome and osteoporosis.
• Hypertension has been shown to resolve in 80% and diabetes mellitus
in up to 70%.
• Recent data suggests that mortality even with successful treatment of
Cushing’s is increased significantly.
CUSHING’S SYNDROME IN CHILDREN 173
Cushing’s syndrome in children

In a series of 59 patients aged 4–20 years, the following factors were found:
Causes
• Pituitary-dependent disease 85%.
• Adrenal disease 10%.
• Ectopic ACTH secretion 5%.
Initial presentation
• Excessive weight gain 90%.
• Growth retardation 83%.
Below the age of 5 years, adrenal causes are common. In neonates
and young children, McCune–Albright syndrome should be considered
whereas, in late childhood and early adolescence, ACTH independence
may suggest Carney complex (b also see Carney complex, p. 583).
Treatment
• Transsphenoidal surgery is used as first-line therapy in
pituitary-dependent Cushing’s in children as in adults and is usually
successful.
• Radiotherapy cures up to 85% children, and this may be considered
first-line in some patients. Ketoconazole is the preferred medical therapy
in this age group, as it is not associated with i adrenal androgens.
• The long-term management of children with Cushing’s syndrome
requires careful attention to growth, as growth failure is a very common
presentation of this condition. Post-operatively or after radiotherapy,
GH therapy may restore growth and final height to normal.
Further reading
Assié G, Bahurel H, Coste J, et al. (2007). Corticotroph tumor progression after adrenalectomy
in Cushing’s disease: a reappraisal of Nelson’s syndrome. J Clin Endocrinol Metab 92, 172–9.
Colao A, et al. (2012). A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med
366, 914–24.
Florez JC, Shepard J-AO, Kradin RL (2013). Ectopic ACTH syndrome. New England J Med 368,
2116–36.
Isidori AM, Kaltsas GA, Pozza C, et al. (2006). The ectopic adrenocorticotropin syndrome: clinical
features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metab 91, 371–7.
Magiakou MA, Mastorakos G, Oldfield EH, et al. (1994). Cushing’s syndrome in children and ado-
lescents. N Engl J Med 331, 629–36.
Newell-Price J, Morris DG, Drake WM, et al. (2002). Optimal response criteria for the human
CRH test in the differential diagnosis of ACTH-dependent Cushing’s Syndrome. J Clin Endocrinol
Metab 87, 1640–5.
Newell-Price J, Trainer P, Besser M, et al. (1998). The diagnosis and differential diagnosis of
Cushing’s syndrome and pseudo-Cushing’s states. Endocrinol Rev 19, 647–72.
Nieman LK (2002). Medical management of Cushing’s disease. Pituitary 5, 77–82.
Nieman LK, Biller BM, Findling JW, et al. (2008). The diagnosis of Cushing’s syndrome. An Endocrine
Society clinical practice guideline. JCEM 93, 1526–40.
Ntali G, Asimakopoulou A, Siamatras T, et al. (2013). Mortality in Cushing’s syndrome: Systematic
Analysis of a Large Series with Prolonged Follow-up. Eur J Endocrinol 169, 715–23.
van der Pas R, Leebeek FW, Hofland LJ, et al. (2013). Hypercoagulability in Cushing’s syndrome:
prevalence, pathogenesis and treatment. Clin Endocrinol 78(4), 481–8.
Preda VA, et al. (2012). Etomidate in the management of hypercortisolaemia in Cushing’s syn-
drome: a review. Eur J Endocrinol 167, 137–43.
Tritos NA, et al. (2011). Care 40-2011: A 52-year-old man with weakness, infections, and enlarged
adrenal glands. N Engl J Med 365, 2520–30.
Non-functioning pituitary tumours

Background
These pituitary tumours are unassociated with clinical syndromes of ante-
rior pituitary hormone excess.
Epidemiology
• Non-functioning pituitary tumours (NFA) are the commonest pituitary
macroadenoma. They represent around 28% of all pituitary tumours.
• There is an equal sex distribution, and the majority of cases present in
patients aged >50 years.
• 50% enlarge, if left untreated, at 5 years.
Pathology
• Despite the fact that NFAs are unassociated with hormone
production, they may immunostain for:
• Glycoprotein hormones (most commonly gonadotrophins)—LH,
FSH, the α or B subunits of TSH.
• ACTH (silent corticotroph adenomas), or
• Be –ve on immunostaining—either null cell tumours or
oncocytomas (characteristically contain multiple mitochondria on
electron microscopy).
• Tumour behaviour is variable, with some tumours behaving in a very
indolent, slow-growing manner and others invading the sphenoid and
cavernous sinus.
• K1 67 >3% is a potential marker for aggression.
Clinical features
Mass effects
• Visual field defects (uni- or bitemporal quadrantanopia or hemianopia).
• Headache.
• Ophthalmoplegia (III, IV, and VI cranial nerves—rarely).
• Optic atrophy (rarely, following long-term optic nerve compression).
• Apoplexy (rarely).
Hypopituitarism
b also see Hypopituitarism, p. 122.
At diagnosis, approximately 50% of patients are gonadotrophin-deficient.
Incidental finding
An NFA may be detected on the basis of imaging performed for other reasons.
Investigations
• Pituitary imaging. MRI/CT demonstrates the tumour and/or invasion
into the cavernous sinus or supraoptic recess.
• Visual fields assessment. Abnormal in up to two-thirds of cases.
• PRL. Essential to exclude a PRL-secreting macroadenoma (b see p. 142).
• Mild elevation (<3,000mU/L usually 2,000mU/L) may occur
secondary to stalk compression
• Pituitary function. Assessment for hypopituitarism (b see Pituitary
function—dynamic tests, pp. 114–20).
NON-FUNCTIONING PITUITARY TUMOURS 175
Management
Surgery
(Aspects of pituitary surgery are also covered on b p. 196.)
• The initial definitive management in virtually every case is surgical.
This removes mass effects and may lead to some recovery of pituitary
function in around 10%. The majority of patients can be operated on
successfully via the transsphenoidal route.
• Close follow-up is necessary after surgery, as tumour regrowth can
only be detected using pituitary imaging and visual field assessment.
Radiotherapy
• The use of post-operative radiotherapy remains controversial. Some
centres advocate its use for every patient following surgery; others
reserve its use for those patients who have had particularly invasive
or aggressive tumours removed or those with a significant amount of
residual tumour remaining (e.g. in the cavernous sinus).
• The regrowth rate at 10 years without radiotherapy approaches
45%, and there are no good predictive factors for determining which
tumours will regrow. However, administration of post-operative
radiotherapy reduces this regrowth rate to <10%. As discussed in
b Complications, p. 76, however, there are sequelae to
radiotherapy—with a significant long-term risk of hypopituitarism and
a possible i risk of visual deterioration and malignancy in the field of
radiation.
Medical treatment
• Unlike the case for GH- and PRL-secreting tumours, medical therapy
for NFAs is usually unhelpful, although there have been reports of the
somatostatin agonist octreotide leading to tumour shrinkage and/or
visual field improvement in some cases.
• Hormone replacement therapy is required to treat any hypopituitarism
(b see p. 127).
• Visual field defects at diagnosis may improve following surgery in the
majority, and improvement may continue for a year following tumour
debulking.
Prediction of regrowth of NFAs?
No markers that provide certainty. However, the following have been
suggested as useful markers to raise suspicion of aggressive behaviour:
• Younger age.
• Preoperative cavernous sinus invasion and post-operative suprasellar
extension.
• Atypical features on histology (elevated mitotic index, MIB-1 labelling
index >3%, and macronucleoli).
Biochemical markers for NFAs?
• The majority of patients lack a hormone marker—despite
approximately half immunostaining positively for gonadotrophins and
containing secretory granules at the EM level.
• A minority of patients have elevated circulating FSH/LH levels (b see
Gonadotrophinomas, p. 178).
Follow-up
(See Fig. 2.3.)
• Patients who have not received post-operative irradiation require
careful, long-term follow-up with serial pituitary imaging and visual
field assessment. The optimal protocol is still not known, but an
accepted practice is to image in the first 3 months following surgery,
and then reimage annually for 5 years, and biannually thereafter.
Tumour recurrence has been reported at up to 15 years following
surgery, and, therefore, follow-up needs to be long-term. The amount
of post-operative tumour remnant predicates recurrence risk. Thus,
with an empty sella post-operatively, the 10-year recurrence is around
6%. With an intrasellar remnant, it is 50% and with an extrasellar
remnant 90%.
• Patients who have received post-operative radiotherapy, require
follow-up with annual visual field assessment and imaging only if a
deterioration is noted.
• Dopamine agonists may decrease recurrences, but this needs a proper
prospective study.
Prognosis
Patients with NFAs have a good prognosis once the diagnosis and
appropriate treatment, including replacement of hormone deficiency,
is performed. The main concern is the risk of tumour regrowth, with
subsequent visual failure. As mentioned earlier, the administration of
radiotherapy, although not without potential complications itself, sig-
nificantly reduces this risk. Non-irradiated patients require very close
follow-up in order to detect regrowth and perform repeat surgery or
administer radiotherapy.
Post-Operative Assessment of NFA

Immediately Cortisol – replace if <500nmol/L
6 weeks Pituitary function
Thyroxine/TSH
prolactin
GH/IGF-I
cortisol – synacthen + ITT if necessary
LH/FSH, T/E2
osmolalities
Replace Hydrocortisone, thyroxine, gonadal steroids, GH, DHEA
3 months MRI pituitary
Consider radiotherapy
Yearly MRI if no radiotherapy at least to 5 years
Fig. 2.3 Follow-up of non-functioning pituitary adenomas.
Further reading
Dekkers OM, Pereira AM, Romijn JA (2008). Treatment and follow-up of nonfunctioning pituitary
macroadenomas. J Clin Endocrinol Metab 93, 3717–26.
Karavitaki N, et al. (2007). What is the natural history of nonoperated nonfunctioning pituitary
adenomas? Clin Endocrinol (Oxf) 67, 938–43.
Karavitaki N, Thanabalasingham G, Shore HC, et al. (2006). Do the limits of serum prolactin in dis-
connection hyperprolactinaemia need re-definition? A study of 226 patients with histologically
verified non-functioning pituitary macroadenoma Clin Endocrinol (Oxf) 65, 524–9.
Reddy R, et al. (2011). Can we ever stop imaging in surgically treated and radiotherapy-naive
patients with non-functioning pituitary adenoma? Eur J Endocrinol 165, 739–74.
Gonadotrophinomas
Background
These are tumours that arise from the gonadotroph cells of the pituitary
gland and produce FSH, LH, or the α subunit. They are often indistinguish-
able from other non-functioning pituitary adenomas, as they are usually
silent and unassociated with excess detectable secretion of LH and FSH,
although studies demonstrate gonadotrophin/α subunit secretion in vitro.
Occasionally, however, these tumours do produce detectable excess hor-
mone in vivo.
Clinical features
• Gonadotrophinomas present in the same manner as other
non-functioning pituitary tumours, with mass effects and
hypopituitarism (b see p. 122).
• The rare FSH-secreting gonadotrophinomas may lead to
macroorchidism in ♂.
• May cause ovarian hyperstimulation in premenopausal females.
Investigations
The secretion of FSH and LH from these tumours is usually undetect-
able in the plasma. Occasionally, elevated FSH and, more rarely, LH are
measured. This finding is often ignored, particularly in post-menopausal ♀.
Management
These tumours are managed as non-functioning tumours. The potential
advantage of FSH/LH secretion from a functioning gonadotrophinoma is
that it provides a biochemical marker of presence of tumour for follow-up.
GONADOTROPHINOMAS 179
Thyrotrophinomas
Epidemiology
These are rare tumours, comprising approximately 1% of all pituitary
tumours. The diagnosis may be delayed because the significance of an
unsuppressed TSH in the presence of elevated free thyroid hormone
concentrations may be missed. Approximately one-third of cases in the
literature have received treatment directed at the thyroid in the form of
radioiodine treatment or surgery before diagnosis. Unlike p hyperthyroid-
ism, thyrotrophinomas are equally common in ♂ and ♀; 5% are associ-
ated with MEN-1.
Tumour biology and behaviour
• The majority are macroadenomas (90%) and secrete only TSH, often
with α subunit in addition, but some co-secrete GH (55%) and/or
PRL (15%).
• The pathogenesis of thyrotoxicosis in the presence of normal TSH
levels is poorly understood, but there are reports of secretion of
TSH with i bioactivity, possibly due to changes in post-translational
hormone glycosylation.
• The observation that prior thyroid ablation is associated with
deleterious effects on the size of the tumour suggests some feedback
control and is similar to the aggressive tumours seen in Nelson’s
syndrome after bilateral adrenalectomy has been performed for
Cushing’s disease. Thyrotropin-secreting pituitary carcinoma has been
very rarely reported.
• 5% are associated with MEN-1.
Clinical features
(b see p. 28.)
• Clinical features of hyperthyroidism are usually present but often milder
than expected, given the level of thyroid hormones. In mixed tumours,
hyperthyroidism may be overshadowed by features of acromegaly.
• Mass effects. Visual field defects and hypopituitarism.
Investigations
(b see also pp. 11, 125.)
• TSH is inappropriately normal or elevated. The range of TSH that has
been described is <1–568mU/L, and one-third of untreated patients
had TSH in the normal range. There is no correlation between TSH
and T4.
• Free thyroid hormones. Elevated in 65% of patients.
• α subunit (raised in 65%). Typically, patients have an iα subunit:TSH
molar ratio (>1) (81%).
• Other anterior pituitary hormone levels. PRL and/or GH may be elevated
in mixed tumours (an OGTT may be indicated to exclude acromegaly).
• SHBG. Elevated into the hyperthyroid range.
• TRH test. Absent TSH response to stimulation with TRH (useful to
differentiate TSH-secreting tumours from thyroid hormone resistance
where the TSH response is normal or exaggerated).
THYROTROPHINOMAS 181
• T3 suppression test (lack of suppression of TSH following 100

micrograms/day for 10 days).
• Thyroid antibodies. In contrast to Graves’s disease, the incidence of
thyroid antibodies is similar to that in the general population.
• Pituitary imaging. MRI scan will demonstrate a pituitary tumour
(macroadenoma) in the majority of cases (90%).
Causes of an elevated FT4 in the presence of an inappropriately
unsuppressed TSH
(b see p. 11.)
• TSH-secreting tumour.
• Thyroid hormone resistance.
• Amiodarone therapy.
• Inherited abnormalities of thyroid-binding proteins.
Management
Medical treatment
• Medical treatment with the somatostatin agonists octreotide and
lanreotide is successful in the majority of patients in suppressing TSH
secretion and leading to tumour shrinkage. In one study, octreotide
reduced TSH secretion in almost all patients treated and normalized
thyroid hormone levels in 73% of patients. There was partial tumour
shrinkage in 40%.
• Drug therapy is useful in the preoperative preparation of these
patients to ensure that they are fit for general anaesthetic and also
while waiting for radiotherapy to be effective.
Surgery
• Surgery leads to cure in approximately one-third of patients, as judged
by apparent complete removal of tumour mass and normalization of
thyroid hormone levels, with another third improved with normal
thyroid hormone levels but incomplete removal of the adenoma.
• Microadenomas are cured in higher proportions.
Radiotherapy
Radiotherapy is useful, following unsuccessful surgery, and leads to a grad-
ual (over years) reduction in TSH.
Antithyroid medication
Treatment with antithyroid drugs has been associated with i TSH in
approximately 60% of patients reported. It should be avoided, if possible,
and the more appropriate somatostatin agonist therapy utilized.
Further reading
Beck-Peccoz P, Brucker-Davis F, Persani L, et al. (1996). Thyrotropin-secreting pituitary tumours.
Endocr Rev 17, 610–38.
Chanson P, Weintraub BD, Harris AG (1993). Octreotide therapy for thyroid stimulating
hormone-secreting pituitary adenomas. Ann Intern Med 119, 236–40.
Pituitary incidentalomas
Definition
The term incidentaloma refers to an incidentally detected lesion that is
unassociated with hormonal hyper- or hyposecretion and has a benign
natural history.
The increasingly frequent detection of these lesions with technologi-
cal improvements and more widespread use of sophisticated imaging has
led to a management challenge—which, if any, lesions need investigation
and/or treatment, and what is the optimal follow-up strategy (if required
at all)?
Epidemiology
• Autopsy studies have shown that 10–20% of pituitary glands
unsuspected of having pituitary disease harbour pituitary adenomas.
Approximately half the tumours stain for PRL, and the remainder
is –ve on immunostaining.
• Imaging studies using MRI demonstrate pituitary microadenomas in
approximately 10% of normal volunteers.
• Incidentally detected macroadenomas have been reported when
imaging has been performed for other reasons. However, these are
not true incidentalomas, as they are often associated with visual field
defects and/or hypopituitarism.
• Clinical significant pituitary tumours are present in about 1 in 1,000
patients.
Natural history
Incidentally detected microadenomas are very unlikely (<10%) to increase
in size whereas larger incidentally detected meso- and macroadenomas
are more likely (40–50%) to enlarge. Thus, conservative management in
selected patients may be appropriate for microadenomas which are inci-
dentally detected as long as careful follow-up imaging is in place and patients
are truly asymptomatic. Macroadenomas should be treated, if possible.
Clinical features
By definition, a patient with an incidentaloma should be asymptomatic.
Any patient who has an incidentally detected tumour should have visual
field assessment and a clinical review to ensure that this is not the initial
presentation of Cushing’s syndrome, acromegaly, or a prolactinoma.
Investigations
• Aims:
• Exclude any hormone hypersecretion from the tumour.
• Detect hypopituitarism.
• Investigation of hypersecretion of hormones should include measurement
of PRL, IGF-1 and an OGTT if acromegaly is suspected, 24h urinary free
cortisol and overnight dexamethasone suppression test, and thyroid
function tests (unsuppressed TSH in the presence of elevated T4).
• Others suggest that this approach is unnecessary, but, with limited data,
most endocrinologists would perform investigations as above.
PITUITARY INCIDENTALOMAS 183
Management
• All extrasellar macroadenomas (incidentally detected but, by
definition, not true incidentalomas) require definitive treatment.
• Tumours with excess hormone secretion require definitive treatment.
• Mass <1cm diameter—repeat MRI at 1, 2, and 5 years.
• Mass >1cm diameter—repeat MRI at 6 months, 1, 2, and 5 years.
Further reading
Fernando A, Karavitaki N, Wass JA (2010) Prevalence of pituitary adenomas: a community-based
cross-sectional study in Banbury, Oxfordshire (UK) Clin Endocrinol 72, 377–82.
Frida PU, et al. (2011). Pituitary incidentaloma: an Endocrine Society clinical practice guideline. Clin
Endocrinol Metab. 96, 894–904.
Karavitaki N, Collison K, Halliday J, et al. (2007). What is the natural history of nonoperated non-
functioning pituitary adenomas? Clin Endocrinol (Oxf) 67, 938–43.
Molitch ME (1997). Pituitary incidentalomas. End Met Clin North America 26, 725–40.
Pituitary carcinoma
Definition
Pituitary carcinoma is defined as a p adenohypophyseal neoplasm with
craniospinal and/or distant systemic metastases (see Table 2.5 for types).
Epidemiology
These are extremely rare tumours, and only approximately 60 cases have
been reported in the world literature.
Pathology and pathogenesis
• The initial tumours and subsequent carcinomas show higher
proliferation indices than the majority of pituitary adenomas. They are
also likely to demonstrate p53 positivity and have an i mitotic index.
However, histology is unable to reliably distinguish between benign
invasive pituitary adenomas and carcinomas.
• The aetiology of these tumours is unknown, but the adenoma–
carcinoma sequence is followed in ACTH-secreting tumours: pituitary
adenoma causing Cushing’s disease, followed by locally invasive
adenoma (Nelson’s syndrome), leading to pituitary carcinoma.
• Metastatic spread outside the CNS is via lymphatic and vascular routes
while intra-CNS spread is via local invasion and tumour seeding.
Features
Virtually all pituitary carcinomas initially present as invasive pituitary mac-
roadenomas. After a variable interval of time (mean 6.5 years), the major-
ity presents with local recurrence. There is a tendency to systemic (liver,
lymph nodes, lungs, and bones), rather than craniospinal, metastases, but
metastases do not usually predominate in the clinical picture.
Neuroradiological classification of pituitary adenomas
(modified Hardy criteria)
• Grade 1—microadenoma.
• Grade 2—macroadenoma with or without suprasellar extension.
• Grade 3—locally invasive tumour with bony destruction and tumour in
the cavernous or sphenoid sinus.
• Grade 4—spread within the CNS or extracranial dissemination.
Grades 3 and 4 are termed ‘invasive’.
Treatment
Treatment involves surgery, radiotherapy, and medical treatment. As mass
effects often predominate, initial debulking surgery may provide relief. It
may need to be repeated to maintain local control. Some advocate a
transsphenoidal route as less likely to disseminate tumour.
Radiotherapy or medical treatment provides palliation only.
Radiotherapy has been reported to be successful, in some cases, in con-
trolling growth and occasionally leading to regression. Stereotactic radio-
surgery may play a role. Medical treatment with dopamine agonists for
malignant prolactinomas and acromegaly has been reported, with vary-
ing results. Many pituitary carcinomas are dedifferentiated and, therefore,
PITUITARY CARCINOMA 185
Table 2.5 Types of pituitary carcinoma

Type Proportion of reported cases (%)
PRL 30
ACTH 28
GH 2
Non-functioning 30
NB Many ‘non-functioning’ carcinomas were reported prior to routine measurement of PRL
or routine immunostaining, and, therefore, the true incidence of PRL-producing carcinomas
may be higher.
escape from control. Various chemotherapy regimes have been reported,

with occasional success (e.g. CCNU, 5FU and folinic acid or cisplatin, pro-
carbazine, lomustine, and vincristine). Temozolomide has also recently
been used (b see p. 206) and may be effective but further controlled
trials are needed.
Prognosis
Most patients die within a year of diagnosis.
Further reading
Kaltsas GA, Grossman AB (1998). Malignant pituitary tumours. Pituitary 1, 69–81.
McCormack AI, Wass JA, Grossman AB (2011). Aggressive pituitary tumours: the role of temozo-
lomide and the assessment of MGMT status. Eur J Clin Invest 41(10):1133–48.
Pernicone PJ, Scheithauer BW, Sebo TJ, et al. (1997). Pituitary carcinoma. Cancer 79, 804–12.
Pituitary metastases
Incidence
0.1–28% autopsy series; <1% found at transsphenoidal surgery.
Epidemiology
Equal sex distribution. Age >60 (occasionally younger).
Features
Diabetes insipidus in almost 100%. Symptomatic pituitary failure and cra-
nial nerve defects less common. Often difficult to differentiate neuroradio-
logically from other pituitary mass lesions (adenoma, cyst, or inflammatory
pituitary mass). Many do not have symptoms, as features of end-stage
malignancy predominate. Disconnection hyperprolactinaemia may be a
feature, and very rare cases of endocrine hyperfunction related to metas-
tasis within a primary adenoma have been reported (see Box 2.16).
Diagnosis
Histology is required to confirm.
Treatment
• Of p tumour where possible.
• Management of endocrine symptoms.
• Decompression may be indicated for visual field defects.
Prognosis
Mean survival 6–7 months.
Box 2.16 Primary tumours associated with pituitary

metastases
• Breast.
• Lung.
• GI.
• Prostate.
• Kidney.
Breast and lung primary tumours account for two-thirds of pituitary metastases.
PITUITARY METASTASES 187
Craniopharyngiomas and
perisellar cysts
(See Box 2.17 for Rathke’s cleft cysts.)
Prevalence and epidemiology
• 0.065/1,000.
• Any age; only 50% present in childhood (<16 years).
Pathology
• Tumour arising from squamous epithelial remnants of
craniopharyngeal duct.
• Histology may be either adamantinomatous or squamous papillary.
• Cyst formation and calcification are common.
• Benign tumour, although infiltrates surrounding structures.
Features
• Raised intracranial pressure.
• Visual disturbance.
• Hypothalamo–pituitary disturbance.
• Growth failure in children.
• Precocious puberty and tall stature are less common.
• Anterior and posterior pituitary failure, including DI.
• Weight gain.
Other perisellar cysts
• Arachnoid.
• Epidermoid.
• Dermoid.
Investigations
• MRI/CT (CT may be helpful to evaluate bony erosion).
• Visual field assessment.
• Anterior and posterior pituitary assessment (b see p. 114 and p. 212).
Management
(See Fig. 2.4.)
• Gross total removal is the aim of treatment, as this is associated with
a significantly lower recurrence rate. This may be via a transfrontal
or transsphenoidal route. If total removal cannot be safely achieved,
adjuvant radiotherapy is beneficial in reducing recurrence.
• Restoration of pituitary hormone deficiencies is extremely unlikely
following surgery.
• Cystic lesions may be treated with aspiration alone, although
radiotherapy reduces the likelihood of reaccumulation.
Prognosis
• Craniopharyngiomas are associated with d survival (up to 5x the
mortality of the general population).
• Recurrence following initial treatment may present early or several
decades following initial treatment. Childhood and adult onset lesions
behave similarly.
CRANIOPHARYNGIOMAS AND PERISELLAR CYSTS 189
Box 2.17 Rathke’s cleft cysts

Pathology
Derived from the remnants of Rathke’s pouch, lined by epithelial cells
(ciliated cuboidal/columnar epithelium, compared with squamous for
craniopharyngiomas) and filled with fluid.
Features
Usually asymptomatic although may present with headache and amenor-
rhoea and, rarely, hypopituitarism and hydrocephalus.
Investigation
CT/MRI—variable enhancement.
Management
• Decompression if symptomatic.
• Recurrence is not as rare as originally thought.
Fig. 2.4 Treatment algorithm for craniopharyngiomas. Reproduced with permission

from Karavitaki N, Cudlip S, Adams CB, Wass JA (2006). Craniopharyngiomas. Endocr
Rev 27 (4), pp.371–97. Epub 2006 Mar 16, copyright 2006, The Endocrine Society.
Further reading
Karivitaki N, Cudlip S, Adams CB, et al. (2006). Craniopharyngiomas. Endocr Rev 27, 371–93.
Trifanescu R, et al. (2011). Outcome in surgically treated Rathke’s cleft cysts: long-term monitoring
needed. Eur J Endocrinol 165, 33–7.
Trifanescu R, et al. (2012). Rathke’s cleft cysts. Clin Endocrinol (Oxf) 76, 51–60.
Parasellar tumours
Meningiomas
• Suprasellar meningiomas arise from the tuberculum sellae or the
chiasmal sulcus.
• Usually present with a chiasmal syndrome where loss of visual acuity
occurs in one eye, followed by reduced acuity in the other eye.
• Differentiation from a p pituitary tumour can be difficult where there
is downward extension into the sella.
• MRI is the imaging of choice. T1-weighted images demonstrate
meningiomas as isodense with grey matter and hypointense with
respect to pituitary tissue, with marked enhancement after gadolinium.
• Cerebral angiography also demonstrates a tumour blush.
• Management is surgical and may also be complicated by haemorrhage,
as these are often very vascular tumours. They are relatively
radioresistant, but inoperable or partially removed tumours may
respond. As they are slow-growing, a conservative approach with
regular imaging may be appropriate.
• Associations include type 2 neurofibromatosis (b p. 578).
Clivus chordomas
• Rare. Arise from embryonic crest cells of the notochord.
• May present with cranial nerve palsies (III, VI, IX, X) or pyramidal tract
dysfunction.
• Anterior and posterior pituitary hypofunction is reported.
• Often invasive and relentlessly progressive.
• Treatment is surgical, followed by radiotherapy in some cases,
although they are relatively radioresistant. Data on radiosurgery are
not yet available, but this may be considered.
Hamartomas
• Non-neoplastic overgrowth of neurones and glial cells.
• Rare. May present with seizures—typically gelastic (laughing).
• May release GnRH leading to precocious puberty or, very rarely,
GHRH leading to disorders of growth or acromegaly.
• Appear as homogeneous, isointense with grey matter, pedunculated or
sessile non-enhancing tumours on T1-weighted MRI scans.
Management
Tumours do not enlarge, and, therefore, treatment is of endocrine conse-
quences—most commonly, precocious puberty.
Ependymomas
• Intracranial ependymomas typically affect children and adolescents.
• Pituitary insufficiency may follow craniospinal irradiation.
• Occasionally, third ventricle tumours may interfere with hypothalamic
function.
Further reading
Whittle IR, Smith C, Navoo P, et al. (2004). Meningiomas. Lancet 363, 1535–43.
PARASELLAR TUMOURS 191
Parasellar inflammatory conditions

Neurosarcoidosis
Pituitary and hypothalamus may be affected by meningeal disease. Most
patients with hypothalamic sarcoidosis also have involvement outside
the CNS.
Features
Hypopituitarism and DI, in addition to hypothalamic syndrome of absent
thirst, somnolescence, and hyperphagia.
Investigations
• Serum and CSF ACE may be raised.
• CSF examination may reveal a pleocytosis, oligoclonal bands, and low
glucose.
• MRI may demonstrate additional enhancement, e.g. meningeal.
• Gallium scan may reveal i uptake in lacrimal and salivary glands.
Management
• High doses of glucocorticoids (60–80mg prednisolone) for initial
treatment. Subsequent treatment with 40mg/day is often required
for several months. Pulsed methylprednisolone may also be useful.
Steroid-sparing agents, such as azathioprine, may be helpful.
• Management of hormonal deficiency can be very difficult, particularly
in the context of absent thirst and poor memory.
Langerhans cell histiocytosis
• >50% of cases occur in children.
• Most frequent endocrine abnormalities are DI and growth retardation
due to hypothalamic infiltration by Langerhans cells or involvement of
the meninges adjacent to the pituitary. Rarely, hyperprolactinaemia and
panhypopituitarism develop. In adults, DI may precede the bone and
soft tissue abnormalities, making diagnosis difficult.
Management
The role of radiotherapy is controversial, with some workers reporting
improvement and others questioning the efficacy. If radiotherapy is used,
rapid institution of treatment appears to be important (within 10 days of
diagnosis). High-dose glucocorticoids can lead to transient improvement,
but chemotherapy does not alter the course of DI, although it may lead to
temporary regression of lesions.
Wegener’s granulomatosis
• Systemic vasculitis, affecting mainly 30–50 year olds.
• Necrotizing vasculitis, affecting lungs and kidneys in 85% (cavitating
nodules infiltrates).
• Pituitary involvement 1%.
• Present with diabetes insipidus and hyperprolactinaemia.
• High titres of anti-neutrophil cytoplasmic antibody (ANCA).
• Treated with glucocorticoids and/or cyclophosphamide.
PARASELLAR INFLAMMATORY CONDITIONS 193
Tuberculosis
TB may present as a tuberculoma which may compromise hypothalamic
or pituitary function. DI is common. Most patients have signs of TB else-
where but not invariably so. Transsphenoidal biopsy is, therefore, some-
times required. An alternative strategy is antituberculous treatment with
empirical glucocorticoid treatment.
Further reading
Freda PU, Post KD (1999). Differential diagnosis of sellar masses. Endocrinol Metabol Clin N Am
28, 81.
Lymphocytic hypophysitis
Background
This is a rare inflammatory condition of the pituitary.
Epidemiology
Lymphocytic hypophysitis occurs more commonly in ♀ and usually pre-
sents during late pregnancy or the first year thereafter.
Pathogenesis
Ill understood—probably autoimmune. Approximately 25% of cases of
lymphocytic hypophysitis have been associated with other autoimmune
conditions—Hashimoto’s thyroiditis in the majority but also pernicious
anaemia.
There is a recent association with ipilimumab, immunostimulating agent
a monoclonal antibody against cytotoxic T lymphocyte antigen 4 (CTLA4).
Pathology
• Somatotroph and gonadotroph function are more likely to be
preserved than corticotroph or thyrotroph function, unlike the findings
in hypopituitarism due to a pituitary tumour. The posterior pituitary
is characteristically spared so that DI is not part of the picture, but
there are occasional reports of coexistent or isolated DI, presumably
because of different antigens.
• Lymphocytic hypophysitis has occasionally involved the cavernous
sinus and extraocular muscles.
• Light microscopy typically reveals a lymphoplasmacytic infiltrate,
occasionally forming lymphoid follicles, with variable destruction of
parenchyma and fibrosis.
Clinical features
• Mass effects, leading to headache and visual field defects.
• Often a temporal association with pregnancy.
• Hypopituitarism (ACTH and TSH deficiency, less commonly
gonadotrophin and GH deficiency).
• Posterior pituitary involvement and cavernous sinus involvement occur
less commonly.
• See Box 2.18 for classification.
Investigations
• Investigation of hypopituitarism is essential and may not be thought
of because gonadotrophin secretion often remains intact, leaving the
potentially life-threatening ACTH deficiency unsuspected.
• MRI shows an enhancing mass, with variably loss of hyperintense bright
spot of neurohypophysis, thickening of pituitary stalk, and enlargement
of the neurohypophysis. Suprasellar extension often appears
tongue-like along the pituitary stalk. There may be central necrosis but
no calcification.
• Biopsy of the lesion is often required but may be avoided in the
presence of typical features.
LYMPHOCYTIC HYPOPHYSITIS 195
Box 2.18 Classification of hypophysitis

• Acute:
• Bacterial infections.
• Chronic:
• Lymphocytic hypophysitis.
• Xanthomatous—characterized by lipid-laden macrophages.
• Granulomatous:
• Tuberculosis.
• Sarcoidosis.
• Syphilis.
• Giant cell—? variant of lymphocytic hypophysitis.
• The presence of antipituitary antibodies has been investigated by some

groups and shown to be variably present. This is, however, a research
tool and an unreliable marker.
Treatment
• Most often, no specific treatment is necessary. There is anecdotal
evidence only of the effectiveness of immunosuppressive doses
of glucocorticoids—e.g. prednisolone 60mg/day for 3 months and
progressive reduction for 6 months. This has been reported to be
associated with reduction in the mass and gradual recovery of pituitary
function. However, relapse after discontinuing therapy is also reported.
• Spontaneous recovery may also occur.
• Surgery has also been used to improve visual field abnormalities.
Natural history
Variable—some progress rapidly to life-threatening hypopituitarism while
others spontaneously regress.
Relationship to other conditions
Lymphocytic hypophysitis remains an ill-understood condition but has
been suggested to be the underlying cause of other conditions, such as
isolated ACTH deficiency and the empty sella syndrome.
Further reading
Caturegli P, Newschaffer C, Olivi A, et al (2005). Autoimmune hypophysitis. Endocr Rev 26,
599–614.
Thodou E, Asa SL, Kontogeorgos G, et al. (1995). Clinical case seminar: lymphocytic hypophysi-
tis: clinicopathological findings. J Clin Endocrinol Metab 80, 2302–11.
Surgical treatment of pituitary

tumours
This is currently the favoured technique for pituitary surgery and is
first-line for virtually every case. It is preferred to the previously used
technique of craniotomy because there is minimal associated morbidity as
a result of the fact that the cranial fossa is not opened and there are, there-
fore, no immediate sequelae due to direct cerebral damage (particularly
frontal lobe) and no long-term risk of epilepsy. There is reduced duration
of hospital stay and improved cure rates, as there is better visualization
of small tumours. Unfortunately, the technique may be inadequate to deal
with very large tumours with extensive suprasellar extension. In these
situations, craniotomy is required if adequate debulking is not possible
following the transsphenoidal approach. See Box 2.19 for indications for
surgery. See Table 2.6 for complications.
Preparation for transsphenoidal surgery
Pretreatment before surgery
• Pretreatment with metyrapone or ketoconazole to improve the
condition of patients with Cushing’s syndrome is often given for at
least 6 weeks. This allows some improvement in healing and also
improves the general state of the patient.
• Patients with macroprolactinomas will, in the majority of cases, have
received treatment with dopamine agonists in any case, and surgery is
usually indicated for resistance or intolerance. There is a risk of tumour
fibrosis, with long-term (>6 months) dopamine agonist therapy with
bromocriptine.
Immediately preoperative
• Immediate preoperative treatment requires appropriate anterior
pituitary hormone replacement. In particular, a decision as to whether
perioperative glucocorticoid treatment is required. The majority of
microadenomas will not require perioperative hydrocortisone, but
patients with Cushing’s syndrome will require peri- and post-operative
glucocorticoid treatment. Patients with macroadenomas and an
intact preoperative pituitary–adrenal axis do not usually require
perioperative steroids, but those who are deficient or whose reserve
has not been tested need to be given perioperative glucocorticoids.
TSH deficiency should be corrected with levothyroxine. Ensure the
patient is not taking aspirin.
• Prophylactic antibiotics are started in some centres the night before
surgery to reduce the chances of meningitis.
SURGICAL TREATMENT OF PITUITARY TUMOURS 197
Complications
(See also Box 2.20 and Table 2.6.)
• Patients should be informed about the possible complications
of transsphenoidal surgery prior to consent. The commonest
complications are DI, which may be transient or permanent (5% and
0.1%, respectively; often higher in Cushing’s disease and prolactinoma),
and the development of new anterior pituitary hormonal deficiencies
(uncommon with microadenomas; approximately 10% of TSA for
macroadenomas).
• Other complications include meningitis, CSF leak, visual deterioration,
haemorrhage (rare), and transient hyponatraemia, usually 7 days
post-operatively.
Box 2.19 Indications for pituitary surgery

• Non-functioning pituitary adenoma.
• GH-secreting adenoma.
• ACTH-secreting tumour.
• Nelson’s syndrome. (see Box 2.29, p. 169)
• Prolactinoma—if patient dopamine agonist-resistant or -intolerant.
• Recurrent pituitary tumour.
• Gonadotrophin-secreting tumour.
• TSH-secreting adenoma.
• Craniopharyngioma.
• Pituitary biopsy to define diagnosis, e.g. hypophysitis, pituitary
metastases.
• Chordoma.
• Rathke’s cleft cyst.
• Arachnoid cyst.
Box 2.20 Post-operative disorders of fluid balance

• Acute post-operative transient DI.
• SIADH.
• Triphasic response: initial DI due to axon shock (hours to days),
followed by antidiuretic phase due to uncontrolled release of ADH
from damaged posterior pituitary (2–14 days), followed by DI due to
depletion of ADH.
• Transient hyponatraemia (isolated second phase) at 5–10 days
post-operatively, usually mild and self-limiting.
Table 2.6 Complications of transsphenoidal surgery

Complications of any surgical Anaesthetic-related
procedure
Venous thrombosis and pulmonary
embolism
Immediate Haemorrhage
Hypothalamic damage
Meningitis
Permanent Visual deterioration or loss
Cranial nerve damage (e.g. oculomotor
nerve palsies)
Hypopituitarism
DI
SIADH
Transient DI
CSF rhinorrhoea
Meningitis
Visual deterioration
Cerebral salt wasting
Cerebral salt wasting

A rare, but important, complication of transsphenoidal surgery, more
commonly seen after subarachnoid haemorrhage, is cerebral salt wasting
syndrome (CSW). This typically occurs at day 5–10 post-operatively and
is associated with, often massive, urinary salt loss and hypovolaemia. It
needs to be differentiated from SIADH which may also occur at this stage
(often using central venous pressure measurement to demonstrate hypo-
volaemia in CSW compared with euvolaemia in SIADH). The management
of CSW involves the administration of saline whereas fluid restriction is
indicated for SIADH.
TRANSFRONTAL CRANIOTOMY 199
Transfrontal craniotomy
Indications
• Pituitary tumours with major suprasellar and lateral invasion where
transsphenoidal surgery is unlikely to remove a significant proportion
of the tumour.
• Parasellar tumours, e.g. meningioma.
Complications
• In addition to the complications of transsphenoidal surgery, brain
retraction can lead to cerebral oedema or haemorrhage.
• Manipulation of the optic chiasm may lead to visual deterioration.
• Vascular damage.
• Damage to the olfactory nerve.
Perioperative management
Similar to that for patients undergoing transsphenoidal surgery (b see
Transsphenoidal surgery, p. 196).
Post-operative management
• Recovery is typically slower than after transsphenoidal surgery.
• Prophylactic anticonvulsants are administered for up to 1 year.
• The DVLA must be advised of surgery and relevant regulations to be
followed.
Further reading
Laws ER, Thapar K (1999). Pituitary surgery. Endocrinol Metab Clin N Am 28, 119.
Pituitary radiotherapy
Indications
(b see Box 2.21.)
• Pituitary radiotherapy is an effective treatment used to reduce the
likelihood of tumour regrowth following surgery, to further shrink a
tumour, and to treat persistent hormone hypersecretion (usually after
surgical resection or non-successful medical treatment).
• Pituitary radiotherapy is usually only administrable once in a lifetime.
Technique
(See Box 2.22 for focal forms of radiotherapy.)
• Conventional external beam 3-field radiotherapy is able to deliver a
beam of ionizing irradiation accurately to the pituitary fossa.
• Accurate targeting requires head fixation in a moulded plastic shell
to keep the head immobilized. The fields of irradiation are based on
simulation using MRI or CT scanning, and the volume is usually the
tumour margins plus 0.5cm in all planes. The preoperative tumour
volume is used for planning whereas the post-drug (dopamine agonist)
shrinkage films are used for prolactinomas. There are three portals—
two temporal and one anterior.
• The standard dose is 4500cGy in 25 fractions over 35 days, but 5,000
cGy may be used for relatively ‘radioresistant’ tumours, such as
craniopharyngiomas.
Efficacy
Radiotherapy is effective in reducing the chance of pituitary tumour
regrowth. Comparison of non-functioning tumour recurrence following
surgery and radiotherapy compared with surgery alone shows that radio-
therapy is effective in reducing the likelihood of regrowth (see Fig. 2.5).
Box 2.21 Indications for pituitary radiotherapy

Tumour Aim of treatment
Non-functioning pituitary adenoma To shrink residual mass or reduce
likelihood of regrowth
GH/PRL/ACTH-secreting tumour To reduce persistent hormonal
hypersecretion and shrink residual mass
Craniopharyngioma To reduce likelihood of regrowth
Recurrent tumour To shrink mass and reduce likelihood
of regrowth.
PITUITARY RADIOTHERAPY 201
Box 2.22 Focal forms of radiotherapy

Stereotactic radiosurgery uses focused radiation to deliver a precise
dose of radiation:
• Gamma knife ‘radiosurgery’—ionizing radiation from a cobalt 60
source delivered by convergent collimated beams.
• Linear accelerator focal radiotherapy—photons focused on a
stationary point from a moving gantry.
• Potential advantages are that a single high dose of irradiation is
given which can be sharply focused on the tumour, with minimal
surrounding tissue damage.
• Long-term data are required to demonstrate endocrine efficacy,
but it may have a particular role in recurrent or persistent tumours
which are well demarcated and surgically inaccessible, e.g. in the
cavernous sinus.
• Potential limitations include proximity to the optic chiasm.
100 Radiotherapy Radiotherapy

90
No
Progression-free survival
80
radiotherapy
70
60
50 No
40 radiotherapy
30
20
10
0
10 15
Years after surgery
Fig. 2.5 Recurrence rates following radiotherapy. Modified from Gittoes NJL,
Bates AS, Tse W, et al. (1998). Radiotherapy for non-functioning pituitary tumours.
Clin Endocrinol 48, 331–7. With permission from Wiley Blackwell.
Complications of pituitary
radiotherapy
Short term
• Nausea.
• Headache.
• Temporary hair loss at radiotherapy portals of entry.
Hypopituitarism (see Fig. 2.6)
• Anterior pituitary hormone deficiency occurs due to the effect of
irradiation on the normal pituitary or the hypothalamus, leading to
reduced hypothalamic-releasing hormone secretion. The total dose of
irradiation is one of the main determinants of the speed, incidence, and
extent of hypopituitarism (see Table 2.7).
• The onset of hypopituitarism is gradual, and the order of development
of deficiency is as for any other cause of developing hypopituitarism—
namely, GH first, followed by gonadotrophin and ACTH, followed
finally by TSH. Posterior pituitary deficiencies are very rare, but s
temporary mild hyperprolactinaemia may be seen after about 2 years
which gradually returns to normal.
Visual impairment
• The optic chiasm is particularly radioresistant but may undergo
damage thought to be due to vascular damage to the blood supply.
Visual deterioration typically occurs within 3 years of irradiation and is
progressive.
• The literature suggests that the risk is greatest with high total and daily
doses. A standard total dose of 4,500cGy and daily dose of 180cGy
appear to pose very little, if any, risk to the chiasm.
• Our practice is to avoid administration of radiotherapy, where
possible, when the chiasm is under pressure from residual tumour.
Radiation oncogenesis
• There is controversy as to whether pituitary irradiation leads to
the development of second tumours. There have been reports
of sarcomas, gliomas, and meningiomas developing in the field of
irradiation after 10–20 years. However, there are also reports of
gliomas and meningiomas occurring in non-irradiated patients with
pituitary adenomas. A retrospective review of a large series of patients
given pituitary irradiation suggested a risk of second tumour of 1.9%
by 20 years after irradiation when compared to the normal population
(but not patients with pituitary tumours).
• Subtle changes in neurocognition have also been suggested.
COMPLICATIONS OF PITUITARY RADIOTHERAPY 203
Table 2.7 Development of new hypopituitarism at 10 years following

pituitary radiotherapy
No previous surgery Previous surgery
Gonadotrophin deficiency 47% 70%
ACTH deficiency 30% 54%
Thyrotrophin deficiency 16% 38%
1.0
Probability of normal axis
TSH
0.5
LH/FSH
ACTH
GH
0
0 3 4 6 8 10
Years after treatment
Fig. 2.6 Life-table analysis, indicating the probability of developing pituitary

hormone deficiencies after conventional radiation therapy. Reproduced with
permission from Littley MD, Shalet SM, Beardwell CG, Ahmed, SR, et al. (1989).
Q J Med 70:145–160.
Further reading
Brada M, Ford D, Ashley S, et al. (1992). Risk of second brain tumour after conservative surgery and
radiotherapy for pituitary adenoma. BMJ 304, 1343–6.
Jackson IMD, Noren G (1999). Role of gamma knife therapy in the management of pituitary
tumours. Endocrinol Metab Clin N Am 28, 133.
Jones A (1991). Radiation oncogenesis in relation to treatment of pituitary tumours. Clin Endocrinol
35, 379.
Loeffler JS, Shih HA (2011). Radiation therapy in the management of pituitary adenomas. J Clin
Minniti G, et al. (2005). Risk of second brain tumor after conservative surgery and radiotherapy
for pituitary adenoma: update after an additional 10 years. J Clin Endocrinol Metab 90, 800–4.
Plowman PN (1999). Pituitary adenoma radiotherapy. Clin Endocrinol 51, 265–71.
Drug treatment of pituitary

tumours
Dopamine agonists
(See Box 2.23 for uses.)
Types
• Bromocriptine—the first ergot alkaloid to be used, short-acting, taken
daily. Usually administered orally, although vaginal and IM formulations
can be used and may reduce GI intolerance.
• Quinagolide—non-ergot, longer-acting, taken daily.
• Cabergoline—ergot derivative, long-acting, taken once or twice a week.
• Less commonly used—pergolide and lisuride.
Mechanism of action
Activation of D2 receptors.
Side effects
Commonly at initiation of treatment
• Nausea.
• Postural hypotension.
Less common
• Headache, fatigue, nasal stuffiness, constipation, abdominal cramps, and
a Raynaud-like phenomenon in hands.
• Very rarely, patients have developed hallucinations and psychosis
(usually at higher doses).
• Side effects may be minimized by slow initiation of therapy (e.g. 1.25mg
bromocriptine or 250 micrograms cabergoline), taking medication
before going to bed and taking the tablets with food.
(See Box 2.24 for uses.)
Mechanism of action
• Since the half-life of somatostatin is very short, longer-acting analogues
were synthesized—octreotide and lanreotide. These have a half-life of
110min in the circulation, and inhibit GH secretion 45x more actively
than native somatostatin, with none of the rebound hypersecretion
that occurs with somatostatin.
• The somatostatin analogues act predominantly on somatostatin
receptors 2 and 5. Unlike dopamine agonists, somatostatin analogues
do not lead to dramatic tumour shrinkage, but some shrinkage is still
seen in the majority of tumours.
Types
• Octreotide LAR® (10–30mg IM) administered every 4–6 weeks.
• Lanreotide Autogel® (60–120mg IM) administered every 28 days.
• SC octreotide (50–200 micrograms) administered usually 3× daily.
• Paireotide is a new somatostatin analogue which has increased affinity
for somatostatin receptor 5. It is licensed for use in Cushing’s disease.
DRUG TREATMENT OF PITUITARY TUMOURS 205
Box 2.23 Uses of dopamine agonists

Hyperprolactinaemia (b see p. 144)
• D2 receptor stimulation leads to inhibition of PRL secretion and
reduction in cell size, leading to tumour shrinkage. The PRL often
falls before significant tumour shrinkage is seen.
• Problems may arise when patients are either intolerant of the
medication or resistant. Cabergoline appears to be better tolerated
than bromocriptine, and it is often worth trying an alternative in
the case of intolerance, although true intolerance is probably a
class effect. Dopamine agonist resistance macro- > microadenomas
(10–25% patients) may be due to differences in receptor subtype
(e.g. loss of D2 receptors) or possibly altered intracellular signalling.
GH-secreting tumours
• Although administration of L-dopa to normal individuals leads
to acute increase in GH due to hypothalamic dopamine and
noradrenaline synthesis and inhibition of somatostatin secretion,
>50% of patients with GH-secreting tumours given dopamine
agonists have a fall in GH. Dopamine acts directly on somatotroph
tumours to inhibit GH release.
• Patients with acromegaly often need larger doses of dopamine
agonist than patients with prolactinomas e.g. cabergoline 3mg/
week. Tumour shrinkage is most likely if there is concomitant
secretion of PRL from the tumour. Dopamine agonists are
currently usually reserved for second-line drug therapy in patients
who are somatostatin analogue-resistant or as a co-prescription
with somatostatin analogues in patients with mixed GH- and
PRL-secreting tumours.
Pregnancy
Bromocriptine is licensed for use in pregnancy, but cabergoline is not
licensed in the UK, although it has not thus far been associated with any
i teratogenicity.
Box 2.24 Uses of somatostatin analogues

• Acromegaly.
• Carcinoid tumours.
• Pancreatic neuroendocrine tumours.
• TSH-secreting pituitary tumours.
Side effects
• Gallstones. At least 20–30% of patients develop gallstones or sludge on
octreotide (thought, by most, to antedate stone formation), but only
1%/year develop symptoms. The incidence is unknown on octreotide
LAR® or lanreotide. Symptoms may particularly occur if somatostatin
analogue therapy is withdrawn.
• GI due to inhibition of motor activity and secretion, leading to nausea,
abdominal cramps, and mild steatorrhoea. These usually settle
with time.
• Injection site pain obviated by allowing vial to warm to room
temperature before injecting.
• Hair loss (<10%).
Growth hormone receptor antagonist
Pegvisomant—newly developed treatment for acromegaly.
Mechanism of action
• Binds to GH receptor and induces internalization but blocks receptor
signalling, leading to reduction in IGF-1 (but not GH) production.
• Studies suggest that it is the most potent available medical therapy.
Normalization of IGF-1 in >90% treated patients.
Usage
• May be used with somatostatin analogues to decrease frequency of
injections.
Problems
• High cost.
• Further data required on the effects on pituitary tumour growth.
• Occasional deterioration in liver biochemistry.
• IGF-1 used to monitor effectiveness of treatment.
Temozolomide
• Is an alkylating chemotherapeutic agent effective in glioblastoma and
neuroendocrine tumours.
• It has been successfully used to treat pituitary carcinoma and invasive
and aggressive pituitary adenomas.
• Response may be predicated by O-6-methylguanine DNA
methyltransferase (MGMT) staining, which is lower in responders.
Further reading
McCormack AI, et al. (2011). Aggressive pituitary tumours: the role of temozolomide and the
assessment of MGMT status. Eur J Clin Invest 41, 1133–48.
Sandret L, Maison P, Chanson P (2011). Place of cabergoline in acromegaly: a meta-analysis. J Clin
Sherlock M, Woods C, Sheppard MC (2011). Medical therapy in acromegaly. Nat Rev Endocrinol
7, 291–300.
Trainer PJ, et al. (2000). Treatment of acromegaly with the growth hormone–receptor antagonist
pegvisomant. N Engl J Med 342, 1171–7.
DRUG TREATMENT OF PITUITARY TUMOURS 207
Posterior pituitary
Physiology and pathology
The posterior lobe of the pituitary gland arises from the forebrain and
comprises up to 25% of the normal adult pituitary gland. It produces
arginine vasopressin and oxytocin. Both hormones are synthesized in
the hypothalamic neurons of the supraoptic and paraventricular nuclei
and migrate as neurosecretory granules to the posterior pituitary before
release into the circulation. The hormones are unbound in the circulation,
and their half-life is short.
Oxytocin
• Oxytocin has no known role in ♂. It may aid contraction of the
seminal vesicles.
• In ♀, oxytocin contracts the pregnant uterus and also causes breast
duct smooth muscle contraction, leading to breast milk ejection during
breastfeeding. Oxytocin is released in response to suckling and also to
cervical dilatation during parturition. However, oxytocin deficiency has
no known adverse effect on parturition or breastfeeding.
• There are several, as yet, ill-understood features of oxytocin
physiology. For example, osmotic stimulation may also lead to
oxytocin secretion. Oxytocin may play a role in the ovary and testis,
as ovarian luteal cells and testicular cells have both been shown to
synthesize it, although its subsequent role is not known.
Vasopressin and neurophysin
• Arginine vasopressin is the major determinant of renal water excretion
and, therefore, fluid balance. Its main action is to reduce free water
clearance.
• Vasopressin is a nonapeptide and derives from a large precursor
with a signal peptide and a neurophysin. The vasopressin gene is
located on chromosome 20 and is closely linked to the oxytocin gene.
Vasopressin travels to the posterior pituitary and undergoes cleavage
as it travels. Neurophysin is released with vasopressin but has no
further role after acting as a carrier protein in the neurons.
• Release of vasopressin occurs in response to changes in osmolality
detected by osmoreceptors in the hypothalamus. Large changes
in blood volume (5–10%) also influence vasopressin secretion.
Many substances modulate vasopressin secretion, including the
catecholamines and opioids.
• The main site of action of vasopressin is in the collecting duct and the
thick ascending loop of Henle where it increases water permeability
so that solute-free water may pass along an osmotic gradient to the
interstitial medulla. Vasopressin in higher concentrations has a pressor
effect. It also acts as an ACTH secretagogue synergistically with CRH.
POSTERIOR PITUITARY 209
Diabetes insipidus (DI)

Definition
DI is defined as the passage of large volumes (>3L/24h) of dilute urine
(osmolality <300mOsm/kg).
Classification
Cranial
Due to deficiency of circulating arginine vasopressin (antidiuretic
hormone).
Nephrogenic
Due to renal resistance to vasopressin.
Primary polydipsia
• Polyuria due to excessive drinking.
• In addition to suppressed levels of vasopressin due to low plasma
osmolality, there may be impaired renal effectiveness because of
washout of solute and, therefore, reduced urine-concentrating ability.
Features
• Adults—polyuria, nocturia, and thirst.
• Children—polyuria, enuresis, and failure to thrive.
• NB Clinical syndrome of cranial DI may be masked by cortisol
deficiency as a result of failure to excrete a water load.
• Syndrome may worsen in pregnancy due to placental breakdown
(vasopressinase) of circulating vasopressin.
See Box 2.30 for causes of DI.
DIABETES INSIPIDUS (DI) 211
Box 2.30 Causes of DI

Cranial
10% vasopressin cells should be sufficient to keep the urine volume <4L/
day.
Familial
• Autosomal dominant (vasopressin gene).
• DIDMOAD syndrome (DI, diabetes mellitus, optic atrophy,
deafness).
Acquired
• Trauma—head injury, neurosurgery.
• Tumours—craniopharyngiomas, pituitary infiltration by metastases.
• Inflammatory conditions—sarcoidosis, tuberculosis, Langerhans cell
histiocytosis, lymphocytic hypophysitis, Wegener’s granulomatosis.
• Infections—meningitis, encephalitis.
• Vascular—Sheehan’s syndrome, sickle cell disease.
• Idiopathic.
Nephrogenic
Familial
• X-linked recessive—vasopressin receptor gene.
• Autosomal recessive—aquaporin-2 gene.
Acquired
• Drugs—lithium, demeclocycline.
• Metabolic—hypercalcaemia, hypokalaemia, hyperglycaemia.
• Chronic renal disease.
• Post-obstructive uropathy.
Primary polydipsia
• Psychological.
Investigations of DI
Diagnosis of type of DI
• Confirm large urine output (>3L/day).
• Exclude diabetes mellitus and renal failure (osmotic diuresis).
• Check electrolytes. Hypokalaemia and hypercalcaemia
(nephrogenic DI).
• Fluid deprivation test (see Box 2.31) and assessment of response to
vasopressin.
• Occasionally, further investigations are required, particularly when only
partial forms of the condition are present.
• Measurement of plasma vasopressin, osmolality, and thirst threshold:
• In response to infusion of 0.05mL/kg/min 5% hypertonic saline for
2h for cranial DI (no i vasopressin).
• In response to fluid deprivation for nephrogenic DI (vasopressin
levels rise, with no i urine osmolality).
• An alternative is a therapeutic trial of desmopressin, with monitoring
of sodium and osmolality.
Investigation of the cause
• MRI head:
• Looking for tumours (e.g. hypothalamic, pineal, or infiltration).
• May demonstrate loss of bright spot of posterior pituitary gland.
• Serum ACE (sarcoidosis) and tumour markers, e.g. BhCG (pineal
germinoma).
• Differential diagnosis of pituitary stalk lesions. Includes congenital,
inflammatory (sarcoid, langerhans, lymphocytic hypophysitis,
Wegener’s) and neoplastic (craniopharyngioma, metastases,
germinoma).
INVESTIGATIONS OF DI 213
Box 2.31 Fluid deprivation test

1. Patient is allowed fluids overnight. If psychogenic polydipsia
suspected, consider overnight fluid deprivation to avoid morning
overhydration.
2. Patient is then deprived of fluids for 8h or until 5% loss of body
weight if earlier. Weigh patient hourly.
3. Plasma osmolality is measured 4-hourly and urine volume and
osmolality every 2h.
4. The patient is then given 2 micrograms IM desmopressin with urine
volume and urine and serum osmolality measured over the next 4h.
5. In partial diabetes insipidus and possible psychogenic polydipsia,
the fluid deprivation can be continued, measuring plasma and urine
osmolalities until there is 30mOsm/kg increase in urine osmolality
between three consecutive samples, noting precautions above
(Miller & Moses modified test).
Results
If serum osmolality >305mOsm/kg, the patient has DI and the test is
stopped (see Table 2.11).
Table 2.11 Urine osmolality (mOsm/kg)

Diagnosis After fluid deprivation After desmopressin
Cranial DI <300 >800
Nephrogenic DI <300 <300
p polydipsia >800 >800
Partial DI or polydipsia 300–800 <800
Treatment of DI
Maintenance of adequate fluid input
In patients with partial DI and an intact thirst mechanism, drug therapy
may not be necessary if the polyuria is mild (<4L/24h).
Drug therapy
Desmopressin
• Vasopressin analogue, acting predominantly on the V2 receptors in the
kidney, with little action on the V1 receptors of blood vessels. It thus
has reduced pressor activity and i antidiuretic efficacy, in addition to a
longer half-life than the native hormone.
• Drug may be administered in divided doses, orally (100–1,000
micrograms/day), intranasally (10–40 micrograms/day), parenterally
(SC, IV, IM) (0.1–2 micrograms/day) or buccally. There is wide
variation in the dose required by an individual patient.
• Monitoring of serum sodium and osmolality is essential, as
hyponatraemia or hypo-osmolality may develop.
Lysine vasopressin
• The antidiuretic hormone of the pig family.
• Not used very often, as its effects are short-lived (1–3h) and it may
retain pressor activity. Intranasal administration. Dose 5–20U/day.
Chlorpropamide (100–500mg/day) and carbamazepine enhance the action
of vasopressin on the collecting duct.
Nephrogenic DI
• Correction of underlying cause (metabolic or drugs).
• High doses of desmopressin (e.g. up to 5 micrograms IM) can be
effective.
• Maintenance of adequate fluid input.
• Thiazide diuretics and prostaglandin synthase inhibitors (decrease the
action of prostaglandins which locally inhibit the action of vasopressin
in the kidney), e.g. indometacin, can be helpful.
Polydipsic polyuria
Management is difficult. Treatment of any underlying psychiatric disorder
is important.
Further reading
Fenske W, Allolio B (2012). Clinical review: Current state and future perspectives in the diagnosis
of diabetes insipidus: a clinical review. J Clin Endocrinol Metab 97, 3426–37.
Loh JA, Verbalis JG. (2008). Disorders of water and salt metabolism associated with pituitary
disease. Endocrinol Metab Clin North Am 37, 213–34.
Turcu AF, Erickson BJ, Lin E et al. (2013). Pituitary stalk lesions: The Mayo Clinic Experience. J Clin
Endocrinol Metab 98(5):1812–18.
TREATMENT OF DI 215
Hyponatraemia
(See Table 2.12; for causes, see Box 2.32.)
Incidence
• 1–6% hospital admissions Na <130mmol/L.
• 15–22% hospital admissions Na <135mmol/L.
Box 2.32 Causes of hyponatraemia

Excess water (dilutional)
• Excess water intake.
• i water reabsorption (cirrhosis, congestive cardiac failure, nephrotic
syndrome).
• Reduced renal excretion of a water load (SIADH, glucocorticoid
deficiency).
Salt deficiency
• Renal loss (salt-wasting nephropathy—tubulointerstitial nephritis,
polycystic kidney disease, analgesic nephropathy, recovery phase of
acute tubular necrosis, relief of bilateral ureteric obstruction).
• Non-renal loss (skin, GI tract [bowel sequestration, high fistulae]).
• Renal sodium conservation of sodium is efficient and, therefore, low
salt intake alone never causes sodium deficiency.
Pseudohyponatraemia
• Lipids, proteins (e.g. paraproteinaemia).
• Sodium only in aqueous phase of plasma; therefore, depending
on assay, total sodium concentration may be spuriously low if
concentrations of lipid or protein are high.
Solute
• Glucose, mannitol, ethanol.
• Addition of solute confined to the ECF causes water to shift from
the ICF, lowering ECF sodium concentration.
Sick cell syndrome
• Symptomless hyponatraemia at 120–130mmol/L.
• True clinically apparent hyponatraemia is associated with either
excess water or salt deficiency. The other causes can usually be
easily excluded.
Table 2.12 Hyponatraemia investigations
Hypovolaemic Euvolaemic Hypervolaemic
NaU <20mmol/L NaU >20mmol/L NaU <20mmol/L NaU >20mmol/L NaU <20mmol/L NaU >2
Serum osmolality Serum
<270mOsm/kg <270mO
Urine osmolality Urine o
>100mOsm/kg >100mO
Non-renal sodium Renal sodium loss Depletional ECF loss Distal dilution Excess water
loss with inappropriate fluid
replacement
? GIT loss ? Salt-losing nephropathy SIADH Cirrhosis SIADH
? Skin loss ? Mineralocorticoid deficiency GC deficiency Nephrotic syndrome
CCF
GC = glucocorticoid
Features
• Depend on the underlying cause and also on the rate of development
of hyponatraemia. May develop once sodium reaches 115mmol/L or
earlier if the fall is rapid. Level at 100mmol/L or less is life-threatening.
• Features of excess water are mainly neurological because of brain
injury and depend on the age of the patient and rate of development.
They include confusion and headache, progressing to seizures and
coma. In hypervolaemic forms of excess water (where the fluid is
confined to the ECF, e.g. cardiac failure, nephrotic syndrome, and
cirrhosis), oedema and fluid overload are apparent. In contrast, in
the syndromes of excess water associated with SIADH, the fluid is
distributed throughout the ECF and ICF and there is no apparent fluid
overload. Salt deficiency presents with features of hypovolaemia, with
tachycardia and postural hypotension.
Investigations
(See Table 2.12.)
• Urinary sodium is very helpful in differentiating the underlying cause.
• Assess volume status.
• Other investigations as indicated, e.g. serum and urine osmolality,
cortisol, thyroid function, liver biochemistry, serum electrophoresis.
Treatment
Salt deficiency (renal or non-renal)
• Increase dietary salt.
• May need IV normal saline if dehydrated.
Excess water (cirrhosis, nephrotic syndrome, CCF)
• Fluid restriction to 500–750mL/24h.
• Occasionally, hypertonic (3%) saline (513mmol/L) may be required
in patients with acute symptomatic hyponatraemia. The appropriate
infusion rate can be calculated from the formula:
Rate of sodium replacement (mmol/h) = total body water (60% of body
weight) × desired correction rate (0.5–1mmol/h).
For example, for a 70kg ♂:
Na+ = 60% × 70kg × 1mmol/h = 42mmol/h
1000
= 42 × = 82mL / h of 3% saline
513
• Rapid normalization (faster than 0.5mmol/h) of sodium may be
associated with central pontine myelinolysis.
SIADH
b see Syndrome of inappropriate ADH (SIADH), p. 220.
HYPONATRAEMIA 219
Neurosurgical hyponatraemia
• Injudicious fluids.
• Diuretics.
• Drugs, e.g. carbamazepine, opiates.
• SIADH.
• Glucocorticoid deficiency.
• Cerebral salt wasting.
Unexplained hyponatraemia
• Common in elderly (i ADH release in response to i osmolality and
less effective suppression of ADH).
• i risk of hyponatraemia with SSRIs.
Syndrome of inappropriate ADH

(SIADH)
Definition
SIADH is a common cause of hyponatraemia. It is clinically normovolaemic
hyponatraemia since the i water is distributed through all compartments.
(NB The elderly are more prone to SIADH, as they are unable to suppress
ADH as efficiently and, therefore, investigation is probably only necessary
if Na <130mmol/L in this group.) See Box 2.33 for causes.
Criteria for diagnosis
• Hyponatraemia and hypotonic plasma (osmolality <270mOsm/kg).
• Hyperproteinaemia and hyperlipidaemia may cause hyponatraemia but
not hypotonic plasma.
• Inappropriate urine osmolality >100mOsm/kg.
• Excessive renal sodium loss (>30mmol/L, often >50mmol/L).
• Absence of clinical evidence of hypovolaemia or of volume overload.
• Normal renal, adrenal, and thyroid function (all must be excluded).
• NB Fluid restriction may reduce sodium loss.
• Differentiate from cerebral salt-wasting (b see Transsphenoidal
surgery, p. 198).
See Box 2.33 for causes of SIADH.
Types of SIADH
• Type 1—erratic excess ADH secretion, unrelated to plasma osmolality
commonest (40%), associated (not exclusively) with tumours.
• Type 2—‘reset osmostat’: patients autoregulate around a lower serum
osmolality.
• Chest and CNS disease.
• Type 3—‘leaky osmostat’, normal osmoregulation until plasma
hypotonicity develops when vasopressin secretion continues.
• Type 4—normal osmoregulated vasopressin secretion, possible
receptor defect, or alternative antidiuretic hormone.
Investigation of aetiology of SIADH
• Plasma and serum osmolalities and biochemistry.
• Thyroid function tests.
• Synacthen® test.
• Chest X-ray.
• Optional or if not explained—MRI head, imaging of chest/abdomen,
HIV serology, bronchoscopy, lumbar puncture.
Treatment
• Treatment of the underlying cause.
• Fluid restriction to 500–750mL/24h.
• If the problem is not temporary and fluid restriction long-term can be
difficult for the patient, drug treatment may be tried. Demeclocycline
may be effective by inducing partial nephrogenic DI. New specific
vasopressin antagonists are under trial (e.g. tolvaptan) (see Box 2.34).
SYNDROME OF INAPPROPRIATE ADH (SIADH) 221
Box 2.33 Causes of SIADH

• Tumours.
• Small cell lung carcinoma, thymoma, lymphoma, leukaemia,
sarcoma, mesothelioma.
• Chest disease.
• Infections (pneumonia, tuberculosis, empyema).
• Pneumothorax.
• Asthma.
• Cystic fibrosis.
• Positive pressure ventilation.
• CNS disorders.
• Pituitary, macroadenoma.
• Infections (meningitis, encephalitis, abscess).
• Head injury.
• Guillain–Barré.
• Vascular disorders (subarachnoid haemorrhage, cerebral
thrombosis).
• Psychosis.
• Brain tumour.
• Drugs.
• Chemotherapy (vincristine, vinblastine, cyclophosphamide).
• Psychiatric drugs (phenothiazines, MAOI).
• Carbamazepine.
• Clofibrate.
• Chlorpropamide.
• Metabolic.
• Hypothyroidism.
• Glucocorticoid deficiency.
• Acute intermittent porphyria.
• Idiopathic.
NB The elderly are more prone to SIADH, as they are less able to suppress AVP.
Box 2.34 Tolvaptan

• Competitive vasopressin receptor 2 antagonist.
• Used for resistant hyponatraemia.
• Great care should be taken to avoid overrapid correction of sodium
levels.
• Side effects include thirst, dry mouth, and urination.
• Only rarely indicated.
• In an emergency, saline infusion may be required, e.g. 100mL 3%

over 15/30min IV twice daily—great care is required, as rapid
overcorrection of hyponatraemia may cause central pontine
myelinolysis (demyelination). This can be avoided if the rate of sodium
correction does not exceed 0.5mmol/L per hour.
Further reading
Ellison DH, Berl T (2007). Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J
Med 356, 2064–71.
Eating disorders
Anorexia nervosa
Features
• Typical presentation is a ♀ aged <25 with weight loss, amenorrhoea,
and behavioural changes.
• There is a long-term risk of severe osteoporosis associated with
>6 months of amenorrhoea. There is loss of bone mineral content
and bone density, with little or no recovery after resolution of the
amenorrhoea. Bone loss occurs at 2.5% per annum.
Endocrine abnormalities
• Deficiency of GnRH, low LH and FSH, normal PRL, and low oestrogen
in ♀ or testosterone in ♂.
• Elevated circulating cortisol (usually non-suppressible with
dexamethasone).
• Low normal thyroxine, reduced T3, and normal TSH.
• Elevated resting GH levels.
• In addition, it is common to find various metabolic abnormalities,
such as reduced magnesium, zinc, phosphorus, and calcium levels, in
addition to hyponatraemia, hypoglycaemia, and hypokalaemia.
• Weight gain leads to a reversion of the prepubertal LH secretory
pattern to the adult-like secretion. Administration of GnRH in a
pulsatile pattern leads to normalization of the pituitary–gonadal axis,
demonstrating that the p abnormality is hypothalamic.
Management
• The long-term treatment of these patients involves treatment of the
underlying condition and then management of osteoporosis, although
many patients will refuse oestrogen replacement.
• Resumption of menstrual function is important for recovery of spine
bone mineral density (BMD). Weight gain is important for hip BMD
recovery. Oral contraceptives do not help BMD recovery.
Bulimia
Features
• Typically occurs in ♀ who are slightly older than the group with
anorexia nervosa. Weight may be normal, and patients often deny the
abnormal eating behaviour. Patients gorge themselves, using artificial
means of avoiding excessive weight gain (laxatives, diuretic abuse,
vomiting). This may be a cause of ‘occult’ hypokalaemia.
• These patients may, or may not, have menstrual irregularity. If
menstrual irregularity is present, this is often associated with
inadequate oestrogen secretion and anovulation.
Further reading
Miller KK, Lee EE, Lawson EA, et al. (2006). Determinants of skeletal loss and recovery in anorexia
nervosa. J Clin Endocrinol Metab 91, 2931–7.
HYPOTHALAMUS 223
Hypothalamus
Pathophysiology
• The hypothalamus releases hormones that act as releasing hormones
at the anterior pituitary gland. It produces dopamine that inhibits PRL
release from the anterior pituitary gland. It also synthesizes arginine
vasopressin and oxytocin (b see p. 208).
• The commonest syndrome to be associated with the hypothalamus
is abnormal GnRH secretion, leading to reduced gonadotrophin
secretion and hypogonadism. Common causes are stress, weight loss,
and excessive exercise. Management involves treatment of the cause,
if possible. Administration of pulsatile GnRH is usually effective at
reversing the abnormality but rarely undertaken.
Hypothalamic syndrome
Uncommon but may occur due to a large tumour, following surgery for a
craniopharyngioma, or due to infiltration from, for example, Langerhans
cell histiocytosis. The typical features are hyperphagia and weight gain, loss
of thirst sensation, DI, somnolence, problems with temperature control,
and behaviour change. Management can be challenging, e.g. DI with the
loss of thirst sensation may require the prescription of regular fluid, in
addition to desmopressin, and monitoring with daily weights and fluid bal-
ance as a routine. See Box 2.35 for metabolic effects.
Box 2.35 Metabolic effects of hypothalamic mass lesions

• Appetite:
• Hyperphagia and obesity.
• Anorexia.
• Thirst:
• Adipsia.
• Compulsive drinking.
• Temperature:
• Hyperthermia.
• Hypothermia.
• Somnolence and coma.
Pineal gland
Physiology
• The pineal gland lies behind the third ventricle, is highly vascular, and
produces melatonin and other peptides.
• During daylight, light-induced hyperpolarization of the retinal
photoreceptors inhibits signalling and the pineal gland is quiescent.
• Darkness stimulates the gland, and there is synthesis and release of
melatonin.
• Melatonin levels are usually low during the day, rise during the evening,
peak at midnight, and then decline independent of sleep.
• Exposure to darkness during the day does not increase melatonin
secretion.
Jet lag
• It is claimed that pharmacological doses of melatonin can reset the
body clock.
• Studies have suggested that melatonin may reduce the severity or
duration of jet lag. There are few safety data, and currently melatonin
does not have a product licence in the UK.
Pineal and intracranial germ cell tumours
• Incidence. 0.5–3% intracranial neoplasms.
• Epidemiology.♂ > ♀. All ages. Two-thirds present between age 10 and
21 years.
• Germ cell tumours are now classified as germinomas or
non-germinomatous germ cell tumours (choriocarcinoma, teratoma).
The latter term includes the tumours previously called ‘true’ pinealomas.
Features
• Raised intracranial pressure (compression of cerebral aqueduct),
headache, and lethargy.
• Visual disturbance (pressure on quadrigeminal plate).
• Parinaud’s syndrome (paralysis of upward gaze, convergent nystagmus,
Argyll–Robertson pupils).
• Ataxia.
• Pyramidal signs.
• DI.
• Sexual precocity in boys (excess hCG secretion mimics LH, leading to
Leydig cell testosterone secretion or related to space-occupying mass).
Investigations
• Imaging of craniospinal axis MRI/CT (may detect second tumour/
metastases).
• CSF examination.
• Tumour markers (hCG, alpha fetoprotein).
• Cytology.
• Biopsy if tumour markers unhelpful.
• Pituitary function assessment.
PINEAL GLAND 225
Management
• External beam radiotherapy—standard therapy is to irradiate the
whole craniospinal axis.
• Germinomas are exquisitely radiosensitive.
• Chemotherapy may be indicated, e.g. vincristine, etoposide,
carboplatin.
• Craniospinal irradiation cures the majority of patients (90%).
Prognosis
Excellent for germinomas (70–85% 5-year survival), but non-germinomatous
germ cell tumours have a worse prognosis (15–40% 5-year survival).
Further reading
Hussaini M, et al. (2009). Pineal gland tumors: experience from the SEER database. J Neuro Oncol
94, 351–8.
Chapter 3 227
Adrenal
Anatomy 228
Physiology 230
Imaging 232
Mineralocorticoid excess: definitions 234
Primary aldosteronism 236
Conn’s syndrome—aldosterone-producing adenoma 238
Bilateral adrenal hyperplasia (bilateral idiopathic
hyperaldosteronism) 239
Glucocorticoid-remediable aldosteronism (GRA) 240
Aldosterone-producing carcinoma 241
Screening 242
Localization and confirmation of differential diagnosis 244
Treatment 246
Excess other mineralocorticoids 248
Adrenal Cushing’s syndrome 250
Treatment of adrenal Cushing’s syndrome 252
Adrenal surgery 256
Renal tubular abnormalities 258
Liddle’s syndrome 258
Bartter’s syndrome 259
Gitelman’s syndrome 260
Mineralocorticoid deficiency 262
Adrenal insufficiency 264
Addison’s disease 266
Autoimmune adrenalitis 268
Autoimmune polyglandular syndrome (APS) type 1 270
APS type 2 271
Investigation of primary adrenal insufficiency 272
Treatment of primary adrenal insufficiency 276
Long-term glucocorticoid administration 280
Adrenal incidentalomas 282
Phaeochromocytomas and paragangliomas 284
Investigations of phaeochromocytomas and paragangliomas 288
Screening for associated conditions 292
Management 294
228 CHAPTER 3 Adrenal
Anatomy
The normal adrenal glands weigh 4–5g. The cortex represents 90% of the
normal gland and surrounds the medulla. The arterial blood supply arises
from the renal arteries, aorta, and inferior phrenic artery. Venous drainage
occurs via the central vein into the inferior vena cava on the right and into
the left renal vein on the left. See Figs. 3.1 and 3.2.
Fig. 3.1 Pathways and enzymes involved in synthesis of glucocorticoids,

mineralocorticoids, and adrenal androgens from a cholesterol precursor.
Reproduced from Besser M and Thorner GM (1994). Clinical Endocrinology 2nd edn.
Mosby. With permission from Elsevier.
ANATOMY 229
Hypothalamus Aldosterone
ACTH
Glomerulosa cells
Angiotensin III ?
Adrenal
Angiotensin II
Converting
enzyme
(ACE)
Lungs
Angiotensin I
Renin
Angiotensinogen
Juxtaglomerular
cells
Sympathetic input
Blood pressure
Na
Kidney
Fig. 3.2 Physiological mechanisms governing the production and secretion

of aldosterone. Reproduced from Besser GM and Thorner M (1994). Clinical
Endocrinology 2nd edn. Mosby. With permission from Elsevier.
Physiology
Glucocorticoids
Glucocorticoid (cortisol 10–20mg/day) (see Table 3.1) production occurs
from the zona fasciculata, and adrenal androgens arise from the zona retic-
ularis. Both of these are under the control of ACTH, which regulates both
steroid synthesis and also adrenocortical growth.
Mineralocorticoids
Mineralocorticoid (aldosterone 100–150 micrograms/day) (see Table 3.1)
synthesis occurs in zona glomerulosa, predominantly under the control of
the renin–angiotensin system (see Fig. 3.2), although ACTH also contrib-
utes to its regulation.
Androgens
The adrenal gland (zona reticularis and zona fasciculata) also produces sex
steroids in the form of dehydroepiandrostenedione (DHEA) and andros-
tenedione. The synthetic pathway is under the control of ACTH.
Urinary steroid profiling provides quantitative information on the bio-
synthetic and catabolic pathways. Profiling can be useful in:
• Mineralocorticoid hypertension.
• Polycystic ovary syndrome.
• Congenital adrenal hyperplasia.
• Steroid-producing tumours.
• Precocious puberty/virilization.
• Hirsutism.
Pathophysiology
Urine steroid profile useful in:
• Mineralocortoid hypertension (dK).
• Cushing’s Syndrome.
• Androgen resistance.
Table 3.1 Adrenal cortex steroid production

Adrenal cortex Cortisol Aldosterone DHEA DHEAS
Production rate/24h 10 100 micrograms 10mg 25mg

Half-life 80min 20min 20min 9h
Control ACTH Renin ACTH ACTH
Further reading
Taylor NF (2006). Urinary steroid profiling. Method Mol Biol 324, 159–75.
PHYSIOLOGY 231
Imaging
Computed tomography (CT) scanning
CT is the most widely used modality for imaging the adrenal glands. It is
able to detect masses >5mm in diameter. It can be useful in differentiating
between different adrenal pathologies, in particular by identifying benign
adrenal tumours with high fat content (adrenocortical adenoma, adreno-
myelolipoma), as indicated by pre-contrast tumour density of less than
10HU (Hounsfield units) (see Fig. 3.3).
Magnetic resonance imaging (MRI)
MRI can also reliably detect adrenal masses >5–10mm in diameter and, in
some circumstances, provides additional information to CT, in particular
by determining signal loss in opposed phase, T2-weighted sequences. Rapid
signal loss is indicative of a benign tumour whereas malignant tumours, and
also phaeochromocytomas, show a delay or lack in signal loss.
Ultrasound (US) imaging
US detects masses >20mm in diameter, but normal adrenal glands are not
usually visible, except in children. Body morphology and bowel gas can
provide technical difficulties.
Normal adrenal
Normal adrenal cortex is assessed by measuring limb thickness and
is considered enlarged at >5mm approximately the thickness of the
diaphragmatic crus nearby.
Adrenal
adenoma Adrenal
glands
Fig. 3.3 Typical appearance of adrenal adenoma on CT scan.

IMAGING 233
Radionucleotide imaging
• 123
Iodine-metaiodobenzylguanidine (MIBG) is a guanethidine analogue,
concentrated in some phaeochromocytomas, paragangliomas,
carcinoid tumours, and neuroblastomas, and is useful diagnostically.
A different isotope 131I-MIBG may be used therapeutically, e.g. in
malignant phaeochromocytomas, when the diagnostic imaging shows
uptake.
• 75Se 6B-selenomethyl-19-norcholesterol. This isotope is concentrated in
functioning steroid synthesizing tissue and has, in the past, been used
to image the adrenal cortex. However, high resolution CT and MRI
have largely replaced it in localizing functional adrenal adenomas.
• 123Iodo-metomidate is an isotope that is derived from etomidate, which
is a known 11β-hydroxylase (CYP11B1) inhibitor. Metomidate binds
CYP11B1, which is specifically expressed in the adrenal gland, and thus
iodo-metomidate SPECT can identify adrenocortical tissue.
Positron emission tomography (PET)
PET can be useful in locating tumours and metastases. Radiopharma-
ceuticals for specific endocrine tumours are being developed, e.g.
11
C-metahydroxyephedrine for phaeochromocytoma—combined with CT
(PET-CT), it may offer particular value in localizing occult neuroendocrine
tumours. 11C-metomidate PET-CT has recently been shown to be of value
for the lateralization of aldosterone-producing adrenal masses.
Venous sampling
Adrenal vein sampling (AVS) (b p. 244) can be useful to lateralize an
adenoma or to differentiate an adenoma from bilateral hyperplasia. It
is technically difficult—particularly, catheterizing the right adrenal vein
because of its drainage into the IVC. There is no widespread agreement
on the exact protocol, e.g. consecutive or concurrent adrenal vein cath-
erization, with and without concurrent or preceding ACTH stimulation.
Usually, samples are drawn from the vena cava, superior and inferior to
the renal veins, and separately from both adrenal veins, with subsequent
determination of plasma aldosterone and serum cortisol levels (correct
localization of the catheter in the adrenal vein is only confirmed when
cortisol >3-fold of vena cava cortisol). AVS is of particular value in lateral-
izing small aldosterone-producing adenomas that cannot easily be visual-
ized on CT or MRI.
Further reading
Boland GW (2011). Adrenal imaging: from Addison to algorithms. Radiol Clin North Am 49, 511–28.
Guest P (2011). Imaging of the adrenal gland. In: Wass JAH, Stewart PM (eds.) Oxford textbook of
endocrinology, pp. 763–73. Oxford University Press, Oxford.
Hahner S, Sundin A (2011). Metomidate-based imaging of adrenal masses. Horm Cancer 2, 348–53.
Pacak K, Eisenhofer G, Goldstein DS (2004). Functional imaging of endocrine tumors: role of
positron emission tomography. Endocr Rev 25, 568–80.
Mineralocorticoid excess: definitions

The majority of cases of mineralocorticoid excess are due to excess aldos-
terone production, which may be p or s, and are typically associated with
hypertension and hypokalaemia.
• Primary hyperaldosteronism is a disorder of autonomous aldosterone
hypersecretion with suppressed renin levels.
• Secondary hyperaldosteronism occurs when aldosterone hypersecretion
occurs s to elevated circulating renin levels. This is typical of heart
failure, cirrhosis, or nephrotic syndrome but can also be due to renal
artery stenosis and, occasionally, a very rare renin-producing tumour
(reninoma).
• Other mineralocorticoids may occasionally be the cause of this
syndrome (see Box 3.1).
Box 3.1 Causes of mineralocorticoid excess

Primary hyperaldosteronism
• Conn’s syndrome (aldosterone-producing adrenal adenoma) 35%.
• Bilateral adrenal hyperplasia 60%.
• Glucocorticoid-remediable aldosteronism (GRA) <1%.
• Aldosterone-producing adrenal carcinoma <1%.
Secondary hyperaldosteronism
• Renal artery stenosis.
• Renal hypoperfusion.
• Cirrhosis.
• Congestive cardiac failure.
• Nephrotic syndrome.
• Renin-secreting tumour.
Other mineralocorticoid excess syndromes
• Apparent mineralocorticoid excess (b see p. 248).
• Liquorice ingestion (b see p. 249) (inhibits II B HSD2) d
aldosterone, d renin, d K– found in sweets, chewing tobacco, cough
mixtures, herbal medicines.
• Deoxycorticosterone and corticosterone (b see p. 249).
• Ectopic ACTH secretion (b see p. 164).
• Congenital adrenal hyperplasia (b see p. 320).
• Exogenous mineralocorticoids.
‘Pseudoaldosteronism’ due to abnormal renal tubular transport
• Bartter’s syndrome (b see p. 259).
• Gitelman’s syndrome (b see p. 260).
• Liddle’s syndrome (b see p. 258).
MINERALOCORTICOID EXCESS: DEFINITIONS 235
Primary aldosteronism
Epidemiology
Primary hyperaldosteronism is present in around 10% of hypertensive
patients. It is the most prevalent form of secondary hypertension. The
most common cause is bilateral adrenal hyperplasia (see Table 3.2).
Pathophysiology
Aldosterone causes renal sodium retention and potassium loss. This results
in expansion of body sodium content, leading to suppression of renal renin
synthesis. The direct action of aldosterone on the distal nephron causes
sodium retention and loss of hydrogen and potassium ions, resulting in a
hypokalaemic alkalosis, although serum potassium may not be significantly
reduced and may be normal in up to 50% of cases.
Aldosterone has pathophysiological effects on a range of other tis-
sues, causing cardiac fibrosis, vascular endothelial dysfunction, and
nephrosclerosis.
Clinical features
• Moderately severe hypertension, which is often resistant to
conventional therapy. There may be disproportionate left ventricular
hypertrophy.
• Hypokalaemia is usually asymptomatic. Occasionally, patients may
present with tetany, myopathy, polyuria, and nocturia (hypokalaemic
nephrogenic diabetes insipidus) due to severe hypokalaemia.
• There may be an association with osteoporosis.
PRIMARY ALDOSTERONISM 237
Table 3.2 Causes of primary hyperaldosteronism

Condition Relative Age Pathology
frequency
Aldosteronoma 35% 3rd–6th decade Benign, adenoma,
(Conn’s adenoma) <2.5cm diameter,
yellow because of
high cholesterol
content
Idiopathic 60% Older than Conn’s, Macronodular
hyperaldosteronism ♂>♀ or micronodular
(bilateral adrenal hyperplasia
hyperplasia)
Adrenal carcinoma Rare 5th–7th decade Tumour >4cm in
(occasionally young) diameter—often
larger, may be
evidence of local
invasion
Glucocorticoid- Rare Childhood Chimeric crossover
suppressible between CYP11B1
hyperaldosteronism and CYP11B2
genes results in an
ACTH-responsive
aldosterone synthase
Conn’s syndrome—
aldosterone-producing adenoma
Very high levels of the enzyme aldosterone synthase are expressed in
tumour tissue. Recently, inactivating mutations in the potassium chan-
nel KCJN5 have been identified as the cause of disease in approximately
40% of aldosterone-producing adrenal adenomas. Very rarely, Conn’s
adenomas may be part of the MEN-1 syndrome.
BILATERAL ADRENAL HYPERPLASIA 239
Bilateral adrenal hyperplasia

(bilateral idiopathic
hyperaldosteronism)
This is the most common form of p hyperaldosteronism in adults.
Hyperplasia is more commonly bilateral than unilateral and may be asso-
ciated with micronodular or macronodular hyperplasia. Note, however,
that CT-demonstrable nodules have a prevalence of 2% in the general
population, including hypertensive patients without excess aldosterone
production. The pathophysiology is not known, although aldosterone
secretion is very sensitive to circulating angiotensin II. The pathophysiol-
ogy of bilateral adrenal hyperplasia is not understood, and it is possible
that it represents an extreme end of the spectrum of low renin essential
hypertension.
Glucocorticoid-remediable
aldosteronism (GRA)
This is a rare autosomal dominantly inherited condition due to the pres-
ence of a chimeric gene (8q22) containing the 5′ sequence, which deter-
mines regulation of the 11B-hydroxylase gene (CYP11B1) coding for the
enzyme catalysing the last step in cortisol synthesis, and the 3′ sequence
from the aldosterone synthase gene (CYP11B2) coding for the enzyme
catalysing the last step in aldosterone synthesis. This results in the expres-
sion of aldosterone synthase in the zona fasciculata as well as the zona
glomerulosa, and aldosterone secretion comes under ACTH control.
Glucocorticoids are the treatment of choice and lead to suppression of
ACTH and suppression of aldosterone production.
• Early hypertension and family history.
• Hybrid steroids (18OHcortisol and 18oxocortisol) elevated.
ALDOSTERONE-PRODUCING CARCINOMA 241
Aldosterone-producing carcinoma
Rare and usually associated with excessive secretion of other corticoster-
oids (cortisol, androgen, oestrogen). Hypokalaemia may be profound and
aldosterone levels very high. A tumour larger than 2.5cm associated with
aldosterone excess has to be treated as suspicious.
Screening
Indications
• Patients resistant to conventional antihypertensive medication (i.e. not
controlled on three agents).
• Hypertension associated with hypokalaemia (potassium <3.7mmol/L,
irrespective of thiazide use). NB: d K only present in 40%.
• Hypertension developing before age of 40 years.
• Adrenal incidentaloma.
Method
• Give oral supplements of potassium to control hypokalaemia;
screening and confirmation should be carried out in the
normokalaemic situation.
• There is no need to stop all concomitant antihypertensive medication
for the first screening by paired plasma aldosterone and plasma
renin measurements; the only medication that must be stopped are
mineralocorticoid receptor antagonists (spironolactone, eplerenone)
that must be stopped 4 weeks prior to diagnostic tests.
• Measure aldosterone:renin ratio.
• A high ratio is suggestive of p hyperaldosteronism (aldosterone
(pmol/L)/plasma renin activity (ng/mL/h) >750 or aldosterone
(ng/dL)/plasma renin activity (ng/mL/h) >30–50). Note that newer
assays that measure renin mass (rather than activity) will require
the development of different cut-offs.
• Test results should be interpreted, having the effects of
antihypertensive drugs in mind (see Table 3.3); B-blockers can cause
false +ves while ACE/AT1R blockers can cause false –ves in borderline
cases. In doubt, the test can be repeated off these drugs; BP can be
controlled using doxazosin or calcium antagonists. False –ve results
can also occur in patients with chronic renal failure due to upregulated
plasma renin.
Confirmation of diagnosis
Confirmation of autonomous aldosterone production is made by demon-
strating failure to suppress aldosterone in face of sodium/volume loading.
This can be achieved by a number of mechanisms after optimizing test
conditions as described.
• Test of choice—saline infusion test:
• Administer 2L normal saline over 4h.
• Measure plasma aldosterone at 0, 2, 3, and 4h.
• Aldosterone fails to suppress to <140pmol/L (140–280 equivocal)
in 80–90% of p aldosteronism.
• Most used test; caution in patients with fluid overload and/or
evidence of heart failure.
• Fludrocortisone suppression test:
• Give fludrocortisone 100 micrograms 6-hourly for 4 days.
• Measure plasma aldosterone basally and on last day.
• Aldosterone fails to suppress in p aldosteronism.
• Caveat: difficult to execute in hypokalaemic, hypertensive patients.
SCREENING 243
Table 3.3 Interpreting test results of aldosterone/renin ratios

Antihypertensive Effect on renin Effect on Net effect on ARR
aldosterone
B-blockers d i i
A1-blockers l l l
A2-sympathomimetics l l l
ACE inhibitors i d d
AT1R blockers i d d
Calcium antagonists l l l
Diuretics (i) (i) l/(d)
• Dietary sodium loading test:

• Patients are given instructions antagonists to take a diet with a high
sodium content (sufficient to raise the sodium intake to 200mmol
per day for 3 days. If necessary, this can be achieved by adding
supplemental sodium chloride tablets).
• It is important to ensure that potassium is maintained as normal
during this period, and potassium supplementation may also be
required.
• Failure to suppress aldosterone in p aldosteronism.
• Caveat: cumbersome to execute, limited diagnostic value in
populations with a high background sodium intake.
• Other tests, such as the captopril suppression test, are described but
are of lesser value in this circumstance, lacking appropriate sensitivity
or specificity in the diagnosis of p aldosteronism.
• A number of tests have been described that are said to differentiate
between the various subtypes of p aldosteronism (solitary Conn’s
adenoma; bilateral adrenal hyperplasia; GRA). However, none of
these are sufficiently specific to influence management decisions, and
more specific investigations (imaging and adrenal vein sampling) are
necessary if there is doubt. Additional tests, such as postural response
of aldosterone and the measurement of urinary 18-hydroxycortisol,
have been largely superseded because of this. Diagnosis of GRA is
best made using a specific genetic test, rather than on the ability of
dexamethasone (0.5mg 6-hourly for 3 days) to suppress aldosterone;
the diagnosis is confirmed by genetic analysis (chimeric crossover
between CYP11B1 (11B-hydroxylase) and CYP11B2 (aldosterone
synthase) promoter regions that brings CYP11B2 under the regulatory
control of ACTH).
Localization and confirmation of

differential diagnosis
CT/MRI scan
CT and MRI scanning are of value in identifying adrenal nodules >5mm
diameter. It should be noted, however, that the frequency of adrenal inci-
dentalomas rises with age and, for this reason, it is prudent to consider
adrenal vein sampling if in doubt.
• In bilateral adrenal hyperplasia, both glands can appear enlarged or
normal in size.
• Macronodular hyperplasia may result in identifiable nodules on
imaging.
• A mass >4cm in size is suspicious of carcinoma but is unusual in
Conn’s syndrome.
• NB In essential hypertension, nodules are described.
Adrenal vein sampling
Is indicated in patients with bilateral adrenal changes and in older patients
(age >50) with p aldosteronism who have an apparent solitary adenoma
on scanning, as the incidence of adrenal nodules rises with age (3–4% at
40 years, 70–80% at 70 years). The procedure should only be undertaken
in patients in whom surgery is feasible and desired.
Catheterization of the adrenal veins may not be necessary if there is a
unilateral adrenal mass (>10mm) plus a potassium 3.5 on presentation, as
this predicts an adenoma.
Aldosterone measurements from both adrenal veins allow a gradient
between the two sides to be identified in the case of unilateral disease. It
is the gold standard for differentiation between uni- and bilateral aldoster-
one production, but cannulating the right adrenal vein is technically diffi-
cult as it drains directly into the inferior vena cava. Cortisol measurements
must also be taken concomitantly with aldosterone to confirm successful
positioning within the adrenal veins and should be more than thrice a
peripheral sample (central/peripheral ratio >3).
Adrenal vein sampling should be carried out in specialist centres only;
centres with <20 procedures per year have been shown to have poor
success rates for bilateral catheterization of the adrenal vein (8–10%), thus
producing mostly non-informative results, whereas experienced centres
achieve around 70%.
Radiolabelled scanning
The iodocholesterol test has low sensitivity/specificity and offers no
advantage over a high resolution CT or MRI with, where necessary, adre-
nal vein sampling. Recent data with 11C-metomidate scanning are promis-
ing but warrant further confirmation prior to widespread use.
LOCALIZATION & CONFIRMATION OF DIFFERENTIAL DIAGNOSIS 245
Treatment
Surgery
• Laparascopic adrenalectomy is the treatment of choice for
aldosterone-secreting adenomas and is associated with lower
morbidity than open adrenalectomy.
• Surgery is not indicated in patients with idiopathic hyperaldosteronism,
as even bilateral adrenalectomy may not cure the hypertension.
• Presurgical spironolactone treatment may be used to correct
potassium stores before surgery.
• The BP response to treatment with spironolactone (50–400mg/day)
before surgery can be used to predict the response to surgery of
patients with adenomas.
• Hypertension is cured in about 70%.
• If it persists (more likely in those with long-standing hypertension and
increased age), it is more amenable to medical treatment.
• Overall, 50% become normotensive in 1 month and 70% within 1 year.
• Adrenal carcinoma. Open surgery and post-operative adrenolytic
therapy with mitotane is usually required, but the prognosis is usually
poor (b see Treatment, p. 252).
Medical treatment
Medical therapy remains an option for patients with bilateral disease and
those with a solitary adrenal adenoma who are unlikely to be cured by
surgery, who are unfit for operation, or who express a preference for
medical management.
• The mineralocorticoid receptor antagonist spironolactone
(50–400mg/day; once daily administration) has been used successfully
for many years to treat the hypertension and hypokalaemia associated
with bilateral adrenal hyperplasia and idiopathic hyperaldosteronism
profile.
• There may be a delay in response of hypertension of 4–8 weeks.
However, combination with other antihypertensive agents (ACEI and
calcium channel blockers) is usually required.
• Spironolactone also interacts with the androgen and the progesterone
receptor, which contributes to its side effect. Side effects are
common—particularly, gynaecomastia and impotence in ♂, menstrual
irregularities in ♀, and GI effects.
• Eplerenone (50–200mg/day; twice daily administration) is a
mineralocorticoid receptor antagonist without antiandrogen effects
and hence greater selectivity and less side effects than spironolactone.
• Alternative drugs include the potassium-sparing diuretics amiloride
and triamterene. Amiloride may need to be given in high dose (up to
40mg/day) in p aldosteronism, and monitoring of serum potassium is
essential. Calcium channel antagonists may also be helpful.
• Glucocorticoid-remediable aldosteronism can be treated with
low-dose dexamethasone (0.25–0.5mg on going to bed). If needed,
spironolactone and/or amiloride can be added.
TREATMENT 247
Further reading
Allolio B, Hahner S, Weismann D, et al. (2004). Management of adrenocortical carcinoma. Clin
Espiner EA, Ross DG, Yandle TG, et al. (2003). Predicting surgically remedial primary aldosteron-
ism: role of adrenal scanning, posture testing, and adrenal vein sampling J Clin Endocrinol Metab
88, 3637–44.
Funder JW, et al. (2008). Case detection, diagnosis, and treatment of patients with primary aldo-
steronism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 93, 3266–81.
Ganguly A (1998). Primary aldosteronism. N Engl J Med 339, 1828–33.
Mulatero P (2002). Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism.
Hypertension 40, 897–902.
Young WF (2007). Primary aldosteronism—renaissance of a syndrome. Clin Endocrinol 66, 607–18.
Excess other mineralocorticoids

Epidemiology
Occasionally, the clinical syndrome of hyperaldosteronism is not associ-
ated with excess aldosterone. This can be due either to an increase in
an alternative mineralocorticoid or due to i mineralocorticoid effect of
cortisol.
These conditions are rare.
Apparent mineralocorticoid excess (AME)
• The mineralocorticoid receptor has an equal affinity for cortisol and
aldosterone, but there is a 100-fold excess of circulating cortisol over
aldosterone.
• The mineralocorticoid receptor is usually protected from the
effects of stimulation by cortisol by the 11B-hydroxysteroid type 2
dehydrogenase enzyme, which converts cortisol to cortisone.
• In AME, there is a deficiency of the 11B-hydroxysteroid
dehydrogenase (HSD) enzyme type 2. This can be caused either
by inactivating mutations in the corresponding gene encoded on
chromosome 16q22 or due to exogenous intake of substances that
inhibit 11B-HSD2, such as liquorice.
• Congenital absence (autosomal recessive) of the enzyme or inhibition
of its activity allows cortisol to stimulate the receptor and leads to
severe hypertension.
Type 1 is seen predominantly in children, presenting with failure to thrive,
thirst, polyuria, and severe hypertension, which can lead to brain haemor-
rhage in childhood or adolescence. The urinary cortisol over cortisone
metabolites ratio (tetrahydrocortisol + allo-tetrahydrocortisol/tetrahy-
drocortisone) is raised to 10× normal.
Type 2 is a milder form that may be a cause of hypertension in adoles-
cence/early adulthood.
However, multiple mutations have been found in the 11B-HSD2 gene
for both types, and some authors believe there is a spectrum of dis-
ease: mild forms may present with salt-sensitive hypertension.
Biochemistry
• Suppression of renin and aldosterone.
• Hypokalaemic alkalosis.
• Urinary free cortisol/cortisone ratio i.
• Ratio of urinary tetrahydrocortisol and allo-tetrahydrocortisol to
tetrahydrocortisone is raised (>10×) in type 1 but is normal in type 2.
• Confirm with genetic testing (HSD11B2 gene).
Treatment
• Dexamethasone leads to suppression of ACTH secretion, reduced
cortisol concentrations, and lowered BP in 60%. It has a much lower
affinity for the mineralocorticoid receptor.
• Other antihypertensive agents are often required.
• One patient with hypertensive renal failure was cured with a renal
transplant.
EXCESS OTHER MINERALOCORTICOIDS 249
Liquorice ingestion
• Liquorice contains glycyrrhetinic acid which is used as a sweetener.
• It inhibits the action of 11B-HSD2, which allows circulating cortisol
to get increased access to the mineralocorticoid receptor causing
hypertension.
• Liquorice can be found in sweets, chewing tobacco, cough mixtures,
and some herbal medicines.
Ectopic ACTH syndrome
(b see p. 164.)
In the syndrome of ectopic ACTH and generally in very severe Cushing’s
cases, the 11B-HSD2 protection is overcome because of high cortisol
secretion rates, which saturate the enzyme, leading to impaired conver-
sion of cortisol to cortisone. Therefore, cortisol has greater access to the
mineralocorticoid receptor in the kidney, which results in hypokalaemia
and hypertension.
Deoxycorticosterone (DOC) excess
Two forms of congenital adrenal hyperplasia (b see p. 320) are asso-
ciated with excess production of deoxycorticosterone (DOC), as they
result in inhibition of enzymes downstream of DOC and thus lead to its
accumulation. DOC acts as an agonist at the mineralocorticoid receptor,
resulting in hypertension with suppression of renin.
• 17α-hydroxylase (CYP17A1) deficiency.
• 11B-hydroxylase (CYP11B1) deficiency.
Glucocorticoid replacement to inhibit ACTH is effective treatment for
these conditions.
Adrenal tumours, in particular adrenocortical carcinomas, rarely secrete
excessive amounts of deoxycorticosterone. This may be concomitant
with excessive aldosterone production, but occasionally it may occur in
an isolated fashion.
Adrenal Cushing’s syndrome

Definition and epidemiology
• Cushing’s syndrome results from chronic excess cortisol and is
described in Chapter 2 (b see Cushing’s disease, p. 158).
• The causes may be classified as ACTH-dependent and
ACTH-independent. This section describes ACTH-independent
Cushing’s syndrome, which is due to adrenal tumours (benign and
malignant), and is responsible for 10–15% cases of Cushing’s syndrome.
• Adrenal tumours causing Cushing’s syndrome are commoner in ♀.
The peak incidence is in the fourth and fifth decade.
• Causes and relative frequencies of adrenal Cushing’s syndrome in
adults:
• Adrenal adenoma 10%.
• Adrenal carcinoma 2%.
• Bilateral micronodular adrenal hyperplasia <1%.
• Bilateral macronodular hyperplasia <1%.
Pathophysiology
• Benign adrenocortical adenomas (ACA) are usually encapsulated
and <4cm in diameter. They are usually associated with pure
glucocorticoid excess.
• Adrenocortical carcinomas (ACC) are usually >6cm in diameter,
although they may be smaller, and are not infrequently associated
with local invasion and metastases at the time of diagnosis. Adrenal
carcinomas are characteristically associated with the excess secretion
of several hormones; most frequently found is the combination
of cortisol and androgen (precursors); occasionally, they may be
associated with mineralocorticoid or oestrogen secretion.
• Bilateral adrenal hyperplasia may be micronodular (<1cm diameter)
or macronodular (>1cm), but increasingly mixed cases of combined
micro- and macronodular hyperplasia are observed.
• ACTH-dependent Cushing’s results in bilateral adrenal hyperplasia,
thus one has to firmly differentiate between ACTH-dependent and
independent causes of Cushing’s before assuming bilateral adrenal
hyperplasia as the primary cause of disease.
• The majority of cases of ACTH-independent bilateral macronodular
adrenal hyperplasia (AIMAH) do not have an identifiable cause.
• Abnormal expression of receptors that would not normally be
expressed in the adrenal has been described as the cause of disease,
including gastric inhibitory peptide (GIP), vasopressin, B-adrenoceptor,
human chorionic gonadotrophin (hCG)/luteinizing hormone (LH), and
serotonin receptors.
• Several ‘food-dependent’ Cushing’s syndrome cases have been
described due to ectopic GIP receptor expression.
• Carney complex (b see Carney complex, p. 583) is an autosomal
dominant condition characterized by a variable penetrance of atrial
myxomas, spotty skin pigmentation (hyperlentiginosis), peripheral
nerve tumours, and endocrine disorders, including Sertoli cell
ADRENAL CUSHING’S SYNDROME 251
tumours and Cushing’s syndrome due to primary pigmented nodular

adrenal disease (PPNAD), which can be micro- or macronodular in
appearance. PPNAD, in the context of Carney complex, has been
shown to be caused by mutations in the PRKAR1A gene that encodes a
regulatory subunit of protein kinase A (PKA), which is a key regulator
of the adrenal ACTH response.
• McCune–Albright syndrome b p. 576 can be associated with
polyostotic fibrous dysplasia, unilateral café-au-lait spots, precocious
puberty, and ACTH-independent Cushing’s with bilateral macronodular
adrenal hyperplasia, caused by activating mutations in the GNAS-1 gene
that encodes the GSalpha protein, which is a key component of the
transmembrane signal transduction cascade of the ACTH receptor.
GNAS-1 mutations have also been found in bilateral macronodular
adrenal hyperplasia without other features of McCune–Albright’s.
• Recent work has described phosphodiesterase (PDE) 11A and 8B
mutations in patients with bilateral micronodular adrenal hyperplasia
and ACTH-independent Cushing’s.
Clinical features
• The clinical features of ACTH-independent Cushing’s syndrome are
as described in b Clinical features, p. 160 in Chapter 2, Cushing’s
disease.
• It is important to note that, in patients with adrenal carcinoma, there
may also be features related to excessive androgen production in ♀
and also a relatively more rapid time course of development of the
syndrome.
Investigations
• Once the presence of Cushing’s syndrome is confirmed (b see
Clinical features, p. 160), subsequent investigation of the cause
depends on whether ACTH is suppressed (ACTH-independent) or
measurable/elevated (ACTH-dependent).
• Patients with ACTH-independent Cushing’s syndrome do not suppress
cortisol to <50% basal on high-dose dexamethasone testing and fail
to show a rise in cortisol and ACTH following administration of CRH.
(The latter test is often important when patients have borderline/low
ACTH to differentiate pituitary-dependent disease from adrenal.)
• ACTH-independent causes are adrenal in origin, and the mainstay of
further investigation is adrenal imaging by CT, which allows excellent
visualization of the adrenal glands and their anatomy.
Treatment of adrenal Cushing’s

syndrome
(b see Treatment, p. 168.)
Adrenal adenoma
• Unilateral adrenalectomy (normally laparoscopic) is curative.
• Post-operative temporary adrenal insufficiency ensues because of
long-term suppression of ACTH and the contralateral adrenal gland
requiring glucocorticoid replacement for up to 2 years.
• Steroid cover is, therefore, required.
Adrenal carcinoma
(See Table 3.4 for staging classification.)
• Treatment of adrenocortical carcinoma (ACC) should be carried
out in a specialist centre, with expert surgeons, oncologists, and
endocrinologists with extensive expertise in treating ACC. This
improves survival.
• The primary approach is surgical, aiming at complete removal of
the primary tumour without capsule violation; in case of stage III
disease with invasion of adjacent organs or venous thrombosis,
a radical surgical approach with en bloc resection and removal
of tumour thrombus, if necessary, in collaboration with vascular
and cardio-thoracic surgeons is beneficial. Single metastases can
also be approached surgically (lung, liver) or by radiofrequency
ablation (liver). Surgical debulking can be helpful, even in metastatic
disease, in case of florid and difficult-to-control Cushing’s, but
needs to be carefully weighed against the resulting delay in initiating
chemotherapy.
• Disease-free and total survival is defined by tumour stage and the
presence or absence of capsule violation or invasion. Histopathology
is notoriously difficult, as it insufficiently differentiates between
benign and malignant tumours. The most predictive marker for
recurrence of disease after successful and apparently complete
removal of the primary tumour is the proliferation index marker
Ki67 (high risk of recurrence in patients with Ki67 >10%), but one
regularly observes patients with Ki67 of 1%, indicative of benign
disease, who later present with recurrence/metastasis. The majority
of recurrences occur within 2–3 years of the removal of the primary
tumour.
• Post-operative adjuvant treatment with the adrenolytic agent mitotane
(ortho-para DDD) has been shown to prolong survival in high-risk
patients. It should be given for 2 years. Mitotane treatment should
be monitored by experienced physicians; it is invariably associated
with the development of glucocorticoid deficiency, requiring
permanent glucocorticoid replacement. Due to the induction of the
major drug-metabolizing enzyme CYP3A4 by mitotane, a significant
amount of hydrocortisone is immediately inactivated. Thus, patients
TREATMENT OF ADRENAL CUSHING’S SYNDROME 253
Table 3.4 European Network for the Study of Adrenal Tumours

(ENSAT) staging classification for adrenocortical carcinoma
ENSAT stage TNM stage TNM definitions
I T1, N0, M0 T1, tumour ≤5cm
N0, no positive lymph node
M0, no distant metastases
II T2, N0, M0 T2, tumour >5cm
N0, no positive lymph node
M0, no distant metastases
III T1–T2, N1, M0 N1, positive lymph node(s)
T3–T4, N0–N1, M0 M0, no distant metastases
T3, tumour infiltration into
surrounding tissue
T4, tumour invasion into adjacent
organs or venous tumour thrombus in
vena cava or renal vein
IV T1–T4, N0–N1, M1 M1, presence of distant metastases
on mitotane treatment require glucocorticoid replacement with an

increased dose, e.g. hydrocortisone 20–20–10mg. There are other
important drug interactions with mitotane caused by induction of
CYP3A4 (e.g. statins, benzodiazepines, opioid analgesias, oestrogen,
and macrolide antibiotics). Monitoring of drug levels is mandatory
to ensure that concentrations within the therapeutic range (14–20
micrograms/mL) are achieved in a timely fashion. Plasma mitotane
level monitoring also limits unwanted side effects, including neurotoxic
effects (‘trouble talking, trouble walking’) that usually occur when
plasma levels increase above 20–25 micrograms/mL but resolve within
days to weeks after transiently stopping mitotane treatment. Other
possible side effects include diarrhoea, fatigue, allergic skin rashes, and
moderate elevation of liver transaminases.
• Other drugs may be required to control cortisol hypersecretion (e.g.
metyrapone, ketoconazole, in extreme cases non-anaesthetic doses of
etomidate).
• Mitotane also represents the first-line treatment in metastatic
adrenal cancer. In patients with metastatic disease occurring on
mitotane treatment or in patients with rapidly progressive disease,
cytotoxic chemotherapy should be initiated. First choice is the
so-called Berruti regimen (cisplatin, etoposide, doxorubicin, and
continued mitotane treatment). Newer treatments options, such
as PI3 kinase inhibitors and IGF receptor antagonists, are currently
under investigation.
Bilateral adrenal hyperplasia

• Bilateral adrenalectomy is curative. Lifelong glucocorticoid and
mineralocorticoid treatment is required. In some cases of bilateral
macronodular adrenal hyperplasia, there is a dominant, larger
adrenal nodule on one side, and it has been described that unilateral
adrenalectomy can lead to resolution of Cushing’s for a number
of years, but ultimately removal of the remaining adrenal may be
necessary if Cushing’s reoccurs due to further nodules developing.
• Medical treatment may be possible for some of the rare cases with
aberrant receptors, e.g. octreotide for GIP-dependent disease.
Prognosis
• Adrenal adenomas, which are successfully treated with surgery, have
a good prognosis, and recurrence is unlikely. The prognosis depends
on the long-term effects of excess cortisol before treatment—in
particular, atherosclerosis and osteoporosis.
• The prognosis for adrenal carcinoma is very poor despite surgery.
Reports suggest a 5-year survival of 22% and median survival time
of 14 months, but recent data have shown that survival significantly
improves when patients are managed in a specialist centre and receive
mitotane treatment.
Subclinical Cushing’s syndrome
• Describes a subset of 5–10% of patients with an adrenal incidentaloma
with signs of autonomous glucocorticoid production, which, however,
is insufficient to produce clinically overt Cushing’s syndrome.
• Urinary free cortisol measurement may be within the normal
range, but there is a failure to sufficiently suppress with low-dose
dexamethasone, and ACTH may be low or suppressed.
• An associated i risk of diabetes mellitus, osteoporosis, and
hypertension has been reported.
• Current data are insufficient to indicate the superiority of a surgical or
non-surgical approach to management.
• Hypoadrenalism post-adrenalectomy has been reported due to
suppression of the contralateral adrenal gland. Perioperative steroid
cover is, therefore, required with re-evaluation post-operatively.
Further reading
Allolio B, Fassnacht M (2006). Clinical review: Adrenocortical carcinoma: clinical update. J Clin
Fassnacht M, et al. (2012). Combination chemotherapy in advanced adrenocortical carcinoma.
N Engl J Med 366, 2189–97.
Kroiss M (2011). Drug interactions with mitotane by induction of CYP3A4 metabolism in the
clinical management of adrenocortical carcinoma. Clin Endocrinol (Oxf) 75, 585–91.
Lacroix A, N’Diaye N, Tremblay J, et al. (2001). Ectopic and abnormal hormone receptors in
adrenal Cushing’s syndrome. Endocr Rev 22, 75–110.
Terzolo M, Angeli A, Fassnacht M, et al. (2007). Adjuvant mitotane treatment for adrenocortical
carcinoma. N Engl J Med 356, 2372–80.
TREATMENT OF ADRENAL CUSHING’S SYNDROME 255
Adrenal surgery
Adrenalectomy
Open adrenalectomy may still be necessary for large and complex pathol-
ogy. However, laparoscopic adrenalectomy (first performed in 1992) has
become the procedure of choice for removal of most adrenal tumours.
Retrospective comparisons with open approaches suggest reduced hospi-
tal stay and analgesic requirements and lower post-operative morbidity.
This may be improved even further by the recently introduced retroperi-
toneoscopic approach. However, there are few long-term outcome data
on this technique. It is most useful in the management of small (<6cm)
benign adenomas. Laparoscopic bilateral adrenalectomy, although techni-
cally demanding, offers a useful approach to patients with macronodular
hyperplasia and in selected patients with ACTH-dependent Cushing’s syn-
drome where alternative therapeutic options are not appropriate.
Preoperative preparation of patients
• Cushing’s—metyrapone or ketoconazole (b see p. 170).
• Phaeochromocytoma—α- and B-blockade (b see p. 294).
See Box 3.2.
ADRENAL SURGERY 257
Box 3.2 Perioperative management of patients

undergoing adrenalectomy
Adrenal cortical tumours (benign and malignant)/bilateral adrenalec-
tomy for Cushing’s syndrome.
• Perioperative glucocorticoid cover is required in all patients who
fail to adequately suppress serum cortisol in the 1mg overnight
dexamethasone suppression test. If in doubt, replace, as even ‘silent’
adenomas may be associated with subclinical excess cortisol and
hence suppression of the contralateral adrenal gland.
• Hydrocortisone is given as for pituitary surgery—100mg IM with the
premedication and then continued every 6h for 24–48h, until the
patient can take oral medication and is eating and drinking.
• This is changed to oral hydrocortisone at double replacement
dose—20mg on waking, 10mg at lunchtime, and 10mg at 5 p.m.,
and mineralocorticoid replacement commenced if bilateral
adrenalectomy has been performed (100 micrograms fludrocortisone
daily). Electrolytes and BP guide adequacy of treatment. Normal
replacement hydrocortisone (e.g. 10, 5, 5mg) can be commenced
when the patient is recovered and may be omitted altogether if the
patient did not have preoperative evidence of Cushing’s syndrome/
suppression of the contralateral gland/bilateral adrenalectomy.
Mineralocorticoid replacement is only required in patients who have
had bilateral adrenalectomy.
• A short Synacthen® test (off hydrocortisone for at least 24h)
is performed after at least 2 weeks to demonstrate adequate
function of the contralateral adrenal. However, in patients with
ACTH-independent Cushing’s syndrome, it may take up to 2 years
for full recovery of the contralateral adrenal gland and thus the first
assessment by SST should be done only after 4–6 months.
• The exception is patients undergoing adrenalectomy for
mineralocorticoid-secreting tumours. These patients do not usually
require perioperative glucocorticoid replacement, but preoperative
amiloride or spironolactone allows recovery of potassium stores and
control of hypertension prior to surgery.
Further reading
Dudley NE, Harrison BJ (1999). Comparison of open posterior versus transperitoneal laparoscopic
adrenalectomy. Br J Surg 86, 656–60.
McCallum R, Connell JMC (2001). Laparoscopic adrenalectomy. Clin Endocrinol 55, 435–6.
Wells SA, Merke DP, Cutler GB, et al. (1998). The role of laparoscopic surgery in adrenal disease.
Renal tubular abnormalities

Background
Bartter’s syndrome and Gitelman’s syndrome are both associated with
hypokalaemic alkalosis and the activation of the renin–angiotensin system
but without hypertension—in contrast, BP tends to be low in these con-
ditions. Liddle’s syndrome is associated with hypokalaemic alkalosis and
hypertension but low renin and aldosterone levels.
Liddle’s syndrome
A rare autosomal dominant (AD) condition with variable penetrance that
is caused by mutations in the gene encoding for the epithelial sodium
channel (ENaC), usually by mutations in the gene encoding the B or G sub-
unit of ENaC, which is highly selective and located in the distal nephron.
This leads to constitutive activation of sodium transport, independent of
circulating mineralocorticoids; consequently, s activation of the sodium/
potassium exchange occurs.
Features
Hypokalaemia and hypertension.
Investigation
• Suppressed renin and aldosterone levels.
• See Table 3.5.
Treatment
Hypertension responds to amiloride (doses up to 40mg/day) but not
spironolactone because amiloride acts on the sodium channel directly
whereas spironolactone acts on the mineralocorticoid receptor.
BARTTER’S SYNDROME 259
Bartter’s syndrome
Cause
Loss of function of the bumetanide-sensitive Na–K–2Cl co-transporter
in the thick ascending limb of the loop of Henle. Mutations in three
genes have been reported to account for the phenotype—these encode
regulatory ion channels (NKCC2; ROMK; CLCNKB). Inactivation of the
co-transporter leads to salt wasting, activation of the renin–angiotensin
system, and i aldosterone which leads to i sodium reabsorption at the
distal nephron and causes hypokalaemic alkalosis. Reabsorption of calcium
also occurs in the thick ascending loop, and thus inactivation leads to
hypercalciuria. The lack of associated hypertension is thought to be due to
i prostaglandin production from the renal medullary interstitial tissue in
response to hypokalaemia.
• Rare (~1/million) autosomal recessive hypokalaemic metabolic
alkalosis associated with salt wasting and normal or reduced BP.
• Usually present at an early age (<5 years).
Features
• Intravascular volume depletion.
• Seizures.
• Tetany.
• Muscle weakness.
There is also an antenatal variant which is a life-threatening disorder of
renal tubular hypokalaemic alkalosis and hypercalciuria.
Investigations
• i PRA and aldosterone.
• Hypercalciuria.
Treatment
Potassium replacement. Potassium-sparing diuretics may be helpful. However,
they are usually inadequate in correcting hypokalaemia. Prostaglandin syn-
thase inhibitors (NSAIDs), e.g. indometacin 2–5mg/kg per day or ibuprofen,
may be required.
Gitelman’s syndrome
Cause
• Loss of function in the thiazide-sensitive Na–Cl transporter of the
distal convoluted tubule (DCT) due to mutations in the SCL12A3 gene
that encodes it (located on chromosome 16q13). This leads to salt
wasting, hypovolaemia, and metabolic alkalosis.
• Hypovolaemia leads to activation of the renin–angiotensin system and
i aldosterone levels.
• Hypokalaemic alkalosis, in conjunction with hypocalciuria and
hypomagnesaemia.
• Present at older ages without overt hypovolaemia (essentially, a less
severe phenotype of Bartter’s syndrome).
Investigations
• Hypokalaemic alkalosis, in association with i renin and aldosterone.
• Hypomagnesaemia.
• Hypocalciuria.
Treatment
• Potassium and magnesium replacement.
• Potassium-sparing diuretics may be required.
• See Table 3.5.
Table 3.5 Summary of features of renal tubular abnormalities

Syndrome* BP Renin Aldosterone Urinary calcium Other
Bartter’s N i i i
Gitelman’s N i i d d Mg
Liddle’s i d d N
* All three conditions have hypokalaemic alkalosis. N = normal.
Further reading
Amirlak I, Dawson KP (2000). Bartter’s syndrome. QJM 93, 207–15.
Furuhashi M, Kitamura K, Adachi M, et al. (2005). Liddle’s syndrome caused by a novel mutation
in the proline-rich PY motif of the epithelial sodium channel B-subunit. J Clin Endocrinol Metab
90, 340–4.
Graziani G, Fedeli C, Moroni L et al. (2010) Gitelman syndrome: pathophysiological and clinical
aspects. QJM 103, 741–8.
Nakamura A, Shimizu C, Yoshida M et al. (2010) Problems in diagnosing atypical Gitelman’s syn-
drome presenting with normomagnesaemia. Clin Endocrinol 72, 272–6.
GITELMAN’S SYNDROME 261
Mineralocorticoid deficiency
Epidemiology
Rare, apart from the hyporeninaemic hypoaldosteronism associated with
diabetes mellitus.
Causes
Congenital
• Primary adrenal insufficiency due to:
• CAH—certain types, most commonly 21-hydroxylase deficiency, are
associated with MC deficiency; b see p. 320.
• Congenital lipoid adrenal hyperplasia (CLAH) caused by mutations in
the genes encoding steroidogenic acute regulatory protein (StAR),
responsible for rapid import of cholesterol into the mitochondrion,
and the side chain cleavage protein (CYP11A1), responsible for
the conversion of cholesterol to pregnenolone, i.e. the first step of
steroidogenesis.
• Adrenal hypoplasia congenita (AHC) caused by mutations in the
genes encoding the transcription factors SF-1 (NR5A1) and DAX-1
(NR0B1) that play a crucial role in adrenal development.
• Adrenoleukodystrophy affecting 1/20,000 ♂; very long chain fatty
acids (VLCFA) cannot be oxidized in peroxisomes and accumulate
in tissues and the circulation. CNS symptoms may be absent
initially, in particular, in the milder form adrenomyeloneuropathy,
but progressive demyelination can lead to hypertonic tetraparesis,
dementia, epilepsy, coma, or death (in particular, in the early
childhood onset variant adrenoleukodystrophy).
• Rare inherited disorders of aldosterone biosynthesis.
• Pseudohypoaldosteronism—inherited resistance to the action of
aldosterone (b see p. 665). Autosomal dominant and recessive
forms are described. Usually presents in infancy. Treated with sodium
chloride.
Acquired
• All forms of non-congenital primary adrenal insufficiency—b see
p. 266. In secondary adrenal insufficiency, the adrenals are anatomically
intact, and thus regulation of mineralocorticoid secretion by the renin–
angiotensin–aldosterone (RAA) system is intact.
• Drugs—heparin (heparin for >5 days may cause severe hyperkalaemia
due to a toxic effect on the zona glomerulosa); ciclosporin.
• Hyporeninaemic hypoaldosteronism—interference with the renin–
angiotensin system leads to mineralocorticoid deficiency and
hyperkalaemic acidosis (type IV renal tubular acidosis), e.g. diabetic
nephropathy. Treatment is fludrocortisone and potassium restriction.
ACEI may produce a similar biochemical picture, but here the PRA will
be elevated, as there is no angiotensin II feedback on renin.
Treatment
Fludrocortisone.
MINERALOCORTICOID DEFICIENCY 263
Adrenal insufficiency
Definition
Adrenal insufficiency is defined by the lack of cortisol, i.e. glucocor-
ticoid deficiency, and may be due to destruction of the adrenal cortex
(p, Addison’s disease and congenital adrenal hyperplasia (CAH); b see
p. 266) or due to disordered pituitary and hypothalamic function (s).
Epidemiology
• Permanent adrenal insufficiency is found in 5 in 10,000 population.
• The most frequent cause is hypothalamic–pituitary damage, which is
the cause of AI in 60% of affected patients.
• The remaining 40% of cases are due to primary failure of the adrenal
to synthesize cortisol, with almost equal prevalence of Addison’s
disease (mostly of autoimmune origin, prevalence 0.9–1.4 in 10,000)
and congenital adrenal hyperplasia (0.7–1.0 in 10,000).
• s adrenal insufficiency due to suppression of pituitary–hypothalamic
function by exogenously administered, supraphysiological
glucocorticoid doses for treatment of, for example, COPD or
rheumatoid arthritis, is much more common (50–200 in 10,000
population). However, adrenal function in these patients can recover,
following tapering and cessation of exogenous glucocorticoid
administration.
Causes of secondary adrenal insufficiency
Lesions of the hypothalamus and/or pituitary gland
• Tumours—pituitary tumour, metastases, craniopharyngioma.
• Infection—tuberculosis.
• Inflammation—sarcoidosis, histiocytosis X, haemochromatosis,
lymphocytic hypophysitis.
• Iatrogenic—surgery, radiotherapy.
• Other—isolated ACTH deficiency, trauma.
Suppression of the hypothalamo–pituitary–adrenal axis
• Glucocorticoid administration.
• Cushing’s disease (after pituitary tumour removal).
Features of secondary adrenal insufficiency
As p (b see Clinical features, p. 123), except:
• Absence of pigmentation—skin is pale.
• Absence of mineralocorticoid deficiency.
• Associated features of underlying cause, e.g. visual field defects if
pituitary tumour.
• Other endocrine deficiencies may manifest due to pituitary failure
(b see p. 122).
• Acute onset may occur due to pituitary apoplexy.
ADRENAL INSUFFICIENCY 265
Isolated ACTH deficiency

• Rare.
• Pathogenesis unclear—may be autoimmune (associated with other
autoimmune conditions and antipituitary antibodies described in some
patients); can be associated with autoimmune hypothyroidism.
• Absent ACTH response to CRH.
• POMC mutations and POMC processing abnormalities (e.g.
proconvertase PC1).
Pathophysiology
Primary
• Adrenal gland destruction or dysfunction occurs due to a disease
process which usually involves all three zones of the adrenal cortex,
resulting in inadequate glucocorticoid, mineralocorticoid, and adrenal
androgen precursor secretion. The manifestations of insufficiency do
not usually appear until at least 90% of the gland has been destroyed
and are usually gradual in onset, with partial adrenal insufficiency
leading to an impaired cortisol response to stress and the features
of complete insufficiency occurring later. Acute adrenal insufficiency
may occur in the context of acute septicaemia (e.g. meningococcal or
haemorrhage).
• Mineralocorticoid deficiency leads to reduced sodium retention and
hyponatraemia and hypotension with d intravascular volume, in addition
to hyperkalaemia due to d renal potassium and hydrogen ion excretion.
• Androgen deficiency presents in ♀ with reduced axillary and pubic
hair and reduced libido. (Testicular production of androgens is more
important in ♂.)
• Lack of cortisol –ve feedback increases CRH and ACTH secretion.
Stimulation of skin melanocortin 1 receptors (MC1R) leads to skin
pigmentation and other mucous membranes.
Secondary
• Inadequate ACTH results in deficient cortisol production (and d
androgens in ♀).
• There is no pigmentation because ACTH and POMC secretion is
reduced. Mineralocorticoid secretion remains normal, as its primary
regulator is the RAA system in kidney and adrenal gland which are
intact. However, hyponatraemia may be present due to mild SIADH
arising from the cortisol deficiency.
• The onset is usually gradual, with partial ACTH deficiency resulting in
reduced response to stress. Prolonged ACTH deficiency leads to atrophy
of the zona fasciculata and reduced ability to respond acutely to ACTH.
• Lack of stimulation of skin MC1R due to ACTH deficiency results in
pale skin appearance.
Investigations
b see p. 125 for pituitary/hypothalamic disease and p. 268 for long-term
endogenous or exogenous glucocorticoids.
Addison’s disease
Causes of primary adrenal insufficiency
• Autoimmune—commonest cause in the developed world
(approximately 70% cases).
• Autoimmune polyglandular deficiency—type 1 or 2 (b see p. 270).
• Malignancy:
• Metastatic (lung, breast, kidney—adrenal metastases found in
~50% of patients, but symptomatic adrenal insufficiency much less
common and only observed with bilateral metastases).
• Lymphoma (primary adrenal lymphoma, AI only if bilateral).
• Infiltration:
• Amyloid.
• Sarcoidosis.
• Haemochromatosis.
• Infection:
• Tuberculosis (medulla more frequently destroyed than cortex).
• Fungal, e.g. histoplasmosis, cryptococcosis.
• Opportunistic infections in, for example AIDS—CMV,
Mycobacterium intracellulare, cryptococcus (up to 5% patients with
AIDS develop p adrenal insufficiency in the late stages).
• Vascular haemorrhage:
• Anticoagulants.
• Waterhouse–Friderichsen syndrome in meningococcal septicaemia.
• Infarction—e.g. s to thrombosis in antiphospholipid syndrome.
• Adrenoleukodystrophy:
• Inherited disorder caused by mutations in the X-linked ALD gene
that encodes for the peroxisomal transporter protein ABCD1.
• Diagnosed by measuring very long chain fatty acids.
• Presents in childhood and adolescence.
• Progresses in 50% to quadriparesis and dementia, in
association with adrenal failure (= cerebral ALS); milder variant
adrenomyeloneuropathy (AMN) causes spinal neurology only, and
AI may precede manifestation of neurological symptoms; in 10–20%,
AI is the sole manifestation of disease.
• Congenital adrenal hyperplasia—b see p. 320.
• Adrenal hypoplasia congenita—very rare familial failure of adrenal
cortical development due to mutations/deletion of the NR0B1
(DAX-1) or the NR5A1 (SF-1) genes.
• Congenital lipoid adrenal hyperplasia—very rare familial failure of
adrenal steroidogenesis due to mutations in the genes encoding
the steroidogenic acute regulatory protein (StAR; responsible for
mitochondrial import of cholesterol) or the side chain cleavage
enzyme CYP11A1 (responsible for conversion of cholesterol to
pregnenolone, i.e. the first step of steroidogenesis).
ADDISON’S DISEASE 267
• Familial glucocorticoid deficiency (FGD) due to mutations in genes

encoding for proteins involved in the regulation of ACTH action, e.g.
the ACTH receptor MC2R or the MC2R accessory protein MRAP
that transfers MC2R to the adrenal cell membrane to facilitate ACTH
binding.
• Triple A syndrome (Achalasia, Addisonianism, Alacrimia) (Allgrove
syndrome):
• Addison’s due to ACTH resistance.
• Autosomal recessive.
• May get autonomic dysfunction, hypoglycaemia, and mental
retardation.
• Caused by mutations on the AAAS gene (12g13).
• Iatrogenic:
• Bilateral adrenalectomy.
• Drugs: ketoconazole, fluconazole, trilostane, abiraterone,
etomidate, aminoglutethimide (inhibits cortisol synthesis),
phenytoin, rifampicin (increases cortisol metabolism), mitotane
(adrenolytic and increases cortisol metabolism).
Autoimmune adrenalitis
• Mediated by humoral and cell-mediated immune mechanisms.
Autoimmune insufficiency associated with polyglandular autoimmune
syndrome is more common in ♀ (70%).
• Adrenal cortex antibodies are present in the majority of patients at
diagnosis, and although titres decline and eventually disappear, they are
still found in approximately 70% of patients 10 years later. Up to 20%
patients/year with +ve adrenal antibodies develop adrenal insufficiency.
Antibodies to 21-hydroxylase are commonly found, although the exact
nature of other antibodies that block the effect of ACTH, for example,
is yet to be elucidated.
• Antiadrenal antibodies are found in <2% of patients with other
autoimmune endocrine disease (Hashimoto’s thyroiditis, diabetes
mellitus, autoimmune hypothyroidism, hypoparathyroidism, pernicious
anaemia). In addition, antibodies to other endocrine glands are
commonly found in patients with autoimmune adrenal insufficiency
(thyroid microsomal in 50%, gastric parietal cell, parathyroid, and ovary
and testis). However, the presence of antibodies does not predict
subsequent manifestation of organ-specific autoimmunity.
• Polyglandular autoimmune conditions (b see Autoimmune
polyglandular syndrome (APS) type 1, p. 270; APS type 2, p. 271).
The presence of 17-hydroxylase antibodies, in association with
21-hydroxylase antibodies, is a good marker of patients at risk of
developing premature ovarian failure in association with p adrenal
failure.
• Patients with type 1 diabetes mellitus and autoimmune thyroid disease
only rarely develop autoimmune adrenal insufficiency. Approximately
60% of patients with Addison’s disease have other autoimmune or
endocrine disorders.
Clinical features
Chronic
• Anorexia and weight loss (>90%).
• Tiredness.
• Weakness—generalized, no particular muscle groups.
• Pigmentation—generalized but most common in skin areas exposed
to friction or pressure (elbows and knees, and under bras and belts),
mucosae, and scars acquired after onset of adrenal insufficiency. Look
at palmar creases in Caucasians.
• Dizziness and postural hypotension.
• GI symptoms—nausea and vomiting, abdominal pain, diarrhoea.
• Arthralgia and myalgia.
• Symptomatic hypoglycaemia—rare in adults.
• d axillary and pubic hair and reduced libido in ♀.
• Pyrexia of unknown origin—rarely.
Associated conditions
• Vitiligo.
• Features of other autoimmune endocrinopathies.
AUTOIMMUNE ADRENALITIS 269
Laboratory investigations
• Hyponatraemia.
• Hyperkalaemia.
• Elevated urea.
• Anaemia (normocytic normochromic).
• Elevated ESR.
• Eosinophilia.
• Mild hypercalcaemia—d absorption, d renal absorption of calcium.
Autoimmune polyglandular
syndrome (APS) type 1
• Also known as autoimmune polyendocrinopathy, candidiasis, and
ectodermal dystrophy (APECED).
• Autosomal recessive with childhood onset.
• Chronic mucocutaneous candidiasis.
• Hypoparathyroidism (90%), p adrenal insufficiency (60%).
• p gonadal failure (41%)—usually after Addison’s diagnosis.
• p hypothyroidism.
• Rarely hypopituitarism, diabetes insipidus, type 1 diabetes mellitus.
• Associated chronic active hepatitis (20%), malabsorption (15%),
alopecia (40%), pernicious anaemia, vitiligo.
• Mutations in the AIRE (autoimmune regulator) gene located on
chromosome 21p22.3.
APS TYPE 2 271
APS type 2
• Polygenic inheritance, association with HLADR3 and CTL4 regions,
mixed penetrance.
• Adult onset.
• Adrenal insufficiency (100%).
• p autoimmune thyroid disease (70%), mostly hypothyroidism but also
hyperthyroidism.
• Type 1 diabetes mellitus (5–20%)—often before Addison’s diagnosis.
• p gonadal failure in affected women (5–20%).
• Rarely diabetes insipidus (<0.1%).
• Associated vitiligo, myasthenia gravis, alopecia, pernicious anaemia,
immune thrombocytopenic purpura.
Eponymous syndromes
• Schmidt’s syndrome:
• Addison’s disease, and
• Autoimmune hypothyroidism.
• Carpenter syndrome:
• Addison’s disease, and
• Autoimmune hypothyroidism, and/or
Investigation of primary adrenal

insufficiency
Electrolytes
• Hyponatraemia is present in 90% and hyperkalaemia in 65%.
• Elevated urea.
Serum cortisol and ACTH
• Undetectable serum cortisol is diagnostic of adrenal insufficiency, but
the basal cortisol is often in the normal range. A cortisol >550nmol/L
precludes the diagnosis. At times of acute stress, an inappropriately
low cortisol is very suggestive of the diagnosis.
• Simultaneous 9 a.m. cortisol and ACTH will show an elevated ACTH
for the level of cortisol. This is a very sensitive means of detecting
Addison’s disease but performs poorly in less clear-cut cases.
• NB Drugs causing i cortisol-binding globulin (e.g. oestrogens) will
result in higher total cortisol concentration measurements.
Response to ACTH
Short Synacthen® test
• Following basal cortisol measurement, 250 micrograms Synacthen® is
administered IM and serum cortisol checked at 30 or 60min.
• Serum cortisol should rise to a peak of 550nmol/L (note that this
cut-off may depend on local assay conditions).
• Failure to respond appropriately suggests adrenal failure.
• A long Synacthen® test may be required to confirm 2° adrenal
failure if ACTH is equivocal.
• Recent onset of s adrenal failure (up to 4 weeks) may produce a
normal response to a short Synacthen® test.
Long Synacthen® test
• Following basal cortisol level, depot Synacthen® 1mg IM is
administered, and serum cortisol measured at 30, 60, 120min, and 4,
8, 12, and 24h. A normal response is an elevation in serum cortisol to
>1,000nmol/L.
• Differentiation of 2° from 1° adrenal failure can be made more reliably
following 3 days IM ACTH 1mg. This is because the test relies on
the ability of the atrophic adrenal glands to respond to ACTH in 2°
adrenocortical failure whereas, in 1° adrenal failure, the diseased gland
is already maximally stimulated by elevated endogenous levels of
ACTH and, therefore, unable to respond to further stimulation.
• Serum cortisol responses within the first 60min are superimposable
with the short Synacthen® test.
• There is a progressive rise in cortisol secretion in 2° adrenal
insufficiency but little or no response on 1° adrenal insufficiency.
Increased plasma renin activity (assessment
of mineralocorticoid sufficiency)
This is one of the earliest abnormalities in developing p adrenal insufficiency.
INVESTIGATION OF PRIMARY ADRENAL INSUFFICIENCY 273
Thyroid function tests

Reduced thyroid hormone levels and elevated TSH may be due to a direct
effect of glucocorticoid deficiency (cortisol inhibits TRH) or due to associ-
ated autoimmune hypothyroidism; TSH is usually less than 10U/L in the
former and above 10 in the latter. Re-evaluation is, therefore, required
after adrenal insufficiency has been appropriately replaced for a few
weeks. Initiation of thyroxine replacement prior to glucocorticoid replace-
ment can trigger adrenal crisis, as thyroxine will speed up the inactivation
of residual cortisol.
Establish cause of adrenal insufficiency
• Adrenal autoantibodies (detect antibodies to adrenal cortex and, more
recently, specific antibodies to 21-hydroxylase, side chain cleavage
enzyme, and 17-hydroxylase). 21-hydroxylase antibodies are the
major component of adrenal cortex antibodies and are present in 80%
of recent-onset autoimmune adrenalitis. Adrenal cortex antibodies
(present in 80% patients of recent-onset autoimmune adrenalitis) are
not detectable in non-autoimmune p adrenal failure.
• Imaging:
• Adrenal enlargement, with or without calcification, may be seen
on CT of the abdomen, suggesting tuberculosis, infiltration, or
metastatic disease. The adrenals are small and atrophic in chronic
autoimmune adrenalitis.
• Percutaneous CT-guided adrenal biopsy is occasionally required.
• Specific tests—e.g. serological or microbiological investigations
directed at particular infections, very long chain fatty acids
(adrenoleukodystrophy) in ♂ and ♀ with antibody –ve isolated p
adrenal insufficiency.
Acute adrenal insufficiency (risk higher in primary
disease)
Clinical features
• Shock.
• Hypotension (often not responding to measures, such as inotropic
support).
• Abdominal pain (may present as ‘acute abdomen’).
• Unexplained fever.
• Often precipitated by major stress, such as severe bacterial infection,
major surgery, unabsorbed glucocorticoid medication due to vomiting.
• Occasionally occurs due to bilateral adrenal infarction.
Investigations
• As chronic.
• In the acute situation if the diagnosis is suspected, an inappropriately
low cortisol (i.e. <600nmol/L) is often sufficient to make the diagnosis.
See Box 3.3 for emergency management.
Box 3.3 Emergency management of acute adrenal

insufficiency
• This is a life-threatening emergency and should be treated if there
is strong clinical suspicion rather than waiting for confirmatory test
results.
• Blood should be taken for urgent analysis of electrolytes and glucose,
in addition to cortisol and ACTH.
Fluids
Large volumes of 0.9% saline may be required to reverse the volume
depletion and sodium deficiency. Several litres may be required in the
first 24–48h, but caution should be exercised where there has been
chronic hyponatraemia; in this circumstance, rapid correction of the def-
icit exposes the patient to risk of central pontine myelinolysis. If plasma
sodium is <120mmol/L at presentation, aim to correct by no more than
10mmol/L in the first 24h.
Hydrocortisone
• A bolus dose of 100mg hydrocortisone is administered intravenously.
Hydrocortisone 100mg IM is then continued 6-hourly for 24–48h or
until the patient can take oral therapy. Double replacement dose
hydrocortisone (20, 10, and 10mg orally) can then be instituted
until well.
• This traditional regimen causes supraphysiological replacement, and
some authors suggest lower doses, e.g. 150mg IV/24h.
• Specific mineralocorticoid replacement is not required, as
the high-dose glucocorticoid has sufficient mineralocorticoid
effects (40mg hydrocortisone equivalent to 100 micrograms
fludrocortisone). Once the daily dose of glucocorticoid is reduced to
less than 50mg after a couple of days and the patient is taking food
and fluids by mouth, fludrocortisone 100 micrograms/day can be
commenced.
Glucose supplementation
Occasionally required because of risk of hypoglycaemia (low glycogen
stores in the liver as a result of glucocorticoid deficiency).
Investigate and treat precipitant
This is often infection.
Monitoring treatment
Electrolytes, glucose, and urea.
INVESTIGATION OF PRIMARY ADRENAL INSUFFICIENCY 275
Treatment of primary adrenal

insufficiency
Maintenance therapy
Glucocorticoid replacement
• Hydrocortisone is the treatment of choice for replacement therapy,
as it is reliably and predictably absorbed and allows biochemical
monitoring of levels.
• It is administered twice to thrice daily, e.g. 10mg immediately on
waking, 5mg at midday, and 5mg at 4–5 p.m, or 15mg on waking and
5mg at midday.
• Longer-acting glucocorticoid preparations can be advantageous
in patients with co-incident type 1 diabetes mellitus, e.g. 3mg
prednisolone on waking and 1mg at 5pm.
Mineralocorticoid replacement
• Fludrocortisone (9-fluorohydrocortisone) is given at a dose of 100–150
micrograms daily; occasionally, lower (50 micrograms) or higher
(200–250 micrograms) doses may be required. Aim to avoid significant
postural fall in BP (>10mmHg).
• Plasma renin should be within the upper third of the normal
reference range.
• 40mg hydrocortisone has the equivalent mineralocorticoid effect of
100 micrograms fludrocortisone.
DHEA replacement
• Dehydroepiandrosterone (DHEA) synthesis is also deficient in
hypoadrenalism, resulting in reduced production of adrenal androgen
precursors and thus invariably androgen deficiency in affected women.
• DHEA replacement (25–50mg/day) may improve mood and well-being
as well as libido in women with AI.
• DHEA is not available as a UK-licensed preparation but is available
from the USA as a dietary supplement.
Monitoring of therapy
Clinical
• For signs of glucocorticoid excess, e.g i weight.
• BP (including postural change).
• Hypertension and oedema suggest excessive mineralocorticoid
replacement whereas postural hypotension and salt craving suggest
insufficient treatment.
Biochemical
• Serum electrolytes.
• Plasma renin (elevated if insufficient fludrocortisone replacement).
• Cortisol day curve to assess adequacy.
TREATMENT OF PRIMARY ADRENAL INSUFFICIENCY 277
Intercurrent illness
• Cortisol requirements increase during severe illness or surgery.
• For moderate elective procedures or investigations, e.g. endoscopy
or angiography, patients should receive a single dose of 100mg
hydrocortisone before the procedure.
• For major surgery, patients should receive 100mg intravenously or
intramuscularly with the premedication and receive:
• 50–100mg IM hydrocortisone 6-hourly for the first 3 days, or
• 100–150mg per 24h IV in 5% glucose before reverting rapidly to a
maintenance dose.
• To cover severe illness, e.g. pneumonia, patients should receive
50–100mg IM hydrocortisone 6-hourly until resolution of the illness.
• See Box 3.4 for pregnancy.
Drug interactions
• Rifampicin:
• Increases the clearance of cortisol.
• Double usual dose of hydrocortisone.
• Mitotane:
• Increases cortisol-binding globulin and induces CYP3A4, resulting in
rapid inactivation of hydrocortisone.
• Double usual dose of hydrocortisone, e.g. 20–10–10mg.
• Topiramate—also induces CYP3A4 and accelerates clearance of
glucocorticoids.
Box 3.4 Pregnancy

b also see Normal changes during pregnancy, p. 436.
• During normal pregnancy:
• Cortisol-binding globulin gradually increases.
• Free cortisol increases in the third trimester.
• Progesterone increases, exerting an antimineralocorticoid effect.
• Renin levels increase.
• In Addison’s disease, therefore:
• The usual glucocorticoid and mineralocorticoid replacement is
continued initially.
• Increase the hydrocortisone 25–50% in the third trimester.
• Adjust mineralocorticoids to BP and serum potassium (not renin).
• Severe hyperemesis gravidarum during the first trimester may
require temporary parenteral therapy, and patients should be
warned about this to avoid precipitation of a crisis.
• During labour and for 24–48h:
• Parenteral glucocorticoid therapy is administered (100mg IM
every 6h), or
• Hydrocortisone 100mg IV in 5% glucose per 24h.
• Fluid replacement with IV 0.9% saline may be required.
Education of the patient

• Patient education is the key to successful management. Patients must
be taught never to miss a dose. They should be encouraged to wear a
MedicAlert/SOS bracelet or necklace and always to carry a steroid card.
• Every patient should know how to double the dose of glucocorticoid
during febrile illness and to get medical attention if unable to take
the tablets because of vomiting. They should have a vial of 100mg
hydrocortisone, with syringe, diluent, and needle for times when
parenteral treatment may be required (see Box 3.5).
Box 3.5 Emergency pack contents for Addison’s patients

• 100mg vial hydrocortisone.
• Water for injection.
• 2mL syringe.
• 1 green needle.
• 1 blue needle.
• Cotton wool.
• Plaster.
NB Check expiry date of hydrocortisone.
Further reading
Arlt W (2009). The approach to the adult with newly diagnosed adrenal insufficiency. J Clin
Arlt W, Allolio B (2003). Adrenal insufficiency. Lancet 361, 1881–93.
Bornstein SR (2009). Predisposing factors for adrenal insufficiency. N Engl J Med 360, 2328–39.
Lebbe M, Arlt W (2013). What is the best diagnostic and therapeutic management strategy for an
Addison patient during pregnancy? Clin Endocrinol (Oxf) 78, 497–502.
Mitchell AL, Pearce SH (2012). Autoimmune Addison disease: pathophysiology and genetic
complexity. Nat Rev Endocrinol 8, 306–16.
Wass JAH, Arlt W (2012). How to avoid precipitating an acute adrenal crisis. BMJ 345, 6333.
TREATMENT OF PRIMARY ADRENAL INSUFFICIENCY 279
Long-term glucocorticoid
administration
Both exogenous glucocorticoid administration and endogenous excess
glucocorticoids (Cushing’s syndrome) lead to a –ve feedback effect on
the hypothalamo–pituitary axis (HPA), leading to suppression of both
CRH and ACTH secretion and atrophy of the zonae fasciculata and
reticularis of the adrenal cortex. Administration (or endogenous over-
production) of >50mg hydrocortisone equivalent per day will result in
downregulation of mineralocorticoid production. However, the renin–
angiotensin–aldosterone axis continues to function when the glucocorti-
coid excess ceases while the HPA axis will suffer from lasting suppression,
with the time of recovery dependent on the duration of the preceding
period of hypercortisolism. See Box 3.6 for steroid equivalents.
Short-term steroids
• Any patient who has received glucocorticoid treatment for <3 weeks
is unlikely to have clinically significant adrenal suppression, and if the
medical condition allows it, glucocorticoid treatment can be stopped
acutely. A major stress within a week of stopping steroids should,
however, be covered with glucocorticoids.
• Exceptions to this are patients who have other possible reasons for
adrenocortical insufficiency, who have received >40mg prednisolone
(or equivalent), where a short course has been prescribed within
1 year of cessation of long-term therapy, or evening doses (i HPA axis
suppression).
Steroid cover
While receiving glucocorticoid treatment and within 1 year of steroid
withdrawal, patients should receive standard steroid supplementation at
times of stress, e.g. major trauma, surgery, and infection (b see p. 277).
Long-term steroids
• When patients are receiving supraphysiological doses (>5mg
prednisolone or equivalent) of glucocorticoid, dose reduction depends
on the activity of the underlying disease requiring glucocorticoid
treatment.
• If the disease has resolved, the dose can be rapidly reduced to 5mg
prednisolone by a reduction of 2.5mg every 3–5 days.
• Once the patient is established on 5mg prednisolone, consider
changing to hydrocortisone (20mg in the morning), as this has a
shorter half-life and will, therefore, lead to less prolonged suppression
of ACTH.
• Daily hydrocortisone dose should be reduced by 2.5mg every
1–2 weeks, or as tolerated, until a dose of 10mg is reached.
After 2–3 months, a short Synacthen® test should be performed.
Once a short Synacthen® test demonstrates a normal response,
hydrocortisone replacement can be stopped. Supplemental steroids
during intercurrent illness are not required.
LONG-TERM GLUCOCORTICOID ADMINISTRATION 281
Patients with Cushing’s syndrome on metyrapone or with recently treated
disease, whatever the cause, may also have HPA axis suppression and may,
therefore, need steroid replacement at times of stress.
Box 3.6 Steroid equivalents

• 1mg hydrocortisone.
• 1.5mg cortisone acetate.
• 0.20mg prednisolone.
• 0.0375mg dexamethasone.
4mg prednisolone ≡ 20mg hydrocortisone ≡ 0.075mg dexamethasone.
Adrenal incidentalomas
Definition and epidemiology
• An adrenal incidentaloma is an adrenal mass that is discovered
incidentally upon imaging (e.g. CT chest or abdomen) carried out for
reasons other than a suspected adrenal pathology.
• The incidental detection of an adrenal mass is becoming more
common, as i numbers of imaging procedures are performed and with
technological improvements in imaging.
• Autopsy studies suggest incidence prevalence of adrenal masses of
1–6% in the general population.
• Imaging studies suggest that adrenal masses are present 2–3% in the
general population. Incidence increases with ageing, and 8–10% of
70-year olds harbour an adrenal mass.
Importance
It is important to determine whether the incidentally discovered adrenal
mass is:
• Malignant.
• Functioning and associated with excess hormonal secretion.
Differential diagnosis of an incidentally detected
adrenal nodule
• Cortisol-secreting adrenal adenoma causing Cushing’s syndrome or
subclinical Cushing’s syndrome (5%).
• Mineralocorticoid-secreting adrenal adenoma.
• CAH.
• Adrenocortical carcinoma (5–12%).
• Metastasis (2–10%; most prevalent breast, lung, kidney).
• Phaeochromocytoma (10–15%).
• Adrenal cysts (5%).
• Adrenal myelolipoma (5–10%).
• Haematoma.
• Ganglioneuroma (4%).
Investigations
• Clinical assessment for symptoms and signs of excess hormone
secretion and signs of extra-adrenal carcinoma.
• Urinary free cortisol and overnight dexamethasone suppression test.
• Plasma free metanephrines (most sensitive and specific screening test;
alternatively, urinary metanephrine—however, more cumbersome and
less specific) (b see p. 288).
• Aldosterone/renin ratio and serum potassium.
• A homogeneous mass with a low attenuation value prior to contrast
administration (<10HU) on CT scan is likely to be a benign adenoma
(low density = high fat content = benign) whereas a mass with high
density (>20HU) has to be considered suspicious (differential diagnosis
phaeochromocytoma/adrenocortical carcinoma/metastasis but also
lipid-poor adenoma).
ADRENAL INCIDENTALOMAS 283
• Additional tests if adrenal carcinoma suspected:

• 24h urinary excretion of corticosteroid metabolites.
• DHEAS, 17α OH progesterone, progesterone.
• 17α oestradiol (in ♂ only).
• Androstenedione, testosterone.
Management
• Up to 20% of patients may develop hormonal excess during follow-up.
• Unlikely if tumour <3cm.
• Cortisol is the commonest excess hormone.
• Surgery if there is/are:
• Evidence of a syndrome of hormonal excess attributable to the
tumour.
• Biochemical evidence of phaeochromocytoma.
• Mass diameter >4cm (i likelihood of malignancy according to
imaging or biochemistry (co-secretion of several corticosteroids
indicative of malignancy) and definitely if >6cm in diameter).
• Imaging features suggestive of malignancy (e.g. lack of clearly
circumscribed margin, vascular invasion).
• It should be noted that post-operative adrenal suppression
may occur if, preoperatively, there is biochemical evidence
of glucocorticoid excess and, therefore, glucorticoids may be
necessary post-operatively.
• Non-surgical management:
• Repeat biochemical screening annually.
• In patients with tumours that remain stable on two imaging
studies carried out at least 6 months apart or tumours that show
clear criteria suggesting a benign adrenal mass (pre-contrast CT
density <10HU) and do not exhibit hormonal hypersecretion
over 3 years, further follow-up may not be warranted. As most
adrenal incidentalomas are detected upon contrast CT, a follow-up
investigation without contrast to determine pre-contrast tumour
density is preferable; for larger nodules (>3cm), this might be
combined with CT washout studies (<40% 15min after contrast
indicative of malignancy).
Further reading
Mansmann G, Lau J, Balk E, et al. (2004). The clinically inapparent adrenal mass: update in diagnosis
and management. Endocr Rev 25, 309–40.
Turner HE, Moore NR, Byrne JV, et al. (1998). Pituitary, adrenal and thyroid incidentalomas. Endocr
Rel Cancer 5, 131–50.
Young WF Jr (2007). Clinical practice. The incidentally discovered adrenal mass. N Engl J Med
356, 601–10.
Phaeochromocytomas and
paragangliomas
Definition
• Phaeochromocytomas (aPCA) are chromaffin tumours arising from the
adrenal medulla and secreting catecholamines.
• Paragangliomas are tumours arising from extra-adrenal sympathetic or
parasympathetic nervous tissue.
• Sympathetic paraganglia occur as follows: in prevertebral, paravertebral,
thoracoabdominal, in the pelvis area and close to reproductive organs,
prostate, bladder, liver, and the organ of Zuckerkandl (at the bifurcation
of the aorta). Tumours arising from this sympathetic tissue are termed
extra-adrenal functional paraganglioma (eFPGL).
Parasympathetic paraganglia are located close to major arteries and
nerves, e.g. carotid body, glomus jugulare, vagal, tympanic, pulmonary,
and aorta. Tumours arising from the parasympathetic nervous system are
referred to as head and neck paraganglioma (HNPGL), and only a minority
of those shows endocrine activity (~25%).
Incidence
Rare tumours, accounting for <0.1% of causes of hypertension. However,
it is a very important diagnosis due to:
• The development of potentially fatal hypertensive crises.
• The reversibility of all its manifestations after surgical removal of the
tumour.
• The lack of long-term efficacy of medical treatment.
• The appreciable incidence of malignancy.
• The implications of the identification of an underlying genetic cause
(>25% of cases, e.g. RET mutations and co-incident medullary
carcinoma, VHL mutations and co-incident angiomas, or SDHB
mutations and their potential for recurrent and malignant tumours).
Epidemiology
• Equal sex distribution, and most commonly present in the third and
fourth decades. Up to 50% may be diagnosed post-mortem.
• Tumours may be bilateral, particularly where part of an inherited
syndrome (see Table 3.6).
• 10% of aPCA/eFPGL occur in patients with a family history of
phaeochromocytoma, and currently 25% of patients with apparently
sporadic phaeochromocytoma are found to harbour a disease-causing
mutation upon genetic analysis.
Multiple tumours, extra-adrenal location, or evidence of malignancy are
indicators of a high likelihood of an underlying genetic cause. See Box 3.7
for who should be screened.
PHAEOCHROMOCYTOMAS AND PARAGANGLIOMAS 285
Table 3.6 Genetically caused syndromes associated with

phaeochromocytomas
Familial phaeochromocytomas Isolated autosomal dominant trait
MEN-2A and 2B Mutation in RET proto-oncogene
(b see p. 592) (chromosome 10)
Primary hyperparathyroidism and
medullary thyroid carcinoma associated
with phaeochromocytoma (aPCA)
MEN-2B also associated with marfanoid
phenotype and mucosal neuromas
(tongue) (b see p. 592)
von Hippel–Lindau syndrome Mutation of VHL tumour suppressor
gene (chromosome 3)
(b see p. 580)
Renal cell carcinoma, cerebellar
haemangioblastoma, retinal angioma,
renal and pancreatic cysts
Phaeochromocytomas (aPCA/eFPGL)
in 25%
Neurofibromatosis Autosomal dominant condition
caused by mutations of NF1 gene on
(b see p. 578)
chromosome 17
Phaeochromocytomas (aPCA/eFPGL)
in 1.0% and mostly late presentation
(>30 years)
Succinate dehydrogenase (SDH) SDHA: rare, autosomal dominant cause
mutations of aPCA, eFPGL, HNPGL
SDHB: autosomal dominant cause
of aPCA, eFPGL, HNPGL, and renal
cell carcinoma. High frequency of
malignancy and extra-adrenal tumours
SDHC: autosomal dominant cause of
HNPGL (rarely, also of aPCA, eFPGL)
SDHD: autosomal dominant cause
of HNPGL, aPCA, eFPGL (disease
manifestation only in individuals with
paternal inheritance of mutation)
TMEM127 (transmembrane encoding Autosomal dominant cause of aPCA,
gene (chromosome 2q11)) eFPGL, HNPGL
MAX (MYC associated factor X, Autosomal dominant cause of aPCA,
a tumour suppressor susceptibility higher incidence of bilateral and
gene) malignant tumours (as in SDHD
parent-of-origin effect: disease
manifestation only in individuals with
paternal transmission of the mutation)
Box 3.7 Who should be screened for the presence of a

phaeochromocytoma?
• Patients with a family history of MEN, VHL, neurofibromatosis, SDH,
TMEM127, MAX gene mutations.
• Patients with paroxysmal symptoms.
• Young patients with hypertension.
• Patient developing hypertensive crisis during general anaesthesia/
surgery.
• Patients with unexplained heart failure.
• Patients with an adrenal incidentaloma.
Pathophysiology
Sporadic tumours are usually unilateral and <10cm in diameter. Tumours
associated with familial syndromes are more likely to be bilateral and asso-
ciated with pre-existing medullary hyperplasia.
Malignancy
• Approximately 15–20% are malignant, and these are characterized by
local invasion or distant metastasis rather than capsular invasion.
• Differentiating benign and malignant tumours is difficult and mainly
based on the presence of metastases, although chromosomal ploidy
may be useful.
• Paragangliomas are more likely to be malignant and to recur.
• Typical sites for metastases are retroperitoneum, lymph nodes, bone,
liver, and mediastinum.
Secretory products
• Catecholamine secretion is usually adrenaline or noradrenaline and
may be constant or episodic.
• Phenylethanolamine-N-methyltransferase (PNMT) is necessary for
methylation of noradrenaline to adrenaline and is cortisol-dependent.
• Paragangliomas (exception—organ of Zuckerkandl) secrete
noradrenaline only, as they lack PNMT.
• Small adrenal tumours tend to produce more adrenaline whereas
larger adrenal tumours produce more noradrenaline, as a proportion
of their blood supply is direct, rather than corticomedullary, and
therefore, lower in cortisol concentrations.
• Pure dopamine secretion is rare and may be associated with
hypotension. These tumours are more likely to be malignant.
• Other non-catecholamine secretory products may also be produced,
including VIP, neuropeptide Y, ACTH (associated with Cushing’s
syndrome), PTH, and PTHrP.
PHAEOCHROMOCYTOMAS AND PARAGANGLIOMAS 287
Clinical features
• Sustained or episodic hypertension often resistant to conventional
therapy (BUT: more and more phaeochromocytomas are found
incidentally following CT imaging, thus may not show any clinical signs
and symptoms).
• The presence of palpitation, headaches, or sweating in a
patient with hypertension should raise the diagnostic query of
phaeochromocytoma.
• General:
• Sweating and heat intolerance >80%.
• Pallor or flushing.
• Feeling of apprehension.
• Pyrexia.
• Neurological—headache (throbbing or constant) (65%), paraesthesiae,
visual disturbance, seizures.
• Cardiovascular—palpitations (65%), chest pain, dyspnoea, postural
hypotension.
• GI—abdominal pain, constipation, nausea.
• Skin—livedo reticularis.
• Endocrine—paroxysmal thyroid swelling (noradrenaline-secreting).
Complications
• Cardiovascular—left ventricular failure, dilated cardiomyopathy
(reversible), dysrhythmias.
• Respiratory—pulmonary oedema.
• Metabolic—carbohydrate intolerance, hypercalcaemia.
• Neurological—cerebrovascular, hypertensive encephalopathy.
Factors precipitating a crisis
• Straining.
• Exercise.
• Pressure on abdomen—tumour palpation, bending over.
• Surgery.
• Drugs:
• Anaesthetics.
• Unopposed B-blockade.
• IV contrast agents.
• Opiates.
• Tricyclic antidepressants.
• Phenothiazines.
• Metoclopramide.
• Glucagon.
Investigations of phaeochromocytomas
and paragangliomas
Demonstrate catecholamine hypersecretion
24h urine collection is the standard test for screening for a phaeochro-
mocytoma. In a patient with suggestive symptoms, this is usually suffi-
cient to confirm or exclude the diagnosis. False –ves are more common
when patients are asymptomatic and early in the disease. Particular care
is needed in familial cases, incidentalomas, and in those in whom a gen-
eral anaesthetic has precipitated a hypertensive episode. Metadrenalines
(either urine or plasma) offer more specific diagnostic tools than measure-
ment of unmetabolized catecholamines and provide the best biochemical
tests for diagnosing phaeochromocytoma. See Table 3.8 for sensitivity and
specificity of tests.
24h urine collection for catecholamines/metanephrines (see Tables 3.7
and 3.8)
• Urine is collected into bottles containing acid (warn patient).
• Because of the episodic nature of catecholamine secretion, at least
2× 24h collections should be performed. It is useful to perform a
collection while a patient is having symptoms if episodic secretion is
suspected.
• The sensitivity of urinary VMAs is less than free catecholamines or
metadrenalines and also influenced by dietary intake and should not be
used. Urinary metanephrines are of similar sensitivity but of superior
specificity to urinary catecholamines.
• NB Tricyclic antidepressants and labetalol interfere with adrenaline
measurements and should be stopped for 4 days (Box 3.8).
• For marginal elevation, urine collections should be repeated, avoiding
nuts (walnuts), fruit (bananas and pineapple), potatoes, and beans.
Plasma metanephrine measurement
• Plasma metanephrines are the most sensitive test for detection of
catecholamine excess and have only slightly lower specificity than
urinary metanephrines (Table 3.8).
• If plasma metanephrines are borderline, urinary metanephrines may be
used for confirmation.
• Routine measurement requires controlled conditions—supine and
cannulated for 30min; however, false +ves are rare, thus screening
can be carried out in the sitting position without 30min rest, and only
borderline positive cases require repeat after 30min supine rest.
• Plasma catecholamines are elevated by renal failure, caffeine, nicotine,
exercise, and some drugs.
• Catecholamine levels in asymptomatic individuals investigated for
an adrenal incidentaloma or due to a familial condition are often
diagnosed at an earlier stage and may, therefore, have lower
catecholamines.
INVESTIGATIONS OF PHAEOCHROMOCYTOMAS 289
Table 3.7 Substances interfering with urinary catecholamine levels

Increased catecholamines Decreased Variable effect
catecholamines
A-blockers Monoamine oxidase Levodopa
inhibitors
B-blockers, e.g. Clonidine Tricyclic antidepressants
phenoxybenzamine
Levodopa Guanethidine and Phenothiazines
other adrenergic
neurone blockers
Drugs containing Calcium channel inhibitors
catecholamines, e.g.
decongestants
Metoclopramide ACE inhibitors
Domperidone Bromocriptine
Hydralazine
Diazoxide
Glyceryl trinitrate
Sodium nitroprusside
Nicotine
Theophylline
Caffeine
Amphetamine
Table 3.8 Sensitivity and specificity of tests

Test Sensitivity (%) Specificity (%)
Plasma metanephrines 97 92
Urinary metanephrines 85 95
Urinary catecholamines 88 78
Urinary VMA 65 88
Clonidine suppression test 97
MRI 98 70
CT 93 70
MIBG 80 95
• Plasma and urinary methoxytyramine levels are indicators of

malignancy and can show isolated increases in patients with
‘biochemically negative’ malignant phaeochromocytoma.
Clonidine suppression tests (b see Box 3.8, p. 291)
This test may be used to differentiate patients who have borderline cat-
echolamine levels but may offer little advantage over the screening tests
already described.
• Clonidine 300 micrograms orally—failure of suppression of plasma
catecholamines into the normal range at 120 and 180min is suggestive
of a tumour.
Provocative tests
These are not used routinely, as they do not enhance diagnostic accuracy
and are potentially dangerous.
Localization of tumour
Imaging
• These are large tumours, in contrast to Conn’s syndrome, and not
easily missed with good quality imaging to the bifurcation of the aorta.
Approximately 98% will be detected in the abdomen.
• <2% are in the chest, and 0.02% are in the head.
• Adrenal imaging with non-ionic contrast should be performed initially,
then body imaging (ideally MRI) if tumour not localized in adrenal.
• MRI. Bright hyperintense image on T2.
• CT. Less sensitive and specific—less good at distinguishing between
different types of adrenal tumours.
I-MIBG scan (b see Box 3.9, p. 293)
123
• Meta-iodobenzylguanidine is a chromaffin-seeking analogue. Imaging

using MIBG is +ve in 60–80% phaeochromocytomas and may locate
tumours not visualized on MRI, e.g. multiple and extra-adrenal tumours
and also metastases of the primary tumour.
• Specificity is nearly 100%.
• Performed preoperatively to exclude multiple tumours.
• NB Phenoxybenzamine may lead to false –ve MIBG imaging, so these
scans should be performed before commencing this drug where
possible.
• 18F fluorodopamine PET scanning is superior to MIBG in localizing
metastatic disease. No K+ iodide is necessary to block thyroid uptake.
INVESTIGATIONS OF PHAEOCHROMOCYTOMAS 291
Positron emission tomography

• [18F]fluorodeoxyglucose (FDG) and the norepinephrine analogue
[11C]metahydroxyephedrine (mHED) have both been used as
radionucleotides.
• Current data are insufficient to determine which radionucleotide has
the greatest sensitivity and specificity.
• Sensitivity is better than MIBG and approaches 100%, but specificity is
worse, with false +ves being reported.
Box 3.8 Test procedures

Clonidine suppression test
• Patient supine and cannulated for 30min.
• Clonidine 300 micrograms orally.
• Plasma catecholamines measured at time 0, 120, and 180min.
• Failure to suppress into the normal range is suggestive of a tumour.
• 1.5% false +ve rate in patients with essential hypertension.
Screening for associated conditions

Up to 24% of patients with apparently sporadic phaeochromocytomas
may have a familial disorder, and high-risk patients should, therefore, be
screened for the presence of associated conditions, even if asymptomatic.
Screening can be performed either by looking for associated clinical mani-
festations or by genetic testing.
Genetic testing in non-syndromic phaeochromocytoma has shown a
hereditary predisposition in 24%, of which 45% had germline mutations in
VHL, 20% had mutations in RET, 18% mutations in SDHD, and 17% muta-
tions in SDHB. See Box 3.8 for test procedures.
MEN 2 (b see p. 592)
• Serum calcium.
• Serum calcitonin (phaeochromocytomas precede medullary thyroid
carcinoma in 10%).
VHL (b see p. 580)
• Ophthalmoscopy—retinal angiomas are usually the first manifestation.
• MRI—posterior fossa and spinal cord.
• US of kidneys—if not adequately imaged on MRI of adrenals.
NF1 (b see p. 578)
Clinical examination for café-au-lait spots and cutaneous neuromas.
Succinate dehydrogenase (subunits B, C, D)
• Reports of renal carcinomas: ensure adequate imaging of kidneys.
• The SDH enzyme consists of four subunits (A, B, C, and D). SDHC
and SDHD anchor the two other components which form the
catalytic core to the inner mitochondrial membrane. The enzyme is a
component of Krebs’ cycle and also regulates the downregulation of
the transcription factor HIF1α.
• The succinate dehydrogenase D subunit gene is located at
chromosome 11q21–23 and the B subunit on chromosome 1p35–6.
• Mutations in SDHB, SDHC, and SDHD may cause aPCA, eFPGL,
and HNPGL.
• Mutations in SDHD have been associated with familial carotid body
tumours.
• Germline SDHA mutations are associated with juvenile
encephalopathy.
• SHD mutations show maternal imprinting so that only carriers who
inherit the mutation paternally are at risk of developing a tumour.
• Rates of penetrance and malignancy vary: SDHB mutation may be
associated with a more malignant phenotype.
Indications for screening for genetic conditions as a
cause for phaeochromocytoma
• Bilateral tumours.
• Extra-adrenal tumour, including head and neck.
• Age of onset (<50 years 45% +ve, >40 years 7% +ve, >50 years 1% +ve).
• Malignancy.
SCREENING FOR ASSOCIATED CONDITIONS 293
Box 3.9 Drugs interfering with MIBG uptake in

phaeochromocytoma*
• Opioids.
• Cocaine.
• Tramadol.
• Tricyclic antidepressants:
• Amitriptyline, imipramine.
• Sympathomimetics:
• Phenylpropanolamine, pseudoephedrine, amphetamine,
dopamine, salbutamol.
• Antihypertensives/cardiovascular agents:
• Labetalol, metoprolol, amiodarone, reserpine, guanethidine,
calcium channel blockers—nifedipine and amlodipine, ACE
inhibitors—captopril and enalapril.
*
Should be discontinued 7–14 days prior to scan.
Management
Medical
• It is essential that any patient is fully prepared with α- and B-blockade
before receiving IV contrast or undergoing a procedure, such as
venous sampling or surgery.
• α-blockade must be commenced before B-blockade to avoid
precipitating a hypertensive crisis due to unopposed α-adrenergic
stimulation.
• α-blockade—commence phenoxybenzamine as soon as diagnosis
made. Start at 10mg 2× day by mouth, and increase up to 20mg 4× day
(doxazosin is an accepted alternative).
• B-blockade—use a B-blocker, such as propranolol 20–80mg 8-hourly
by mouth, 48–72h after starting phenoxybenzamine and with evidence
of adequate α-blockade (generally noted by a postural fall in BP).
• Treatment is commenced in hospital. Monitor BP, pulse, and
haematocrit. The goal is a BP of 130/80 or less sitting and 100mg
systolic standing, pulse 60–70 sitting and 70–80 standing. Reversal of
α-mediated vasoconstriction may lead to haemodilution (check Hb
preoperatively).
• To ensure complete blockade before surgery, IV phenoxybenzamine
(1mg/kg over 4h in 100mL 5% glucose) can be administered on the
3 days before surgery. There is less experience with competitive
α-adrenergic blockade, such as prazosin.
• See Table 3.9 for contraindicated drugs.
Surgical (also considered in b see p. 610)
• Surgical resection is curative in the majority of patients, leading to
normotension in at least 75%.
• Mortality from elective surgery is <2%. It is essential that the
anaesthetic and surgical teams have expertise of management of
phaeochromocytomas perioperatively.
• Surgery may be laparoscopic if the tumour is small and apparently
benign. Careful perioperative anaesthetic management is essential,
as tumour handling may lead to major changes in BP and also
occasionally cardiac arrythmias. Phentolamine, nitroprusside, or IV
nicardipine are useful to treat perioperative hypertension, and esmolol
or propranolol for perioperative arrythmias. Hypotension (e.g. after
tumour devascularization) usually responds to volume replacement but
occasionally requires inotropic support.
• Risk factors for haemodynamic instability during surgery include a high
noradrenaline concentration, large tumour size, postural drop after
B-blockade, and a mean arterial pressure >100mmHg.
MANAGEMENT 295
Table 3.9 Contraindicated drugs in phaeochromocytomas

Drug Examples
B-blockers Propranolol
D2 receptor antagonists Metoclopramide
Sulpiride
Chlorpromazine
Tricyclic antidepressants Imipramine
Amitriptyline
Paroxetine
Fluoxetine
Monoamine oxidase inhibitors
Sympathomimetics Ephedrine
Salbutamol
Cocaine
Chemotherapeutic agents
Opioid analgesics
Neuromuscular blocking agents Tubocurarine
Suxamethonium
Peptide and corticosteroid hormones Glucagon
ACTH
Dexamethasone
Follow-up
• Cure is assessed by 24h urinary free catecholamine measurement, but
since catecholamines may remain elevated for up to 10 days following
surgery, these should not be performed until 2 weeks post-operatively.
• Lifelong follow-up is essential to detect recurrence of a benign tumour
or metastasis from a malignant tumour, as it is impossible to exclude
malignancy on a histological specimen.
• Chromogranin A is also a useful marker (falsely elevated with proton
pump therapy, steroids, liver and renal failure, essential hypertension,
atrophic gastritis, prostatic carcinoma, and thyrotoxicosis).
Malignancy
• Malignant tumours require long-term α- and B-blockade. The tyrosine
kinase inhibitor α-methylparatyrosine may help control symptoms.
• High-dose 131I-MIBG can be used to treat metastatic disease.
• Chemotherapy, using cyclophosphamide, vincristine, doxorubicin, and
dacarbazine, has been associated with symptomatic improvement.
• Radiotherapy can be useful palliation in patients with bony metastases.
• Novel treatment options for malignant phaeochromocytoma are
urgently needed, and current studies explore VEGF inhibitors on the
basis of the highly vascularized nature of the tumours.
Prognosis
• Hypertension may persist in 25% patients who have undergone
successful tumour removal.
• 5-year survival for ‘benign’ tumours is 96%, and the recurrence rate
is <10%.
• 5-year survival for malignant tumours is 44%.
• SHB gene mutation patients are associated with a shorter survival.
Further reading
Astuti D, Latif F, Dallol A, et al. (2001). Gene mutations in the succinate dehydrogenase subunit
SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J
Hum Genet 69, 49–54.
Ayala-Ramirez M, Chougnet CN, Habra MA, et al. (2012). Treatment with sunitinib for patients
with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin
Eisenhofer G, Lenders JW, Timmers H, et al. (2011). Measurements of plasma methoxytyramine,
normetanephrine and metanephrine as discriminators of different hereditary forms of phaeo-
chromocytoma. Clin Chem 57, 411–20.
Erickson D, Kudva YC, Ebersold MJ, et al. (2001). Benign paragangliomas: clinical presentation and
treatment outcomes in 236 patients. J Clin Endocrinol Metab 86, 5210–16.
Gimm O, Armanios M, Dziema H, et al. (2000). Somatic and occult germ-line mutations in SDHD,
a mitochondrial complex II gene, in nonfamilial phaeochromocytoma. Cancer Res 60, 6822–5.
Ilias I, Yu J, Carrasquillo JA, et al. (2003). Superiority of 6-[18F]-fluorodopamine positron emission
tomography versus [131I]-metaiodobenzylguanidine scintigraphy in the localization of metastatic
pheochromocytoma. J Clin Endocrinol Metab 88, 4083–7.
Jafri M, Maher ER (2012). The genetics of phaeochromocytoma: using clinical features to guide
genetic testing. Eur J Endocrinol 166,151–8.
Lenders JW, Eisenhofer G, Mannelli M, Pacak K (2005). Phaeochromocytoma. Lancet 366, 665–75.
Neumann HP, Bausch B, McWhinney SR, et al. (2002). Germ-line mutations in nonsyndromic
pheochromocytoma. N Engl J Med 346, 1459–66.
Chapter 4 297
Reproductive
endocrinology
Reproductive physiology 298 Combined oral contraceptive pills

Regulation of gonadal (COCP) 356
function 300 Emergency contraception 360
Reproductive physiology 365 Hypogonadotrophic
Hirsutism 304 hypogonadism (HH) 362
Evaluation of hirsutism 306 Male hypogonadism 365
Polycystic ovary syndrome Secondary hypogonadism 366
(PCOS) 308 Primary hypogonadism 370
Investigations of PCOS 312 Clinical assessment of
Management of PCOS 314 hypogonadism 374
Congenital adrenal hyperplasia Androgen replacement
(CAH) in adults 320 therapy 378
Investigations of CAH in Risks and side effects of androgen
adults 322 replacement therapy 380
Management of CAH in Gynaecomastia 382
adults 324 Evaluation of gynaecomastia 384
Monitoring of treatment 326 Management of
Androgen-secreting tumours 328 gynaecomastia 386
Menstrual function Testicular tumours 387
disorder—assessment and Erectile dysfunction 388
investigation 330 Evaluation of erectile
Menstrual function disorder— dysfunction 390
clinical evaluation 332 Management of erectile
Menstrual function dysfunction 392
disorder—investigations 334 Infertility 396
Management of amenorrhoea 335 Evaluation of female infertility 398
Premature ovarian insufficiency Evaluation of male infertility 402
(POI), including Turner’s Management of female
syndrome in adults 336 infertility 406
Investigation of POI 339 Management of male
Management of POI 340 infertility 408
Menopause 342 Unexplained infertility 409
Clinical presentation of Ovulation induction 410
menopause 344 Disorders of sexual
Evaluation of menopause (e.g. if differentiation 414
HRT is being considered) 345 Androgen insensitivity
Hormone replacement therapy syndrome 416
(HRT) 346 Ovotesticular DSD 417
HRT regimens 352 General principles of
Hormonal control of management 418
contraception 355 Transsexualism 420
298 CHAPTER 4 Reproductive endocrinology
Reproductive physiology
Anatomy
• Normal adult ♂ testicular volume 15–30mL.
• Normal adult ♀ ovarian volume 5–10mL.
• Two gonadotrophins LH and FSH address two gonadal cell types, with
feedback from sex steroids and inhibin.
• Three important cells of the gonad:
• Interstitial cells.♂ Leydig cells, ♀ theca cells—which are found
in between the seminiferous tubules and follicles, respectively.
Produce testosterone under LH drive.
• Cells supporting gametogenesis. ♂ Sertoli cells, ♀ granulosa
cells—secrete various hormones, including inhibin and Müllerian
inhibitory factor (AMH) under FSH drive. The former inhibits FSH
secretion from the pituitary gland, and the latter is responsible for
suppressing ♀ sex organ development during sexual differentiation
in utero. In adult ♀, AMH is produced in proportion to germ cell
number and is, therefore, a marker of ovarian ageing.
• Germ cells.♂ continue to make new germ cells throughout adult
life in the basal membrane of tubules. ♀ cease to make new germ
cells after birth and are, therefore, born with all of the ‘eggs’ that
they will ever make.
• Functional units:
• ♂ seminiferous tubules. Make up 90% of testicular volume.
Spermatogenesis occurs here in the presence of high intratesticular
concentrations of testosterone. Made up of germ cells and Sertoli
cells through which spermatogonia mature to be released into the
lumen of the tubule.
• ♀ Graafian follicle. Primordial follicles are recruited in batches,
mature over 2 months, with selection of a dominant follicle with
single central oocyte surrounded by granulosa cells which convert
theca-derived testosterone to oestradiol for ovulation. Follicles
which do not proceed to ovulation become atretic.
See Fig. 4.6 for the sex steroid biosynthesis pathway.
REPRODUCTIVE PHYSIOLOGY 299
Cholesterol
StAR
17α HSD 17, 20 lyase
Pregnenolone 17OH Pregnenolone Dehydroepiandrosterone
3β HSD 17β HSD Aromatase
Progesterone 17OH Progesterone Androstenedione Testosterone Oestradiol
21 OH
Deoxy- 11-Deoxycortisol
corticosterone
11β OH
Corticosterone Cortisol
18-OH Corticosterone
Aldosterone
Fig. 4.6 Sex steroid biosynthesis pathway.

Regulation of gonadal function

(See Fig. 4.7 for normal menstrual cycle.)
Hypothalamus
• Gonadotrophin-releasing hormone (GnRH) is secreted by the
hypothalamus in a pulsatile manner in response to stimuli from the
cerebral cortex and limbic system via various neurotransmitters, e.g.
leptin, kisspeptin, endorphins, catecholamines, and dopamine.
• GnRH release initially occurs during sleep in early puberty and then
throughout the day in adulthood. It stimulates the secretion of
luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the
pituitary gland. The pattern of GnRH secretion is crucial for normal
gonadotrophin secretion. Faster pulse frequencies are essential for LH
secretion, whereas slower frequencies favour FSH secretion.
• Continuous administration of GnRH abolishes both LH and FSH
secretion; therefore, superactive GnRH analogues (e.g. goserelin,
triptorelin, leuprorelin) are used to suppress gonadal function.
Pituitary
• LH drives interstitial cell synthesis and secretion of testosterone in both
sexes and triggers ovulation in ♀. Negative feedback by sex steroids.
• FSH in ♂ drives Sertoli cell-mediated sperm maturation and
production of seminiferous tubule fluid as well as a number of
substances thought to be important for spermatogenesis and inhibin.
FSH in ♀ drives granulosa cell-mediated aromatization of androgens to
oestradiol. Negative feedback mainly by inhibin.
Gonads
• Testosterone and small amounts of androstenedione (DHEA)
and dihydrotestosterone (DHT) are produced by Leydig cells. ♂
testosterone has a circadian rhythm, with maximum secretion at
around 8 a.m. and minimum around 9 p.m. ♀ testosterone production
peaks at ovulation.
• Oestradiol production in ♂ mainly from peripheral conversion from
androgens. In ♀, oestradiol rises with follicle maturation under FSH
drive of granulosa cells. Oestradiol is also made by the placenta and
corpus luteum.
• Progesterone secreted from corpus luteum, which is derived from
granulosa cells, only after ovulation occurs. Peak production on day 21
of a 28-day cycle.
Regulation of gametogenesis
• Both FSH and LH are required for gametogenesis.
• LH ensures high intragonadal concentrations of testosterone
(exogenous testosterone cannot substitute).
• FSH, through its action on Sertoli and granulosa cells, is vital for sperm
and oocyte maturation.
• ♂. The whole process of spermatogenesis takes approximately
74 days, followed by another 12–21 days for sperm transport
REGULATION OF GONADAL FUNCTION 301
through the epididymis. This means that events which may affect
spermatogenesis may not be apparent for up to 3 months, and
successful induction of spermatogenesis treatment may take 2 years.
• ♀. From primordial follicle to primary follicle, it takes about 180 days
(a continuous process). It is then another 60 days to form a preantral
follicle which then proceeds to ovulation three menstrual cycles later.
Only the last 2–3 weeks of this process is under gonadotrophin drive,
during which time the follicle grows from 2 to 20mm.
Pituitary cycle
FSH LH
Ovarian cycle
Maturation of Corpus luteum

follicle Ovulation
E2
P
Endometrial cycle
M
−12 −8 −4 0 +4 +8 +12
Follicular phase Luteal phase

Ovulatory
phase
Fig. 4.7 The normal menstrual cycle.

Reproductive physiology
Sex steroid transport
Testosterone daily production rate in ♂ is 5–15mg; 2–4% of total tes-
tosterone circulates as free biologically active hormone. The rest is
bound to proteins, particularly albumin and sex hormone-binding globulin
(SHBG). Several equations are used to estimate free testosterone: free
androgen index ((total testosterone/SHBG) × 100) is of limited value, and
web-based calculators of bioactive testosterone have better validation.
Androstenedione is only about 6% SHBG-bound.
Oestradiol daily production rate in ♀ is 40–400 micrograms; 2–3% free
oestradiol is biologically active; the rest is bound to SHBG.
Sex steroid metabolism
• Testosterone is converted in target tissues to the more potent
androgen DHT in the presence of the enzyme 5A-reductase. There are
multiple 5A-reductase isoenzymes; type 2 is the isoenzyme responsible
for DHT synthesis in the genitalia, genital skin, and hair follicles. It is,
therefore, essential for normal ♂ virilization and sexual development.
• Testosterone may alternatively be converted into oestradiol through
the action of the aromatase enzyme, found in greatest quantities in
testes and adipose tissue.
• Many effects previously attributed to testosterone are now known
to be mediated by oestrogen—especially closure of epiphyses and
maintenance of bone density.
• Testosterone and its metabolites are inactivated in the liver and
excreted in the urine.
• Oestradiol is conjugated in the liver to sulphates and glucuronates and
then extracted in the urine.
Androgen action
• Both testosterone and DHT exert their activity by binding to androgen
receptors, the latter more avidly than testosterone.
• ♂ sexual differentiation during embryogenesis.
• Development and maintenance of ♂s sex characteristics after
puberty.
• Normal ♂ sexual function and behaviour.
• Spermatogenesis.
• Regulation of gonadotrophin secretion.
Oestrogen action
• Oestradiol binds to A (reproductive tissues) and B (bone, brain, heart,
etc.) receptors.
• Development of ♀s sex characteristics.
• Increase fat stores.
• Increase vaginal wall and uterine thickening.
Further reading
De Ronde W, Pols HAP, Van Leeuwen JPTM, et al. (2003). The importance of oestrogens in males.
Clin Endocrinol 58, 529–42.
REPRODUCTIVE PHYSIOLOGY 303
Hirsutism
Definition
Hirsutism (not a diagnosis in itself) is the presence of excess hair growth in
♀ as a result of i androgen production and i skin sensitivity to androgens.
See Table 4.1 for causes. See Box 4.1 for signs of virilization.
Physiology of hair growth
Before puberty, the body is covered by fine unpigmented hairs or vel-
lus hairs. During adolescence, androgens convert vellus hairs into coarse,
pigmented terminal hairs in androgen-dependent areas. The extent
of terminal hair growth depends on the concentration and duration of
androgen exposure as well as on the sensitivity of the individual hair
follicle. Idiopathic hirsutism refers to those with normal investigations and
presumably greater than average androgen receptor sensitivity.
The reason different body regions respond differently to the same
androgen concentration is unknown but may be related to the number of
androgen receptors in the hair follicle. Genetic factors play an important
role in the individual susceptibility to circulating androgens, as evidenced
by racial differences in hair growth.
Androgen production in women
In ♀, testosterone is secreted primarily by the ovaries and adrenal glands,
although a significant amount is produced by the peripheral conversion of
androstenedione and DHEA. Ovarian androgen production is regulated
by luteinizing hormone, whereas adrenal production is ACTH-dependent.
The predominant androgens produced by the ovaries are testosterone
and androstenedione, and the adrenal glands are the main source of
DHEA. Circulating testosterone is mainly bound to sex hormone-binding
globulin (SHBG), and it is the free testosterone which is biologically active.
Testosterone is converted to dihydrotestosterone in the skin by the
enzyme 5A-reductase. Androstenedione and DHEA are not significantly
protein-bound. See Fig. 4.1.
HIRSUTISM 305
Table 4.1 Causes of hirsutism

Ovarian PCOS 95%
Androgen-secreting tumours <1%
Adrenal Congenital adrenal hyperplasia 1%
Cushing’s syndrome <1%
Androgen-secreting tumours <1%
Acromegaly <1%
Severe insulin resistance <1%
Idiopathic Normal US and endocrine profile 3%
Box 4.1 Signs of virilization

• Frontal balding.
• Deepening of voice.
• i muscle size.
• Clitoromegaly.
Pituitary
ACTH LH
Adrenals Ovaries
Androstenedione/ Testosterone DHT

DHEA
Fig. 4.1 Regulation of androgen production in ♀.

Evaluation of hirsutism
(See Box 4.2 for androgen-independent hair growth.)
Androgen-dependent hirsutism
Normally develops following puberty. Hairs are coarse and pigmented and
typically grow in ♂ pattern. It is often accompanied by other evidence
of androgen excess, such as acne, oily skin and hair, and male pattern
alopecia.
History
• Age and rate of onset of hirsutism. Slowly progressive hirsutism
following puberty suggests a benign cause, whereas rapidly progressive
hirsutism of recent onset requires further immediate investigation to
rule out an androgen-secreting neoplasm.
• Menstrual history. ?oligomenorrhoeic.
• Presence of other evidence of hyperandrogenism, e.g. acne or
bitemporal hair recession.
• Drug history. Some progestins used in oral contraceptive preparations
may be androgenic (e.g. norethisterone).
• Treatments are often based on subjective appearance, so be cautious if
there is a great disparity between subjective and objective assessment.
Consider psychological background.
Physical examination
• Distinguish between androgen-dependent and androgen-independent hair
growth.
• Assess the extent and severity of hirsutism. The Ferriman–Gallwey
score assesses the degree of hair growth in 11 regions of the body.
This provides a semi-objective method of monitoring disease
progression and treatment outcome but is mainly used in research
rather than routine practice.
• Virilization should be looked for only in suspected cases of severe
hyperandrogenism (b see Box 4.1, p. 305).
• Acanthosis nigricans is indicative of insulin resistance and
probable PCOS.
• Rare causes of hyperandrogenism, such as Cushing’s syndrome and
acromegaly, should be ruled out.
Box 4.2 Androgen-independent hair growth

Excess vellus hairs over face and trunk, including forehead. It does not
respond to antiandrogen treatment.
Causes of androgen-independent hair growth
• Drugs, e.g. phenytoin, ciclosporin, glucocorticoids.
• Anorexia nervosa.
• Hypothyroidism.
• Familial.
EVALUATION OF HIRSUTISM 307
Laboratory investigation
Serum testosterone should be measured in all ♀ presenting with hir-
sutism. If this is <5nmol/L, then the risk of a sinister cause for her hirsutism
is low. Further investigations and management of the individual disorders
will be discussed in the following chapters.
Imaging
Pelvic ultrasound may be useful to diagnose PCOS. Idiopathic hirsutism
refers to those with normal ovarian morphology, but this distinction is
not clear-cut, as the level of detection of PCO morphology on US is
operator-dependent.
Further reading
Koulori O, Conway G (2009). Management of hirsutism. BMJ 338, 823–6.
Loriaux DL (2012). An approach to the patient with hirsutism. JCEM 97, 2957–68.
Martin KA, Chang JR, Ehrmann DA, et al. (2008). Evaluation and treatment of hirsutism in premeno-
pausal women: an Endocrine Society clinical practice guideline. JCEM 93, 1105–20.
Polycystic ovary syndrome (PCOS)

Definition
• A heterogeneous clinical syndrome characterized by
hyperandrogenism, mainly of ovarian origin, menstrual irregularity,
and hyperinsulinaemia, in which other causes of androgen excess have
been excluded (see Box 4.3).
• The diagnosis is further supported by the presence of characteristic
ovarian morphology on US. Note the misnomer: the ovarian
appearance refers to >12 follicles, i.e. polyfollicle syndrome.
• A distinction is made between polycystic ovary morphology on
ultrasound (PCO which also occurs in congenital adrenal hyperplasia,
acromegaly, Cushing’s syndrome, and testosterone-secreting tumours)
and PCOS—the syndrome. See Box 4.4 for secondary causes
of PCOS.
• See Fig. 4.2 for abnormalities of hormone secretion.
Epidemiology
• PCOS is the most common endocrinopathy in ♀ of reproductive age;
>95% of ♀ presenting to outpatients with hirsutism have PCOS.
• The estimated prevalence of PCOS ranges from 5 to 10% on clinical
criteria. Polycystic ovaries on US alone are present in 20–25% of ♀ of
reproductive age.
• First-degree ♂ relatives of women with PCOS have increased
prevalence of metabolic syndrome and obesity than the general
population.
Pathogenesis (b see Fig. 4.2, p. 309)
The fundamental pathophysiological defect is unknown, but both genetic
and environmental factors are thought to play a role.
Genetic
• Familial aggregation of PCOS in 50% of ♀. A family history of type 2
diabetes mellitus is also more common in ♀ with PCOS.
• PCOS is probably a polygenic disorder.
• Implicated genes include those of the insulin pathway, testosterone
biosynthesis enzymes, and obesity-related genes, including FTO gene.
Hyperandrogenism
• The main source of hyperandrogenaemia is the ovaries, although
there may also be adrenal androgen hypersecretion which is poorly
defined.
• The biochemical basis of ovarian dysfunction is unclear. Studies suggest
an abnormality of cytochrome P450c17 activity, but this is unlikely
to be the primary event but rather an index of i steroidogenesis by
ovarian theca cells.
• There is also an increase in the frequency and amplitude of GnRH
pulses, resulting in the increase in LH concentration which is
characteristic of the syndrome. This is probably due to anovulation and
low progesterone levels.
POLYCYSTIC OVARY SYNDROME (PCOS) 309
Box 4.3 2003 Joint European Society of Human

Reproduction and Embryology and American Society of
Reproductive Medicine Consensus on the diagnosis criteria
for PCOS (Rotterdam criteria)
At least two out of three of the following:
• Oligo-/amenorrhoea.
• Hyperandrogenism (clinical or biochemical).
• Polycystic ovaries on US and exclusion of other disorders.
Box 4.4 Secondary causes of polycystic ovary syndrome

• Acromegaly.
• Cushing’s syndrome.
• Testosterone-secreting tumours.
Pituitary
i Insulin i LH secretion
Adrenal
i Androstenedione i Androstenedione
Ovary i Testosterone i DHEAS
Obesity
Hyperinsulinaemia ??
Genetic
susceptibility
d SHBG i Free testosterone
i Free oestradiol
Fig. 4.2 Abnormalities of hormone secretion in PCOS.
Hyperinsulinaemia
• Approximately 70% of ♀ with PCOS are insulin-resistant, depending
on the definition. The defect in insulin sensitivity appears to be
selective, mainly affecting the metabolic effects of insulin (effects
on muscle and liver) but sparing the ovaries where insulin acts as a
co-gonadotrophin to amplify LH-mediated testosterone synthesis.
Hyperinsulinaemia is exacerbated by obesity but can also be present in
lean ♀ with PCOS.
• There is also evidence in a number of ♀ with PCOS of insufficient
B-cell response to a glucose challenge, which is known to be a
precursor to type 2 diabetes mellitus.
• Insulin also inhibits SHBG synthesis by the liver, with a consequent rise
in free androgen levels.
Features
• Onset of symptoms. Symptoms often begin around puberty, after weight
gain, or after stopping the oral contraceptive pill but can present at
any time.
• Oligo-/amenorrhoea (70%). Due to anovulation. ♀ are usually well
oestrogenized, so there is little risk of osteoporosis, unlike other
causes of amenorrhoea.
• Hirsutism (66%):
• 25% of ♀ also suffer from acne or male pattern alopecia. Virilization
is not a feature of PCOS.
• There is often a family history of hirsutism or irregular periods.
• Slower onset of hirsutism makes a distinction from adrenal
or ovarian tumours which are rapidly progressive and more
likely to be associated with virilization and higher testosterone
concentrations.
• <1% of hirsute ♀ have non-classic congenital adrenal hyperplasia
(b see Clinical presentation, p. 321), and this should be excluded,
particularly in ♀ with significantly raised serum testosterone levels.
• Obesity (50%). Symptoms worsen with obesity, as it is accompanied
by i testosterone concentrations as a result of hyperinsulinaemia.
Acanthosis nigricans may be found in 1–3% of insulin-resistant ♀
with PCOS.
• Infertility (30%). PCOS accounts for 75% of cases of anovulatory
infertility. The risk of spontaneous miscarriage is also thought to be
higher than the general population, mainly because of obesity.
POLYCYSTIC OVARY SYNDROME (PCOS) 311
Rule out an androgen-secreting tumour

If there is:
• Evidence of virilization.
• Testosterone >5nmol/L (or >3nmol/L in post-menopausal ♀).
• Rapidly progressive hirsutism.
• CT of adrenals or ultrasound of ovaries will detect tumours >1cm.
• Selective venous sampling occasionally necessary to locate virilizing
tumours undetected by imaging.
• Ovarian suppression test using GnRH analogues can establish ovarian
origin of androgens.
• Adrenal tumours usually co-secrete cortisol as part of Cushing’s
syndrome.
Risks associated with PCOS
Type 2 diabetes mellitus
Type 2 diabetes mellitus is 2–4x more common in ♀ with PCOS. Impaired
glucose tolerance affects 10–30% of ♀ with PCOS, and gestational diabe-
tes is also more prevalent. The prevalence of diabetes mellitus is i in ♀
with PCOS, independent of weight, but is highest in the obese group. Most
important risk factor is family history of T2DM.
Dyslipidaemia
Several studies have shown an i risk of hypercholesterolaemia, hypertri-
glyceridaemia, and low HDL cholesterol in ♀ with PCOS, but epidemio-
logical studies of ♀ with PCOS have shown an i mortality from ischaemic
heart disease, despite their multiple cardiovascular risk factors.
Endometrial hyperplasia and carcinoma
In anovulatory ♀, endometrial stimulation by unopposed oestrogen
results in endometrial hyperplasia. Several studies have also shown that
this results in a 2–4-fold excess risk of endometrial carcinoma in ♀ with
PCOS. The combination of obesity with adipose-derived oestrogen and
oligomenorrhoea constitute the major risk group for uterine carcinoma.
Arterial disease
Meta-analyses suggest a 2-fold risk of arterial disease in women with
PCOS relative to women without PCOS. This may not be entirely due
to a high BMI.
Investigations of PCOS
The aims of investigations are mainly to exclude serious underlying disor-
ders and to screen for complications, as the diagnosis is primarily clinical
(see Box 4.3).
Confirmation of diagnosis
• Testosterone concentration:
• Performed primarily as a screen for the presence of other causes of
hyperandrogenism.
• Often normal in ♀ with PCOS, and serum androgen concentrations
do not reflect the degree of hirsutism because of variable androgen
receptor sensitivity.
• LH concentration:
• The higher the LH level, the more likely the risk of anovulation and
infertility.
• Cannot be used to diagnose PCOS, as it is normal in many affected
♀. Similarly, the traditional LH:FSH ratio is not a useful indicator.
• SHBG:
• Low in 50% of ♀ with PCOS, owing to the hyperinsulinaemic state,
with a consequent increase in circulating free androgens.
• Useful indirect marker of insulin resistance.
• Free androgen index: FAI = 100 x (total testosterone/SHBG).
• Anti-Müllerian hormone (AMH) made by preantral follicles raised in
PCOS but overlaps with normal range.
• Pelvic US of ovaries and endometrium:
• Ultrasound criteria for PCO defined >12 follicles between 2–9mm
in diameter or ovarian volume >10cm3.
• US is sensitive but not specific (occurs in CAH and
Cushing’s). Usually transvaginal but transabdominal possible in
experienced hands.
• False –ve results common in non-specialist scans.
• Measurement of endometrial thickness is of major importance
in the diagnosis of endometrial hyperplasia in the presence of
anovulation. Endometrial hyperplasia is diagnosed if the endometrial
thickness is >10mm.
• Transvaginal US will also identify 90% of ovarian virilizing tumours.
INVESTIGATIONS OF PCOS 313
Associated endocrinopathy
• Serum prolactin. In the presence of infertility or oligoamenorrhoea.
• Mild hyperprolactinaemia (up to 2000mU/L) is present in up to 30%
of ♀ with PCOS, and dopamine agonist treatment of this may be
necessary if pregnancy is desired.
• 17OH progesterone (17OHP) level:
• Used to exclude late-onset congenital adrenal hyperplasia.
• Indicated in those with testosterone concentrations in excess of
5nmol/L or with evidence of virilization.
• May also perform a Synacthen test, looking for an exaggerated
®
rise in 17OHP in response to ACTH in the presence of non-classic

21-hydroxylase deficiency (b see Clinical presentation, p. 321).
• If the patient is ovulating, then all 17OHP measurements should
be performed during the follicular phase of the cycle to avoid
false +ves.
• DHEAS and androstenedione concentrations:
• Both can be moderately raised in PCOS. DHEAS, although
traditionally an adrenal marker, is probably of ovarian origin in
most cases.
• Do not need to measure routinely in ♀ with PCOS but indicated
if serum testosterone >5nmol/L, in the presence of rapidly
progressive hirsutism, or in the presence of virilization.
• Other:
• Depending on clinical suspicion, e.g. urinary free cortisol or
overnight dexamethasone suppression test if Cushing’s syndrome is
suspected, or IGF-1 if acromegaly suspected—but not routinely.
Screening for complications
• Serum lipids and blood glucose. All obese ♀ with PCOS should have
an annual fasting glucose and fasting lipid profile. Consider OGTT in
those with family history of T2DM.
• All ♀ with PCOS who fall pregnant should be screened for gestational
diabetes.
Management of PCOS
(See Table 4.2.)
Weight loss
Studies have uniformly shown that weight reduction in obese ♀ with
PCOS will improve insulin sensitivity and significantly reduce hyperan-
drogenaemia. Obese ♀ are less likely to respond to antiandrogens and
infertility treatment. With a loss of 5%, ♀ with PCOS show improvement
in hirsutism, restoration of menstrual regularity, and fertility.
Metformin
In obese and lean insulin-resistant ♀ with PCOS, metformin (1g–2.5g
daily) improves insulin sensitivity, with a corresponding reduction in
serum androgen and LH concentrations and an increase in SHBG levels.
Metformin may regulate menstruation by improving ovulatory function but
improved live birth rate not established. Metformin does not seem to
improve response rates to ovulation induction using clomifene or gon-
adotrophins. Some benefits of metformin may be related to other lifestyle
measures, such as diet and weight loss. Metformin is usually stopped at
the diagnosis of pregnancy, as benefit in pregnancy is not proved outside
of established GDM.
There have been few long-term studies looking at the effect of met-
formin on hirsutism, but it appears that its effects are modest at best, and
most ♀ with significant hirsutism will require an antiandrogen.
♀ should be warned of its gastrointestinal side effects. In order to
minimize these, they should be started on a low dose (500mg once daily)
which may be i gradually to a therapeutic dose over a number of weeks.
Hirsutism
Pharmacological treatment of hirsutism (see Table 4.2) is directed at slow-
ing the growth of new hair. It can be combined with mechanical methods
of hair removal, such as electrolysis and laser therapy. Therapy is most
effective when started early. There is slow improvement over the first
6–12 months of treatment. Patients should be warned that facial hair is
slow to respond, treatment is prolonged, and symptoms may recur after
discontinuation of drugs. Adequate contraception is mandatory during
pharmacological treatment of hirsutism because of possible teratogenicity.
MANAGEMENT OF PCOS 315
Table 4.2 Pharmacological treatment of hirsutism

Ovarian androgen suppression Combined oral contraceptive pill
GnRH analogues (rarely)
Adrenal androgen suppression Corticosteroids (rarely)
Androgen receptor antagonists Spironolactone
Cyproterone acetate
Flutamide
Reductase inhibitor Finasteride
Insulin sensitizers Metformin
Topical inhibitors of hair follicle growth Eflornithine
Ovarian androgen suppression

Combined oral contraceptive pill (COCP)
• The oestrogen component increases SHBG levels and thus reduces
free androgen concentrations; the progestagen component inhibits LH
secretion and thus ovarian androgen production.
• Dianette® (co-cyprindiol), which contains cyproterone acetate (2mg),
or Yasmin®, which contains drospirenone, are preferred because the
progestagens are antiandrogenic. Benefit of these brands over third
generation COCP has not been established, so brands, such as Cilest®,
Marvelon®, and Femodene®, make suitable alternatives.
• The effect of the COCP alone on hair growth is modest, so it may be
combined with an antiandrogen.
GnRH analogues
• Suppress gonadotrophin secretion and thus ovarian androgen
production.
• Rarely used. They cause oestrogen deficiency so have to be combined
with ‘add-back’ oestrogen treatment. Also, they are expensive and
need to be given parenterally.
• Use is confined to ♀ with severe hyperandrogenism in whom
antiandrogens have been ineffective or not tolerated.
Androgen receptor blockers
These are most effective when combined with oral contraceptives. All are
contraindicated in pregnancy. They act by competitively inhibiting the bind-
ing of testosterone and dihydrotestosterone to the androgen receptor.
Spironolactone
• Antiandrogen of choice, particularly in overweight ♀.
• Dose. 100–200mg a day.
• Side effects. Polymenorrhoea if not combined with the COCP. A fifth
of ♀ complain of GI symptoms when on high doses of spironolactone.
Potassium levels should be monitored, and other potassium-sparing
drugs should be avoided.
Cyproterone acetate (CPA)

• Dose. 25–100mg, days 1–10 of the pill cycle, in combination with
the COCP.
• Side effects. Amenorrhoea if given alone for prolonged periods or
in higher doses. Progesterone side effects. Hepatic toxicity rare, but
monitoring of liver function 6-monthly is recommended.
• A washout period of 3–4 months is recommended prior to attempting
conception.
Flutamide
• A potent antiandrogen.
• Dose. 125–250mg a day; 1mg/kg daily may be effective and associated
with a lower frequency of hepatic adverse effects.
• Side effects. Dry skin, nausea in 10%. However, there is a 0.4% risk
of hepatic toxicity, and it should, therefore, be used with extreme
caution.
5α-reductase inhibitors
Block the conversion of testosterone to the more potent androgen
dihydrotestosterone.
• Finasteride:
• Dose. 1–2.5mg a day. A weak antiandrogen.
• Side effects. No significant adverse effects.
• Can be used as monotherapy, or to combine with other
antiandrogens or COCP.
• Adequate contraceptive measures are mandatory because of its
teratogenicity. In addition, pregnancy should not be attempted until
at least 3 months after drug cessation.
Eflornithine 11.5%
• Irreversibly blocks the enzyme ornithine decarboxylase which is
involved in growth of hair follicles.
• It is administered as a topical cream on the face to reduce new hair
growth. Studies have shown its efficacy in the management of mild
facial hirsutism, following at least 8 weeks of treatment. Treatment
should be discontinued if there is no benefit at 4 months. It is not a
depilatory cream and so must be combined with mechanical methods
of hair removal.
• Side effects. Skin irritation with burning or pruritus, acne, hypersensitivity.
Amenorrhoea
• A minimum of a withdrawal bleed every 3 months minimizes the risk
of endometrial hyperplasia.
• Treatment:
• COCP.
• Cyclical progestagen: Cerazette (desogestrel) is a
®
progesterone-only contraceptive pill with minimal androgenic

properties. Medroxyprogesterone acetate 5–10mg bd for 12 days
of each calendar month. Norethisterone should be avoided, as it is
more androgenic.
• Metformin (up to 1g bd) which also improves lipoprotein pattern.
Infertility
Ovulation induction regimens are indicated. Obesity adversely affects fer-
tility outcome, with poorer pregnancy rates and higher rates of miscar-
riage, so weight reduction should be strongly encouraged.
Metformin
• Use remains controversial but probably does not improve pregnancy
rates in insulin-resistant, particularly overweight, ♀ with PCOS. No
reported teratogenic or neonatal complications.
• Dose. 500mg od after meals, to be i gradually to 1g bd. If ovulation
restored following 6 months of treatment, then continue for up to
1 year. If pregnancy does not occur, then consider other treatments.
• Side effects. Nausea, bloating, diarrhoea, vomiting.
Clomifene citrate
• Inhibits oestrogen negative feedback, i FSH secretion and thus
stimulating ovarian follicular growth.
• Dose. 25–150mg a day from day 2 of menstrual cycle for 5 days.
• Response rates. 80% ovulation rate, 67% pregnancy rate.
• Complications. 8% twins, 0.1% higher order multiple pregnancy. Risk of
ovarian neoplasia following prolonged clomiphene treatment remains
unclear, so limit treatment to a maximum of six cycles.
Gonadotrophin preparations (hMG or FSH)
• Used in those unresponsive to clomifene. Low-dose regimes show
better response rates and fewer complications, e.g. 75IU/day for
2 weeks, then increase by 37.5IU/day every 7 days, as required.
• 94% ovulation rate and 50% pregnancy rate.
• Complications. Hyperstimulation, multiple pregnancies.
• Close ultrasonic monitoring is essential.
Surgery
• Laparoscopic ovarian diathermy or laser drilling may restore ovulation
in up to 90% of ♀, with cumulative pregnancy rates of 80% within
8 months of treatment. Particularly effective in slim ♀ with PCOS and
high LH concentrations.
• Complications. Surgical adhesions although usually mild.
In vitro fertilization
• In ♀ who fail to respond to ovulation induction.
• 60–80% conception rate after six cycles.
Acne
Treatment for acne should be started as early as possible to prevent scar-
ring. All treatments take up to 12 weeks before significant improvement
is seen. All treatments, apart from benzoyl peroxide, are contraindicated
in pregnancy.
Mild-to-moderate acne
Topical benzoyl peroxide 5%. Bactericidal properties. May use in conjunc-
tion with oral antibiotic therapy to reduce the risk of developing resistance
to antibiotics. Side effects: skin irritation and dryness. Add oral antibiotics
if no improvement after 2 months of treatment.
Moderate-to-severe acne
• Topical retinoids, e.g. tretinoin, isotretinoin. Useful alone in mild acne
or in conjunction with antibiotics in moderately severe acne. Continue
as maintenance therapy to prevent further acne outbreaks. Side
effects: irritation, photosensitivity. Apply high factor sunscreen before
sun exposure. Avoid in acne involving large areas of skin.
• Oral antibiotics, e.g. oxytetracycline 500mg bd, doxycycline 100mg od, or
minocycline 100mg od. Response usually seen by 6 weeks and full efficacy
by 3 months. Continue antibiotics for 2 months after control is achieved.
Prescription usually given for a course of 3–6 months. Continue topical
retinoids and/or benzoyl peroxide to prevent further outbreaks.
• COCP and antiandrogens. As for hirsutism.
Severe acne
Isotretinoin is very effective in ♀ with severe acne or acne which has not
responded to other oral or topical treatments. Used early, it can minimize
scarring in inflammatory acne. However, it is highly toxic and can only be
prescribed by a consultant dermatologist. Also consider referring ♀ who
develop acne in their 30s or 40s and ♀ with psychological problems as a
result of acne.
Further reading
Diamanti-Kandarakis E, Dunaif A. (2012). Insulin resistance and the polycystic ovary syndrome
revisited: an update on mechanisms and implications. Endocr Rev 33, 981–1030.
Dunaif A (1997). Insulin resistance and polycystic ovary syndrome: mechanism and implications for
pathogenesis. Endoc Rev 18, 774–800.
Ehrmann DA (2005). Polycystic ovary syndrome. N Engl J Med 352, 1223–36.
Ehrmann DA, Rychlik D (2003). Pharmacological treatment of polycystic ovary syndrome. Semin
Reprod Med 21, 277–83.
Ledger WL, Clark T (2003). Long term consequences of polycystic ovary syndrome. Royal College of
Obsterics and Gynaecology Guideline number 33. Royal College of Obstetrics and Gynaecology,
London.
Lord JM, Flight IHK, Norman RJ (2003). Insulin sensitizing drugs for polycystic ovary syndrome.
Cochrane Database Syst review 2003.
Neithardt AB, Barnes RB (2003). The diagnosis and management of hirsutism. Semin Reprod Med
21,285–93.
Nestler JE (2008). Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med
358, 47–54.
Palomba S (2009). Evidence-based and potential benefits of metformin in the polycystic ovary
syndrome: a comprehensive review. Endocr Rev 30, 1–50.
Paradisi R (2010). Retrospective observational study on the effects and tolerability of flutamide
in a large population of patients with various kinds of hirsutism over a 15-year period. Eur J
Pierpoint T, McKeigue PM, Isaacs AJ, et al. (1998). Mortality of women with polycystic ovary
syndrome at long term follow up. J Clin Epidemiol 51, 581–6.
Randeva HS, et al. (2012). Cardiometabolic aspects of the polycystic ovary syndrome. Endocr Rev
33, 812–41.
The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group (2004). Revised
2003 Consensus on diagnostic criteria and long-term health risks related to polycystic ovary
syndrome. Hum Reprod 19, 41–7.
Tsilchorozidou T, Overton C, Conway GS (2004). The pathophysiology of polycystic ovary
syndrome. Clin Endocrinol 60, 1–17.
Congenital adrenal hyperplasia

(CAH) in adults
Definition
CAH is a group of inherited disorders characterized by a deficiency of one
of the enzymes necessary for cortisol biosynthesis.
• >90% of cases are due to 21A-hydroxylase deficiency.
• Wide clinical spectrum, from presentation in neonatal period with salt
wasting and virilization to non-classic CAH in adulthood.
• Autosomal recessive.
• Clinical presentation depends on severity of mutation.
Epidemiology
• Carrier frequency of classic CAH 1:60–1:100 in Caucasians.
• Carrier frequency of non-classic CAH 19% in Ashkenazi Jews, 13.5% in
Hispanics, 6% in Italians, and 3% in other Caucasian populations.
Pathogenesis
Genetics
• CYP21 encodes for the 21A-hydroxylase enzyme, located on the short
arm of chromosome 6 (chromosome 6p21.3). In close proximity is the
CYP21 pseudogene, with 90% homology but no functional activity.
• 21A-hydroxylase deficiency results from gene mutations, partial
gene deletions, or gene conversions in which sequences from the
pseudogene are transferred to the active gene, rendering it inactive.
There is a correlation between the severity of the molecular defect
and the clinical severity of the disorder. Non-classic CAH is usually
due to a point mutation (single base change); missense mutations
result in simple virilizing disease, whereas a gene conversion or partial
deletion usually results in presentation in infancy, with salt wasting or
severe virilization.
Biochemistry
(See Fig. 4.3.)
21A-hydroxylase deficiency results in aldosterone and cortisol defi-
ciency. Loss of –ve feedback from cortisol results in ACTH hyperse-
cretion, and this causes adrenocortical hyperplasia and accumulation of
steroid precursors ‘above’ the enzyme deficiency, including progesterone
and 17-hydroxyprogesterone (17OHP). These are then shunted into
androgen synthesis pathways, resulting in testosterone and androstenedi-
one excess.
CONGENITAL ADRENAL HYPERPLASIA (CAH) IN ADULTS 321
Cholesterol
17α OH 17α OH
Pregnenolone 17OH Pregnenolone Dehydroepiandrosterone
3βHSD 17β HSD Aromatase
Progesterone 17OH Progesterone Androstenedione Testosterone Oestradiol
21 OH 21 OH
Deoxycorticosterone 11-Deoxycortisol
11βOH 11β OH
Corticosterone Cortisol
18-OH Corticosterone
Aldosterone
Fig. 4.3 Adrenal steroid biosynthesis pathway.
Clinical presentation
Classic CAH
• Most patients are diagnosed in infancy, and their clinical presentation is
discussed elsewhere (b see Congenital adrenal hyperplasia, p. 320).
• Problems persisting into adulthood. Sexual dysfunction and subfertility
in ♀, particularly in salt wasters. Reconstructive genital surgery is
required in the majority of ♀ who were virilized at birth to create an
adequate vaginal introitus. With improvement of medical care, normal
pregnancy rates (90%) can be achieved.
• In ♂, high levels of adrenal androgens suppress gonadotrophins
and thus testicular function. i ACTH results in the development of
testicular adrenal rest tissue (TARTs). These are always benign but
may be misdiagnosed as testicular tumours. TARTs can be destructive,
leading to testicular failure. Spermatogenesis is often low if CAH is
poorly controlled.
• There is a significant risk of adrenal crises over lifetime.
• There is an impaired quality of life.
Non-classic CAH
• Due to partial deficiency of 21A-hydroxylase. Glucocorticoid and
aldosterone production are normal, but there is overproduction of
17OHP and thus androgens.
• Present with hirsutism (60%), acne (33%), and oligomenorrhoea (54%),
often around the onset of puberty. Only 13% of ♀ present with
subfertility.
• Polycystic ovaries on US are common, and adrenal incidentalomas or
hyperplasia are seen in 40%.
• Asymptomatic in ♂. The effect of non-classic CAH on ♂ fertility is
unknown.
Investigations of CAH in adults

Because of the diurnal variation in adrenal hormonal secretion, all investi-
gations should be performed at 9 a.m.
Diagnosis of non-classic CAH—17OHP measurement
Timing of measurement
• Screen in the follicular phase of the menstrual cycle. 17OHP is
produced by the corpus luteum, so false +ve results may occur if
measured in the luteal phase of the cycle.
Interpretation of result
• <5nmol/L—normal.
• >15nmol/L—CAH.
• 5–15nmol/L—proceed to ACTH stimulation test. A fifth will have
non-classic CAH.
ACTH stimulation test
• Measure 17OHP 60min after ACTH administration.
• An exaggerated rise in 17OHP is seen in non-classic CAH.
• 17OHP level <30nmol/L post-ACTH excludes the diagnosis.
• Most patients have levels >45nmol/L.
• Levels of 30–45nmol/L suggest heterozygosity or non-classic CAH.
• Cortisol response to ACTH stimulation is usually low normal.
Other investigations
Androgens
• In poorly controlled classic CAH in ♀, testosterone and
androstenedione levels may be in the adult ♂ range.
Dehydroepiandrosterone sulphate levels are usually only mildly, and
not consistently, elevated in CAH.
• Circulating testosterone, and particularly androstenedione, is elevated
in non-classic CAH, but there is a large overlap with levels seen
in PCOS, so serum androgen concentrations cannot be used to
distinguish between the disorders.
Renin
• Plasma renin activity elevated due to aldosterone deficiency, indicating
inadequate fludrocortisone dose if markedly raised.
• A proportion of ♀ with non-classic CAH may also have mildly
elevated renin concentrations.
ACTH
• Greatly elevated in poorly controlled classic CAH.
• Usually normal levels in non-classic CAH.
See Table 4.3 for a list of enzyme deficiencies in CAH.
INVESTIGATIONS OF CAH IN ADULTS 323
Table 4.3 Enzyme deficiencies in CAH

Enzyme deficiency Incidence Clinical features
(per births)
Classic 1:10,000–1:15,000 Salt wasting, ambiguous genitalia
21A-hydroxylase in females, precocious pubarche
in males
Non-classic 1:27–1:1,000 Hirsutism, oligomenorrhoea
21A-hydroxylase in pubertal girls, asymptomatic
(partial deficiency) in boys
11B-hydroxylase 1:100,000 Ambiguous genitalia, virilization,
hypertension
3B-hydroxylase Rare Mild virilization, salt wasting in
severe cases
17A-hydroxylase Rare Delayed puberty in females,
pseudohermaphroditism in males,
hypertension, hypokalaemia
Management of CAH in adults

The aims of treatment of CAH in adulthood under specialist care are:
• To maintain normal energy levels and weight and avoid adrenal crises.
• To minimize hyperandrogenism and to restore regular menses and
fertility in ♀.
• To avoid glucocorticoid over-replacement.
• To treat stress with adequate extra glucocorticoid.
Classic CAH
• Prednisolone. Total dose 5–7.5mg/day. Given in two divided doses,
with one-third of the total dose given on waking (about 7 a.m.) and
two-thirds of the dose on retiring. The aim is to suppress the early
morning peak of ACTH and thus androgen secretion. The optimum
dose is the minimum dose required to normalize serum androgens.
Occasional patients who are not controlled on prednisolone may be
optimally treated with nocturnal dexamethasone instead (0.25–0.5mg
nocte).
• As with other forms of adrenal insufficiency, glucocorticoid doses
should be doubled during illness. This is discussed in detail elsewhere
(b see p. 274).
• Those with salt-losing form of CAH and who require
mineralocorticoid replacement therapy with fludrocortisone in a dose
of 50–200 micrograms/day is given as a single daily dose. The aim is
to avoid suppression of plasma renin activity and risk of hypertension.
Normal or slightly elevated levels are accepted.
• Bilateral adrenalectomy may, very occasionally, be considered for
intractable infertility in females.
• Pregnancy. Patient and partners require prior CYP21 mutation analysis
at the earliest opportunity to enable genetic counselling. If partner
is a carrier, 50% risk of affected child (1 in 63 is a carrier of the 21
OH gene).
Non-classic CAH
• Oligo-/amenorrhoea. Prednisolone 2.5–5mg/day may be used but is
often reserved to normalize ovulatory function.
• Hirsutism and acne. May alternatively, and more effectively, be treated
as for PCOS (b see Management, p. 314). Spironolactone should
be avoided because of the potential risk of salt wasting and thus
hyperreninaemia.
• If plasma renin level is elevated, then fludrocortisone, given in a dose
sufficient to normalize renin concentrations, may improve adrenal
hyperandrogenism.
• ♂ may not require treatment. The occasional ♂ may need
glucocorticoids to treat subfertility.
MANAGEMENT OF CAH IN ADULTS 325
Management of pregnancy in CAH

• Maternal classic CAH. Screen patient/partner using basal ±
ACTH-stimulated 17OHP levels (b see Investigations, p. 322). If levels
elevated, proceed to genotyping. If heterozygote, then preimplantation
genetic diagnosis or prenatal treatment of fetus may be considered.
• Physiological prednisolone or hydrocortisone rarely needs adjusting in
pregnancy. Routine biochemical markers cannot be used in pregnancy,
so treat symptomatically.
• Adjust fludrocortisone against BP.
• Placental aromatase protects fetus from maternal androgens. >200
pregnancies reported to mothers with CAH—no case of fetal
virilization recorded, so monitoring testosterone not required.
• >75% Caesarian section rate because of masculinized pelvis and
surgical scarring following vaginoplasty.
• Routine glucocorticoid boost at delivery.
Prenatal treatment of pregnancies at risk of CAH
Aim of prenatal treatment is to prevent virilization of an affected ♀ fetus.
• Only to be considered if previous child from same partner with CAH
or known mutations in both parents. Mutations must be identified well
before trying to conceive (this cannot be done on the run).
• NOT for mothers with CAH, unless partner is a known carrier of a
severe mutation.
• Only to be considered by experienced unit. Current guidelines
consider this still in the realms of research, as long-term outcome of
dexamethasone exposure to unaffected fetuses is unknown.
Treatment (commenced before 10 weeks’ gestation)
Dexamethasone (20 micrograms/kg maternal body weight), in three
divided doses a day, crosses the placenta and reduces fetal adrenal hyper-
androgenism. Discontinue if ♂ fetus.
Outcome
50–75% of affected ♀ do not require reconstructive surgery.
Monitoring of treatment
Annual follow-up is usually adequate in adults.
• Clinical assessment. Measure BP and weight. Look for evidence of
hyperandrogenism and glucocorticoid excess. Amenorrhoea in ♀
usually suggests inadequate therapy but may have to be accepted as
can often not be achieved without excessive doses of glucocorticoid.
• Suppressed levels of 17OHP, testosterone (T), and renin are an
indication for reduced dose of steroid. Normalizing will often result in
complications from supraphysiological doses of glucocorticoids.
• Modestly raised or high normal levels of 17OHP, T, and renin are
optimal.
• Consider bone density which may be reduced by supraphysiological
steroid doses.
• Testicular function requires special attention. Low LH is a sign of
raised adrenal androgens. Raised FSH may follow adrenal rests as a
sign of testicular failure. US testis every 3–5 years. Consider sperm
count/storage if adrenal rests are present.
• US ovaries not useful routinely, as PCO morphology is common.
• In men, testicular adrenal rest tumours may develop (up to 94%). Their
detection may prevent infertility later. Ultrasound screening of the
scrotum is suggested every 2 years.
Prognosis
Adults with treated CAH have a normal life expectancy. Improvement
in medical and surgical care has also improved QoL for most sufferers.
However, there are a few unresolved issues:
• Height. Despite optimal treatment in childhood, patients with CAH
are, on average, significantly shorter than their predicted genetic
height. Studies suggest that this may be due to overtreatment with
glucocorticoids during infancy.
• Fertility. Mainly a problem in ♂ with poorly controlled classic CAH
and adrenal rests.
• Adrenal incidentalomas. Benign adrenal adenomas have been reported
in up to 50% of patients with classic CAH. ♂ with CAH may develop
gonadal adrenocortical rests.
• Psychosexual issues. Gender dysphoria common in ♀. A significant
number of ♀ with classic CAH, despite adequacy of vaginal
reconstruction, are not sexually active.
MONITORING OF TREATMENT 327
Further reading
Arlt W, et al. (2010). Health status of adults with congenital adrenal hyperplasia: a cohort study of
203 patients. J Clin Endocrinol Metab 95, 5110–21.
Aycan Z, Bas VN, Cetinkaya S, et al. (2013) Prevalence and long-term follow-up outcomes of
testicular adrenal rest tumours in children and adolescent males with congenital adrenal hyper-
plasia. Clin Endocrinol 78, 667–72.
Cabrera MS, Vogiatzi MG, New MI (2001). Long term outcome in adult males with classic congeni-
tal adrenal hyperplasia. J Clin Endocrinol Metab 86, 3070–8.
Joint LWPES/ESPE CAH Working Group (2002). Consensus statement on 21-hydroxylase defi-
ciency from the Lawson Wilkins Paediatric Endocrine Society and the European Society for
Paediatric Endocrinology. J Clin Endocrinol Metab 87, 4048–53.
Merke DP (2008). Approach to the adult with congenital adrenal hyperplasia due to 21-hydroxylase
deficiency. JCEM 93, 653–60.
New MI (2006). Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin
New MI, Carlson A, Obeid J, et al. (2001). Prenatal diagnosis for congenital adrenal hyperplasia in
532 pregnancies. J Clin Endocrinol Metab 86, 5651–757.
Ogilvie CM, Crouch NS, Rumsby G, et al. (2006). Congenital adrenal hyperplasia in adults: a review
of medical, surgical and psychological issues. Clin Endocrinol 64, 2–11.
Premawaradhana LDKE, Hughes IA, Read GF, et al. (1997). Longer term outcome in females with
congenital adrenal hyperplasia: the Cardiff experience. Clin Endocrinol 46, 327–32.
Speiser PW, White PC (2003). Congenital adrenal hyperplasia. N Engl J Med 349, 776–88.
Speiser PW, et al. (2010). Congenital adrenal hyperplasia due to steroid 21-hydroxylase defi-
ciency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95, 4133–60.
Androgen-secreting tumours
Definition
Rare tumours of the ovary or adrenal gland which may be benign or malig-
nant, which cause virilization in ♀ through androgen production.
Epidemiology and pathology
Androgen-secreting ovarian tumours
• 75% develop before the age of 40 years.
• Account for 0.4% of all ovarian tumours; 20% are malignant.
• Tumours are 5–25cm in size. The larger they are, the more likely they
are to be malignant. They are rarely bilateral.
• Two major types:
• Sex cord stromal cell tumours: often contain testicular cell types.
• Adrenal-like tumours: often contain adrenocortical or Leydig cells.
• Other tumours, e.g. gonadoblastomas and teratomas, may also, on
occasion, present with virilization.
Androgen-secreting adrenal tumours
• 50% develop before the age of 50 years.
• Larger tumours, particularly >6cm, are more likely to be malignant.
• Usually with concomitant cortisol secretion as a variant of Cushing’s
syndrome.
Clinical features
• Onset of symptoms. Usually recent onset of rapidly progressive
symptoms.
• Hyperandrogenism:
• Hirsutism of varying degree, often severe; male pattern balding and
acne are also common.
• Usually oligo-/amenorrhoea.
• Infertility may be a presenting feature.
• Virilization. (b see Box 4.1, p. 305.) Indicates severe hyperandrogenism,
is associated with clitoromegaly, and is present in 98% of ♀ with
androgen-producing tumours. Not usually a feature of PCOS.
• Other:
• Abdominal pain.
• Palpable abdominal mass.
• Ascites.
• Symptoms and signs of Cushing’s syndrome are present in many of
♀ with adrenal tumours.
Investigations
See Fig. 4.4.
ANDROGEN-SECRETING TUMOURS 329
Short history of hirsutism and virilization (weeks/months)
Serum testosterone
>5 i nmol/L
DHEAS i in adrenal tumours

Androstenedione i in ovarian tumours
17 OHP may i be in both. Exclude CAH
UFC i in adrenal tumours
Ovarian US
MRI adrenal glands and ovaries
only if −ve imaging
Selective venous sampling
Fig. 4.4 Investigation of androgen-secreting tumours.
Management
Surgery
• Adrenalectomy or ovarian cystectomy/oophorectomy.
• Curative in benign lesions.
Adjunctive therapy
Malignant ovarian and adrenal androgen-secreting tumours are usually
resistant to chemotherapy and radiotherapy.
Prognosis
Benign tumours
• Prognosis excellent.
• Hirsutism improves post-operatively, but clitoromegaly, male pattern
balding, and deep voice may persist.
Malignant tumours
• Adrenal tumours. 20% 5-year survival. Most have metastatic disease at
the time of surgery.
• Ovarian tumours. 30% disease-free survival and 40% overall survival at
5 years.
Further reading
Hamilton-Fairley D, Franks S (1997). Androgen-secreting tumours. In: Sheaves R, Jenkins PJ, Wass
JAH (eds.) Clinical endocrine oncology, pp. 323–9. Blackwell Science, Oxford.
Rothman MS, Wierman ME (2011). How should postmenopausal androgen excess be evaluated?
Clin Endocrinol (Oxf) 75, 160–4.
Menstrual function disorder—

assessment and investigation
Definitions
• Oligomenorrhoea is defined as the reduction in the frequency of
menses to <9 periods a year.
• 1° amenorrhoea is the failure of menarche by the age of 16 years.
Prevalence 70.3%
• 2° amenorrhoea refers to the cessation of menses for >6 months in ♀
who had previously menstruated. Prevalence 73%.
• See Table 4.4 for WHO categorization.
Aetiology
Although the list of causes is long (see Box 4.5 for causes), the majority of
cases of secondary amenorrhoea can be accounted for by four conditions:
• Hypothalamic amenorrhoea.
• Hyperprolactinaemia.
• Ovarian failure.
Table 4.4 WHO categorization of hypogonadism

WHO group LH and FSH Clinical
I d Hypogonadotrophic hypogonadism
II l PCOS or mild hypothalamic amenorrhoea
III i POF
MENSTRUAL FUNCTION DISORDER 331
Box 4.5 Causes of amenorrhoea

Physiological
• Pregnancy and lactation.
• Post-menopause.
Iatrogenic
• Depot medroxyprogesterone acetate.
• Levonorgestrel-releasing intrauterine device.
• Progesterone-only pill.
Pathological—1°
• Chromosomal abnormalities—50%:
• Turner’s syndrome.
• Other X chromosomal disorders.
• s hypogonadism—25%:
• Kallmann’s syndrome.
• Pituitary disease.
• Genitourinary malformations—15%:
• Imperforate hymen.
• Absence of uterus, cervix, or vagina, e.g. Rokitansky syndrome,
androgen insensitivity syndrome.
• Other—10%:
• CAH.
• PCOS.
Most causes of s amenorrhoea can also cause p amenorrhoea.
Pathological—2°
• Ovarian—70%:
• PCOS.
• Premature ovarian failure.
• Hypothalamic—15%:
• Hypogonadotrophic hypogonadism.
• Weight loss.
• Infiltrative lesions of the hypothalamus.
• Drugs, e.g. opiates.
• Pituitary—5%:
• Uterine—5%:
• Intrauterine adhesions—Asherman’s syndrome.
• Other endocrine disorders—5%:
• Thyroid dysfunction.
• Hyperandrogenism—Cushing’s syndrome, CAH, tumour.
Menstrual function disorder—clinical

evaluation
PCOS is the only common endocrine cause of amenorrhoea with normal
oestrogenization—all other causes are oestrogen-deficient. Women with
PCOS, therefore, are at risk of endometrial hyperplasia, and all others are
at risk of osteoporosis.
History
• Oestrogen deficiency, e.g. hot flushes, reduced libido, and dyspareunia.
• Hypothalamic dysregulation, e.g. exercise and nutritional history, body
weight changes, emotional stress, recent or chronic physical illness.
• In p amenorrhoea—history of breast development, history of cyclical
pain, age of menarche of mother and sisters.
• In s amenorrhoea—duration and regularity of previous menses,
family history of early menopause or familial autoimmune disorders, or
galactosaemia.
• Anosmia may indicate Kallman’s syndrome.
• Hirsutism or acne.
• Galactorrhoea.
• History suggestive of pituitary, thyroid, or adrenal dysfunction.
• Drug history—e.g. causes of hyperprolactinaemia, chemotherapy,
hormonal contraception, recreational drug use.
• Obstetric and surgical history.
• Height, weight, BMI.
• Features of Turner’s syndrome or other dysmorphic features.
• s sex characteristics.
• Galactorrhoea.
• Evidence of hyperandrogenism or virilization.
• Evidence of thyroid dysfunction.
• Anosmia, visual field defects.
Amenorrhoea with normal gonadotrophins—WHO
group II
In routine practice, a common differential diagnosis is between mild
version of PCOS and hypothalamic amenorrhoea (HA). The distinc-
tion between these conditions may require repeated testing, as a single
snapshot may not discriminate. The reason to be precise is that PCOS is
oestrogen-replete and will, therefore, respond to clomiphene citrate (an
antioestrogen) for fertility. HA will be oestrogen-deficient and will need
HRT and ovulation induction with pulsatile GnRH or hMG.
For comparison, see Table 4.5.
MENSTRUAL FUNCTION DISORDER—CLINICAL EVALUATION 333
Table 4.5 Comparison of two common causes of amenorrhoea with

normal gonadotrophins
PCOS Hypothalamic amenorrhoea
Exercise programme Rare Common
Androgen excess Common Rare
BMI usually >21 <21
LH i or l d or l
Polycystic ovaries 90% 20%
Endometrial thickness >4mm <5mm
Menstrual function
disorder—investigations
(See Fig. 4.5.)
• Is it p or s ovarian dysfunction?
• FSH, LH, TFT, oestradiol, prolactin.
• Ultrasound:
• Ovarian and uterine morphology—exclude anatomical
abnormalities, PCOS, and Turner’s syndrome.
• Note that PCO morphology is present in 20% of all women, so
their presence may be false +ve.
• Endometrial thickness—to assess oestrogen status.
• Other tests, depending on clinical suspicion:
• Induce withdrawal bleed with progesterone (e.g. 10mg
medroxyprogesterone acetate bd for 7 days). If a bleed occurs,
then there is adequate oestrogen priming and endometrial
development. This test has poor specificity and sensitivity and has
been abandoned in favour of ultrasound in many centres.
• Serum testosterone in the presence of hyperandrogenism.
• Karyotype in ovarian failure or disorder of sexual development
suspects (absent uterus).
• MRI of the pituitary fossa if FSH low or in the presence of
hyperprolactinaemia.
• Bone density if long-term oestrogen deficiency.
History/ Exclude structural

physical exam abnormality
Exclude
pregnancy
FSH, LH,
prolactin
FSH >30IU/I FSH, LH ↓ Prolactin ↑ FSH normal
1º Hypogonadotrophic Hyperprolactinaemia:
ovarian failure: hypogonadism: rule out PCOS
rule out hypothyroidism and
check karyotype pituitary adenoma pituitary adenoma
Fig. 4.5 Investigation of amenorrhoea.

MANAGEMENT OF AMENORRHOEA 335
Management of amenorrhoea
• Treat underlying disorder, for example:
• Dopamine agonists for prolactinomas.
• Pituitary surgery for pituitary tumours.
• Eating disorder clinic in anorexia nervosa.
• Treat oestrogen deficiency—oestrogen/progestagen preparations.
• Treat infertility—b see p. 334.
• In PCOS with endometrial hyperplasia—progesterone withdrawal
bleed, and consider hysteroscopy in resistant cases.
• See Box 4.6 for progesterone sensitivity.
Box 4.6 Progesterone sensitivity

• Skin condition occurs regularly premenstrually—settling with onset
of menses.
• Dermatosis includes eczema, pompholyx, urticaria, and erythema
multiforme.
• Autoantibodies present (+ve challenge test).
Further reading
Baird DT (1997). Amenorrhoea. Lancet 350, 275–9.
Beswick SJ, Lewis HM, Stewart PM (2002). A recurrent rash treated by oophorectomy. QJM
95, 636–7.
Hickey M, Balen A (2003). Menstrual disorders in adolescence: investigation and management. Hum
Reprod Update 9, 493–504.
Premature ovarian insufficiency

(POI), including Turner’s syndrome
in adults
Definition
POI is a disorder characterized by amenorrhoea, oestrogen deficiency,
and elevated gonadotrophins, developing in ♀ <40 years, as a result of
loss of ovarian follicular function. See Box 4.7 for Turner’s syndrome and
Table 4.6 for correlation of karyotype with phenotype.
Epidemiology
• Incidence—0.1% of ♀ <30 years and 1% of those <40 years.
• Accounts for 10% of all cases of s amenorrhoea.
• 20% familial.
• 80% idiopathic.
Causes of POI
• Chromosomal abnormalities (5–10%):
• Fragile X premutations.
• Other X chromosomal abnormalities.
• Gene mutations:
• Galactosaemia.
• A variety of rare single gene defects that are not yet part of routine
testing (e.g. NOBOX, FSHR, FOXL2).
• Autoimmune disease (20%).
• Iatrogenic:
• Chemotherapy.
• Radiotherapy.
• Pelvic surgery.
• Other:
• Enzyme deficiencies, e.g. 17-hydroxylase deficiency.
• Infections, e.g. mumps, CMV.
• Idiopathic:
• ? environmental toxin.
Pathogenesis
POI is the result of accelerated depletion of ovarian germ cells. Previously
used term of ‘resistant ovary syndrome’ describes a mild form of POI that
gradually progresses to amenorrhoea. Ovarian biopsy is no longer used,
as this had no diagnostic value. Conversely, ovarian dysgenesis refers to
early onset with primary amenorrhoea and describes the severe end of
the condition.
POI is usually permanent and progressive, although a remitting course is
also experienced and cannot be fully predicted, so all women must know
that pregnancy is possible, even though fertility treatments are not effec-
tive (often a difficult paradox to describe). Spontaneous pregnancy has
been reported in 5%.
PREMATURE OVARIAN INSUFFICIENCY (POI) 337
Box 4.7 Turner’s syndrome

(b also see Turner’s syndrome, p. 336)
• Most common X chromosome abnormality in ♀, affecting 1:2,500
live ♀ births.
• Result of complete or partial absence of an X chromosome.
• Clinical features. Short stature and gonadal dysgenesis; 80% of
affected ♀ have POI.
• Characteristic phenotype. Webbed neck, micrognathia, low-set ears,
high arched palate, widely spaced nipples, and cubitus valgus.
• Other associated abnormalities. Aortic coarctation and other
left-sided congenital heart defects, hypothyroidism, osteoporosis,
skeletal abnormalities, lymphoedema, coeliac disease, congenital
renal abnormalities, and ENT abnormalities.
• Diagnosis. Lymphocyte karyotype.
• Management in adults:
• Sex hormone replacement therapy.
• Treat complications.
• Follow-up:
• Baseline renal US, thyroid autoantibodies.
• Annual BMI, BP, TFT, lipids, fasting blood glucose, liver function.
• 3–5-yearly echocardiogram and bone densitometry.
• Hearing loss 5 years.
Table 4.6 Correlation of karyotype with phenotype

Karyotype Phenotype
45, X (50%) Most severe phenotype
High incidence of cardiac and renal
abnormalities
46, Xi(Xq) (20%) i prevalence of thyroiditis, inflammatory bowel
disease, and deafness
45, X/46, XX (10%) Least severe phenotype
i mean height
Spontaneous puberty and menses in up to 40%
46, Xr(X) (10%) Spontaneous menses in 33%
Congenital abnormalities uncommon
Cognitive dysfunction in those with a small ring
chromosome
45, X/46, XY (6%) i risk of gonadoblastoma (need gonadectomy)
Other (4%)
• Amenorrhoea:
• May be p or s.
• Symptoms of oestrogen deficiency:
• Not present in those with p amenorrhoea.
• 75% of ♀ who develop s amenorrhoea report hot flushes, night
sweats, mood changes, fatigue, or dyspareunia; symptoms may
precede the onset of menstrual disturbances.
• Autoimmune disease:
• Screen for symptoms and signs of associated autoimmune
disorders.
• Other:
• Past history of radiotherapy, chemotherapy, or pelvic surgery.
• +ve family history in 20% of patients; careful history is required to
detect inheritance through father.
• With idiopathic POI, ovarian function can resume in most within a
year of diagnosis. Spontaneous pregnancies have been recorded, so
ultrasound assessment of follicles and measurement of inhibin B and
oestradiol may be helpful.
• See Box 4.8 for autoimmune diseases.
Box 4.8 Autoimmune diseases and POI

• Responsible for 20% of cases of POI.
• A second autoimmune disorder is present in 10–40% of ♀ with
autoimmune POI:
• Autoimmune thyroid disease 25%.
• Addison’s disease 10%.
• Type 1 diabetes mellitus 2%.
• Myasthenia gravis 2%.
• B12 deficiency.
• SLE is also more common.
• Autoimmune endocrinopathies:
• 60% of ♀ with autoimmune polyglandular syndrome type 1
(b see p. 270).
• 25% of ♀ with autoimmune polyglandular syndrome type 2
(b see p. 271).
• Steroid cell antibodies are +ve in 60–100% of patients with Addison’s
disease in combination with POI. The presence of +ve steroid
cell antibodies in ♀ with Addison’s disease confers a 40% risk of
ultimately developing POI. Other ovarian antibodies have little
predictive value.
INVESTIGATION OF POI 339
Investigation of POI
• Serum gonadotrophins:
• Diagnosis is confirmed by serum FSH >40mIU/L on at least two
occasions at least 1 month apart.
• Disease may have a fluctuating course, with high FSH levels
returning to normal and later regain of ovulatory function.
• LH also elevated but FSH usually disproportionately higher
than LH.
• Serum oestradiol levels are usually low.
• Anti-Müllerian hormone—only useful in early stages or at-risk groups,
not in established cases.
• Karyotype:
• All ♀ presenting with hypergonadotrophic amenorrhoea below age
40 should be karyotyped.
• ♀ with Y chromosomal material should be referred for bilateral
gonadectomy to prevent the development of gonadoblastoma.
• Pelvic US—to identify normal ovarian and uterine morphology.
• Bone mineral density—risk of osteoporosis.
• Screen for autoimmune disease:
• Thyroid autoantibodies: if +ve, extend autoimmune screen to
include adrenal, parietal cell, intrinsic factor.
• Ovarian antibodies are rarely +ve—poor sensitivity.
• TSH, vitamin B12.
• Synacthen test only if adrenal insufficiency is suspected clinically.
®
• Ovarian biopsy—not indicated.

Management of POI
Sex hormone replacement therapy
• Exogenous oestrogens (HRT) are required to alleviate symptoms
and prevent the long-term complications of oestrogen deficiency—
osteoporosis and possibly cardiovascular disease. Initial doses depend
on the duration of amenorrhoea—if oestrogen-deficient for at least
12 months, then start on lowest doses of estradiol available to prevent
side effects, but titrate up to full dose within 6 months. If recently
amenorrhoeic, then full dose may be commenced immediately (see
Table 4.7).
• Doses used in HRT are not contraceptive and do not suppress
spontaneous ovarian follicular activity. Women who do not wish
to conceive may use COCP instead of HRT—beware E2-deficient
symptoms in pill-free week.
• HRT should be continued at least until the age of 50 years, the mean
age of the natural menopause.
• In non-hysterectomized ♀, a progestagen should be added for
12–14 days a month to prevent endometrial hyperplasia.
• Low-dose androgen replacement therapy may improve persistent
fatigue and poor libido, despite adequate oestrogen replacement.
Fertility
• A minority of ♀ with POI and a normal karyotype will recover
spontaneously; 5% spontaneous fertility rate.
• Ovum donation is the only realistic chance of fertility. Pregnancy rate
>50% per patient. Results are less good in ♀ if uterine damage after
pelvic radiotherapy.
• Ovulation induction therapy has been tried, but the results have
been poor.
• Glucocorticoid therapy has been used in autoimmune POI, but efficacy
is poor.
• Recent improvements in methods of oocyte cryopreservation using
rapid freezing in liquid nitrogen (vitrification) have allowed ♀ with high
chance of POI (e.g. before chemo-/radiotherapy, Turner’s syndrome
mosaics with retained ovarian function) to store oocytes collected
after superovulation.
Psychology
• Reduced self-esteem and sexual responsiveness.
• Reactive depression common at diagnosis and may return at critical
times, such as pregnancy in a close friend.
For a full review of hormone replacement therapy, b see Menopause,
p. 342.
MANAGEMENT OF POI 341
Table 4.7 Hormone replacement therapy in POI

Hormone replacement Dose
Oestrogen
Conjugated estrogens 0.625–1.25mg daily
Estradiol valerate 1–2mg daily
Transdermal estradiol 50–100 micrograms twice a week
Progestagen 12–14 days a month
Norethisterone 1mg
Medroxyprogesterone 10mg
Prognosis
• Mortality of ♀ with POI may be i 2-fold.
• Oestrogen deficiency leads to:
• i risk of cardiovascular and cerebrovascular disease.
• i risk of osteoporosis. Up to two-thirds of ♀ with POI and a
normal karyotype have d BMD, with a Z score of –1 or less,
despite at least intermittent hormone replacement therapy.
This may be due to a combination of factors, including an initial
delay in initiating ERT, poor compliance with ERT, and oestrogen
‘underdosing’.
Further reading
Barlow DH (1996). Premature ovarian failure. Baillière Clin Ob Gy 10, 361–84.
Davies MC, Cartwright B (2012). What is the best management strategy for a 20-year-old woman
with premature ovarian failure? Clin Endocrinol (Oxf) 77, 182–6.
Kalantaridou SN, Davis SR, Nelson LM (1998). Premature ovarian failure. Endocrinol Metab Clin
27, 989–1006.
Nelson LM (2009). Clinical practice. Primary ovarian insufficiency. N Engl J Med 360, 606–14.
Welte CK (2008). Primary ovarian insufficiency: a more accurate term for premature ovarian
failure. Clin End 68, 499–509.
Menopause
Definition
• The menopause is the permanent cessation of menstruation as a result
of ovarian failure and is a retrospective diagnosis made after 12 months
of amenorrhoea. The average age of ♀ at the time of the menopause
is 750 years, although smokers reach the menopause 72 years earlier.
• The perimenopause encompasses the menopause transition and the
first year following the last menstrual period.
Physiology
• Ovaries have a finite number of germ cells, with maximal numbers at
20 weeks of intrauterine life. Thereafter, there is a gradual reduction
in the number of follicles until the perimenopause when there is an
exponential loss of oocytes until the store is depleted at the time of
the menopause.
• Inhibin B and anti-Müllerian hormone (AMH) are ovarian glycoproteins
produced by follicles, as they develop from preantral to antral stages.
Both may participate in ovarian paracrine regulation and, with other
molecules, regulate the rate of attrition of follicles.
• Falling inhibin B levels result in fluctuating rise in FSH. Contrary to
previous belief, average serum oestradiol levels may be high at the
onset of the menopause transition as a result of FSH rise, falling only
towards the end as the follicles are depleted.
• AMH is a useful early marker of ovarian ageing, being stable
throughout the cycle and unaffected by COCP and without the
marked fluctuations of FSH. AMH measurements, however, add
nothing in routine practice or established menopause.
• See Table 4.8 for hormonal changes.
Long-term consequences
• Osteoporosis. During the perimenopausal period, there is an
accelerated loss of bone mineral density (BMD), rendering
post-menopausal ♀ more susceptible to osteoporotic fractures.
• Ischaemic heart disease (IHD). Post-menopausal ♀ are 2–3x more likely
to develop IHD than premenopausal ♀, even after age adjustments.
The menopause is associated with an increase in risk factors for
atherosclerosis, including less favourable lipid profile, d insulin
sensitivity, and an i thrombotic tendency.
• Dementia.♀ are 2–3x more likely to develop Alzheimer’s disease than
♂. It is suggested that oestrogen deficiency may play a role in the
development of dementia.
Table 4.8 Hormonal changes during the menopausal transition
Premenopause Early perimenopause Advanced perimenopause Meno
(from age 36 years)
Menstrual Regular, ovulatory Irregular, often short cycles, Oligomenorrhoea Amen
cycle increasingly anovulatory
FSH Rising but within normal Intermittently raised, especially Persistently i ii
range in follicular phase
AMH Declining Low Low Very l
E2 Normal High normal Normal/low Low
Clinical presentation of menopause

There are marked cultural differences in the frequency of symptoms
related to the menopause; in particular, vasomotor symptoms and mood
disturbances are more commonly reported in western countries.
• Menstrual disturbances (90%). Cycles gradually become increasingly
anovulatory and variable in length (often shorter) from about 4 years
prior to the menopause. Oligomenorrhoea often precedes permanent
amenorrhoea. In 10% of ♀, menses cease abruptly, with no preceding
transitional period.
• Hot flushes (40%). Often associated with sweats and skin flushing.
Highly variable and are thought to be related to fluctuations in
oestrogen concentrations. Tend to resolve spontaneously within
5 years of the menopause.
• Urinary symptoms (50%). Atrophy of urethral and bladder mucosa after
the menopause and d sensitivity of A-adrenergic receptors of the
bladder neck in the perimenopausal period. This may result in urinary
incontinence and an i risk of urinary tract infections.
• Sexual dysfunction (40%). Vaginal atrophy may result in dyspareunia and
vaginal dryness. Additionally, falling androgen levels may reduce sexual
arousal and libido.
• Mood changes (25–50%). Anxiety, forgetfulness, difficulty in
concentration, and irritability have all been attributed to the
menopause. ♀ with a history of affective disorders are at i risk of
mood disturbances in the perimenopausal period.
EVALUATION OF MENOPAUSE 345
Evaluation of menopause
(e.g. if HRT is being considered)
History
• Perimenopausal symptoms and their severity.
• Assess risk factors for cardiovascular disease and osteoporosis.
• Assess risk factors for breast cancer and thromboembolic disease.
• History of active liver disease.
Examination
• BP.
• Breasts.
• Consider pelvic examination for dyspareunia.
Investigations
• FSH levels fluctuate markedly in the perimenopausal period and
correlate poorly with symptoms. Remember, a raised FSH in the
perimenopausal period may not necessarily indicate infertility, so
contraception, if desired, should continue until the menopause.
• Mammography indicated prior to starting oestrogen replacement
therapy only in high-risk ♀; otherwise, mammography should be
offered as per national screening programme.
• Endometrial biopsy does not need to be performed routinely but is
essential in ♀ with abnormal uterine bleeding.
Hormone replacement
therapy (HRT)
The aim of treatment of perimenopausal ♀ is to alleviate menopausal
symptoms and optimize quality of life. The majority of women with mild
symptoms require no HRT. See Table 4.9 for alternatives to HRT.
Benefits of HRT
Hot flushes
Respond well to oestrogen therapy in a dose-dependent manner. Start
with a low dose, and increase gradually, as required, to control symptoms.
High doses may be required initially, particularly in younger ♀ or in those
whose symptoms develop abruptly (post-oophorectomy). In 75% of ♀,
vasomotor symptoms settle within 5 years, so consider stopping HRT
after 5 years of treatment. The dose of HRT should be gradually reduced
over weeks, as sudden withdrawal of oestrogen may precipitate the return
of vasomotor symptoms.
In ♀ with a contraindication to HRT or who are intolerant of it,
non-hormonal therapies are summarized in Table 4.9.
Urinary symptoms
A trial of HRT, local or systemic, may improve stress and urge inconti-
nence as well as the frequency of cystitis.
Vaginal atrophy
Systemic or local oestrogen therapy improves vaginal dryness and dys-
pareunia. A maximum of 6 months’ use of vaginal cream is recommended,
unless combined with a progestagen, as systemic absorption may increase
the risk of endometrial hyperplasia. If oestrogens are not successful, then
vaginal lubricants, e.g. Replens®, may help.
Osteoporosis
HRT has been shown to increase bone mineral density in the lumbar spine
by 3–5% and at the femoral neck by about 2% by inhibiting bone resorption.
The Women’s Health Initiative (WHI) trial confirmed that HRT reduces
the risk of both hip and vertebral fractures by 30%. HRT is not primarily
used for bone protection, as other agents may have fewer side effects
Colorectal cancer
WHI showed a 20% reduction in the incidence of colon cancer in HRT
users. However, HRT should currently not be prescribed solely to prevent
colorectal cancer.
Risks of HRT
(Also see Box 4.9.)
Breast cancer
No personal or family history of breast cancer
There is an i risk of breast cancer in HRT users which is related to the
duration of use. The risk increases by 35%, following 5 years of use (over
the age of 50), and falls to never-used risk 5 years after discontinuing HRT.
HORMONE REPLACEMENT THERAPY (HRT) 347
Table 4.9 Alternatives to HRT

Symptom Management
Vasomotor symptoms Venlafaxine (75mg od), paroxetine (20mg od),
and fluoxetine (20mg od) have been shown to
significantly reduce the frequency and severity of
hot flushes with minimal side effects.
Gabapentin (300mg tds) has also been shown to
reduce the frequency and severity of hot flushes.
Side effects include dizziness, somnolescence, and
weight gain.
Megestrol acetate in a dose of 20mg bd also
reduces hot flushes by up to 70%, but its use is
limited by side effects, particularly weight gain.
Clonidine is less effective, reducing the occurrence
of flushes by 20%, and is often associated with
disabling side effects, such as dizziness, drowsiness,
and a dry mouth.
Citalopram (SSRI) 30mg may reduce hot flushes in
50% of patients.
Genitourinary symptoms Vaginal lubricants, e.g. Replens®
Osteoporosis Selective oestrogen receptor modulators (SERMs),
e.g. raloxifene; however, these may exacerbate
vasomotor symptoms, if present.Bisphosphonates,
e.g. alendronic acid and risedronate
Box 4.9 A summary of contraindications to HRT

Absolute Relative—seek advice
• Undiagnosed vaginal bleeding. • Past history of endometrial
cancer.
• Pregnancy. • Family or past history of
thromboembolism.
• Active DVT. • Ischaemic heart disease.
• Active endometrial cancer. • Cerebrovascular disease.
• Breast cancer. • Active liver disease.
• Hypertriglyceridaemia
For ♀ aged 50 not using HRT, about 45 in every 1,000 will have cancer
diagnosed over the following 20 years. This number increases to 47/1,000
♀ using HRT for 5 years, 51/1,000 using HRT for 10 years, and 57/1,000
after 15 years of use. The risk is highest in ♀ on combined HRT compared
with oestradiol alone. Mortality has not been shown to be i in breast
cancer developing in ♀ on HRT.
Family history of breast cancer
The risk of breast cancer may be i 4-fold as a result of the family history,
but there is little evidence that the risk is i further by the use of HRT.
HRT may be used in these ♀ if severe vasomotor symptoms are present
after counselling regarding the above risks.
Past history of breast cancer
Avoid HRT in ♀ with a past history of breast cancer.
Venous thromboembolism (VTE)
Transdermal E2 is generally thought not to have an increased risk of VTE,
which is why this group is favoured in most situations.
Oral HRT increases the risk approximately 3-fold, resulting in an extra
two cases/10,000 woman-years. The risk is highest in the first year of use
of HRT and has been shown to be halved by aspirin or statin therapy. This
risk is markedly i in ♀ who already have risk factors for DVT, including
previous DVT, cardiovascular disease, and within 90 days of hospitalization.
Family history of DVT
If HRT is being considered because of severe vasomotor symptoms, then
do a thrombophilia screen. If +ve, then avoid HRT. ♀ with a +ve fam-
ily history of thromboembolism are still at a slightly i risk themselves,
even if the results of the thrombophilia screen are –ve, so consider
transdermal route.
Past history of DVT/PE
Risk of recurrence is 5% per year, so avoid HRT unless on long-term
warfarin therapy.
Cerebrovascular disease
HRT has been shown to increase the risk of ischaemic stroke in older ♀,
particularly in the presence of atrial fibrillation. HRT should, therefore, not
be used in ♀ with a history of cerebrovascular disease or atrial fibrillation,
unless they are anticoagulated.
Endometrial cancer
No i risk in ♀ taking continuous combined HRT preparations. ♀ using
sequential combined preparations do not appear to have an i risk of
endometrial cancer initially, but the risk of endometrial hyperplasia does
increase with long-term use (>5 years) despite regular withdrawal bleeds,
so these ♀ need regular follow-up. ♀ with cured stage I tumours may
safely take HRT.
Ovarian cancer
HRT may be associated with an i risk of ovarian cancer, but the evidence
is insufficient at present.
Gallstones
The risk of gallstones is i 2-fold in HRT users.
Migraine
Migraines may increase in severity and frequency in HRT users. A trial
of HRT is still worthwhile if indications are present, providing there are
no focal neurological signs associated with the migraine. Modification in
the dose of oestrogen or its preparation may improve symptoms. Avoid
conjugated oestrogens, as these are most commonly associated with an
increase in the frequency of migraines.
Endometriosis and uterine fibroids
The risk of recurrence of endometriosis or of growth of uterine fibroids
is low on HRT.
Liver disease
Use parenteral or transcutaneous oestrogens to avoid hepatic metabo-
lism, and monitor liver function in ♀ with impaired liver function tests. Do
not use HRT in the presence of active liver disease or liver failure.
Areas of uncertainty with HRT
Cardiovascular disease (CVD)
Data from >30 observational studies suggest that HRT may reduce the risk
of developing CVD by up to 50%. However, randomized placebo-controlled
trials, e.g. the Heart and Oestrogen-Progestin Replacement Study (HERS)
and the WHI trial, have failed to show that HRT protects against IHD.
Currently, HRT should not be prescribed to prevent cardiovascular dis-
ease. However, it may be used cautiously in individual patients with CVD
if QoL is significantly reduced from vasomotor symptoms.
Alzheimer’s disease
Recent evidence suggests that the risk of developing Alzheimer’s disease
may be reduced by up to 50% in ♀ receiving HRT, particularly if started
early in the menopause. However, in ♀ with established Alzheimer’s
disease, there is no evidence to suggest reversal of cognitive dysfunc-
tion following initiation of HRT. There is currently insufficient evidence
to recommend the use of HRT to prevent Alzheimer’s disease. In
post-menopausal ♀ without dementia, HRT may improve certain aspects
of cognitive function.
Mood disturbances
There has been a strongly held belief that HRT improves well-being and
QoL in perimenopausal and post-menopausal ♀. However, in recent tri-
als where QoL has been assessed, notably HERS and WHI, the improve-
ment in QoL and improved sleep was only seen in ♀ with vasomotor
symptoms.
Side effects commonly associated with HRT

• Breast tenderness usually subsides within 4–6 months of use. If
troublesome, use lower oestrogen dose and increase gradually.
• Mood changes commonly associated with progestin therapy; manage by
changing dose or preparation of progestin.
• Irregular vaginal bleeding may be a problem in ♀ on a continuous
combined preparation; usually subsides after 6–12 months of
treatment. Spotting persists in 10%—may change to a cyclic
preparation. See Box 4.10.
Summary of WHI trial
(See Table 4.10.)
• Randomized controlled trial of the effects of continuous combined
conjugated estrogens and medroxyprogesterone acetate on healthy
asymptomatic post-menopausal ♀, mean follow-up 5.2 years.
• Mean age 63 years, with 66% of ♀ >60 years of age.
• 70% of participants were overweight or obese, and 50% were current
or past smokers.
• Absolute risk was highest in the older age group (>65 years).
• Results of WHI cannot be extrapolated to younger HRT users
(<55 years of age).
• It is unclear whether different HRT preparations or routes of
administration would necessarily have the same benefit/risk profile.
Dietary phytoestrogens
Phytoestrogens are found in foods, such as soy beans, cereals, and seeds.
Although they have oestrogen-like activity, data from clinical trials are
conflicting. It appears that the effect of phytoestrogens on vasomotor
symptoms is modest at best. Research does suggest that soy protein has a
favourable effect on plasma lipid concentrations and may reduce the risk of
cardiovascular disease. However, the actual daily dose required is unclear.
Finally, data regarding the effect of phytoestrogens on bone loss and breast
cancer risk are inconclusive. Phytoestrogen supplements cannot, there-
fore, be recommended for the prevention of chronic disease in peri- and
post-menopausal ♀ until they are adequately evaluated in clinical trials.
Box 4.10 Who and how to investigate for irregular uterine

bleeding
• Sequential cyclical HRT. Three or more cycles of bleeding before
the ninth day of progestagen therapy, or change in the duration or
intensity of uterine bleeding.
• Continuous combined HRT. In first 12 months if bleeding is heavy or
extended, if it continues after 12 months of use, or if it starts after a
period of amenorrhoea.
• Endometrial assessment. Vaginal US essential in ♀ with irregular
uterine bleeding. Endometrial thickness of <5mm excludes disease in
96–99% of cases, a sensitivity similar to that of endometrial biopsy.
However, specificity is poor, so if the endometrium is >5mm (as it
will be in 50% of post-menopausal ♀ on HRT), endometrial biopsy
will be required to rule out carcinoma.
Table 4.10 Risks and benefits per 10,000 ♀ treated with HRT per
year (WHI trial)
Benefits Number of patients
Hip fractures prevented 5
Colon cancer prevented 6
Adverse events:
Coronary heart disease 7
Cerebrovascular events 8
Pulmonary embolism 5
Breast cancer (>5 years’ use) 8
HRT regimens
Oestrogen preparations
See Table 4.11. In younger, symptomatic, often perimenopausal ♀, higher
doses of oestrogen are often required initially, which can be reduced grad-
ually to the lowest dose effective at controlling symptoms.
Older ♀ who have been amenorrhoeic for over a year should be
started on the lowest possible dose of oestrogen.
Route of administration
• Oral route is the most popular. Disadvantages:
• First pass hepatic metabolism results in increased thrombotic risk.
• May be associated with nausea and may exacerbate liver disease.
• Must be taken daily, so there is no breakthrough of symptoms.
• Transdermal patches avoid first pass effect and are thus ideal in ♀ with
liver disease or hypertriglyceridaemia. Additionally, patches provide
constant systemic hormone levels. However, 10% of ♀ develop skin
reactions. Try to avoid moisture and to rotate patch sites to prevent this.
• Gels have the advantages of patches, but skin irritation is less common.
• SC implants have the advantage of good compliance. However, if
side effects develop, implants are difficult to remove. Additionally,
may release oestradiol for up to 3 years after insertion, and cyclical
progestagens must be given until oestrogen levels are not detectable.
Progestagen preparations
See Table 4.12. Must be added in non-hysterectomized ♀ to avoid endo-
metrial hyperplasia and subsequent carcinoma.
Sequential cyclical regimen
Give progestagen for a minimum of 10 days a month. Usually given for
the first 12 days of each calendar month. Quarterly regimen available—
progestagen given for 14 days 4x a year. However, the risk of endometrial
hyperplasia on such a regimen is unknown.
99% of ♀ have a monthly withdrawal bleed. 10% may be amenorrhoeic,
with no harmful consequences. Bleeding should start after the ninth day
of progestagen therapy.
Continuous combined regimen
Lower doses of progestagen are given on a daily basis. Uterine bleeding is
usually light in amount, but timing is unpredictable. Bleeding should stop in
90% of ♀ within 12 months, the majority in 6 months.
Ideal for older ♀ who do not want monthly withdrawal bleeds.
Contraindicated in perimenopausal ♀, as irregular uterine bleeding is
more likely and difficult to assess.
Tibolone (2.5mg a day)
A synthetic steroid with mixed oestrogenic, progestagenic, and weak andro-
genic activities. An alternative form of HRT, with little stimulation of the
endometrium. It alleviates vasomotor symptoms, may improve mood and
libido, and is protective against osteoporosis. Risks of VTE and breast cancer
similar to oestrogen. 10% of ♀ may experience vaginal bleeding on tibolone.
HRT REGIMENS 353
Table 4.11 Oestrogen preparations

Preparation Dose
Conjugated estrogens (PO) 0.625–1.25mg daily
Estradiol valerate (PO) 2mg daily
Estradiol transdermal patch 100 micrograms twice a week. New patch
twice a week
Estradiol gel 1–1.5mg daily
Estradiol subcutaneous implant 25–100mg every 4–8 months. Check
serum E2 prior to implant
Table 4.12 Progestagen preparations

Progestin Cyclical dose Continuous
(day 1–12) daily dose
Dydrogesterone 10mg 5mg
(least androgenic)
Medroxyprogesterone 10mg 2.5–5mg (higher dose
acetate reduces bleeding)
Levonorgestrel 150 micrograms Unknown
Norethisterone 0.7–1mg 0.5–1mg
(most androgenic)
Androgen replacement therapy

(See Box 4.11.)
• The major androgens in premenopausal ♀ are androstenedione
and testosterone, produced by both the ovaries and adrenal glands.
Over 90% are bound to sex hormone-binding globulin and albumin.
Androgens are thought to play a role in maintaining bone density and
normal sexual and cognitive function in ♀.
• Total and free serum androstenedione and testosterone levels fall by
up to 50% after the menopause as a result of both declining ovarian
and adrenal androgen production.
• Indications for androgen replacement therapy. Poor well-being and
libido, despite adequate oestrogen replacement therapy in ♀ with
ovarian failure.
• Mode of administration. SC testosterone implants 50–100mg every
6–8 months. Testosterone patches (300 micrograms/24h) are also
available. Always combine with oestrogen therapy.
• Side effects and possible complications. Hirsutism, acne, or virilization
have been reported in approximately 20% of ♀. Adverse changes
to lipid profile commonly occur. The effect on cardiovascular risk
is unknown. The long-term effects of androgen therapy on the
endometrium and breast tissue are unknown.
Box 4.11 Monitoring of women receiving androgen

replacement therapy
Clinical Biochemical
• Exclude contraindications. • Lipid profile.
• Polycythaemia. • Liver function tests.
• Breast or endometrial cancer. • FBC (exclude polycythaemia).
• Assess efficacy. • Serum testosterone.
• Evaluate side effects.
Further reading
Arlt W (2006). Androgen therapy in women. Eur J Endocrinol 154, 1–11.
Davis SR, et al. (2008). Testosterone for low libido in postmenopausal women not taking estrogen.
N Engl J Med 359, 2005–17.
Humphries KH, Gill S (2003). Risks and benefits of hormone replacement therapy: the evidence
speaks. Can Med Assoc J 168, 1001–10.
Million Women Study Collaborators (2003). Breast cancer and hormone-replacement therapy in
the Million women Study. Lancet 362, 419–23.
Rymer J, Wilson R, Ballard K (2003). Making decisions about hormone replacement therapy. BMJ
326, 322–6.
Writing Group for Women’s Health Initiative Investigators (2002). Risks and benefits of estrogen
plus progestin in healthy postmenopausal women: principal results from the Women’s Health
Initiative randomized controlled trial. JAMA 288, 321–33.
HORMONAL CONTROL OF CONTRACEPTION 355
Hormonal control of contraception

Formulations:
• Combined oral contraceptive pills.
• Transdermal and vaginal ethinylestradiol.
• Progesterone-only pills.
• Progesterone implants and injections.
• Intrauterine progesterone.
• Emergency contraception.
Combined oral contraceptive

pills (COCP)
• Very effective contraception, with approximately 5 per 100 users falling
pregnant per year.
• Good for cycle control and hyperandrogenic symptoms in young
women, with low risk of thrombosis.
• Oestrogens:
• Ethinylestradiol (EE2)—three doses: 20, 30, and 35 micrograms.
Generally, the lowest effective dose is used, as risks thought to be
dose-dependent—lowest doses less effective for menstrual control.
• Estradiol—combined in one OCP with progestagens.
• Progestagens:
• Second generation: levonorgestrel (150–250mg) and norethisterone
(1mg)—though to have the lowest risk of thrombosis but more
androgenic side effects.
• Third generation: norgestimate and desogestrel are less androgenic
but may be associated with an i risk of thromboembolism.
• Fourth generation: drospirenone—antiandrogenic properties.
• Unclassified: cyproterone acetate—antiandrogenic, marketed for the
treatment of acne rather than as COCP.
For a list of COCP preparations, see Box 4.12.
• Androgenicity: medroxyprogesterone < desogestrel < norethisterone.
COCP side effects
• Breakthrough bleeding.
• Low mood, reduced libido.
• Nausea.
• Fluid retention and weight gain.
• Breast tenderness and enlargement.
• Headache.
• Chloasma.
Benefits
• Ovarian cancer.
• The risks of ovarian cancer are halved in ♀ who have been taking
the COCP for 5 years or more. This risk reduction persists long
after discontinuation of the COCP.
• Acne.
• The COCP reduces free testosterone concentrations by
suppressing ovarian production of androgens and by i hepatic
SHBG production. COCP with low androgenic progestagens often
result in an improvement in acne.
• Menstrual disorders.
• The COCP is associated with reduced menstrual flow and
can, therefore, improve menorrhagia. The COCP can reduce
dysmenorrhoea and premenstrual symptoms.
Risks
(See Table 4.13 for contraindications.)
COMBINED ORAL CONTRACEPTIVE PILLS (COCP) 357
Box 4.12 Examples of COCP preparations

First generation
• Norinyl-1®
Second generation
• BiNovum® • Norimin®
• Brevinor® • Ovranette®
• Loestrin 20/30® • Ovysmen®
• Logynon® • Synphase®
• Microgynon 30/30 ED® • TriNovum®
Third generation
• Cilest® • Marvelon®
• Femodene/ED® • Mercilon®
• Femodette® • Sunya 20/75®
• Katya 30/75® • Triadene®
Fourth generation
• Yasmin®
Table 4.13 COCP contraindications

Absolute Relative
History of heart disease—ischaemic or Migraine
valvular
Pulmonary hypertension Sickle cell disease
History of arterial or venous thrombosis Gallstones
History of cerebrovascular disease Inflammatory bowel disease
High risk of thrombosis, e.g. factor V Leiden, Hypertension
antiphospholipid antibodies
Liver disease Hyperlipidaemia
Migraine if severe or associated with Diabetes mellitus
focal aura
Breast or genital tract cancer Obesity
Pregnancy Smokers
Presence of two or more relative
contraindications
Age >35 years and a smoker Otosclerosis
Family history of thrombosis
Family history of breast cancer
Consider using a progesterone-only pill in women with contraindications to the
combined OCP.
Venous thromboembolism
• The risk of venous thromboembolism in non-pregnant ♀ (5 per
100,000 ♀/year) is i 3-fold in ♀ on the COCP.
• The risk is highest in the first year of use, increases with age, and is i
in obese ♀.
• The risk of venous thromboembolism appears to be higher in ♀ taking
COCPs containing desogestrel, gestodene, cyproterone acetate, or
drospirenone, but absolute risk may be small in those with low risk
and outweighed by benefits.
• ♀ with a family history of thromboembolism should undergo a
thrombophilia screen before starting the COCP.
Arterial thrombosis
• There is a 10-fold excess risk of IHD in ♀ smokers over the age of
35 years who are on the COCP. The risk of IHD does not seem to be
significantly i in non-smokers who take low-dose COCP.
• The relative risk of ischaemic stroke is only slightly i in ♀ taking
low-dose COCP. The risk is i in ♀ over the age of 35 years, smokers,
or in ♀ with hypertension. The risk of haemorrhagic stroke does not
seem to be i by taking the COCP.
• Risk of either arterial or venous thrombosis returns to normal within
3 months of discontinuing the COCP.
Hypertension
May be caused by the COCP and, if already present, may be more resist-
ant to treatment.
Hepatic disease
Raised hepatic enzymes may be seen in ♀ on the COCP. The incidence of
benign hepatic tumours is also i.
Gallstones
The risk of developing gallstones is slightly i by taking the COCP
(RR = 1.2).
Breast cancer
• There may be a slightly i risk of breast cancer in ♀ using the COCP
(RR = 1.3), particularly in those who began taking the COCP in
their teens.
• The risk does not seem to be related to the duration of exposure to
the COCP nor to the EE2 dose.
• The relative risk of developing breast cancer returns to normal
10 years after discontinuing the COCP.
Cervical cancer
• The use of COCP appears to be associated with an excess risk of
cervical cancer in ♀ who are HPV +ve. The risk increases with the
duration of COCP use.
• It is not known whether the risk falls again following the
discontinuation of COCP.
COMBINED ORAL CONTRACEPTIVE PILLS (COCP) 359
Thrombophilia screen
• Antithrombin III.
• Protein C.
• Protein S
• Factor V Leiden.
Practical issues
Age and the COCP
• ♀ with no risk factors for arterial or venous thrombosis may continue
to use the combined COCP until the age of 50 years.
• Those with risk factors for thromboembolism and IHD should avoid
COCP after the age of 35 years, particularly if they are smokers.
• Contraception after the menopause: assume fertile for the first year
after last menstrual period if >50 years.
Breakthrough bleeding
Causes include:
• Genital tract disease.
• Insufficient oestrogen dose.
• Inappropriate progestagen.
• Missed pill.
• Taking two packets continuously.
• Gastroenteritis.
• Drug interactions, e.g. antibiotics, hepatic enzyme inducers.
Antibiotics and the COCP
Broad-spectrum antibiotics interfere with intestinal flora, thereby reducing
bioavailability of the COCP. Additional methods of contraception should
be used.
COCP and surgery
• Stop COCP at least 4 weeks before major surgery and any surgery to
the legs. Do not restart until fully mobile for at least 2 weeks.
• If emergency surgery, then stop COCP and start antithrombotic
prophylaxis.
Emergency contraception
Refers to contraception that a woman can use after unprotected sexual
intercourse to prevent pregnancy.
• A single 1.5mg dose of the progestagen levonorgestrel is highly
efficacious, with a pregnancy rate of 2–4% if taken within 72h of sexual
intercourse. It is most effective the earlier it is taken. The dose is
repeated if vomiting occurs within 3h of taking the pill.
• The mechanism of action is not clear but is thought to be due to
inhibition of ovulation as well as a d likelihood of endometrial
implantation.
• Side effects. Nausea in up to 60% of ♀, vomiting in 10–20%. Consider
antiemetic 1h before taking contraception. Other side effects—breast
tenderness, fatigue, dizziness.
• Contraindication—pregnancy.
• ♀ should be advised to use barrier contraception until their next
period.
• 98% of ♀ menstruate within 3–4 weeks of taking levonorgestrel. They
should be encouraged to seek medical advice if they do not bleed in
that time.
• If pregnancy does occur, levonorgestrel is not known to be
teratogenic.
Further reading
Lidegaard O (2012). Thrombotic stroke and myocardial infarction with hormonal contraception.
N Engl J Med. 366, 2257–66.
Petitti DB (2003). Combination oestrogen-progestin oral contraceptives. N Engl J Med 349, 1443–50.
MALE HYPOGONADISM 361
Male hypogonadism
Definition
Failure of testes to produce adequate amounts of testosterone, sperma-
tozoa, or both.
Epidemiology
• Klinefelter’s syndrome (XXY) (b see p. 370) is the most common
congenital cause and is thought to occur with an incidence of 2:1,000
live births.
• Acquired hypogonadism is even more common, affecting 1:200 ♂.
Evaluation of male hypogonadism
Presentation
• Failure to progress through puberty.
• Sexual dysfunction.
• Infertility.
• Non-specific symptoms, e.g. lethargy, reduced libido, mood changes,
weight gain.
The clinical presentation depends on:
• The age of onset (congenital vs acquired).
• The severity (complete vs partial).
• The duration (functional vs permanent).
Secondary hypogonadism
Definition
Hypogonadism as a result of hypothalamic or pituitary dysfunction.
Diagnosis
• Low 9 a.m. serum testosterone.
• Low normal or low LH and FSH, normal inhibin B and anti-Müllerian
hormone.
Causes
(See Box 4.15.)
Kallmann’s syndrome
A genetic disorder characterized by failure of episodic GnRH secretion 9
anosmia. Results from disordered migration of GnRH-producing neurons
into the hypothalamus.
Epidemiology
• Incidence of 1 in 10,000 ♂.
• ♂:♀ ratio = 4:1.
Diagnosis
• Anosmia in 75%.
• i risk of cleft lip and palate, sensorineural deafness, cerebellar ataxia,
and renal agenesis.
• Low testosterone, LH, and FSH levels.
• Rest of pituitary function normal.
• Normal MRI pituitary gland and hypothalamus; absent olfactory bulbs
may be seen on MRI.
• Normalization of pituitary and gonadal function in response to
physiological GnRH replacement.
Genetics
• Most commonly, a result of an isolated gene mutation.
• May be inherited in an X-linked (KAL1), autosomal dominant FGFR1
mutation/KAL2, or recessive trait.
• KAL1 gene mutation, responsible for some cases of X-linked
Kallmann’s syndrome, is located on Xp22.3. It has a more severe
reproductive phenotype.
• Mutations of FGFR1 (fibroblast growth factor receptor 1) gene, located
on chromosome 8p11, is associated with the autosomal dominant
form of Kallmann’s syndrome. Affected ♂ have an i likelihood of
undescended testes at birth.
• 12–15% incidence of delayed puberty in families of subjects with
Kallman’s syndrome, compared with 1% in general population.
• ♂ with autosomal dominant form (FGFR1 mutation)—50% transmitted
to offspring who have increased likelihood of undescended testes at birth.
Management
• Androgen replacement therapy.
• When fertility is desired, testosterone is stopped and exogenous
gonadotrophins are administered (b see p. 408).
SECONDARY HYPOGONADISM 363
Box 4.15 Causes of secondary hypogonadism

• Idiopathic:
• Other genetic causes, e.g. mutations of GnRHR or GPR54 genes.
• Idiopathic hypogonadotrophic hypogonadism (IHH).
• Fertile eunuch syndrome.
• Congenital adrenal hypoplasia (DAX-1 gene mutation).
• Functional:
• Exercise.
• Weight changes.
• Anabolic steroids.
• Stress—physical/psychological.
• Systemic illness.
• Medication and recreational drugs.
• Structural:
• Tumours, e.g. pituitary adenoma, craniopharyngioma, germinoma.
• Infiltrative disorders, e.g. sarcoidosis, haemochromatosis.
• Head trauma.
• Radiotherapy.
• Surgery to the pituitary gland or hypothalamus.
• Miscellaneous:
• Prader–Willi syndrome.
• Laurence–Moon–Biedl syndrome.
Idiopathic hypogonadotrophic hypogonadism (IHH)

• Congenital form is indistinguishable from Kallmann’s syndrome, apart
from the absence of anosmia. >90% of patients are ♂.
• GnRH receptor gene mutation is an uncommon cause of IHH.
• ♂ with acquired IHH may go through normal puberty and have
normal testicular size but present with infertility or poor libido and
potency. May be temporary, with normalization of gonadal function
after stopping GnRH or testosterone therapy.
Fertile eunuch syndrome
• Incomplete GnRH deficiency. Enough to maintain normal
spermatogenesis and testicular growth but insufficient for adequate
virilization.
• May require testosterone/hCG for fertility.
Congenital adrenal hypoplasia
• Rare X-linked or autosomal recessive disease, caused by a mutation of
the DAX gene which is located on the X chromosome.
• Presents with p adrenal failure in infancy.
• Hypothalamic hypogonadism is also present.
Structural
• Usually associated with other pituitary hormonal deficiencies.
• In children, craniopharyngiomas are the most common cause. Cranial

irradiation for leukaemia or brain tumours may also result in s
hypogonadism.
• The commonest lesions in adulthood are prolactinomas.
Systemic illness
Severe illness of any kind may cause hypogonadotrophic hypogonadism
(see Box 4.14).
Drugs
• Anabolic steroids, cocaine, and narcotic drugs may all result in s
hypogonadism.
All drugs causing hyperprolactinaemia (b see Box 2.12, p. 141) will also
cause hypogonadism.
Prader–Willi syndrome
A congenital syndrome, affecting 1:25,000 births, caused by loss of an
imprinted gene on paternally derived chromosome 15q11–13.
It should be suspected in infancy in the presence of characteristic facial
features (almond eyes, downturned mouth, strabismus, thin upper lip),
severe hypotonia, poor feeding, and developmental delay. The child then
develops hyperphagia due to hypothalamic dysfunction, resulting in severe
obesity. Other characteristic features include short stature, small hands
and feet, hypogonadotrophic hypogonadism, and learning disability.
• Type 2 diabetes occurs in 15–40% of adults.
Laurence–Moon–Biedl syndrome
Congenital syndrome characterized by severe obesity, gonadotrophin
deficiency, retinal dystrophy, polydactyly, and learning disability.
Haemochromatosis
See Box 4.16.
SECONDARY HYPOGONADISM 365
Box 4.16 Haemochromatosis

Complications
• Central and primary hypogonadism.
• Liver cirrhosis.
Diagnosed by genotyping.
Hypogonadotrophic hypogonadism (HH)

Definition
Hypogonadism as a result of gonadotrophin deficiency.
Diagnosis
• Low LH, FSH, oestradiol, testosterone.
• Rest of pituitary function normal.
• MRI: small pituitary gland, normal hypothalamus.
• Small gonads.
• Absent or delayed puberty, p amenorrhoea.
• Tall stature from delayed closure of epiphyses.
• Anosmia and absent olfactory bulbs on MRI in Kallmann’s.
Causes
(See Box 4.13.)
Kallmann’s syndrome
HH 9 anosmia. Results from disordered migration of GnRH-producing
neurons into the hypothalamus.
Epidemiology
• Incidence of 1 in 10,000 ♂.
• ♂:♀ ratio = 4:1.
Associated features
• Anosmia in 75%.
• Cleft lip and palate, sensorineural deafness, cerebellar ataxia, and renal
agenesis.
Genetics
• Variable inheritance: X-linked (KAL1, Xp22.3), autosomal dominant
FGFR1 mutation (KAL2), or recessive trait.
• KAL1 has a more severe reproductive phenotype.
• Mutations of fibroblast growth factor receptor 1 gene (FGFR1, 8p11)
have an i likelihood of undescended testes at birth.
• Variable penetrance: 12–15% incidence of delayed puberty in families
of subjects with Kallmann’s syndrome, compared with 1% in general
population.
Idiopathic hypogonadotrophic hypogonadism (IHH)
• Congenital form is indistinguishable from Kallmann’s syndrome, apart
from the absence of anosmia.
• To date, ten single gene defects described, including FGFR1, GnHR, and
GnRHR genes—none is available for routine screening at present.
• ♂ with acquired IHH may go through normal puberty and have normal
testicular size but present with infertility or poor libido and potency.
• Spontaneous remission with normalization of gonadal function may
occur at any age.
• Fertile eunuch syndrome. A mild form of IHH. Enough GnRH to
maintain normal spermatogenesis and testicular growth but insufficient
for adequate virilization.
HYPOGONADOTROPHIC HYPOGONADISM (HH) 367
Box 4.13 Causes of HH

• Single gene defects:
• Idiopathic hypogonadotrophic hypogonadism (IHH).
• Functional:
• Exercise, weight loss, stress, systemic illness.
• Iatrogenic: anabolic steroids, opiates.
• Associated conditions:
• CAH, especially ♂.
• Syndromic:
• Prader–Willi syndrome.
• Laurence–Moon–Biedl syndrome.
• CHARGE syndrome.
• X-linked adrenal hypoplasia congenita.
Structural
• Usually associated with other pituitary hormonal deficiencies.
• In children, craniopharyngiomas are the most common cause. Cranial
irradiation for leukaemia or brain tumours may also result in s
hypogonadism.
• The commonest lesions in adulthood are prolactinomas.
Systemic illness
Severe illness of any kind may cause hypogonadotrophic hypogonadism
(see Box 4.14).
Prader–Willi syndrome
A congenital syndrome affecting 1:25,000 births, caused by loss of an
imprinted gene on paternally derived chromosome 15q11–13.
It should be suspected in infancy in the presence of characteristic facial
features (almond eyes, downturned mouth, strabismus, thin upper lip),
severe hypotonia, poor feeding, and developmental delay. The child then
develops hyperphagia due to hypothalamic dysfunction, resulting in severe
obesity. Other characteristic features include short stature, hypogonado-
trophic hypogonadism, and learning disability.
• Type 2 diabetes occurs in 15–40% of adults.
Laurence–Moon–Biedl syndrome
Congenital syndrome characterized by severe obesity, gonadotrophin
deficiency, retinal dystrophy, polydactyly, and learning disability.
CHARGE syndrome
The association of coloboma, heart anomaly, choanal atresia, retardation,
genital and ear anomalies. A proportion also has HH.
Box 4.14 Systemic illness resulting in hypogonadism

• Any acute illness (e.g. myocardial infarction, sepsis, head injury).
• Severe stress.
• Endocrine disease (Cushing’s syndrome, hyperprolactinaemia).
• Chronic anaemia (thalassaemia major, sickle cell disease).
• GI disease (coeliac disease, Crohn’s disease).
• AIDS.
• Rheumatological disease (rheumatoid arthritis).
• Respiratory disease (e.g. chronic obstructive airways disease, cystic
fibrosis).
• Cardiac disease (e.g. congestive cardiac failure).
X-linked adrenal hypoplasia congenita

Rare X-linked or autosomal recessive disease, caused by a mutation of the
DAX gene, which is located on the X chromosome.
• Presents with p adrenal failure in infancy.
• Hypothalamic hypogonadism is also present.
Management
• Androgen replacement therapy (b see p. 378).
• Oestrogen replacement therapy (b see p. 340).
• When fertility is desired, testosterone is stopped and exogenous
gonadotrophins are administered (b see pp. 398, 408).
HYPOGONADOTROPHIC HYPOGONADISM (HH) 369
Primary hypogonadism
Due to testicular failure with normal hypothalamus and pituitary function.
See Box 4.17 for clinical characteristics.
Diagnosis
• Low 9 a.m. serum testosterone.
• Elevated LH and FSH, low inhibin B, and anti-Müllerian hormone.
Causes
Genetic
Klinefelter’s syndrome
The most common congenital form of p hypogonadism. It is thought that
a significant number of men with Klinefelter’s syndrome are not diagnosed.
Clinical manifestations will depend on the age of diagnosis. Patients with
mosaicism tend to have less severe clinical features.
• Adolescence:
• Small firm testes (mean 5mL).
• Gynaecomastia.
• Tall stature (i leg length).
• Other features of hypogonadism.
• Cognitive dysfunction.
• Adulthood:
• Reduced libido and erectile dysfunction.
• Gynaecomastia (50%).
• Reduced facial hair.
• Obesity.
• Infertility.
• Risks:
• Osteoporosis.
• Thromboembolism.
• Malignancies, e.g. extragonadal germ cell tumours.
• Diagnosis:
• Karyotyping: 47,XXY in 80%; higher grade chromosomal
aneuploidies (e.g. 48,XXXY) or 46,XY/47,XXY mosaicism in the
remainder.
• Low testosterone, elevated FSH and LH.
• Elevated SHBG and oestradiol.
• Azoospermia.
• Management:
• Lifelong androgen replacement.
• May need surgical reduction of gynaecomastia.
• Fertility: intracytoplasmic sperm injection (ICSI, b see Management
of male infertility, p. 409), using testicular spermatozoa from men
with Klinefelter’s syndrome, has resulted in successful pregnancies.
However, couples should be counselled about the i risk of
chromosomal abnormalities in offspring.
PRIMARY HYPOGONADISM 371
Box 4.17 Testicular dysfunction—clinical characteristics of

male hypogonadism
Testicular failure occurring before onset of puberty
• Testicular volume <5mL.
• Penis <5cm long.
• Lack of scrotal pigmentation and rugae.
• Gynaecomastia.
• High-pitched voice.
• Central fat distribution.
• Eunuchoidism:
• Arm span 1cm greater than height.
• Lower segment > upper segment.
• Delayed bone age.
• No ♂ escutcheon.
• d body and facial hair.
Testicular failure occurring after puberty
• Testes soft, volume <15mL.
• Normal penile length.
• Normal skeletal proportions.
• Gynaecomastia.
• Normal ♂ hair distribution but reduced amount.
• Pale skin, fine wrinkles.
• Central fat distribution.
• Osteoporosis.
• Anaemia (mild).
Other chromosomal disorders

• XX males:
• Due to an X to Y translocation, with only a part of the Y present in
one of the X chromosomes.
• Incidence 1:10,000 births.
• Similar clinical and biochemical features to Klinefelter’s syndrome.
In addition, short stature and hypospadias may be present.
• XX/XO (mixed gonadal dysgenesis):
• Occasionally, phenotypically ♂ with hypospadias and
intra-abdominal dysgenetic gonads.
• Bilateral gonadectomy is essential because of the risk of neoplasia,
followed by androgen replacement therapy.
• XYY syndrome:
• Taller than average but often have primary gonadal failure with
impaired spermatogenesis.
• Y chromosome microdeletions:
• Causes oligo-/azoospermia. Testosterone levels are not usually
affected.
• Noonan’s syndrome:
• Autosomal dominant disorder, with an incidence of 1:1,000 to
1:2,500 live births.
• 46,XY karyotype and s external genitalia. However, several

stigmata of Turner’s syndrome (dysmorphic facial features, short
stature, webbed neck, ptosis, low-set ears, lymphoedema) and
i risk of cardiac anomalies (valvular pulmonary stenosis and
hypertrophic cardiomyopathy). Most have cryptorchidism and p
testicular failure. May have a bleeding diathesis.
Cryptorchidism
• 10% of s neonates have undescended testes, but most of these
will descend into the scrotum eventually so that the incidence of
post-pubertal cryptorchidism is <0.5%.
• 15% of cases have bilateral cryptorchidism.
Consequences
• 75% of ♂ with bilateral cryptorchidism are infertile.
• 10% risk of testicular malignancy; highest risk in those with
intra-abdominal testes.
• Low testosterone and raised gonadotrophins in bilateral cryptorchidism.
Treatment
• Orchidopexy. Best performed before 18 months, certainly before age
5 years, in order to reduce risk of later infertility.
• Gonadectomy. In patients with intra-abdominal testes, followed by
androgen replacement.
Orchitis
• 25% of ♂ who develop mumps after puberty have associated orchitis,
and 25–50% of these will develop p testicular failure.
• HIV infection may also be associated with orchitis.
• p testicular failure may occur as part of an autoimmune disease.
PRIMARY HYPOGONADISM 373
Chemotherapy and radiotherapy

• Cytotoxic drugs, particularly alkylating agents, are gonadotoxic.
Infertility occurs in 50% of patients following chemotherapy for
most malignancies, and a significant number of ♂ require androgen
replacement therapy because of low testosterone levels.
• The testes are radiosensitive, so hypogonadism can occur as a result
of scattered radiation during the treatment of Hodgkin’s disease, for
example.
• If fertility is desired, sperm should be cryopreserved prior to cancer
therapy.
Other drugs
• Sulfasalazine, colchicines, and high-dose glucocorticoids may reversibly
affect testicular function.
• Alcohol excess will also cause p testicular failure.
Chronic illness
Any chronic illness may affect testicular function, in particular chronic
renal failure, liver cirrhosis, and haemochromatosis.
Testicular trauma
Testicular torsion is another common cause of loss of a testis, and it may
also affect the function of the remaining testis.
Clinical assessment of
hypogonadism
History
• Developmental history. Congenital urinary tract abnormalities, e.g.
hypospadias, late testicular descent, or cryptorchidism.
• Delayed or incomplete puberty.
• Infections, e.g. mumps, orchitis.
• Abdominal/genital trauma.
• Testicular torsion.
• Anosmia.
• Drug history, e.g. sulfasalazine, antihypertensives, chemotherapy,
cimetidine, radiotherapy; alcohol and recreational drugs also
important.
• General medical history. Chronic illness, particularly respiratory,
neurological, and cardiac.
• Gynaecomastia. Common (b see Gynaecomastia, pp. 382–3) during
adolescence. Recent-onset gynaecomastia in adulthood—must rule out
oestrogen-producing tumour.
• Family history. Young’s syndrome (reduced fertility, bronchiectasis, and
rhinosinusitis), cystic fibrosis, Kallmann’s syndrome.
• Sexual history. Erectile function, frequency of intercourse, sexual
techniques. Absence of morning erections suggests an organic cause of
erectile dysfunction.
• Body hair distribution.
• Muscle mass and fat distribution.
• Eunuchoidism.
• Gynaecomastia.
• Genital examination:
• Pubic hair. Normal ♂ escutcheon.
• Phallus. Normal >5cm length and >3cm width.
• Testes. Size (using Prader orchidometer) and consistency (normal
>15m and firm).
• Look for nodules or areas of tenderness.
• General examination: look for evidence of systemic disease.
• Assess sense of smell and visual fields.
• Reflexes.
• Peripheral pulses.
• Rectal examination.
Hormonal evaluation of testicular function

Serum testosterone
Diurnal variation in circulating testosterone, peak levels occurring in the
early morning. 30% variation between highest and lowest testosterone
levels, so 9 a.m. plasma testosterone essential. If level is low, this should
be repeated.
CLINICAL ASSESSMENT OF HYPOGONADISM 375
Sex hormone-binding globulin (SHBG)

• Only 2–4% of circulating testosterone is unbound. 50% is bound to
SHBG and the rest to albumin.
• Concentrations of SHBG should be taken into account when
interpreting a serum testosterone result. SHBG levels may be affected
by a variety of conditions (see Table 4.14).
• It is important to measure SBHG when testosterone values at 9 a.m.
are under the normal range.
Gonadotrophins
Raised FSH and LH in p testicular failure and inappropriately low in
pituitary or hypothalamic hypogonadism. Should always exclude hyper-
prolactinaemia in s hypogonadism.
Oestradiol
Results from the conversion of testosterone and androstenedione by
aromatase. See Table 4.15 for causes of an elevated oestradiol. Request
serum oestradiol level if gynaecomastia is present or a testicular tumour
is suspected.
Table 4.14 Factors affecting SHBG concentrations

Raised SHBG Low SHBG
Androgen deficiency Hyperinsulinaemia
GH deficiency Obesity
Ageing Acromegaly
Thyrotoxicosis Androgen treatment
Oestrogens Hypothyroidism
Liver cirrhosis Cushing’s syndrome/glucocorticoid therapy
Nephrotic syndrome
Table 4.15 Causes of raised oestrogens in ♂

Neoplasia:
Testicular
Adrenal
Hepatoma
Primary testicular failure
Liver disease
Thyrotoxicosis
Obesity
Androgen resistance syndromes
Antiandrogen therapy
Inhibin B and AMH

Gonadal glycoproteins secreted into the circulation. Useful markers
of normal testicular functions; low if p testicular failure and normal if
pituitary/hypothalamic dysfunction.
Other investigations
• Scrotal US (testicular volume/blood flow with Doppler/presence of
hydrocele, etc.).
• Semen analysis (a normal semen analysis is indicative of gonadal health;
♂ with low sperm count should consider sperm cryopreservation to
preserve fertility).
Dynamic tests
Of limited clinical value and are thus rarely performed routinely.
• hCG stimulation test:
• Diagnostic test for examining Leydig cell function.
• hCG 2000IU IM given on days 0 and 2; testosterone measured on
days 0, 2, and 4.
• In prepubertal boys with absent scrotal testes, a response to hCG
indicates intra-abdominal testes. Failure of testosterone to rise
after hCG suggests absence of functioning testicular tissue. An
exaggerated response to hCG is seen in s hypogonadism.
• Clomifene stimulation test:
• Used to assess the integrity of the hypothalamo–pituitary
testicular axis.
• A normal response to 3mg/kg (max 200mg) clomiphene daily for
7 days is a 2-fold increase in LH and FSH measured on days 0, 4, 7,
and 10.
• Subnormal response indicates hypothalamic or pituitary
hypogonadism but does not differentiate between the two.
Further reading
AACE Hypogonadism Task Force (2002). American Association of Clinical Endocrinologists
Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in
adult male patients–2002 Update. Endoc Prac 8, 439–56.
Aksglaede L, Juul A (2013). Testicular function and fertility in men with Klinefelter syndrome: a
review. Eur J Endocrinol 168, R67–R76.
Lanfranco F, Kamischke A, Zitzmann M, et al. (2004). Klinefelter’s syndrome. Lancet 364, 273–83.
Miller JF (2012). Approach to the child with Prader-Willi syndrome. J Clin Endocrinol Metab 97,
3837–44.
Semple RK, Topaloglu AK (2010). The recent genetics of hypogonadotrophic hypogonadism—
novel insights and new questions. Clin Endocrinol (Oxf) 72, 427–35.
CLINICAL ASSESSMENT OF HYPOGONADISM 377
Androgen replacement therapy

Treatment aims
• Improve libido and sexual function.
• Improve mood and well-being.
• Improve muscle mass and strength. Testosterone has direct anabolic
effects on skeletal muscle and has been shown to increase muscle
mass and strength when given to hypogonadal men. Lean body mass is
also i with a reduction in fat mass.
• Prevent osteoporosis. Hypogonadism is a risk factor for osteoporosis.
Testosterone inhibits bone resorption, thereby reducing bone
turnover. Its administration to hypogonadal ♂ has been shown to
improve bone mineral density and reduce the risk of developing
osteoporosis.
Androgen replacement therapy does not restore fertility—indeed, it sup-
presses normal spermatogenesis. ♂ with s hypogonadism who desire
fertility may be treated with gonadotrophins to initiate and maintain sper-
matogenesis (b see p. 408). Prior testosterone therapy will not affect
fertility prospects but should be stopped before initiating gonadotrophin
treatment. ♂ with p hypogonadism will not respond to gonadotrophin
therapy and may require donor insemination.
Indications for treatment
• In ♂ with established p or s hypogonadism of any cause.
• See Box 4.18 for contraindications.
• Treatment should be begun slowly with prolonged and/or severe
hypogonadism.
NB Weight reduction is associated with a rise in testosterone.
Pretreatment evaluation
Clinical evaluation
History or symptoms of:
• Prostatic hypertrophy.
• Breast or prostate cancer.
• Cardiovascular disease.
• Sleep apnoea.
Examination
• Rectal examination of prostate.
• Breasts.
Laboratory evaluation
• Prostate-specific antigen (PSA) (NB PSA is often low in hypogonadal
♂, rising to normal age-matched levels with androgen replacement).
• Haemoglobin and haematocrit.
• Cholesterol profile.
See Box 4.19 for monitoring.
ANDROGEN REPLACEMENT THERAPY 379
Box 4.18 Contraindications for androgen replacement

therapy
Absolute Relative
• Prostate cancer. • Benign prostate hyperplasia.
• Breast cancer. • Polycythaemia.
• Sleep apnoea.
Box 4.19 Monitoring of therapy

3 months after initiating therapy and then 6–12-monthly:
• Clinical evaluation—relief of symptoms of androgen deficiency and
exclude side effects.
• Serum testosterone.
• Rectal examination of the prostate (if >45 years).
• PSA (if >45 years).
• Haemoglobin and haematocrit.
• Serum lipids.
Risks and side effects of androgen

replacement therapy
(See Table 4.16 for testosterone preparations.)
Prostatic disease
• Androgens stimulate prostatic growth, and testosterone replacement
therapy may therefore induce symptoms of bladder outflow
obstruction in ♂ with prostatic hypertrophy.
• It is unlikely that testosterone increases the risk of developing prostate
cancer, but it may promote the growth of an existing cancer.
• It may be possible to consider testosterone therapy after 4 years in
low-risk patients with prostatic carcinoma after restaging and with
careful PSA surveillance.
Polycythaemia
Testosterone stimulates erythropoiesis. Androgen replacement therapy
may increase haemoglobin levels, particularly in older ♂. It may be neces-
sary to reduce the dose of testosterone in ♂ with clinically significant
polycythaemia.
Cardiovascular disease
Testosterone replacement therapy may cause a fall in both LDL and HDL
cholesterol levels, the significance of which remains unclear. The effect of
androgen replacement therapy on the risk of developing coronary heart
disease is unknown.
Other
• Acne.
• Gynaecomastia is occasionally enhanced by testosterone therapy,
particularly in peripubertal boys. This is the result of the conversion of
testosterone to oestrogens.
• Fluid retention may result in worsening symptoms in those with
underlying congestive cardiac failure or hepatic cirrhosis.
• Obstructive sleep apnoea may be exacerbated by testosterone therapy.
• Hepatotoxicity only with oral 17A alkylated testosterones.
• Mood swings.
Further reading
Bhasin S, et al. (2010). Testosterone therapy in men with androgen deficiency syndromes: an
Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95, 2536–59.
Handelsman DJ, Zajac JD (2004). Androgen deficiency and replacement therapy in men. Med J
Aust 180, 529–35.
Landau D, et al. (2012). Should testosterone replacement be offered to hypogonadal men treated
previously for prostatic carcinoma? Clin Endocrinol (Oxf) 76, 179–81.
Nieschlag E, Behre HM, Bouchard P, et al. (2004).Testosterone replacement therapy: current
trends and future directions. Hum Reprod Update 10, 409–19.
Rhoden EL, Morgentaler A (2004). Risks of testosterone replacement therapy and recommenda-
tions for monitoring. N Engl J Med 350, 482–92.
Table 4.16 Testosterone preparations
Preparation Dose Advantages Problems
IM testosterone esters 250mg every 2–3 weeks 2–3 weekly dosage Painful IM injection
Monitor predose serum Effective, cheap Contraindicated in bleeding dis
testosterone (should be above Wide variations in serum testo
the lower limit of normal) levels between injections which
associated with symptoms
‘Nebido’® 1g 3-monthly Convenience of infrequent injections
(after loading dose)
Testosterone implants 100–600mg every 3–6 months Physiological testosterone levels Minor surgical procedure
achieved
Monitor predose serum Risk of infection and pellet extr
testosterone 3–6-monthly dosing (3–10%). Must remove pellet su
complications of androgen repl
therapy develop
Transdermal gel (1%) 5–10g gel daily Physiological testosterone levels Skin reactions (rare)
achieved
Possible person-to-person tran
Convenience through direct skin contact
Oral, e.g. testosterone 40mg tds, 25mg tds Oral preparations Highly variable efficacy and bioa
undecanoate and mesterolone
Rarely achieves therapeutic effi
(analogue of DHT)
Multiple daily dosing
Buccal testosterone 30mg bd Physiological testosterone levels Local discomfort, gingivitis, bitte
achieved
Twice daily dosing
Gynaecomastia
Definition
Enlargement of the ♂ breast, as a result of hyperplasia of the glandular
tissue, to a diameter of >2cm (see Fig. 4.8). Common; present in up to
one-third of ♂ <30 years and in up to 50% of ♂ >45 years.
See Box 4.20 for causes.
Aromatase activity
(converts testosterone to LH/hCG
oestrogen)
Testosterone Increased oestrogen

replacement action on breast tissue and
resultant gynaecomastia
SHBG
Testosterone Oestrogen (binds testosterone more
than oestrogen)
Fig. 4.8 Hormonal influences on gynaecomastia.

GYNAECOMASTIA 383
Box 4.20 Causes of gynaecomastia

See Fig. 4.8 for hormonal influences.
• Physiological:
• Neonatal.
• Puberty—about 50% of boys develop transient gynaecomastia.
• Idiopathic—about 25% of all cases.
• Drugs (possible mechanisms: oestrogen-containing, androgen
receptor blockers, inhibiting androgen production):
• Oestrogens, antiandrogens, testosterone.
• Spironolactone, ACE inhibitors, calcium antagonists, digoxin.
• Alkylating agents.
• Alcohol, marijuana, heroin, methadone.
• Cimetidine.
• Ketoconazole, metronidazole, antituberculous agents, tricyclic
antidepressants, dopamine antagonists, opiates, benzodiazepines.
• Antiretroviral drugs.
• Imatinib (chronic myeloid leukaemia).
• Hypogonadism:
• p.
• s.
• Tumours:
• Oestrogen- or androgen-producing testicular or adrenal tumours.
• Human chorionic gonadotrophin-producing tumours, usually
testicular, e.g. germinoma; occasionally ectopic, e.g. lung.
• Aromatase-producing testicular or hepatic tumours.
• Endocrine:
• Thyrotoxicosis.
• Acromegaly.
• Androgen insensitivity syndromes.
• Systemic illness:
• HIV infection.
• Malnutrition.
Evaluation of gynaecomastia
History
• Duration and progression of gynaecomastia.
• Further investigation warranted if:
• Rapidly enlarging gynaecomastia.
• Recent-onset gynaecomastia in a lean post-pubertal ♂.
• Painful gynaecomastia.
• Exclude underlying tumour, e.g. testicular cancer.
• Symptoms of hypogonadism. Reduced libido, erectile dysfunction.
• Symptoms of systemic disease, e.g. hepatic, renal, and endocrine disease.
• Drug history, including recreational drugs, e.g. alcohol.
• Breasts:
• Pinch breast tissue between thumb and forefinger—distinguish
from fat.
• Measure glandular tissue diameter. Gynaecomastia if >2cm.
• If >5cm, hard, or irregular, investigate further to exclude breast
cancer.
• Look for galactorrhoea.
• Testicular palpation:
• Exclude tumour.
• Assess testicular size—? atrophy.
• 2° sex characteristics.
• Look for evidence of systemic disease, e.g. chronic liver or renal
disease, thyrotoxicosis, Cushing’s syndrome, chronic cardiac or
pulmonary disease.
Investigations
(See Fig. 4.9.)
Baseline investigations
• Serum testosterone.
• Serum oestradiol.
• LH and FSH.
• Prolactin.
• SHBG.
• hCG.
• Liver function tests.
Additional investigations
• If testicular tumour is suspected, e.g. raised oestradiol/hCG:
testicular US.
• If adrenal tumour is suspected, e.g. markedly raised oestradiol:
dehydroepiandrosterone sulphate; abdominal CT or MRI scan.
• If breast malignancy is suspected: mammography; FNAC/tissue biopsy.
• If lung cancer is suspected, e.g. raised hCG: chest radiograph.
• Other investigations, depending on clinical suspicion, e.g. renal or
thyroid function.
EVALUATION OF GYNAECOMASTIA 385
hCG, LH, testosterone, E2, TSH
i hCG i LH and d LH, i LH,

d TSH Normal
or E2 testosterone d testosterone d testosterone
Testicular Androgen Prolactin 1º Thyrotoxicosis

U/S resistance hypogonadism
If normal Testicular 2º Prolactinoma

tumour hypogonadism
Abdominal/
chest imaging
Extragonadal E2 or hCG
secreting tumour
Fig. 4.9 Investigations of gynaecomastia.

Management of gynaecomastia
• Treat underlying disorder when present. Withdraw offending drugs
where possible.
• Reassurance in the majority of idiopathic cases. Often resolves
spontaneously.
• Treatment may be required for cosmetic reasons or to alleviate pain
and tenderness.
• Drug treatment only partially effective. May be of benefit in treating
gynaecomastia of recent onset.
Medical
See Table 4.17.
Surgical
Reduction mammoplasty may be required in ♂ with severe and persistent
gynaecomastia.
Table 4.17 Medical treatment of gynaecomastia

Tamoxifen (10–30mg/day) Antioestrogenic effects. Particularly effective
in reducing pain and swelling if used in
gynaecomastia of recent onset. A 3-month
trial before referral for surgery may be of
benefit.
Clomifene (50–100mg/day) Antioestrogenic. May be effective
in reducing breast size in pubertal
gynaecomastia.
Danazol (300–600mg/day) Non-aromatizable androgen. May also
reduce breast size in adults. Its use is limited
by side effects, particularly weight gain and
acne.
Testolactone (450mg/day) Aromatase inhibitor. May be effective in
reducing pubertal gynaecomastia. However,
tamoxifen appears to be more effective and
better tolerated.
Anastrozole (1mg/day) Another aromatase inhibitor. Clinical trials
have failed to show a beneficial effect on
gynaecomastia compared with placebo.
Further reading
Carlson HE (2011). Approach to the patient with gynecomastia. J Clin Endocrinol Metab 96, 15-21.
Khan HN, Blarney RW (2003). Endocrine treatment of physiological gynaecomastia. BMJ 327, 301–2.
TESTICULAR TUMOURS 387
Testicular tumours
Epidemiology
• 6/100,000 ♂ per year.
• Incidence rising, particularly in North West Europe.
See Table 4.18 for classification.
Risk factors
• Cryptorchidism.
• Gonadal dysgenesis.
• Infertility/reduced spermatogenesis.
Prognosis
Seminomas
• 95% cure for early disease; 80% cure for stages II/IV.
• i incidence of second tumours and leukaemias 20 years after therapy.
Non-seminoma germ cell tumours
• 90% cure in early disease, falling to 60% in metastatic disease.
• i incidence of second tumours and leukaemias 20 years after therapy.
Stromal tumours
• Excellent prognosis for benign tumours.
• Malignant tumours are aggressive and are poorly responsive to
treatment.
Table 4.18 Classification of testicular tumours

Tumours Tumour markers
Germ cell tumours (95%) Seminoma None
Non-seminoma hCG, A-fetoprotein, CEA
Mixed
Stromal tumours (2%) Leydig cell
Sertoli cell
Gonadoblastoma (2%)
Other (1%) Lymphoma
Carcinoid
Further reading
Griffin JE, Wilson JD (1998). Disorders of the testes and male reproductive tract. In: Wilson JD,
Foster DW, Kronenberg HM, Larson PR (eds.) Williams textbook of endocrinology, 9th edn,
pp. 819–76. WB Saunders, Philadelphia.
Erectile dysfunction
Definition
The consistent inability to achieve or maintain an erect penis sufficient for
satisfactory sexual intercourse. Affects approximately 10% of ♂ and >50%
of ♂ >70 years.
Physiology of male sexual function
• The erectile response is the result of the coordinated interaction of
nerves, smooth muscle of the corpora cavernosa, pelvic muscles, and
blood vessels.
• It is initiated by psychogenic stimuli from the brain or physical
stimulation of the genitalia, which are modulated in the limbic
system, transmitted down the spinal cord to the sympathetic and
parasympathetic outflows of the penile tissue.
• Penile erectile tissue consists of paired corpora cavernosa on
the dorsum of the penis and the corpus spongiosum. These are
surrounded by fibrous tissue known as the tunica albuginea.
• In the flaccid state, the corporeal smooth muscle is contracted,
minimizing corporeal blood flow and enhancing venous drainage.
• Activation of the erectile pathway results in penile smooth muscle
relaxation and cavernosal arterial vasodilatation. As the corporeal
sinuses fill with blood, the draining venules are compressed against the
tunica albuginea, so venous outflow is impaired. This results in penile
rigidity and an erection.
• Corporeal vasodilatation is mediated by parasympathetic neuronal
activation, which induces nitric oxide release by the cavernosal nerves.
This activates guanyl cyclase, thereby i cGMP and causing smooth
muscle relaxation.
• Detumescence occurs after the inactivation of cGMP by the enzyme
phosphodiesterase, resulting in smooth muscle contraction and
vasoconstriction.
• Ejaculation is mediated by the sympathetic nervous system.
Pathophysiology
Erectile dysfunction may thus occur as a result of several mechanisms:
• Neurological damage.
• Arterial insufficiency.
• Venous incompetence.
• Androgen deficiency.
• Penile abnormalities.
ERECTILE DYSFUNCTION 389
Evaluation of erectile dysfunction

History
Sexual history
• Extent of the dysfunction, its duration and progression.
• Presence of nocturnal or morning erections.
• Abrupt onset of erectile dysfunction which is intermittent is often
psychogenic in origin.
• Progressive and persistent dysfunction indicates an organic cause.
Symptoms of hypogonadism
Reduced libido, muscle strength, and sense of well-being.
Full medical history
• For example, diabetes mellitus, liver cirrhosis, neurological,
cardiovascular, or endocrine disease.
• Intermittent claudication suggests a vascular cause.
• A history of genitourinary trauma or surgery is also important.
• Recent change in bladder or bowel function may indicate
neurological cause.
• Psychological history.
Drug history
Onset of impotence in relation to commencing a new medication.
Social history
• Stress.
• Relationship history.
• Smoking history.
• Recreational drugs, including alcohol.
• Evidence of p or s hypogonadism.
• Evidence of endocrine disorders:
• Hyperprolactinaemia, thyroid dysfunction, hypopituitarism.
• Other complications of diabetes mellitus, if present.
• Evidence of neurological disease:
• Autonomic or peripheral neuropathy.
• Spinal cord lesions.
• Evidence of systemic disease, for example:
• Chronic liver disease.
• Chronic cardiac disease.
• Peripheral vascular disease.
• Genital examination:
• Assess testicular size—? atrophy.
• Penile abnormalities, e.g. Peyronie’s disease.
See Box 4.21 for causes of erectile dysfunction.

EVALUATION OF ERECTILE DYSFUNCTION 391
Box 4.21 Causes of erectile dysfunction

• Psychological (20%):
• Stress, anxiety.
• Psychiatric illness.
• Drugs (25%):
• Alcohol.
• Antihypertensives, e.g. diuretics, B-blockers, methyldopa.
• Cimetidine.
• Marijuana, heroin, methadone.
• Major tranquillizers.
• Tricyclic antidepressants, benzodiazepines.
• Digoxin.
• Glucocorticoids, anabolic steroids.
• Oestrogens, antiandrogens.
• Endocrine (20%):
• Hypogonadism (p or s).
• Diabetes mellitus (30–50% of ♂ with DM >6 years).
• Neurological:
• Spinal cord disorders.
• Peripheral and autonomic neuropathies.
• Multiple sclerosis.
• Vascular:
• Peripheral vascular disease.
• Trauma.
• Venous incompetence.
• Other:
• Debilitating diseases.
• Penile abnormalities, e.g. priapism, Peyronie’s disease.
• Prostatectomy.
Investigation of erectile dysfunction

Baseline investigations
• Serum testosterone. • Liver function tests.
• Prolactin, LH, and FSH if serum • Renal function.
testosterone low. • Serum lipids.
• Fasting blood glucose. • Serum ferritin
• Thyroid function tests. (haemochromatosis).
Additional investigations
Rarely required. To assess vascular causes of impotence if corrective sur-
gery is contemplated:
• Intracavernosal injection of a vasodilator, e.g. alprostadil E1 or papaverine.
A sustained erection excludes significant vascular insufficiency.
• Penile Doppler ultrasonography. Cavernous arterial flow and venous
insufficiency are assessed.
Management of erectile dysfunction

Treat underlying disorder or withdraw offending drugs where possible.
Androgens
This should be first-line therapy in ♂ with hypogonadism (b see p. 378).
Hyperprolactinaemia, when present, should be treated with dopamine
agonists and the underlying cause of hypogonadism treated.
Phosphodiesterase (PDE) inhibitors
(See Table 4.19 and Box 4.22.)
• Act by enhancing cGMP activity in erectile tissue by blocking the
enzyme PDE-5, thereby amplifying the vasodilatory action of nitric
oxide and thus the normal erectile response to sexual stimulation.
• Trials indicate a 50–80% success rate.
Alprostadil
• Alprostadil results in smooth muscle relaxation and vasodilatation.
• It is administered intraurethrally and is then absorbed into the erectile
bodies.
• 60–66% success rate.
• Side effects. Local pain.
Intracavernous injection
• 70–100% success rate, highest in men with non-vasculogenic
impotence.
• Alprostadil is a potent vasodilator. The dose should be titrated in 1
microgram increments until the desired effect is achieved in order to
minimize side effects.
• Papaverine, a phosphodiesterase inhibitor, induces cavernosal
vasodilatation and penile rigidity but causes more side effects.
• Side effects:
• Priapism in 1–5%. Patients must seek urgent medical advice if an
erection lasts >4h.
• Fibrosis in the injection site in up to 5% of patients. Minimize risk by
alternating sides of the penis for injection and injecting a maximum
of twice a week.
• Infection at injection site is rare.
• Contraindication. Sickle cell disease.
• Injection technique. Avoid the midline so as to avoid urethral and
neurovascular damage. Clean the injection site; hold the penis under
slight tension, and introduce the needle at 90°. Inject after the
characteristic ‘give’ of piercing the fibrous capsule. Apply pressure to
injection site after removing the needle to prevent bruising.
Vacuum device
Results are good, with 90% of ♂ achieving a satisfactory erection. The
flaccid penis is put into the device and air is withdrawn, creating a vacuum
which then allows blood to flow into the penis. A constriction band is then
placed on to the base of the penis so that the erection is maintained. This
should be removed within 30min.
• Side effects. Pain, haematoma.
MANAGEMENT OF ERECTILE DYSFUNCTION 393
Table 4.19 PDE-5 inhibitors

Sildenafil Vardenafil Tadalafil
Dose (mg/day) 50–100 10–20 10–20
Recommended interval 60min 30–60min >30min
between drug administration
and sexual activity
Half-life (h) 3–4 4–5 17
Adverse effects (%)
Headaches 15–30 7–15 7–20
Facial flushing 10–25 10 1–5
Dyspepsia 2–15 0.5–6 1–15
Nasal congestion 1–10 3–7 4–6
Visual disturbance 1–10 0–2 0.1
Box 4.22 PDE-5 inhibitors—contraindications and cautions

Contraindications
• Recent myocardial infarction/stroke.
• Unstable angina.
• Current nitrate use, including isosorbide mononitrate/GTN.
• Hypotension (<90/50mmHg).
• Severe heart failure.
• Severe hepatic impairment.
• Retinitis pigmentosa.
• Ketoconazole or HIV protease inhibitors.
Cautions (reduce dose)
• Hypertension.
• Heart disease.
• Peyronie’s disease.
• Sickle cell anaemia.
• Renal or hepatic impairment.
• Elderly.
• Leukaemia.
• Multiple myeloma.
• Bleeding disorders, e.g. active peptic ulcer disease.
Avoid concomitant opiates, including dihydrocodeine—may get pro-
longed erections (opiates increase cGMP in nerve endings).
Penile prosthesis
• Is usually tried in ♂ either reluctant to try other forms of therapy
or when other treatments have failed. They may be semi-rigid or
inflatable.
• Complications. Infection, mechanical failure.
Psychosexual counselling
Particularly for ♂ with psychogenic impotence and in ♂ who fail to
improve with the above therapies.
Surgical
• Rarely indicated, as results are generally disappointing.
• Revascularization techniques may be available in specialist centres.
• Ligation of dorsal veins may restore erectile function temporarily in
men with venous insufficiency, although rarely permanently.
Further reading
Beckman TJ, et al. (2006). Evaluation and medical management of erectile dysfunction. Mayo Clinic
Proc 81, 385–90.
Cohan P, Korenman SG (2001). Erectile dysfunction. J Clin Endocrinol Metab 86, 2391–4.
Fazio L, Brick G (2004). Erectile dysfunction: management update. Can Med Assoc J 170, 1429–37.
Shamloul R, Ghanem H (2013). Erectile dysfunction. Lancet 381, 153–65.
MANAGEMENT OF ERECTILE DYSFUNCTION 395
Infertility
Definition
• Infertility, defined as failure of pregnancy after 1 year of unprotected
regular (2x week) sexual intercourse, affects 710% of all couples.
• Couples who fail to conceive after 1 year of regular unprotected
sexual intercourse should be investigated.
• If there is a known predisposing factor or the ♀ partner is over
35 years of age, then investigation should be offered earlier.
Causes
(See Boxes 4.23 and 4.24.)
• ♀ factors (e.g. PCOS, tubal damage) 35%.
• ♂ factors (idiopathic gonadal failure in 60%) 25%.
• Combined factors 25%.
• Unexplained infertility 15%.
Box 4.23 Causes of female infertility

• Anovulation:
• PCOS (80% of anovulatory disorders).
• s hypogonadism.
• Hypothalamic disease.
• Systemic illness.
• Drugs, e.g. anabolic steroids.
• POF (5% of anovulatory disorders).
• Tubal disorders:
• Infective, e.g. Chlamydia.
• Endometriosis.
• Surgery.
• Cervical mucus defects.
• Uterine abnormalities:
• Congenital.
• Intrauterine adhesions.
• Uterine fibroids.
INFERTILITY 397
Box 4.24 Causes of male infertility

• Primary gonadal failure:
• Genetic, e.g. Klinefelter’s syndrome, Y chromosome
microdeletions, immotile cilia/Kartagener’s syndrome, cystic
fibrosis.
• Congenital cryptorchidism.
• Orchitis.
• Torsion or trauma.
• Chemotherapy and radiotherapy.
• Other toxins, e.g. alcohol, anabolic steroids.
• Varicocele.
• Idiopathic.
• s gonadal failure:
• Structural hypothalamic/pituitary disease.
• Genital tract abnormalities:
• Obstructive congenital, infective, post-surgical.
• Sperm autoimmunity.
• Erectile dysfunction.
• Drugs, e.g. spironolactone, corticosteroids, sulfasalazine.
• Systemic disease, e.g. cystic fibrosis, Crohn’s disease, and other
chronic debilitating diseases.
Evaluation of female infertility

Sexual history
• Frequency of intercourse. Sexual intercourse every 2–3 days should be
encouraged.
• Use of lubricants. Should be avoided because of the detrimental effect
on semen quality.
Female factors
History
• Age. Fertility declines rapidly after the age of 36 years.
• Menstrual history:
• Age at menarche.
• Length of menstrual cycle and its regularity (e.g. oligo-/amenorrhoea).
• Presence or absence of intermenstrual spotting.
• Hot flushes may be indicative of oestrogen deficiency.
• Spontaneous galactorrhoea may be caused by hyperprolactinaemia.
• Hypothalamic hypogonadism, suggested by excessive physical exercise
(e.g. running >4 miles/day) or weight loss in excess of 10% in 1 year.
• Drug history:
• Drugs which may cause hyperprolactinaemia (b see Box 2.12,
p. 141), including cocaine and marijuana.
• Smoking is thought to have an adverse effect on fertility.
• The use of anabolic steroids may cause s hypogonadism.
• Cytotoxic chemotherapy or radiotherapy may cause ovarian failure.
• Medical history. Diabetes mellitus, thyroid or pituitary dysfunction, and
other systemic illnesses.
• Exclude tubal disease:
• Recurrent vaginal or urinary tract infections may predispose to
pelvic inflammatory disease (PID).
• Dyspareunia and dysmenorrhoea are often present.
• Sexually transmitted disease and previous abdominal or
gynaecological surgery all predispose to Fallopian tube obstruction.
• s infertility. Details of previous pregnancies, including abortions
(spontaneous and therapeutic), and ectopic pregnancies should be
ascertained.
• Family history. Suggestive of risk of POF, PCOS, endometriosis.
• BMI. The ideal BMI for fertility is 20–29.
• s sexual characteristics. If absent, look for evidence of Turner’s
syndrome.
• Hyperandrogenism. PCOS.
• Galactorrhoea. Hyperprolactinaemia.
• External genitalia and pelvic examination.
EVALUATION OF FEMALE INFERTILITY 399
Investigations
(See Fig. 4.10.)
• General assessment:
• Measure TSH, free T4, and serum prolactin in ♀ with irregular
menstrual cycles or who are not ovulating.
• Serum testosterone, SHBG, 17OH progesterone if there is clinical
evidence of hyperandrogenism, in the presence of irregular
menstrual cycles, or if anovulation is confirmed.
• MRI of the pituitary fossa in hyperprolactinaemia and
hypogonadotrophic hypogonadism.
• Assess ovarian reserve:
• Check serum FSH and LH. In ♀ who are not amenorrhoeic, this
should be measured on days 2–6 of the menstrual cycle (day
1 = first day of menses). Follicular phase (FSH >10) is indicative of
reduced ovarian reserve. Ovarian failure is diagnosed if FSH >30.
• Pelvic US. Not only for uterine and ovarian anatomy but also for
antral follicle count (number of small follicles as an estimate of
ovarian ageing).
• Consider AMH measurement.
• Assess ovulatory function:
• Home ovulation kit testing of urinary LH reliable in regular cycles.
Home temperature testing less reliable.
• In ♀ with regular menstrual cycles—measure a midluteal
progesterone (day 21 or approximately 7 days before expected
onset of menses >30pmol/L consistent with ovulation).
• Consider ovulation tracking by serial ultrasound if uncertain.
• Exclude infection. Send vaginal discharge for bacteriology, and do
Chlamydia trachomatis serology.
• Assess tubal patency (refer to specialist multidisciplinary fertility clinic):
• Hysterosalpingography (HSG) or laparoscopy and dye test (do in
the early follicular phase of cycle to avoid doing during pregnancy).
Assess ovulation
in 2−3 cycles
Ovulating (d21) Not ovulating

midluteal progesterone midluteal progesterone
>30pmol/L <30pmol/L
If normal
semen analysis FSH, LH, E2
Laparoscopy
i FSH (>30) Normal FSH d FSH
Hypogonadotrophic
Tubal factor Normal POF PCOS hypogonadism
Cervical factors Karyotype Androgens PRL

(PCT, bacteriology, autoantibodies SHBG MRI pituitary
sperm antibody)
Fig. 4.10 Investigation of ♀ infertility.

EVALUATION OF FEMALE INFERTILITY 401
Evaluation of male infertility

Male factors
History and physical examination
• Symptoms of androgen deficiency:
• Reduced libido and potency.
• Reduced frequency of shaving.
• May be asymptomatic.
• Drug history:
• Drug or alcohol abuse and the use of anabolic steroids may all
contribute to hypogonadism.
• Other drugs that may affect spermatogenesis, e.g. sulfasalazine,
methotrexate.
• Cytotoxic chemotherapy may cause p testicular failure.
• History of infection, e.g. mumps, orchitis, sexually transmitted disease,
or epididymitis.
• Bronchiectasis may be associated with epididymal obstruction (Young’s
syndrome) or severe asthenospermia (immotile cilia syndrome).
• Testicular injury or surgery may cause disordered spermatogenesis.
• s sex characteristics may be absent in congenital hypogonadism.
• Anosmia. Kallmann’s syndrome.
• Eunuchoid habitus (b see Box 4.17, p. 371) suggestive of prepubertal
hypogonadism.
• Gynaecomastia may suggest hypogonadism.
• Testicular size (using orchidometer):
• Normal 15–25mL.
• Reduced to <15mL in hypogonadism.
• In Klinefelter’s syndrome, they are often <5mL.
• In patients with normal testicular size, suspect genital tract
obstruction, e.g. congenital absence of vas deferens.
• Examine rest of external genitalia. Look for penile/urethral
abnormalities and epididymal thickening.
Investigations
(See Fig. 4.11.)
Semen analysis
Essential in the diagnostic work-up of any infertile couple.
• If normal (see Table 4.20), then a ♂ cause is excluded.
• If abnormal, then repeat semen analysis approximately
6–12 weeks later.
• Semen collection should be performed after 3 days of sexual
abstinence. See Table 4.20 for interpretation of results.
• If azoospermia is present, then rule out obstruction if FSH and
testosterone concentrations are normal.
• Asthenospermia, or immotile sperm, is usually due to immunological
infertility or infection, e.g. of the prostate (high semen viscosity and
pH, and leukocytospermia).
EVALUATION OF MALE INFERTILITY 403
Semen analysis
Normal Abnormal
Investigate FSH, testosterone

partner
FSH Normal FSH FSH
Hypogonadotrophic Exclude obstructive Primary

hypogonadism lesions, immunological gonadal failure
causes and infection
Prolactin
Karyotype
Pituitary MRI
Fig. 4.11 Investigation of ♂ infertility.
Table 4.20 WHO criteria for normal semen analysis1

Test Normal values (fertile) Nomenclature for
abnormal values
Volume >2mL Aspermia (no ejaculate)
pH >7.2
Total sperm number >40 x 106/ejaculate Azoospermia (no sperm
in ejaculate)
Sperm concentration >48 x 106/mL Oligozoospermia
Motility >63% progressive motility Asthenospermia
Morphology >12% normal forms Teratospermia
Live sperm >75% Necrospermia
Leukocytes <1 x 106/mL Leukocytospermia
1
Reproduced with permission from Guzick DS, Overstreet JW, Factor-Litvak P, et al. (2001).
Sperm morphology, motility, and concentration in fertile and infertile men. New Engl J Med
345, 1388–93.
FSH, LH, testosterone, SHBG levels

• FSH may be elevated in the presence of normal LH and testosterone
levels and oligospermia. This may be seen in ♂ who are normally
virilized but infertile as a result of disordered spermatogenesis.
• Low FSH, LH, and testosterone concentrations suggest s
hypogonadism. An MRI of the pituitary gland and hypothalamus is
necessary to exclude organic disease.
Further investigations
• Urinary bacteriology should be performed in ♂ with leukocytospermia.
• Scrotal US may help in the diagnosis of chronic epididymitis. ♂ being
investigated for infertility are at i risk of testicular tumours.
• Karyotyping may be helpful in ♂ with p testicular failure. Klinefelter’s
syndrome (47,XXY) is a cause of infertility, and deletions on the long
arm of the Y chromosome have been found in a significant proportion
of azoospermic ♂.
• Sperm antibodies in semen should not be measured routinely, as
specific treatment is rarely effective.
• Testicular biopsy is rarely diagnostic but may be used to retrieve sperm
for assisted reproduction techniques in specialist fertility centres.
• Sperm function tests are not performed routinely.
EVALUATION OF MALE INFERTILITY 405
Management of female infertility

Anovulation
• Hypogonadotrophic (WHO class I):
• If hyperprolactinaemic, then dopamine agonists are usually effective.
• Lifestyle changes if underweight/excessive exercise.
• Otherwise, ovulation induction (b see Ovulation induction, p. 410).
• Normogonadotrophic (WHO class II):
• Usually PCOS; weight reduction if obese.
• Ovulation induction (b see Ovulation induction, p. 410).
• Hypergonadotrophic (WHO class III):
• POF; ovum donation is only option.
• Spontaneous transient remission possible in early POF.
• If still cycling and FSH 15–25IU/L, ovarian hyperstimulation and IVF
may be attempted but poor results.
Tubal infertility
• Surgical tubal reconstruction may be attempted in specialist centres.
• 50–60% 2-year cumulative pregnancy rate in patients with mild
disease, but only 10% in more severe disease and high risk of ectopic
pregnancy, so IVF may be more appropriate in ♀ with severe disease.
• Cumulative pregnancy rate at least 50% following IVF (20–35% per
cycle), unless hydrosalpinx is present. ♀ with hydrosalpinx should be
offered salpingectomy prior to IVF to improve success rates.
Endometriosis
• Minimal/mild:
• GnRH agonists, danazol, and progestagens do not improve fertility.
• Laparoscopic destruction of superficial disease improves pregnancy
chances. Resection of ovarian endometriomas may improve ovarian
folliculogenesis and thus fertility.
• Assisted reproductive techniques (ART) (see Table 4.21) give
pregnancy rate of 25–35% per cycle.
• Moderate/severe:
• Surgery may improve fertility. However, ART often necessary.
Vaginal/cervical factors
• Each episode of acute PID causes infertility in 10–15% of cases.
• Trachomatis is responsible for half the cases of PID in developed
countries. Treat both partners with antibiotics.
Uterine factors
• Intracavity fibroids, polyps, uterine septum can be resected
hysteroscopically, with high chance of restoring fertility.
• Intramural fibroids may also reduce fertility and may require
myomectomy.
• Fibroid embolization is not recommended for ♀ wishing fertility, as
safety in pregnancy not established.
Table 4.21 Assisted reproductive techniques (ART)
Technique Indications Pregnancy rates Notes
Intrauterine insemination Unexplained infertility <15% per cycle Washed and prepared motile spermatozoa are inje
(IUI) (usually offered up Mild oligozoospermia 15% the uterine cavity through a catheter just before ov
to six cycles) (>2 x 106 motile sperm) Superovulation may improve success rates but is
Mild endometriosis associated with an increased risk of multiple pre
In vitro fertilization (IVF) Most forms of infertility 20–30% pregnancy rate per cycle After superovulation, ovarian follicles are aspirate
unless severe male factor 80–90% delivery rate after six ultrasonic guidance and are fertilized with prepare
cycles in women under the age in vitro. The embryos are then transferred back in
of 35 years uterine cavity, usually 48h after insemination. Lute
Success rates markedly reduced using progesterone supplementation (pessaries o
after 40 years of age then provided until pregnancy is confirmed.
Babies conceived by IVF have a 2x May adopt a similar technique in women with pr
increased risk of low birthweight ovarian failure using donated ova which are then
and preterm delivery in vitro with partner’s sperm. Hormonal support
required following embryo transfer.
Gamete intrafallopian Most forms of infertility Similar to IVF Similar to IVF, except that retrieved follicles and
transfer (GIFT) unless severe male factor injected laparoscopically into a Fallopian tube to
Do not use in women naturally.
with tubal disease Rarely performed in the UK, as it offers little adv
over IVF.
Intracytoplasmic sperm Male infertility 20–30% per cycle if female partner Viable spermatozoa are injected directly into ooc
injection (ICSI) under 40 years of age retrieved following superovulation. Embryos are
There is a small risk of sex then implanted into the uterus. Spermatozoa may
chromosome abnormalities in males concentrated from an ejaculate or be aspirated fr
(1%) conceived following ICSI epididymis or testis in men with obstructive azoo
Management of male infertility

Hypogonadotrophic hypogonadism
• Gonadotrophins: chorionic gonadotrophin 1,500–2,000IU IM 2x
week. Most also require FSH/hMG 150IU IM 3x week. Monitor serum
testosterone and testicular size. Main side effect: gynaecomastia.
Or
• Pulsatile GnRH is not generally used in men.
• Once testes are >8mL, semen analysis every 3–6 months. Takes
at least 2 years to maximize spermatogenesis. Normalization of
spermatogenesis in 80–90% of ♂.
• Once spermatogenesis is induced, it may be maintained by hCG alone.
Idiopathic semen abnormalities

There is no evidence to suggest that the use of androgens, gonadotro-
phins, or antioestrogens help to improve fertility in ♂ with idiopathic
disorders of spermatogenesis.
Obstructive azoospermia
• Reversal of vasectomy will result in successful pregnancy in up to 50%
of cases within 2 years.
• Microsurgery is possible for most other causes, with successful
pregnancies in 25–35% of couples within 18 months of treatment.
During surgery, sperm is often retrieved and stored for possible future
intracytoplasmic sperm injection (ICSI).
Varicocele
Controversial association with ♂ subfertility. Surgical correction is cur-
rently not recommended for fertility treatment, as there is little evidence
that surgery improves pregnancy rates.
UNEXPLAINED INFERTILITY 409
Unexplained infertility
Definition
Infertility despite normal sexual intercourse occurring at least twice
weekly, normal semen analysis, documentation of ovulation in several
cycles, and normal patent tubes (by laparoscopy).
Management
30–50% will become pregnant within 3 years of expectant management. If
not pregnant by then, chances that spontaneous pregnancy will occur are
greatly reduced, and ART should be considered. In ♀ >34 years of age,
then expectant management is not an option, and up to six cycles of IUI
or IVF should be considered.
Results
• Superovulation with IUI can achieve a pregnancy rate of 15% per cycle
and cumulative delivery rate after several cycles of 50%.
• IVF offers a live birth rate per cycle of >30% in younger ♀ and a
cumulative delivery rate approaching 80%.
• ICSI allows IVF to be offered in severe oligospermia, with pregnancy
rates equivalent to standard IVF. Slight increase in congenital
malformations after ICSI. Significant risk of multiple pregnancies with
any form of ART.
Ovulation induction
Indications
• Anovulation due to:
• PCOS.
• Controlled ovarian hyperstimulation for IVF.
Pretreatment assessment
• Exclude thyroid dysfunction and hyperprolactinaemia.
• Check rubella serology.
• Confirm normal semen analysis.
• Confirm tubal patency (laparoscopy, hysterosalpingogram (HSG),
or hysterosalpingo-contrast-sonography (HyCoSy)) prior to
gonadotrophin use and/or after failed clomiphene use.
• Optimize lifestyle: maintain satisfactory BMI, exercise in moderation,
reduce alcohol intake, and stop smoking.
• Baseline pelvic US is essential to exclude ovarian masses and uterine
abnormalities prior to treatment.
Clomifene citrate
• Mode of action:
• Antioestrogen blocking normal –ve feedback, thereby i pulse
frequency of GnRH. This stimulates FSH and LH release, thereby
stimulating the production of one or more dominant ovarian follicles.
• Antioestrogen effect on endometrium, cervix, and vagina.
• Indications. Eugonadotrophic anovulation, e.g. PCOS. May also be used
in unexplained infertility. Requires normal hypothalamo–pituitary–
ovarian axis to work, therefore ineffective in hypogonadotrophic
hypogonadism.
• Administration. Start on days 2–5 of menstrual cycle (may have to
induce bleed by giving a progestagen for 10 days), and take for a total
of 5 days.
• Dose:
• Most require 50–100mg/day for 5 days.
• Should be used with ovulation tracking by ultrasound to avoid
multiple pregnancies and to confirm effectiveness.
• Spontaneous ovulation should occur 5–10 days after last day of
medication.
• Remain on optimum dose for 6–12 months.
• Efficacy:
• 80–90% ovulate, with conception rates of 50–60% in first six ovulatory
cycles. May enhance chances of ovulation in non-responders by
the administration of 10,000IU of hCG midcycle (use US guidance;
administer hCG when leading follicle is at least 20mm).
• Side effects:
• Hot flushes in 10%, mood swings, depression and headaches in 1%,
pelvic pain in 5%, nausea in 2%, breast tenderness in 5%, hair loss in
0.3%, visual disturbances in 1.5%.
OVULATION INDUCTION 411
• Ovarian hyperstimulation syndrome (OHSS) in 1%.

• Multiple pregnancies in 7–10%.
• Risk of ovarian cancer. Unknown. Infertility is associated with an i risk
of ovarian cancer. Additionally, one study suggests a 2-fold i risk of
low-grade ovarian cancer, following long-term clomifene use. Further
studies necessary, but currently recommended maximum treatment
duration is 6–12 months.
• Tamoxifen is also an antioestrogen which has similar properties to
clomifene. It can be used to induce ovulation, with results comparable
to clomifene. The dose used is 20–40mg od for 5–7 days, starting
on days 2–5 of menstrual cycle. Letrozole 5mg also used in some
countries—similar effectiveness.
Ovarian diathermy
• Laparoscopic ovarian diathermy in 4–10 points on the surface of the
ovaries may be used in ♀ with PCOS who have failed to conceive on
clomiphene.
• Its ovulation rate of >80% and pregnancy rate of >60% are comparable
to gonadotrophin therapy without the risk of multiple pregnancies or
OHSS. It is most effective in slim ♀ with PCOS with a high LH.
• There is a low risk of pelvic adhesions following ovarian diathermy and
a theoretical risk of premature ovarian failure.
Gonadotrophins
• Indications:
• ♀ with PCOS who are clomiphene-resistant.
• For superovulation, as part of ART.
• Dose and administration. Several regimens available; all require close
monitoring with vaginal US.
• One suggested regime (low-dose step-up approach):
• Start at 50–75IU/day hMG (or FSH) on days 2–4 of the menstrual
cycle. Titrate the dose up at approximately weekly intervals, according
to follicle development to achieve up to three follicles over 14mm.
• If >3 mature follicles (>14mm) develop or E2 >3,000pmol/L, then
abandon cycle and restart on half-dose hMG/FSH because of risk
of OHSS.
• Otherwise, give hCG at a dose of 5,000IU to trigger ovulation when
follicle >18mm diameter. May increase to 10,000IU in subsequent
cycle if ovulation does not occur.
• May use gonadotrophins for a total of six cycles. If unsuccessful,
then consider IVF.
• Efficacy. 80–85% pregnancy rate after six cycles.
• Side effects:
• Multiple pregnancies (20%).
• OHSS:
• A potentially fatal syndrome of ovarian enlargement and i vascular
permeability, with accumulation of fluid in the peritoneal, pleural,
and pericardial cavities. Occurs after hCG stimulation and is more
severe if pregnancy occurs due to endogenous hCG production.
Withhold hCG in at-risk cycles.
• Mild OHSS occurs in up to 25% of stimulated cycles and results in

abdominal bloating and nausea. It resolves with bed rest and fluid
replacement. Severe OHSS, associated with hypotension, markedly
enlarged ovaries, ascites, and pleural and pericardial effusions,
occurs in <0.1%. ♀ need to be hospitalized and resuscitated, as
there is an i mortality from disseminated intravascular coagulation
and pulmonary emboli. Management should be led by an expert
reproductive endocrinologist.
• Risk factors for OHSS are multiple follicles, young age, PCOS, and
previous OHSS.
• IVF superovulation should be accompanied by use of a GnRH agonist,
starting from midluteal phase of the preceding cycle (long protocol) or
a GnRH antagonist starting in the midfollicular phase of the stimulation
cycle (antagonist protocol). These strategies prevent premature
ovulation before eggs can be collected and significantly improve
pregnancy rates.
Pulsatile GnRH
• Indications. Hypothalamic hypogonadism with normal pituitary function.
• Dose and administration. Pulsatile GnRH using an infusion pump which
is worn continuously. This delivers a dose of GnRH every 90min,
delivered subcutaneously (15–20 micrograms/90min).
• This treatment is favoured over hMG because of lower risk of OHSS
or multiple pregnancies.
• Side effects. Allergic reaction.
• Efficacy. Cumulative pregnancy rate of 70–90%.
Cryopreservation, fertility, and cancer treatment
• Chemotherapy and/or radiotherapy for some cancers can adversely
affect ♂ and ♀ fertility, resulting in gonadal failure.
• ♂ patients should be offered the chance of sperm cryopreservation
and storage prior to commencing cancer treatment so that future
fertility may be an option.
• ♀ cancer patients may consider either superovulation with oocyte
cryopreservation or IVF with embryo freezing if with established
partner. Requires a 3–6 weeks’ delay in initiation of chemo-/
radiotherapy which must be sanctioned by oncologist.
Human Fertilisation and Embryology Act (UK)
• The Human Fertilisation and Embryology Authority (HFEA) is a
statutory body set up to inspect, monitor, and license fertility centres
offering IUI, IVF, ICSI, and/or donor sperm or egg insemination and to
regulate all research involving human embryos. It is also required to
keep a register of all IVF treatment cycles and of all children born as
a result of IVF or donor sperm or oocytes. The HFEA also provides
information to couples seeking fertility treatment or potential donors.
• The HFEA is accountable to the Secretary of State for Health and
advises government ministers, as required, particularly regarding new
developments in fertility technology or research.
OVULATION INDUCTION 413
Further reading
Braude P, Muhammed S (2003). Assisted conception and the law in the United Kingdom. BMJ
327, 978–81.
Farhat R, et al. (2010). Outcome of gonadotropin therapy for male infertility due to hypogonado-
trophic hypogonadism. Pituitary 13, 105–10.
Hamilton-Fairley D, Taylor A (2003). Anovulation. BMJ 327, 546–9.
Hirsh A (2003). Male subfertility. BMJ 327, 669–72.
Royal College of Obstetrics and Gynaecology (2004). Fertility assessment and treatment for peo-
ple with fertility problems. RCOG, pp.1–208. Royal College of Obstetrics and Gynaecology,
London.
Disorders of sexual differentiation

Definition
Discordance between three elements of sexual development: genetic sex,
gonadal structure, or genital appearance.
• Infancy. Ambiguous genitalia (b see evaluation discussed in
Assessment of ambiguous genitalia, p. 545).
• Puberty:
• Failure to progress through puberty (♂ or ♀ phenotype).
• p amenorrhoea in a ♀ phenotype.
• Virilization of a ♀ phenotype.
• Adulthood:
• Hypogonadism.
• Infertility.
Evaluation
• Karyotype. 46,XX vs 46,XY ♂ or ♀.
• Imaging:
• Look for presence of testes or ovaries and uterus.
• Most easily performed using pelvic US, but MRI may be more
sensitive in identifying internal genitalia and abnormally sited gonads
in cryptorchidism.
Hormonal evaluation
• LH, FSH, testosterone, oestradiol, SHBG.
• hCG stimulation test (b see Clinical assessment, p. 119)—to assess
the presence of functioning testicular material. Measure testosterone,
androstenedione, DHT, and SHBG post-stimulation.
• Others, depending on clinical suspicion, for example:
• 5A-reductase deficiency—check DHT levels before and after hCG
stimulation.
• 21-hydroxylase deficiency—17-hydroxyprogesterone 9 ACTH
stimulation (b see Investigations, p. 322).
• Urinary steroid profile—mass spectrometry and gas
chromatography as screen for some enzyme defects.
DISORDERS OF SEXUAL DIFFERENTIATION 415
Box 4.25 Causes of disorders of sexual differentiation

(b see also Assessment of ambiguous genitalia, p. 545.)
46,XY DSD
• XY gonadal dysgenesis (Swyer syndrome):
• Cause unknown in the majority.
• 20% SRY gene mutation.
• Leydig cell hypoplasia:
• LH receptor gene mutation.
• Biochemical defects of androgen synthesis, for example:
• 3B-HSD, 17A-hydroxylase/17,20-desmolase or 17B-HSD
deficiencies.
• Androgen receptor defects:
• Androgen insensitivity syndrome (b see pp. 416, 546).
• 5A-reductase deficiency:
• Mutation of 5A-reductase type 2 gene.
• Autosomal recessive inheritance.
• High testosterone but low DHT concentrations.
• Phenotype can range from ♀ external genitalia to ♂ with
hypospadias. Characteristically virilize after puberty.
• Persistent Müllerian duct syndrome:
• Müllerian inhibitory substance (MIS), also called anti-Müllerian
hormone (AMH), or MIS receptor gene mutation.
• Ovotesticular DSD.
46,XX DSD
• Excess fetal androgens—CAH:
• 21-OH deficiency (90%).
• 11B-OH deficiency.
• Excess maternal androgens:
• Drugs.
• Virilizing tumours.
• Placental aromatase deficiency.
• 46,XX ♂
• Due to a Y to X translocation so that the SRY gene is present.
• Phenotype similar to Klinefelter’s syndrome.
• Ovotesticular DSD.
Androgen insensitivity syndrome

Pathogenesis
• Results from a mutation in androgen receptor gene (Xq11–12).
Inherited in an X-linked recessive fashion, but approximately 40% of
patients have a –ve family history, i.e. de novo mutations.
• Severity of mutation variable—results in phenotype spectrum
from normal female, through partially virilized XY DSD, to infertile
male: Reifenstein’s syndrome (undervirilized ♂ with gynaecomastia
and hypospadias).
• Incidence 1:20,000–1:64,000.
Clinical features
• Complete androgen insensitivity results in normal ♀ external genitalia.
However, the vagina is often shorter than normal and may rarely be
absent. Testes are usually located in the abdomen or in the inguinal
canal. There is no spermatogenesis.
• Presents in childhood with inguinal testicular hernia or p amenorrhoea
at puberty. Pubertal development is normal, apart from little or no
pubic and axillary hair. Body habitus, gender identity, and psychological
development are ♀.
• Partial androgen insensitivity has a wide phenotypic spectrum, ranging
from ambiguous genitalia to a normal ♂ phenotype, presenting with
infertility.
Evaluation
• Key features are raised LH, normal FSH, and testosterone levels
normal or slightly raised (♂ range). hCG stimulation results in a
further rise in testosterone, with little increase in SHBG.
• Androgen receptor mutation screening if possible female carriers exist
in pedigree.
Management
• Orchidectomy to prevent malignancy. Exact timing of surgery
is controversial, but it is usually performed in adolescence after
attaining puberty. In phenotypic ♀ with partial androgen insensitivity,
gonadectomy may be performed before puberty to avoid virilization.
• Oestrogen replacement therapy in phenotypic ♀.
• High-dose androgen therapy in ♂ with Reifenstein’s syndrome may
improve virilization.
OVOTESTICULAR DSD 417
Ovotesticular DSD
Pathogenesis
• Unknown. May be familial.
• Previously known as true hermaphroditism.
• Affected individuals have both ovarian and testicular tissue, either in
the same gonad (ovotestis) or an ovary on one side and a testis on the
other. A uterus and a Fallopian tube are usually present, the latter on
the side of the ovary or ovotestis. Wolffian structures may be present
in a third of individuals on the side of the testis. The testicular tissue is
usually dysgenetic, although the ovarian tissue may be normal.
Clinical features
• Most individuals have ambiguous genitalia and are raised as ♂, but just
under 10% have normal ♀ external genitalia.
• At puberty, 50% of individuals menstruate, which may present as cyclic
haematuria in ♂, and most develop breasts.
• Feminization and virilization vary widely. Most are infertile, but fertility
has been reported.
• 2% risk of gonadal malignancy, higher in 46,XY individuals.
Evaluation
• 46,XX in 70%, 46,XX/46,XY in 20%, and 46,XY in 10%.
• Hypergonadotrophic hypogonadism is usual.
• Diagnosis can only be made on gonadal biopsy.
General principles of management

Assignment of gender and reconstructive surgery
Virilized females
• The majority are brought up as ♀.
• The timing of feminizing surgery remains controversial but is usually
deferred until adolescence. The decision should be made on an
individual basis by a multidisciplinary specialist team, the parents, and
ideally the patient. It appears that a significant number of children who
have surgery performed during infancy will require further surgery
in their teens. The results of feminizing genitoplasty, which involves
clitoral reduction and vaginoplasty, with regard to sexual function are
unclear.
Undervirilized males
• The decision regarding gender reassignment is complex and depends
on the degree of sexual ambiguity, aetiology, the potential for normal
sexual function and fertility, and social circumstances.
• Individuals with complete androgen insensitivity are assigned a ♀
sex, as they are resistant to testosterone therapy, develop ♀ sexual
characteristics, and have a ♀ gender identity.
• Sex assignment of other forms depends on phallic size. A trial of
3 months of testosterone may be used to enhance phallic growth.
• Penile reconstruction and orchidopexy by an experienced urologist
may be considered in some patients. Testicular prostheses may be
required if orchidopexy is not possible. The optimal procedure and
timing of surgery remain controversial, and the decision should ideally
be made involving the patient when he is old enough to give informed
consent. Results of surgery on sexual function are mixed.
Gonadectomy
• i risk of gonadoblastoma in most individuals with abdominal testes.
Risk is highest in those with dysgenetic gonads and Y chromosome
material. Bilateral gonadectomy should, therefore, be performed
(usually laparascopically).
• Optimal timing of the gonadectomy is unknown. In androgen
insensitivity, the risk of gonadoblastoma appears to rise only after the
age of 20 years, so orchidectomy is recommended in adolescence
after attaining puberty. In most other disorders, gonadectomy prior to
puberty is recommended.
• Early bilateral orchidectomy should also be performed in 46,XY
subjects with 5A-reductase deficiency or 17B-HSD deficiency who are
being raised as ♀ to prevent virilization at puberty.
GENERAL PRINCIPLES OF MANAGEMENT 419
Hormone replacement therapy

• Patients with disorders of adrenal biosynthesis, e.g. CAH, require
lifelong glucocorticoid and usually mineralocorticoid replacement
therapy.
• Gender-assigned ♂ require long-term testosterone replacement
therapy.
• Individuals with 5A-reductase deficiency usually receive
supraphysiological doses of testosterone in order to achieve
satisfactory DHT levels.
• Gender-assigned ♀ should receive oestrogen replacement therapy to
induce puberty, and this should be continued until about the age of 50.
Psychological support
• Disorders relating to sexual identity and function require expert
counselling.
• Patient support groups are often helpful.
Further reading
Creighton S, Minto C (2001). Managing intersex. BMJ 323, 1264–5.
MacLaughlin DT, Donahoe PK (2004). Sex determination and differentiation. N Engl J Med 350,
367–78.
Vogiatzi MG, New MI (1998). Differential diagnosis and therapeutic options for ambiguous genitalia.
Curr Opin Endocrinol Diabet 5, 3–10.
Warne GL, Zajac JD (1998). Disorders of sexual differentiation. Endocrinol Metab Clin North Am
27, 945–67.
Transsexualism
Definition
A condition in which an apparently anatomically and genetically normal
person feels that he or she is a member of the opposite sex. Gender dys-
phoria is an irreversible discomfort with the anatomical gender, which may
be severe, often developing in childhood.
Epidemiology
• More common in ♂.
• Estimated prevalence of 1:13,000 ♂ and 1:30,000 ♀.
Aetiology
• Unknown and controversial.
• Some evidence that it may have a neurobiological basis. There appear
to be sex differences in the size and shape of certain nuclei in the
hypothalamus. ♂ to ♀ transsexuals have been found to have ♀
differentiation of one of these nuclei, whereas ♀ to ♂ transsexuals
have been found to have a ♂ pattern of differentiation.
Management
Standards of care
• Multidisciplinary approach between psychiatrists, endocrinologists, and
surgeons. Patient should be counselled about the treatment options,
risks, and implications, and realistic expectations should be discussed.
• Endocrine disorders should be excluded prior to entry into the gender
reassignment programme, i.e. ensure normal internal and external
genitalia, karyotype, gonadotrophins, and testosterone/oestradiol.
• Psychiatric assessment and follow-up is essential before definitive
therapy. The transsexual identity should be shown to have been
persistently present for at least 2 years to ensure a permanent diagnosis.
• Following this period, the subject should dress and live as a member
of the desired sex under the supervision of a psychiatrist. This should
continue for at least 3 months before hormonal treatment and 1 year
before surgery.
• Psychological follow-up and expert counselling should be available, if
required, throughout the programme, including after surgery.
• In adolescents, puberty can be reversibly halted by GnRH analogue
therapy to prevent irreversible changes in the wrong gender until a
permanent diagnosis is made.
• See Box 4.27 for monitoring of therapy.
TRANSSEXUALISM 421
Box 4.26 Contraindications to hormone manipulation

Feminization Masculinization
• Prolactinoma. • Cardiovascular disease.
• Family history of breast cancer. • Active liver disease.
• Risk of thromboembolism. • Polycythaemia.
• Active liver disease. • Cerebrovascular disease.
• Cardiovascular or cerebrovascular
disease.
• Other contraindication to
oestrogen therapy (b see p. 347).
Box 4.27 Monitoring of therapy

• Every 3 months for first year, then every 6 months.
• Hormonal therapy is lifelong, and so patients should be followed up
indefinitely.
Male to female Female to male
• Physical examination. • Physical examination.
• Liver function tests. • Liver function tests.
• Serum lipids and glucose. • Serum lipids and blood glucose.
• LH, oestradiol, prolactin. • LH, testosterone.
• PSA (>50 years). • FBC (exclude polycythaemia).
• ? mammogram (>50 years).
• Bone densitometry. • Bone densitometry.
Hormonal manipulation
See Box 4.26 for contraindications.
Male to female transsexuals
• Suppress ♂ s sex characteristics: cyproterone acetate (CPA)
(100mg/day).
• Induce ♀ s sex characteristics:
• Ethinylestradiol 100 micrograms/day or estradiol valerate 2mg bd/
tds or estradiol patch 100 micrograms 2x/week (stop smoking).
• Medroxyprogesterone acetate 10mg od.
• Aims:
• Breast development—maximum after 2 years of treatment.
• Development of ♀ fat distribution.
• d body hair and smoother skin. However, facial hair is often
resistant to treatment.
• d muscle bulk and strength.
• Reduction in testicular size.
• Hormonal manipulation has little effect on voice.
• Reduce dose of CPA following gender reassignment surgery, and

discontinue, if possible. However, some subjects will require an
antiandrogen in order to keep oestradiol doses to a minimum (see
Table 4.22).
• The dose of oestrogen may be reduced after gender reassignment
surgery (see Table 4.22).
• Change to transdermal oestrogens if >40 years old. Change to HRT
doses once >50 years old.
• Adjust oestrogen dose, depending on plasma LH and oestradiol levels.
• Side effects (particularly while on high-dose EE2 + CPA therapy):
• Venous thromboembolism.
• Abnormal liver enzymes.
• Depression.
• ? i risk of breast cancer.
Female to male transsexuals

• Induce ♂ s sex characteristics and suppress ♀s sex
characteristics: parenteral testosterone (see Table 4.22).
• Aims:
• Cessation of menstrual bleeding.
• Atrophy of uterus and breasts.
• Increase muscle bulk and strength.
• Deepening of voice (after 6–10 weeks).
• Hirsutism.
• ♂ body fat distribution.
• Increase in libido.
• Once sexual characteristics are stable (after approximately 1 year of
treatment) and following surgery, reduce testosterone dose, based on
serum testosterone and LH levels.
• Side effects:
• Acne (in 40%).
• Weight gain.
• Abnormal liver function.
• Adverse lipid profile.
Gender reassignment surgery

• Performed at least 6–9 months after starting sex hormone therapy.
• A second psychiatric opinion should be sought prior to referral for
surgery.
• Usually performed in several stages.
Male to female transsexuals
• Bilateral orchidectomy and resection of the penis.
• Construction of a vagina and labia minora.
• Clitoroplasty.
• Breast augmentation.
TRANSSEXUALISM 423
Table 4.22 Maintenance hormone regimens in the treatment of

transsexualism
Feminization (post-surgery) Masculinization (pre- and
post-surgery)
<40 years: Testosterone 250mg IM every 2 weeks
Ethinylestradiol 30–50 micrograms od Transdermal testosterone (gel or
Estradiol valerate (oral) 2–4mg od patch) 5mg od
Estradiol valerate (transdermal) 50
micrograms 2x/week
Conjugated estrogens 1.25mg od
>40 years:
Transdermal estradiol 50 micrograms
2x/week
May need to continue cyproterone
acetate 50mg od or add
spironolactone 100–200mg od
Role of progestin not established
Female to male transsexuals

• Bilateral mastectomy.
• Hysterectomy and salpingo-oophorectomy.
• Phalloplasty and testicular prostheses.
Prognosis
• Significantly i morbidity in ♂ to ♀ transsexuals from
thromboembolism.
• Hyperprolactinaemia and elevation in liver enzymes are self-limiting in
the majority of cases.
• The risk of osteoporosis is not thought to be i in transsexuals.
• There may be a slightly i risk of breast cancer in ♂ to ♀ transsexuals.
• Results from reconstructive surgery, particularly in ♀ to ♂
transsexuals, remain suboptimal.
• There is an i risk of depressive illness and suicide in transsexual
individuals.
Further reading
Gooren LJ (2011). Clinical practice. Care of transsexual persons. N Engl J Med 364, 1251–7.
Gooren LJ, Giltay EJ, Brunck MC (2008). Long-term treatment of transsexuals with cross-sex
hormones: extensive personal experience. J Clin Endocrinol Metab 93, 19–25.
Levy A, Crown A, Reid R (2003). Endocrine intervention for transsexuals. Clin Endocrinol 59, 409–18.
Moore E, Wisniewski A, Dobs A (2003). Endocrine treatment of transsexual people: a review of
treatment regimens, outcomes and adverse effects. J Clin Endocrinol Metab 88, 3467–73.
Schlatterer K, von Werder K, Stalla GK (1996). Multistep treatment concept of transsexual
patients. Exp Clin Endocrinol Diabet 104, 413–19.
Chapter 5 425
Endocrinology in
pregnancy
Thyroid and parathyroid disorders 426

Maternal hyperthyroidism 428
Maternal hypothyroidism 431
Post-partum thyroid dysfunction 432
Thyroid cancer in pregnancy 433
Parathyroid disorders 434
Pituitary disorders 436
Prolactinoma in pregnancy 437
Management of prolactinoma 438
Cushing’s syndrome 439
Management of Cushing’s syndrome 440
Acromegaly 441
Non-functioning pituitary tumours 441
Hypopituitarism in pregnancy 442
Adrenal disorders 444
Addison’s disease in pregnancy 445
Congenital adrenal hyperplasia 446
Phaeochromocytoma 447
Management of phaeochromocytoma 448
426 CHAPTER 5 Endocrinology in pregnancy
Thyroid and parathyroid disorders

Normal physiology
Effect of pregnancy on thyroid function
• Iodine stores. Fall due to i renal clearance and transplacental transfer
to fetus.
• Thyroid size. Increase in thyroid volume by 10–20% due to hCG
stimulation and relative iodine deficiency.
• Thyroglobulin. Rise corresponds to rise in thyroid size.
• Thyroid-binding globulin (TBG). Twofold i in concentration as a result
of reduced hepatic clearance, and i synthesis stimulated by oestrogen.
Concentration plateaus at 20 weeks’ gestation and falls again
post-partum.
• Total T4 and T3.i concentrations, corresponding to rise in TBG.
• Free T4 and T3. There may be a small rise in concentration in first
trimester due to hCG stimulation, then fall into normal range. During
second and third trimester, FT4 concentration is often just below the
normal reference range.
• Thyroid-stimulating hormone (TSH). Within normal limits in pregnancy.
However, suppressed in 13.5% in first trimester, 4.5% in second
trimester, and 1.2% in third trimester due to hCG thyrotropic effect.
+ve correlation between free T4 and hCG levels, and –ve correlation
between TSH and hCG levels in first half of pregnancy. Upper limit of
normal range is higher in pregnancy.
• Thyrotropin-releasing hormone (TRH). Normal.
• TSH receptor antibodies. When present in high concentrations in
maternal serum, may cross the placenta. Antibody titre decreases with
progression of pregnancy.
Fetal thyroid function
• TRH and TSH synthesis occurs by 8–10 weeks’ gestation, and thyroid
hormone synthesis occurs by 10–12 weeks’ gestation.
• TSH, total and freeT4 and T3, and TBG concentrations increase
progressively throughout gestation.
• Maternal TSH does not cross the placenta, and although TRH crosses
the placenta, it does not regulate fetal thyroid function. Iodine crosses
the placenta, and excessive quantities may induce fetal hypothyroidism.
Maternal T4 and T3 cross the placenta in small quantities and are
important for fetal brain development in the first half of gestation.
THYROID AND PARATHYROID DISORDERS 427
Maternal hyperthyroidism
(b see Thyrotoxicosis in pregnancy, p. 44.)
Incidence
• Affects 0.2% of pregnant women.
• Most are diagnosed before pregnancy or in the first trimester of
pregnancy.
• In women with Graves’s disease in remission, exacerbation may occur
in first trimester of pregnancy.
Graves’s disease
• The commonest scenario is pregnancy in a patient with pre-existing
Graves’s disease on treatment, as fertility is low in patients with
untreated thyrotoxicosis. Newly diagnosed Graves’s disease in
pregnancy is unusual.
• Aggravation of disease in first trimester, with amelioration in second
half of pregnancy because of a decrease in maternal immunological
activity at that time.
• Symptoms of thyrotoxicosis are difficult to differentiate from
normal pregnancy. The most sensitive symptoms are weight loss and
tachycardia. Goitre is found in most patients.
Management
• Risks of uncontrolled hyperthyroidism to mother: heart failure/
arrhythmias.
• Antithyroid drugs (ATDs) are the treatment of choice but cross the
placenta.
• Propylthiouracil (PTU) should be used in the first trimester in case
of teratogenic effects of carbimazole (check liver function monthly).
Thereafter, carbimazole is recommended.
• Carbimazole use in pregnancy was discouraged, as it was thought to be
associated with aplasia cutis, a rare scalp defect, though recent studies
have shown no increase in rate. Studies have shown that carbimazole
may be associated with choanal and oesophageal atresia, but the
maternal hyperthyroidism may be a factor in this.
• Propylthiouracil may rarely be associated with hepatocellular
inflammation, which, in severe cases, can lead to liver failure and
death. A recent study also showed that PTU was associated with low
birthweight infants.
• A short course of 40mg of propranolol tds can be used initially for 2–3
weeks while antithyroid drugs take affect.
• Most patients will be on a maintenance dose of ATD. A high dose of
ATD may be necessary initially to achieve euthyroidism as quickly as
possible (carbimazole 20–40mg/day or propylthiouracil 200–400mg/
day) in newly diagnosed patients, then use the minimal dose of ATD to
maintain euthyroidism.
• Do not use block and replace regime as higher doses of ATDs
required, and there is minimal transplacental transfer of T4, thereby
risking fetal hypothyroidism.
• Monitor TFTs every 4–6 weeks.
MATERNAL HYPERTHYROIDISM 429
• Aim to keep FT4 at upper limit of normal and TSH low normal
(<2.5mU/L—first trimester, <3.0mU/L—second trimester,
<3.5mU/L—third trimester).
• In 730% of women, ATD may be discontinued at 32–36 weeks’
gestation. Consider if euthyroid for at least 4 weeks on lowest dose
of ATD, but continue to monitor TFTs frequently. The presence of
a large goitre or ophthalmopathy suggests severe disease and the
chances of remission are low, so do not stop ATD. Graves’s disease
can flare in the post-natal period due to increase in the maternal
antibody levels, so patients should be monitored closely in the
post-partum period.
• Risks of neonatal hypothyroidism and goitre are reduced if woman on
carbimazole 20mg or less (200mg propylthiouracil or less) in last few
weeks of gestation.
• Breastfeeding is safe at doses of less than 150mg of PTU and 15mg
carbimazole, as only small amounts pass into the breast milk (<0.7%
PTU and 0.5% carbimazole).
• If higher doses are given, we recommend breastfeeding prior to taking
medication, and the dose can be divided throughout the day. Neonatal
thyroid function needs to be monitored.
• Surgical management of thyrotoxicosis is rarely necessary in pregnancy.
Only indication: serious ATD complication (e.g. agranulocytosis) or
drug resistance. There is a possible i risk of spontaneous abortion
or preterm delivery associated with surgery during pregnancy. The
second trimester is the optimal time for surgery, as organogenesis is
complete and less chance of anaesthesia and surgery inducing labour.
• Radioiodine therapy is contraindicated in pregnancy, during
breastfeeding, and for 4 months prior to conception.
Infants born to mothers with Graves’s disease
• Risks to fetus of uncontrolled thyrotoxicosis:
• i risk of spontaneous miscarriage and stillbirth.
• Intrauterine growth restriction (IUGR).
• Preterm labour.
• Fetal or neonatal hyperthyroidism.
• Follow-up of babies born to mothers on ATDs show normal weight,
height, and intellectual function.
• Fetal hypothyroidism. May occur following treatment of mother
with high doses of ATDs (>200mg PTU/day; >20mg carbimazole),
particularly in the latter half of pregnancy. This is rare and may be
diagnosed by demonstrating a large fetal goitre on fetal US in the
presence of fetal bradycardia.
• Fetal hyperthyroidism. May occur after week 25 of gestation. It results
in IUGR, fetal goitre, and tachycardia (fetal heart rate >160bpm) and
has high mortality if not treated. It may develop if the mother has
high titres of TSH-stimulating antibodies (TSAb) which can cross the
placenta. Treat by giving mother ATD, and monitor fetal heart rate (aim
<140bpm), growth, and goitre size. It is important to remember women
with Graves’s disease who have been treated with radioiodine or
surgery can still have high antibody titres and therefore need monitoring.
• Neonatal thyrotoxicosis. Develops in 1% of infants born to thyrotoxic

mothers. Transient, usually subsides by 6 months, but up to 30%
mortality if untreated. Treat with ATD and B-blockers.
Hyperemesis gravidarum (gestational hyperthyroidism)
• Characterized by severe vomiting and weight loss. Cause unknown.
• Begins in early pregnancy (weeks 6–9 of gestation) and tends to
resolve spontaneously by week 20 of gestation.
• Biochemical hyperthyroidism in two-thirds of affected women, but T3
is less commonly elevated. Mechanism: hCG has TSH-like effect, thus
stimulating the thyroid gland and suppressing TSH secretion.
• Degree of thyroid stimulation correlates with severity of vomiting.
• No other evidence of thyroid disease, i.e. no goitre, no history of
thyroid disease, no ophthalmopathy, and –ve thyroid autoantibodies
(10% population is +ve for thyroid antibodies).
• Antithyroid drugs not required and do not improve symptoms of
hyperemesis.
Causes of maternal hyperthyroidism
• Graves’s disease (85% of cases).
• Toxic nodule.
• Toxic multinodular goitre.
• Hydatidiform mole.
MATERNAL HYPOTHYROIDISM 431
Maternal hypothyroidism
Prevalence
• 2.5% subclinical hypothyroidism.
• 1–2% overt hypothyroidism.
Risks of suboptimal treatment during pregnancy
• Spontaneous miscarriage. Twofold i risk.
• Pre-eclampsia. 21% of suboptimally treated mothers have
pregnancy-induced hypertension (PIH).
• Also i risk of anaemia during pregnancy and post-partum
haemorrhage.
• The fetus is dependent on maternal thyroxine until fetal production
starts at 12 weeks.
• Risk of impaired fetal intellectual and cognitive development.
• i risk of perinatal death.
• Other risks to fetus are those associated with PIH (IUGR, preterm
delivery, etc.).
• The risk of congenital malformations is not thought to be i.
Management
• Spontaneous pregnancy in overtly hypothyroid women is unusual, as
hypothyroid women are likely to have anovulatory menstrual cycles.
• Levothyroxine therapy. Start on 100 micrograms. Measure TSH and free
T4 4 weeks later.
• For women on thyroxine, optimize therapy prior to pregnancy.
• If already on T4 before pregnancy, on confirmation of pregnancy,
increase dose by 30% (25–50 micrograms) because of increased TBG
and thyroid hormone requirements.
• Aim. TSH—lower part of normal range; FT4—upper end of normal.
• Many women are suboptimally replaced prior to pregnancy, so their
dose needs to be increased in response to abnormal TFTs. After
delivery, they should continue on this increased dose, with monitoring
of biochemistry.
• NB Do not give FeSO4 simultaneously with T4—reduces its efficacy.
Separate times for drug ingestion by at least 2h.
Causes of maternal hypothyroidism
• Hashimoto’s thyroiditis (most common cause).
• Previous radioiodine therapy or thyroidectomy.
• Previous post-partum thyroiditis.
Positive thyroid antibodies but euthyroid
• Twofold excess risk of spontaneous miscarriage.
• No other complications.
• No risk of neonatal hypothyroidism.
• Risk of PIH not i.
• The occasional mother will develop hypothyroidism towards the end
of the pregnancy, so check TFTs between weeks 28–32 of gestation.
• i risk of post-partum thyroiditis, so check TSH at 3 months
post-partum.
Post-partum thyroid dysfunction

Prevalence
• 5–10% of women within 1 year of delivery or miscarriage.
• 3x more common in women with type 1 diabetes mellitus.
Aetiology
• Chronic autoimmune thyroiditis (b see Other types of
thyroiditis, p. 72).
• Hyperthyroidism (32%):
• Within 4 months of delivery.
• The most common symptom is fatigue.
• Usually resolves spontaneously in 2–3 months.
• Hypothyroidism (43%):
• Develops 4–6 months after delivery.
• Symptoms may be mild and non-specific.
• There may be an i risk of post-partum depression.
• Hyperthyroidism followed by hypothyroidism (25%).
• Spontaneous recovery in 80% within 6–12 months of delivery.
Differential diagnosis
• Graves’s disease may relapse in the post-partum period. This is
differentiated from post-partum thyroiditis by a high uptake on
radioiodine scanning.
• Lymphocytic hypophysitis may cause hypothyroidism. However, serum
TSH concentrations are inappropriately low.
Investigation
• Thyroid peroxidase antibodies are +ve in 80%.
• Radionuclide uptake scans are rarely necessary. However, there is low
uptake during the thyrotoxic phase, differentiating it from Graves’s
disease where uptake is i.
Management
• B-blockers if thyrotoxic and symptomatic until TFTs normalize.
Antithyroid medication is unnecessary.
• Levothyroxine if TSH >10 or if TSH between 4–10 and symptomatic.
• No consensus as to how long to treat with thyroxine. Two options:
• Halve dose at about 12 months post-natal, and check TFTs 6 weeks
later. If normal, then withdraw T4, and check TFTs 6 weeks later.
• Withdraw treatment 1 year after completion of family.
Prognosis
• Recurrence in future pregnancies in 25% of women.
• Permanent hypothyroidism develops in up to 30% of women within
10 years. If treatment is withdrawn, then annual TSH measurements
are essential.
THYROID CANCER IN PREGNANCY 433
Thyroid cancer in pregnancy

(b see Thyroid cancer and pregnancy, p. 102.)
Parathyroid disorders
Calcium metabolism in pregnancy
• There are increased calcium requirements in pregnancy; 25–30g is
transferred to the baby.
• There is increased maternal intestinal absorption of calcium.
• Due to increased renal blood flow, there is increase in the renal
excretion of calcium.
Primary hyperparathyroidism in pregnancy
• Rare—8 cases in 100,000 in women of childbearing age.
• In pregnancy, the hypercalcaemia may improve due to the fetal transfer
of calcium.
• Diagnosis is made by finding a raised PTH in the presence of a raised
calcium.
• Ultrasound can be used to locate the adenoma.
• Can cause serious maternal morbidity which includes hyperemesis,
nephrolithiasis, peptic ulcers, and pancreatitis. It is also associated with
pre-eclampsia, recurrent miscarriage, preterm labour.
• Fetal complications include IUGR and neonatal death. The high
circulating maternal calcium can lead to suppression of fetal
parathyroid development, leading to hypocalcaemia of the fetus after
delivery. Neonates normally present at days 5–14 with poor feeding,
tetany, and convulsions.
Management
• Hypercalcaemia is treated with IV fluids.
• If mild, women can be advised to increase their fluid intake. Calcium
levels should be monitored throughout pregnancy, with surgery
arranged post-partum.
• If calcium remains persistently high (>2.85mmol/L), then
parathyroidectomy can be arranged in the second or early third
trimester.
Hypoparathyroidism
• Pregnancy increases the demand for vitamin D. Therefore,
replacement doses will need to be increased in pregnancy.
• Maternal levels of corrected calcium and vitamin D should be checked
monthly.
• Untreated hypoparathyroidism leads to miscarriage, fetal
hypocalcaemia, and neonatal rickets.
PARATHYROID DISORDERS 435
Further reading
Abalovich M, Amino N, Barbour LA, et al. (2007). Management of thyroid dysfunction during preg-
nancy and post-partum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab
92(8 Suppl), S1–47.
Alexander EK, Marqusee E, Lawrence J, et al. (2004). Timing and magnitude of increases in levothy-
roxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 351, 241–9.
Azizi F, Amouzegar A (2011). Management of hyperthyroidism during pregnancy. Eur J Endocrinol
164, 871–6.
Chen C, Xirasager S, et al. (2011). Risk of adverse perinatal outcomes with antithyroid treatement
during pregnancy: a national population based study. BJOG 118, 1365–73.
Cooper S, Rivkees S (2009). Putting propylthiouracil in perspective. J Clin Endocrinol Metab 94,
1881–2.
De Groot L, et al. (2012). Management of thyroid dysfunction during pregnancy and post-partum: an
Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 97, 2543–65.
Lazarus JH. (2011).Thyroid function in pregnancy. Br Med Bull 97, 137–48.
LeBeau SO, Mandell SJ (2006). Thyroid disorders during pregnancy. Endocrinol Metab Clin North
Am 35, 117–36.
Norman J, et al. (2009). Hyperparathyroidism during pregnancy and the effect of rising calcium on
pregnancy loss: a call for earlier intervention. Clin Endocrinol (Oxf) 71, 104–9.
Poppe K, Glinoer D (2003). Thyroid autoimmunity and hypothyroidism before and during preg-
nancy. Hum Reprod Update 9, 149–61.
Sato K (2008). Hypercalcemia during pregnancy, puerperium and lactation: Review and a case
report of hypercalcemic crisis after delivery due to excessive productin of PTH-related protein
(PTHrP) without malignancy (humoral hypercalcemia of pregnancy). Endocrin J 55, 959–66.
Stagnaro-Green A (2002). Post-partum thyroiditis. J Clin Endocrinol Metab 87, 4042–7.
Pituitary disorders
Normal anatomical changes during pregnancy
• Prolactin (PRL)-secreting cells. Marked lactotroph hyperplasia during
pregnancy.
• Gonadotrophin-secreting cells. Marked reduction in size and number.
• TSH and ACTH-secreting cells. No change in size or number.
• Anterior pituitary. Size increases by up to 70% during pregnancy. May
take 1 year to shrink to near pre-pregnancy size in non-lactating
women. Gradual slight increase in size with each pregnancy.
• MRI. Enlarged anterior pituitary gland, but stalk is midline. Posterior
pituitary gland may not be seen in late pregnancy.
Normal physiology during pregnancy
• Serum PRL. Concentrations increase markedly during pregnancy and fall
again to pre-pregnancy levels approximately 2 weeks post-partum in
non-lactating women.
• Serum LH and FSH. Undetectable levels in pregnancy and blunted
response to GnRH because of –ve feedback inhibition from high levels
of sex hormones and PRL.
• Serum TSH, T4, and T3. TSH may be suppressed in the first trimester
of pregnancy. Free thyroid hormones usually at the lower end of the
normal range.
• Growth hormone (GH) and IGF-I. Low maternal GH levels and blunted
response to hypoglycaemia due to placental production of GH-like
substance. IGF-I levels are normal or high in pregnancy.
• ACTH and cortisol. CRH, ACTH, and cortisol levels are high in
pregnancy, as both CRH and ACTH are produced by the placenta. In
addition, oestrogen-induced increase in cortisol-binding globulin (CBG)
synthesis during pregnancy will further increase maternal plasma
cortisol concentrations. During the latter half of pregnancy, there is
a progressive increase of ACTH and cortisol levels, peaking during
labour. Incomplete suppression of cortisol, following dexamethasone
suppression test, and exaggerated response of cortisol to CRH
stimulation. However, normal diurnal variation persists.
PROLACTINOMA IN PREGNANCY 437
Prolactinoma in pregnancy
Effect of pregnancy on tumour size
Risk of significant tumour enlargement (i.e. resulting in visual field distur-
bances or headaches):
• Microadenoma 1–2%.
• Macroadenoma 15–35%.
• Macroadenoma treated with surgery and/or radiotherapy before
pregnancy 4–7%.
Effect of dopamine agonists on the fetus
Bromocriptine
Over 6,000 pregnancies have occurred in women receiving bromocriptine
in early pregnancy, and the incidence of complications in these pregnancies
with regard to fetal outcome is similar to that of the normal population,
indicating that bromocriptine is probably safe in early pregnancy. Data are
available on children whose mothers received bromocriptine throughout
pregnancy, and again the incidence of congenital abnormalities is negligible.
Children who are exposed to bromocriptine in utero have normal psycho-
logical development in follow-up.
The FDA has withdrawn the licence for use of bromocriptine
post-partum to suppress lactation, as there was an increased incidence
of adverse incidents which included myocardial infarction and stroke. We
would advise caution, particularly in women with pre-eclampsia.
Cabergoline
Also probably safe in early pregnancy and has been used in >380 pregnan-
cies, with no i risk of fetal loss or congenital abnormalities, but fewer data
are available. There are more data on the long-term safety of bromocrip-
tine, but cabergoline is being used increasingly as it is better tolerated.
Quinagolide
It has been used in >176 pregnancies, with a slightly higher rate of congeni-
tal abnormalities compared to the background rate.
Recent controversy
The Medicine and Health Regulatory Authority issued guidance on the
use of cabergoline in pregnancy, stating it should be stopped 1 month
pre-pregnancy. This recommendation is based on data in Parkinson’s
patients where high doses are used and an increased rate of cardiac and
pulmonary fibrosis has been reported. There are no published data on
similar conditions occurring in the fetus. Current practice is to use bro-
mocriptine first-line in women hoping to conceive, and cabergoline if they
cannot tolerate bromocriptine. Quinagolide is reserved for patients who
are unable to tolerate the other dopamine agonists.
Management of prolactinoma
Microprolactinoma
• After recent MRI, initiate dopamine agonist therapy to induce normal
ovulatory cycles and fertility.
• Stop bromocriptine as soon as pregnancy is confirmed.
• Assess for visual symptoms and headache at each trimester, although
the risk of complications is low (<5%). Serum PRL levels are difficult to
interpret during pregnancy, as they are normally elevated; therefore,
they are not measured.
• MRI is indicated in the occasional patient who becomes symptomatic.
• In the post-partum period, recheck serum PRL level 2 months after
cessation of breastfeeding. Reassess size of microprolactinoma by MRI
only if serum PRL level is higher than pre-pregnancy concentrations.
• 40–60% chance of remission of microprolactinoma following
pregnancy.
Macroprolactinoma
Management is controversial and must, therefore, be individualized. Three
possible approaches:
• Bromocriptine (because cabergoline does not have a licence in
pregnancy) may be used throughout pregnancy to reduce the risk
of tumour growth. The patient is monitored by visual fields at each
trimester or more frequently if symptoms of tumour enlargement
develop. This is probably the safest, and thus preferred, approach.
• May use bromocriptine or cabergoline to induce ovulation, and then
stop it after conception. However, patient must be monitored very
carefully during pregnancy with monthly visual field testing.
• If symptoms of tumour enlargement develop or there is deterioration
in visual fields, then MRI should be performed to assess tumour
growth. If significant tumour enlargement develops, then
bromocriptine therapy should be initiated.
• Alternatively, the patient may undergo surgical debulking of the
tumour and/or radiotherapy before seeking fertility. This will
significantly reduce the risk of complications associated with
tumour growth. However, this approach may render them
gonadotrophin-deficient. These patients should again be monitored
during pregnancy, using regular visual fields.
MRI should be performed in the post-partum period in women with
macroprolactinomas to look for tumour growth.
Breastfeeding
• There is no contraindication to breastfeeding.
• If the mother would like to breastfeed, dopamine receptor agonists
will have to be discontinued prior to birth, as they inhibit lactation.
The decision to discontinue medication should be assessed on a
case-by-case basis, dependent upon the potential risk of optic nerve/
chiasm compression.
CUSHING’S SYNDROME 439
• Pregnancy is rare in women with untreated Cushing’s syndrome, as
75% of them will experience oligo- or amenorrhoea.
• Adrenal disease is the most common cause of Cushing’s syndrome
developing in pregnancy, responsible for over 50% of reported cases.
• The diagnosis of Cushing’s syndrome is difficult to establish during
pregnancy. However, the presence of purple striae and proximal
myopathy should alert the physician to the diagnosis of Cushing’s
syndrome.
• If suspected, the investigation of Cushing’s syndrome should be carried
out as in the non-pregnant state.
• The circulating levels of cortisol rise during normal pregnancy. This
is due to a combination of the increased levels of cortisol-binding
globulin, stimulated by the raised oestrogen, and the placental CRH
production which is biologically active.
• 24h urinary free cortisol measurements remain normal in the first
trimester but can increase by 3x by term in a normal pregnancy.
• Non-suppression of cortisol production on a low-dose dexamethasone
suppression test may be a feature of a normal pregnancy. There are no
internationally agreed normal values in pregnancy, so interpretation of
dynamic testing is difficult.
• The diurnal variation of cortisol secretion is, however, preserved in
normal pregnancy.
• Diagnosis is important, as pregnancy in Cushing’s syndrome is
associated with a high risk of maternal and fetal complications (see
Table 5.1).
Management of Cushing’s syndrome

• First trimester:
• Offer termination of pregnancy and instigate treatment, particularly
if adrenal carcinoma.
• Alternatively, surgical treatment early in the second trimester.
• Second trimester:
• Surgery, e.g. adrenalectomy or pituitary adenomectomy. Minimal
risk to fetus.
• Third trimester:
• i risk of diabetes mellitus.
• Deliver baby as soon as possible (preferably by vaginal delivery to
minimize the risk of poor wound healing following a Caesarean
section), and instigate treatment.
• Metyrapone used in doses of <2g/day generally well tolerated in
pregnancy. It can cause hypertension and has been associated with
development of pre-eclampsia and fetal hypoadrenalism.
• Ketoconazole has been used successfully in a few pregnancies; it is
antiandrogenic in rats, so caution should be used if the infant is male.
• Aminoglutethimide causes fetal masculinization so is not
recommended.
• Post-operative glucocorticoid replacement therapy will be required.
• Treatment of Cushing’s syndrome in pregnancy may reduce maternal
and fetal morbidity and mortality.
• See Table 5.1 for complications.
Table 5.1 Complications of Cushing’s syndrome in pregnancy

Maternal complications Incidence (%) Fetal complications Incidence (%)
Hypertension 70 Spontaneous abortion 12
Diabetes mellitus 27 Perinatal death 18
Congestive cardiac 7 Prematurity 60
failure
Poor wound healing 6 Congenital Low risk;
malformations no risk of
virilization
Death 4
Acromegaly
• Fertility in acromegaly is reduced, partly due to hyperprolactinaemia (if
present), in addition to secondary hypogonadism. However, there have
been several reported cases of pregnancy in acromegaly.
• Diagnosis in pregnancy is difficult, as the placenta secretes growth
hormone and, though different from maternal GH, assays may not be
able to detect this. IGF-1 also increases in normal pregnancy.
• Acromegaly increases the risk of gestational diabetes and hypertension,
so women should be screened.
• However, in the absence of diabetes mellitus, there does not appear
to be an excess of perinatal morbidity or mortality in babies born to
women with acromegaly.
• Significant tumour enlargement occasionally occurs, together with
enlargement of the normal pituitary lactotrophs, so monthly visual
field testing is recommended.
• Bromocriptine can be used in pregnancy, but there is less response
compared to prolactinomas.
• There are limited reports of somatostatin analogues and somatostatin
receptor agonists use in pregnancy, with no apparent adverse events.
They do cross the placenta. We would not advocate their use until
more data are available on their safety in pregnancy. Women are
generally advised to stop medication on conception.
• Headaches may be helped with both somatostatin analogues and
bromocriptine.
• Treatment may be deferred until after delivery in the majority of
patients.
Non-functioning pituitary tumours

• These tumours are the second commonest pituitary tumours, but
there is little reported about the incidence in pregnancy. Women may
present with compression effects due to tumour enlargement.
• If diagnosed pre-pregnancy, then visual field assessment in each
trimester is sufficient.
• If field defects develop during pregnancy, bromocriptine may be used
which will decrease the size of the normal lactotrophs and thereby
improving field defects.
Hypopituitarism in pregnancy
Pre-existing hypopituitarism
• Most commonly due to surgical treatment of and/or radiotherapy for a
pituitary adenoma.
• May require ovulation induction and thus conception by
gonadotrophin stimulation.
Lymphocytic hypophysitis
(b see also Lymphocytic hypophysitis, p. 194.)
• Rare disorder thought to be autoimmune in origin.
• Characterized by pituitary enlargement on imaging and variable loss of
pituitary function.
• Most commonly seen in women in late pregnancy or in the first year
post-partum.
• Symptoms are due to pressure effects, e.g. visual field defects and
headaches, or due to hormonal deficiency.
• Most common hormonal deficiencies:
• ACTH and vasopressin deficiency.
• TSH deficiency may also exist.
• Gonadotrophins and GH levels are usually normal.
• PRL levels may be mildly elevated in a third, and low in a third.
• Differential diagnosis:
• Pituitary adenoma.
• Sheehan’s syndrome.
• MRI often reveals diffuse homogeneous contrast enhancement of the
pituitary gland. However, the diagnosis is often only made definitively
by pituitary biopsy.
• There is an association with other autoimmune diseases, particularly
Hashimoto’s thyroiditis.
• Course variable. Pituitary function may deteriorate or improve with time.
Management
• Pituitary hormone replacement therapy, as required.
• Surgical decompression if pressure symptoms persist.
• A course of high-dose steroid therapy is controversial, with mixed
results.
Causes of hypopituitarism during pregnancy
• Pre-existing hypopituitarism.
• Pituitary adenoma.
• Lymphocytic hypophysitis.
• Sheehan’s syndrome.
Management of pre-existing hypopituitarism during pregnancy
• Hydrocortisone. Dose may need to be i in the third trimester of
pregnancy by 10mg a day, as the increase in CBG will reduce the
bioavailability of hydrocortisone. Parenteral hydrocortisone in a dose of
100mg IM every 6h should be given during labour and the dose reduced
back to maintenance levels in the post-partum period (24–72h).
HYPOPITUITARISM IN PREGNANCY 443
• Thyroxine. Requirements may increase, as pregnancy progresses.

Monitor free T4 each trimester, and increase T4 dose accordingly.
• GH. There are little data on the effects of GH on pregnancy, but
case reports do not suggest a detrimental effect on fetal outcome.
However, until more data accrue, GH should be stopped prior to
pregnancy. Moreover, as the placenta synthesizes a GH variant, GH
therapy is unnecessary.
• Vasopressin. The placenta synthesizes vasopressinase, which breaks down
vasopressin but not desmopressin. Women with partial diabetes insipidus
may, therefore, require desmopressin treatment during pregnancy. Those
already receiving desmopressin may require a dose increment during
pregnancy. Vasopressinase levels fall rapidly after delivery.
Sheehan’s syndrome
Post-partum pituitary infarction/haemorrhage, resulting in hypopituitarism.
Increasingly uncommon in developed countries with improvements in
obstetric care and management of post-partum haemorrhage.
Pathogenesis
• The enlarged pituitary gland of pregnancy is susceptible to any
compromise to its blood supply.
• Investigations will confirm hypopituitarism.
Risk factors
• Post-partum haemorrhage.
• Sickle cell disease.
Clinical features
• Failure of lactation.
• Involution of breasts.
• Fatigue, lethargy, and dizziness.
• Amenorrhoea.
• Loss of axillary and pubic hair.
• Symptoms of hypothyroidism.
• Diabetes insipidus is rare.
Management
Pituitary hormone replacement therapy (b see Background, p. 127).
Further reading
Caron P, et al. (2010). Acromegaly and pregnancy: a retrospective multicenter study of 59 pregnan-
cies in 46 women. J Clin Endocrinol Metab 95, 4680–7.
Karaca Z, et al. (2010). Pregnancy and pituitary disorders. Eur J Endocrinol 162, 453–75.
Kovacs K (2003). Sheehan syndrome. Lancet 361, 520–2.
Lindsay JR, et al. (2005). Cushing’s syndrome during pregnancy: personal experience and review of
the literature. J Clin Endocrinol Metab 90, 3077–83.
Medicines and Healthcare Products Regulatory Agency (2008). Drug safety update 2(3).
Molitch M (2006). Pituitary disorders in pregnancy. Endocrinol Metab Clin North Am 35, 99–116.
Molitch ME (2011). Prolactinoma in pregnancy. Best Pract Res Clin Endocrinol Metab 25, 885–96.
Sam S, Molitch M (2003). Timing and special concerns regarding endocrine surgery during preg-
nancy. Endocrinol Metab Clin North Am 32, 337–54.
Webster J (1996). A comparative review of the tolerability profiles of dopamine agonists in the
treatment of hyperprolactinaemia and inhibition of lactation. Drug Saf 14, 228–38.
Adrenal disorders
Normal changes during pregnancy
Changes in maternal adrenocortical function
Markedly i concentrations of all adrenal steroids due to i synthesis and
d catabolism.
Feto-placental unit
• Fetal adrenal gland. DHEAS is produced in vast quantities by the fetal
adrenal gland. This is the major precursor for oestrogen synthesis
by the placenta. The fetal adrenal gland has a large capacity for
steroidogenesis. Stimulus for fetal adrenal gland unknown—possibly
hCG or PRL.
• Placenta:
• Maternal glucocorticoids are largely inactivated in the placenta by
11B-HSD. Maternal androgens are converted to oestrogens by
placental aromatase, thus protecting 5 fetus from virilization.
• Maternal catecholamines are broken down by placental
catechol-O-methyl transferase and monoamine oxidase activity.
ADDISON’S DISEASE IN PREGNANCY 445
Addison’s disease in pregnancy

• No associated fetal morbidity in women who have pre-existing primary
adrenal insufficiency, as fetus produces and regulates its own adrenal
steroids.
• Management of Addison’s disease does not differ in pregnancy.
• Glucocorticoids which are metabolized by placental 11B-HSD
preferred (i.e. prednisolone or hydrocortisone) to avoid fetal adrenal
suppression.
• Increase hydrocortisone dose by about 10mg during the third
trimester of pregnancy and at any time in case of intercurrent illness.
• High-dose intramuscular hydrocortisone should be given at the time of
delivery to cover the stress of labour.
• Doses may be tapered to normal maintenance doses in the
post-partum period (see Box 5.1).
• Addison’s disease developing in pregnancy may result in an adrenal
crisis, particularly at the time of delivery, because of a delay in
diagnosis.
• In early pregnancy, vomiting, fatigue, hyperpigmentation, and low
BP may be wrongly attributed to pregnancy. However, persisting
symptoms should alert the clinician.
• If suspected, the diagnosis is confirmed by the presence of low
serum cortisol concentrations, with failure to rise following ACTH
stimulation, and high ACTH levels. However, the normal ranges for
serum ACTH and cortisol concentrations have not been established
in pregnancy. One review suggests a value of <828nmol/L 30min after
short Synacthen® test would be diagnostic in pregnancy, but this has
yet to be agreed internationally.
• Chronic maternal adrenal insufficiency may be associated with
intrauterine fetal growth restriction.
• There is no i risk of developing Addison’s disease in the immediate
post-partum period.
Box 5.1 Management of adrenal insufficiency during

pregnancy
• Hydrocortisone 20–30mg PO in divided doses, as per pre-pregnancy
dose. Increase in third trimester.
• Fludrocortisone 50–200 micrograms PO, as per pre-pregnancy dose,
but requirements may increase. As renin goes up during pregnancy,
this is monitored by BP and K.
During uncomplicated labour
• Hydrocortisone 100mg IM 6-hourly for 24h, then reduce to
maintenance dose over 72h.
• Keep well hydrated.
• Fludrocortisone may be discontinued while on high doses of
hydrocortisone.

• Fertility is reduced, particularly women with the salt-wasting form
of CAH.
• Reasons:
• Inadequate vaginal introitus despite reconstructive surgery.
• Anovulation as a result of hyperandrogenaemia.
• Adverse effects of elevated progestagen levels on endometrium.
• 60–80% of women with CAH and an adequate vaginal introitus are
fertile.
• Fertility may be maximized by optimal suppression of hyperandrogenism
by glucocorticoid therapy (b see Management, p. 324).
• No major complications in pregnancy are known in women with CAH,
apart from a possibly i incidence of pre-eclampsia.
• However, women are more likely to require Caesarean section for
cephalopelvic disproportion.
• Management is the same as in the non-pregnant woman, and steroids
are i at the time of delivery as for Addison’s disease (b see p. 266).
• Monitor serum testosterone and electrolytes every 6–8 weeks; if levels
increase, then increase dose of corticosteroids.
• Risk to fetus:
• No risk of virilization from maternal hyperandrogenism, as placenta
will aromatize androgens to oestrogens.
• Glucocorticoids do not increase the risk of congenital abnormalities.
• If partner is a heterozygote or homozygote for CAH, then the fetus
has a 50% risk of CAH. Prenatal treatment with dexamethasone
will then be necessary to avoid virilization of a 5 fetus (b see
Management of pregnancy in CAH, p. 325).
PHAEOCHROMOCYTOMA 447
Phaeochromocytoma
• Rare but potentially lethal in pregnancy. Maternal mortality may still
be as high as 17% and fetal mortality as high as 30% if not treated
promptly.
• Maternal death can be due to stroke, pulmonary oedema, arrhythmia,
and myocardial infarction, with the greatest risk during labour.
Placental vasoconstriction can lead to spontaneous fetal death,
intrauterine growth restriction, and fetal hypoxia.
• Hypertensive crisis can be precipitated by labour, delivery, opiates,
metoclopramide, and general anaesthesia.
• Women can present with palpitations, sweating, headache, anxiety,
dyspnoea, vomiting, and hyperglycaemia.
• Phaeochromocytoma needs to be differentiated from women with
pre-eclampsia, so suspect in women with hypertension, persistent or
intermittent, especially in:
• The absence of proteinuria or oedema, or presence of other
features.
• Hypertension developing before 20 weeks’ gestation, or
• Persistent glycosuria.
• Prenatal screening in high-risk women, e.g. those with a history or
family history of MEN-2 or von Hippel–Lindau syndrome.
• Diagnose by 24h urinary catecholamine collection (normal ranges are
unaltered in pregnancy) or raised plasma catecholamines.
• Labetalol and methyldopa can give false +ves.
• Tumour localization is important—MRI is the imaging of choice in
pregnancy.
Management of phaeochromocytoma
• A-blockade: phenoxybenzamine. Reduces fetal and maternal morbidity
and mortality. Appears to be safe in pregnancy. The starting dose is
10mg 12-hourly and is built up gradually to a maximum of 20mg every
8h. Oral prazosin and IV phentolamine can also be used.
• B-blockade: propranolol. Only after adequate A-blockade. May increase
the risk of intrauterine fetal growth restriction if started in the first
trimester, but benefits outweigh risks. Give in a dose of 40mg 8-hourly.
• Surgery. Timing is controversial. Some recommend, before 24 weeks’
gestation, surgical removal of phaeochromocytoma (relatively safe
following A- and B-blockade). After 24 weeks’ gestation, surgery
should be deferred until fetal maturity. The preferred method of
delivery is usually elective Caesarean section. Ensure adequate
adrenergic blockade before surgery. Surgery can be delayed until after
delivery.
Conn’s syndrome
• Rare in pregnancy, with <50 cases reported.
• Diagnosed with hypertension and hypokalaemia.
• Has been associated with placental abruption.
• Maternal mortality has been reported.
Diagnosis
• A suppressed renin and raised aldosterone (compared to normal
pregnancy ranges) confirm the diagnosis.
• US or MRI can be used to localize tumour.
Management
• Standard treatment for hypertension in pregnancy.
• Amiloride can be used in pregnancy.
• Spironolactone should be avoided, as associated with ambiguous
sexual genitalia in male rats.
Further reading
Ahlawat SK, Jain S, Kumaro S, Varma S, Sharma BK (1999). Phaeochromocytoma associated with
pregnancy: case report and review of the literature. Obstet Gynecol Surv 54, 728–37.
Hadden DR (1995). Adrenal disorders of pregnancy. Endocrinol Metab Clin North Am 24, 139–51.
Lindsay JR, Nieman LK (2006). Adrenal disorders in pregnancy. Endocrinol Metab Clin North Am
35, 1–20.
Robar C, Porremba J, Pelton J, Hudson L, Higby K (1998). Current diagnosis and management of
aldosterone-producing adenomas during pregnancy. Endocrinologist 8, 403–8.
Sam S, Molitch M (2003). Timing and special concerns regarding endocrine surgery during preg-
nancy. Endocrinol Metab Clin North Am 32, 337–54.
Chapter 6 449
Calcium and bone

metabolism
Calcium and bone physiology 450

Calcium 451
Investigation of bone 452
Bone imaging 453
Bone mass measurements 454
Bone biopsy 455
Investigation of calcium, phosphate, and magnesium 456
Urine excretion 457
Calcium-regulating hormones 458
Hypercalcaemia 460
Primary hyperparathyroidism 462
Treatment of hyperparathyroidism 466
Complications of parathyroidectomy 468
Other causes of hypercalcaemia 469
Familial hypocalciuric hypercalcaemia (FHH) 470
Vitamin D intoxication 472
Sarcoidosis 472
Hypocalcaemia 474
Treatment of hypocalcaemia 478
Rickets and osteomalacia and hypophosphataemia 480
Vitamin D deficiency 484
Hypophosphataemia 486
Hypomagnesaemia 488
Osteoporosis 490
Pathology of osteoporosis 492
Epidemiology of osteoporosis 494
Presentation of osteoporosis 495
Investigation of osteoporosis 496
Treatment of osteoporosis 498
Complications of therapy for osteoporosis 502
Paget’s disease 506
Inherited disorders of bone 510
450 CHAPTER 6 Calcium and bone metabolism
Calcium and bone physiology

Bone turnover
In order to ensure that bone can undertake its mechanical and metabolic
functions, it is in a constant state of turnover (see Fig. 6.1).
• Osteoclasts—derived from the monocytic cells; resorb bone.
• Osteoblasts—derived from the fibroblast-like cells; make bone.
• Osteocytes—buried osteoblasts; sense mechanical strain in bone.
Bone mass during life
(see Fig. 6.2)
Bone is laid down rapidly during skeletal growth at puberty. Following
this, there is a period of stabilization of bone mass in early adult life. After
the age of 740, there is a gradual loss of bone in both sexes. This occurs
at the rate of approximately 0.5% annually. However, in ♀ after the
menopause, there is a period of rapid bone loss. The accelerated loss is
maximal in the first 2–5 years after the cessation of ovarian function and
then gradually declines until the previous gradual rate of loss is once again
established. The excess bone loss associated with the menopause is of the
order of 10% of skeletal mass. This menopause-associated loss, coupled
with higher peak bone mass acquisition in ♂, largely explains why osteo-
porosis and its associated fractures are more common in ♀.
Lining cells
Bone lining cells
d
eoi Formation
Osteoclasts ost
alized
mi ner
Osteocytes Un Mineralized
bone
Resorption
21 21 100
Days of remodelling cycle
Fig. 6.1 Bone turnover during remodelling cycle.
120
100
(% female peak)
80
Bone mass
60
40
20
0
0 20 40 60 80
Age (years)
Fig. 6.2 Bone mass and age.
CALCIUM 451
Calcium
Roles of calcium
• Skeletal strength.
• Neuromuscular conduction.
• Stimulus secretion coupling (e.g. chromaffin cells).
Calcium in the circulation
Circulating calcium exists in several forms (see Fig. 6.3).
• Ionized—biologically active.
• Complexed to citrate, phosphate, etc.—biologically active.
• Bound to protein, mainly albumin—inactive.
Ionized
45% 50% Complexed
Protein bound
5%
Fig. 6.3 Forms of circulating calcium.
Investigation of bone
Bone turnover markers
Used in some centres.
May be useful in:
• Assessing overall risk of osteoporotic fracture.
• Judging response to treatments for osteoporosis.
Resorption markers
• Collagen crosslinks. These are products of collagen degradation. The
small fragments of the ends of the collagen molecule are known as
telopeptides (NTX and CTX), and the measurement of these in blood
is the preferred biochemical measure of bone resorption.
Formation markers
• Total alkaline phosphatase is not specific to bone and is also found in
liver, intestine, and placenta. It is also insensitive to small changes in
bone turnover and is only of general use in monitoring the activity of
Paget’s disease.
• Bone-specific alkaline phosphatase is a more specific and reliable
measure of bone formation.
• Osteocalcin is a component of bone matrix, and the serum level of
osteocalcin reflects osteoblast activity.
• P1NP is a procollagen fragment released from the N terminal as type
1 collagen is laid down. When measured in serum, it is the most
sensitive and specific marker of bone formation.
The clinical utility of routine measurements of bone turnover markers is
not yet established.
BONE IMAGING 453
Bone imaging
Skeletal radiology
• Useful for:
• Diagnosis of fracture.
• Diagnosis of specific diseases (e.g. Paget’s disease and
osteomalacia).
• Identification of bone dysplasia.
• Not useful for assessing bone density.
Isotope bone scanning
Bone-seeking isotopes, particularly 99mtechnetium-labelled bisphospho-
nates, are concentrated in areas of localized i bone cell activity. Isotope
bone scans are useful for identifying localized areas of bone disease, such
as fracture, metastases, or Paget’s disease. However, isotope uptake is not
selective, and so i activity on a scan does not indicate the nature of the
underlying bone disease. Hence, subsequent radiology of affected regions
is needed to establish the diagnosis.
Isotope bone scans are particularly useful in Paget’s disease to establish
the extent and sites of skeletal involvement and the underlying disease
activity.
Bone mass measurements

(See Table 6.1.)
Interpretation of results
• Bone mass is quoted in terms of the number of standard deviations
(SD) from an expected mean. The most useful way of expressing this
is as T scores. T scores represent observed bone mass in comparison
to a sex-matched young, healthy population. Z scores are sometimes
quoted and relate to bone density, according to a sex- and an
age-matched group.
• A reduction of one SD in bone density will approximately double the
risk of fracture.
• WHO has established criteria for the diagnosis of osteoporosis in
post-menopausal ♀ (see b p. 493).
• No similar criteria have been set in ♂, but the same thresholds are
generally accepted.
• For some s causes of osteoporosis, particularly glucocorticoid use,
a less stringent criterion of T score <–1.5 should be used as a bone
density-determined treatment intervention threshold.
Table 6.1 Measurement of bone density

Technique Site Measures Radiation Reproducibility
Dual-energy Spine* Bone mineral 71µSv per <1% at spine
absorptiometry Femur* per unit area site <2% at femur
(DXA) Whole body (g/cm2)
Forearm
Quantitative Spine True bone 750µSv at ~1%
computed Forearm mineral density spine
tomography (BMD) (g/cm3)
(QCT)
*
Accepted as ‘gold standard’ measurement.
BONE BIOPSY 455
Bone biopsy
Bone biopsy is occasionally necessary for the diagnosis of patients with
complex metabolic bone diseases. This is usually in the context of sus-
pected osteomalacia. Bone biopsy is not indicated for the routine diagno-
sis of osteoporosis. It should only be undertaken in highly specialist centres
with appropriate expertise.
Investigation of calcium, phosphate,

and magnesium
Blood concentration
Calcium
Measurement of serum calcium does not require patients to be fasted.
Blood for parathyroid hormone (PTH) and phosphate level measurements
should, however, ideally be collected after an overnight fast.
In most clinical situations, direct measurement of ionized calcium con-
centration is unnecessary. However, it is important to adjust the measured
calcium concentration for the prevailing serum albumin concentration (see
Box 6.1).
Phosphate and magnesium
Measurements of plasma phosphate and magnesium are not convention-
ally adjusted for plasma protein concentrations.
Box 6.1 Adjustment of measured calcium concentration

Adjusted Ca = measured Ca + 0.02 × (40 – albumin)
(Where calcium is in mmol/L and albumin in g/L.)
URINE EXCRETION 457
Urine excretion
Calcium
Measurement of 24h urinary excretion of calcium provides a measure
of risk of renal stone formation or nephrocalcinosis in states of chronic
hypercalcaemia. In other circumstances, particularly in the assessment
of the cause of hypercalcaemia (p hyperparathyroidism versus familial
hypocalciuric hypercalcaemia), an estimate of the renal handling of cal-
cium is more useful. This is most commonly estimated from the ratio of
the renal clearance of calcium to that of creatinine in the fasting state (see
Box 6.2). If all values are in mmol/L, the ratio is typically >0.02 in p hyper-
parathyroidism; values <0.01 are suggestive of hypocalciuric hypercalcae-
mia. (Exclude other causes of hypocalciuria, including renal insufficiency,
vitamin D deficiency.)
Phosphate
A 24h measurement of phosphate excretion largely reflects dietary phos-
phate intake and has little clinical utility.
Box 6.2 Calculation of calcium/creatinine excretion ratio

CaE = [Urine calcium (mmol)/urine creatinine (mmol)]
x [(plasma creatinine (micromol)/1000)/plasma calcium (mmol)]
= <0.01 in FHH
= >0.02 in primary hyperparathyroidism
Calcium-regulating hormones
Parathyroid hormone
Careful attention should be paid to local requirements for collecting blood
for PTH measurement. Since PTH secretion is suppressed by calcium
ingestion, it should be measured in the fasting state. The reference range
depends on the precise assay employed, but typical values are 10–60pg/
mL (1–6pmol/L).
Vitamin D and its metabolites
25OH vitamin D (25OHD)
This is the main storage form of vitamin D, and the measurement of ‘total
vitamin D’ is the most clinically useful measure of vitamin D status.
Internationally, there remains controversy around a ‘normal’ or ‘opti-
mal’ concentration of vitamin D. Levels over 50nmol/L are generally
accepted as satisfactory and values <25nmol/L representing deficiency.
True osteomalacia occurs with vitamin D values <15nmol/L.
Low levels of 25OHD can result from a variety of causes (b see
Vitamin D deficiency, p. 484). It is unlikely that serious intoxication will
occur with 25OHD concentrations of <125nmol/L.
1,25(OH)2 vitamin D (1,25(OH)2D)
Although this is the active form of vitamin D, measurement of its concen-
tration is rarely indicated. It is sometimes useful diagnostically in condi-
tions of extrarenal synthesis of 1,25(OH)2D, such as in sarcoidosis.
Parathyroid hormone-related peptide (PTHrP)
It is possible to measure the level of this oncofetoprotein in serum, but this
is very rarely indicated. Sample collection involves specific requirements.
Calcitonin
Calcitonin assays are available, but their utility is confined to the diagnosis
and monitoring of medullary carcinoma of the thyroid. There is no role
for calcitonin measurements in the routine investigation of calcium and
bone metabolism.
CALCIUM-REGULATING HORMONES 459
Hypercalcaemia
Epidemiology
Hypercalcaemia is found in 5% of hospital patients and in 0.5% of the gen-
eral population.
Causes
Many different disease states can lead to hypercalcaemia. These are listed
by order of importance in hospital practice in Box 6.3. In asymptomatic
community-dwelling subjects, the vast majority of hypercalcaemia is the
result of hyperparathyroidism.
Clinical features
Notwithstanding the underlying cause of hypercalcaemia, the clinical fea-
tures are similar. With adjusted serum calcium levels <3.0mmol/L, signifi-
cant related symptoms are unlikely. With progressive increases in calcium
concentration, the likelihood of symptoms increases rapidly.
The clinical features of hypercalcaemia are well recognized (see Box
6.4); unfortunately, they are non-specific and may relate to underlying
illness.
Clinical signs of hypercalcaemia are rare. With the exception of band
keratopathy, these are not specific. It is important to seek clinical evidence
of underlying causes of hypercalcaemia, particularly malignant disease.
In addition to specific symptoms of hypercalcaemia, symptoms of
long-term consequences of hypercalcaemia should be sought. These
include the presence of bone pain or fracture and renal stones. These
indicate the presence of chronic hypercalcaemia.
Investigation of hypercalcaemia
Confirm the diagnosis
Serum calcium (adjusted for albumin).
Determine the mechanism
• i PTH. Parathyroid overactivity (p or tertiary hyperparathyroidism
can also occur in familial hypocalciuric hypercalcaemia and in lithium
therapy due to faulty calcium-sensing).
• d PTH. Parathyroid-independent cause.
• Normal PTH:
• May imply parathyroid overactivity—incomplete suppression.
• May imply altered calcium sensor—familial hypocalciuric
hypercalcaemia—calcium/creatinine excretion ratio will be low.
• Urine calcium to determine calcium/creatinine excretion ratio (not
correlated with the risk of stones).
Seek underlying illness (where indicated)
• History and examination.
• Chest X-ray.
• FBC and ESR.
• Biochemical profile (renal and liver function).
• Thyroid function tests (exclude thyrotoxicosis).
HYPERCALCAEMIA 461
• 25OHD (rarely 1,25(OH)2D).

• Plasma and urine protein electrophoresis (exclude myeloma).
• Serum cortisol (short Synacthen® test (exclude Addison’s disease)).
To determine end-organ damage
• 24h urine calcium (9 urine creatinine for reproducibility).
• Renal tract ultrasound (calculi, nephrocalcinosis).
• Skeletal radiographs (lateral thoracolumbar spine, hands).
• BMD by DXA.
• (Bone turnover markers.)
Box 6.3 Causes of hypercalcaemia

Common
• Hyperparathyroidism:
• p.
• Tertiary.
• Malignancy:
• Humoral hypercalcaemia.
• Bony metastases.
Uncommon
• Vitamin D intoxication.
• Familial hypocalciuric hypercalcaemia.
• Sarcoidosis and other granulomatous diseases.
• Thiazide diuretics.
• Lithium.
• Immobilization.
• Hyperthyroidism.
• Renal failure.
• Vitamin A intoxication.
Box 6.4 Clinical features of hypercalcaemia

Renal Gastrointestinal CNS Other
• Polyuria. • Anorexia. • Confusion. • Pruritus.
• Polydipsia. • Vomiting. • Lethargy. • Sore eyes.
• Constipation. • Depression.
• Abdominal pain.
Primary hyperparathyroidism
Present in up to 1 in 500 of the general population where it is predomi-
nantly a disease of post-menopausal ♀ (14/100,000 ♂, 28/100,000 ♀).
The normal physiological response to hypocalcaemia is an increase in
PTH secretion. This is termed s hyperparathyroidism and is not patho-
logical in as much as the PTH secretion remains under feedback control.
Continued stimulation of the parathyroid glands can lead to autonomous
production of PTH. This, in turn, causes hypercalcaemia which is termed
tertiary hyperparathyroidism. This is usually seen in the context of renal dis-
ease but can occur in any state of chronic hypocalcaemia, such as vitamin
D deficiency or malabsorption.
Pathology
• 85% single adenoma.
• 14% hyperplasia (may be associated with other endocrine
abnormalities, particularly multiple endocrine neoplasia (MEN) types
1 and 2 (b see MEN type 1, pp. 586–7; MEN type 2, pp. 592–3).
• <1% carcinoma (express the lectin galectin-3).
Clinical features
• Majority of patients are asymptomatic.
• Features of hypercalcaemia.
• End-organ damage—see Box 6.5.
Natural history
• In majority of patients without end-organ damage, disease is benign
and stable.
• A significant minority (2–3% per annum) will develop new indications
for surgery.
• Excess deaths probably linked to cardiovascular diseases and possibly
malignancy.
Investigation
(See Box 6.6.) Potential diagnostic pitfalls:
• FHH—differentiate with calcium/creatinine excretion ratio (b see
Familial hypocalciuric hypercalcaemia (FHH), pp. 457, 470) (<0.01 in
FHH; >0.02 in hyperparathyroidism).
• Long-standing vitamin D deficiency where the concomitant
osteomalacia and calcium malabsorption can mask hypercalcaemia
which becomes apparent only after vitamin D repletion. Consider
other causes of a raised PTH (see Box 6.7).
• Drugs associated with hypercalcaemia (e.g. thiazides and lithium).
Investigation is, therefore, primarily aimed at determining the presence of
end-organ damage from hypercalcaemia in order to determine whether
operative intervention is indicated.
PRIMARY HYPERPARATHYROIDISM 463
Box 6.5 End-organ damage in hyperparathyroidism

Bone
• Osteoporosis:
• Common.
• Affects all sites, but predominant loss is in peripheral
cortical bone.
• Radiographic changes:
• Uncommon.
• Include subperiosteal resorption, abnormal skull vault, eroded
lamina dura (around teeth), and bone cysts.
• Osteitis fibrosa cystica:
• Rare.
• Usually with tertiary hyperparathyroidism.
Kidneys
• Renal calculi.
• Nephrocalcinosis.
• Renal impairment.
Joints
• Chondrocalcinosis.
• Pseudogout.
Pancreatitis
Box 6.6 Diagnosis of primary hyperparathyroidism

• Ca > NR (2.60mmol (adjusted) × 2).
• U&E normal.
• Not on lithium or thiazide diuretic.
• PTH >3.0pmol (20% patients have PTH within upper part NR).
• Urine Ca >2.5mmol/day.
Box 6.7 Other causes of raised PTH

• Renal insufficiency.
• Vitamin D deficiency.
• Renal hypercalciuria.
• Drugs (e.g. lithium, thiazides).
Exclusion of underlying condition

• p hyperparathyroidism (PHP) can be associated with genetic
abnormalities, especially MEN-1 and 2, as well as familial
hyperparathyroidism.
• These conditions should be sought in patients presenting with PHP
and a family history in ≥1 first-degree relatives or at a young age
(<40 years).
Localization of abnormal parathyroid glands

This should only form part of a preoperative assessment and is not indi-
cated in the initial diagnosis of hyperparathyroidism.
• Localization with two separate techniques (usually US and
99m
Tc-sestamibi) is imperative before minimally invasive
parathyroidectomy.
• Otherwise, open bilateral neck exploration by an experienced surgeon
is optimal in the first instance.
• After failed neck exploration, other localizing techniques are required,
which include:
• 99mTc-sestamibi.
• Thallium/technetium subtraction scanning (less sensitive).
• CT.
• US.
• Angiography with selective venous sampling may be employed in
difficult cases but should be confined to specialist centres with
experience in this technique.
PRIMARY HYPERPARATHYROIDISM 465
Treatment of hyperparathyroidism
Parathyroid surgery
(Aspects of parathyroid surgery also covered on b see p. 608.)
• For indications, see Table 6.2.
• Only by experienced surgeon (>20 procedures per year):
• Adenoma. Remove affected gland—often by minimally invasive
surgery.
• Hyperplasia. Partial parathyroidectomy (perhaps with reimplantation
of tissue in more accessible site).
Observation
• Suitable for patients with mild disease with no evidence of end-organ
damage.
• Most such patients have stable disease over many years but do require
monitoring:
• Annual serum calcium and renal function, BP.
• Every 2–3 years—BMD, renal US.
• Any significant deterioration is an indication for surgery.
Medical management
Only indicated if patient not suitable for surgery.
• Hormone replacement therapy:
• Preserves bone mass.
• Consider long-term risks (breast cancer, venous thrombosis, heart
disease, and stroke).
• Bisphosphonates:
• Clinically inconsequential effect on plasma and urine calcium.
• Preserve bone mass.
• Calcium-sensing receptor agonists:
• Cinacalcet (30mg twice daily) reduces serum but not urinary calcium
concentration. It increases sensitivity of calcium-sensing receptor,
decreasing PTH secretion. It is licensed for patients with severe
s hyperparathyroidism on dialysis, parathyroid carcinoma, and
patients with PHP in whom parathyroid surgery is contraindicated
or clinically inappropriate. It may also be used if the neck has been
explored and the parathyroid adenoma has not been found.
Indications for surgery in primary hyperparathyroidism
It is generally accepted that all patients with symptomatic hyperparathy-
roidism or evidence of end-organ damage should be considered for par-
athyroidectomy. This would include:
• Definite symptoms of hypercalcaemia. There is less good evidence
that non-specific symptoms, such as abdominal pain, tiredness, or mild
cognitive impairment, benefit from surgery.
• Impaired renal function.
• Renal stones (symptomatic or on radiograph).
• Parathyroid bone disease, especially osteitis fibrosis cystica.
• Pancreatitis.
TREATMENT OF HYPERPARATHYROIDISM 467
Guidelines for the management of asymptomatic hyperparathyroidism

have been produced on the basis of a consensus development conference
in the USA1 and following review of evidence in the UK.2 Although there
are some differences between these approaches, there is also consider-
able similarity.
Conservative management
• Patients not managed with surgery require regular follow-up.
• Again, there is some difference between recommendations in the UK
and USA (see Table 6.3).
Table 6.2 Table comparing indications for parathyroidectomy in

asymptomatic patients in the USA compared with the UK
UK USA
Serum calcium 3.00mmol/L 72.85mmol/L
Urine calcium 10mmol/day (perhaps) Test not indicated
Creatinine clearance No guidance <60mL/min
BMD T score <–2.5 T score <–2.5 or previous
fragility fracture
Age <50 <50
Table 6.3 Table comparing management recommendations for

patients in the USA compared with the UK
UK USA
Serum calcium 6 months 12 months
Serum creatinine 6 months 12 months
BP 6 months No recommendation
PTH 12 months No recommendation
Urine calcium 12 months Not indicated
Urine creatinine 12 months Not indicated
BMD 24–36 months 12–24 months
Abdominal X-ray/US 36 months Not indicated
References
1. Bilezikian JP, Khan AA, Potts JT Jr, et al. (2009). Guidelines for the management of asymptomatic
primary hyperparathyroidism: Summary Statement from the Third International Workshop. J
Clin Endocrinol Metab 94, 335–9.
2. Davies M, Fraser WD, Hoskin DJ (2002). The management of primary hyperparathyroidism. Clin
Complications of parathyroidectomy
Mechanical
• Vocal cord paresis:
• May be permanent, particularly with repeated surgery.
• Tracheal compression from haematoma.
Metabolic (hypocalcaemia)
• Transient:
• Due to suppression of remaining glands.
• May sometimes require oral therapy with calcium 9 vitamin D
metabolites.
• Severe:
• Due to hungry bones—rare. Treatment with calcitriol 1 microgram/
day (sometimes higher dose required) and oral calcium, 3× daily,
may be required for several weeks.
• Occurs in patients with pre-existing bone disease.
• Minimize risk by pretreatment of any vitamin D deficiency for
several weeks. Risk of significant worsening of hypercalcaemia is
low, but monitoring of serum calcium is recommended.
• Acute severe hypocalcaemia requires initial IV calcium to stabilize
metabolic status.
Outcome after surgery
• <5% fail to become normocalcaemic, and these should be considered
for a second operation.
• All patients with hyperplasia (including MEN) identified on
histopathology should have long-term monitoring of serum calcium to
detect recurrent primary hyperparathyroidism.
• Patients rendered permanently hypoparathyroid by surgery require
lifelong supplements of active metabolites of vitamin D with calcium.
This can lead to hypercalciuria, and the risk of stone formation may
still be present in these patients. Target serum calcium in these
patients should be towards the low end of the reference range to
minimize hypercalciuria.
OTHER CAUSES OF HYPERCALCAEMIA 469
Other causes of hypercalcaemia

Hypercalcaemia of malignancy
Mechanism
See Table 6.4.
Clinical features
Hypercalcaemia is usually a late manifestation of malignant disease, and the
primary lesion is usually evident by the time hypercalcaemia is expressed
(50% of patients die within 30 days). One exception to this is in small
endocrine tumours, such as carcinoids and islet cell tumours, which can
produce humoral mediators of hypercalcaemia (PTHrP) in the absence
of significant spread. Symptoms of hypercalcaemia are non-specific and
frequently difficult to distinguish from those of the underlying disease.
Investigation
See investigation of hypercalcaemia in b Clinical features, p. 460.
Factors suggesting hypercalcaemia of malignancy include:
• i calcium.
• d PTH.
• Other features of malignant disease.
• i PTHrP—not usually measured in clinical practice.
Steroid suppression tests are rarely indicated. May suppress with malig-
nancy but not with primary hyperparathyroidism.
Treatment
Frequently, patients requiring treatment will have severe symptomatic
hypercalcaemia. Often, emergency treatment is necessary to stabilize the
patient. In such circumstances, the principles of management are the same
as those of severe hypercalcaemia from any cause (b see Box 6.8, p. 470).
Table 6.4 Types of hypercalcaemia associated with cancer

Type Frequency (%) Bone metastases Causal agent Tumour type
Local 20 Common Cytokines Breast
osteolysis Extensive Chemokines Myeloma
PTHrP Lymphoma
Humoral 80 Minimal PTHrP Squamous
carcinoma
Renal
Ovarian
Endometrial
Breast
HTLV
Lymphoma
1,25OH vit D <1 Variable 1,25(OH)2D Lymphoma
Ectopic PTH <1 Variable PTH Variable
Box 6.8 Management of severe hypercalcaemia

• Vigorous rehydration 200–500mL/h.
• Disodium pamidronate 60–90mg or zoledronic acid 5mg IV.
• Calcium falls within 12h, nadir 4–7 days.
• Duration of effect is variable but usually 1–6 weeks.
1. Stabilize the level of hypercalcaemia, and prevent any further decline
in renal function. This requires the IV infusion of large quantities of 0.9%
saline, frequently 3–6L over the first 24h. If there is a danger of salt and
water retention, a loop diuretic may be added. This is the only role of
diuretics in the management of hypercalcaemia and is not routine prac-
tice, contrary to previous historical texts. Loop diuretics can precipitate
intravascular volume depletion and worsening hypercalcaemia. In severe
renal impairment, dialysis may be of value.
2. Once the patient is volume-replete, it is necessary to treat the cause
of the hypercalcaemia. The most effective therapy available for this is
IV bisphosphonate—pamidronate (60–90mg) or zoledronic acid (5mg)
are the most frequently used. Repeat doses may be required. Even
patients who are acutely hypercalcaemic can rarely develop hypocalcae-
mia following IV bisphosphonate therapy, especially if they are vitamin
D-deficient.
3. Calcitonin and glucocorticoids are rarely used in the acute manage-
ment of hypercalcaemia nowadays.
FAMILIAL HYPOCALCIURIC HYPERCALCAEMIA (FHH) 471
Familial hypocalciuric
hypercalcaemia (FHH)
FHH—also known as familial benign hypercalcaemia. Three types
exist: FHH 1–3 (see Table 6.5).
• Very rare cause of hypercalcaemia.
• Autosomal dominant, with virtually complete penetrance, but may also
be autosomal recessive.
• Mutation in the calcium-sensing receptor which reduces its sensitivity
such that the body behaves as if it were experiencing normocalcaemia,
even though the serum calcium level is elevated.
• Generally benign and is not usually associated with symptoms or
adverse effects, such as renal stones or bone disease.
• Does not usually show any sustained benefit from parathyroidectomy.
• The homozygous state produces severe life-threatening hypercalcaemia
soon after birth (neonatal severe hyperparathyroidism). In such cases,
total parathyroidectomy is lifesaving.
• See Box 6.8 for management of hypercalcaemia.
Patients have low urine calcium excretion (24h <2.5mmol, fasting calcium/
creatinine excretion ratio <0.01 (Box 6.2, p. 457)).
Table 6.5 Three types of FHH

FHH 1 FHH 2 FHH 3
60% 20%
Autosomal dominant Autosomal dominant Autosomal dominant
Disorder of extracellular calcium homeostasis
i Ca in serum
d Ca in urine (Ca/Cr ratio <0.01)
Chromosome 3q 21.1 19p 13q 133
Normal PTH i PTH
Mild i Mg d PO4
Osteomalacia
Asymptomatic
Occasional pancreatitis
Chondrocalcinosis
p hyperparathyroidism
Osteoporosis
Kidney stones
Further reading
Lietman SA, et al. (2009). A novel loss-of-function mutation, Gln459Arg, of the calcium-sensing
receptor gene associated with apparent autosomal recessive inheritance of familial hypocalciuric
hypercalcemia. J Clin Endocrinol Metab 94, 4372–9.
Nesbit MA, et al. (2013). Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat
Genet 45, 93–7.
Nesbit MA, Hannan FM, Howles SA, et al. (2013). Mutations affecting G-protein subunit α11 in
hypercalcemia and hypocalcemia. N Engl J Med 368(26):2476–86.
Pallais JC, Kifor O, Chen YB, et al. (2004). Acquired hypocalciuric hypercalcemia due to autoanti-
bodies against the calcium-sensing receptor. N Engl J Med 351, 362–9.
Vitamin D intoxication
• The diagnosis is established by the presence of greatly elevated
concentrations of 25OHD (>125nmol/L) and 1,25(OH)2D, together
with suppressed PTH. If calcitriol or alfacalcidol is the offending
compound, then 25OHD levels will not be elevated.
• In mild cases, particularly when the active vitamin D metabolites are
involved, the only treatment necessary is to withdraw the offending
treatment and let the calcium settle. If the longer-acting vitamin D
metabolites are involved, then active treatment may be necessary.
• Patients should first be stabilized with a saline infusion (see
Box 6.8).
Following this, the traditional management has been to give high-dose oral
glucocorticoid, such as prednisolone 40mg daily, although IV bisphospho-
nates should also be considered in the acute setting.
Sarcoidosis
• Together with other granulomatous disorders, sarcoidosis causes
hypercalcaemia by extrarenal production of 1,25(OH)2D in
granulomata. This process is not under feedback inhibition but is
substrate-regulated. The hypercalcaemia is, therefore, dependent on
vitamin D supply. Patients may present with hypercalcaemia in summer
or following foreign holidays when the endogenous production of
vitamin D is maximal.
• The biochemical picture is of normal 25OHD, raised 1,25(OH)2D, and
suppressed PTH. In addition, other markers of sarcoid activity, such
as raised angiotensin-converting enzyme (ACE) activity, are frequently
present.
• Treatment with high-dose glucocorticoids is recommended to
control sarcoid activity and to minimize the GI effects of the excess
1,25(OH)2D.
Further reading
Bilezikian JP, Watts JT Jr, Fuleihan Gel-H, et al. (2002). Summary statement from a workshop on
asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol
Metab 87, 5353–61.
Marcocci C, et al. (2011). Primary hyperparathyroidism. N Engl J Med 365, 2389–97.
Palazzo FF, Sadler GP (2004). Minimally invasive parathyroidectomy. BMJ 328, 849–50.
Peacock M, Bilezikian JP, Klassen PS, et al. (2005). Cinacalcet hydrochloride maintains long-term
normocalcemia in patients with primary hyperthyroidism. J Clin Endocrinol Metab 90, 135-41.
Stewart AF (2005). Clinical practice. Hypercalcemia associated with cancer. N Engl J Med
352, 373–9.
Yu N, et al. (2011). A record linkage study of outcomes in patients with mild primary hyperpar-
athyroidism: the Parathyroid Epidemiology and Audit Research Study (PEARS). Clin Endocrinol
(Oxf) 75,169–76.
SARCOIDOSIS 473
Hypocalcaemia
Causes
Although hypocalcaemia can result from failure of any of the mechanisms
by which serum calcium concentration is maintained, it is usually the result
of either failure of PTH secretion or because of the inability to release
calcium from bone. These causes are summarized in Box 6.9.
Clinical features
The clinical features of hypocalcaemia are largely as a result of i neuro-
muscular excitability. In order of i severity, these include:
• Tingling—especially of fingers, toes, or lips.
• Numbness—especially of fingers, toes, or lips.
• Cramps.
• Carpopedal spasm.
• Stridor due to laryngospasm.
• Seizures.
The symptoms of hypocalcaemia tend to reflect the severity and rapidity
of onset of the metabolic abnormality.
Clinical signs of hypocalcaemia depend upon the demonstration of neu-
romuscular irritability before this necessarily causes symptoms:
• Chvostek’s sign is elicited by tapping the facial nerve in front of the
ear. A +ve result is indicated by twitching of the corner of the mouth.
Slight twitching is seen in up to 15% of normal ♀, but more major
involvement of the facial muscles is indicative of hypocalcaemia or
hypomagnesaemia.
• Trousseau’s sign is produced by occlusion of the blood supply to the
arm by inflation of a sphygmomanometer cuff above arterial pressure
for 3min. If +ve, there will be carpopedal spasm which may be
accompanied by painful paraesthesiae.
In addition, there may be clinical signs and symptoms associated with the
underlying condition:
• Vitamin D deficiency may be associated with generalized bone pain,
fractures, or proximal myopathy (b see p. 484).
• Hypoparathyroidism can be accompanied by mental slowing and
personality disturbances as well as extrapyramidal signs, cataracts, and
papilloedema.
• If hypocalcaemia is present during the development of permanent
teeth, these may show areas of enamel hypoplasia. This can be a useful
physical sign, indicating that the hypocalcaemia is long-standing.
HYPOCALCAEMIA 475
Box 6.9 Causes of hypocalcaemia

Hypoparathyroidism
• Destruction of parathyroid glands:
• Surgical.
• Autoimmune.
• Radiation.
• Infiltration.
• Failure of parathyroid development:
• Isolated, e.g. X-linked.
• With other abnormalities, e.g. di George syndrome (with thymic
aplasia, immunodeficiency, and cardiac anomalies).
• Failure of PTH secretion:
• Magnesium deficiency.
• Overactivity of calcium-sensing receptor.
• Failure of PTH action:
• Pseudohypoparathyroidism—due to G protein abnormality.
Failure of release of calcium from bone
• Osteomalacia:
• Vitamin D deficiency.
• Vitamin D resistance.
• Renal failure.
• Inhibition of bone resorption:
• Hypocalcaemic drugs, e.g. cisplatin, calcitonin, oral phosphate.
• i uptake of calcium into bone:
• Osteoblastic metastases (e.g. prostate).
• Hungry bone syndrome.
Complexing of calcium from the circulation
• i albumin-binding in alkalosis.
• Acute pancreatitis:
• Formation of calcium soaps from autodigestion of fat.
• Abnormal PTH and vitamin D metabolism.
• Phosphate infusion.
• Multiple blood transfusions—complexing by citrate.
Pseudohypoparathyroidism
• Resistance to parathyroid hormone action.
• Due to defective signalling of PTH action via cell membrane receptor.
• Also affects TSH, LH, FSH, and GH signalling.
• Most commonly caused by autosomal dominant mutation of
GNAS1 gene.
• Significant imprinting:
• Maternal transmission leads to full blown syndrome of hormone
resistance.
• Paternal transmission causes only phenotypic features of Albright’s
hereditary osteodystrophy.
Albright’s hereditary osteodystrophy

Patients with the most common type of pseudohypoparathyroidism (type
Ia) have a characteristic set of skeletal abnormalities, known as Albright’s
hereditary osteodystrophy. This comprises:
• Short stature.
• Obesity.
• Round face.
• Short metacarpals.
Some individuals with Albright’s hereditary osteodystrophy do not appear
to have a disorder of calcium metabolism. In the past, the term pseudop-
seudohypoparathyroidism has been used to describe these. However, it is
now clear that these reflect different manifestations of the same underly-
ing genetic defect as a result of imprinting. In the light of the same underly-
ing aetiology, there has been a tendency to avoid the more cumbersome
designations and to refer to all such patients as having Albright’s hereditary
osteodystrophy.
Investigation
• Serum calcium.
• PTH—the presence of a low, or even normal, PTH concentration
implies failure of PTH secretion in the presence of hypocalcaemia.
• Total vitamin D.
• Magnesium.
• Ellsworth–Howard test can be performed if pseudohypoparathyroidism
suspected (measurement of serum and urinary phosphorous after IV
administration of parathyroid hormone).
HYPOCALCAEMIA 477
Treatment of hypocalcaemia
• Acute symptomatic hypocalcaemia is a medical emergency and demands
urgent treatment whatever the cause (see Box 6.10).
• Treatment of chronic hypocalcaemia is more dependent on the cause.
Chronic hypocalcaemia
Hypoparathyroidism
• In hypoparathyroidism, the target serum calcium should be at the
low end of the reference range. The reason for this is that the renal
retention of calcium brought about by PTH has been lost. Thus,
any attempt to raise the plasma calcium well into the normal range
is likely to result in unacceptable hypercalciuria, with the risk of
nephrocalcinosis and renal stones.
• In patients with mild parathyroid dysfunction, it may be possible
to achieve acceptable calcium concentrations by using calcium
supplements alone. If used in this way, these need to be given in large
doses, perhaps as much as 1g elemental calcium 3× daily.
• The majority of patients will not achieve adequate control with such
treatment. In those cases, it is necessary to use vitamin D or its
metabolites in pharmacological doses to maintain plasma calcium. The
more potent analogues of vitamin D, such as calcitriol or alfacalcidol,
have the advantage over high-dose calciferol that it is easier to
make changes in therapy in response to plasma calcium levels. If
hypercalcaemia does occur, it settles much more quickly following
withdrawal of these compounds than calciferol. The dose of vitamin D
metabolite is determined by the clinical response but usually lies in the
range of 0.5–2 micrograms daily of one of the potent activated vitamin
D analogues. Serum calcium must be checked on an ongoing basis, and
close monitoring should occur around times of dose adjustments.
• It is essential to ensure an adequate intake of calcium as well as
appropriate doses of activated vitamin D analogues. In some patients,
it is necessary to give calcium supplementation, particularly in
the young.
• PTH (1-84) is a not yet approved therapy but may improve quality of
life.
Pseudohypoparathyroidism
• The principles underlying the treatment of pseudohypoparathyroidism
are the same as those underlying hypoparathyroidism.
• Patients with the most common form of pseudohypoparathyroidism
may have resistance to the action of other hormones which rely on
G protein signalling. They, therefore, need to be assessed for thyroid
and gonadal dysfunction (because of defective TSH or gonadotrophin
action). If these deficiencies are present, they need to be treated in the
conventional manner.
Vitamin D deficiency
Treatment of osteomalacia and vitamin D deficiency is described on
b see p. 484.
TREATMENT OF HYPOCALCAEMIA 479
Box 6.10 Treatment of acute hypocalcaemia

• Patients with tetany or seizures require urgent IV treatment with
calcium gluconate (less irritant than calcium chloride).
• This is a 10% w/v solution (10mL = 2.25mmol elemental calcium).
• The solution should always be further diluted to minimize the risk
of phlebitis or tissue damage if extravasation occurs.
• Initially, 20mL of 10% calcium gluconate should be diluted in 100–
200mL of 0.9% saline or 5% glucose and infused over about 10min.
• Repeat if symptoms not resolved.
• Care must be taken if the patient has heart disease, especially if
taking digoxin, as too rapid elevation of the plasma calcium can cause
arrhythmias. Cardiac monitoring is advisable.
• In order to maintain the plasma calcium, a calcium infusion is
required. 40mL of 10% calcium gluconate should be added to 1L of
saline or glucose solution and infused over 24h.
• The plasma calcium should be checked regularly (not less than
6-hourly) and the infusion rate adjusted in response to the change in
concentration.
• Failure of the plasma calcium to respond to infused calcium should
raise the possibility of underlying hypomagnesaemia. This can
be rapidly ascertained by plasma magnesium estimation and, if
appropriate, a magnesium infusion commenced (b see Treatment,
p. 488).
• In circumstances where hypoparathyroidism could be predicted
(such as block dissection of the neck), infusion of calcium gluconate
in an initial dose of 50mL 10% solution (711mmol Ca) diluted in
normal saline over 24h should be given to avoid post-operative
hypocalcaemia. This dose should be adjusted in the light of regular
calcium estimations.
• Once oral or NG tube intake is possible, calcium and active vitamin
D metabolites should be substituted as above.
Overactivity of calcium-sensing receptor

This leads to a condition known as autosomal dominant hypocalcaemia.
It is a benign condition in which the hypocalcaemia is usually asympto-
matic. Treatment should be avoided in the absence of symptoms, as eleva-
tion of calcium levels, even to within the normal range, may cause renal
impairment.
Further reading
Bilezikian JP, et al. (2011). Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiol-
ogy, target-organ involvement, treatment, and challenges for future research. J Bone Miner Res
26, 2317–37.
Cooper MS, Gittoes NJ (2008). Diagnosis and management of hypocalcaemia. BMJ 336, 1298–302.
Shoback D (2008). Hypoparathyroidism N Engl J Med 359, 391–403.
Rickets and osteomalacia and

hypophosphataemia
Definitions
Osteomalacia occurs when there is inadequate mineralization of mature
bone. Rickets is a disorder of the growing skeleton where there is inad-
equate mineralization of bone as it is laid down at the epiphysis. In most
instances, osteomalacia leads to build-up of excessive unmineralized
osteoid within the skeleton. In rickets, there is build-up of unmineralized
osteoid in the growth plate. This leads to the characteristic radiological
appearance of rickets, with widening of the growth plate and loss of defini-
tion of the ossification centres. These two related conditions may coexist.
See Box 6.11 for vitamin D resistance and Box 6.12 for abnormal vitamin
D metabolism.
Clinical features
Osteomalacia
• Bone pain.
• Deformity.
• Fracture.
• Proximal myopathy.
• Hypocalcaemia (in vitamin D deficiency).
Rickets
• Growth retardation.
• Bone pain and fracture.
• Skeletal deformity:
• Bowing of the long bones.
• Widening of the growth plates, widening of the wrists, ‘rickety
rosary’ (costochondral junctions enlarged).
Diagnosis
• The diagnosis of osteomalacia is usually based on the appropriate
biochemical findings (see Table 6.6).
• The majority of patients with osteomalacia will show no specific
radiological abnormalities.
• The most characteristic abnormality is the Looser’s zone or
pseudofracture. If these are present, they are virtually pathognomonic
of osteomalacia.
• In clinical practice, bone biopsy is rarely indicated.
RICKETS AND OSTEOMALACIA AND HYPOPHOSPHATAEMIA 481
Box 6.11 Vitamin D resistance

Several different kindreds have been shown to have a defective vitamin
D receptor. This condition is inherited as an autosomal recessive condi-
tion. It produces hypocalcaemia and osteomalacia, with elevated serum
levels of 1,25(OH)2D. Approximately two-thirds of affected individuals
have total alopecia. This condition is known as vitamin D-dependent
rickets type II. If alopecia is present, it is often termed type IIA in con-
trast to type IIB where hair growth is normal.
Treatment usually requires administration of large doses of active
vitamin D metabolites, sometimes reaching doses of 60 micrograms of
calcitriol daily.
Box 6.12 Abnormal vitamin D metabolism

The most common cause of failure of 1A-hydroxylase is renal failure.
Congenital absence of this enzyme leads to a condition known as vita-
min D-dependent rickets type I. This is inherited in an autosomal reces-
sive fashion. It leads to profound rickets, with myopathy and enamel
hypoplasia. Very large doses of calciferol are needed to heal the bone
lesions which, in contrast, will respond to physiological doses of alfacal-
cidol or calcitriol.
In practice, liver disease seldom results in clinical problems of vitamin
D metabolism.
Table 6.6 Biochemical findings and causes of rickets and osteomalacia
Ca PO4 Alkaline phosphatase 25OHD 1,25(OH)2D PTH Other
Vitamin D deficiency d d i d d i
Renal failure d i i N d i d GFR
VDDR type I (deficient d d i N d i
1A-hydroxylase)
VDDR type II (deficient d d i N i i
vitamin D receptor)
X-linked hypophosphataemia N d i N N N or i
(vitamin D-resistant rickets)
Oncogenic N or d d i N d N May have aminoaciduria, p
Phosphate depletion N d i N i N i urine Ca
Fanconi syndrome d or N d i N i N Acidosis, aminoaciduria, gl
Renal tubular acidosis d or N d i N N or d N Acidosis
Toxic (etidronate, fluoride) N N N N N N Diagnosed on biopsy
RICKETS AND OSTEOMALACIA AND HYPOPHOSPHATAEMIA 483
Vitamin D deficiency
Causes
• Poor sunlight exposure:
• Elderly housebound.
• Extensive skin coverage with clothes.
• Poor diet (especially vegetarians):
• Malabsorption.
• i catabolism of vitamin D.
• s hyperparathyroidism:
• Malabsorption.
• Post-gastrectomy.
• Enzyme-inducing drugs, e.g. phenytoin.
Investigation
The diagnosis of vitamin D deficiency is based on the characteristic bio-
chemical abnormalities (see Table 6.6). Frank osteomalacia is usually asso-
ciated with very low levels of 25OHD (<15nmol/L), but the associated
s hyperparathyroidism frequently results in normal, or even elevated,
concentrations of 1,25(OH)2D.
Treatment
• Treatment is best given in the form of calciferol to restore body
stores, correct biochemical abnormalities, and heal bony abnormalities.
Although the use of the active metabolites of vitamin D will heal the
bony abnormalities, it will not correct the underlying biochemical
problem and is associated with i risk of hypercalcaemia.
• In adults, treatment can be given as a daily dose of calciferol (800–
1,000IU) which is often most easily administered in combination with
a calcium supplement. An alternative, which is particularly helpful if
poor compliance is suspected, is to give a single large dose of 150,000–
300,000IU. This is most effectively given as a single oral dose (3–6 ×
1.25mg tablets of ergocalciferol) which can be supervised in clinic. It is
possible to give a similar dose by IM injection, but the absorption from
this route is variable.
• Following treatment, there is usually a rapid improvement of myopathy
and symptoms of hypocalcaemia. Bone pain frequently persists longer,
and biochemical abnormalities may not settle for several months.
Indeed, following the onset of therapy, markers of bone turnover, such
as alkaline phosphatase, might even show a transient increase, as the
osteoid is mineralized and remodelled.
X-linked hypophosphataemia
• X-linked dominant genetic disorder.
• Severe rickets and osteomalacia.
• Mutation of an endopeptidase gene (PHEX).
Clinical features
• The abnormal phosphate levels are often detected early in infancy, but
skeletal deformities are not apparent until walking commences.
VITAMIN D DEFICIENCY 485
• Typical severe rickets, with short stature and bony deformity.

• Continues into adult life, with bone pain, deformity, and fracture in the
absence of treatment.
• Proximal myopathy is absent.
• Adults suffer from excessive new bone growth, particularly
affecting entheses and the longitudinal ligaments of the spinal canal.
This can cause spinal cord compression which may need surgical
decompression.
Oncogenic osteomalacia
Certain tumours appear to be able to produce FGF23 which is phospha-
turic. This is rare and usually occurs with mesenchymal tumours (such as
haemangiopericytomas, haemangiomata, or osteoid tumours) but has also
been reported with a variety of adenocarcinomas (particularly prostatic
cancer) and haematological malignancies (e.g. myeloma and chronic lym-
phocytic leukaemia). A similar picture can also be seen in some cases of
neurofibromatosis. Clinically, such patients usually present with profound
myopathy as well as bone pain and fracture. Biochemically, the major
abnormality is hypophosphataemia, but this is usually accompanied by
marked reduction in 1,25(OH)2D concentrations. In some patients, other
abnormalities of renal tubular function, such as glycosuria or aminoaci-
duria, are also present.
• FGF3 levels are elevated and fall with tumour removal.
• Tumour may be localized by CT, MRI or PET, or selective venous
catheterization for FGF23.
• Medical treatment may include supplemental phosphate, 1,25OH
vitamin D, or cinacalcet.
Complete removal of the tumour results in resolution of the biochemi-
cal and skeletal abnormalities. If this is not possible or if a causal tumour
is not identified, treatment with vitamin D metabolites and phosphate
supplements (as for X-linked hypophosphataemia) may help the skeletal
symptoms.
Fanconi syndrome
The Fanconi syndrome is a combination of renal tubular defects which can
result from several different pathologies. In particular, there is renal wast-
ing of phosphate, bicarbonate, glucose, and amino acids. The combination
of hypophosphataemia with renal tubular acidosis means that osteoma-
lacia is a frequent accompaniment. This can be exacerbated by defective
1A-hydroxylation of vitamin D to its active form. The osteomalacia is
treated by correction of the relevant abnormalities. This might involve the
administration of phosphate, alkali, or 1,25(OH)2D (calcitriol), depending
on the precise circumstances.
Further reading
Carpenter TO (2003). Oncogenic osteomalacia—a complex dance of factors. N Engl J Med 348,
1705–8.
Chong WH, et al. (2011). The importance of whole body imaging in tumor-induced osteomalacia.
Holick MF, et al. (2011). Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine
Society clinical practice guideline. J Clin Endocrinol Metab 96, 1911–30.
Hypophosphataemia
Phosphate is important for normal mineralization of bone. In the absence
of sufficient phosphate, osteomalacia results. Clinically, osteomalacia is
often indistinguishable from other causes, although there may be features
that will help distinguish the underlying cause of hypophosphataemia. In
addition, phosphate is important in its own right for neuromuscular func-
tion, and profound hypophosphataemia can be accompanied by encepha-
lopathy, muscle weakness, and cardiomyopathy. It must be remembered
that, as phosphate is primarily an intracellular anion, a low plasma phos-
phate does not necessarily represent actual phosphate depletion. Several
different causes of hypophosphataemia are recognized (see Box 6.13).
Treatment
• Mainstay is phosphate replacement, usually Phosphate-Sandoz®, each
tablet of which provides 500mg of phosphate.
• Ideally, patients should receive 2–3g of phosphate daily between
meals, but this is not easy to achieve. All phosphate preparations are
unpalatable and act as osmotic purgatives, causing diarrhoea.
• Long-term administration of phosphate supplements stimulates
parathyroid activity. This can lead to hypercalcaemia, a further
fall in phosphate, with worsening of the bone disease due to the
development of hyperparathyroid bone disease which may necessitate
parathyroidectomy.
• To minimize parathyroid stimulation, it is usual to give one of the
active metabolites of vitamin D in conjunction with phosphate.
Typically, alfacalcidol or calcitriol in a dose of 1–2 micrograms daily
is used.
• Patients receiving such supraphysiological doses of vitamin D
metabolites are at continued risk of hypercalcaemia and require
regular monitoring of plasma calcium, preferably at least every
3 months. The adequacy of calcitriol replacement can be assessed by
maintaining 24h urinary calcium excretion >4–6mmol/day.
• In adults, the role of treatment for X-linked hypophosphataemia is
probably confined to symptomatic bone disease.
• There is little evidence that it will improve the long-term outcome.
• There has even been some evidence that treatment might
accelerate new bone formation.
• In children, treatment is usually given in the hope of improving final
height and minimizing skeletal abnormality—the evidence that it is
possible to achieve these goals is conflicting.
HYPOPHOSPHATAEMIA 487
Box 6.13 Causes of hypophosphataemia

d intestinal absorption
• Phosphate binding antacids.
• Malabsorption.
• Starvation/malnutrition.
i renal losses
• Hyperparathyroidism:
• p.
• s, e.g. in vitamin D deficiency.
• Renal tubular defects:
• Fanconi syndrome.
• X-linked hypophosphataemia.
• Oncogenic osteomalacia.
• Alcohol abuse.
• Poorly controlled diabetes.
• Acidosis.
• Drugs:
• Diuretics.
• Corticosteroids.
• Calcitonin.
Shift into cells
• Septicaemia.
• Insulin treatment.
• Glucose administration.
• Salicylate poisoning.
• Catecholamine.
• Hyperventilation.
Further reading
Bergwitz C, Collins MT, Kamath RS et al. (2011) A 56-year old with hypophosphataemea NEJM
365, 1625–35.
Liamis G, Milionis HJ, Elisaf M et al. (2010) Medication-induced hypophosphatemia. QJM 103,
449–59.
Hypomagnesaemia
Introduction
• Low plasma magnesium levels are common in acutely ill patients.
Clinical manifestations of this are less common. The most common
clinical feature of magnesium deficiency is neuromuscular excitability,
muscular weakness which is virtually indistinguishable from that
associated with hypocalcaemia, which frequently coexists. Arrhythmias
can also occur, as can coma.
• Positive Chvostek’s and Trousseau’s signs are seen.
• Is associated with hypocalcaemia and hypokalaemia.
• In the presence of magnesium deficiency, PTH secretion is inhibited
and the peripheral action of PTH is also attenuated. Resultant
hypomagnesaemia-induced hypocalcaemia will not respond to
calcium treatment, unless the magnesium deficiency is corrected
first. Hypokalaemia is also frequently seen in association with
hypomagnesaemia. Treatment with potassium supplementation is often
unsuccessful, unless magnesium is replaced at the same time.
• See Box 6.14 for causes.
Treatment
Symptomatic magnesium deficiency, especially if associated with hypocal-
caemia or hypokalaemia, requires parenteral treatment.
• Magnesium sulfate 50% solution contains 72mmol magnesium/mL. This
should be administered IV, although IM is feasible but painful. An initial
4–8mmol should be given over 15min, followed by a slow infusion
of 1mmol/h. The rate of the infusion can be adjusted in light of the
response in plasma magnesium.
• In the presence of renal impairment, plasma magnesium can rise
quickly, and so particular care must be undertaken if magnesium
infusion is contemplated in the presence of renal failure.
• After repletion has been achieved intravenously, or in less severe
cases, treatment can be continued orally.
• Various salts of magnesium have been used, including chloride, oxide,
and glycerophosphate. Dosing is frequently limited by the purgative
properties of magnesium salts.
HYPOMAGNESAEMIA 489
Box 6.14 Causes of hypomagnesaemia

• GI losses:
• Vomiting.
• Diarrhoea.
• Losses from fistulae.
• Malabsorption.
• Renal losses:
• Chronic parenteral therapy.
• Osmotic diuresis.
• Gitelman’s syndrome.
• Diabetes.
• Drugs:
• Alcohol.
• Loop diuretics.
• Proton pump inhibitors.
• Aminoglycosides.
• Cisplatin.
• Ciclosporin.
• Amphotericin.
• Metabolic acidosis.
• Hypercalcaemia.
• Other causes:
• Phosphate depletion.
• Hungry bone syndrome.
Further reading
Ayuk J, Gittoes NJ (2011). How should hypomagnesaemia be investigated and treated? Clin
Osteoporosis
Introduction
Although the term osteoporosis refers to the reduction in the amount
of bony tissue within the skeleton, this is generally associated with a loss
of structural integrity of the internal architecture of the bone. The com-
bination of both these changes means that osteoporotic bone is at high
risk of fracture, even after trivial injury. The most common osteoporotic
fractures are those of the hip, wrist (Colles’), and compression fractures of
vertebral bodies. Patients who fracture ribs, the upper humerus, leg, and
pelvis also have a higher incidence of osteoporosis.
Over recent years, there has been a change in focus in the treatment
of osteoporosis. Historically, there has been a primary reliance on bone
mineral density as a threshold for treatment, whereas currently there is
far greater emphasis on assessing individual patients’ risk of fracture that
incorporates multiple clinical risk factors as well as bone mineral density.
Box 6.15 Underlying causes of osteoporosis

• Gonadal failure:
• Premature menopause (age <45).
• Hypogonadism in men.
• Conditions leading to amenorrhoea, with low oestrogen (persisting
>6 months):
• Anorexia nervosa.
• Endocrine disorders:
• GH deficiency.
• Hyperparathyroidism.
• Acromegaly with hypogonadism.
• Hyperthyroidism (within 3 years).
• GI disorders:
• Malabsorption.
• Post-gastrectomy.
• Coeliac disease.
• Crohn’s disease.
• Liver disease:
• Cholestasis.
• Cirrhosis.
OSTEOPOROSIS 491
Box 6.15 (Continued)

• Neoplastic disorders:
• Systemic mastocytosis.
• Inflammatory conditions:
• Rheumatoid arthritis.
• Cystic fibrosis.
• Nutritional disorders:
• Parenteral nutrition.
• Lactose intolerance.
• Drugs:
• Systemic glucocorticoids.
• Heparin (when given long-term, particularly in pregnancy).
• Chemotherapy (primarily through gonadal damage).
• Gonadotrophin-releasing hormone agonists.
• Ciclosporin.
• Anticonvulsants (long-term).
• Aromatase inhibitors for breast cancer.
• Androgen deprivation therapy (prostate cancer).
• Proton pump inhibitors.
• Selective serotonin reuptake inhibitors.
• Metabolic abnormalities:
• Homocystinuria.
• Hereditary disorders.
• Osteogenesis imperfecta.
• Marfan’s syndrome.
• Hajdu–Cheney syndrome (autosomal dominant), with marked
bone loss (acroosteolysis with osteoporosis and changes in skull
and mandible).
Pathology of osteoporosis
Osteoporosis may arise from a failure of the body to lay down sufficient
bone during growth and maturation; an earlier than usual onset of bone
loss following maturity; or an i rate of that loss.
See Table 6.7 for definitions and Box 6.16 for causes.
Peak bone mass
• Mainly genetically determined:
• Racial effects (bone mass higher in Afro-Caribbean and lower in
Caucasians).
• Family influence on the risk of osteoporosis—may account for 70%
of variation.
• So far, >9 separate genetic associations described.
• Also influenced by environmental factors:
• Exercise—particularly weight-bearing.
• Nutrition—especially calcium.
• Exposure to oestrogen is also important:
• Early menopause or late puberty (in ♂ or ♀) is associated with
i risk of osteoporosis.
Early onset of loss
• Early menopause.
• Conditions leading to bone loss, e.g. glucocorticoid therapy.
Increased net loss
• Ageing:
• Vitamin D insufficiency.
• Declining bone formation.
• Declining renal function.
• Underlying disease states (see Box 6.15).
Lifestyle factors affecting bone mass
Increase
• Weight-bearing exercise.
Decrease
• Smoking.
• Excessive alcohol.
• Nulliparity.
• Poor calcium nutrition.
PATHOLOGY OF OSTEOPOROSIS 493
Table 6.7 WHO definitions for osteoporosis and low bone mass
T score Fragility fracture Diagnosis
–1 Normal
<–1 but ≥–2.5 Low bone mass (osteopenia)
<–2.5 No Osteoporosis
<–2.5 Yes Established (severe) osteoporosis
Box 6.16 Causes of increased bone mineral density

Artefacts Generalized increase
• Excess skeletal calcium. • Acquired osteosclerosis, e.g.
• Extraskeletal calcium. renal osteodystrophy, fluorosis,
• Vertebral fracture. mastocytosis, myelofibrosis,
• Radiodense material. acromegaly.
Focal increase in bone Genetic
• Paget’s. • Sclerosing bone dysplasias.
• Tumours. • Decreased absorption, e.g.
osteoporosis, increased
formation sclerosteosis, LRP5
mutation.
Epidemiology of osteoporosis
• The risk of osteoporotic fracture increases with age. Fracture rates in
♂ are approximately half of those seen in ♀ of the same age. A ♀
aged 50 has approximately a 1:2 chance of sustaining an osteoporotic
fracture in the rest of her life. The corresponding figure for a ♂ is 1:5.
• In the UK each year, in ♀, there are in excess of 25,000 vertebral
fractures that come to clinical attention, together with over 40,000
wrist fractures and 50,000 hip fractures. The latter are a particular
health challenge, as they invariably result in hospital admission.
One-fifth of hip fracture victims will die within 6 months of the injury,
and only 50% will return to their previous level of independence. It has
been estimated that the overall cost of osteoporotic fractures in the
UK is £2.1 billion annually.
• See Box 6.17 for investigations.
Box 6.17 Investigations to consider an underlying cause of

osteoporosis
Useful in most patients
• FBC.
• ESR.
• Biochemical profile.
• Renal function.
• Liver function.
• Calcium.
• Thyroid function.
• Testosterone and LH (only in ♂).
• Vitamin D.
Useful in specific instances
• Oestradiol and FSH (in ♀ where menopausal status not clear).
• Serum and urine electrophoresis (if raised ESR or plasma globulin
elevated).
• Anti-tissue transglutaminase antibodies (if any suggestion of coeliac
disease).
• 24h urinary calcium excretion (to detect idiopathic hypercalciuria).
• Other investigations for specific diseases.
Low-trauma fractures associated with osteoporosis
Any fracture, other than those affecting fingers, toes, or face, which
is caused by a fall from standing height or less is called a fragility
(low-trauma) fracture, and underlying osteoporosis should be consid-
ered. Patients suffering such a fracture should be considered for investi-
gation and/or treatment for osteoporosis.
PRESENTATION OF OSTEOPOROSIS 495
Presentation of osteoporosis
• Usually clinically silent until an acute fracture.
• Two-thirds of vertebral fractures do not come to clinical attention.
• Typical vertebral fracture:
• Sudden episode of well-localized pain.
• May, or may not, have been related to injury or exertion.
• May be radiation of the pain in a girdle distribution.
• Pain may initially require bed rest but gradually subsides over
4–8 weeks; even after this time, there may be residual pain at the
fracture site.
• Osteoporotic vertebral fractures only rarely lead to neurological
impairment.
• Any evidence of spinal cord compression should prompt a search for
malignancy or other underlying cause.
• Following vertebral fracture, a patient may be left with persistent back
pain, kyphosis, or height loss.
• Although height loss and kyphosis are often thought of as being
indicative of osteoporosis, they are more frequently the result of
degenerative disease, including disc disease. These changes cannot be
attributed to osteoporosis in the absence of vertebral fractures.
• Peripheral fractures are also more common in osteoporosis.
• If a bone breaks from a fall from less than standing height, that
represents a low-trauma fracture which might indicate underlying
osteoporosis.
• Osteoporosis does not cause generalized skeletal pain.
Investigation of osteoporosis
Establish the diagnosis
• Plain radiographs are useful for determining the presence of
fracture. Apart from this, they are of little utility in the diagnosis of
osteoporosis. Bone density cannot be assessed reliably from a plain
radiograph.
• Bone densitometry. In order to identify the presence of T score-defined
osteoporosis, it is important to measure BMD appropriately. This
is usually carried out at the hip and lumbar spine, using dual-energy
X-ray absorptiometry (DXA). The presence of degenerative disease
or arterial calcification can elevate the apparent bone density of the
spine without adding to skeletal strength. i reliance is, therefore, being
placed on measurements derived from the hip. The diagnostic criteria
for osteoporosis have been derived through the WHO (see Table 6.7).
• Biochemical markers of bone turnover may be helpful in the
calculation of fracture risk and in judging the response to drug
therapies, but they have no role in the diagnosis of osteoporosis.
• Use of fracture risk algorithms is now available to determine
individuals’ fracture risk (e.g. M http://www.shef.ac.uk/FRAX). Such an
approach can help tune therapies to those patients at heightened risk
of fracture.
Exclude underlying causes
An underlying cause for osteoporosis is present in approximately 10–30%
of women and up to 50% of men with osteoporosis. Many of the underly-
ing causes (see Box 6.15) should be apparent from a careful history and
physical examination. A few basic investigations are useful to exclude the
more common underlying causes. Other investigations may be needed to
exclude other specific conditions.
It is helpful to target investigations at those people who have a signifi-
cantly lower than expected bone mass for their age (Z score <–2).
Monitoring therapy
• Repeat bone densitometry is not obligatory for monitoring, as there
is no direct correlation between changes in bone density and the
anti-fracture effects of drugs. This is an area of controversy.
• Minimum time interval should be 2 years between scans.
• Effective treatment leads to modest rise (75% at spine) in bone density.
• Biochemical markers of bone turnover may be helpful in specific
settings (e.g. P1NP and NTX).
• See Table 6.8 for efficacy for types of treatments
INVESTIGATION OF OSTEOPOROSIS 497
Table 6.8 Grade of evidence of anti-fracture efficacy of approved

treatments for post-menopausal women with osteoporosis (when
given with calcium + vitamin D)
Treatment Vertebral Non-vertebral Hip fracture
fracture fracture
Alendronic acid A A A
Etidronate A B NAE
Ibandronic acid A A# NAE
Risedronate A A A
Zoledronic acid A A A
Denosumab A A A
Calcitonin A B B
Calcitriol A B NAE
Raloxifene A NAE NAE
Strontium ranelate A A A#
Teriparatide A A NAE
Recombinant human PTH A NAE NAE
(1-84)
HRT A A A
NAE, not adequately evaluated; PTH, parathyroid hormone; HRT, hormone replacement
therapy; #, in subsets of patients only.
Treatment of osteoporosis
Treatments should be considered according to their effect on fracture risk
reduction and side effect profile.
In addition to pharmacological treatments aimed at reducing fracture
risk, it must be remembered that non-pharmacological measures are also
important. Thus, it is prudent to minimize the risk of falling by adjusting
the home environment and reviewing the need for medications, such as
hypnotics and antihypertensives, for instance.
Lifestyle measures
• Stop smoking.
• Avoid alcohol excess.
• Encourage weight-bearing exercise:
• Lower-impact exercise, e.g. walking outdoors for 20min 3× weekly,
may reduce fracture risk.
• Encourage well-balanced diet.
• Ensure adequate calcium and vitamin D intake.
• If necessary, give supplements to achieve calcium intake of 71g daily.
Choice of therapy and who to treat
The National Institute for Health and Care Excellence (NICE) has
produced guidance on the s prevention of osteoporotic fractures in
post-menopausal women with a low-trauma fracture (M http://guidance.
nice.org.uk/TA161; M http://guidance.nice.org.uk/TA204). The guidelines
focus on age, bone density, clinical risk factors, and cost effectiveness to
derive recommendations.
The National Osteoporosis Guideline Group (NOGG) has also derived
alternative clinical guidelines that are based on a fracture risk assess-
ment tool (FRAX) that links into a web-based guideline tool to derive
recommendations regarding prescribing (M http://www.shef.ac.uk/FRAX;
M http://www.shef.ac.uk/NOGG).
Therapy is given for 5 years in the first instance. Reassessment should
occur at this time. If the T score at the femoral neck is below –2.5, then
therapy should be continued. Consideration should also be given to con-
tinue therapy if there has been a previous vertebral fracture. Patients with
a T score above –2.0 at the femoral neck are unlikely to benefit from
continued treatment.
See Box 6.18 for vertebroplasty.
Glucocorticoid-induced osteoporosis
Glucocorticoid treatment is one of the major s causes of osteoporosis.
Not all patients receiving steroid treatment do lose bone, and it is not
clear what determines this. Patients who sustain fractures while taking glu-
cocorticoids do so at higher bone density levels than in post-menopausal
women, leading to the assertion that such patients should be treated at a
higher bone density (T <–1.5) than would be the case for post-menopausal
osteoporosis.
The Royal College of Physicians (UK) has produced guidelines for the
management of glucocorticoid-induced osteoporosis (see Fig. 6.4).
TREATMENT OF OSTEOPOROSIS 499
Box 6.18 Vertebroplasty

• Percutaneous injection of bone cement into the fractured
vertebral body.
• Effective at resolving pain in the short and longer term.
• Best for patients with acute fractures and persistent pain (>6 weeks).
* In patients with
Men and women previous fragility
fracture:
Commitment or exposure • FBC, ESR.
Fragility fracture: to oral glucocorticoids
for >3 months • Bone and liver function
tests (Ca, PO4, alk phos,
• Defined as a fracture Age >65 years Age < 65 years albumin, AST/γGT).
occurring on minimal
• Serum creatinine.
trauma after age 40
Previous fragility fracture • Serum TSH.
years and includes
Investigations* or incident fracture during No previous
forearm, spine, hip, If indicated:
glucocorticoid therapy fragility
ribs, and pelvis. • Lateral thoracic and
fracture lumbar spine X-rays
General measures: Measure BMD • Serum paraproteins and
• Reduce dose of urine Bence ones protein.
glucocorticoid when T score –1.5 or lower** T score between T score >0 • Isotope bone scan.
possible. 0 and –1.5 • Serum FSH if hormonal
status unclear (women).
• Consider General measures and • Serum testosterone, LH
glucocorticoid-sparing advise treatment*** Reassure and SHBG (men).
General measures
therapy. General measures • Serum 25OHD and
• Alendronic acid (L).
• Consider alternative PTH.
route of glucocorticoid • BMD if monitoring
• Alfacalcidol.
administration. Repeat BMD in Repeat BMD not required.
• Calcitonin. 1–3 years required, except if **Consider treatment,
• Recommend adequate if glucocorticoids very high dose of depending on age and
nutrition, especially with continued glucocorticoids required
• Calcitriol. fracture probability.
calcium and vitamin D.
• Recommend regular *** Treatments listed in
• Clodronate.
weight-bearing exercise. alphabetical order.
• Cyclic etidronate(L). Vitamin D and calcium are
• Maintain body weight. generally regarded as
• HRT. adjuncts to treatment.
• Avoid tobacco use and HRT: oestrogen in women
alcohol abuse. • Pamidronate. and testosterone in men.
(L) indicates that the
• Falls risk assessment and agent is licensed for
• Risedronate (L).
advice, if appropriate. glucocorticoid-induced
osteoporosis.
Fig. 6.4 Guidelines for the management of glucocorticoid-induced osteoporosis.

TREATMENT OF OSTEOPOROSIS 501
Complications of therapy for

osteoporosis
(See Boxes 6.19 and 6.20 for special considerations.)
HRT
• Because of adverse effects (breast cancer, venous thromboembolism,
coronary disease, and stroke), HRT is no longer regarded as a p
treatment for osteoporosis in post-menopausal ♀.
• When a woman is receiving HRT for climacteric symptoms, however,
there will be a beneficial effect on fracture risk reduction.
• Skeletal protection is rapidly lost on cessation of HRT.
• In ♀ with a premature menopause, HRT remains the most appropriate
means of preventing bone loss in the absence of other contraindications.
Bisphosphonates
• Weekly (PO), daily (PO), monthly (PO), 3-monthly (IV), and annual
(IV) preparations are available.
• Oral preparations require patients to follow strict dosing instructions.
Oral bisphosphonates should be taken on an empty stomach, and
30–60min (dependent on drug) should pass prior to additional oral
intake.
• GI disturbance, including nausea and oesophagitis, are common.
• Osteonecrosis of the jaw is a very rare side effect of bisphosphonates
in doses given to treat osteoporosis (<0.5%). It may be treated with
teriparatide.
• Flu-like symptoms occur in 20–30%, following IV administration of
zoledronate (acute phase response commoner in younger patients).
• There is a possible association between atypical subtrochanteric
femoral fractures in patients who have taken several years of
bisphosphonates.
• If treated for 5 years, consider therapeutic holiday, unless T worse
than 2.5 at the hips or, with existing history of vertebral fractures, T is
worse than –2.0.
Calcium and vitamin D
• Constipation.
• Recent reports have raised queries of a link between exogenous
calcium supplementation and increased risk of cardiovascular disease.
Calcitonin
• Very rarely used nowadays.
• Parenteral administration.
• Flushing.
• Nausea and diarrhoea.
Raloxifene
• Similar increase in risk of venous thrombosis as HRT.
• May induce/worsen climacteric symptoms.
• Reduces risk of breast cancer.
COMPLICATIONS OF THERAPY FOR OSTEOPOROSIS 503
Strontium ranelate
• Diarrhoea.
• Venous thromboembolism.
Denosumab
• Effective for at least 6 years.
• Skin infections/eczema.
• Hypocalcaemia (ensure Ca and vitamin D levels normal prior).
Teriparatide
• Contraindications: hypercalcaemia, renal impairment, unexplained
elevation of alkaline phosphatase—Paget’s disease, prior irradiation.
• Risk of hypercalcaemia is not great. and no specific monitoring of
treatment is recommended.
• Vomiting.
• Leg cramps.
• i risk of osteosarcoma seen in rats given teriparatide for most of
their life. It should be avoided in patients with i risk of bone tumours
(Paget’s disease, raised alkaline phosphatase, previous skeletal
radiotherapy).
Causes of increased bone mineral density
Artefacts
• Excess skeletal calcium (lumbar spondylosis, ankylosing spondylitis).
• Extraskeletal calcium (vascular, gallstones).
• Vertebral fracture.
• Radiodense material (surgical implants, strontium).
Focal increase in bone
• Paget’s disease.
• Tumours (e.g. haemangioma, Hodgkin’s, plasmacytoma).
Generalized increase in bone
Acquired osteosclerosis (general osteodystrophy, fluorosis, mastocytosis,
hepatitis C, myelofibrosis, acromegaly).
Genetic sclerosing bone dysplasias
• d absorption (e.g. osteopetrosis).
• i formation (e.g. sclerosteosis).
• Disturbed balance of formation and resorption.
Box 6.19 Special considerations in men

(For algorithm, b see Fig. 6.4, p. 500.)
• s causes of osteoporosis are more common in ♂ and need to be
excluded in all ♂ with osteoporotic fracture.
• Bisphosphonates benefit bone mass in ♂ in a similar way to
post-menopausal ♀.
• Hypogonadal ♂ show an improvement in bone mass on
testosterone replacement. However, hypogonadal ♂ respond
to bisphosphonates as do those with normal testosterone levels.
Replacement testosterone along with bisphosphonate therapy is
appropriate.
Box 6.20 Special considerations in premenopausal women

• ‘Osteoporosis’ in premenopausal ♀ is rare but well recognized.
• Younger women have a lower risk of fracture.
• It is important to exclude underlying causes of accelerated rates of
bone loss.
• Osteoporosis can very rarely occur in conjunction with pregnancy
or lactation. This is frequently self-limiting and usually requires little
treatment other than calcium supplementation.
• In the absence of a pre-existing fracture, fracture risk is low.
Advice regarding positive lifestyle factors is always prudent. Further
assessment should be made around the age of natural menopause.
• In other situations, particularly where low-trauma fractures have
occurred, other therapies may be carefully considered, recognizing
there are no data to support the use of anti-fracture drugs in
premenopausal women.
• Some caution needs to be exercised over the use of
bisphosphonates in younger people:
• Teratogenic in animals.
• Long skeletal retention time.
• In such patients, it may be worth considering alternative agents,
such as calcitriol.
In general, the management of premenopausal women with osteoporo-
sis and high fracture risk should be assessed by a clinician with a special-
ist interest in metabolic bone diseases.
COMPLICATIONS OF THERAPY FOR OSTEOPOROSIS 505
Further reading
Black DM, Delmas PD, Eastell R, et al. (2007). Once-yearly zoledronic acid for treatment of post-
menopausal osteoporosis. N Engl J Med 356, 1809–22.
Boonen S, et al. (2012). Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl
J Med 367, 1714–23.
Ebeling PR (2008). Osteoporosis in men. N Engl J Med 358, 1474–82.
Khosla S, et al. (2008). Osteoporosis in men. Endocr Rev 29, 441–64.
Klazen CA, et al. (2010). Vertebroplasty versus conservative treatment in acute osteoporotic ver-
tebral compression fractures (Vertos II): an open-label randomised trial. Lancet 376, 108–92.
Meunier PJ, Roux C, Seeman E, et al. (2004). The effects of strontium ranelate on the risk of
vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 350, 459–68.
Ranney A, Tugwell P, Wells G, et al. (2002). Meta-analyses of therapies for postmenopausal osteo-
porosis. I. Systematic reviews of randomized trials in osteoporosis: induction and methodology.
Endocr Rev 23, 496–507.
Russell RGG (2011). Bisphosphonates: the first 40 years. Bone 49, 2–19.
Sambrook P, Cooper C (2006). Osteoporosis. Lancet 367, 2010–28.
Schilcher J, et al. (2011). Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J
Med. 364, 1728–37.
Watts NB, at al. (2012). Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin
Weinstein RS (2011). Clinical practice. Glucocorticoid-induced bone disease. N Engl J Med
365, 62–70.
Paget’s disease
Paget’s disease is the result of greatly i local bone turnover, which occurs
particularly in the elderly but can affect younger people.
Pathology
• The p abnormality in Paget’s disease is gross overactivity of the
osteoclasts, resulting in greatly i bone resorption. This secondarily
results in i osteoblastic activity. The new bone is laid down in a highly
disorganized manner and leads to the characteristic pagetic abnormality,
with irregular packets of woven bone being apparent on biopsy and
disorganized internal architecture of the bone on plain radiographs.
• Paget’s disease can affect any bone in the skeleton but is most
frequently found in the pelvis, vertebral column, femur, skull, and tibia.
In most patients, it affects several sites, but, in about 20% of cases, a
single bone is affected (monostotic disease). Typically, the disease will
start in one end of a long bone and spread along the bone at a rate of
about 1cm per year. Although it can spread within an affected bone,
it appears that the pattern of disease is fixed by the time of clinical
presentation, and it is exceedingly rare for new bones to become
involved during the course of the disease.
• Paget’s disease alters the mechanical properties of the bone. Thus,
pagetic bones are more likely to bend under normal physiological
loads and are thus liable to fracture. This can take the form of
complete fractures, which tend to be transverse, rather than the more
common spiral fractures of long bones. More frequently, fissure or
incremental fractures are seen on the convex surface of bowed pagetic
bones. These may be painful in their own right but are also liable to
proceed to complete fracture. Pagetic bones are also larger than their
normal counterparts. This can lead to i arthritis at adjacent joints and
to pressure on nerves, leading to neurological compression syndromes
and, when it occurs in the skull base, sensorineural deafness.
Aetiology of Paget’s disease
Unclear. There are two major theories:
• Familial:
• Some genetic associations, especially with a sequestasome-1
mutation.
• These are not invariable.
• Viral:
• Inclusion bodies, similar to those seen in viral infections, have been
identified in osteoclasts from patients with Paget’s.
• Some workers have found paramyxoviral (measles or canine
distemper) protein or nucleic acid in pagetic bone; others have not
been able to replicate this.
PAGET’S DISEASE 507
Epidemiology
Paget’s disease is present in about 2% of the UK population over the
age of 55. Its prevalence increases with age, and it is more common in
♂ than ♀. Only about 10% of affected patients will have symptomatic
disease. It is most common in the UK or in migrants of British descent
in North America and Australasia but rare in Africa. Studies in the UK
and New Zealand have suggested that the prevalence may be declining
with time.
Clinical features
• 90% asymptomatic.
• Most notable feature is pain. This is frequently multifactorial:
• i metabolic activity of the bone.
• Changes in bone shape.
• Fissure fractures.
• Nerve compression.
• Arthritis.
• Pagetic bones tend to increase in size or become bowed (16%
cases): bowing can be so severe as to interfere with function.
• Fractures (either complete or fissure) present in 10%.
• Risk of osteosarcoma is increased in active Paget’s disease but is a very
rare finding.
Investigation
The diagnosis of Paget’s disease is primarily radiological.
Radiological features of Paget’s disease
• Early disease—primarily lytic:
• V-shaped ‘cutting cone’ in long bones.
• Osteoporosis circumscripta in skull.
• Combined phase (mixed lytic and sclerotic):
• Cortical thickening.
• Loss of corticomedullary distinction.
• Accentuated trabecular markings.
• Late phase—primarily sclerotic:
• Thickening of long bones.
• Increase in bone size.
• Sclerosis.
An isotope bone scan is frequently helpful in assessing the extent of skel-
etal involvement with Paget’s disease. It is particularly important to identify
Paget’s disease in a weight-bearing bone because of the risk of fracture.
The uptake of tracer depends on the disease activity, and isotope bone
scans can also be used to assess the response to therapy.
In active disease, plasma alkaline phosphatase activity is usually (85%)
elevated. An exception to this is in monostotic disease when there may
be insufficient bone involved to raise the enzyme levels above normal.
Alkaline phosphatase activity responds to successful treatment. There is
little advantage in using the more modern markers of bone turnover over
the total alkaline phosphatase activity for the monitoring of pagetic activity.
A possible exception to this is in patients with liver disease where changes
in bone alkaline phosphatase might be masked by the liver isoenzyme.
Complications
• Deafness is present in up to half of cases of skull base Paget’s.
• Other neurological complications are rare. These can include:
• Compression of other cranial nerves with skull base disease.
• Spinal cord compression. Most common with involvement of the
thoracic spine and is thought to result as much from a vascular steal
syndrome as from physical compression. It frequently responds to
medical therapy without need for surgical decompression.
• Platybasia which can lead to an obstructive hydrocephalus that may
require surgical drainage.
• Osteogenic sarcoma:
• Very rare complication of Paget’s disease.
• Rarely amenable to treatment.
• Presents with i pain/radiological evidence of tumour, a mass, and
very elevated alkaline phosphatase.
• Any increase of pain in a patient with Paget’s disease should arouse
suspicion of sarcomatous degeneration. A more common cause,
however, is resumption of activity of disease.
Pagetic sarcomas are most frequently found in the humerus or femur but
can affect any bone involved with Paget’s disease.
Treatment
Treatment with agents that decrease bone turnover reduces disease
activity, as indicated by bone turnover markers and isotope bone scans.
There is evidence to suggest that such treatment leads to the deposi-
tion of histologically normal bone. Although such treatment has been
shown to help pain, there is little evidence that it benefits the other con-
sequences of Paget’s disease. In particular, the deafness of Paget’s disease
does not regress after treatment, although its progression may be halted.
Nonetheless, it has become generally accepted to treat patients in the
hope that future complications of the disease will be avoided. Typical indi-
cations for treatment of Paget’s disease are listed in Box 6.21.
Bisphosphonates have become the mainstay of treatment. IV zoledro-
nate is the drug of choice and results in long-term normalization of alkaline
phosphatase in the majority of patients. Calcitonin and plicamycin are no
longer used.
Goals of treatment
• Minimize symptoms.
• Prevent long-term complications.
• Normalize bone turnover.
• Alkaline phosphatase in normal range.
• No actual evidence that treatment achieves this.
PAGET’S DISEASE 509
Box 6.21 Typical indications for treating Paget’s disease

Evidence in this area is minimal.
• Pain likely due to Paget’s.
• Neurological complications (e.g. deafness, spinal cord compression).
• Disease in weight-bearing bones.
• Disease in periarticular location.
• Prevention of long-term complications (e.g. bone deformation,
osteoarthritis).
• Young patients.
• In preparation for surgery.
• Hypercalcaemia.
• Following fracture.
Monitoring therapy
• Plasma alkaline phosphatase every 6–12 months.
• Clinical assessment.
Re-treat if symptoms recur with objective evidence of disease recurrence
(alkaline phosphatase or +ve isotope scan). There is no evidence that
treating a raised alkaline phosphatase in the absence of symptoms affects
outcome in Paget’s.
Further reading
Albagha OM, et al. (2011). Genome-wide association identifies three new susceptibility loci for
Paget’s disease of bone. Nat Genet 43, 685–9.
Ralston SH (2013). Clinical practice. Paget’s disease of bone. N Engl J Med 368, 644–50.
Ralston SH, et al (2008). Pathogenesis and management of Paget’s disease of bone. Lancet 372,
155–163.
Selby PL, Davie MW, Ralston SH, et al. (2002). National Association for the Relief of Paget’s
Disease: guidelines on the management of Paget’s disease of the bone. Bone 31, 366–73.
Inherited disorders of bone

Osteogenesis imperfecta
Osteogenesis imperfecta is an inherited form of osteoporosis where, in
the vast majority of cases, there is a genetic defect in one of the two genes
(COLIA1 and COLIA2) encoding the A-chain of collagen type I collagen pro-
duction. Several different mutations are recognized, and these produce
different clinical pictures; these are generally separated into at least four
types (see Table 6.9).
In addition to the osteoporosis and easy fracture, there may also be
abnormalities of the teeth (dentinogenesis imperfecta), blue sclerae and
hearing loss, hypermobility, and cardiac valvular lesions.
Radiological features include:
• Generalized osteopenia.
• Multiple fractures with deformity.
• Abnormal shape of long bones.
• Wormian bones in skull (Accessory skull bones completely
surrounded by a suture line).
Diagnosis
• Features described in previous section and family history.
• Analysis of collagen type I genes (detect 90%).
• Three criteria:
• Three fragility fractures aged <20 years.
• At least one of: blue sclerae, scoliosis, hearing loss, joint laxity,
dentinogenesis imperfecta, and family member.
• Osteoporosis.
Recent studies have demonstrated that infusions of pamidronate lead to
i bone mass and reduced fracture incidence in affected children. Patients
with milder disease might only be recognized in adulthood. There is no
established role for bisphosphonates in young adults with osteogenesis
imperfecta, although each case should be assessed on balance of risk fac-
tors for fracture. It is also noteworthy that fracture risk increases steeply
with ageing in patients with osteogenesis imperfecta, and thus considera-
tion should be given to interventions, including use of anti-fracture drugs.
Prenatal diagnosis of severe types is possible, and genetic counselling
should be offered to all at-risk families.
INHERITED DISORDERS OF BONE 511
Table 6.9 Classification of osteogenesis imperfecta

Type Inheritance Stature Teeth Sclerae Hearing Genetic defect
I AD Normal Normal Blue Variable Substitution
Mild loss for glycine in
COL1A1
II AD/AR Lethal Rearrangement
deformity of COL1A1 and
COL1A2
III AD/AR (Very Abnormal Variable Loss Glycine
(Progressive short, common substitution in
deforming) severe COL1A1 and
scoliosis) COL1A2
IV AD Mild Abnormal Normal Occasional Point mutations
loss in a2(I) or a1(I)
Further reading
Bitton A, et al. (2009). Clinical problem-solving. A fragile balance. N Engl J Med 361, 74–9.
Rauch F, Glorieux FH (2004). Osteogenesis imperfecta. Lancet 363, 1377–85.
Chapter 7 513
Paediatric endocrinology
Growth 514
Short stature 518
Constitutional delay of growth and puberty 520
Primary GH deficiency 522
Secondary GH deficiency 524
Treatment of GH deficiency 526
GH resistance 528
Hypothyroidism 529
Coeliac disease 530
Skeletal dysplasias 530
Small for gestational age (SGA) and intrauterine growth
restriction 531
Turner’s syndrome 532
Tall stature and rapid growth 534
Normal puberty 536
Precocious puberty 538
Delayed/absent puberty 542
Normal sexual differentiation 544
Assessment of ambiguous genitalia 545
Disorders of sex development (DSD) 546
Congenital adrenal hyperplasia 550
514 CHAPTER 7 Paediatric endocrinology
Growth
Regulation of growth
Normal human growth can be divided into three overlapping stages (the
Karlberg model), each under the control of different factors:
• Infancy. Growth is largely under nutritional regulation, and wide
inter-individual variation in rates of growth is seen. Many infants show
significant ‘catch-up’ or ‘catch-down’ in weight and length, and by
2 years, length is much more predictive of final adult height than at birth.
• Childhood. Growth is regulated by growth hormone (GH) and thyroxine.
It is characterized by alternating periods of mini-growth spurts with
intervening stasis, each phase lasting several weeks. However, over
years, a child will tend to maintain their centile position on height charts,
with a height velocity between the 25th and 75th centiles.
• Puberty. The combination of GH and sex hormones promotes bone
maturation and a rapid growth acceleration or ‘growth spurt’. In both
sexes, oestrogen eventually causes epiphyseal fusion, resulting in the
attainment of final height.
Sex differences
Adult heights differ between ♂ and♀ by, on average, 13cm. However,
during childhood, onset of the pubertal growth spurt is earlier in ♀, who
are therefore, on average, taller than ♂ between the ages of 10–13 years.
Tempo
Within each sex, there may also be marked inter-individual differences
in tempo of growth (or rate of attainment of final height) and the timing
of puberty. Delay or advance of bone maturation is linked with timing of
puberty. Constitutional delay in growth and puberty often runs in families,
reflecting probable genetic factors. Comparison of bone age (estimated
from a hand radiograph) with chronological age is, therefore, an important
part of growth assessment.
Final height
Final height is estimated as the height reached when growth velocity
slows to <2cm/year and can be confirmed by finding epiphyseal fusion
on hand radiograph ± knee radiograph. Final height is largely genetically
determined, and a target height can be estimated in each individual from
their parent’s heights.
Assessment of growth
Measurement
• From birth to 2 years old, supine length is measured ideally using a
measuring board (e.g. Harpenden neonatometer). Two adults are
needed to ensure that the child is lying straight and legs extended.
• From 2 years old, standing height is measured against a wall-mounted
or free-standing stadiometer, with the measurer applying moderate
upwards neck traction and the child looking forward in the
horizontal plane.
GROWTH 515
• To minimize error in the calculation of height velocity (cm/year),

height measurements should be taken at least 6 months apart, using
the same equipment and ideally by the same person.
• Measurement of sitting height and comparison with leg length (standing
height – sitting height) allows an estimate of body proportion.
Growth charts (see Figs. 7.1 and 7.2)
Height and weight velocity should be compared to age and sex appropriate
reference data by plotting values on standard growth charts (e.g. the UK
1990 Growth Reference, Child Growth Foundation, London, UK). Charts
based on the World Health Organization (WHO) child growth stand-
ards are becoming available and define the optimal growth for children
who have been breastfed as a baby. The data are based on the UK90 and
WHO data (M http://www.rcpch.ac.uk/child-health/research-projects/
uk-who-growth-charts/).
Mid-parental height (MPH)
MPH is an estimate of the child’s genetic height potential and is calculated as:
[(Mother’s height + father’s height)/2] + 7cm (for boys)
or – 7cm (for girls).
It can be used to estimate a child’s expected final height, but there is a
wide target range (MPH ± 10cm for boys and ± 8.5cm for girls), and it is
more commonly used to assess whether the child’s current height centile
is consistent with genetic expectation.
Bone age
Skeletal maturation proceeds in an orderly manner from the first appear-
ance of each epiphyseal centre to the fusion of the long bones. From
chronological age 3–4 years, bone age may be quantified from radiographs
of the left hand and wrist by comparison with standard photographs (e.g.
Greulich and Pyle method) or by an individual bone scoring system (e.g.
Tanner–Whitehouse method). The difference between bone age and
chronological age is an estimation of tempo of growth. The initiation of
puberty usually coincides with a bone age around 10.5–11 years in girls
and 11–11.5 years in boys, although the correlation between bone age and
pubertal timing is approximate. Girls reach skeletal maturity at a bone age
of 15 years and boys when bone age is 17 years. Thus, bone age allows
an estimation of remaining growth potential and can be used to aid in the
prediction of final adult height.
Final height prediction
Predictions of final height can be derived from information on current
height, age, pubertal status, and bone age, using calculations described by
Tanner and Whitehouse or Bayley and Pinneau, among others.1
Secular trends
Children’s heights i by >1cm in England and by >2cm in Scotland during
the period from 1972–94, and similar trends are seen in many other coun-
tries. Population growth references used should be appropriate to the
population studied and may occasionally need to be updated. However,
secular trends in height over the last decade have reduced significantly in
some countries.
190
180 Boys
170
Girls
160
150
140
130
Height (cm)
120
110
100
90
80
70
60
50
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Age (years)
Fig. 7.1 Typical individual height-attained curves for boys and girls (supine length
to the age of 2; integrated curves of Fig. 7.2).
GROWTH 517
24
23
22
21
20
19
18
17
16
15
14
Height (cm)
13
12
11
10
Boys
9
Girls
8
7
6
5
4
3
2
1
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Age (years)
Fig. 7.2 Typical individual velocity curves for supine length or height in boys and
girls. These curves represent the velocity of the typical boy and girl at any given
instant.
Reference
1. De Waal WJ, Greyn-Fokker MH, Stijnen T, et al. (1996). Accuracy of final height prediction and
effect of growth-reductive therapy in 362 constitutionally tall children. J Clin Endocrinol Metab
81, 1206–16.
Short stature
Definition
Short stature is defined as height <2nd centile for age and sex on the UK
1990 growth chart. However, abnormalities of growth may be present long
before attained height falls below this level and may be detected much
earlier by assessing growth velocity and observing height measurements.
Assessment
History
• Who is concerned, child or parents?
• What are the parental heights?
• Has the child always been small or does the history suggest recent
growth failure? Try to obtain previous measurements (e.g. from
parents, GP, health visitor, school).
• Ask about maternal illness in pregnancy, drug intake and possible
substance abuse in pregnancy, gestation at delivery, size at birth
(weight/length/head circumference), childhood illnesses, medication,
and developmental milestones.
• Systematic enquiry for headaches, visual disturbance, asthma/
respiratory symptoms, abdominal symptoms, and diet.
• Is there a family history of short stature or pubertal delay?
• What are the psychosocial circumstances of the child and the family?
Examination
• Assess height and height velocity over at least 6 months.
• Measure sitting height, and derive subischial leg length (standing
height – sitting height (cm)) if skeletal disproportion suspected.
• Assess for the presence and severity of chronic disease. Low weight
for height suggests a nutritional diagnosis, GI cause, or other significant
systemic disease.
• Pubertal stage using Tanner’s criteria (see b p. 537).
• Observe for dysmorphic features and signs of endocrinolopathy,
presence and severity of chronic disease.
• Measure parents’ heights, and calculate MPH.
Investigations
• Laboratory tests should include FBC, ESR, electrolytes, thyroid
function, calcium, phosphate, antigliadin and antiendomysial
antibodies, IGF-I level, karyotype (of particular importance in girls),
and urinalysis.
• These tests may also be clinically indicated: GH provocation testing
(e.g. arginine, glucagon, or ITT) (see Table 7.1) with other anterior
pituitary function tests, MRI scan with specific reference to the
hypothalamus and pituitary, skeletal survey (for bone dysplasia),
and, very rarely, an IGF-1 generation test (for GH resistance, b see
Growth hormone deficiency, p. 521).
Causes
• Genetic short stature.
SHORT STATURE 519
Table 7.1 Comparison of GH provocation tests

Insulin (IV) Arginine (IV) Glucagon (IM)
Age >2 years Any <5 years and in
neonates
Advantages Gold standard Safe, consistent Safe
response
Also tests ACTH– Also tests ACTH–
cortisol axis cortisol axis
Disadvantages Risk of severe Occasional nausea Nausea may last
hypoglycaemia but and vomiting 3–4h
good safety record in
Can cause skin Great care
experienced centres
irritation because of late
hypoglycaemia
Other agents (e.g. L-dopa or clonidene) are less commonly used. Measurement of GH levels
after exercise has poor sensitivity and specificity for detecting GH deficiency.
• Constitutional delay in growth and puberty—these first two together

account for 740% of cases.
• Chronic illness (including untreated coeliac disease, congenital heart
disease, chronic renal failure, inflammatory bowel disease).
• Psychosocial deprivation (which may be associated with reversible GH
deficiency, see b p. 371).
• Small for gestational age (SGA), including intrauterine growth
restriction (7.5%).
• Dysmorphic syndromes (e.g. Turner’s syndrome, Noonan’s syndrome
(short stature, congenital heart defects, webbed neck), Down’s syndrome).
• Malnutrition (p, rare in the UK).
• GH deficiency (8%):
• Undefined aetiology (‘idiopathic’, including those with abnormal
pituitary morphology on MRI).
• Congenital malformation in the hypothalamus/pituitary (HP)
(e.g. septo-optic dysplasia) or acquired HP disorders (e.g.
craniopharyngioma, trauma), the GH-1 gene or the GH-releasing
hormone receptor gene, or rarely mutations in transcription factors
controlling pituitary development (see b p. 126).
• GH resistance (rare genetic mutations in the GH receptor or
GH-signalling molecules).
• Endocrine disorders (hypothyroidism, hypoparathyroidism,
Cushing’s syndrome).
• Skeletal dysplasia (e.g. achondroplasia, hypochondroplasia).
• Metabolic bone disease (e.g. nutritional or hypophosphataemic rickets).
• Inhaled glucocorticoids.
Genetic short stature
Although stature does not follow strict Mendelian laws of inheritance, it
does relate to parental height and is probably a polygenic trait. It should
be remembered that short parents may themselves have an unidentified
dominantly inherited condition (e.g. hypochondroplasia).
Constitutional delay of growth and

puberty
Clinical features
• This condition often presents in adolescence but may also be
recognized in earlier childhood, although it is more prevalent in ♂.
• Characteristic features include short stature and delay in pubertal
development by >2 standard deviations (SD), and/or bone age delay in
an otherwise healthy child. In the adolescent years, short sitting height
percentile, compared to leg length, is typical.
• There is often a family history of delayed puberty.
• Bone age delay may also develop in a number of other conditions, but,
in constitutional delay, bone age delay usually remains consistent over
time and height velocity is normal for the bone age. Final height may
not reach target height.
• GH secretion is usually normal, although provocation tests should be
primed by prior administration of exogenous sex hormones if bone
age is >10 years (see Box 7.1).
Management
Often only reassurance is necessary. Treatment is sometimes indicated
in adolescent boys who have difficulty coping with their short stature or
delayed sexual maturation.
• For the younger child with concerns about growth: low-dose
oxandrolone (1.25mg/day for up to 12 months, oral). A synthetic
derivative of testosterone which has significant growth-promoting, but
minimal virilizing, actions and does not affect final height.
• For the older boy (>14 years) with concerns about
puberty: testosterone (50–100mg IM, monthly for 3–6 months).
• For the older girl (>13 years) with concerns about
puberty: ethinylestradiol (2 micrograms/day for 3–6 months).
See Box 7.1 for GH assessment.
CONSTITUTIONAL DELAY OF GROWTH AND PUBERTY 521
Box 7.1 GH assessment

GH is normally secreted overnight in regular pulses (pulse frequency
180min). Frequently sampled overnight GH profiles are costly and labo-
rious, and therefore standardized stimulation tests are more commonly
useful. Peak GH <10 micrograms/L indicates GH deficiency (values >5
and <10 micrograms/L indicate partial GH deficiency). However, there
can be large variation between different assay methods, and exact
cut-offs must be locally validated. In late prepuberty, there is a physi-
ological blunting of GH secretion, and when bone age is >10 years, sex
steroid priming (testosterone 100mg IM in boys or oral ethinylestradiol
20 micrograms daily for 3 days in either sex) is necessary before GH
testing.
A number of different agents may be used to stimulate GH secre-
tion (arginine, insulin, or glucagon; see Table 7.1). All tests should be
performed in the morning following an overnight fast, and serial blood
samples are collected over 90–180min.
An IGF-1 level should also be measured in the baseline sample, as an
additional marker of GH status.
IGF-I generation test
In those with high basal and stimulated GH levels, measurement of IGF-I
levels before and following administration of GH (30 micrograms/kg/day)
SC for 4 days allows an assessment of GH sensitivity/resistance. This test
is rarely necessary.
Primary GH deficiency
p GH deficiency is usually sporadic, but rarely it may be inherited as
autosomal dominant, recessive, or X-linked recessive and may be associ-
ated with other pituitary hormone deficiencies. It may represent a defect
in homeobox genes (e.g. Pit1 (leading to GH, TSH, and PRL deficiency),
Prop1 (leading to GH, TSH, PRL, gonadotrophin, and later ACTH deficien-
cies), or Hesx1) which control HP development. Mutation in Hesx1 has
been associated with midline defects, such as optic nerve hypoplasia and
corpus callosum defects (i.e. ‘septo-optic dysplasia’). GH deficiency usu-
ally arises because of failure of release of GHRH from the hypothalamus.
Clinical features
• Infancy. GH deficiency may present with hypoglycaemia. Coexisting
ACTH, TSH, and gonadotrophin deficiencies may cause prolonged
hyperbilirubinaemia and micropenis. Size may be normal, as fetal and
infancy growth is more dependent on nutrition and other growth
factors than on GH.
• Childhood. Typical features include slow growth velocity, short stature,
d muscle mass, and i SC fat. Underdevelopment of the mid-facial
bones, relative protrusion of the frontal bones because of mid-facial
hypoplasia, delayed dental eruption, and delayed closure of the
anterior fontanelle may be seen. These children have delayed bone age
and delayed puberty.
PRIMARY GH DEFICIENCY 523
Secondary GH deficiency
Brain tumours and cranial irradiation
Pituitary or hypothalamic tumours may impair GH secretion, and deficien-
cies of other pituitary hormones may coexist. Cranial irradiation, used to
treat intracranial tumours, facial tumours, and acute leukaemia, may also
cause GH deficiency. Risk of HP damage is related to total dose adminis-
tered, fractionation (single dose more toxic than divided), location of the
irradiated tissue, and age (younger children are more sensitive to radiation
damage).
GH secretion is most sensitive to radiation damage, followed by gon-
adotrophins, TSH, and ACTH. Central precocious puberty may also occur
and may mask GH deficiency by promoting growth but will compromise
final height if untreated. At-risk children should, therefore, be screened
regularly by careful examination and multiple pituitary hormone testing.
These survivors of childhood cancer may also have other endocrine
problems, including gonadal damage related to concomitant chemother-
apy or radiation scatter, hypothyroidism related to spinal radiation, or
glucose intolerance related to total body irradiation. It is recommended
that all such patients should undergo endocrine surveillance.
Psychosocial deprivation
Severe psychosocial deprivation may cause reversible disturbance of GH
secretion and growth failure. GH secretion improves within 3 weeks of
hospitalization or removal from the adverse environment, and catch-up
growth is often dramatic (see Fig. 7.3), although these children may con-
tinue to exhibit other features of emotional disturbance.
SECONDARY GH DEFICIENCY 525
190 97
90
180 BOYS Height 75
50 F
170 97 25
10
Longitudinal 50 3 M
160 standards
3
150
140
130
Height (cm)
120
110
100
90
80
70 human growth hormone
60
50
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Age (years)
Fig. 7.3 Height of child with psychosocial short stature. Note catch-up on
removal, marked by arrow, from parental home. Reproduced from Brook C (2001).
Brook’s Clinical Pediatric Endocrinology, Blackwell Publishing. With permission
from Wiley Blackwell.
Treatment of GH deficiency
(See Fig. 7.4.)
Recombinant human GH has been available since 1985 and is adminis-
tered by daily SC injection.
Dose
The replacement dose for childhood GH deficiency is 25–50 micrograms/
kg/day (70.7–1.4 micrograms/m2 per day). Catch-up growth is optimized if
GH is commenced early. A higher dose can be used in puberty, reflecting
the normal elevation in GH levels at Tanner stage 3–4.
Side effects
Local lipoatrophy and benign intracranial hypertension occur rarely.
Slipped upper femoral epiphyses are associated with GH deficiency, but
the incidence is similar before or after GH treatment. Other pituitary hor-
mone deficiencies may be unmasked by GH therapy, and thyroid function
should be checked within 4–6 weeks of commencing therapy.
Retesting in adulthood
Once final height is achieved, GH secretion should be retested, as a
significant percentage of subjects (25–80%) with GH deficiency in child-
hood subsequently have normal GH secretion in adulthood. In those with
confirmed GH deficiency, continuation of GH treatment (at a dose of
0.2–0.5mg/day) through the late adolescent years into early adulthood
(the transition phase) is recommended in order to complete somatic
development (increasing lean body mass and muscular strength, reducing
fat mass, improving bone density, and maintaining a healthy lipid profile).
GH treatment may need to be continued beyond this phase as adult GH
replacement.
The transition from paediatric to adult care is an important time, not
only to re-evaluate GH status but also to reassess other pituitary function
and management of any underlying disorder.
It is also recommended that assessment of bone mineral density, body
composition, fasting lipid profile, and QoL by questionnaire should be
undertaken at this time and repeated at 3–5-yearly intervals for those
restarting GH treatment.
TREATMENT OF GH DEFICIENCY 527
190 F
97
90
180 BOYS Height 75
50 M
170 97 25
Longitudinal 10
50 3
160 standards
3
150
140
130
Height (cm)
120
110
100
90
80 Penis
stage
70
Pubic hair
60 stage
Testes
50 vol.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Age (years)
Fig. 7.4 Height of one brother with isolated growth hormone deficiency treated
with human GH from age 6 years. Catch-up is partly by high velocity and partly
by prolonged growth and is incomplete. F and M, parents’ height centiles; vertical
thick line, range of expected heights for family. Reproduced from Brook C (2001).
GH resistance
GH resistance may arise because of p GH receptor defects or
post-receptor defects s to malnutrition, liver disease, type 1 diabetes,
or, very rarely, circulating GH antibodies. Laron syndrome is a rare auto-
somal recessive condition caused by a genetic defect of the GH receptor.
Affected individuals have extreme short stature, high levels of GH, low
levels of IGF-I, and impaired GH-induced IGF-I generation (b see Box 7.1,
p. 521). Treatment with recombinant IGF-I is available.
HYPOTHYROIDISM 529
Hypothyroidism
(See Fig. 7.5.)
• Congenital p hypothyroidism is detected by neonatal screening.
• Hypothyroidism presenting in childhood is usually autoimmune in
origin.
• Incidence is higher in girls and those with personal or family history of
other autoimmune disease.
• In childhood, hypothyroidism may present with growth failure alone,
and bone age is often disproportionately delayed. Very rarely, early
puberty may occur.
• Investigations show low T4 and T3, high TSH, +ve antithyroglobulin and
antithyroid peroxidase (microsomal) antibodies.
• Replacement therapy with oral levothyroxine (100 micrograms/m2 per
day, titrated with thyroid function) results in catch-up growth, unless
diagnosis is late.
190
180 GIRLS Height

97
170 97 90
75
Longitudinal 50 50
160 standards 25
3 10
3
150
140
130
Height (cm)
120
110
100
Thyroxine
90
80 Breast
stage
70
Pubic hair
60 stage
Menarche
50
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Age (years)
Fig. 7.5 Response of hypothyroid child treated with thyroxine. Solid circles,
height for age; open circles, height for bone age. Reproduced from Brook C (2001).
Coeliac disease
More common in children with other autoimmune disorders. Although the
classical childhood presentation is an irritable toddler with poor weight
gain, diarrhoea, abdominal pain, and distension, in later childhood, poor
growth with bone age delay may be the presenting feature. Measurement
of tissue transglutaminase and antiendomysial and antigliadin antibod-
ies are valuable screening tests, but diagnosis needs to be confirmed by
small bowel biopsy. Catch-up growth usually follows commencement of
a gluten-free diet.
Skeletal dysplasias
• This heterogeneous group of mostly dominantly inherited disorders
includes achondroplasia and hypochondroplasia.
• These children usually have severe disproportionate short stature and
a +ve or suspicious family history.
• Radiological assessment by skeletal survey often allows a specific
diagnosis to be made.
• High-dose GH therapy has been used in these disorders, with variable
success. Surgical leg lengthening procedures before and/or after
puberty are also an additional option.
SGA AND INTRAUTERINE GROWTH RESTRICTION 531
Small for gestational age (SGA) and

intrauterine growth restriction (IUGR)
• SGA is defined as birthweight and/or length at least 2 SDs below the
mean for gestational age. IUGR is defined as growth failure on serial
antenatal US scans and would usually lead to a baby being born SGA.
However, IUGR in late gestation may result in a baby who is within 2
SDs of the mean for birthweight or length.
• 90% of infants with SGA show catch-up growth by age 3 years. 8%
of subjects born SGA will remain small at 18 years of age. Catch-up
growth is more common in infants, with relative sparing of birth length
and head circumference (>10th centile).
• In severe IUGR, length and head circumference are also reduced.
Severe IUGR may be due to maternal factors, such as hypertension in
pregnancy, placental dysfunction, or a wide range of chromosomal or
genetic conditions in the fetus.
• Silver–Russell syndrome is characterized by severe IUGR, lateral
asymmetry, triangular facies, clinodactyly (curvation of fifth finger), and
extremely poor infancy feeding and post-natal weight gain.
• Children with severe IUGR who do not undergo catch-up growth
may have early-onset puberty, despite bone age delay, and therefore
achieve a very poor final height.
• Numerous epidemiological studies have shown a relationship between
low birthweight and an i risk of a number of disorders in later life,
including hypertension, ischaemic heart disease, cerebrovascular
disease, metabolic syndrome, and type 2 diabetes. The risk is i with
rapid post-natal weight gain. These associations relate to relatively low
birthweight and not exclusively to those born SGA. It is recommended
that those born SGA do not require any additional health surveillance
above that indicated by clinical circumstances.
Management
GH therapy is used in the SGA/IUGR child who has failed to show
catch-up growth by age 4 years. GH (at doses of 35–67 micrograms/kg/
day) can increase growth velocity and final height. The effect of GH on
later risk of insulin resistance as type 2 diabetes is not known.
Turner’s syndrome
(b also see Box 4.7, p. 337.)
Turner’s syndrome should always be considered in a girl who is short
for her parental target, and the classical dysmorphic features may be dif-
ficult to identify at younger ages. Karyotype usually confirms the diag-
nosis, although sufficient cells (>30) should be examined to exclude the
possibility of mosaicism.
Clinical features
There may be a history of lymphoedema in the newborn period. Typically,
growth velocity starts to decline from 3–5 years old (see Fig. 7.6), and
gonadal failure, combined with a degree of skeletal dysplasia, results in
loss of the pubertal growth spurt. Mean final height is consistently 20cm
below the normal average within each population (143–146cm in the UK).
GH secretion is normal, although IGF-I levels may be low. 10% progress
through puberty spontaneously, but only 1% develop ovulatory cycles.
Management
• High-dose GH therapy (45 micrograms/kg/day) increases final height,
although individual responses are variable. The height gained is related
to time on GH treatment, and thus GH therapy should be commenced
early; if the diagnosis has been made in early life, treatment is usually
started from 3–5 years of age.
• The anabolic steroid oxandrolone can be used, in addition to GH, to
promote growth from the age of 9 years. It has a positive effect on
final height at a dose of 0.05mg/kg/day, max 2.5mg/day.
• Oral oestrogen is commenced between 12–14 years to promote s
sexual development and pubertal growth. It should be started in low
dose (ethinylestradiol 2 micrograms/day) and gradually i with age.
Progesterone should be added if breakthrough bleeding occurs or when
oestrogen dose reaches 10 micrograms/day.
TURNER’S SYNDROME 533
180 Turner syndrome
170
160 +2SD
150 +1SD
x
140 −1SD
−2SD
Height (cm)
130
120
110
100 Height SDS
90
80
70
2 4 6 8 10 12 14 16 18 20
Age (years)
Fig. 7.6 Height SDS for chronological age extrapolated to final height.
Reproduced from Brook C, (2001). Brook’s Clinical Pediatric Endocrinology,
Blackwell publishing. With permission from Wiley Blackwell.
Tall stature and rapid growth

Definition
Although statistically as many children have heights >2 SDs above the
mean as have heights >2 SDs below the mean, referral for evaluation
of tall stature is much less common than for short stature. Socially, for
boys, heights up to 200cm are acceptable, whereas, for many girls, heights
>182cm may be unacceptable. However, tall stature, and particularly
accelerated growth rates in early childhood, can indicate an underlying
hormonal disorder, such as precocious puberty. For causes, see Box 7.2.
Assessment
History
• Is tall stature long-standing or does the history suggest recent growth
acceleration? Try to obtain previous measurements.
• Enquire about size at birth, infancy weight gain, intellectual
development, and neurological development.
• Enquire about headaches, visual disturbance, and evidence of puberty.
• Is there a family history of tall stature or early puberty?
Examination
• Assess height and height velocity over at least 4–6 months.
• Measure sitting height and arm span.
• Pubertal stage?
• Dysmorphic features?
• Measure parents’ heights, and calculate MPH (b see Assessment of
growth, p. 514).
Investigations
The following investigations may be clinically indicated:
• Wrist radiograph for bone age.
• Sex hormone levels (testosterone, oestrogen, androstenedione,
DHEAS), baseline and LHRH-stimulated LH and FSH levels.
• Karyotype.
• Serum IGF-I and IGFBP-3 levels.
• Oral glucose tolerance test—GH levels normally suppress to low or
undetectable levels (<0.5 microgram/L).
• Specific molecular tests for overgrowth syndromes.
Management of tall stature
After excluding abnormal pathology, often only reassurance and informa-
tion on predicted final height is necessary. In younger children, early induc-
tion of puberty, using low-dose sex steroids, advances the pubertal growth
spurt and promotes earlier epiphyseal fusion. In older children already in
puberty, high-dose oestrogen therapy in girls, or testosterone in boys, has
been used to induce rapid skeletal maturation. However, theoretical side
effects of high-dose oestrogen therapy include thromboembolic disease
and oncogenic risk.
TALL STATURE AND RAPID GROWTH 535
Box 7.2 Causes of tall stature in childhood

Normal variants
• Familial tall stature.
• Early maturation (largely familial but also promoted by early
childhood nutrition and obesity. Height is not excessive for bone age
which is advanced).
Hormonal
• b see Precocious puberty, p. 538.
• GH or GHRH excess (‘pituitary gigantism’), resulting from pituitary
adenoma or ectopic adenomas, is a very rare cause of tall stature
(b see p. 181).
• Other hormonal excess, e.g. hyperthyroidism, congenital
adrenal hyperplasia (associated with signs of virilization), familial
glucocorticoid deficiency.
• Rarely, oestrogen receptor or aromatase deficiencies delay puberty
and epiphyseal fusion, resulting in tall adult height.
Chromosomal abnormalities
• XXY (Klinefelter’s syndrome) (see b p. 370).
• XYY, XYYY (each ‘extra Y’ confers, on average, 13cm additional height).
Other rare syndromes
Overgrowth and dysmorphic features are seen in Marfan’s syndrome,
homocystinuria, Sotos syndrome (early excessive growth ± autism),
Beckwith–Wiedemann syndrome (overgrowth disorder and increased
risk of childhood cancer), and Weaver’s syndrome.
Further reading
Allen DB, Cuttler L, (2013). Clinical practice. Short stature in childhood - challenges and choices.
N Engl J Med 368, 1220–8.
Carel JC, Léger J (2008). Precocious puberty. N Engl J Med 358, 2366–77.
Clayton PE, Cianfarani S, Czernichow P, et aI. (2007). Management of the child born small for
gestational age child (SGA) through to adulthood: a consensus statement of the International
Societies of Paediatric Endocrinology and the Growth Hormone Research Society. J Clin
Endocrinology Metab Epub 2 January.
Clayton PE, Cuneo RC, Juul A, et al. (2005). Consensus statement on the management of the
GH-treated adolescent in the transition to adult care. Eur J Endocrinol 152, 165–70.
Conway GS (2009). Adult care of pediatric conditions: lessons from Turner’s syndrome. J Clin
Dattani M, Preece M (2004). Growth hormone deficiency and related disorders: insights into causa-
tion, diagnosis, and treatment. Lancet 363, 1977–87.
De Waal WJ, Greyn-Fokker MH, Stijnen T, et al. (1996). Accuracy of final height prediction and
effect of growth-reductive therapy in 362 constitutionally tall children. J Clin Endocrinol Metab
81, 1206–16.
Growth Hormone Research Society (2000). Consensus guidelines for the diagnosis and treatment
of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the
GH Research Society. GH Research Society. J Clin Endocrinol Metab 85, 3990–3.
Kelly WH, et al. (2012). Effect of inhaled glucocorticoids in childhood on adult height. N Engl J
Med 367, 904–12.
Saenger P, Wikland KA, Conway GS, et al. (2000). Recommendations for the diagnosis and manage-
ment of Turner’s syndrome. J Clin Endocrinol Metab 86, 3061–9.
Normal puberty
Puberty is the sequence of physical and physiological changes occurring at
adolescence, culminating in full sexual maturity.
Age at onset
Average age at onset of puberty is earlier in girls (711 years) than in boys
(712 years) but varies widely (792 years from the mean age of onset) and
is influenced by a number of factors:
• Historical. Age of menarche has d this century from 17 years in 1900
to 12.8 years today, presumably as a result of improved childhood
nutrition and growth.
• Genetic. Age at onset of puberty is partly familial.
• Ethnicity. Afro-Caribbean girls tend to have earlier puberty than
Caucasians.
• Weight gain. Earlier puberty is seen in girls who are overweight,
whereas girls who engage in strenuous activity and are thin often have
delayed puberty.
Hormonal changes prior to and during puberty
• Adrenal androgens (DHEAS and androstenedione) rise 2 years before
puberty starts (‘adrenarche’). This usually causes no physical changes
but occasionally results in early pubic hair and acne (‘premature
adrenarche’).
• Pulsatile secretion of LHRH from the hypothalamus at night is the first
step in the initiation of puberty and occurs well before physical signs
of puberty. This results in pulsatile secretion of LH and FSH from the
pituitary, and the gonadotrophin response to LHRH administration
reverses from the prepubertal FSH predominance to a higher response
in LH levels.
Physical changes
The first indication of puberty is breast development in girls and increase
in testicular size in boys. In each sex, puberty then progresses in an orderly
or ‘consonant’ manner through distinct stages (see Table 7.2). Puberty
rating by an experienced observer involves identification of pubertal
stage—particularly, breast development in girls and testicular volume (by
comparison with an orchidometer) in boys.
Pubertal growth spurt
i oestrogen levels in both boys and girls leads to i GH secretion. Peak
height velocity occurs at puberty stages 2–3 in girls and is later in boys at
stages 3–4 (testicular volume 10–12mL).
NORMAL PUBERTY 537
Table 7.2 The normal stages of puberty (‘Tanner stages’)

Boys
Stage Genitalia Pubic hair Other events
I Prepubertal Vellus not thicker TVa <4mL
than on abdomen
II Enlargement of Sparse, long TV 4–8mL
testes and scrotum pigmented strands at
Voice starts to change
base of penis
III Lengthening of Darker, curlier, and TV 8–10mL
penis spreads over pubes
Axillary hair
IV Increase in penis Adult-type hair but TV 10–15mL
length and breadth covering a smaller
Upper lip hair
area
Peak height velocity
V Adult shape and Spread to medial TV 15–25mL
size thighs (stage
Facial hair spreads
6: spread up linea
to cheeks
alba)
Adult voice
Girls
Stage Breast Pubic hair Other events
I Elevation of papilla Vellus not thicker
only than on abdomen
II Breast bud Sparse, long Peak height velocity
stage: elevation of pigmented strands
breast and papilla along labia
III Further elevation Darker, curlier, and
of breast and spreads over pubes
areola together
IV Areola forms a Adult type hair but Menarche
second mound on covering a smaller
top of breast area
V Mature Spread to medial
stage: areola thighs (stage
recedes and only 6: spread up linea
papilla projects alba)
a
TV, testicular volume: measured by size comparison with a Prader orchidometer. Adapted
with permission from Tanner JM (1962) Growth at adolescence, 2nd edn. Blackwell Scientific
Publications, Oxford.
Precocious puberty
Definition
• Early onset of puberty is defined as <8 years in girls and <9 years in boys.
• Gonadotrophin-dependent (‘central’ or ‘true’) precocious puberty
is characterized by early breast development in girls or testicular
enlargement in boys.
• Gonadotrophin-independent puberty occurs due to abnormal
peripheral sex hormone secretion, resulting in isolated development
of certain s sexual characteristics. This may involve autonomous
testosterone production in a boy or autonomous oestrogen
production in a girl. In addition, testosterone production from the
adrenal or an ovarian tumour can induce virilization in a girl.
Assessment of precocious puberty
History
• Age when s sexual development first noted.
• What features are present and in what order did they appear? For
example, virilization (pubic, axillary, or facial hair; acne; body odour),
genital or breast enlargement, galactorrhoea (very rare), menarche, or
cyclical mood changes?
• Is there evidence of recent growth acceleration?
• Family history of early puberty?
• Past history of adoption or early weight gain or prior CNS abnormality
or insult (e.g. radiation)?
Examination
• Breast or genital and testicular size; degree of virilization
(clitoromegaly in girls indicates abnormal androgen levels).
• Neurological examination, particularly visual field assessment and
fundoscopy.
• Abdominal or testicular masses.
• Skin (? café-au-lait patches—McCune–Albright (b see Chapter 9,
McCune–Albright syndrome, pp. 576–7) or NF-1578).
• Assess height and height velocity over 4–6 months.
Investigations
• Wrist radiograph for bone age.
• Thyroid function.
• Sex hormone levels (testosterone, oestrogen, androstenedione, DHEAS).
• LH and FSH levels (baseline and 30 and 60min post-IV LHRH).
• 17AOH progesterone levels (baseline and 30 and 60min post-IV
Synacthen®) if congenital adrenal hyperplasia suspected.
• Tumour markers (AFP, B-hCG).
• 24h urine steroid profile (see b p. 230).
• Abdominal US scan (adrenal glands, ovaries).
• MRI scan (cranial, adrenal glands).
• For those with hypogonadotrophic hypogonadism, mutation screening for
a monogenic cause (e.g. KA11, FGFRI, GnRHR, KISS1R) may be indicated
(see b p. 366).
PRECOCIOUS PUBERTY 539
Central precocious puberty

This is due to premature activation of pulsatile LHRH secretion from the
hypothalamus, and the normal progression in physical changes is main-
tained (‘consonance’). As precocious puberty is defined as occurring
younger than 2 SDs before the average age, in a normal distribution, 2.5%
of children will have early-onset puberty. In practice, in girls, central preco-
cious puberty is more likely to be idiopathic or familial, whereas boys have
a greater risk of intracranial or other pathology.
Causes
• Idiopathic or familial.
• Intracranial tumours, hydrocephalus, or other lesions.
• Post-cranial irradiation or trauma.
• Intracranial tumours (in particular, optic nerve glioma and
hypothalamic germinoma), hamartoma, hydrocephalus, and
non-specific brain injury (e.g. cerebral palsy).
• May also be triggered by long-standing elevation in sex hormones
resulting from any peripheral source or adrenal enzyme defect (e.g.
late-presenting simple virilizing CAH or inadequately treated CAH).
• Hypothyroidism (elevated TRH stimulates FSH release)—rare.
• Gonadotrophin-secreting tumours (e.g. pituitary adenoma or
hepatoblastoma) are rare.
Treatment
Aims of treatment are:
• To avoid psychosocial problems for the child or family.
• To prevent reduced final height due to premature bone maturation
and early epiphyseal fusion. A final height prediction is often necessary
when considering the need for inhibition of puberty. Significant sparing
of adult height is only likely to be achieved if presentation occurs and
treatment is started ≤6 years of age.
Pituitary LH and FSH secretion can be inhibited by the use of LHRH ana-
logues, e.g. goserelin 3.6mg SC monthly or 10.8mg SC 3-monthly, or trip-
torelin 3.75mg SC or deep IM (lower doses if weight <30kg) every 2 weeks
for the first three injections, then 3–4-weekly thereafter. Treatment effi-
cacy should be monitored regularly by clinical observation and ensuring
that LH and FSH levels post-IV LHRH remain at low prepubertal levels.
The dosing intervals may need to be reduced if there is evidence of inad-
equate suppression of pubertal development.
Gonadotrophin-independent precocious puberty
At least two genetic syndromes have been identified, both resulting in
abnormal activation of gonadotrophin receptors, independent of normal
ligand binding. Thus, in these conditions, the gonads autonomously secrete
sex hormones, and levels of LH and FSH are suppressed by feedback
inhibition.
McCune–Albright syndrome
(b also see McCune–Albright syndrome, pp. 576–7). This is a sporadic
condition due to a somatic activating mutation of the GSA protein subu-
nit which affects bones (polyostotic fibrous dysplasia), skin (café-au-lait
spots), and potentially multiple endocrinopathies.
A number of different hormone receptors share the same G
protein-coupled cyclic AMP second messenger system, and hyperthyroid-
ism or hyperparathyroidism may also be present.
All cells descended from the mutated embryonic cell line are affected
while cells descended from non-mutated cells develop into normal tissues.
Thus, the phenotype is highly variable in physical distribution and severity.
Testoxicosis
This is a rare familial condition, resulting in precocious puberty only in
boys due to an activating LH receptor mutation. Testes show only little
increase in size, and, on biopsy, Leydig cell hyperplasia is characteristic.
Treatment is by use of androgen receptor-blocking agents (cyproterone
acetate) and aromatase inhibitors.
Peripheral sex hormone secretion
• Excessive peripheral androgen secretion may occur due to CAH, or
androgen-secreting adrenal or gonadal tumours. These children usually
have rapid growth, advanced bone age, and moderate-to-severe
virilization in the absence of testicular or breast development.
(NB A testicular tumour may cause asymmetrical enlargement.)
• Peripheral oestrogen production from ovarian tumours is a rare cause
of precocious breast development in girls.
Premature thelarche
Premature breast development, in the absence of other signs of puberty,
may present at any age from infancy. Breast size may fluctuate and is often
asymmetrical. The cause is unknown, although typically FSH levels (but
not LH) are elevated, and ovarian US may reveal a single large cyst. Bone
maturation, growth rate, and final height are unaffected.
‘Thelarche variant’
This is an intermediate condition between premature thelarche and central
precocious puberty. The aetiology is unknown. These girls demonstrate i
height velocity and rate of bone maturation, and ovarian US reveals a
more multicystic appearance, as seen in true puberty. There is probably a
whole spectrum of presentations between premature thelarche and true
precocious puberty. Decision to treat should take into account height
velocity and final height prediction as well as the rate of physical matura-
tion and the severity of accompanying pubertal features (e.g. mood swings
and difficult behaviour).
PRECOCIOUS PUBERTY 541
‘Premature adrenarche’ and ‘pubarche’

The normal onset of adrenal androgen secretion (‘adrenarche’) occurs
1–2 years before the onset of puberty. ‘Premature’ or ‘exaggerated’
adrenarche is thought to be due to i androgen production or sensitiv-
ity and presents with mild features of virilization, such as onset of pubic
hair (‘pubarche’) or acne, in the absence of other features of puberty. NB
Clitoromegaly in girls suggests a more severe pathology with excessive
androgen production (e.g. CAH or androgen-secreting tumour).
The diagnosis is made in the presence of pubic hair and/or axillary hair;
the absence of breast/testicular development in children aged <8 years. It
is more common in girls.
Management
The management of premature adrenarche usually only requires reassur-
ance after exclusion of other causes, as there is no significant impact on
final height and onset/progression of puberty. Some of these girls may
subsequently develop features of polycystic ovary disease. In these cases,
treatment should be directed at the presenting feature (e.g. hirsutism,
menstrual irregularities).
Delayed/absent puberty
Definition
Delayed puberty is defined as failure to progress into puberty by >2
SDs later than the average, i.e. >13 years in girls and >14 years in boys.
Clinically, boys are more likely to present with delayed puberty than girls.
In addition, some children present with delay in progression from one
pubertal stage to the next for >2 years.
Psychological distress may be exacerbated by declining growth velocity
relative to their peers. In the long term, severe delay may be a risk factor
for d bone mineral density and osteoporosis.
Causes
General
• Constitutional delay of growth and puberty (this is the most common
cause; b see Constitutional delay of growth and puberty, p. 520).
• Chronic childhood disease, malabsorption (e.g. coeliac disease,
inflammatory bowel disease), or undernutrition.
Hypergonadotrophic hypogonadism
Gonadal failure may be:
• Congenital (e.g. Turner’s syndrome in girls (b p. 336), Klinefelter’s
syndrome in boys (b p. 370)).
• Acquired (e.g. following chemotherapy, local radiotherapy, infection,
torsion).
In these conditions, basal and stimulated gonadotrophin levels are raised.
Gonadotrophin deficiency
• Kallman’s syndrome (b p. 362) (including anosmia).
• HP lesions (tumours, post-radiotherapy, dysplasia).
• Rare inactivating mutations of genes encoding LH, FSH (or their
receptors).
These conditions may also present in the newborn period with micropenis
and undescended testes in boys.
Investigation
• LH and FSH levels (basal and post-IV LHRH stimulation).
• Plasma oestrogen or testosterone levels.
• Measurement of androgen levels before and after hCG therapy may be
used to indicate presence of functional testicular tissue in boys.
• Karyotype.
• Pelvic US in girls to determine ovarian morphology.
• US or MRI imaging in boys to detect intra-abdominal testes.
• For those with hypogonadotropic hypogonadism, mutation screening for
a monogenic cause (e.g. KALI, FGFRI, GnRHR, KISSIR) may be indicated.
It may be difficult to distinguish between constitutional delay and gonadotro-
phin deficiency, as gonadotrophin levels are low in both conditions. In these
cases, induction of puberty may be indicated, with regular assessment of testi-
cular growth in boys (which is independent of testosterone therapy), followed
by withdrawal of treatment and reassessment when final height is reached.
DELAYED/ABSENT PUBERTY 543
Management
Depending on the age and concern of the child and parents, short-course
exogenous sex steroids can be used to induce pubertal changes. If gonado-
trophin deficiency is permanent or the gonads are dysfunctional or absent,
then exogenous sex steroids are required to induce and maintain pubertal
development (b see Constitutional delay of growth and puberty, p. 520).
Long-term treatment
(See Table 7.3.)
Table 7.3 Suggested schema for pubertal induction and maintenance

in boys and girls
Testosterone Testosterone Duration Ethinylestradiol Duration
dose interval dose (daily)
50mg 4 weeks 6 months 2 micrograms 6 months
100mg 4 weeks 6 months 5 micrograms 6 months
125mg 4 weeks 6 months 10 micrograms (+ a 6 months
progesterone when bleed)
250mg 3–4 weeks Onwards 20 micrograms ‘pill’ Onwards
Treatment could be started at age 12–13 years in boys and 11–12 years in girls. Duration for
each stage of treatment is determined by individual responses.
Boys
Testosterone (by IM injection) 50mg 4–6-weekly, gradually i to 250mg
4-weekly.
• Monitor penis enlargement, pubic hair, height velocity, and adult body
habitus.
• Side effects include severe acne and, rarely, priapism.
Girls
Oestrogen (oral). Start at low dose (ethinylestradiol 2 micrograms daily),
and gradually increase.
• Promotes breast development and adult body habitus.
• Progesterone (oral) should be added if breakthrough bleeding occurs or
when oestrogen dose reaches 10 micrograms/day.
Further reading
Hindmarsh PC (2009). How do you initiate oestrogen therapy in a girl who has not undergone
puberty? Clin Endocrinol (Oxf) 71, 7–10.
Miller JF (2012). Approach to the child with Prader-Willi syndrome. J Clin Endocrinol Metab 97,
3837–44.
Palmert MR, Dunkel L (2012). Clinical practice. Delayed puberty. N Engl J Med 366, 443–53.
Normal sexual differentiation

Gonadal development
• In the ♂ or ♀ embryo, the bipotential gonad develops as a thickening
of mesenchymal cells and coelomic epithelium around the primitive
kidney. This genital ridge is then colonized by primordial germ cells
which migrate from the yolk sac to form the gonadal ridge. In the
absence of a Y chromosome, the gonad will develop into an ovary.
• In the presence of a normal Y chromosome, immature Sertoli cells,
germs cells, and seminiferous tubules can be recognized by 7 weeks,
and testis differentiation is complete by 9 weeks. The SRY gene is an
essential ‘sex-determining region’ on the Y chromosome which signals
for testis differentiation.
Internal genitalia
• Embryonic Müllerian structures form the uterus, Fallopian tubes, and
upper third of the vagina.
• In ♂, anti-Müllerian hormone is secreted by immature Sertoli cells
in the testis by 6 weeks, and this causes regression of the Müllerian
structures. Leydig cells appear in the testis at around day 60 and
produce testosterone under placental hCG stimulation. Testosterone
promotes growth and differentiation of the Wolffian ducts to form the
epididymis, vas deferens, and seminal vesicles.
External genitalia
• In the absence of any androgen secretion, labia majora, labia minora,
and clitoris develop from the embryonic genital swelling, genital fold,
and genital tubercle, respectively.
• Development of normal ♂ external genitalia requires testosterone
production from the testis and its conversion to dihydrotestosterone by
the enzyme 5A-reductase. In the presence of dihydrotestosterone, the
genital tubercle elongates to form the corpora cavernosa and glans
penis; the urethral fold forms the penile shaft, and the labioscrotal
swelling forms the scrotum. This process commences around 9 weeks
and is completed by 13 weeks. Testicular descent in ♂ occurs
in the later two-thirds of gestation under control of fetal LH and
testosterone.
ASSESSMENT OF AMBIGUOUS GENITALIA 545
Assessment of ambiguous genitalia

Most cases of ambiguous genitalia present at birth. Involvement of an
experienced paediatric endocrinologist and surgeon should be sought as
early as possible.
History
• Any maternal medication during pregnancy?
• Are parents consanguineous or is there a family history of ambiguous
genitalia?
• Is there a neonatal history of hypoglycaemia or prolonged jaundice?
Examination
• Assess clitoris/phallus size; degree of labial fusion; position of urethra/
urogenital sinus (anterior or posterior).
• Are gonads palpable? Check along line of descent.
• Are there any signs indicating panhypopituitarism? For example,
midline defects/hypoglycaemia/hypocortisolaemia/prolonged jaundice.
• Dysmorphic features of Turner’s syndrome may be seen in XO/XY
mosaicism.
Investigations
• Bloods for karyotype, electrolytes, blood glucose, 17AOH
progesterone.
• US of pelvis and labial folds (for Müllerian structures and gonads).
• Arrange for clinical photographs.
• After 48h old, when the neonatal hormonal surge has decreased,
repeat bloods for 17AOH progesterone, cortisol, LH, FSH, and
androgen levels. Collect a 2h urine sample to measure the steroid
profile.
• Examination under anaesthesia (EUA) and cystogram may be required.
Specific tests
• Short Synacthen® test in a virilized XX (when CAH is suspected) may
be required.
• 3-day hCG test in an undervirilized ‘♂’ (testes present or 46,XY)
assesses stimulated gonadal production of androgens and may be
diagnostic of androgen biosynthesis defects or androgen insensitivity.
• LHRH test examines pituitary gonadotrophin secretion (this test is
only informative in the neonatal period).
• Glucagon test examines cortisol and GH secretion.
• Androgen receptor function can be tested on cultured fibroblasts from
a genital skin biopsy.
• DNA analysis for androgen receptor mutation, CAH mutations, and
androgen biosynthesis mutations.
Disorders of sex development (DSD)

♂ and ♀ internal and external genitalia develop from common embryonic
structures. In the absence of ♂ differentiating signals, normal ♀ genitalia
develop. Genital ambiguity may, therefore, occur as a result of chromo-
somal abnormality, gonadal dysgenesis, biochemical defects of androgen
synthesis, inappropriate exposure to external androgens, or androgen
receptor insensitivity. See Box 7.3 for definitions.
46XX DSD
Disorders of ovarian development
Normal ♂ differentiation can occur if the SRY gene has been translocated
onto an autosome.
Biochemical defects leading to androgen oversecretion
Congenital adrenal hyperplasia (CAH, 21-hydroxylase deficiency most
commonly) is the most common cause of ambiguous genitalia in 46,XX.
Maternal hyperandrogenism
• The ♀ fetus may be virilized if maternal androgen levels exceed the
capacity of placental aromatase to convert these to oestrogen.
• This may occur due to maternal disease (e.g. CAH, adrenal and ovarian
tumours) or use of androgenic medication in pregnancy or, rarely,
placental aromatase deficiency.
46XY DSD
Disorders of testis development
• XY gonadal dysgenesis can be caused by mutations in a number of
genes controlling ♂ sexual differentiation, including SRY, SF-1, WT-1
and SOX, and can present with normal external genitalia.
• Early testicular failure resulting from torsion or infarction.
Biochemical defects of androgen synthesis
Rare deficiencies of the enzymes 5A-reductase, 17B-hydroxysteroid dehy-
drogenase, or 3B-hydroxysteroid dehydrogenase, which is also associated
with glucocorticoid and mineralocorticoid deficiencies, are autosomal
recessively inherited and may result in variable degrees of undervirilization.
Androgen receptor insensitivity syndrome
(b also see Androgen insensitivity syndrome, p. 416).
Defects of the androgen receptor gene on the X chromosome or auto-
somal post-receptor signalling genes may result in complete or partial
androgen insensitivity.
• Complete androgen insensitivity. Results in normal ♀ external genitalia
and usually only presents with testicular prolapse in childhood or
primary amenorrhoea in adolescence.
• Partial androgen insensitivity. Presentation may vary from mild
virilization to micropenis, hypospadias, undescended testes, or only
d spermatogenesis.
DISORDERS OF SEX DEVELOPMENT (DSD) 547
Box 7.3 Definitions

Disorders of chromosomes
Including:
• 45X Turner’s and variants.
• 47XXY and variants.
• 45X/46XY mixed gonadal dysgenesis.
• 46XX/46XY gonadal chimera.
46XX DSD
Including:
• Disorders of gonadal (ovarian) development.
• Androgen excess.
• Structural disorders, e.g. cloacal exstrophy, vaginal atresia.
46XY DSD
Including:
• Disorders of gonadal (testicular) development.
• Disorders in androgen synthesis and action.
• Structural disorders, e.g. severe hypospadias, cloacal exstrophy.
Gonadotrophin defects
• Gonadotrophin deficiency may occur in hypopituitarism or may be
associated with anosmia (Kallmann’s syndrome). It usually presents
with delayed puberty but is an occasional cause of micropenis and
undescended testes.
• LH receptor gene defects are rare and result in complete absence of
virilization, as the testes are unable to respond to placental hCG.
Anti-Müllerian hormone deficiency or insensitivity
Testes are usually undescended, and uterus and Fallopian tubes present.
Management of ambiguous genitalia
In the newborn period, the infant should be monitored in hospital for:
• Hypoglycaemia (until hypopituitarism is excluded).
• Salt wasting (until CAH is excluded).
Explain to the parents that the infant appears to be healthy but has a
defect that interferes with determining sex. It is helpful to show the par-
ents the physical findings as you explain this. Advise them to postpone
the registration of the birth until after further investigations, and discuss
what they will say to relatives and friends. The sex of the baby should be
assigned as soon after birth as is practicable, given the need for accurate
diagnosis.
Sex assignment
Decision on the sex of rearing should be based on the optimal expected
outcome in terms of psychosexual and reproductive function. Parents
should, therefore, be encouraged discussion with an endocrinologist,
a surgeon specializing in urogenital reconstruction, a psychologist, and a
social worker. Following the necessary investigations and discussions, early
gender assignment optimizes the psychosexual outcome.
Further management
• If ♀ sex is assigned, any testicular tissue should be removed.
• Reconstructive surgery may include clitoral reduction, gonadectomy,
and vaginoplasty in girls, and phallus enlargement, hypospadias repair,
and orchidopexy in boys. In both sexes, multiple-stage procedures may
be required.
• Topical or systemic dihydrotestosterone may enhance phallus size
in ♂ infants, and a trial of therapy is sometimes useful before sex
assignment.
• Hormone replacement therapy may also be required from puberty
into adulthood.
• Continuing psychological support for the parents and children is very
important.
DISORDERS OF SEX DEVELOPMENT (DSD) 549

(b also see Chapter 4, Congenital adrenal hyperplasia (CAH) in adults,
p. 320.)
A number of autosomally inherited enzyme deficiencies result in
cortisol deficiency, excess pituitary ACTH secretion, and adrenal gland
hyperplasia.
21-hydroxylase deficiency (>90%)
The most common cause of CAH results in cortisol and mineralocor-
ticoid deficiency while the build-up of precursor steroids is channelled
towards excess adrenal androgen synthesis. Different gene defects in the
21-hydroxylase gene (e.g. deletion, splice site or point mutation) result
in different degrees of enzyme dysfunction and thus wide variation in
phenotypes.
Clinical features
• Virilization of ♀ fetuses may result in clitoromegaly and labial fusion
at birth. 75% have sufficient mineralocorticoid deficiency to cause
renal salt wasting. Because ♂ have normal genitalia at birth, they may
present acutely ill in the neonatal period with vomiting, dehydration,
collapse, hyponatraemia, and hyperkalaemia. Non-salt-wasting boys
present with early genital enlargement, pubarche, and rapid growth.
• If untreated or poorly treated, both sexes may develop pubic hair,
acne, rapid height velocity, advanced bone maturation, and precocious
puberty which may result in very short final height.
• ‘Non-classical CAH’ is due to milder 21-hydroxylase deficiency, and
affected girls present in later childhood or adulthood with hirsutism,
acne, premature/exaggerated adrenarche, menstrual irregularities, and
infertility.
11B-hydroxylase deficiency (75%)
This enzyme, which converts 11-deoxycortisol to cortisol, is the final step
in cortisol synthesis. In addition to excess adrenal androgens, the overpro-
duced precursor corticosterone has mineralocorticoid activity. Thus, in
contrast to salt wasting in 21-hydroxylase deficiency, these subjects may
have hypernatraemia and hypokalaemia. Hypertension is rarely seen in
infancy but may develop during childhood and affects 50–60% of adults.
Specific investigations for CAH
(b see also Assessment of ambiguous genitalia, p. 545.)
• Plasma 17AOH progesterone. An elevated level indicates
21-hydroxylase deficiency. It may be difficult to distinguish this from
the physiological hormonal surge which occurs in the first 2 days
of life. This test should, therefore, be repeated (together with
11-deoxycortisol) after 48h of age.
• A 24h urine steroid profile (also collected after 48h of age) should
confirm the diagnosis and allows detection of the rarer enzyme defects.
• A Synacthen® stimulation test may be required to discriminate
between the different enzyme deficiencies.
CONGENITAL ADRENAL HYPERPLASIA 551
• Plasma and urine electrolytes may need to be monitored over the first
2 weeks.
• Plasma renin level is also useful to confirm salt wasting in those with
normal serum sodium and relatively mild 21-hydroxylase deficiency.
Other rare enzyme deficiencies
• 17A-hydroxylase deficiency. Impairs cortisol, androgen, and oestrogen
synthesis, but overproduction of mineralocorticoids leads to
hypokalaemia and hypertension.
• 3B-hydroxysteroid dehydrogenase deficiency. Impairs cortisol,
mineralocorticoid, and androgen biosynthesis. ♂ have hypospadias
and undescended testes; however, excess DHEA, a weak androgen,
may cause mild virilization in ♀.
Steroid acute regulatory protein
• STAR mutation: 46XY sex reversal and severe adrenal failure.
Heterozygous defect. Extremely rare.
• CYPIIAI (P450: side chain cleavage cytochrome enzyme): 46XY sex
reversal and severe adrenal failure. Heterozygous defect. Extremely rare.
• P450 oxidoreductase deficiency: biochemical picture of combined
21-hydroxylase/17A-hydroxylase/17,20 lyase deficiencies. Spectrum of
presentation from children with ambiguous genitalia, adrenal failure,
and the Antley–Bixler skeletal dysplasia syndrome through to mildly
affected individuals with polycystic ovary syndrome.
Management
• Hydrocortisone (15mg/m2 per day orally in three divided doses).
In addition to treating cortisol deficiency, this therapy suppresses
ACTH and thereby limits excessive production of adrenal androgens.
Occasionally, higher doses are required to achieve adequate androgen
suppression; however, overtreatment may suppress growth.
• In salt losers, initial IV fluid resuscitation (10–20mL/kg normal
saline) may be required to treat circulatory collapse. Long-term
mineralocorticoid replacement (fludrocortisone 0.05–0.3mg/day) may
have incomplete efficacy, particularly in infancy, and sodium chloride
supplements are also needed. Up to 10mmol/kg per day may be
needed in infancy.
• Reconstructive surgery (clitoral reduction, vaginoplasty). Often
performed in infancy, and further procedures may be required during
puberty. Needs experienced surgeon.
• Patients and families need to be aware of the need for extra
hydrocortisone during intercurrent illness or significant stress.
Instructions on what to do for mild, moderate, and severe illnesses
(‘Sick Day Rules’) and for operative procedures should be made
available (see b Addison disease treatment, p. 266). Patients and
families should have parenteral hydrocortisone available to give in
emergency situations.
Monitoring of hormonal therapy

• Height velocity and bone age. If hydrocortisone therapy is insufficient,
growth rate will be above normal and bone age will be advanced.
Conversely, if hydrocortisone therapy is excessive, growth is
suppressed.
• 17AOHP. Blood levels should be assessed several times each year.
Levels should be measured before and after each hydrocortisone
dose; these may be collected at home by the parents, using ‘spot’
capillary blood samples. In girls and prepubertal boys, androgen levels
(testosterone and androstenedione) can be measured if there is
concern about poor control and/or virilization.
• Mineralocorticoid and sodium replacement. Should be monitored by
measuring plasma electrolytes and renin levels, and by regular blood
pressure assessments.
Genetic advice
• The inheritance of CAH is autosomal recessive, and parents should be
informed of a 25% risk of recurrence in future offspring.
• If the mutation is identifiable on DNA analysis in the child and parents,
chorionic villus sampling may allow prenatal diagnosis.
• Maternal dexamethasone therapy from around 5–6 weeks of pregnancy
is used to prevent virilization of the ♀ fetus without significant
maternal complications (see b p. 446).
Further reading
Brook CGD (ed.) (1995). Clinical Paediatric Endocrinology, 3rd edn. Blackwell Science, Oxford.
Consensus Statement on 21 hydroxylase deficiency. Joint LWPES/ESPE Working Group (2002).
Fluck CE, Miller WL (2006). P450 oxidoreductase deficiency: a new form of congenital adrenal
hyperplasia. Curr Opin Paediatric 18, 435–41.
Hochberg Z (ed.) (1998). Practical Algorithms in Pediatric Endocrinology. Karger, Basel.
Hughes IA (1989). Handbook of Endocrine Investigations in Children. John Wright & Sons, Bristol.
Hughes IA, Houk C, Ahmed SF, et al. (2006). Consensus statement on management of intersex
disorders. Arch Dis Child 91, 554–63.
Wilkins L (1994). In Kappy MS, Blizzard RM, Migeon CJ (eds.) The diagnosis and treatment of endo-
crine disorders in childhood and adolescence, 4th edn. Charles C Thomas, Springfield, Illinois.
Chapter 8 553
Neuroendocrine disorders
The neuroendocrine system 554

Classification of neuroendocrine neoplasias (NENs) 556
Diagnostic investigations of NENs 557
Treatment of NENs 558
Insulinomas 562
Tumour localization 563
Treatment of insulinomas 564
Prognosis of insulinomas 564
Gastrinomas 565
Diagnosis of Zollinger–Ellison syndrome 566
Treatment of gastrinomas 567
Prognosis of gastrinomas 567
Glucagonomas 568
VIPomas 570
Somatostatinomas 572
554 CHAPTER 8 Neuroendocrine disorders
The neuroendocrine system

Introduction
• Neuroendocrine cells are found in many sites throughout the body.
They are particularly prominent in the GI tract and pancreas and
share a common embryological origin. These cells have the ability to
synthesize, store, and release peptide hormones.
• Due to the prevalence of neuroendocrine cells, the majority of
neuroendocrine tumours occur within the gastroenteropancreatic axis.
Of these tumours, >50% are traditionally termed carcinoid tumours
and have been usually subclassified into foregut, midgut, and hindgut
lesions, with the remainder largely comprising pancreatic islet cell
tumours.
• Carcinoid and islet cell tumours are generally slow-growing.
Further reading
Barakat MT, Meeran K, Bloom SR (2004). Neuroendocrine tumours. Endocr Relat Cancer 11, 1–18.
THE NEUROENDOCRINE SYSTEM 555
Classification of neuroendocrine
neoplasias (NENs)
• There is a move towards standardizing the terminology of
these tumours; the European Neuroendocrine Society (ENETS)
recommends the use of the umbrella term neuroendocrine neoplasia
(NEN). The term NEN includes low- and intermediate-grade neoplasia
(previously referred to as carcinoid or atypical carcinoid) which are
now referred to as neuroendocrine tumours (NETs) and high-grade
neoplasia (neuroendocrine carcinoma, NEC). There is a confusing
array of classifications of NENs, based on anatomical origin, histology,
and secretory activity.
• Many of these classifications are well established and widely used.
• The WHO classifications of lung and thymic NETs and
gastroenteropancreatic (GEP) NETs are shown in Table 8.1.
• The name carcinoid continues to be used in the WHO classification of
lung and thymic NETs. See Table 8.1.
• It is important to understand the differences between ‘differentiation’,
which is the extent to which the neoplastic cells resemble their
non-tumourous counterparts, and ‘grade’, which is the inherent
aggressiveness of the tumour.
• The grades (low, intermediate, or high grade) in lung and thymic
NETs are based on mitoses and necrosis. In GEP NETs, in addition
to mitoses, the Ki67 index (a marker of proliferation) determines
the grade.
• Neuroendocrine carcinomas are the most aggressive NENs and can
either be small or large cell type.
Clinical features of NENs
NENs are diagnosed based on histological features of biopsy specimens.
The presenting features of the tumours vary like any other tumour, based
on their anatomical location, such as abdominal pain, intestinal obstruc-
tion. Many are incidentally discovered during endoscopy or imaging for
unrelated conditions. In a database study, 49% of NENs were localized,
24% had regional metastases, and 27% had distant metastases. The NENs
most associated with metastases are pancreatic, followed by caecal,
colonic, and small intestine in reducing frequency. These tumours rarely
manifest themselves due to their secretory effects.
Table 8.1 WHO classification of neuroendocrine tumours

Grade WHO lung and thymic NETs WHO GEP NETs
Low grade Carcinoid NET G1
Intermediate grade Atypical carcinoid NET G2
High grade (neuroendocrine Small/large cell carcinoma NET G3
carcinoma)
DIAGNOSTIC INVESTIGATIONS OF NEN S 557
Diagnostic investigations of NENs

Pathology
• Macroscopically, the exact anatomical site, distance from margins, and
the size of the tumour need to be described.
• Histological characterization comprises of structure and presence of
necrosis.
• Immunohistochemistry needs to be performed, including
neuroendocrine markers chromogranin A and synaptophysin.
• Mitotic counts and the Ki67 index are used to grade tumours. The
standards for these depend on the anatomical location of the primary
tumour.
Biochemical investigations
• Only a third of patients with neuroendocrine tumours develop
symptoms due to hormone secretion.
• Relatively common neuroendocrine syndromes are hyperinsulinaemic
hypoglycaemia associated with insulinomas, Zollinger–Ellison
syndrome associated with gastrinomas, and the carcinoid syndrome
which is characterized by flushing, diarrhoea, hypo- or hypertension,
arrhythmias, and wheezing.
• 5HIAA (a serotonin metabolite) has been the traditional mainstay in
screening for, and in the follow-up of, HIAA-secreting NENs.
• 5HIAA levels are only elevated in GEP NETs after metastasis to the
liver, with the exceptions of ovarian and lung NENs or retroperitoneal
metastases.
• Elevated 5HIAA levels have 75% sensitivity and near 100% specificity,
as long as false +ves due to dietary sources of serotonin, such as
bananas, avocados, pineapples, and chocolate, are excluded.
• 5HIAA levels correlate well with the carcinoid syndrome and are a
useful guide to monitoring treatment.
• Serum chromogranin A is a useful diagnostic indicator and also a
marker of disease progression and response to treatment.
• False +ves—renal failure, liver failure, PPI, atrophic gastritis,
inflammatory bowel disease.
• False –ves—levodopa, phenothiazines.
Imaging
• The current approach to visualizing primary tumours and secondaries
involves the use of high resolution CT and MRI.
• The RECIST criteria are used to assess tumour burden, disease
progression, and response to treatment.
• The involvement of the GI wall is best visualized by endoscopic
ultrasonography and endomicroscopy.
• Somatostatin receptor scintigraphy involves the use of the radiotracers
111
In, 68Ga, and 99Tc and can help identify somatostatin-avid lesions.
• PET CT or PET MRI may replace somatostatin receptor scintigraphy in
the future.
• The availability of these techniques varies considerably across different
centres.
Treatment of NENs
A multidisciplinary approach to the treatment of NENs is essential.
Surgical treatment
• Surgery is the treatment of choice for NENs grades 1 and 2, except
in the presence of widespread distant metastases and extensive local
invasion.
• Preoperative octreotide may prevent carcinoid crisis.
• In patients with widespread local disease or distant metastases, surgery
could still be beneficial by reducing tumour bulk. When debulking
liver metastases, intraoperative ablation may be used as adjunctive
treatment. This is helpful in symptom control.
• Surgery may be required to alleviate intestinal obstruction.
• There are surgical standards (ENETS) for the treatment of GEP NENs.
• There are limited data to set standards for the surgical management of
bronchial and extra-gastrointestinal tumours.
Ablative therapies
• For NENs with liver metastases, radiofrequency ablation or
transarterial chemoembolization are used.
Medical management
• The endpoints of clinical trials are either progression-free survival or
time to progression due to their slow growth. This is a fundamental
difference compared with adenocarcinomas.
• For neuroendocrine carcinomas, chemotherapeutic options are similar
to those for small cell lung cancer.
• Medical management for symptom control and disease progression is
applicable when potentially curative surgery and ablative procedures
are not possible.
See Box 8.1 for non-functioning pancreatic NENs.
Medical therapies that are available are:
• Somatostatin analogues (SSA) have relatively minor side effects and
provide long-term symptom control.
• Octreotide and lanreotide and their longer-acting analogues reduce
the level of biochemical tumour markers in the majority of patients
and control symptoms in around 70% of cases.
• SSAs may be beneficial in functioning and non-functioning metastatic
small intestinal G1 NET for tumour stabilization. They are not
recommended for use in metastatic G3 NEC.
• Radiolabelled somatostatin analogues with yttrium-90 alleviate
symptoms of metastatic tumours and may improve quality of life.
• Pasireotide, a newer somatostatin analogue which has a high binding
affinity to four out of the five human somatostatin receptor subtypes,
has a longer half-life. This drug is being investigated for use in NENs in
conjunction with newer molecular targeted therapies.
TREATMENT OF NENS 559
Box 8.1 Non-functioning pancreatic NENs

These are defined by the absence of a hormone secretion syndrome.
They may present as incidental small tumours or large neoplasia, with
symptoms related to tumour burden. At presentation, 30–70% have liver
metastases, and this is associated with poorer prognosis. Treatment
includes curative surgery for localized tumours ≥2cm or those that show
evidence of growth on follow-up under this size. Palliative surgery may
be offered to patients with inoperable primaries. In advanced disease,
the treatment options include chemotherapy, PRRT (see b p. 560),
molecular targeted therapy.
Interferon α
• There is reasonable biochemical response (about 45%), with
improvement in symptoms.
• A combination of interferon with octreotide has been shown to
produce biochemical and symptomatic improvement in patients who
have previously had no significant benefit from either drug alone.
Chemotherapy
Cytotoxic chemotherapy may be considered in patients with progressive,
advanced, or uncontrolled symptomatic disease. It is recommended in
metastatic pancreatic NET, foregut metastatic G2 NET, and NEC G3 of
any primary. It is not recommended in well-differentiated midgut NET.
• Streptozotocin-based combinations, such as with fluorouracil, have
been historically in use. Three-drug regimens, including cisplatin or
doxorubicin, show superior response rates compared to the two-drug
regimen.
• Capecitabine (prodrug of 5FU) is administered orally and may offer
more antitumour effect.
• Like streptozotocin, dacarbazine is an alkylating agent and has shown
to be of benefit in the treatment of pancreatic NETs.
• Temozolomide, another alkylating agent and an orally administered
analogue of dacarbazine, is associated with less toxicity. However, data
are limited.
Molecular therapies
These therapies target signalling pathways, such as tyrosine kinase (TK)
and mammalian target of rapamycin (sirolimus) (mTOR), which have a
regulatory role in neuroendocrine cell growth.
• The small molecule TK inhibitor sunitinib has been shown to
significantly increase progression-free survival in patients with
malignant pancreatic NETs when compared with placebo.
• The mTOR inhibitor everolimus has been shown to reduce the risk of
progression by 65% vs placebo in a recent study. It may also be used
with octreotide.
Peptide receptor radioligand therapy (PRRT)

• In a large study using 90Y-DOTA tyr3-octreotide in patients with
metastatic neuroendocrine tumours with uptake on pretreatment
somatostatin receptor scintigraphy, 34% had a measurable decrease
in tumour size, 15% had a biochemical response, and 30% improved
symptomatically.
• In another trial using 177Lu-DOTA, there was a tumour response rate
of 30%.
• These are relatively newer modalities of treatment, with few
long-term data.
Radiolabelled MIBG
• MIBG is structurally related to noradrenaline, and, after IV injection, a
proportion of NETs concentrate significant amounts of the compound.
• In retrospective studies, reduction in 5HIAA excretion was seen in
37% of patients with GEP NETs and objective tumour responses seen
in 15–30% of patients. Symptomatic benefit was achieved in 25–50% of
patients treated with radiolabelled MIBG.
3 Carcinoid crisis
Despite the changes in nomenclature of NENs and the tumours that were
traditionally described as carcinoids being included under the classification
of NENs, the ‘carcinoid crisis’ is still an important descriptive term. It is
a potentially life-threatening condition that should be prevented, where
possible, and treated as an emergency.
• Clinical features include hypotension, tachycardia, arrhythmias, flushing,
diarrhoea, bronchospasm, and altered sensorium.
• The carcinoid crisis can be triggered by manipulation of the tumours,
such as during biopsy, surgery, or palpation.
• These result in the release of biologically active compounds from the
tumours.
• Preoperatively, the risk of a crisis can be reduced by the administration
of SC octreotide (300 micrograms).
• During a crisis, commence an IV infusion of octreotide at a rate of
50–150 micrograms/h, in addition to fluid resuscitation and supportive
management.
Carcinoid heart disease
Carcinoid heart disease is characterized by thickening of valve leaflets, val-
vular cups, and chordae. These result in valvular stenosis or regurgitation
and eventually heart failure.
This condition is seen in 40–50% of patients with carcinoid syndrome and
3–4% of patients with neuroendocrine tumours, typically with right-sided
involvement (tricuspid regurgitation or pulmonary regurgitation). Left side
is involved in <10%.
Patients with carcinoid syndrome and carcinoid heart disease should
have an annual echocardiographic assessment. During the first evaluation,
a patent foramen ovale should be sought, and, in the presence of this con-
dition, there can be left-sided valve disease. The timing of valve replace-
ment should be made by experienced cardiologists and cardiac surgeons.
TREATMENT OF NENS 561
Further reading
European Neuroendocrine Tumour Society. Available at: M http://www.enets.org.
Pavel ME, et al. (2011). Everolimus plus octreotide long-acting repeatable for the treatment of
advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a ran-
domised, placebo-controlled, phase 3 study. Lancet 378, 2005–12.
Raymond E, et al. (2011). Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.
N Engl J Med 364, 501–13.
Yao JC, et al. (2011). Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med
364, 514–23.
Insulinomas
Definitions and background
• An insulinoma is a functioning neuroendocrine tumour of the pancreas
that causes hypoglycaemia through inappropriate secretion of insulin.
• Unlike other neuroendocrine tumours of the pancreas, more than 90%
of insulinomas are benign.
• >80% of insulinomas are solitary, but some are multiple, either
simultaneously or consecutively, a situation likely to be associated with
MEN-1 in approximately 10%.
• Insulinomas are found with equal frequency throughout the head,
body, and tail of the pancreas.
Epidemiology
• The annual incidence of insulinomas is of the order of 1–2 per million
population.
• There is a slight female preponderance in the fifth decade of life.
• 5–10% of insulinomas are associated with MEN-1.
• Patients may present with neuroglycopenic symptoms, including
headaches, diplopia, blurred vision, altered behaviour, and sometimes
seizures.
• Whipple’s triad remains as useful as ever in diagnosing
insulinoma: symptoms of hypoglycaemia, plasma glucose (laboratory
glucose—and not fingerprick readings) of 2.2mmol/L or less, and
resolution of symptoms with glucose.
• The gold standard investigation for establishing the diagnosis of
insulinomas is the 72h fast.
• Shorter durations of fast (15h), repeated on three separate occasions,
may be used as a screening tool.
Diagnostic criteria
• Laboratory blood glucose of ≤2.2mmol/L.
• Concomitant inappropriate insulin elevation.
• Elevated C-peptide and proinsulin.
• β-hydroxybutyrate of <2.7mmol/L.
• Absence of sulfonylureas and metabolites in plasma or urine.
TUMOUR LOCALIZATION 563
Tumour localization
(See Table 8.2.)
• Islet cell tumours are often small and may not be detected by any
imaging technique. The available radiological modalities have a wide
reported range of sensitivity which is frequently dependent on the
equipment and the operator.
• MRI or spiral CT correctly detects >60% of tumours, but preoperative
localization can be difficult in tumours <1cm in diameter.
• Arterial stimulation (with calcium or secretin), followed by venous
sampling, can localize approximately 90% of insulinomas but carries the
risks of a more invasive technique.
• Endoscopic US, which requires specialized equipment and expertise,
may identify tumours as small as 5mm. The head of the pancreas is
visualized with the probe in the duodenum, and the body and tail with
it in the stomach.
• Intraoperative US, using a transducer applied directly to the pancreas,
improves the sensitivity of US to 790%.
• Experienced surgeons can frequently identify the lesions
intraoperatively by palpation alone, and the risk of multiple tumours
makes a thorough examination of the whole pancreas essential at
operation.
• Somatostatin receptor scintigraphy has been shown to be useful in
detecting insulinomas, but it is dependent on somatostatin receptor
subtype expression by the tumour.
• Glucagon-like peptide-1 receptor imaging has also been shown to be
useful.
Table 8.2 Radiological localization of pancreatic insulinomas

Localization technique Reported sensitivity (%)
Transabdominal US 30–61
Endoscopic US 80
Intraoperative US 90
CT 42–78
MRI 20–100
Octreotide scanning 68–86
Pancreatic arteriography 29–90
Venous sampling 84
Treatment of insulinomas
• The treatment of choice in all, but poor, surgical candidates is
operative removal.
• Surgical options include enucleation of tumours, partial
pancreatectomy, Whipple procedure, or rarely total pancreatectomy.
• In experienced surgical hands, the mortality is less than 1%. The
mortality is largely influenced by the incidence of acute post-operative
pancreatitis and peritonitis.
• Post-operative hyperglycaemia may occur, even following partial
pancreatectomy.
• Medical treatment to control symptoms may be achieved using
diazoxide alone or in combination with octreotide pending surgery or
in those patients who have high surgical risk.
• Radiolabelled somatostatin analogue therapy may induce a biochemical
and symptomatic response in patients with malignant insulinomas.
• Everolimus, the M Tor inhibitor, may be useful in metastatic insulinoma
but has significant side-effects.
Prognosis of insulinomas
• Following the removal of a solitary insulinoma, life expectancy is
restored to normal.
• Malignant insulinomas, with metastases usually to the liver, have a
natural history of years, rather than months, and may be controlled
with medical therapy or specific antitumour therapy using
streptozotocin and fluorouracil. The management goals are targeted at
managing blood glucose and tumour load.
• Average 5-year survival estimated to be approximately 35% for
malignant insulinomas.
Further reading
Carl Pallais J, et al. (2012). Case records of the Massachusetts General Hospital. Case 33-2012.
A 34-year-old woman with episodic paresthesias and altered mental status after childbirth. N
Engl J Med 367, 1637–46.
de Herder WW, et al. (2011). New therapeutic options for metastatic malignant insulinomas. Clin
Placzhowski KA, et al. (2009). Secular trends in the presentation and management of functioning
insulinoma at the Mayo Clinic, 1987-2007. J Clin Endocrinol Metab 94, 1069–73.
GASTRINOMAS 565
Gastrinomas
Definitions
• Gastrin, synthesized in the G cells, predominantly in the gastric
antrum, is the principal gut hormone stimulating gastric acid secretion.
• The Zollinger–Ellison (ZE) syndrome is characterized by gastric acid
oversecretion and manifests itself as severe peptic ulcer disease
(PUD), gastro-oesophageal reflux, and diarrhoea.
Incidence
The incidence of gastrinomas is 0.5–2/million population/year.
Sites of origin
• Gastrinomas are the most common functional malignant pancreatic
endocrine tumours.
• The most common extrapancreatic site of origin is the duodenum in
50–80% of sporadic ZE and 70–100% of patients with MEN-1.
• Less common sites are stomach, liver, bile duct, heart, and small cell
lung cancer.
• Pancreatic tumours are more aggressive than duodenal tumours.
• The mean age of presentation of patients with sporadic gastrinomas is
48–55 years and is almost equally found in ♂ and ♀.
• Most patients with ZE syndrome present with a single duodenal ulcer
or gastro-oesophageal reflux.
• Abdominal pain is a presenting feature (due to PUD) in 75–98% of
patients.
• Diarrhoea is present at diagnosis in 30–70%.
• 20–30% of patients with gastrinomas have MEN-1.
• At diagnosis, 5–10% of duodenal gastrinomas and 20–25% of pancreatic
gastrinomas have hepatic metastases.
• Suspect ZE syndrome when there is severe PUD without Helicobacter
pylori, resistance to PPIs, or in the presence of hypercalcaemia.
Diagnosis of Zollinger–Ellison syndrome

• The diagnosis rests on demonstrating an inappropriate elevation of
fasting gastrin levels in the presence of hyperchlorhydria (pH ≤2).
• Patients should have antisecretory treatment stopped prior to the
test (3 days for H2 blockers and 2 weeks for PPIs), as these drugs are
associated with hypergastrinaemia. However, gastrin levels above
250pmol/L are rarely due to PPI therapy alone.
• A gut hormone profile may identify elevated plasma levels of
pancreatic polypeptide or other gut hormones.
• The tumour localization techniques described for insulinomas are also
relevant for gastrinomas (see Table 8.3).
• Very small tumours or duodenal tumours can be very hard to localize,
and even small tumours are frequently associated with local lymph
node disease.
• Selective arterial angiography may be combined with a provocative
test for gastrin release, using a bolus of calcium gluconate or secretin
for elusive small tumours. 3mL calcium gluconate is injected into the
gastroduodenal, superior mesenteric, splenic, and hepatic artery, in
turn, with a 5min gap in between. After 30s at each site, sampling is
undertaken.
• For causes of hypergastrinaemia, see Box 8.2.
Box 8.2 Causes of hypergastrinaemia

Low or normal gastric acid production
• H2 blockers.
• PPIs.
• Vagotomy.
• Hypochlorhydria.
• Short gut syndrome.
• Renal failure.
• Hypercalcaemia.
Elevated gastric acid production
• Gastrinoma.
• G cell hyperplasia.
PROGNOSIS OF GASTRINOMAS 567
Treatment of gastrinomas
(See Table 8.3.)
• The treatment of choice is complete surgical tumour removal,
although this is usually only considered after the tumour has been
identified preoperatively.
• Surgery is rarely justified in patients with known hepatic metastases,
although some small studies have raised the possibility of benefit from
tumour debulking.
• Where preoperative imaging has failed to identify a tumour, the
patient is often best maintained on high-dose PPI therapy (e.g. 60mg of
omeprazole), with regular imaging to reassess. Check B12 annually.
• Somatostatin analogues do not appear to be more effective at
controlling gastric acid hypersecretion and relieving symptoms than
PPIs or H2 blockers.
• The data are currently few, but, as for insulinomas, radiolabelled
somatostatin analogues may be a future treatment option for
gastrinomas.
• In patients with MEN-1, management is more controversial, but
the usual policy is to operate when a well-defined tumour can be
identified.
Table 8.3 Treatment options for gastrinomas

Medical treatment Surgery Palliation
PPIs Tumour resection Chemotherapy
H2 blockers Tumour debulking Hepatic artery
Octreotide Liver transplant embolization
Prognosis of gastrinomas
• 10-year survival without liver metastases is 95%.
• 10-year survival with single or limited metastases in both lobes is
approximately 80%.
• Where there are diffuse metastases, the outlook is less favourable,
with a 10-year survival of approximately 15%.
Further reading
Simmons LH, et al. (2013). Case records of the Massachusetts General Hospital. Case 6-2013.
A 54-year-old man with recurrent diarrhea. N Engl J Med 368, 757–65.
Glucagonomas
Definitions
• Glucagonomas are neuroendocrine tumours that usually arise from
the A cells of the pancreas and produce the glucagonoma syndrome
through the secretion of glucagon and other peptides derived from the
preproglucagon gene.
• The large majority of glucagonomas are malignant, but they are also very
indolent tumours, and the diagnosis may be overlooked for many years.
• Up to 90% of patients will have lymph node or liver metastases at the
time of presentation.
• They are classically associated with the rash of necrolytic migratory
erythema.
Epidemiology
• The annual incidence is estimated at 1 per 20 million population.
• Glucagonomas are uncommon in MEN-1.
(See Table 8.4.)
• The characteristic rash—necrolytic migratory erythema—occurs in
>70% of cases and usually manifests initially as a well-demarcated area
of erythema in the groin before migrating to the limbs, buttocks, and
perineum.
• Mucous membrane involvement is common, with stomatitis, glossitis,
vaginitis, and urethritis being frequent features.
• Glucagon antagonizes the effects of insulin, particularly on hepatic
glucose metabolism, and glucose intolerance is a frequent association
(>90%).
• Sustained gluconeogenesis also causes amino acid deficiencies and
results in protein catabolism which can be associated with unrelenting
weight loss in >60% of patients.
• Glucagon has a direct suppressive effect on the bone marrow, resulting
in a normochromic normocytic anaemia in almost all patients.
• The diagnosis is confirmed on finding raised plasma glucagon levels.
• A gut hormone profile may also show elevated neuroendocrine
markers, such as pancreatic polypeptide, chromogranin A.
• Impaired glucose intolerance and hypoaminoacidaemia may be present.
Tumour localization
• At the time of diagnosis, 50–100% of glucagonomas will have
metastasized to the liver, and most p tumours will be >3cm in
diameter.
• These tumours rarely present problems of radiological localization,
and transabdominal US and CT scanning are usually adequate.
• Small tumours may require more sophisticated imaging techniques,
including endoscopic ultrasound (see Table 8.4). Octreotide scanning
probably offers the best means of evaluating the extent of metastatic
disease.
GLUCAGONOMAS 569
Table 8.4 Clinical features of the glucagonoma syndrome

Site Clinical features
Skin Necrolytic migratory erythema
Mucous membranes Angular stomatitis
Atrophic glossitis
Vulvovaginitis
Urethritis
Nails Onycholysis
Scalp Alopecia
Metabolism Glucose intolerance
Protein catabolism and weight loss
Haematological Anaemia
Venous thromboses
Psychiatric Depression
Psychosis
Treatment
• Surgery is the only curative therapeutic option, but the potential for a
complete cure may be as low as 5%.
• Somatostatin (SST) analogues are the treatment of choice, with
excellent response rates in treating the necrolytic migratory erythema.
They are less effective at reversing the weight loss and have an
inconsistent effect on glycaemic control such that diabetes mellitus
may need to be managed with insulin therapy.
• If SST analogues fail, the rash may be improved using IV amino acids
and fatty acids.
• Experience with chemotherapy is limited. However, palliative
chemotherapy, using streptozotocin and fluorouracil, has been shown
to produce a 50% reduction in glucagon levels in 75% of patients, but
the benefit is frequently only temporary. Antitumour activity has also
been shown with the alkylating agent temozolomide.
• Hepatic artery embolization may result in a dramatic relief of
symptoms, with remissions of several months recorded.
• As for the other pancreatic islet cell tumours, there are data to suggest
that radiolabelled somatostatin analogues may be therapeutic in the
glucagonoma syndrome.
• Nutritional support is essential, as patients may experience a
prolonged catabolic state.
VIPomas
Definitions
• In 1958, Verner and Morrison1 first described a syndrome consisting
of refractory watery diarrhoea and hypokalaemia, associated with a
neuroendocrine tumour of the pancreas.
• The syndrome of watery diarrhoea, hypokalaemia, and acidosis
(WDHA) is due to secretion of vasoactive intestinal polypeptide (VIP).
• Tumours that secrete VIP are known as VIPomas.
• VIPomas account for <10% of islet cell tumours and mainly occur as
solitary tumours.
• >60% are malignant and metastasize to the lymph nodes, liver, kidneys,
and bone.
• The most prominent symptom in most patients is profuse watery
diarrhoea which is secretory in nature and, therefore, rich in
electrolytes (see Box 8.3).
• Other causes of secretory diarrhoea should be considered in the
differential diagnosis (see Box 8.4).
• VIPomas are rare in MEN-1 patients, occurring in <1% of cases.
• Elevated levels of plasma VIP are found in all patients with the VIPoma
syndrome, although false +ves may occur in dehydrated patients due
to diarrhoea from other causes.
• A gut hormone profile may identify other raised tumour markers, such
as pancreatic polypeptide, and aid detection of some other causes of
watery diarrhoea, e.g. gastrinomas.
• A phaeochromocytoma screen should be performed, especially in
children in whom it is common to find the tumours residing in the
adrenal medulla.
Box 8.3 Clinical features of the VIPoma syndrome

• Watery diarrhoea.
• Hypokalaemia.
• Achlorhydria.
• Metabolic acidosis.
• Hypercalcaemia.
• Hyperglycaemia.
• Hypomagnesaemia.
• Facial flushing.
VIPOMAS 571
Box 8.4 Differential diagnosis of secretory diarrhoea

• Infection e.g. Escherichia coli or cholera toxins.
• Laxative abuse.
• Villous adenoma.
• Other gut neuroendocrine tumours, e.g. carcinoid tumours or
gastrinomas.
• Carcinoma of the lung.
• Medullary carcinoma of the thyroid.
• Systemic mastocytosis.
• Immunoglobulin A deficiency.
Tumour localization
• The majority of tumours secreting VIP originate in the pancreas while
others arise from the sympathetic chain.
• p VIPomas have very rarely been reported to arise from a variety
of other sites, such as the lung, oesophagus, small bowel, colon, and
kidney.
• Most patients present with large tumours which can be easily identified
by transabdominal US or CT, although small tumours may require
additional methods of tumour localization, as previously discussed (see
Table 8.2).
Treatment
• Severe cases require IV fluid replacement and careful correction of
electrolyte disturbances.
• Surgery to remove the tumour is the treatment of first choice, if
technically possible, and may be curative in around 40% of patients.
Surgical debulking may also be of palliative benefit.
• Somatostatin analogues produce effective symptomatic relief from the
diarrhoea in most patients. Long-term use does not result in tumour
regression.
• Glucocorticoids in high dosage have also been shown to provide good
relief of symptoms.
• A trial of lithium may be warranted in resistant cases, and this therapy
may be combined with octreotide.
• Chemotherapy using streptozotocin, in combination with fluorouracil,
has resulted in response rates of >30%.
• Hepatic artery embolization can offer temporary respite from severe
diarrhoea.
Reference
1. Verner JV, Morrison AB (1958) Islet cell tumor and a syndrome of refractory watery diarrhea
and hypokalemia. Am J Med 25, 374–380.
Somatostatinomas
Definitions
• Somatostatinomas are very rare neuroendocrine tumours, occurring
both in the pancreas and in the duodenum.
• >60% are large tumours located in the head or body of the pancreas.
• The clinical syndrome may be diagnosed late in the course of the
disease when metastatic spread to local lymph nodes and the liver has
already occurred.
Clinical features
(See Box 8.5.)
• Glucose intolerance or frank diabetes mellitus may have been
observed for many years prior to the diagnosis and retrospectively
often represents the first clinical sign. It is probably due to the
inhibitory effect of somatostatin on insulin secretion.
• A high incidence of gallstones has been described similar to that seen
as a side effect with long-term somatostatin analogue therapy.
• Diarrhoea, steatorrhoea, and weight loss appear to be consistent
clinical features and may be associated with inhibition of the exocrine
pancreas by somatostatin.
• Small duodenal somatostatinomas may occur in association with NF-1,
and, although these rarely cause the inhibitory clinical syndrome, they
present with obstructive biliary disease through local spread of the
tumour.
• Somatostatinomas are infrequently associated with MEN-1 (7%).
• Plasma somatostatin levels will be raised and may also be associated
with raised levels of other neuroendocrine tumour markers, including
ACTH and calcitonin.
• Multisecretory activity is commoner with pancreatic (33%) than with
duodenal (16%) somatostatinomas.
Tumour localization
• Transabdominal US and CT scanning may demonstrate the tumour
since metastatic disease is often apparent at presentation.
• Additonal methods of tumour localization, as previously described,
may also be required (see Table 8.2).
Treatment
• Surgery should be considered as first-line treatment as, although a
cure is rare, even debulking surgery may result in significant palliation.
• Hepatic embolization can be considered, and chemotherapy with
streptozotocin and fluorouracil may be used to control malignant
disease.
SOMATOSTATINOMAS 573
Box 8.5 Clinical features of the somatostatin syndrome

• Glucose intolerance/diabetes mellitus (95%).
• Gallstones (68%).
• Diarrhoea and steatorrhoea.
• Weight loss (25%).
• Anaemia (14%).
• Hypochlorhydria.
Chapter 9 575
Inherited endocrine
syndromes and MEN
McCune–Albright syndrome 576

Neurofibromatosis 578
von Hippel–Lindau disease 580
Carney complex 583
Cowden syndrome 584
POEMS syndrome 585
MEN type 1 586
Management of MEN type 1 588
MEN type 2 592
Management of MEN type 2 594
Inherited primary hyperparathyroidism 596
Inherited renal calculi 598
576 CHAPTER 9 Inherited endocrine syndromes
McCune–Albright syndrome
Definitions
The syndrome is characterized by:
• Polyostotic fibrous dysplasia.
• Café-au-lait pigmented skin lesions.
• Autonomous function of multiple endocrine glands.
A clinical diagnosis requires two of these pathologies.
Epidemiology
The condition affects 1:100,000 to 1:1,000,000 people.
Genetics
• A genetic, but not an inherited, condition due to a post-zygotic
somatic mutation in the gene (GNAS1) that encodes the A-chain of the
stimulating G protein of adenyl cyclase (GSA mutation). This results in
activation of adenyl cyclase.
• The somatic mutation results in mosaicism, and consequently the
proportion and distribution of affected cells in a tissue will be
determined by the precise stage in development at which the mutation
occurred.
• Mutational analysis of the GNAS1 gene from affected tissues or blood
is available in some centres in the UK.
Clinical features
Polyostotic fibrous dysplasia
• Solitary or multiple expansile bony lesions which can cause fracture
deformities and nerve entrapment typically develop before the age of
10 years.
• The femora and the pelvic bones are most frequently affected, and
radiographs of these bones are useful for screening.
• Osteosarcomas are a rare complication.
• For treatment, see Box 9.1.
Café-au-lait pigmentation
The lesions are characterized by an irregular border (in neurofibroma-
tosis, the border is smooth), do not cross the midline, and tend to be
ipsilateral to the bone lesions.
Endocrinopathies
See Table 9.1.
Involvement of other organs
• Hepatobiliary complications, such as neonatal jaundice, elevated
transaminases, and cholestasis are relatively common.
• Cardiomegaly, tachyarrhythmias, and sudden cardiac death may occur.
• Gastrointestinal polyps, splenic hyperplasia, and pancreatitis are
reported complications.
• Recognized CNS associations include microcephaly, failure to thrive,
and developmental delay.
MCCUNE–ALBRIGHT SYNDROME 577
Table 9.1 Endocrinopathies in McCune–Albright syndrome

Condition Presentation Treatment
Precocious puberty Frequent initial presentation Cyproterone acetate
Typically aged 1–9 years
Low gonadotrophins
Adults fertile
Less frequent in boys
Thyroid nodules Present in almost 100% of Antithyroid drugs,
patients radioiodine, surgery
50% become toxic due to
autonomous nodule function
GH-secreting Present with features Somatostatin
pituitary tumours of acromegaly or analogues, dopamine
and prolactinomas hyperprolactinaemia agonists, surgery
Cushing’s syndrome Adrenal hyperplasia or Adrenalectomy
adenoma
Hypophosphataemic d phosphate Calcitriol, phosphate
rickets d 1,25 vit D supplements
i ALP
Normal calcium, 25OH vit D,
and PTH
Box 9.1 Treatment of polyostotic fibrous dysplasia

• Surgery may be complicated by bleeding, and radiotherapy has a
limited effect.
• There is some recent evidence to support the use of
bisphosphonates, particularly pamidronate, for both symptomatic
pain relief and the radiological healing of bone.
Prognosis
• Most patients live well beyond reproductive age.
• Bone deformities may reduce life expectancy.
• Sudden cardiac death, although recognized, is uncommon.
Further reading
Lumbroso S, Paris F, Sultan C (2002). McCune–Albright syndrome: molecular genetics. J Paediatr
Spiegel AM, Weinstein LS (2004). Inherited diseases involving G proteins and G protein-coupled
receptors. Annu Rev Med 55, 27–39.
Neurofibromatosis
Definitions
• Neurofibromatosis type 1 (NF1) is also known as von Recklinghausen
disease and refers to the occurrence of multiple neurofibromas,
café-au-lait spots, and Lisch nodules (pigmented hamartomas nodules
of aggregated dendritic melanocytes) affecting the iris.
• Endocrinopathies are sometimes associated with NF1.
• NF type 2 (NF2) is characterized by the presence of bilateral acoustic
neuromas, typically resulting in deafness.
• Other features of NF2 include posterior subcapsular cataracts, retinal
gliomas, pigmented retinopathy, and gaze palsies.
• NF2 has no common associated endocrinopathies.
• NF2 is rare, with an estimated frequency of 1 in 40,000 live births.
NF1
Genetics
• NF1 is a highly penetrant, autosomal dominant condition.
• The NF1 gene is located on chromosome 17 and encodes a
GTPase-activating protein (neurofibromin).
• Neurofibromin promotes cleavage of GTP to GDP.
Epidemiology
• The incidence of NF1 is 1 per 3,000 of the population.
• NF1 is nearly 100% penetrant but shows variable clinical expression.
• Approximately 50% of cases are sporadic.
Clinical features
• Diagnosis is generally apparent by the age of 1 year.
• The café-au-lait spots become visible shortly after birth (95%); 70%
have axillary or groin freckling.
• The multiple cutaneous and subcutaneous neurofibromas appear
around puberty (95%).
• Lisch nodules, affecting the iris, start to appear typically after the age of
5 years (95%).
• The endocrine features are detailed in Box 9.2.
• Learning disabilities occur in 60% of patients with NF1.
• Gliomas may be found in around 15% of patients, most commonly
affecting the optic pathways.
• Neurofibrosarcomas complicate around 6% of cases.
• Skeletal dysplasias (e.g. sphenoid wing dysplasia, scoliosis, tibial
pseudoarthrosis, pectus excavatum, etc.) may be found in up to 5%
of cases.
• Vascular dysplasia may occur, with the commonest region affected
being the renal vasculature, resulting in renovascular hypertension in
up to 3% of cases.
• Macrocephaly (16%), seizures (5%), and short stature (6%) are all
reported features of NF1.
• Associated phaeochromocytomas are seen in <5% of NF1 patients.
NEUROFIBROMATOSIS 579
Box 9.2 Endocrine features of NF1

• Puberty and pregnancy:
• Both are associated with a change in size of neurofibromas.
• Hypothalamus and pituitary:
• Optic gliomas impinge on adjacent tissues and may affect
hypothalamic and/or pituitary function.
• Phaeochromocytoma 0.1–5.0%:
• Serious complication of NF1.
• Uncommon before age 20 years.
• Most commonly adrenal (20% bilateral), but extra-adrenal lesions
are reported.
• Gut neuroendocrine tumours:
• Found in around 1% of NF1 patients.
Further reading
Arun D, Gutmann DH (2004). Recent advances in neurofibromatosis type 1. Curr Opin Neurol
17, 101–5.
Rose VM (2004). Neurocutaneous syndromes. Mo Med 101, 112–16.
von Hippel–Lindau disease

Definitions
Characterized by:
• CNS haemangioblastomas.
• Retinal angiomas.
• Renal cysts and carcinomas.
• Phaeochromocytomas.
• Pancreatic neuroendocrine tumours (less common) and
pancreatic cysts.
• Occasional endolymphatic sac tumours.
See Box 9.3.
Clinical diagnosis established by:
• Two or more haemangioblastomas.
• A haemangioblastoma and a visual manifestation.
• A haemangioblastoma or visual manifestation and a family history of
haemangioblastoma.
• The condition occurs in approximately 1 in 36,000 live births.
• The average age of presentation is 27 years, and the condition is nearly
100% penetrant by the age of 65 years.
• VHL may be subdivided into type 1 and type 2 disease.
• Type 1 VHL is the commonest form of the disease and is characterized
by a tendency to develop tumours in the eyes, brain, spinal cord,
kidney, and pancreas.
• Affected family members with VHL type 2 are also susceptible to
developing phaeochromocytomas, and this may be further subdivided
into VHL type 2A (develop phaeochromocytomas and renal cell
carcinomas).
Genetics
• VHL is a highly penetrant autosomal dominant condition.
• The VHL gene is on chromosome 3 and is a tumour suppressor gene.
• Mutations which result in loss of the VHL protein lead to VEGF
expression in normoxia as well as hypoxia, thus enhancing the growth
of these tumours which are often very vascular.
• Mutational analysis of the VHL gene is available in the UK.
• Genetic testing in affected families is recommended from the age of
5 years.
• With appropriate counselling, prenatal diagnosis with amniocentesis
and chorion villous sampling is an option.
See Table 9.2 for surveillance.
VON HIPPEL–LINDAU DISEASE 581
Box 9.3 Less common manifestations of von Hippel–

Lindau disease
Pancreas Cysts
Adenomas
Epididymis Cystadenoma
CNS Syringomyelia
Meningioma
Liver Adenoma
Haemangioblastoma
Cysts
Lung Angioma
Cysts
Spleen Angioma
Table 9.2 Surveillance in VHL

Condition Screening test
Retinal angiomas Annual ophthalmic examination from infancy/
early childhood
CNS haemangioblastomas MRI head 9 spine every 12–36 months, starting
from adolescence
Renal cell carcinoma MRI abdomen 12-monthly from the age of
16 years
Phaeochromocytoma Plasma/urine metanephrines from early
childhood
Imaging if biochemical abnormalities detected
Clinical features
• Retinal angiomas are the initial manifestation of VHL in 40% of patients.
They are uncommon before the age of 10 years but continue to
develop throughout life. They tend to be peripheral in the retina,
appearing as red oval lesions. Bleeding and retinal detachment may
occur, and treatment is with laser therapy.
• 75% of haemangioblastomas occur in the cerebellum, and they are the
initial presenting feature in 40% of VHL patients. Treatment is with
surgery or radiotherapy.
• Renal carcinoma is the commonest cause of death in VHL patients. By
the age of 60 years, 70% of VHL patients will be affected, with a mean
age of presentation of 44 years. The lesions tend to be multifocal. The
management of choice is surgical resection.
• Phaeochromocytomas occur in up to 20% of VHL families and are

bilateral in 40% of cases. The frequency of this condition varies widely
between families, as certain mutations are particularly associated with
a high risk of phaeochromocytoma. Regular biochemical screening is
essential in these high-risk families.
• The majority of pancreatic tumours associated with VHL are
non-functioning, but they may secrete VIP, insulin, glucagons, or
calcitonin. They occur in 10–20% of VHL patients and should be
treated expectantly, unless symptomatic, enlarging, or >2–3cm.
Prognosis
• Until recently, the median survival for a VHL patient was 40–50 years
of age, with the majority of deaths attributable to renal cell carcinoma.
• Currently, the prognosis for individual patients depends upon the
location and complications of the tumours but overall is improving as
a result of the institution of screening programmes and consequent
earlier therapeutic interventions.
• For surveillance in VHL, see Table 9.2.
Further reading
Kaelin WG Jr (2003). The von Hippel–Lindau gene, kidney cancer and oxygen sensing. Am Soc
Nephrol 14, 2703–11.
Lonser RR, et al. (2003). Von Hippel-Lindau disease. Lancet 361, 2059–67.
Maher RM, Hartmut PH, Richard S (2011). Von Hippel–Lindau disease: a clinical and scientific
review. Eur J Hum Genet 19, 617–23.
Richard S, Graff J, Lindau J, et al. (2005). Von Hippel–Lindau disease. Lancet 363, 1231–4.
CARNEY COMPLEX 583
Carney complex
Definitions
A clinical diagnosis is made by finding two of the clinical features listed in
Clinical presentation below or one of these features plus either an affected
first-degree relative or an inactivating mutation in the gene PRKARIα.
Genetics
• Autosomal dominant.
• An inactivating mutation of the PRKARIA gene on the long arm of
chromosome 17q2 can be identified in approximately 50% of families.
• Spotty skin pigmentation.
• Cardiac, skin, or mucosal myxomas.
• Endocrine tumours (see Box 9.4).
• Psammomatous melanotic schwannoma.
Box 9.4 Endocrine tumours associated with Carney

complex
• The commonest endocrine manifestation is p pigmented nodular
adrenocortical disease (PPNAD), causing Cushing’s syndrome.
• Large cell calcifying Sertoli cell tumour (LCCSCT).
• GH/PRL-secreting pituitary adenoma (also somatotroph/
mammotroph hyperplasia).
• Thyroid adenoma.
• Ovarian cysts.
Further reading
Bertherat J, et al. (2009). Mutations in regulatory subunit type 1A of cyclic adenosine
5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients
and 80 different genotypes. J Clin Endocrinol Metab 94, 2085–91.
Sandrini F, Stratakis C (2003). Clinical and molecular genetics of Carney complex. Mol Genet Metab
78, 83–92.
Stergiopolous SG, Abu-Asab MS, Tsokos M, et al. (2004). Pituitary pathology in Carney complex
patients. Pituitary 7, 73–82.
Stratakis CA, Kirschner LS, Carney JA (2001). Clinical and molecular features of the Carney com-
plex. J Clin Endocrinol Metab 86, 4041–6.
Cowden syndrome
(Also see Box 9.5.)
• The condition is characterized by multiple hamartomas, involving organ
systems derived from all three germ cell layers.
• Patients are also at risk from breast, thyroid, and endometrial
carcinomas.
• Thyroid pathology occurs in >75% of patients, and the lesions may be
multifocal.
• Weight gain is common.
Epidemiology
Estimated to affect 1 in 200,000 individuals.
Genetics
• Autosomal dominant condition.
• Inactivating mutations in the PTEN tumour suppressor gene can be
identified in approximately 80% of affected probands.
Box 9.5 Endocrine features of Cowden syndrome

• Non-medullary thyroid carcinomas, especially follicular thyroid
carcinoma.
• Multinodular goitre.
• Thyroid adenomas.
• Parathyroid adenomas are extremely rare.
Further reading
Pilarski R, Eng C (2004). Will the real Cowden syndrome please stand up (again)? Expanding muta-
tional and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 41, 323–6.
POEMS SYNDROME 585
POEMS syndrome
Definitions
Progressive polyneuropathy, organomegaly, endocrinopathy, monoclo-
nal gammopathy, and skin changes (POEMS) is a rare disorder of unclear
pathogenesis which is probably mediated by i production of lambda light
chains from abnormal plasma cells.
• Progressive polyneuropathy.
• Organomegaly, especially hepatosplenomegaly and lymphadenopathy.
• Common endocrinopathies (84%) (multiple in 65%) include
hypogonadotrophic hypogonadism (70%—2/3 central, 1/3 p),
hypothyroidism (60%), hypoadrenalism (60%), diabetes mellitus (50%),
hyperprolactinaemia (20%).
• Monoclonal gammopathy.
• Skin changes.
Treatments
Include chemotherapy, irradiation, and surgery.
Further reading
Dispenzieri A, Gertz MA (2004). Treatment of POEMS syndrome. Curr Treat Options Oncol 5,
249–57.
MEN type 1
Definitions
Characterized by:
• Parathyroid tumours/hyperplasia.
• Anterior pituitary adenomas.
• Pancreatic neuroendocrine tumours.
A clinical diagnosis of MEN-1 is made by the presence of two out of three
of these tumours or one of these tumours in the context of a family his-
tory of MEN-1.
The prevalence of MEN-1 has been estimated at 1 in 10,000 of the
population.
Genetics
• MEN-1 is an autosomal dominant condition, with an estimated
penetrance of 99% by the age of 50 years.
• The MEN-1 gene is located on the long arm of chromosome 11
(11q13) and is a tumour suppressor gene. The function of the encoded
protein MENIN is under investigation.
• The mutations causing MEN-1 are inactivating in nature.
• More than 1,300 mutations in the MEN-1 gene have been described
in affected families, and there is no clear genotype–phenotype
correlation.
• Mutational analysis is available in the UK, although it is important to
note that up to 10% of patients will not have mutations identifiable
within the coding region of the MEN-1 gene.
Clinical features
• The disease has been reported to manifest itself from the ages of 5 to
80 years.
• MEN-1 is associated with a high mortality due to aggressive tumours
or biochemical sequelae of the tumours.
• p hyperparathyroidism is the commonest presenting feature in MEN-1
and occurs in 85–95% of patients with MEN-1. The next commonest
presenting features are insulinomas or prolactinomas.
• Pituitary adenomas are found in approximately 30% of MEN-1 patients
(see Table 9.3).
• The incidence of pancreatic endocrine tumours varies between 30%
and 80% in different series (see Table 9.4).
• Other lesions are also associated with MEN-1 (see Table 9.5).
MEN TYPE 1 587
Table 9.3 Pituitary tumours in MEN-1

Tumour Frequency (%)
Prolactinoma 60
Acromegaly 25
Non-functioning tumour 1
Cushing’s disease <1
Table 9.4 Pancreatic tumours in MEN-1

Gastrinoma 60
Non-functioning tumour 30–80
Insulinoma 30
Glucagonoma 2
PPoma <1
VIPoma <1
Table 9.5 Other lesions in MEN-1

Adrenal cortical tumours (including 5
carcinoma)
Carcinoid tumours 4
Lipomas 1
Phaeochromocytoma 0.5
Malignant melanoma 0.5
Testicular teratoma 0.5
Multiple (>3) angiofibromas 75 (specificity 95%)
Management of MEN type 1

• The hypercalcaemia is frequently mild, with an early age of onset, and
is the first manifestation of the disease in 85–95% of patients.
• Multiple gland disease (adenomas or hyperplasia) is common, in
contrast with sporadic p hyperparathyroidism where usually a single
adenoma is found.
• Surgical management is the gold standard. However, the timing of
surgery remains controversial.
• In view of the potential for multigland disease, total parathyroidectomy
with lifelong oral calcitriol replacement should always be considered.
• One surgical approach is a 3.5 gland parathyroidectomy. Other
options include total parathyroidectomy, with autotransplantation of
parathyroid tissue into the forearm.
• Cinacalcet may be used where surgery fails or in patients with high
surgical risk.
• Due to the risk of malignant tumours, a near total transcervical
thymectomy at the time of parathyroidectomy should be considered.
Pituitary tumours
These are managed with surgery, medical therapies, or radiotherapy, as
per sporadic pituitary tumours (b see Chapter 2, Pituitary tumours,
p. 136).
Gastrinomas
• These can be pancreatic or extrapancreatic.
• Most of these gastrinomas are malignant and frequently metastatic.
• The role of surgery in the management of gastrinomas in the setting of
MEN-1 is controversial. For non-metastatic disease, surgery is the ideal
treatment.
• Surgery for tumours >2cm has been recommended and has been
shown to improve disease-related survival.
• An experienced surgeon is essential if these tumours are to be
resected.
• Gastrinomas are a significant cause of morbidity and mortality in
MEN-1 patients and respond to medical therapy with high-dose proton
pump inhibitors (PPI) at a dose of omeprazole 40–60mg bd. The aim
of PPI therapy is to reduce basal gastric acid output. The prognosis of
patients with MEN-1 has improved considerably with the use of PPIs
to manage the Zollinger–Ellison syndrome.
Non-functioning pancreatic neuroendocrine neoplasia
• Non-functioning pancreatic neuroendocrine neoplasia (NEN) can
occur in patients <15 years.
• Due to advances in imaging, these tumours are being more frequently
diagnosed than before.
• Malignant pancreatic NENs are now the commonest cause of death in
patients with MEN-1.
MANAGEMENT OF MEN TYPE 1 589
• Endoscopic ultrasound is the most sensitive technique for detecting

these tumours, and somatostatin receptor scintigraphy the most
sensitive for diagnosing metastases.
• The timing of surgery for these tumours is controversial. Some
centres recommend removing tumours >2cm or growing tumours and
surveillance for tumours under this size. However, malignancy can be
missed in smaller tumours with this approach.
Mutational analysis
The criteria for performing mutational analysis are controversial and vary
from centre to centre in the UK. One approach is to recommend assess-
ing the following categories of patient:
• Patients with two MEN-1 tumours.
• First- and second-degree relatives of patients with MEN-1.
• Consider screening in patients with p hyperparathyroidism <40 years
of age, particularly in the presence of multigland disease.
• Consider screening in patients with isolated pancreatic neuroendocrine
tumours, especially gastrinomas.
• Mutational analysis should be considered in patients with parathyroid
adenomas under the age of 30 years.
• Within a family known to have MEN-1, mutational analysis
should still be offered to people with hyperparathyroidism
or hyperprolactinaemia, as ‘phenocopies’ (those with disease
manifestation without mutations) have been reported to occur in
5–10% of MEN-1 kindreds. Biochemical diagnosis alone should not
be relied upon. These phenocopies do not have MEN-1 and can be
reassured.
Screening for MEN type 1
(See Box 9.6 and Table 9.6.)
• Screening is relevant for affected patients, asymptomatic mutation
carriers, and first- and second-degree relatives in families with a clinical
diagnosis of MEN-1, but where a mutation has not been identified.
• Manifestations of MEN-1 are very rare before the teenage years but
have been described as young as 5 years. Careful parental counselling
can encourage some childhood monitoring which ideally should
include a careful history for symptoms (e.g. hypoglycaemia) and
height and weight assessment, in addition to calcium and prolactin
measurements.
• Screening involves both careful clinical history and examination as well
as biochemical assessment and imaging modalities (see Table 9.6).
• Age-related penetrance: age 10–7%, 20–52%, 30–87%, 40–99%,
60–100%.
• Current evidence supports commencing screening for pituitary lesions
and insulinomas from the age of 5 years, hyperparathyroidism from the
age of 8, gastrinomas and other NETs from the age of 20.
Table 9.6 Screening adults in MEN-1

Test Frequency
Calcium, phosphate, and PTH Annual
Basal anterior pituitary function (particularly Annual
prolactin and IGF-1)
Fasting gut hormones Annual
Fasting glucose Annual
24h urinary 5HIAA and chromogranin A Annual
MRI abdomen 9 endoscopic ultrasound Annual to 3-yearly
MRI pituitary Baseline, 3-yearly
Box 9.6 Prognosis

MEN-1 is associated with a mortality of nearly 50% by the age of
50 years. The commonest cause of death is metastatic pancreatic NENs.
With modern management of gastrinomas, improved surveillance, and
timely intervention, patients with MEN-1 are living longer.
Further reading
Brandi ML, Gagel AF, Angeli A, et al. (2001). Guidelines for diagnosis and therapy of MEN type 1
and 2. J Clin Endocrinol Metab 86, 5658–71.
Thakker RV, Newey PJ, Walls GV, et al. (2012). Clinical practice guidelines for multiple endocrine
neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97, 2990–3011.
MEN type 2
Definitions
MEN-2 may be divided into three forms:
• MEN-2A comprises of familial medullary thyroid carcinoma (FMTC)
in combination with phaeochromocytoma and parathyroid tumours.
MEN-2A accounts for nearly 90–95% of all MEN-2 cases.
• MEN-2B is defined as the occurrence of FMTC in association with
phaeochromocytoma, mucosal neuromas, and a marfanoid habitus.
• FMTC may also occur in isolation.
• See Table 9.7 for classification.
Genetics
• MEN-2 is an autosomal dominant condition.
• The C-RET proto-oncogene, activating mutations of which cause
MEN-2, is located on the long arm of chromosome 10 (10q11.2).
• This gene encodes RET which is a transmembrane receptor with an
extracellular cysteine-rich domain and an intracellular tyrosine kinase
domain. The protein plays a role in the development of the neural
crest and the enteric nervous system.
• The C-RET proto-oncogene is also involved, via inactivating mutations,
in the aetiology of Hirschsprung’s disease.
• Different germline mutations cause different clinical syndromes. In
contrast to MEN-1, MEN-2 shows a strong genotype–phenotype
correlation.
• Approximately 50% of MEN-2A is caused by a codon 634 mutation,
and nearly all MEN-2B is caused by the Met918Thr mutation.
• Mutational analysis is available in the UK.
Clinical features—MEN-2A
MTC
• MTC is often the initial manifestation and is generally multifocal.
• Phaeochromocytoma and parathyroid disease typically develop later.
• Diagnosis of MTC requires histological analysis which reveals C cell
hyperplasia and stromal amyloid.
• Circulating calcitonin levels are generally elevated, but hypocalcaemia
is not seen.
• CEA is also elevated and is a useful tumour marker.
• With metastatic disease, diarrhoea is common (30%).
• Rarely, these tumours secrete ACTH, resulting in Cushing’s syndrome
due to ectopic ACTH secretion.
Phaeochromocytoma
• Usually presents later than MTC.
• Most commonly associated with codon 634 mutations.
• 50% will be bilateral, but malignancy is rare (<10%).
• These lesions must be excluded prior to surgery for any other
indication.
MEN TYPE 2 593
Table 9.7 Classification and presentation of MEN-2

Pathology MEN-2A MEN-2B FMTC
MTC 95% 7100% 7100%
Phaeochromocytoma 50% 50% Not present
Parathyroid neoplasia 20–30% Not present Not present
Marfanoid habitus Not present 75% Not present
Mucosal neuromas Not present 10–20% Not present
Intestinal Not present 740% Not present
ganglioneuromatosis
• Generally results from hyperplasia of the glands.
• Mainly associated with codon 634 mutations, less commonly with
other RET mutations.
• Can present as early as 5 years with codon 634 mutations, and
commencement of early screening is recommended.
Clinical features—MEN-2B
• Mucosal neuromas can be found on the distal tongue, conjunctiva, and
throughout the gastrointestinal tract (may cause malabsorption).
• A marfanoid habitus is typically evident.
• MTC tends to present earlier than in MEN-2A and frequently follows a
more aggressive course.
Management of MEN type 2

(See Box 9.7 for prognosis.)
MTC
• The definitive treatment is adequate surgery by total thyroidectomy
and careful lymph node dissection by an experienced surgeon. (Check
calcitonin 3 months post-operatively.)
• Post-operative levothyroxine is administered to all patients. These
tumours are not TSH-driven, therefore TSH suppression is not
recommended.
• Tumour spread is usually local, but distant metastases do occur.
• Regular post-operative calcitonin assessment (first 3 months, then
6–12-monthly) is used to monitor for disease recurrence.
• MRI, octreotide scanning, and venous catheterization may all be helpful
in staging disease recurrence.
• Treatment of recurrent disease responds poorly to radiotherapy or
chemotherapy and, consequently, is generally surgical, if appropriate.
• Somatostatin analogues may help symptom control, e.g. diarrhoea, but
do not appear to have an antitumour effect.
• Few data are available to date, but therapy with radiolabelled MIBG
or somatostatin analogues appears to offer significant symptomatic
improvement, although tumour stabilization and/or regression was
observed only rarely.
• Molecular therapies that inhibit RET and other tyrosine kinases may be
of benefit in metastatic MTC, e.g. vandetanib.
• Children with MEN-2 should be considered for early prophylactic
surgery. This should generally be performed before the age of 5 years
and before the age of 1 year in patients with the highest risk of
mutations.
• Different mutations are associated with specific phenotypes. Risk
stratifications of mutations should guide planning of management in
terms of screening, timing, and extent of surgery, in conjunction with
clinical, imaging, and biochemical data.
Phaeochromocytoma
• These tumours are best treated medically with A- and B-blockade,
followed by surgical removal.
• The risk of multifocal and/or recurrent disease must be considered,
although malignant phaeochromocytomas are rare.
• Screening has resulted in the earlier detection of these lesions.
The criteria for diagnosis and the indications for surgery are broadly simi-
lar to those for sporadic p hyperparathyroidism.
Mutational analysis
• First- and second-degree relatives of patients with MEN-2 and genetic
analysis should be performed as early as possible in at-risk children so
that appropriate treatment can be planned early.
• Consider screening in patients with sporadic MTC or sporadic
phaeochromocytoma or in patients with mucosal neuromas or other
phenotypic features compatible with MEN-2B.
• Somatic RET oncogene mutations confer a worse prognosis in sporadic
medullary carcinoma.
Screening for MEN type 2
Biochemical and radiological screening is relevant for affected patients,
asymptomatic mutation carriers, and first- and second-degree relatives in
families with a clinical diagnosis of MEN-2, but where a mutation has not
been identified (see Table 9.8).
Table 9.8 Screening in MEN-2

Test Frequency
Calcitonin, CEA Annual
Phaeochromocytoma screen Annual
Calcium 9 PTH Annual
MRI adrenals Annual to 3-yearly
Box 9.7 Prognosis

• Variable.
• Overall, 10-year survival rate for MEN-2B is 65% and for MEN-2A
80%. The outcomes depend on the presence of metastases
from MTC.
• The prognosis for these patients is improving with earlier screening
and intervention.
• Children who have had timely and appropriate thyroidectomy are
leading healthy lives.
Further reading
Brandi ML, Gagel AF, Angeli A, et al. (2001). Guidelines for diagnosis and therapy of MEN type 1
and 2. J Clin Endocrinol Metab 86, 5658–71.
Carling T (2005). Multiple endocrine neoplasia syndrome: genetic basis for clinical management. J
Curr Opin Oncol 17, 7–12.
Constante G, Meringolo D, Durante C, et al. (2007). Predictive value of serum calcitonin levels for
preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients
with thyroid nodules. J Clin Endocrinol Metab 92, 450–5.
Marx SJ (2005). Molecular genetics of multiple endocrine neoplasia types 1 and 2. J Nat Rev Cancer
5, 367–75.
Waguespack SG, Rich TA, Perrier ND, et al. (2011). Management of medullary thyroid carcinoma
and MEN2 syndromes in childhood. Nat Rev Endocrinol 7, 596–607.
Wirth LJ, et al. (2013). Case records of the Massachusetts General Hospital. Case 5-2013.
A 52-year-old woman with a mass in the thyroid. N Engl J Med 368, 664–73.
Inherited primary hyperparathyroidism

Definitions
• Parathyroid tumours affect 1 per 1,000 population.
• p hyperparathyroidism is inherited in up to 10% of patients.
Causes
• MEN-1.
• MEN-2A.
• Hyperparathyroidism-jaw tumour syndrome (HPT-JT).
• Familial isolated hyperparathyroidism (FIHP).
HPT-JT
• Characterized by pathology in three main tissues:
• Parathyroid tumours which show a high penetrance in these
patients and, in up to 15% of cases, will be parathyroid carcinomas.
• Ossifying fibromas which affect the maxilla and/or mandible in
around 30% of HPT-JT patients.
• Renal manifestations may also occur, the commonest are bilateral
renal cysts (19% of patients) but also include hamartomas and Wilms’
tumours.
• Benign and malignant uterine pathology is seen in up to 75% of women
with HPT-JT and reduces reproductive fitness.
• In sporadic parathyroid cancer, HRPT2 somatic mutations have been
identified in 75% of tumours.
• Other tumours have also been reported in these patients, including
pancreatic adenocarcinomas, testicular mixed germ cell tumours,
Hürthle cell thyroid adenomas, and benign and malignant uterine
tumours.
• The gene (HRPT2), inactivating mutations of which are responsible
for HPT-JT, has been identified on the long arm of chromosome 1
(1q31.2), and mutational analysis is available in the UK.
• The function of the protein product (parafibromin) encoded by this
tumour suppressor gene is unknown.
FIHP
• Affected individuals within a kindred suffer only from p
hyperparathyroidism as an isolated endocrinopathy.
• In some kindreds, mutations in the MEN-1 or HRPT2 genes have been
identified, but, in the majority, the cause is still unknown.
Further reading
Carpten JD, Robbins CM, Villablanca A, et al. (2002). HRPT2, encoding parafibromin, is mutated in
hyperparathyroidism-jaw tumor syndrome. Nat Genet 32, 676–80.
Marx SJ (2002). Hyperparathyroidism in hereditary syndromes: special expressions and special man-
agements. J Bone Miner Res 17, N37–43.
INHERITED PRIMARY HYPERPARATHYROIDISM 597
Inherited renal calculi

Definitions
• Renal calculi affect 12% of ♂ and 5% of ♀ by the 7th decade of life.
• Renal calculi arise due to a reduced urine volume or i excretion of
stone-forming components, such as calcium, oxalate, urate, cystine,
xanthine, and phosphate.
• A variety of causes for renal stones are established (see Box 9.11 for
general causes of nephrolithiasis), but the commonest aetiology is
hypercalciuria.
• Calcium stones account for >80% of all renal calculi.
• Uric acid stones comprise 5–10% of all renal calculi.
• The commonest cause of hypercalciuria is hypercalcaemia, and this, in
turn, is most frequently s to p hyperparathyroidism.
• Nephrolithiasis is frequently a recurrent condition, with a relapse rate
of 75% in 20 years.
• Features associated with recurrence include early age of onset, +ve
family history, and lithiasis related to infection or underlying medical
conditions.
Genetics
• Renal calculi generally arise from complex multifactorial disease
resulting from an interaction between genetic and environmental
factors.
• The disorder may be familial in up to 45% of patients.
• The majority of causative genes are probably, as yet, unidentified and
account for much of ‘idiopathic’ calcium nephrolithiasis.
• Many cases of hypercalciuria are likely to be polygenic, but two
examples of monogenic causes are Dent’s disease and autosomal
dominant hypocalcaemic hypercalciuria (ADHH).
Dent’s disease
• X-linked condition.
• Due to inactivating mutations in a chloride channel (CLC5) gene.
• Characterized by hypercalciuria, nephrocalcinosis, B2 microglobinuria,
progressive glomerular disease, and mild rickets due to renal
phosphate loss in affected ♀.
Familial hypocalciuric hypercalcaemia (FHH)
• Due to activating mutations in the calcium-sensing receptor gene.
• May be asymptomatic or present early with neonatal or childhood
seizures.
See Box 9.8 for causes and Box 9.9 for mutational analysis.
INHERITED RENAL CALCULI 599
Box 9.8 Causes of renal calculi

• Hypercalciuria.
• Hyperoxaluria.
• Hyperuricosuria.
• Hypocitraturia.
• Urinary tract infection, e.g. Proteus, Pseudomonas, Klebsiella.
• p renal disease, e.g. polycystic kidney disease.
• Drugs, e.g. indinavir (protease inhibitor-antiretroviral), diuretics,
salicylates, allopurinol, some chemotherapeutic agents.
Box 9.9 Mutational analysis

• Currently, largely a research tool.
• Mutations in a variety of genes have been reported to result in
renal calculi due to hypercalciuria, hyperoxaluria, cystinuria, or
hyperuricosuria.
• As these research tests move into the clinical domain, then family
screening will become increasingly relevant.
Investigation of renal calculi (see also Table 9.9)

• 24h urine volume and urine osmolarity (low urine volume raises
production of solutes).
• 24h urinary calcium excretion.
• Urine pH.
• Stone composition, if possible.
• Exclude causes of hypercalcaemia (hyperparathyroidism,
immobilization, or renal tubular acidosis).
• Exclude hypercalciuria (excess chloride, excess sodium, malignancy,
sarcoidosis, renal calcium leak, and drugs, e.g. levothyroxine or loop
diuretics).
• Exclude causes of hyperoxaluria (p hyperoxaluria, vitamin B6
deficiency, short bowel syndrome, and excess dietary oxalates).
• Exclude urinary tract infection.
• Exclude causes of hyperuricosuria (gout, dietary, uricosuric drugs,
binge drinking, or myeloproliferative disorders).
• Exclude causes of hypocitraturia—citrate is the p agent for removal
of excess calcium (renal tubular acidosis, potassium or magnesium
deficiency, urinary tract infection, renal failure, and chronic diarrhoea).
• Exclude cysteine (usually genetic in origin) or xanthine (usually s to
allopurinol treatment) stones.
Management
• Increase fluid intake.
• Appropriate dietary modifications.
• Treat underlying cause.
Table 9.9 Acid load test for diagnosis of renal tubular acidosis
Side effects Nausea
Procedure Normal breakfast
Fluid intake 200–300ml/h
08.00 empty bladder
Hourly collection of urine for pH over 10h
10.00 ammonium chloride capsules 0.1g/kg taken over 1h to
avoid gastric irritation
Sampling Urine hourly–pH
Electrolytes 10:00 14:00 18:00
Interpretation Urine pH should fall <5.2
Plasma bicarbonate should fall (ammonium chloride
absorbed)
Causes of hypercalciuria
With hypercalcaemia
• Primary hyperparathyroidism.
• Granulomatous disease.
• Vitamin D excess.
• Malignancy (rare as a cause of stone).
• Hyperthyroidism.
With normocalcaemia
• Distal renal tubular acidosis.
• Granulomatous disease.
• Cushing’s disease.
• Idiopathic hypercalciuria.
• Dent’s disease.
• Bartter syndrome.
• Hypocalcaemic hypercalciuria.
• Hereditary hypophosphataemic rickets.
• Acromegaly.
Further reading
Langman CB (2004). The molecular basis of kidney stones. Curr Opin Paediatr 16, 188–93.
Sakhaee K, et al. (2012). Clinical review. Kidney stones 2012: pathogenesis, diagnosis, and manage-
ment. J Clin Endocrinol Metab 97,1847–60.
Thakker RV (2004). Diseases associated with the extracellular calcium-sensing receptor. Cell
Calcium 35, 275–82.
Worcester EM, Coe FL. (2010). Clinical practice. Calcium kidney stones. N Engl J Med 363, 954–63.
Chapter 10 601
Endocrine surgery
Transsphenoidal surgery/craniotomy 602

Thyroidectomy 606
Parathyroidectomy 608
Phaeochromocytoma 610
602 CHAPTER 10 Endocrine surgery
Transsphenoidal surgery/craniotomy
Preoperative assessment
Confirm the following:
• Anterior and posterior pituitary function normal or on adequate
replacement:
• Short Synacthen® test (note both the 0 and 30min values), and/
or normal ACTH/9 a.m. cortisol. NB Patients with recent loss of
ACTH will have a normal response to SST, as adrenal atrophy will
not have evolved. If in any doubt, replace with glucocorticoids.
• FT4.
• LH, FSH, oestradiol, or testosterone.
• Prolactin.
• Serum and urine osmolality, and electrolytes if polyuric.
• Recent (<3 months) MRI pituitary.
• Formal visual field perimetry and visual acuity assessment.
• Document extraocular muscle movements.
• Urea and electrolytes (<1 week presurgery).
• Group and save serum.
• MRSA screen should be done at least 2 weeks prior to admission for
surgery if the patient has been in hospital within the last year.
• Record therapeutic options discussed with patient, including:
• Risks of surgery (e.g. CSF leakage, meningitis, bleeding, partial or
total hypopituitarism, including diabetes insipidus, and potential
effects on fertility and visual deterioration).
• Risk of recurrence requiring further surgery or radiotherapy.
• Warn patients that a sample of fat may be taken from their thigh or
abdomen for packing of the pituitary fossa.
• Reiterate the need for lifelong follow-up.
• Ensure antibiotic prophylaxis is given prior to surgery (the precise
regimen may vary, depending on the centre and patient, e.g.
flucloxacillin 500mg qds and amoxicillin 500mg tds PO/IV; use
erythromycin if penicillin-allergic). Some surgeons advocate a
prolonged course of antibiotics if CSF leakage occurs whilst others
recommend close surveillance and prompt treatment if concern
regarding possible meningitis (NB lower threshold for patients with
Cushing’s disease).
• MRSA +ve patients require prophylaxis with IV vancomycin.
• If steroid-deficient, steroid reserve is unknown, or if a patient has
Cushing’s disease (inadequate stress response), give hydrocortisone
20mg orally with morning premedication.
• If on levothyroxine preoperatively (for s hypothyroidism), change to
equivalent dose of T3.
TRANSSPHENOIDAL SURGERY/CRANIOTOMY 603
Post-operative
• Start hydrocortisone (20mg at 8 a.m./10mg at 12 noon/10mg at 6p.m.)
after surgery. Reduce to hydrocortisone 10mg/5mg/5mg on day 3
post-operatively.
• Watch for: headache, fever/photophobia/other signs of meningitis,
CSF leak, deterioration of vision, diplopia, bleeding, symptoms of
hyponatraemia.
• Fluid balance—watch for diabetes insipidus:
• Review the clinical status of the patient at regular intervals (?
euvolaemic/hypovolaemic/hypervolaemic).
• Record fluid input/output assiduously (NB fluid replacement in
theatre may be excessive; therefore, always include perioperative
fluids in fluid balance charts, and note sodium content).
• Check U&Es, plasma and urine osmolalities on a regular basis (at
least once daily and more frequently if clinical concerns).
• Post-operatively, restrict to 2L total fluid input (IV and PO).
• If patient becomes polyuric, i.e. >200mL/h for ≥3 consecutive hours
(in the context of a 2L/24h fluid restriction), then urgently check
plasma U&Es, plasma and urine osmolalities, and urinary sodium.
While waiting for results, allow free fluids; aim to replace the fluid
deficit.
• If diabetes insipidus confirmed by the results, give a single dose of
desamino-D-arginine vasopressin (desmopressin) (1 microgram SC).
• When fluid deficit has been replaced (usually orally), restart 2–3L
fluid restriction (again, include IV and PO routes).
• If polyuria recurs, treat as before.
• Regular U&Es, plasma and urine osmolalities required.
• If polyuria continues to recur up to and after 96h post-operatively,
consider regular DDAVP orally or intranasally, if possible (not if a
transsphenoidal approach is used).
• Hyponatraemia occurring 1 week after a transsphenoidal adenectomy
is most commonly due to SIADH; rarely, cerebral salt wasting may
occur. Check urinary sodium, and assess fluid status (cerebral salt
wasting causes very high urinary sodium and is associated with
dehydration and a high urine volume).
• Check for CSF leakage: bedside-test nasal fluid with Glucostix® and
send a sample for beta-transferrin/tau-protein (abundant in neurons)
for confirmation (+ve if CSF).
• If patients sent home on day 3 post-operatively, they should be advised
to watch for a fever, headache, excessive sensitivity to light, confusion,
drowsiness, vomiting, nasal discharge, deterioration of vision, excessive
urination (>200mL/h for ≥3 consecutive hours).
• In patients with Cushing’s disease, check 9 a.m. cortisol concentrations
on day 7, having omitted hydrocortisone dose on the evening before
and on the morning of the test. 9 a.m. cortisol <50nmol/L suggests cure;
occasionally, cortisol takes a few days to fall to undetectable levels.
• For all patients on day 7, recheck visual acuity and formal visual field
perimetry and eye movements, along with FBC, ESR, LFTs, U&Es,
plasma and urine osmolalities, glucose, TFTs (for those patients not
on T3).
• Comment on results:
• If FT4 and FT3 low, offer T3 and recheck TFTs in 6 weeks.
• If serum cortisol >450nmol/L, stop hydrocortisone.
• If serum cortisol 150–450nmol/L, stop hydrocortisone and cover
with steroids in times of stress.
• If serum cortisol <150nmol/L, continue on hydrocortisone.
• Recheck HPA axis 6 weeks post-operatively.
• Give information to patient, including advice on driving:
• For an ordinary driving licence (group 1, car or motorcycle), a
minimum horizontal field of 120 degrees is required as well as no
significant defect within the central 20 degrees. For a licence to
drive a group 2 vehicle (bus or lorry), then normal binocular field is
required. Taxi driver licence regulations vary locally.
• If an individual has normal visual fields and acuity and an
uncomplicated transsphenoidal operation, they may restart to drive
once recovered from the surgery (group 1 and group 2 licences).
• Following a craniotomy, group 2 licence holders are suspended
for 6 months; however, group 1 licence holders can restart driving
once recovered, providing their vision is satisfactory and there is no
history of seizures.
• All patients should inform their insurance company about the
pituitary tumour and pituitary surgery.
• Give information to patient on contact details for the Pituitary
Foundation support group and DVLA:
• The Pituitary Foundation, 17/18 The Courtyard, Woodlands,
Bradley Stoke, Bristol BS12 4NQ. Tel: 01454 201612.
• Medical Adviser, The Drivers’ Medical Branch, 2 Sandringham Park,
Swansea Vale, Llansamlet, Swansea SA6 8QD. Tel: 0870 0600 0301.
TRANSSPHENOIDAL SURGERY/CRANIOTOMY 605
Thyroidectomy
Preoperative
• Ensure euthyroidism. Surgery in the presence of poorly controlled
hyperthyroidism is associated with an increased post-operative
mortality (often by precipitation of a thyroid storm).
• If surgery is required in the presence of hyperthyroidism, give
potassium iodide (60mg 3× a day for 10 days); this reduces thyroid
hormone release and probably decreases perioperative blood loss.
The radiographic contrast agent iopanoic acid, which is rich in iodine,
provides a useful alternative and has the additional benefit of potently
inhibiting the 5-deiodinase, thus reducing T4 to T3 conversion. Oral
propranolol (40–120mg 3× a day) reduces clinical manifestations of
thyrotoxicosis. Steroids (e.g. hydrocortisone 100mg IV 4× a day) can
be used to decrease T4 to T3 conversion.
• Check vocal cord function by indirect laryngoscopy.
• Warn of post-operative risks: recurrent laryngeal nerve damage <1%,
keloid scarring, haemorrhage, permanent hypoparathyroidism <0.5%,
and hypothyroidism (10% of partial thyroidectomy patients).
Post-operative
• Risk of haemorrhage in first 24h, particularly major haemorrhage deep
to the strap muscles leading to airway compression. Watch for stridor,
respiratory difficulties, and wound swelling. Drainage from wound
drains is unhelpful. Treat by evacuating the haematoma; consider
intubation or a tracheostomy. Clip removers and artery forceps should
be kept to hand on the ward.
• Recurrent laryngeal nerve damage is permanent in <1% and
transient in 2–4%. Patient’s voice is often husky for about 3 weeks
post-operatively and may be treated with lozenges and humidified air.
• Symptomatic unilateral damage can be treated by stabilization of the
affected cord in adduction by submucosal Teflon® injection under
direct laryngoscopy.
• Bilateral damage leads to unopposed adductor action of the
cricothyroid muscle which causes glottis closure and airway
obstruction. Treatment involves reintubation, paralysis, hydrocortisone
(100mg 4× a day IM for oedema), and extubation at 24h—if that fails, a
tracheostomy should be performed.
• If recurrent laryngeal nerve damage is persistent at 9 months, an
attempt can be made to resuture the nerve.
• Monitor calcium. Transient hypoparathyroidism is usually evident
within 7 days (for treatment, b see Hypoparathyroidism, p. 478).
• Patients undergoing thyroidectomy are at high risk of post-operative
nausea and vomiting.
• Following total thyroidectomy for malignancy, the patient should be
converted to T3, which should be stopped at least 10 days prior to
the post-operative radioiodine uptake scan to allow the TSH to rise
(b see Follow-up of papillary and FTC, p. 100). Alternatively,
recombinant TSH can be used for the scan.
THYROIDECTOMY 607
• If total thyroidectomy is performed for hyperthyroidism, levothyroxine

(71.6 micrograms/kg) should be commenced 4–5 days post-operatively,
as, during the operation, handling of the thyroid results in release of
stored thyroid hormones, and levothyroxine has a long half-life. Check
TSH in 6–8 weeks.
• Following partial thyroidectomy, transient biochemical hypothyroidism
may occur during the first 2 months and does not warrant treatment,
unless the patient is symptomatic or it becomes persistent.
Parathyroidectomy
Parathyroidectomy of one or two glands undertaken for p hyperpar-
athyroidism may result in transient and self-limiting hypocalcaemia. Total
parathyroidectomy (e.g. for MEN-1 or as part of surgical management of
advanced head and neck malignancy) may be complicated by severe and
permanent hypocalcaemia which may be very difficult to manage.
Post-operative care for patients undergoing
parathyroidectomy of 1–2 glands
• Check calcium, phosphate, magnesium, albumin on the evening of
surgery and daily thereafter. Calcium begins to fall post-operatively
after about 4–12h; the nadir is usually reached by 24h. Calcium may
recover spontaneously; however, one-third of patients will require
calcium support perioperatively. With the advent of minimally invasive
parathyroidectomy and short hospital stays (<24h), many centres
advocate prophylactic calcium and vitamin D replacement in all cases
in the immediate aftermath of surgery, which is continued until the
patient is reviewed 1–2 weeks later in the outpatient clinic.
• Symptoms of hypocalcaemia (mainly due to neuromuscular
irritability): perioral paraesthesiae, Chvostek’s sign, Trousseau’s sign,
tetany, laryngospasm, bronchospasm, seizures, prolonged QT interval
on ECG, extrapyramidal movement disorders, and delirium. Calcium
levels often <1.75mmol/L before symptoms manifest, although rapid
changes in calcium result in more pronounced symptomatology.
• Magnesium deficiency is common due to previous hyperparathyroidism
(causes renal wasting of magnesium). Chronic magnesium deficiency
impairs release of PTH and causes functional hypoparathyroidism and
hypocalcaemia.
Causes of hypocalcaemia post-1–2 gland removal
• ‘Functional hypoparathyroidism’ common. Causes: delayed recovery
of the other parathyroid glands due to long-term suppression;
parathyroid gland ischaemia; parathyroid gland ‘stunning’ by
intraoperative handling; hypomagnesaemia. PTH level will be
detectable; phosphate should be normal. Usually spontaneously
improves over days to weeks. Management of symptomatic
hypocalcaemia (Ca usually <1.8mmol/L) with calcium (up to 2g/day in
divided doses). Add in vitamin D/vitamin D metabolites if persistent
hypocalcaemia. Replace magnesium, as necessary. Gradual withdrawal
of therapy to assess recovery.
• ‘Hungry bone syndrome’ due to extensive skeletal remineralization
once skeleton released from PTH excess. Ongoing i ALP, d calcium,
d PO4, d Mg. PTH levels may be normal or high. Pre-existing vitamin
D deficiency will exacerbate hypocalcaemia. May require large
doses of calcium and vitamin D/vitamin D metabolites for weeks to
months.
• Permanent hypoparathyroidism. Rare (<2% of cases). Check PTH level
after day 3; level will be undetectable (<1pg/mL). Replace with oral
calcium and vitamin D/vitamin D metabolites long-term.
PARATHYROIDECTOMY 609
• Other complications:
• Recurrent laryngeal nerve palsy (<1%).
• Failure to correct hypercalcaemia.
• Overall, both minimally invasive and conventional parathyroidectomy
are very safe operations, with low morbidity and mortality.
Calcium management following total
parathyroidectomy
• Hypocalcaemia is inevitable unless management instituted.
• Pre-emptive treatment is worth considering (e.g. 1A-calcidol 1–2
micrograms/day—this dose may be insufficient to completely prevent
hypocalcaemia but may prevent life-threatening hypocalcaemia and is
unlikely to cause serious toxicity in the short term).
• Acute management in patients with life-threatening hypocalcaemia (e.g.
Trousseau’s sign, laryngospasm, seizures):
• 10mL of 10% calcium gluconate, diluted 1 in 10 in normal saline
or glucose 5%, infused into large vein over 10min. Monitor cardiac
rhythm.
• Repeat, as necessary, to control acute emergency.
• Patients will need ongoing calcium replacement: 100mL of 10%
calcium gluconate in 1L of 5% glucose or 0.9% sodium chloride,
infused over 24h (monitor calcium regularly (4–6-hourly), and
adjust rate as necessary).
• Start oral vitamin D analogues and oral calcium.
Vitamin D analogues (1A-calcidol; calcitriol)
• Potent and effective in acute hypocalcaemia due to rapid correction
of calcium. Short half-lives allows for rapid and careful titration of
dose in response to calcium levels. Narrow therapeutic window
(but hypercalcaemia much shorter lived if it develops).
• Dose for dose, calcitriol twice as efficacious as 1A-calcidol (i.e.
1 microgram calcitriol equivalent to 2 micrograms 1A-calcidol).
1A-calcidol can be given down an NG tube.
• Starting doses usually high (e.g. 4–8 micrograms/day of 1A-calcidol in
divided doses), rapidly weaned to maintenance doses (typically 1–2
micrograms/day 1A-calcidol).
• Reassess often (at least every 1–2 days) in early stages of management.
Longer-term options include ergocalciferol or colecalciferol, but
hypercalcaemia will be more prolonged if it develops.
Calcium
• 1–2g/daily in divided doses. A maximum daily absorbable dose of
calcium is probably 3g day.
• Absorption may vary from different types of calcium salts and may be
greater when calcium is given away from food.
• The long-term aim is to manage without calcium, just on vitamin
D/vitamin D metabolites.
Long-term goal of management is to prevent symptoms of hypocalcaemia
without toxicity. Aim for lower half of normal range (2.0–2.3mmol/L), with
normal urinary calcium excretion (to minimize risk of nephrolithiasis and
nephrocalcinosis).
Phaeochromocytoma
Preoperative
• Check for bilateral disease or metastases: MRI chest and abdomen, and
an MIBG scan (10% multiple).
• Ensure adequate A- and B-blockade once the diagnosis is made.
• Start B-blockade only AFTER patient has been adequately A-blocked
(unopposed B-blockade can lead to marked vasoconstriction,
ischaemic damage, and hypertension).
• A-blockade. Start phenoxybenzamine (10–20mg PO, 3–4x day)—an
irreversible A-blocker. Adequacy of dose assessed by monitoring
haematocrit and postural BP drop (reflex vasodilation). Side effects
include dizziness, lethargy, and ankle swelling. Some centres use
doxazosin; others are concerned that this does not offer both A1-
and A2-blockade.
• Start treatment at least 1 week before surgery, ideally >3 weeks.
• B-blockade. Start propranolol (20–80mg PO, 3x day) when patient
adequately A-blocked. Titrate to maximum tolerated or a total
dose of 240mg/day in divided doses.
• Control BP: A- and B-blockers often sufficient; if not, add a calcium
channel blocker or an ACE inhibitor; A-methyltyrosine 1–4g/day (a
false catecholamine precursor which inhibits tyrosine hydroxylase,
the rate-limiting step for catecholamine synthesis) is rarely used to
control BP.
• Some centres advocate the use of additional IV phenoxybenzamine
(0.5–1.0mg/kg in 250mL 5% dextrose, given over 2h) for 3 days prior to
surgery (titrate the dose according to BP; often, 0.5mg/kg is sufficient).
• Monitor haemoglobin/haematocrit (because of haemodilution,
preoperative blood transfusions may be necessary) and postural BP.
• Group and save serum, and cross-match 2 units of blood.
• Ensure that the patient is well hydrated (if necessary, use an IV infusion
of saline) prior to going to theatre.
Post-operative
• Stop A- and B-blockers.
• Watch for d BP: sudden withdrawal of catecholamines leads
to marked arterial and venous dilatation. This is worsened by
inadequate volume loading and should initially be treated with volume
replacement rather than by pressor agents.
• If hypertension persists 2 weeks post-operatively, then residual tumour
or metastases must be considered.
• Long-term monitoring required, as approximately 14% recur.
• If bilateral adrenalectomy performed, see next section.
PHAEOCHROMOCYTOMA 611
Bilateral adrenalectomy
• Give hydrocortisone (100mg, 4x day IM) post-operatively; this will
provide adequate mineralocorticoid as well as glucocorticoid cover.
Continue this until eating and drinking (often <48h). Monitor U&Es.
• From day 3, give hydrocortisone PO (double usual replacement dose,
e.g. 20mg/10mg/10mg), and add fludrocortisone PO (100 micrograms
daily).
• Long-term replacement with hydrocortisone 10mg/5mg/5mg, and
fludrocortisone 50–150 micrograms daily.
Phaeochromocytoma in pregnancy (b see p. 447)
• Rare condition; may present as paradoxical supine hypertension, with
pressure from the gravid uterus causing release of catecholamines, and
normal blood pressure in the supine and erect positions.
• Start A-blockade, then B-blockade; phenoxybenzamine can cross the
placenta but is generally safe for the fetus (may cause perinatal CNS
depression and transient hypotension). Propranolol has been reported
to be associated with intrauterine growth retardation, fetal bradycardia
and hypoglycaemia, and premature labour.
• Surgery is more controversial, although some authors advocate
surgery in the first and second trimesters up to 24 weeks’ gestation.
• Caesarian section is advocated, with a combined tumour resection.
Vaginal delivery carries a significant maternal risk.
Chapter 11 613
Endocrinology
and ageing
Endocrinology and ageing 614

Bone disease in the elderly 616
GH and IGF-1 in the elderly 618
Gonadal function in the elderly 620
Adrenal function in the elderly 622
Thyroid disease in the elderly 624
614 CHAPTER 11 Endocrinology and ageing
Endocrinology and ageing

Introduction
• Ageing causes changes in many hormonal axes. How much of this
change is normal physiology associated with ageing and how much
represents true endocrine dysfunction, and thus warrants treatment, is
unclear.
• Concomitant disease and polypharmacy are common in the elderly
population, with frequent s effects upon the endocrine system.
Fluid and electrolyte homeostasis in the elderly
• Elderly patients are particularly prone to fluid and electrolyte
disturbances due to changes associated with ageing, concomitant
disease, and drug usage.
• Elderly patients have d renal function compared with younger patients:
• d glomerular filtration rate, with creatinine clearance d
by 8mL/min/1.73m2 per decade after age 30.
• i renovascular disease.
• d renal sensitivity to circulating hormones:
— Aldosterone.
— Vasopressin.
— Atrial natriuretic peptide (probable).
• d ability to dilute or concentrate urine.
• Elderly patients have d renin levels, with s decreases of aldosterone
levels (both basal and stimulated levels). Aldosterone levels may be
<50% normal by 70 years of age. d renal sensitivity to aldosterone
may result in isolated mineralocorticoid deficiency (distal renal tubular
acidosis (type 4) with hyponatraemia, hyperkalaemia, hyperchloraemia,
and normal anion gap acidosis); this is more common with diabetes
mellitus.
Vasopressin/ADH
• Unlike many other hormones, vasopressin (ADH) responses
are potentiated in elderly patients, with i release from the
neurohypophysis in response to an osmotic stimulus and less effective
suppression. Normal vasopressin release is a balance of inhibitory and
stimulatory effects at baroreceptors and osmoreceptors. It may be
that loss of inhibition with ageing due to degenerative changes results
in relatively unopposed stimulation of ADH and a d ability to suppress
ADH release.
• In addition, altered renal sensitivity to vasopressin results in d ability to
excrete free water.
ENDOCRINOLOGY AND AGEING 615
Hypernatraemia and dehydration

• Perception of thirst is altered in elderly persons (in younger people,
thirst is perceived at plasma osmolalities >292mOsm/kg, whereas in
older people, thirst is perceived at plasma osmolalities >296mOsm/kg).
Elderly patients may also be unable to ingest fluids because of other
disabilities and/or effects of medications.
• Thus, elderly persons are particularly susceptible to dehydration when
there are increased fluid losses (e.g. during hot summers). This is
exacerbated by impaired renal concentrating ability.
Hyponatraemia
• Common. Hyponatraemia affects 7% of healthy elderly people, 15–18%
of elderly people in residential care facilities, and 53% of elderly people
in nursing care facilities.
• Mortality rates in hospitalized elderly patients with hyponatraemia
are high (in patients aged >65 years, 16% mortality in those with
hyponatraemia, compared with 8% without hyponatraemia).
• Often associated with medication (e.g. diuretics).
• Commonest electrolyte disturbance in cancer (b see SIADH due to
ectopic vasopressin production, p. 648).
• Symptoms include confusion, lethargy, coma, seizures.
• Overall approach to investigation and management is similar to that of
hyponatraemia in younger patients (b see Hyponatraemia, p. 216).
• Mild idiopathic hyponatraemia is also recognized in elderly patients,
without necessarily having sinister cause or consequence, and is
thought to be s to altered threshold for ADH secretion.
Further reading
Ayus JC (1996). Abnormalities of water metabolism in the elderly. Semin Nephrol 16, 277–88.
Beck LH (1998). Changes in renal function with ageing. Clin Geriatr Med 14,199–209.
Bone disease in the elderly

Osteoporosis
Osteoporosis is not an inevitable part of ageing, but it is a common disease
in elderly people and is associated with high morbidity and mortality in
both males and females (b see Osteoporosis, p. 490).
Vitamin D deficiency (b p. 484)
• Very common in the elderly.
• Vitamin D insufficiency (evidence of s hyperparathyroidism, i bone
turnover, BMD loss) occurs at levels of 25OH vitamin D <50nmol/L.
• Vitamin D deficiency usually defined as concentrations <25nmol/L.
• Vitamin D deficiency and/or insufficiency is common, particularly in
elderly institutionalized patients, in extreme latitudes, and in fracture
patients.
• Supplementation in free-living elderly patients (>65 years of age)
d fracture risk.
• Prevalence of p hyperparathyroidism is 10/100,000 in ♀ <40 years
old, rising to 190/100,000 in ♀ >65 years old. Half of all cases of p
hyperparathyroidism occur in ♀ >60 years old.
• Elderly people are more prone to symptoms (weakness, fatigue,
confusion) at relatively mild levels of hypercalcaemia (2.8–3.0mmol/L).
• Other causes of hypercalcaemia must be excluded.
• Coexisting vitamin D insufficiency and deficiency is common.
• Management is similar to that described in b Chapter 6,
Hypercalcaemia, p. 460.
• Surgery is not contraindicated by age alone.
Paget’s disease
b see Chapter 6, Paget’s disease, pp. 506–9.
Further reading
Mosekilde L (2005). Vitamin D and the elderly. Clin End 62, 265–81.
BONE DISEASE IN THE ELDERLY 617
GH and IGF-1 in the elderly

• Many of the features of normal ageing resemble those of growth
hormone deficiency in younger patients.
• Changes in body composition with ageing include d lean body mass
(d body water, d muscle mass, and d bone mass) and i total body fat
and visceral fat mass, associated with abnormal lipid profile (i total
and LDL cholesterol, i TGs), insulin resistance, and d exercise and
cardiac capacity.
• Overall, integrated GH concentrations show a decrease with age, with
d GH pulse amplitude and duration, but pulse frequency unchanged.
For ♂ over 25 years old, GH secretion d by 750% every 7 years.
• IGF-1 d with i age (reflected in age-adjusted normative ranges).
• IGFBP-3 d with i age (and is also GH-dependent).
• The d in GH concentration with age is likely to be related to altered
hypothalamic regulation, rather than a decreased secretory capacity.
• Other factors may also d GH/IGF-1 concentrations with ageing, such
as d physical fitness, d production of sex hormones, fragmented sleep
(GH is secreted mainly during slow-wave sleep), and malnutrition
(inhibiting IGF-1 synthesis).
• The use of replacement GH therapy in healthy elderly people has been
debated.
• A systematic review of the use of GH in healthy elderly patients
found fat mass d by 2.1kg and lean body mass i by 2.1kg. There
were no clear benefits to serum lipid measurements or bone density.
Side effects were frequently observed (oedema, arthralgias, carpal
tunnel syndrome, glucose intolerance), and theoretical concerns of
malignancy related to raised IGF-1 levels remain. Furthermore, no
functional benefits have been demonstrated.
• Older patients with GH deficiency related to pituitary disease are
usually easily differentiated from other subjects with age-related
decline in IGF-1, using standard provocative testing (GH response to
insulin-induced hypoglycaemia, arginine, or glucagon).
• A systematic review of the use of GH in elderly patients (aged
60–80 years) with GH deficiency found d total cholesterol (4–8%),
d LDL-C (11–16%), d waist circumference (73cm), and increased
quality of life (measured by AGHDA score). No effects have been
clearly demonstrated on HDL-C or TG concentrations, BP, or
bone density. Data on the effects of GH on body composition were
conflicting in studies.
• Few data exist on the benefits of GH in patients with GH deficiency
over the age of 80.
• GH is not licensed in the UK for healthy elderly people without clear
evidence of clinical and biochemical GH deficiency.
Further reading
Kokshoorn N (2011). GH replacement therapy in elderly GH-deficient patients: a systematic
review. Eur J Endocrinol 164, 657–65.
Liu H (2007). Systematic review: the safety and efficacy of growth hormone in the healthy elderly.
Ann Int Med 146 104–15.
GH AND IGF-1 IN THE ELDERLY 619
Gonadal function in the elderly

Women
• The mean age of menopause is 51 years (range 35–58 years) and
is defined retrospectively after 12 months of amenorrhoea as the
permanent cessation of menstruation due to loss of ovarian follicular
activity.
• FSH 10–15× higher than premenopausal levels.
• LH 3–5× higher.
• Oestrogen 10% of previous level (often lower than ♂ of
similar age).
• Inhibin often undetectable.
• The adrenal gland is the major source of sex steroids
post-menopausally, with oestrogen production mainly from
aromatization of adrenal androgens (androstenedione) in adipose
tissue.
• Low FSH/LH may indicate hypopituitarism, although gonadotrophins
may be depressed by serious illness.
• For further discussion, b see Chapter 4, Menopause, p. 342.
Men
• ♂ may remain potent and fertile until their death. However, sexual
activity, libido, and potency decline gradually and progressively from
midlife.
• As with GH deficiency, there is an overlap between clinical features
of hypogonadism and ‘normal ageing’ (d lean body mass and muscle
function, i fat mass, d virility, d libido, and d overall well-being).
Functional s hypogonadism is common in serious chronic illness,
especially when associated with malnutrition and debilitation.
• Normal ranges for testosterone in ♂ of different ages have not been
well established.
• Free testosterone levels d slowly from age 20 to 80, but there
is significant intra- and inter-individual variation. The underlying
mechanism is that of d testosterone production, rather than i
clearance of testosterone. Testosterone production d with ageing, as
testicular weight, Leydig cell function, and FSH/LH response to GnRH
stimulation d.
• The extent to which lower testosterone per se and/or a lower
free androgen index explain the age-related decline in sexual
function is not clear. Although testosterone concentrations may
be lower than in younger ♂, testosterone concentrations are still
sufficient for normal libido and sexual function. Profoundly low
testosterone concentrations (<8nmol/L in a 9 a.m. blood sample)
in the appropriate clinical setting should prompt investigation for
hypoandrogenism. Gonadotrophins should be raised in p testicular
failure, and low levels associated with low testosterone should
prompt a search for s causes, though gonadotrophins may be low
because of other serious disease.
GONADAL FUNCTION IN THE ELDERLY 621
• Fat body mass increases more than lean body mass with age; thus,
there is i aromatization of androgens to oestrogens. The effects of
this are unclear.
• Hypoandrogenism may also result from hyperprolactinaemia due to
pituitary/hypothalamic disease, renal dysfunction, hypothyroidism,
drugs (psychotropic and anti-dopaminergic agents); all more common
in the elderly population.
Testosterone therapy (b p. 378)
• Few small studies in elderly ♂, either as replacement in patients with
clear hypogonadism or in healthy ♂.
• Data point towards a +ve effect on well-being, muscle mass and
strength, and d fat mass in elderly patients, with greatest effect in
patients with clear hypogonadism.
• Risk of s polycythaemia, liver dysfunction (particularly if testosterone
taken orally), prostatism, exacerbation of prostate adenocarcinoma,
and possibly dyslipidaemia.
Erectile dysfunction (b p. 388)
• Common in elderly ♂. 50% of ♂ >60 have erectile dysfunction; 90%
of these ♂ have concurrent medical problems or are on medication
potentially causing impotence.
• Aetiology often multifactorial:
• Atherosclerosis—commonest cause with both macro- and
microvascular disease.
• Penile denervation—autonomic neuropathy (most commonly due
to diabetes mellitus); pelvic surgery (including prostatectomy—30%
of ♂ >75 develop erectile dysfunction after prostatectomy
(compared with 7% of younger ♂ after prostatectomy)).
• Drugs (B-blockers, calcium channel antagonists, other
antihypertensive agents, psychotropic drugs).
• Psychogenic.
Delayed/absent ejaculation
• i common with age due to autonomic nerve dysfunction, drugs,
previous surgery, and usually the harbinger of erectile dysfunction.
• Evaluation similar to that of younger patients (b see Evaluation of
erectile dysfunction, p. 390).
• Management similar to younger patients, with caveat that
phosphodiesterase inhibitors may interact with nitrates and
antihypertensive agents.
Fertility
• Testicular morphology, semen production, and testicular
steroidogenesis are maintained into old age.
• There is some evidence for a small increase in specific genetic
disorders in the children of older men.
Adrenal function in the elderly

Cortisol
• Overall, cortisol secretion generally very similar in elderly persons to
younger persons.
• Dynamic testing shows more prolonged release of ACTH and cortisol
to stress (physiological, insulin-induced hypoglycaemia, and/or CRH
administration) and slower inhibition of ACTH secretion by cortisol.
Dehydroepiandrosterone sulphate
• DHEA and DHEAS levels peak in humans aged 20–30 years and
thereafter decline with age (20% of peak values in ♂ and 30% of peak
values in ♀ by age 70 years). Responsiveness to ACTH-stimulated
secretion also reduces with age.
• The physiological relevance of the fall of DHEA and DHEAS levels
with age is not established.
• Although DHEA therapy is sometimes used in patients with adrenal
insufficiency, its use in, otherwise healthy, elderly patients (who
experience an age-related d in DHEA) is not recommended; there
have been no demonstrated clinical benefits (in terms of longevity,
well-being, bone density, cognitive function, body mass composition,
or cardiovascular status).
Aldosterone
b see Fluid and electrolyte homeostasis in the elderly, p. 614.
ADRENAL FUNCTION IN THE ELDERLY 623
Thyroid disease in the elderly

Thyroid disease is twice as common in the elderly as in younger patients
(see Table 11.1).
Abnormal thyroid function tests
• Concomitant disease and polypharmacy are common in the elderly and
may alter the interpretation of results. For example, glucocorticoids
(prescribed to 2.5% of the population aged 70–79 years) cause
decreased TSH, d thyroid hormone release, d concentration of
thyroid hormone-binding proteins, d T4 to T3 conversion.
• Sick euthyroid syndrome is more common in the elderly due to
frequent concurrent non-thyroidal illness (see b p. 24), with reduced
free triiodothyronine (FT3), i reverse free tri-iodothyronine, and (less
commonly) reduced free thyroxine (FT4), with inappropriately normal
or suppressed TSH levels.
• See Table 1.4 for effects on thyroid function of drugs frequently
prescribed for elderly patients.
Hypothyroidism (see b p. 74)
• Commonest thyroid problem in elderly people.
• 7–17% of elderly people.
• ♂:♀ ratio increases with ageing.
• Commonest causes are autoimmune thyroiditis, previous surgery,
or radioiodine therapy (post-ablative hypothyroidism occurs more
frequently in people >55 years old than in younger patients).
• 25% present with classical symptoms of hypothyroidism. 50% complain
of fatigue and weakness. Elderly patients with hypothyroidism report
cold intolerance, weight gain, paraesthesiae, and muscle cramps less
frequently than do younger patients with hypothyroidism.
• The elderly are more susceptible to hypothyroid (myxoedema) coma
than younger people; it remains rare, however.
• Elderly patients with unrecognized hypothyroidism may be at
greater risk of the development of perioperative and intraoperative
complications (including intraoperative hypotension, heart
failure, and post-operative gastrointestinal and neuropsychiatric
complications).
• Hypothyroidism should be considered in elderly patients with i CK or
transaminases, d Na, macrocytic anaemia, or dyslipidaemia.
• Thyroid replacement therapy should be done cautiously, as ischaemic
heart disease may be unmasked or exacerbated, e.g. 12.5–25
micrograms/day of levothyroxine, i by 12.5–25 micrograms increments
every 3–8 weeks until TSH is normalized.
• Total replacement T4 dose is lower in the elderly than in younger
patients (in younger patients, approximately 1.6 micrograms/kg is
required, but older patients require 20–30% less).
• Compliance may be problematic. Supervised therapy or administration
using a Dosette® box may help. Alternatively, calculate the total
weekly dose of levothyroxine, and give 70% of the total dose once a
week or 50% of the total dose twice weekly.
THYROID DISEASE IN THE ELDERLY 625
Table 11.1 Changes in thyroid-related investigations with ageing

TSH No significant change; secretion remains
pulsatile, but loss of physiological nocturnal
TSH rise is blunted
T4 Unchanged overall (both secretion and
clearance d)
T3 10–50% decrease; occurs at an earlier age in
♀ than in ♂
rT3 i
Thyroid antibodies Prevalence i with age; significance uncertain
(2% at age 25, 15–32% at age 75)
24h radioactive iodine uptake Unchanged
Hyperthyroidism (see b p. 26)

• 0.3–2% of elderly people.
• Presentation is often atypical, often with few signs or symptoms.
• Clinical symptoms of hyperthyroidism are different in the elderly;
non-specific symptoms, such as weight loss, depression, or agitation,
predominate. Consider the diagnosis with muscle weakness; heart
failure, arrhythmias, atrial fibrillation; weight loss; and osteoporotic
fracture.
• An isolated suppressed TSH concentration is associated with an i
cardiovascular mortality and a 3-fold higher risk of atrial fibrillation in
the next 10 years. 2–24% of elderly patients with atrial fibrillation are
hyperthyroid, and 9–35% of elderly patients with hyperthyroidism have
atrial fibrillation.
• Underlying cause may be toxic multinodular goitre; Graves’s disease.
• Treatment options are similar to those in younger patients (b see
Treatment, p. 30).
• Radioactive iodine is favoured because it is definitive and it avoids risks
of surgery. Hypothyroidism is common after radioiodine therapy in
elderly people.
Goitre
• Diffuse goitre becomes less frequent with age in both ♂ and ♀
(found in 31% of ♀ aged <45 years, compared with 12% of ♀ aged
>75 years on clinical examination).
• Multinodular goiter, as assessed by both clinical and US examination,
increases with age (incidence of US-detected multinodular goitre 90%
of ♀ >70 years, 60% of ♂ >80 years).
• Management similar to that of multinodular goitre in younger patients
(b see Multinodular goitre and solitary adenomas, pp. 64–7).
Thyroid cancer (see b p. 91)

• Total incidence rate for all thyroid cancers is unchanged, but the
relative frequencies are altered.
• Papillary carcinoma is more common in young and middle-aged
patients and accounts for only 50% of thyroid cancers in patients over
60 years old. Older patients have a higher mortality rate.
• Follicular carcinoma: peak incidence in 6th decade of life. Prognosis is
poorer in older patients, possibly due to the increased frequency of
extraglandular recurrences in older patients.
• Anaplastic thyroid carcinoma: peak incidence in 7th decade.
Two-thirds of all cases occur in patients >65 years. It presents with a
rapidly growing hard mass which is often locally invasive and may be
associated with metastatic lesions. The prognosis is poor.
• Sarcomas and p thyroid lymphomas are more common in elderly
patients.
• Medullary thyroid cancer: sporadic forms have a mean age at
presentation of 47 years; hereditary forms more common in younger
patients. Older age at diagnosis and more advanced stage are
independent markers of a poorer prognosis.
• Overall evaluation and treatment is similar to that of younger patients,
but accurate preoperative histology is very important, as tumours
not treated surgically (e.g. anaplastic carcinoma and lymphoma) are
relatively more common.
Further reading
Grimley Evans J, Williams TF, Michel J-P, et al. (eds.) (2000). Oxford Textbook of Geriatric Medicine.
Oxford University Press, Oxford.
Vermeulen A (ed.) (1997). Endocrinology of ageing. Ballière’s Clin Endocrinol Metab 11, 223–50.
Chapter 12 627
Endocrinology aspects
of other clinical or
physiological situations
Hypoglycaemia 628
Symptoms of hypoglycaemia 630
Investigations of hypoglycaemia 632
Management of hypoglycaemia 634
Postprandial reactive hypoglycaemia (PRH) 636
Mastocytosis 638
Cancer 640
Endocrine sequelae of survivors of childhood cancer 642
Syndromes of ectopic hormone production 646
SIADH due to ectopic vasopressin production 648
Humeral hypercalcaemia of malignancy 650
Cushing’s syndrome due to ectopic ACTH production 652
Endocrine dysfunction and HIV/AIDS 654
Liver disease and endocrinology 658
Renal disease and endocrinology 660
Endocrinology in the critically ill 662
Syndromes of hormone resistance 664
Differential diagnosis of possible manifestations of endocrine
disorders 666
Stress and the endocrine system 670
Endocrinology of exercise 672
Complementary and alternative therapy and endocrinology 674
Alternative therapy used in patients with diabetes mellitus 676
Alternative therapy used in menopause 678
Alternative therapy used by patients with osteoporosis 680
Miscellaneous alternative therapy 682
628 CHAPTER 12 Other clinical/physiological situations
Hypoglycaemia
Definition (Whipple’s triad)
• Plasma glucose of <2.2mmol/L, associated with
• Symptoms of neuroglycopenia, and
• Reversal of symptoms with correction of glucose levels.
Epidemiology
Uncommon in adults, apart from patients with diabetes being treated with
certain agents, either alone or in combination (e.g. insulin, sulfonylureas).
Pathophysiology
Physiology of glucose control
Plasma glucose concentrations are usually kept within narrow limits
(~3.3–5.6mmol/L), providing an uninterrupted supply of glucose to the
brain (which can consume up to 50% of hepatic glucose output).
The liver is the major regulator (80–85%) of circulating blood glucose
concentrations in healthy individuals and responds to changes in circulat-
ing insulin, GH, cortisol, glucagon, and adrenaline.
• Postprandial state: hepatic glucose production is inhibited by i plasma
glucose and i insulin concentrations.
• Fasting state: plasma glucose d with consequent d in insulin secretion,
stimulating hepatic glucose efflux (due to i cortisol, GH, and
glucagon).
Mechanisms of hypoglycaemia
• Excessive/inappropriate action of insulin (or IGF-1): inhibiting hepatic
glucose production, despite adequate glycogen stores, while peripheral
glucose uptake is enhanced.
• Impaired neuroendocrine response with inadequate counter-regulatory
response (e.g. cortisol) to insulin.
• Impairment of hepatic glucose production due to either structural
damage or abnormal liver enzymes.
Classification of hypoglycaemia
Traditionally, hypoglycaemia has been classed as fasting or postprandial.
• Fasting hypoglycaemia: occuring several hours (typically >5h) after food
(e.g. early morning, following prolonged fasting or exercise).
• Postprandial (reactive) hypoglycaemia: occuring 2–5h after food.
Causes of hypoglycaemia can fit into both categories, so another clas-
sification has been proposed, based on whether the patient is unwell (see
Box 12.1.)
HYPOGLYCAEMIA 629
Box 12.1 Causes of hypoglycaemia in adults

Ill or medicated individual
• Drug-induced (commonest cause; both accidental and
non-accidental):
• Insulin or insulin secretagogue.
• Alcohol (impairs hepatic gluconeogenesis and is often associated
with poor glycogen stores).
• Others (e.g. pentamidine, quinine, indometacin, glucagon (during
endoscopy)).
• Organ failure or critical illness:
• Liver failure (over 80% of liver needs to be destroyed/removed).
• Sepsis, e.g. malaria, Gram –ve, or meningococcal; related to high
metabolic requirements, reduced energy intake, and possibly
cytokines from the inflammatory process.
• Hormone deficiency:
• Cortisol deficiency, e.g. Addison’s disease, hypopituitarism.
• Non-islet cell tumours:
• Excessive IGF-II secretion from large mesenchymal tumours
(non-islet cell tumour hypoglycaemia), e.g. fibrosarcoma,
mesothelioma (71/3 retroperitoneal, 1/3 intra-abdominal, and 1/3
intrathoracic).
Seemingly well individual
• Insulinoma:
• Benign 85%, malignant 15%.
• Occasionally, part of MEN-1 (710%).
• Non-islet cell tumours:
• Adrenal carcinoma, phaeochromocytoma.
• Hepatocellular carcinoma
• Lymphoma, myeloma, leukaemia.
• Advanced metastatic malignancy.
• Functional B-cell disorders (nesidioblastosis):
• Non-insulinoma pancreatogenous hypoglycaemia (typically after
eating).
• Post-gastric bypass hypoglycaemia (incidence and mechanisms
unclear; may require treatment with A-glucosidase inhibitor,
diazoxide, or octreotide).
• Autoimmune:
• Antibodies to insulin (antibody-bound insulin dissociates, leading
to elevated free insulin; typically associated with late postprandial
hypoglycaemia; mainly reported amongst people of Japanese or
Korean descent).
• Insulin receptor-activating antibodies (rare; may require treatment
with plasmapheresis or immunosuppression).
• Accidental or surreptitious hypoglycaemia (e.g. insulin or insulin
secretagogue administration).
From Cryer PE (1997).
Symptoms of hypoglycaemia
• See Table 12.1 for classification of symptoms.
• Adrenergic symptoms have been identified at arterialized plasma
glucose concentrations of 3.3mmol/L (equivalent to a venous plasma
concentration of 3.1mmol/L).
• Neuroglycopaenic symptoms have been identified at arterialized
plasma glucose concentrations of 2.8mmol/L (equivalent to a venous
plasma concentration of 2.6mmol/L).
• EEG changes occur at 2.0mmol/L.
• The majority of symptoms of acute hypoglycaemia are adrenergic,
but neuroglycopaenic symptoms occur with subacute and chronic
hypoglycaemia.
• The rate of decrease in the plasma glucose concentration does not
influence the occurrence of the symptoms.
• Patients with recurrent hypoglycaemia may not get symptoms until
glucose concentrations are very low (so-called ‘hypo unawareness’),
whilst patients with poorly controlled diabetes mellitus may
experience hypoglycaemic symptoms at ‘normal’ blood glucose levels.
Table 12.1 Classification of symptoms and signs of hypoglycaemia

Adrenergic Neuroglycopaenic
Sweating Visual disturbance (e.g. diplopia, blurred vision)
Hunger Poor concentration
Tingling Drowsiness
Trembling Lethargy
Palpitations Unusual behaviour
Anxiety Personality change
Confusion
Focal neurological abnormality
Seizures
Coma
SYMPTOMS OF HYPOGLYCAEMIA 631
Investigations of hypoglycaemia
• Glucose (BM) strip: unreliable for low glucose concentrations.
• Liver and renal function tests.
• Blood ethanol concentration.
• Synacthen® test.
• Insulin, C-peptide, pro-insulin, and glucose during hypoglycaemia
(see Table 12.2).
• Inappropriately elevated insulin in presence of hypoglycaemia suggests
insulinoma, self-administration of insulin/sulfonylurea, post-gastric
bypass hypoglycaemia, non-insulinoma pancreatogenous hypoglycaemia
syndrome, or insulin autoimmune hypoglycaemia.
• Absence of C-peptide, but the presence of insulin, during hypoglycaemia
suggests exogenous insulin administration or raised IGF-II.
• Insulinomas often associated with elevated pro-insulin:insulin ratio.
• Consider assay for presence of sulfonylureas.
• Fasting B-hydroxybutyrate (elevated in most causes of hypoglycaemia
but suppressed if insulin present, e.g. insulinoma, self-administration of
insulin, or sulfonylureas).
• Consider IGF-I and II and pro-IGF-II. IGF-II may be normal in non-islet
cell hypoglycaemia, but this is in association with suppressed IGF-I
and GH; usual IGF-II:IGF-I ratio 3:1, ratio >10 seen in non-islet cell
hypoglycaemia. Tumours tend to secrete pro-IGF-II, leading to a raised
pro-IGF-II:IGF-II ratio.
• Chest and abdominal radiographs/CT.
• Consider insulin and insulin receptor antibodies.
Further investigation of fasting hypoglycaemia
• 15h fast:
• Measure plasma glucose and insulin after fasting for 15h.
• Glucose <2.2mmol/L and insulin >5mU/L is inappropriate.
• Good screening test if repeated 3 times.
• 75% of patients with an insulinoma will develop hypoglycaemia
within 18h of beginning a fast.
• 72h fast:
• The most reliable test for hypoglycaemia (detects 98% patients with
insulinoma, compared with >70% at 24h).
• The patient should remain hydrated and active.
• Measure plasma glucose, insulin, C-peptide, and pro-insulin
6-hourly (unless the patient is symptomatic or the glucose level is
<3.5mmol/L when measurements are made every 1–2h); the test is
terminated if the laboratory glucose <2.2mmol/L or after 72h.
• B-hydroxybutyrate should be measured at the end of the fast (its
presence makes insulinoma unlikely).
• C-peptide suppression test:
• Rationale: insulin administration to induce hypoglycaemia should
suppress endogenous insulin secretion. C-peptide serves as a
measure of endogenous insulin secretion and is suppressed during
hypoglycaemia to a lesser degree in people with an insulinoma than
in normal persons.
INVESTIGATIONS OF HYPOGLYCAEMIA 633
Table 12.2 Biochemical features of insulinoma and factitious

hypoglycaemia
Plasma marker Insulinoma Sulfonylurea Insulin injection
Glucose d d d
Insulin i i i
C-peptide i i d
• Useful when 72h fast test is inconclusive.

• Method: IV insulin administered over 2h and measurements of
plasma C-peptide and glucose made.
• Results should be interpreted using age- and BMI-matched
normative data.
Further investigation of postprandial hypoglycaemia
• Prolonged oral glucose tolerance test:
• Not physiological.
• 10% of the normal (asymptomatic) population have a +ve response,
with blood glucose levels <2.6mmol/L.
• Mixed meal test over 5h:
• More physiological.
• Uses foods with a medium-to-low glycaemic index (‘hyperglucidic’).
• 47% of patients with suspected postprandial hypoglycaemia have a
+ve test vs 1% of asymptomatic subjects.
• However, diagnostic criteria not formally agreed for this test.
• Ambulatory glucose sampling:
• Gaining favour, as it may correlate symptoms with low sugar
readings and improvement of symptoms with recovery from
hypoglycaemia.
Other investigations may be indicated if there is clinical and biochemical
evidence of an insulinoma (e.g. b see Tumour localization, p. 563).
Management of hypoglycaemia
Acute hypoglycaemia
• If conscious:
• 15–20g oral carbohydrate (ideally food and a sugary drink) should
be administered as soon as possible.
• Dextrogel®/Glucogel® (formerly known as Hypostop Gel®), a
glucose-containing gel which is absorbed by the buccal mucosa, may
be used in drowsy, but conscious, individuals.
• If unconscious:
• 75–80mL of 20% glucose intravenously into a large vein (over
10–15min), followed by a saline flush as the high concentration
of glucose is an irritant and may even lead to venous thrombosis.
A maintenance infusion of 5% or 10% dextrose is often required
thereafter, especially if there is an ongoing risk of recurrent
hypoglycaemia (e.g. overdose of a long-acting insulin/analogue).
• 1mg glucagon IM may be administered if there is no IV access.
This increases hepatic glucose efflux, but the effect only lasts for
30min, allowing other means of blood glucose elevation (e.g. oral)
before the blood glucose falls again. It is ineffective with hepatic
dysfunction and if there is glycogen depletion, e.g. ethanol-related
hypoglycaemia, and is relatively contraindicated in patients with
known insulinoma, as it may induce further insulin secretion.
Glucagon is ineffective if given within 3 days of a previous dose of
glucagon.
• s cerebral oedema may complicate hypoglycaemia and should be
considered in cases of prolonged coma despite normalization of
plasma glucose. Mannitol and/or dexamethasone may be helpful.
Recurrent chronic hypoglycaemia
If definitive treatment of the underlying condition is unsuccessful or
impossible, symptoms may be alleviated by frequent (e.g. 4-hourly) small
meals, including overnight. Diazoxide, administered by mouth, is useful
in the management of patients with chronic hypoglycaemia from excess
endogenous insulin secretion due to an insulinoma or islet cell hyperplasia.
MANAGEMENT OF HYPOGLYCAEMIA 635
Postprandial reactive hypoglycaemia

(PRH)
Definition
Hypoglycaemia following a meal, due to an imbalance between glucose
influx into (exogenous from food and endogenous glucose production)
and glucose efflux out of the circulation.
Pathophysiology and causes
• Exaggerated insulin response. Related to rapid glucose absorption, e.g.
post-gastrectomy dumping syndrome. This results in a delayed insulin
peak with respect to the peak blood glucose, probably related to an
exaggerated GLP-1 (glucagon-like peptide-1) response.
• Incipient diabetes mellitus. Occasionally presents with postprandial
hypoglycaemia, possibly related to disordered insulin secretion.
• Insulin resistance-related hyperinsulinaemia, e.g. obese subjects with or
without impaired glucose tolerance.
• Impaired glucagon sensitivity and secretion. In response to
hypoglycaemia; involved in the pathogenesis of PRH.
• Renal glycosuria. Accounts for up to 15% of patients with PRH.
• Body composition:
• 20% of very lean people are prone to PRH.
• Massive weight reduction increases the risk of PRH.
• Lower body obesity (especially in ♀) is associated with high normal
insulin sensitivity and PRH.
• Diet:
• High-carbohydrate, low-fat diet, by i insulin sensitivity.
• Prolonged very low calorie diets (>2 weeks) by reducing
counter-regulatory hormones, especially GH.
• Alcohol:
• Inhibits hepatic glucose output.
• Increases insulin secretion in response to glucose and sucrose.
• Idiopathic.
Investigation
• Prolonged oral glucose tolerance test. Not physiological; 10% of the
normal (asymptomatic) population have a +ve response with blood
glucose levels <2.6mmol/L.
• Hyperglucidic mixed meal test. More physiological; 47% of patients with
suspected PRH have a +ve test vs 1% of asymptomatic subjects.
• Ambulatory glucose sampling. Gaining favour, as it may correlate
symptoms with low sugar readings and improvement of symptoms
with recovery from hypoglycaemia.
POSTPRANDIAL REACTIVE HYPOGLYCAEMIA (PRH) 637
Management
Diet
• Frequent, small, low-carbohydrate, high-protein meals.
• Avoid rapidly absorbed carbohydrates.
• Avoid sugary drinks, especially in combination with alcohol.
• Addition of soluble dietary fibres, e.g. 5–10g guar gum or pectin or
hemicellulose per meal, delays absorption and lowers the glycaemic
and insulinaemic indices (especially effective in rapid gut transit time).
Drugs
• Acarbose, an intestinal A-glucosidase inhibitor, delays sugar and starch
absorption, thus reducing the insulin response to a meal.
• Metformin can be useful, 500mg with meals.
• Supplemental chromium is reported to downregulate B-cell activity
and increase glucagon secretion.
• In exceptional cases, with debilitating PRH, diazoxide (side effects—
water retention, hypertrichosis, digestive disorders) or somatostatin
analogues may be required.
• Propranolol and calcium antagonists have been used; however,
controlled studies are lacking.
Further reading
Brun JF, Fedou C, Mercier J (2000). Postprandial reactive hypoglycaemia. Diabet Metab 26, 337–51.
Cryer PE (1997). Hypoglycemia: pathophysiology, diagnosis, and treatment. Oxford University
Press, New York.
Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori V, Seaquist ER, Service FJ (2009). Evaluation
and management of adult hypoglycaemic disorders: an Endocrine Society clinical practice guide-
line. J Clin Endocrinol Metab 94, 709–28.
de Groot, et al. (2009). Non-islet cell tumour-induced hypoglycaemia: a review of the literature
including two new cases. Endocr Relat Cancer 14, 979–93.
Gama R, Teale JD, Marks V (2003). Clinical and laboratory investigation of adult spontaneous
hypoglycaemia. J Clin Path 56, 641–6.
Service FJ (1995). Hypoglycaemic disorders. N Engl J Med 350, 2272–9.
Mastocytosis
Background and definitions
Mastocytosis is a heterogenous group of disorders characterized by the
pathological accumulation of mast cells in tissues. The main types of mas-
tocytoses are cutaneous and systemic. Systemic mastocytosis is frequently
diagnosed but seldom established as a differential diagnosis in the work-up
of flushing (sensation of warmth, usually on the face and neck, due to vaso-
dilation and increased cutaneous circulation). Flushing due to neurogenic
stimuli are likely to be associated with sweating (wet flushing), and flush-
ing due to vasodilator substances associated with ‘dry’ flushing. Systemic
mastocytosis usually features in the latter category.
See Box 12.2 for causes of raised tryptase.
Classification
Mastocytosis is broadly classified into cutaneous and systemic mastocyto-
sis (see Box 12.3).
Clinical features
• Urticaria pigmentosa and dermographism are the usual cutaneous
manifestations (exacerbated when rubbed—Darier’s sign).
• Systemic manifestations include flushing, anaphylaxis, abdominal pain,
and diarrhoea.
• Anaemia, hepatosplenomegaly, peptic ulceration, and steatorrhoea can
occur due to mast cell infiltration.
Epidemiology
• It is a rare disorder.
• Affects both sexes equally.
• Children usually have cutaneous mastocytosis, and adults the systemic
variety.
Investigations
• Serum tryptase, which is predominantly produced in mast cells, is
usually elevated.
• Skin biopsy stained with Giemsa and immunohistochemical staining for
tryptase and c-kit (mast cell growth factor receptor).
• Bone marrow biopsy is warranted for adults with evidence of
mastocytosis to diagnose systemic mastocytosis.
MASTOCYTOSIS 639
Box 12.2 Causes of raised tryptase level

• Acute myeloid leukaemia.
• Myelodysplastic disorders.
• Hypereosinophilic syndrome.
• Asthma (mild elevation).
Box 12.3 WHO classification of systemic mastocytosis

• Indolent systemic mastocytosis.
• Systemic mastocytosis with clonal haematological non-mast cell
lineage disease.
• Mast cell leukaemia.
• Mast cell sarcoma.
• Extracutaneous mastocytosis.
Treatment
• Avoidance of triggers (e.g. alcohol, aspirin).
• Treat anaphylaxis as a medical emergency.
• Preparation of patients appropriately before surgery and other medical
procedures with antihistamines, glucocorticoids, H2 blockade, and
montelukast.
• Antihistamines, such as cetirizine, fexofenadine, can be used to reduce
flushing and itching.
• H2 blockers and proton pump inhibitors, such as ranitidine and
omeprazole, can help with abdominal symptoms, such as pain and
heartburn.
• In patients who are not intolerant of NSAIDs, aspirin may help reduce
flushing.
• Additional antileukotriene agents, such as montelukast, may help some
with ongoing symptoms.
• Other treatment options, including tyrosine kinase inhibitors, have
been assessed, but their effectiveness is not convincing.
Further reading
Liu AY, et al. (2010). Clinical problem-solving. A rash hypothesis. N Engl J Med 363, 72–8.
Murali MR, et al. (2011). Case records of the Massachusetts General Hospital. Case 9-2011.
A 37-year-old man with flushing and hypotension. N Engl J Med 364, 1155–65.
Cancer
Chemotherapy and radiotherapy may have endocrine effects.
Anticancer chemotherapy
There are three types of anticancer chemotherapeutic agents:
• Cytotoxics. These have no direct hormonal sequelae. Alkylating agents
are more likely to induce permanent ♂ sterility (without affecting
potency), and, in ♀, they may induce premature menopause which
may increase the likelihood of osteoporosis.
• Immunomodulators. Prednisolone in excess causes Cushing’s
syndrome, and acute withdrawal may precipitate adrenal insufficiency.
Cyclophosphamide, in particular, may cause early menopause. Thyroid
dysfunction has been reported rarely with tacrolimus and interferon
therapy.
• Hormones:
• Progestagens are used in breast cancer; of these, megestrol acetate
has potent glucocorticoid activity and thus may cause Cushing’s
syndrome in excess or adrenal insufficiency if abruptly withdrawn.
• Aromatase inhibitors, such as aminoglutethimide, may cause adrenal
insufficiency, and corticosteroid replacement is necessary.
• Trilostane, which inhibits 3B-hydroxysteroid dehydrogenase, may
also cause adrenal insufficiency.
• Gonadorelin analogues, used for prostatic cancer and breast cancer,
cause an initial increase in LH levels and then suppression and cause
side effects similar to orchidectomy in ♂ and the menopause in ♀.
• Antiandrogens, used in prostatic cancer, have predictable side
effects, such as gynaecomastia, hot flushes, impotence, and impaired
libido.
Radiotherapy
• Cranial radiotherapy, whose field encompasses the hypothalamo–
pituitary area, may result in hypopituitarism (b see Chapter 2,
Hypopituitarism, p. 202). The most radiosensitive axis is the GH axis,
followed by the FSH/LH axis, then the ACTH and TSH axes. Even low
radiation doses of <40Gy can affect the GH axis. Panhypopituitarism is
generally seen with doses of >60Gy, doses often used in the presence
of nasopharyngeal or skull base tumours.
• Head and neck irradiation may result in hypothyroidism and
hypoparathyroidism.
• After 5 or more years of follow-up, 50% of patients treated with
radiotherapy only for laryngeal and pharyngeal carcinoma will
develop hypothyroidism; combined surgery and radiotherapy results
in roughly 90% of patients developing hypothyroidism. The rates for
hypoparathyroidism were 88% and 90%, respectively.
• Radiotherapy affects the testes dose-dependently. Fertility is affected
much more than androgen-synthesizing capacity so that most ♂ have
normal testosterone levels unless given testicular doses >20–30Gy.
• The effects of radiotherapy to both ovaries are amplified with age.
Premature menopause may be elicited by doses >10Gy.
CANCER 641
Endocrine sequelae of survivors

of childhood cancer
Background
It is estimated that approximately 1:900 adults in the developed world has
survived a childhood cancer. The treatment of childhood malignancies in
the form of surgery, chemotherapy, and, perhaps most important of all,
supportive care is now more advanced than ever and has resulted in very
significant improvements in survival. For example, the 5-year survival of the
commonest childhood and adolescent malignancies acute lymphoblastic
leukaemia (ALL) and Hodgkin’s lymphoma is >80% and 90%, respectively.
Basic concepts and definitions
Alkylating agents (e.g. cyclophosphamide, busulfan, procarbazine) work by
damaging DNA in rapidly dividing cancer calls. Non-neoplastic cells can
also be subjected to damage by these agents.
Gray (Gy) is the unit of absorbed dose of ionizing radiation correspond-
ing to 1 joule/kg. Like alkylating agents, ionizing radiation causes damage
to the DNA of proliferating cancer cells (and other normal tissues in
the way).
The dose of radiation measured in Gy depends on the type of cancer
and its stage. For example, for solid tumours of epithelial origin, the dose
can vary between 60 and 80Gy, and the dose for lymphomas could be
20–40Gy. To put this in perspective, the dose of radiation to the stomach
from an AP chest X-ray is approximately 0.25mGy, and from a CT scan of
the abdomen, it is at least 12.5mGy.
Children who survive cancers are at risk of a number of hormone defi-
ciencies and sometimes overactivity of some endocrine organs, such as
hyperthyroidism. The common endocrine complications include growth
hormone deficiency, hypothyroidism, and disrupted puberty. Awareness
of these hormonal imbalances has increased, and they need to be actively
sought and treated in order to improve quality of life.
The endocrine sequelae of craniopharyngiomas specifically has been
covered in Chapter 2 (b see p. 188).
Growth hormone deficiency
Adult short stature is common in survivors of childhood cancers
(b pp. 130 and 524). The disease and its treatment, precocious puberty,
growth hormone deficiency (GHD), primary hyperthyroidism, depression,
or a combination of all of these could result in short stature.
GHD could be due to direct tumour invasion or as a consequence of
surgery, as in the case of craniopharyngiomas (b see p. 188). GHD is a
common, and sometimes the only, anterior pituitary deficit after cranial
irradiation. The risk of developing GHD is 90% within 5 years of external
beam radiotherapy of doses ≥30Gy. With doses between 18 and 24Gy, it
may take 10 years to develop GHD. The likelihood of developing GHD
with chemotherapy is low.
ENDOCRINE SEQUELAE OF SURVIVORS OF CHILDHOOD CANCER 643
Clinical assessment
• Growth velocity.
• Weight and BMI.
• Sitting height (radiotherapy can cause vertebral dysplasia).
• Arm span.
• Pubertal assessment for evidence of precocious puberty (precocious
puberty can result in a falsely reassuring growth spurt).
Investigations
The diagnosis can be difficult to make. GHD is suspected when a
decreased growth velocity is found over a 6-month period. The diagnosis
is made using a combination of clinical features and investigations.
• Bone age to assess skeletal maturation.
• Insulin tolerance test (b see p. 114).
• GHRH with arginine may lack sensitivity in patients who have received
radiotherapy.
• IGF-1 and IGFBP-3 are not reliable markers of GH secretion following
radiotherapy or those with CNS lesions.
Treatment
• There is no clear evidence of either increased risk of recurrence of
the original tumour or death associated with GH therapy, despite the
anti-apoptotic and pro-proliferative effects of GH and IGF-1.
• There is evidence to suggest an increased risk of a secondary tumour
in survivors of acute leukaemia. Meningiomas are the commonest
second neoplasms.
• GH therapy in survivors of childhood cancers for adult GHD has
been shown to improve quality of life and modest improvements in
metabolic parameters.
• See section on growth hormone replacement (b see p. 134).
Thyroid abnormalities
Thyroid abnormalities are common endocrine sequelae in survivors of
childhood cancers.
Primary hypothyroidism
Primary hypothyroidism can develop up to 25 years after radiotherapy.
It is usually seen after mantle irradiation for Hodgkin’s lymphoma and
craniospinal irradiation for HS tumours. It is more likely to occur in girls.
Long-term surveillance with thyroid function tests, early detection, and
treatment are important.
Central hypothyroidism
Rare and usually associated with irradiation to the hypothalamic/pituitary
area of doses >30Gy. There is a small association between chemotherapy
and central hypothyroidism.
Hyperthyroidism
Much rarer than hypothyroidism and associated with doses of ≥35Gy to
the thyroid.
Thyroid neoplasia
There is an increased likelihood of developing papillary and follicular can-
cers of the thyroid after radiotherapy. Children treated before the age of
10 and with doses between 20 and 30Gy are at highest risk. There can
be a very long latent period before the development of thyroid cancers;
therefore, ongoing long-term follow-up is essential.
Thyroid cancers secondary to radiotherapy do not behave more aggres-
sively than those occurring in people without radiotherapy.
Disruption of puberty
Puberty can be affected in survivors of childhood cancers in terms of pre-
cocious puberty, accelerated rate of progression through puberty, delayed
progression through puberty, or hypogonadotrophic hypogonadism.
Precocious puberty (see b p. 538)
Precocious puberty (<8 years for girls and <9 years for boys) is caused
by premature activation of the hypothalamo–pituitary–gonadal axis and
is associated with irradiation. It is more likely in girls and those who are
overweight and is associated with radiotherapy at an early age.
Clinical assessment
• Height and weight on growth charts, assessing growth velocity.
• An early sign of precocious puberty is an increase in growth velocity.
However, this can be masked either by concomitant GHD or
hypothyroidism.
• Tanner staging—in girls, evidence of breast development <8 years
is a sign of precocious puberty; in boys, however, testicular volume
is an unreliable marker, as there may be concomitant seminiferous
dysfunction.
• A bone age on X-ray of >2 SDs for the chronological age is a
consistent finding.
Management
Delaying the progression of puberty with GnRH agonists results in better
outcomes for height, especially in conjunction with GH where appropriate
for GHD (b see section on Precocious puberty, p. 538).
Hypogonadotrophic hypogonadism
Gonadotrophin deficiency is less common than GH deficiency and is
dependent on the dose of radiotherapy received to the hypothalamic–
sellar area. Whether chemotherapy alone results in gonadatrophin defi-
ciency is uncertain.
Assessment and management
b see section on delayed puberty, p. 542.
ENDOCRINE SEQUELAE OF SURVIVORS OF CHILDHOOD CANCER 645
Male gonadal dysfunction

• Leydig cells are vulnerable to radiation damage but relatively tolerant
of chemotherapy due to their slow turnover. Children who receive
>24Gy for testicular relapse of ALL have a high risk of developing
testosterone deficiency.
• Germ cells, on the other hand, are at risk of damage from both
chemo- and radiotherapy.
• Fertility is impaired in 40–60% of ♂ survivors of childhood cancer.
• Alkylating agents are associated with highest risk in terms of
chemotherapeutic agents.
• Relatively low doses, such as 0.15Gy, are associated with ♂
subfertility.
Female gonadal dysfunction
• Ovarian failure can occur either acutely or as a delayed effect,
following the treatment of cancer.
• In young girls, if ovarian dysfunction occurs before the onset of
puberty, there can be delayed puberty and primary amenorrhoea.
• During puberty, ovarian failure can result in arrested pubertal
development, secondary amenorrhoea, and menopausal symptoms.
• Alkylating agents are associated with a high risk of developing ovarian
failure.
• Abdominopelvic irradiation increases the risk of ovarian failure. This
risk is higher when used in conjunction with alkylating agents.
• Women with ovarian failure are at higher risk of osteoporosis and
cardiovascular disease.
Osteoporosis
• Survivors of childhood cancers are at risk of osteopenia, osteoporosis,
and consequently fractures as a result of the primary disease,
glucocorticoids, chemotherapy, hypogonadism, and GHD.
• DEXA scans should be interpreted with caution, taking into
consideration age, pubertal stage, and height.
Obesity
Obesity is strongly associated with craniopharyngiomas and other CNS
tumours and their treatment. Hypothalamic damage can result in morbid
obesity. For other cancers, a combination of GHD, steroids, and other
undetermined factors are also believed to cause obesity. Insulin resistance
is also common, and the risk of type 2 diabetes is increased.
Syndromes of ectopic hormone

production
Definition
The secretion into the systemic circulation of a hormone or other biologi-
cally active molecule by a neoplasm (benign or malignant) that has arisen
from a tissue that does not normally produce that hormone or molecule,
resulting in a clinically significant syndrome. See Table 12.3 for common
syndromes associated with ectopic hormone production.
Table 12.3 Common syndromes associated with ectopic hormone

production
Syndrome Ectopic hormone Typical tumour types
Hypercalcaemia PTHrP Squamous cell lung carcinoma
of malignancy Other squamous cell carcinoma
(skin, oesophagus, head and neck)
Renal cell carcinoma
Breast adenocarcinoma
Adult T-cell lymphoma
associated with HTLV-1
1,25(OH)2 colecalciferol Lymphomas
SIADH Vasopressin/ADH Small cell lung carcinoma
Squamous cell lung carcinoma
Bronchial carcinoid
Mesothelioma
Pancreatic or gut carcinoid
Adenocarcinoma of the
duodenum, pancreas, prostate
Phaeochromocytoma
Medullary thyroid carcinoma
Haematopoietic malignancies
(lymphoma, leukaemia)
SYNDROMES OF ECTOPIC HORMONE PRODUCTION 647
Table 12.3 (Continued)

Syndrome Ectopic hormone Typical tumour types
Cushing’s ACTH (most commonly) Small cell lung carcinoma
syndrome Thymic carcinoid tumour
Bronchial carcinoid tumour
Pancreatic endocrine tumours
(including carcinoid tumours)
Carcinoid tumours of the gut
Phaeochromocytoma
Medullary thyroid carcinoma
Other lung cancers
(adenocarcinoma, squamous cell
carcinoma)
CRH (rarely) Carcinoid tumour
Ectopic expression of Macronodular adrenal
receptors for GIP; LH hyperplasia
Non-islet cell IGF-2 Mesenchymal tumours
hypoglycaemia Mesothelioma
Fibrosarcomas
Oncogenic FGF23 Sarcomas
osteomalacia Haemangiomas
Fibromas
Prostate adenocarcinoma
Osteoblastomas
Male feminization hCG Testicular neoplasms
(seminomas, teratomas)
Germinomas
Choriocarcinomas
Acromegaly GHRH Pancreatic islet cell tumours
Carcinoid tumours
GH Lung, pancreatic islet cell
tumours
SIADH due to ectopic vasopressin

production
Diagnosis
• Hyponatraemia (plasma Na <130mmol/L).
• Dilute plasma (serum osmolality <270mOsm/kg).
• Inappropriately concentrated urine (in the face of hyponatraemia and
plasma hypo-osmolality, any urine osmolality > plasma osmolality is
inappropriate).
• Persistent renal Na excretion (urinary Na >20mmol/L).
• Euvolaemia (or very mild hypervolaemia).
• Normal renal, adrenal, and thyroid function.
• Plasma urea and uric acid levels can be helpful markers of plasma
dilution.
• The commonest tumours causing SIADH are tumours with
neuroendocrine features, most commonly small cell lung carcinoma
and carcinoid tumours. Small cell lung carcinomas have usually
metastasized by the time SIADH is present.
• Lung diseases and neurological disorders (including malignancies)
may cause SIADH due to aberrant hypothalamic vasopressin release,
rather than vasopressin release from the tumour per se. In SIADH
due to ectopic hormone secretion, release of vasopressin from the
neurohypophysis may be suppressed.
• Other causes of SIADH must be excluded (b see Syndrome of
inappropriate ADH (SIADH), p. 220).
Management
Hyponatraemia
• The initial management is fluid restriction, with daily monitoring
of the plasma sodium and osmolality. Hyponatraemia has usually
developed gradually, and its correction should be similarly gradual.
Fluid restriction to 500mL total fluid intake per day may be needed
for several days. Urate levels can be useful as a marker of water
intoxication and its resolution. As hyponatraemia is corrected,
fluid restriction can be relaxed, depending on the plasma sodium.
1500–2000mL/day is usual.
• For patients in whom fluid restriction is insufficient or not possible,
demeclocycline (150–300mg tds–qds) can be used to produce a
nephrogenic diabetes insipidus to achieve a normal plasma sodium.
Demeclocyline can result in photosensitivity, and patients should be
warned to avoid prolonged exposure to sunlight.
• Life-threatening hyponatraemia (e.g. convulsions) may rarely require
hypertonic saline and furosemide; however, rapid correction of
hyponatraemia may result in central pontine myelinolysis, and, in the
vast majority of cases, water restriction is safe, effective, and sufficient.
• Tolvaptan (see b p. 221): a competitive vasopressin V2-receptor
antagonist may also be useful.
SIADH DUE TO ECTOPIC VASOPRESSIN PRODUCTION 649
Management of the underlying tumour

Curative surgery will also cure the SIADH, as will curative chemother-
apy and/or radiotherapy. Chemotherapy and radiotherapy may have an
important palliative role, as the tumour is usually incurable by the time
hyponatraemia is detected.
Humeral hypercalcaemia
of malignancy
Hypercalcaemia is a common complication of malignancy; may be due
to ectopic hormone secretion (PTHrP; rarely 1,25(OH)2 colecalciferol);
cytokine and inflammatory mediators that activate osteoclastic bone
resorption (such as IL-6 and RANK-L production by myeloma cells); or
due to bone destruction by metastases.
Parathyroid hormone-related peptide (PTHrP)
• PTHrP binds to and activates PTH/PTHrP receptor type 1, resulting in
osteoclast-mediated bone resorption and reduced renal excretion of
calcium.
• The biochemical picture of hypercalcaemia and hypophosphataemia
may be indistinguishable from p hyperparathyroidism. However, PTH
levels are suppressed in PTHrP-mediated hypercalcaemia (NB p
hyperparathyroidism can coexist with malignancy).
• PTHrP secretion by metastatic cells within bone also causes
hypercalcaemia by causing local osteolysis.
• PTHrP can be measured directly and is elevated in 80% of cancer
patients with hypercalcaemia.
• Tumours that metastasize to bone are more prone to produce PTHrP
than tumours that do not metastasize to bone (50% of p breast cancer
express PTHrP, compared with 92% of metastases of breast cancer to
bone). This may be due to induction of PTHrP secretion by the bone
microenvironment; alternatively, PTHrP production by tumour cells
may enhance their ability to metastasize to bone.
• For tumours associated with humeral hypercalcaemia, b see
Table 12.3, p. 646.
Management
• As per normal management of hypercalcaemia (b see Other causes
of hypercalcaemia, p. 469).
• Glucocorticoids may be particularly effective in treatment of
hypercalcaemia associated with malignancy. This may be due to direct
effects of glucocorticoids on the tumour cells (e.g. haemopoietic
malignancies) and/or because of downregulation of production of
1,25(OH)2 colecalciferol.
• Bisphosphonates may also have antitumour effects in myeloma as well
as control osteoclastic destruction of bone.
HUMERAL HYPERCALCAEMIA OF MALIGNANCY 651
Cushing’s syndrome due to ectopic

ACTH production
• Ectopic ACTH production is responsible for 10–20% of all endogenous
Cushing’s syndrome.
• Commonest tumour types are those with neuroendocrine features.
50% of ectopic ACTH secretion is due to small cell lung carcinoma.
Carcinoid tumours are also very common (thymic carcinoid 15%;
pancreatic endocrine tumours, including pancreatic carcinoids, 10%;
bronchial carcinoid 10%). Ectopic CRH production has been described
but is extremely rare.
Diagnosis
• Despite often extremely high cortisol levels, patients often do not
manifest central weight gain due to the underlying malignant process
with its rapid progress and associated cachexia.
• Hypertension, hypokalaemia, metabolic alkalosis are common features
(overwhelming of the 11B-hydroxysteroid dehydrogenase enzyme,
resulting in exposure of the mineralocorticoid receptor to high
circulating glucocorticoids).
• Glucose intolerance, susceptibility to infection, thin skin, poor wound
healing, and steroid-associated mood disturbance are all common
features.
• Patients may be pigmented due to MSH arising from high POMC
levels.
• ACTH levels may be extremely high (usually >100pg/mL).
• In 90% of ectopic ACTH-secreting tumours, high-dose dexamethasone
testing (2mg qds) shows a failure of cortisol levels to drop to 50%
of baseline values due to a lack of any normal physiological feedback
upon ACTH production. However, some carcinoid tumours may
behave indistinguishably from pituitary-dependent ACTH production.
CRH testing and/or inferior petrosal sinus sampling may be necessary
to distinguish these conditions (see b p. 162).
• Ectopic ACTH-producing tumours can be extremely difficult to
localize and may require multiple modalities of imaging.
Management
Excision of the underlying tumour may be possible. Other options include
medical management using metyrapone and/or ketoconazole, although
very high doses may be needed (b see Table 2.10, p. 171). Bilateral adre-
nalectomy with glucocorticoid and mineralocorticoid replacement is also
an option.
CUSHING’S SYNDROME DUE TO ECTOPIC ACTH PRODUCTION 653
Macronodular adrenal hyperplasia

• A rare cause of ectopic Cushing’s syndrome.
• Most are sporadic; a few are familial.
• Most commonly due to synthesis of ectopic GIP receptors in adrenal
tissues.
• GIP secretion associated with meals results in activation of adrenal
glands and food-related hypercortisolaemia.
• Other ectopic receptors reported include B-adrenergic receptors and
LH receptors.
Carcinoid tumours and ectopic hormone production
b See p. 556 and Table 12.3, p. 646.
Endocrine dysfunction and HIV/AIDS

Adrenal
Subclinical changes can be detected, including elevated basal cortisol con-
centrations and lower DHEA concentrations.
Adrenal insufficiency
Uncommon (<4% of patients with AIDS). In patients with clinical signs
suggestive of hypoadrenalism (hyponatraemia and hypovolaemia), 30%
incidence of inadequate response to Synacthen®.
Causes
• Infection. Histologically common. Adrenal function usually maintained
(10% of residual adrenal tissue is adequate for normal function).
• CMV (adrenalitis found post-mortem in 40–90% of patients with
advanced disease).
• Mycobacterium avium intracellulare (MAI) complex, tuberculosis.
• Cryptococcus.
• Neoplasm. Lymphoma, Kaposi’s sarcoma.
• Haemorrhage.
• Drug-induced:
• Rifampicin induces i hepatic metabolism of corticosteroids. In
subjects with already compromised adrenal reserve, this may
precipitate an Addisonian crisis.
• Ketoconazole inhibits cortisol synthesis.
• Megestrol acetate possesses glucocorticoid activity and may cause
s adrenal insufficiency. Abrupt cessation after long-term treatment
may precipitate an adrenal crisis.
• s adrenal insufficiency:
• Drugs (megestrol acetate).
• Hypopituitarism s to toxoplasmosis, Cryptococcus, CMV.
• Idiopathic anterior pituitary necrosis.
Hypercortisolism
Mild hypercortisolaemia common in all stages of HIV infection, without
clinical manifestation of Cushing’s syndrome.
Possible causes
• Chronic stress.
• Proinflammatory cytokines.
• Binding protein dysfunction.
• Glucocorticoid resistance.
• Concomitant use of ritonavir and inhaled fluticasone.
ENDOCRINE DYSFUNCTION AND HIV/AIDS 655
Gonads
Males
• SHBG concentrations are often elevated; this can lead to normal total
testosterone concentrations but low free testosterone concentrations.
• Testosterone deficiency common in ♂ patients with AIDS (6% of
patients with asymptomatic HIV infection, compared with 50% of
patients with AIDS).
• Hypogonadism is associated with wasting, d muscle mass, fatigue, loss
of libido, and impotence. Hypogonadism may be p or s; up to 75%
of patients with hypogonadism have low or inappropriately normal
gonadotrophins.
Causes
• p hypogonadism:
• Testicular destruction/infiltration. Due to infection (CMV most
commonly, MAI, toxoplasmosis, TB) or neoplasm (lymphoma,
Kaposi’s sarcoma, germ cell tumours).
• Drug-induced. Ketoconazole (inhibits steroidogenesis, causing
lowered testosterone levels), megestrol acetate, other
glucocorticoids.
• s hypogonadism. Due to malnutrition, severe acute illness, destructive
disorders of pituitary/hypothalamus (CMV, toxoplasmosis, lymphoma);
medications, such as megestrol acetate (glucocorticoid-like action
causes hypogonadotrophic hypogonadism).
Females
• Hypogonadism in ♀, as evidenced by oligo-/amenorrhoea, less
common than in ♂ unless advanced disease. Fertility rates not affected
until advanced disease.
• Hypoandrogenism (testosterone, DHEA) common in ♀ with wasting
syndrome.
Electrolyte disturbance due to endocrine perturbation
in HIV/AIDS
Hyponatraemia
Very common in advanced disease. Due to SIADH in 50%; adrenal insuf-
ficiency also a common cause.
Calcium disorders
• Hypocalcaemia. Common (18% of patients with AIDS). Main cause is
vitamin D deficiency. Other causes: severe illness; hypomagnesaemia;
altered PTH secretion/metabolism; malabsorption of calcium and
vitamin D due to GIT opportunistic infection; medications (foscarnet
(complexes with calcium), pentamidine (induces renal magnesium
wasting and s PTH deficiency)).
• Hypercalcaemia. Rare. May relate to lymphoma or granulomatous disease.
Thyroid
• Overt thyroid dysfunction is uncommon. Most common thyroid
dysfunction is sick euthyroid syndrome (non-thyroidal illness). i
thyroid-binding globulin often observed (significance unknown).
• Subclinical hypothyroidism may occur during HAART (highly acitve
antiretroviral therapy).
• Infections. Rare; usually post-mortem diagnoses. Thyroid function
usually euthyroid or sick euthyroid.
• Pneumocystis carinii (may also cause a thyroiditis).
• Mycobacteria.
• Cryptococcus neoformans.
• Aspergillosis.
• Neoplasm. Rare. Usually eu- or sick euthyroid; may be hypothyroid due
to infiltrative destruction.
• Kaposi’s sarcoma.
• Lymphoma.
Pituitary
• Anterior hypopituitarism. Very rare.
• Posterior pituitary dysfunction, causing diabetes insipidus (DI). Common.
• Infection. Toxoplasmosis, TB.
• Neoplasm. Cerebral lymphoma.
Wasting syndrome
Definition
The involuntary loss of >10% of baseline body weight, in combination
with diarrhoea, weakness, or fever. Wasting is an AIDS-defining condition.
Cause
Unknown but, in part, reflects d calorie intake due to anorexia associ-
ated with s infection. Underlying i resting energy expenditure associ-
ated with HIV infection per se. Hypogonadism common in ♂ with wasting
syndrome.
Treatment
• Highly active antiretroviral therapy (HAART). Associated with overall
weight gain, though lean body mass may remain unchanged.
• Nutritionally-based strategies. Adequate caloric intake to meet
metabolic demands. Efficacy limited, as refeeding generally increases fat
body mass, with little/less effect on lean body mass.
• Appetite stimulants. Megestrol acetate increases caloric intake and
weight compared to placebo, though most of weight gain due to i fat
mass. Dronabinol stimulates appetite, but weight gain is minimal.
• Exercise. Although exercise can increase total and lean body mass
in patients with AIDS, its role in patients with wasting syndrome is
not known.
• Androgen therapy. In hypogonadal ♂ patients with wasting syndrome,
testosterone increases overall weight and, in particular, lean body
mass. Both IM and transdermal testosterone effective. Testosterone
therapy not indicated in eugonadal ♂ with wasting.
ENDOCRINE DYSFUNCTION AND HIV/AIDS 657
• Growth hormone therapy. Patients with the wasting syndrome generally

have GH resistance, as suggested by high serum GH and low IGF-I
levels. The most likely cause for this is undernutrition. High-dose GH has
shown improvements in lean body mass and protein balance in patients
with acquired GH deficiency or severe catabolic states. Side effects
(peripheral oedema, arthralgias, myalgias) common due to high doses
required. GH may improve fat redistribution that occurs with refeeding.
• Cytokine modulators. Although many inflammatory cytokines are i
during acute illness and sepsis, their specific role in wasting syndrome
is not known. Thalidomide, a potent inhibitor of TNF, can increase
body weight and reduce protein catabolism but has a very high rate of
serious side effects and is contraindicated in ♀ of childbearing age due
to phocomelia (limit malformation).
Lipodystrophy
• Loss of SC fat, particularly in the face, peripheries, and buttocks; in
some cases, with concomitant subcutaneous fat deposition, particularly
in the abdominal area, neck, dorsocervical area (‘buffalo hump’).
Visceral fat deposition also occurs.
• Associated dyslipidaemia with hypertriglyceridaemia, low HDL
cholesterol, insulin resistance, glucose intolerance, and (less
commonly) frank diabetes mellitus. i cardiovascular mortality from
myocardial infarction.
• Associated with HIV-1 protease inhibitors (PIs), used as part of
HAART. 40% of patients treated with PIs will develop lipodystrophy
by 1 year. HIV protease inhibitor-naive patients have similar body
composition and fat distribution to that of non-HIV-infected men.
Indinavir may be less potent in inducing lipodystrophy than ritonavir
and saquinavir.
• Abnormal body composition and hypertriglyceridaemia may be part of
refeeding phenomenon consequent upon improved well-being and loss
of anorexia per se.
• Nucleoside reverse transcriptase inhibitors may be associated with fat
loss and accumulation also, but this may be a separate phenomenon to
that seen with PIs.
Management
• Observation in mild cases.
• Very low-fat diets and exercise (particularly resistance exercise).
• Withdrawal or switching of PIs in some circumstances may be
warranted.
• Anabolic agents (testosterone, GH) not effective.
• Liposuction from areas of fat accumulation; fat pad insertions for areas
of lipoatrophy also used.
• Standard lipid-lowering agents for hypertriglyceridaemia (e.g.
gemfibrozil).
• HMG CoA reductase inhibitors metabolized by P4503A4 (which is
inhibited by PIs), so risk of myopathy may be i.
• Role for thiazolidinediones unclear.
Liver disease and endocrinology

Sex hormones—males
(See Table 12.4.)
• Hypogonadism occurs in 70–80% of ♂ with chronic liver disease.
There is a combination of p testicular failure and failure of
hypothalamo–pituitary regulation.
• Alcohol acts independently to produce hypogonadism. There is a
combination of p testicular failure and failure of hypothalamo–pituitary
regulation.
• The effects of elevated oestrogens result in i loss of the ♂
escutcheon, loss of body hair, redistribution of body fat, palmar
erythema, spider naevi, and gynaecomastia.
• The i conversion of testosterone and androstenedione to oestrone
is attributed, at least in part, to portosystemic shunting. In addition,
the large increase in SHBG concentration will increase the oestrogen/
testosterone ratio, as testosterone has a higher affinity for SHBG.
• Spironolactone may result in iatrogenic feminization by inhibiting
testosterone action.
• There is no evidence that exogenous administration of androgens
reverses hypogonadism in chronic liver disease.
Sex hormones—females
(See Table 12.4.)
• Alcoholism increases the frequency of menstrual disturbances and
spontaneous abortion but does not affect fertility.
• Liver dysfunction of whatever aetiology is associated with an early
menopause.
• Alcohol, rather than liver disease, is the prime cause of hypogonadism.
Non-alcoholic liver disease is only associated with hypogonadism in
advanced liver failure when it is accompanied by encephalopathy and
impaired GnRH secretion.
• Plasma testosterone and oestrone concentrations are usually normal;
androstenedione concentration is i, and dehydroepiandrostenedione
and dehydroepiandrostenedione sulphate levels are reduced.
Thyroid
• The liver synthesizes albumin, T4-binding prealbumin (TBPA), and
T4-binding globulin (TBG), all of which bind thyroid hormones
covalently and reversibly.
• Thyroid function tests must be interpreted with caution in patients
with liver disease. In acute liver disease, e.g. acute viral hepatitis, TBG
levels are i which increases the measured total circulating T4 and T3
levels. In biliary cirrhosis and chronic active hepatitis, TBG may be i. In
other chronic liver disease and in hepatomas, TBG is also i. In severe
cases of acute liver disease, TBG may be low due to reduced synthesis.
The liver deiodinates T4 to T3, and this is impaired in liver disease.
T4 is preferentially converted to rT3, and there is an increase in the
rT3/T3 ratio.
LIVER DISEASE AND ENDOCRINOLOGY 659
Table 12.4 Sex hormone changes in liver disease

Hormone Level
Testosterone dd
SHBG i
Oestrone i
Oestradiol i/normal
LH Inappropriately low/normal
FSH Inappropriately low/normal
Prolactin i/normal
IGF-1 d
IGFBP-3 d
Table 12.5 Thyroid function changes in liver disease

Hormone Acute hepatitis CAH/PBC Cirrhosis
T4 id i d
fT4 il l i
T3 d i d
fT3 d d d
rT3 i l il
TSH i i il
TBG i i d
CAH, chronic active hepatitis; PBC, primary biliary cirrhosis.
• In liver cirrhosis, TBG, T4, and T3 are low.

• Table 12.5 summarizes the changes in TFTs with liver disease. Free T4
and T3 assays are essential for the accurate interpretation of thyroid
status in liver disease.
Adrenal hormones
• Patients who abuse alcohol may develop a clinical phenotype of
Cushing’s syndrome, with moon facies, centripetal obesity, striae,
and muscle wasting, and may have increased plasma cortisol
concentrations. This is termed pseudo-Cushing’s syndrome.
• Reversible (on abstention) adrenocorticoid hyperresponsiveness
occurs in alcoholics. In liver disease, cortisol metabolism may be
impaired, leading to elevated plasma cortisol levels, loss of diurnal
cortisol variation, and failure to suppress with dexamethasone.
Further reading
Malik R, Hodgson H (2002). The relationship between the thyroid gland and the liver. QJM 95,
559–69.
Renal disease and endocrinology

Calcitriol
There is impaired renal conversion of 25-hydroxyvitamin D3 to
1,25(OH)2D3 in end-stage renal failure (ESRF), leading to metabolic bone dis-
ease (b see Table 6.6, p. 482).
Parathyroid hormone and renal osteodystrophy
• Serum parathyroid hormone (PTH) secretion is stimulated by low
serum calcium in ESRF. This is due to:
• d renal phosphate clearance (resulting in i calcium/phosphate
mineral ion product, precipitation of vascular calcification with
consequent hypocalcaemia triggering PTH release). Vascular
calcification is a major contributor to vascular death in ESRF. High
phosphate per se may increase PTH secretion directly, but evidence
of the mechanism for this is lacking.
• Impaired renal calcitriol secretion.
• As renal function declines, an elevated PTH and a d calcitriol can be
detected, with creatinine clearance of 50mL/min. This rise in PTH is
initially sufficient to maintain the serum calcium in the normal range.
• In ESRF, patients are markedly hyperphosphataemic and
hypocalcaemic. The degree of hyperparathyroidism progresses
inversely with the fall in renal function. Tertiary hyperparathyroidism
occurs when PTH secretion becomes autonomous, and
hypercalcaemia will persist even after renal transplantation.
• Hyperparathyroid bone disease and osteomalacia are the main
mechanisms behind the development of high turnover bone disease in
renal osteodystrophy. Hypogonadism is also common in both ♂ and
♀ with ESRF. Adynamic bone disease also contributes, probably due
to direct toxic effects from urea and other nitrogenous compounds
upon bone cells. Renal osteodystrophy causes bone pain and fractures.
Treatment of renal osteodystrophy
• Maintenance of normal phosphate levels with phosphate binders (such
as calcium carbonate) and the treatment of osteomalacia. The i use of
calcium carbonate has been suggested as the cause of the i incidence
of adynamic renal osteodystrophy, but intensive vitamin D therapy and
peritoneal dialysis are probably also contributory.
• Alfacalcidol or calcitriol (which do not require renal 1A-hydroxylation)
are effective in treating osteomalacia.
• Calcitriol at a dose of 1–2 micrograms/day is used for established
renal osteodystrophy. Lower doses of calcitriol (0.25–0.5 micrograms/
day) are used in early ESRF to prevent the development of renal
osteodystrophy.
• Parathyroidectomy is advocated in bone disease uncontrolled by
vitamin D therapy or the development of tertiary hyperparathyroidism.
• Cinacalcet acts directly at the calcium-sensing receptor to lower PTH
secretion. This markedly improves s hyperparathyroidism, calcium and
phosphate levels, and renal osteodystrophy. Improvement in mortality
due to d vascular calcification has not yet been demonstrated.
RENAL DISEASE AND ENDOCRINOLOGY 661
Prolactin
Hyperprolactinaemia is common in ESRF but is usually mild, i.e.
<1,000mU/L. The cause is both i secretion and d renal clearance.
Gonadal function
• Hypogonadism—clinical and biochemical—is common in ESRF.
• In ♂, there is impaired pulsatile release of LH, although basal LH
levels are usually elevated due to impaired renal clearance. Serum FSH
is usually normal or mildly elevated.
• In ♀, levels of oestradiol, progesterone, and FSH are reported to
be within the normal range in the early follicular phase but fail to
show the usual cyclical changes. Menstrual disturbance is common.
Amenorrhoea, polymenorrhoea, and menorrhagia can also occur
on dialysis. Infertitility is the rule, and conception on dialysis is the
exception.
• Sexual dysfunction is common in both sexes but has been better
studied in ♂. 60% of ♂ have some degree of impotence, and
examination yields 80% to have testicular atrophy and 14% to have
gynaecomastia.
• Treatment of hypogonadism in ESRF is suboptimal. Testosterone
therapy is not associated with any clinical benefit in ♂.
Growth hormone and growth retardation
• Basal GH levels are normal, but there is impaired secretion following
an adequate hypoglycaemic stimulus in 40–70% of patients with ESRF.
• There is impaired growth in children, particularly during periods of
greatest growth velocity, and puberty is delayed. This combination
leads to short stature. The improved growth velocity after renal
transplantation is often too little too late in order to attain a normal
stature.
• Recombinant human GH (rhGH) has been shown to be an effective
treatment for growth retardation in children with stable chronic renal
failure (CRF) and ESRF as well as after renal transplantation.
Thyroid
The ‘sick euthyroid’ finding is common in CRF (b see Sick euthyroid
syndrome, p. 24).
Adrenal
• The adrenal axis is not impaired clinically by CRF.
• There is evidence of blunted cortisol response to hypoglycaemia, but
this is not relevant clinically.
• Patients with amyloidosis are at risk of hypoadrenalism due to adrenal
amyloid infiltration.
Endocrinology in the critically ill

(See Table 12.6.)
ACTH and cortisol
• CRH, ACTH, and cortisol increase rapidly during all forms of acute illness.
• Low albumin and CBG cause free cortisol to be substantially higher.
• This physiological adaptation results in:
• Provision of substrates for major organ energy expenditure
(via catabolism).
• Haemodynamic advantages (enhanced sensitivity to angiotensin II, i
vasopressor and inotropic response to catecholamines).
• Prevention of an excessive immune response.
• Inflammatory cytokines result in i cortisol metabolism and reduced
receptors, i.e. peripheral cortisol resistance.
• After moderate-to-severe injuries, plasma cortisol starts to fall after a
day or two but only reach normal levels after a week.
• Cortisol is elevated for at least 2 weeks in patients with severe burns.
• Prolonged critical illness results in low CRH and ACTH, with a
‘normal’ or slightly raised cortisol, perhaps driven by an alternative
pathway involving endothelin.
• Cortisol deficiency should be suspected in an acutely ill patient with
a plasma cortisol of <690nmol/L or an increment of <250nmol/L on a
250 micrograms short Synacthen® test.
• Drugs used in intensive care may contribute to adrenal insufficiency by:
• Reducing cortisol metabolism, e.g. etomidate (frequently used in
induction of anaesthesia) and ketoconazole.
• Promoting cortisol metabolism, e.g. phenytoin, carbamazepine, and
rifampicin.
Metabolism
• Hyperglycaemia is common in critical illness (even in non-diabetic
subjects) due to i cortisol, catecholamines, GH, and glucagon.
• These hormones and inflammatory cytokines also contribute to insulin
resistance.
• IV insulin, titrated to maintain normoglycaemia (glucose <6.1mmol/L),
reduces mortality by >40%.
TSH and thyroid hormones
• TSH levels usually remain stable in acute injury. Total T4 and T3 tend
to fall but may remain within the normal range.
• Enhanced thyroid hormone metabolism by i activity of liver
deiodinase type 3 (peripheral hormone deactivator).
• With prolonged illness, total T4 tends to fall below the normal range.
FT4 remains in the normal range.
• Total and free T3 levels fall after injury and may remain suppressed for
2–3 weeks after a severe injury. The rT3 level rises.
• In prolonged critical illness, the thyroid function conforms to the ‘sick
euthyroid syndrome’ (b see Sick euthyroid syndrome, p. 24).
Gonadotrophins and gonadal steroids
In prolonged illness, hypogonadotrophic hypogonadism occurs.
ENDOCRINOLOGY IN THE CRITICALLY ILL 663
Table 12.6 Endocrine and other changes seen in the ill

Acute illness
ACTH/CRH iii
Albumin/CBG d
Free cortisol ii
Catabolism ii
Immune response d
Inflammatory response ii
Cortisol resistance i
Glucose i
Insulin resistance ii
TSH l
FT4 and FT3 ld
IGF-1, IGFBPs, GHBPs d
Prolonged critical illness
ACTH/CRH dd
Free cortisol l or i
TSH, total T4 d
rT3 i
LH/FSH/T/oestradiol d
GH d
Response to GHRH d
Growth hormone
• In critical illness, the GH axis is profoundly affected, with initially raised
GH secretion but low IGF-1, IGFBPs, and GHBP related to peripheral
GH resistance.
• Prolonged critical illness >5–7 days results in low GH and a blunted
response to GHRH.
• Recombinant GH was proposed as a beneficial agent for critical
illness; however, the evidence is lacking, and there are reports of a
detrimental effect.
Hormone replacement and critical illness
There is no evidence that, other than insulin, hormonal supplementation
in the critically ill improves outcome.
Further reading
Elleger B, Debaveye Y, Van den Berghe G (2005). Endocrine interventions in the ICU. Eur J Intern
Med 16, 71–82.
Isidori AM, Kaltsas GA, Pozza C, et al. (2006). The ectopic adrenocorticotropin syndrome: clinical
features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metab 91, 371–7.
Syndromes of hormone resistance

Definition
Reduced responsiveness of target organs to a particular hormone, usually
secondary to a disorder of the receptor or distal signalling pathways. This
leads to alterations in feedback loops and elevated circulating hormone
levels.
Thyroid hormone resistance
b see Resistance to thyroid hormones, pp. 10, 50.
Androgen resistance
b see Androgen insensitivity syndrome, pp. 416, 546.
Glucocorticoid resistance
• Autosomal dominant and recessive forms have been described.
• The resistance can be generalized or tissue-specific, partial or
complete, and transient or permanent.
• Several mutations of the human glucocorticoid receptor gene have
been described.
• Diminished sensitivity to glucocorticoid leads to reduced
glucocorticoid feedback on CRH and ACTH, leading to i CRH,
ACTH, and cortisol concentrations.
• The clinical features are not due to excess glucocorticoid, as there is
reduced peripheral tissue sensitivity. However, elevated ACTH leads
to i secretion of mineralocorticoid (e.g. deoxycorticosterone) and
androgens (DHEA and DHEAS). This may lead to hypertension and
hypokalaemic alkalosis, hirsutism, acne, oligomenorrhoea in ♀, and
sexual precocity in ♂.
• Glucocorticoid resistance may be differentiated from Cushing’s
syndrome as, despite evidence of i urinary cortisol, abnormal
suppression with dexamethasone, and i responsiveness to CRH,
the diurnal rhythm of cortisol secretion persists, there are no clinical
features of Cushing’s syndrome, BMD is normal or i, and there is a
normal response to insulin-induced hypoglycaemia.
• Low-dose dexamethasone treatment (1–3mg/day) may efficiently
suppress ACTH and androgen production.
ACTH resistance
• Rare autosomal recessive disorders where the adrenal cortex fails
to respond to ACTH in the presence of an otherwise normal gland
(mineralocorticoid secretion is preserved under angiotensin II control).
Very rarely can be due to autoantibodies blocking the ACTH receptor.
• The presenting clinical features include hypoglycaemia, which is
often neonatal, neonatal jaundice, i skin pigmentation, and frequent
infections.
• Occasionally, ACTH resistance is a component of the triple A syndrome
of alacrima (absence of tears), achalasia of the cardia, and ACTH
resistance plus neurological disorders.
SYNDROMES OF HORMONE RESISTANCE 665
• Biochemical features. Undetectable or low 9 a.m. cortisol, with grossly

elevated ACTH (often >1,000ng/mL), and normal renin, aldosterone,
and electrolytes, and impaired response to short Synacthen® test.
• Treatment. Steroid replacement.
Mineralocorticoid resistance (see b p. 262)
Also known as type 1 pseudohypoaldosteronism, this is a rare inherited
disorder which usually presents in children with vomiting and anorexia,
soon after birth, failure to thrive, salt loss, and dehydration. Both autoso-
mal dominant and recessive forms have been described.
• Biochemical features:
• d serum sodium.
• i serum potassium (hyperkalaemic acidosis).
• i urinary sodium (despite hyponatraemia).
• i plasma and urinary aldosterone.
• i plasma renin activity.
• Diagnosis requires proof of unresponsiveness to mineralocorticoids
(no effect of fludrocortisone on urinary sodium).
• Treatment is with sodium supplementation, and carbenoxolone has
been used successfully. With time, treatment can often be weaned,
and salt wasting is unusual following childhood.
Further reading
Charmandari E, Kino T, Ichijo T, et al. (2008). Generalized glucocorticoid resistance: clinical aspects,
molecular mechanisms, and implications of a rare genetic disorder. JCEM 93, 1563–72.
Differential diagnosis of possible

manifestations of endocrine
disorders
Sweating
• Menopause/gonadal failure.*
• Thyrotoxicosis.*
• Intoxication.*
• Drug/alcohol withdrawal.*
• Phaeochromocytoma.
• Acromegaly.
• Carcinoid syndrome.
• Hypoglycaemia.
• Parkinsonism.
• Autonomic neuropathy (gustatory sweating).
• Renal cell carcinoma.
• Chronic/subacute infection (e.g. TB, endocarditis).
• Haematological malignancy (e.g. lymphoma).
• Anxiety.
• Idiopathic.
• Drugs, e.g. fluoxetine, tricyclics, aspirin, NSAIDs, tamoxifen,
omeprazole.
• Fabry’s disease (most commonly causes anhidrosis).
Investigation of sweating
• History.
• Clinical examination.
• Thyroid function tests, serum gonadotrophin levels, blood
glucose level.
• Specific investigations, according to clinical suspicion.
Management of sweating
• Treat the underlying cause where possible.
• Antiperspirants.
• Topical aluminium chloride ± ethanol.
• Anticholinergics—glycopyrronium bromide (oral or topical).
• Clonidine—taken at night to avoid sedation.
• Iontophoresis.
• Botulinum toxin A injections into affected areas (inhibits the release of
acetylcholine at the synaptic junction of local nerves).
• Local excision of axillary sweat glands.
• Sympathetic denervation:
• Video-assisted endoscopic thoracic sympathectomy: excision or
radioablation.
• Sympathotomy (chain disconnection between T2 ganglion and
stellate ganglion).
* Commonest causes.
DIFFERENTIAL DIAGNOSIS OF POSSIBLE ENDOCRINE DISORDERS 667
Palpitations (often associated with sweating)

• Thyrotoxicosis.
• Hypoglycaemia (insulinoma).
• Phaeochromocytoma.
• Anxiety states.
• Cardiac arrhythmia.
• Caffeine excess.
• Alcohol/drug withdrawal.
General malaise, tiredness
• Hypo- or hyperthyroidism.
• Hypogonadism.
• Hypopituitarism/GH deficiency.
• Osteomalacia.
• Anaemia.
• Drugs (prescription and recreational drugs):
• Antihistamines, antidepressants, antihypertensives (B-blockers,
methyldopa, clonidine), neuroleptics, corticosteroids.
• Malignancy.
• Chronic fatigue syndrome (may be associated with reduced cortisol
output, both basally and in response to a variety of challenges).
• Chronic illness (cardiac, respiratory, hepatic).
• Chronic pain.
• Fibromyalgia.
• Depression.
• Sleep disorders (obstructive sleep apnoea).
• Infection.
• Musculoskeletal/neurological disease (myasthenia gravis).
• Toxins.
• Idiopathic.
Investigation of fatigue
• Careful history-taking:
• Duration, onset, recovery, and type of fatigue.
• Person’s usual activity level.
• Clinical examination.
• Serum electrolytes.
• Haemoglobin ± serum ferritin level.
• Inflammatory markers (ESR, CRP).
• Liver function tests.
• Serum calcium and phosphate levels.
• Thyroid function tests.
• Short Synacthen® test.
Flushing
• Gonadal failure (with flushing and sweats).
• Drugs.
• Chlorpropamide.
• Nicotinic acid.
• Antioestrogens.
• LHRH agonists.
• Carcinoid (dry flushing—no sweats).
• Mastocytosis.
• Medullary thyroid cancer.
• Anaphylaxis.
• Pancreatic cell carcinoma.
• Phaeochromocytoma (more often pallor).
• Fever.
• Alcohol.
• Autonomic dysfunction.
• Some foods:
• Fish.
• Tyramine-containing food (cheese).
• Nitrites (cured meat).
• Monosodium glutamate.
• Spicy food.
• Gustatory flushing.
• Benign cutaneous flushing.
• Idiopathic.
Initial evaluation of patients with flushing
• Careful history.
• Physical examination (ideally during a flush although not often
possible):
• Examine skin carefully.
• Pulse rate.
• BP.
• Thyroid examination.
• Respiratory examination (wheeze).
• Careful abdominal examination.
• Urine dipstix.
• Biochemistry:
• Gonadotrophin levels.
• 2x 24h urinary 5HIAA measurements.
• Serum chromogranin A.
• 2x 24h urinary catecholamine measurements.
• Plasma metanephrines (if high level of suspicion).
• Serum tryptase level (if suspecting mastocytosis).
• Calcitonin level (if suspecting medullary thyroid cancer).
• Plasma VIP (if suspecting pancreatic carcinoma).
• Immunoglobulin levels (raised IgE may suggest allergies).
• Specific investigations, according to suspected diagnosis.
DIFFERENTIAL DIAGNOSIS OF POSSIBLE ENDOCRINE DISORDERS 669
Management of flushing
• Treat the underlying cause.
• Nadolol (non-selective B-blocker) effective in some cases of benign
cutaneous flushing.
• Somatostatin analogues can be used to treat flushing associated with
carcinoid syndrome.
• Antihistamines may be effective in some histamine-secreting carcinoid
tumours.
Further reading
Cleare A (2003). The neuroendocrinology of chronic fatigue syndrome. Endocr Rev 24, 236–52.
Cornuz J, Guessous I, Favrat B (2006). Fatigue: a practical approach to diagnosis in primary care.
CMAJ 174, 765–7.
Eisenach J, Atkinson J, Fealey R (2005). Hyperhidrosis: evolving therapies for a well established
phenomenon. Mayo Clin Proc 80, 657–66.
Izikson L, English J, Zirwas M (2006). The flushing patient: differential diagnosis, workup and
treatment. J Am Acad Derm 55, 193–208.
Paisley AN, Buckler HM (2010). Investigating secondary hyperhidrosis. BMJ 341, c4475.
Stress and the endocrine system

Definition
Stress may be considered as a state of threatened, or perceived as
threatened, homeostasis. The principal effectors of the stress response
are corticotrophin-releasing hormone (CRH), glucocorticoids (GCs), cat-
echolamines, arginine vasopressin (AVP), and POMC-derived peptides
(especially A-melanocyte-stimulating hormone) and B-endorphins.
Endocrine effects of stress
The endocrine response to stress is mediated by CNS and peripheral
components. The CNS components mediating the endocrine response
to stress are located in the hypothalamus and brainstem and consist of
the neurons releasing CRH, AVP, and the noradrenergic cell groups in the
medulla/pons. Peripheral components of the endocrine stress response
include the sympathetic–adrenal medulla system, the parasympathetic
system, and the hypothalamo–pituitary–adrenal axis.
Hypothalamo–pituitary axis
• i amplitude of synchronized pulsatile release of CRH and AVP (potent
synergistic factor of CRH) into the hypophyseal portal system.
• i stimulated ACTH production.
• i adrenal glucocorticoid and androgen secretion.
• GCs also play a role in termination of the normal stress response
by –ve feedback at the pituitary, hypothalamus, and extrahypothalamic
regions.
Growth hormone axis
• GCs suppress GH production and inhibit the effects of IGF-1 (thus,
children with anxiety disorders may have short stature).
• CRH increases somatostatin production, inhibiting GH production.
• GH response to IV glucagon is blunted.
Thyroid axis
• GCs reduce the production of TSH and limit the conversion of T4 to
the more active T3 by reducing deiodinase activity.
• Somatostatin suppresses both TRH and TSH release.
• b see Sick euthyroid syndrome, p. 24.
Reproductive axis
• CRH reduces GnRH secretion.
• GCs suppress GnRH neurons and pituitary gonadotrophs and render
the gonads resistant to gonadotrophins.
• GCs also render peripheral tissues resistant to oestradiol.
• Chronic stress leads to amenorrhoea in ♀ and low LH and
testosterone in ♂.
• Oestrogens increase CRH expression via an oestrogen response
element in the promoter region of the CRH gene. This may account for
the sex-related differences in the stress response and HPA axis activity.
• CRH is produced by the ovary, endometrium, and placenta during the
latter half of pregnancy, leading to physiological hypercortisolism.
STRESS AND THE ENDOCRINE SYSTEM 671
Metabolism
• GCs, via their direct effect and via reduced GH and sex hormone
activity, result in muscle and bone catabolism and fat anabolism.
• Chronic activation of the stress system is associated with i visceral
adiposity, d lean body mass, and suppressed osteoblastic activity
(which may ultimately lead to osteoporosis).
• GCs induce insulin resistance and other features of the metabolic
syndrome.
Other effects
• Immune: activation of the HPA axis inhibits the immune/inflammatory
response; most components of the immune response are inhibited by
glucocorticoids (>20% of genes expressed in human leukocytes are
regulated by glucocorticoids), increasing the susceptibility to infections.
Further reading
Charmandari E, Tsigos C, Chrousos G (2005). Endocrinology of the stress response. Annu Rev Physiol
67, 259–84.
Endocrinology of exercise
Exercise and the hypothalamo–pituitary axis
Exercise presents a significant challenge to physiological homeostasis. The
endocrine system is integral to the body’s ability to adapt to exercise,
allowing the mobilization of metabolic fuels and also assisting in key cardi-
orespiratory responses.
• A ‘stress’ response is a significant part of this, with both CRH
and ADH stimulating the release of ACTH and hence cortisol.
This response promotes gluconeogenesis and helps to limit
exercise-induced inflammation. Chronically trained athletes
demonstrate a background hypercortisolaemia, although an attenuated
cortisol rise in response to exercise is also seen.
• GH is released in response to acute exercise and remains i until
around 2h afterwards, although the mechanisms underlying this are not
clear. The response is proportional to both the intensity and duration
of the exercise. In longer term, both 24h GH secretion and IGF-1
levels correlate well with physical activity and VO2max.
• In order that fluid homeostasis can be maintained, ADH is released
in response to exercise in response to osmotic stimuli. However,
non-osmotic stimuli can also affect ADH release, and this may
contribute to the development of exercise-associated hyponatraemia.
• Prolactin is secreted in response to an exercise bout, although regular
exercise does not seem to affect prolactin levels long-term. The role of
prolactin in exercise is not clear, but it may impact on immune function.
• Both prolactin and cortisol suppress GnRH secretion, and hence
LH/FSH secretion, which may explain why exercise can suppress
gonadal function. Potential effects of this are discussed in The female
athlete triad on b p.673.
• TSH is rapidly stimulated in response to acute exercise, but
longer-term effects are not clear. Exercise training can inhibit
peripheral thyroid hormone metabolism, leading to increased levels of
reverse T3 and increased levels of T3.
Exercise and bone health
• Physical activity has been shown to i bone mass, especially at
load-bearing sites. Approximately 26% of total adult bone mass is
gained in 2 years around the time of peak bone gain (12.5 years in
girls and 14.1 years in boys), meaning that physical activity may be
particularly important around this time.
• Bone strength may be a more important measure than bone mass.
Small, but significant, exercise-related i in bone strength have also
been seen in the lower extremities in children.
• In older adults, bone mass is improved with weight-bearing exercise,
compared with controls, in general due to the attenuation of normal
bone loss rather than an i in bone mass in the intervention group.
• Rates of stress fracture in athletes have been d with calcium and
vitamin D supplementation, although the evidence is not yet strong
enough for supplementation to be recommended routinely. Dosing is
also not clear.
ENDOCRINOLOGY OF EXERCISE 673
The female athlete triad

This has been recognized since the 1990s and is defined as the interplay
between:
• Energy deficit (with or without an eating disorder).
• Amenorrhoea.
• Osteoporosis.
Hypothalamic amenorrhoea can develop in the context of stress, weight
loss, and exercise. An energy deficit (between intake and expenditure)
appears to be essential for weight loss and exercise-related forms, with
leptin also playing a key role. Problems with bone health may result from
a combination of poor intake of calcium and vitamin D and disruption of
gonadal function.
2 It is vital to ask about energy intake, weight, and menstrual function
in young female athletes. A detailed history is key to diagnosis of amenor-
rhoea, and investigation should rule out alternative causes,
Successful management often takes a multidisciplinary approach, includ-
ing both dietetic and psychological input. Strategies include:
• Exercise reduction and dietary modification to eliminate the energy
deficit and ensure adequate nutrient intake are important. Weight gain
may be required.
• For bone health, ensuring an adequate intake of calcium and vitamin
D is important. Whether supplemental doses are required (and if so,
what they should be) is not clear. There is no clear evidence for OCP
use in this context, although it is widespread.
• Bone densitometry is likely to be helpful both to assess bone health
and to evaluate the effectiveness of interventions.
Doping
Unfortunately, a small, but significant, number of athletes use banned
performance-enhancing substances in order to gain a competitive advan-
tage. Many of these are endocrine in origin. While their effects can be
advantageous, side effects are also a significant issue. Some of the most
popular are:
• Androgenic anabolic steroids. These improve performance by
increasing muscle mass and strength. The main side effects are
endocrine dysfunction, including virilization, hepatotoxicity, adverse
cardiac effects, and psychiatric problems.
• EPO. This improves performance by improving oxygen delivery to
muscle. The main side effect is an increased risk of thrombosis.
• GH. This results in improved muscle mass and reduced fat mass,
although there is limited evidence of a performance benefit. Adverse
effects are similar to those seen in acromegaly.
• Insulin. This can have beneficial anabolic effects, although side effects,
such as hypoglycaemia and weight gain, may make it less attractive.
Further reading
Gordon CM (2010). Clinical practice. Functional hypothalamic amenorrhea. N Engl J Med 363, 365–71.
Mastorakos G, Pavlatou M, Diamanti-Kandarakis E, Chrousos GP (2005). Exercise and the stress
system. Hormones (Athens) 4, 73–89.
McGrath JC, Cowan D (2008). Drugs in sport. Br J Pharmacol 154, 493–5.
Complementary and alternative

therapy and endocrinology
Introduction
• Many patients use natural products alongside, or instead of,
conventional therapy. Products and information are available from
many sources, but in particular the Internet.
• Patients need to be asked specifically about usage.
• Hospital pharmacists can be extremely helpful in sourcing information
about natural products, including interactions with conventional
medicines.
• Quality control of natural products is usually poor, with content
ranging anywhere from 0% of stated level to several fold higher.
• Safety data are often absent or inadequate. Some preparations may
also contain pharmacologically active compounds which can interact
with other treatments or worsen comorbidities (e.g. alternative and
complementary therapies for menopausal symptoms have been shown
to contain oestrogenic properties which would be a concern for
women with hormone-dependent diseases, such as breast cancer).
• Discussion of any natural products listed here is not intended in any
way to imply efficacy or safety of these products or to recommend
their usage, but rather to illustrate the compounds being promoted for
these conditions by alternative information sources.
COMPLEMENTARY AND ALTERNATIVE THERAPY 675
Alternative therapy used in patients

with diabetes mellitus
A major concern with natural products used by patients with diabetes
mellitus is that of interaction with conventional medicines, placing the
patient at risk of hypoglycaemia.
Hypoglycaemic agents
These work by i insulin secretion from the pancreas or due to direct
insulin-like action at the insulin receptor.
• Banaba (Lagerstroemia speciosa)—crepe myrtle. Banaba extracts
contain corosolic acid and ellagitannins, which may have direct
insulin-like effects at insulin receptors.
• Bitter melon (Momordica charantia). Contains a polypeptide with
insulin-like effects. Used as juice, powder, extracts, and fried food.
Often part of Asian and Indian foods.
• Fenugreek (Trigonella foenum-gracum). Used as powder, seeds, or as
part of dietary supplement. May enhance insulin release and may also
decrease carbohydrate absorption due to laxative effect. May also
inhibit platelets and thus increase bleeding diathesis.
• Gymnema (Gymnema sylvestre), ‘gurmar’ in Hindi (‘sugar-destroying’).
Extract ‘GS4’ also used. May increase endogenous insulin secretion
(i C-peptide levels noted in users). In some preliminary studies,
gymnema improved HbA1c and d insulin or OHA requirements.
• Berberine (from Coptis chinensis). AMP kinase activator and promotes
GLUT4 translocation to the cell membrane. Some studies suggest an
HbA1c-lowering effect.
Insulin sensitizers
• Cassia cinnamon (Cinnamomum aromaticum)—also known as Chinese
cinnamon (Cinnamomum verum is the usual cinnamon used in the
UK, although cassia cinnamon may be contained in ground cinnamon
mixes). May increase insulin sensitivity and lower fasting blood glucose
levels. Appears safe and well tolerated.
• Chromium. Chromium deficiency is associated with impaired glucose
tolerance, hyperglycaemia, and d insulin sensitivity. Chromium
forms part of a ‘glucose tolerance factor’ complex, and therefore
supplements are sometimes labelled ‘chromium GTF’. In patients with
diabetes and chromium deficiency, addition of chromium improves
glycaemic control. However, the role of chromium in patients without
deficiency is not clear. The American Diabetes Association only
recommends chromium usage in patients with documented chromium
deficiency. Excessive chromium may cause renal impairment.
• Vanadium. Thought to stimulate hepatic glycogenolysis; inhibit
gluconeogenesis, lipolysis, and intestinal glucose transport; increase
skeletal muscle glucose uptake, utilization, and glycogenolysis.
High-dose vanadium (taken as vanadyl sulphate) may improve insulin
sensitivity and glycaemic control in patients with type 2 diabetes,
with large doses of elemental vanadium required for these effects—
however, doses >1.8mg/day vanadium may cause renal impairment.
ALTERNATIVE THERAPY USED IN PATIENTS WITH DM 677
• Ginseng (both Panax ginseng and American ginseng (Panax

quinquefolius)). Contain ginsenoisides which may improve insulin
sensitivity. Efficacy and safety not established.
• Prickly pear cactus (Opuntia ficus-indica), also called opuntia or ‘nopals’
(referring to the cooked leaves of the cactus). Prominent in Mexican
folk medicine as a treatment for diabetes. Opuntia streptacantha stems
may improve glycaemic control, either acting as an insulin sensitizer
or by slowing carbohydrate absorption; however, this is not observed
with other prickly pear cactus species.
• Reservatrol. Extracted from grapes and red wine. Activates sirtuin
1 (with an indirect effect on substrates, including PPARG) and AMP
kinase.
• Cannabinoids activate AMPK and PPARG. Only anecdotal data on
glucose lowering available; formal trials ongoing.
Carbohydrate absorption inhibitors
• Soluble fibre. Increases viscosity of intestinal contents, thus slowing
gastric emptying time and carbohydrate absorption, resulting in lower
postprandial blood glucose levels.
• The following products have some evidence of reducing postprandial
blood glucose levels and may also improve total and LDL cholesterol
levels in patients. They may also interfere with absorption of drugs
and, therefore, should not be taken at the same time as conventional
medicines:
• Blond psyllium seed (Plantago ovata).
• Guar gum (Cyamopsis tetragonoloba).
• Oat bran (Avena sativa).
• Soy (Glycine max)—contains both soluble and insoluble fibre and
may improve insulin resistance, fasting BM, lipid profile, and HbA1c
in type 2 diabetes.
• Insoluble fibre. Glucomannan (Amorphophallus konjac)—can delay
glucose absorption.
Other products used by patients with diabetes mellitus
• Alpha-lipoic acid. Antioxidant. May improve insulin resistance. May
help symptoms of diabetic neuropathy (? mechanism).
• Stevia (Stevia rebaudiana). May enhance insulin secretion. May be toxic.
• Huangqi (Radix astragali). Used to treat hypoglycaemia unawareness.
May increase neural activation in central glucose-sensing regions in
response to hypoglycaemia.
Alternative therapy used in menopause

Phytoestrogens
• Main types are isoflavones (most potent and most widespread),
lignans, and coumestans.
• Sources:
• Isoflavones: legumes (soy, chickpea, garbanzo beans, red clover,
lentils, beans). Main active isoflavones are genistein and daidzein.
• Lignans: flaxseed, lentils, whole grains, beans, many fruits and
vegetables.
• Coumestans: red clover, sunflower seeds, sprouts.
• Other phytoestrogens: chasteberry (Vitex agnus-castus).
• Not structurally similar to oestrogen or to selective oestrogen
receptor modulators (SERMs) but contain a phenolic ring that allows
binding to oestrogen receptors-A and -B. Effects of binding depend
upon ambient oestrogen levels, relative ratio and concentration of
ER-A and ER-B; tissue type and location. Relatively much less potent
than endogenous oestrogen (by 100–10,000-fold).
• Phytoestrogens in vitro stimulate proliferation of normal human breast
tissue and of oestrogen-sensitive breast tumour cells. Theoretically,
phytoestrogens may stimulate ER +ve breast cancer and other
oestrogen-sensitive tumours. Phytoestrogens may also antagonize
the effects of tamoxifen or other SERMs. Phytoestrogens have not
been shown to stimulate endometrial growth; however, they are not
usually taken with progestagenic compounds. It is not known whether
the other serious side effects of conventional oestrogens (e.g. DVT,
pulmonary emboli, IHD, stroke) occur with phytoestrogen use. Many
sources of phytoestrogens (e.g. coumestans) interfere with warfarin.
• Soy protein (20–60mg/day, containing 34–76mg isoflavones) modestly
decreases frequency and severity of vasomotor symptoms in a
proportion of menopausal women.
• Synthetic isoflavones (ipriflavone) do not have antivasomotor activity.
• Phytoestrogens from red clover have not shown consistent
improvement in vasomotor symptoms. Other sources of phytoestrogens
have not shown improvement in menopausal symptoms.
• Compounds with oestrogenic activity should not be used in women
who should not take oestrogen (e.g. in women with breast cancer).
• For use in osteoporosis, b see Alternative therapy used by patients
with osteoporosis, pp. 680–1.
Other compounds with oestrogenic activity
• Kudzu (Pueraria lobata).
• Alfalfa (Medicago sativa).
• Hops (Humulus lupulus).
• Liquorice (Glycyrrhiza glabra).
• Panax ginseng (ginseng)—in vitro evidence of stimulation of breast
cancer cells.
ALTERNATIVE THERAPY USED IN MENOPAUSE 679
Other substances used

• Black cohosh (Actaea racemosa, formerly Cimicifuga racemosa)—not
to be confused with blue cohosh and white cohosh which are entirely
separate plants. Widely used in menopause. Although often advertised
as such, black cohosh does not bind to oestrogen receptors or have
oestrogen effects and little evidence for efficacy for hot flushes.
• Dong quai (Angelica sinensis)—not clear if oestrogenic. In vitro evidence
of promotion of breast cancer cells.
Alternative therapy used by patients

with osteoporosis
Calcium
• Hundreds of preparations available.
• Several types of calcium salts available (including citrate, carbonate,
lactate, gluconate, phosphate), with little evidence of superiority of
absorption, etc. between different compounds, other than calcium
citrate useful in patients with low gastric acidity (e.g. on concomitant
proton pump inhibitors or H2 antagonists).
Magnesium
• Necessary for release of PTH.
• In itself, not effective in treating osteoporosis, unless patients are
deficient in magnesium.
Fluoride
Increases bone density but not strength—bones less elastic, more
brittle—with resultant i fracture rate.
Trace elements
• For example, manganese, zinc, boron, copper.
• Whilst many trace elements are important for multiple enzyme
systems, including those in bone, most patients are not deficient,
and thus supplements have negligible +ve effect upon osteoporosis.
Moreover, many minerals in high doses cause serious side effects (e.g.
manganese doses >11mg/day can cause extrapyramidal side effects).
Vitamin D
Multiple preparations available, mainly as ergocalciferol or colecalciferol
(vitamin D metabolites require prescription). Tablets containing >200IU
vitamin D require a prescription in the UK.
Isoflavones
• For more detail about the mechanism of action of phytoestrogens,
b see Alternative therapy used in menopause, p. 678.
• Soy protein in doses >80mg/day may improve bone mineral density,
but no studies of soy have shown improvement in fracture rate.
Possible adverse effects upon oestrogen-sensitive tissues, such as ER
+ve breast cancer.
• Ipriflavone—semisynthetic isoflavone, produced from daidzein. No
oestrogenic effects. No evidence of improved fracture outcome. Some
studies of ipriflavone with calcium have reported improved BMD,
although other studies have not shown an improvement. Ipriflavone
can cause serious lymphopenia (<1 x 109mL) which may take up to a
year to recover.
ALTERNATIVE THERAPY USED BY PATIENTS WITH OSTEOPOROSIS 681
Tea
• Tea consists of green tea (unfermented), oolong tea (partially
fermented), and black tea (completely fermented).
• All teas contain fluoride and have high isoflavonoid content, in addition
to caffeine.
• Coffee (with a high caffeine content) has been associated with i hip
fracture risk. However, tea-drinking of all types has been associated
with higher BMD, although no fracture outcome has been reported.
DHEA
b see Miscellaneous alternative therapy p. 682.
Wild yam
Wild yam contains diosgenin which is used commercially as a source for
DHEA synthesis; however, this does not occur in humans.
Other compounds used by patients for osteoporosis
• Flaxseed (alpha-linolenic acid and lignans).
• Gelatin.
• Dong quai.
• Panax ginseng.
• Alfalfa.
• Liquorice.
There is no evidence of a +ve effect upon bone of these compounds.
Miscellaneous alternative therapy

Iodine and the thyroid
• Sources: kelp, shellfish-derived products.
• Effects: iodine-induced goitre or hypothyroidism, particularly in
patients with underlying thyroid disease (may have a Wolff–Chaikoff
effect in patients with Graves’s disease, causing inhibition of iodide
organification and thus thyroid hormone production).
• Iodine-induced hyperthyroidism in areas of endemic goitre and iodine
deficiency.
DHEA—‘elixir of youth’
• Reported to slow or improve changes associated with ageing, including
general well-being, cognitive function, sexual function, energy levels,
body composition, muscle strength, and to aid weight loss and treat
the metabolic syndrome.
• Mechanism of action: DHEA is secreted by the adrenal glands and
interconverted to DHEAS. Both DHEAS and DHEA are converted to
androgens and oestrogens that then act directly at their receptors.
• DHEA and DHEAS may play a role in replacement of adrenal
androgens in patients with adrenal insufficiency, resulting in improved
well-being, particularly with respect to sexual function.
• Not proven in controlled trials to improve health in other patients
without adrenal insufficiency.
• Risks of androgenic effects in women when taken at high
doses (100–200mg/DHEA daily). Theoretical risk of promoting
hormone-sensitive cancers, such as prostate and breast cancers. DHEA
may also interfere with antioestrogen effects of anastrazole and other
aromatase inhibitors.
Further information
Natural Medicines Comprehensive Database. Available at: M http://www.naturaldatabase.com
(requires subscription).
Chapter 13 683
Diabetes
Classification and diagnosis of Perioperative management of

diabetes 684 diabetes 742
Assessment of the newly Management of hypoglycaemia 746
diagnosed patient 688 The management of stroke
Genetics 690 patients with diabetes 748
Expert management of type 1 The critically ill patient 750
diabetes 694 Diabetes and pregnancy 752
Structured education in flexible Gestational diabetes 756
insulin therapy 698 Contraception and diabetes 760
Sick day rules 700 Paediatric and transition
Hypoglycaemia 702 diabetes 762
Insulin pump therapy 704 Management of children with
Continuous glucose diabetes 764
monitoring 708 Puberty and diabetes 766
Emerging therapies 710 Diabetic eye disease 768
Islet cell transplantation 711 Clinical and histological features of
Pancreas transplantation 712 diabetic eye disease 770
Expert management of type 2 Eye screening 774
diabetes 713 Medical treatment for diabetic eye
Oral glucose control disease 776
therapies 714 Surgical treatment for diabetic eye
Insulin therapy 718 disease 778
Bariatric surgery 719 Diabetic renal disease 782
The delivery of diabetes care 720 Making the diagnosis of diabetic
Diabetes and life 722 renal disease 784
Sport and exercise and diabetes 724 Treatment for diabetic renal
Alcohol and diabetes 726 disease 788
Recreational drug use and Diabetic neuropathy 792
diabetes 727 Peripheral sensorimotor
Travel and diabetes 728 neuropathy 794
Ramadan and diabetes 729 Mononeuropathies 795
Weight management with insulin Proximal motor neuropathy
treatment 730 (diabetic amyotrophy) 796
Annual review for patients with Foot examination for diabetic
diabetes 731 neuropathy 798
Hospital inpatient diabetes Autonomic neuropathy 800
management and diabetic The diabetic foot 804
emergencies 732 Treatment of the diabetic foot 806
Diabetic hyperglycaemic The Charcot foot 808
emergencies 734 Macrovascular disease 810
Hyperosmolar hyperglycaemic Lipid abnormalities found in
state 738 patients with diabetes 814
Intravenous insulin infusions used Hypertension 818
in hyperglycaemia 740 Management of hypertension 820
684 CHAPTER 13 Diabetes
Classification and diagnosis

of diabetes
Background
Diabetes mellitus (DM) is a metabolic disorder characterized by chronic
hyperglycaemia due to defects in insulin secretion and/or insulin action.
Currently, 4–6% of the UK population have diabetes. Worldwide,
285 million people were diagnosed with diabetes in 2010, and this number
is predicted to exceed 400 million by 2030.
Diagnosis
DM is a biochemical diagnosis based on fasting and postprandial (2h)
glucose levels during a 75g OGTT. In 1997, the American Diabetes
Association (ADA) proposed lowering the normal fasting plasma glucose
level to <6.1mmol/L and the threshold for diabetes to ≥7.0mmol/L. They
also recommended that fasting plasma glucose was the preferred diagnos-
tic test (outside of pregnancy) in order to reduce the number of OGTTs
needed. Table 13.1 describes the plasma glucose thresholds associated
with different stages of dysglycaemia; these range from normal glucose
tolerance through impaired glucose tolerance (IGT), impaired fasting
hyperglycaemia (IFG), and on to frank DM. In 2010, the ADA and WHO
introduced HbA1c ≥48mmol/mol or 6.5% as a diagnostic criterion for DM.
A diagnosis of diabetes is confirmed in any person with typical hypergly-
caemic symptoms (e.g. polyuria, polydipsia, weight loss), with a random
or postprandial blood glucose ≥11.1mmol/L or fasting plasma glucose
≥7mmol/L. In asymptomatic patients or those with intercurrent illness,
a second abnormal result is necessary to establish a definitive diagnosis
of diabetes.
Table 13.1 WHO glucose thresholds for diagnosis of diabetes mellitus

and other stages of dysglycaemia
Venous plasma
glucose (mmol/L)
Normal Fasting <6.1
and 2h glucose during an OGTT <7.8
Diabetes Fasting ≥7.0

or 2h glucose during an OGTT ≥11.1
IGT Fasting <7.0
and 2h glucose during an OGTT ≥7.8 and <11.1
IFG Fasting ≥6.1 and <7.0
CLASSIFICATION AND DIAGNOSIS OF DIABETES 685
Classification
During the 1980s, the WHO published the first widely accepted classifica-
tion of diabetes. Diabetes was classified as insulin-dependent DM (IDDM)
or type 1 diabetes, and non-insulin-dependent DM (NIDDM) or type 2
diabetes. In 1997, the updated classification of diabetes retained the terms
type 1 and type 2 diabetes, discarding the terms IDDM and NIDDM. The
updated classification system focused on the specific underlying aetiology
of diabetes. These aetiological groups are listed in Box 13.1.
Box 13.1 Aetiological classification of diabetes mellitus1

1. Type 1 diabetes (5–10% of cases): B-cell destruction.
• Includes autoimmune and idiopathic forms.
2. Type 2 diabetes (90% of cases): defective insulin secretion, usually
with defective insulin action.
3. Other specific types:
• Genetic defects of B-cell function:
• Maturity onset diabetes of the young (MODY).
• Mitochondrial DNA mutations.
• Neonatal diabetes.
• Genetic defects of insulin action:
• Lipodystrophies.
• Insulin receptor mutations (includes type A insulin resistance,
leprechaunism, Rabson–Mendenhall syndrome).
• Rare downstream insulin-signalling defects.
• Monogenic obesity/hyperphagia (e.g. leptin deficiency).
• Diseases of the exocrine pancreas:
• Pancreatitis, trauma, pancreatectomy, neoplasia, pancreatic
destruction (including cystic fibrosis and haemochromatosis),
others.
• Endocrinopathies:
• Cushing’s syndrome, acromegaly, phaeochromocytoma,
glucagonoma, hyperthyroidism, autoimmune polyglandular
syndrome 1 and 2, others.
• Drug- or chemical-induced:
• Glucocorticoids, thyroid hormone, diazoxide, B-adrenergic
agonists, thiazides, G-interferon, antiretroviral treatment (HIV).
• Infections:
• Congenital rubella, cytomegalovirus (CMV), others.
• Uncommon forms of immune-mediated diabetes:
• ‘Stiff man’ syndrome (type 1 diabetes, rigidity of muscles,
painful spasms), anti-insulin receptor antibodies, others.
• Other genetic syndromes associated with diabetes:
• Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome,
Wolfram syndrome (or DIDMOAD—diabetes insipidus,
DM, optic atrophy, and sensorineural deafness), Friedreich’s
ataxia, Huntington’s chorea, Lawrence–Moon–Biedl syndrome,
myotonic dystrophy, Prader–Willi syndrome, others.
4. Gestational diabetes mellitus.
1
Adapted from ADA classification.
The vast majority of patients with diabetes have either type 1 diabe-
tes (secondary to autoimmune-mediated B-cell destruction and absolute
insulin deficiency) or type 2 diabetes (due to insulin resistance and defects
of insulin secretion). Table 13.2 outlines the key differences. Although the
remaining aetiological subtypes account for <10% of all diabetes cases, it
is important to consider these rarer causes of diabetes, which comprise
the entire differential diagnosis, in order to facilitate personalized manage-
ment of these patients. Rarer forms, such as maturity onset diabetes of the
young (MODY), largely arise in young adults. These individuals are often
assumed to have type 1 or type 2 diabetes and frequently experience long
delays before the correct diagnosis is reached. Fig. 13.1 illustrates a sug-
gested diagnostic algorithm for young adults.
Table 13.2 Differences between type 1 and type 2 diabetes

Type 1 diabetes Type 2 diabetes
Peak age of onset 12 60
(years)
UK prevalence 0.25% 5–7% (10% of those
>65 years of age)
Initial presentation Polyuria, polydipsia, weight Hyperglycaemic symptoms,
loss, ketoacidosis often with complications
of diabetes
Aetiology Autoimmune B-cell Combination of insulin
destruction resistance, B-cell
destruction, and B-cell
dysfunction
Presence of B-cell >90% No
antibodies
Insulin-dependent Yes No
Diabetic Common Rare
ketoacidosis
Obesity Uncommon Common
Insulin resistance Uncommon Common
Treatment Insulin from outset Diet 9 oral hypoglycaemic
agents 9 insulin
CLASSIFICATION AND DIAGNOSIS OF DIABETES 687
Yes
Diabetes diagnosed ≤6 months
Genetic testing for neonatal diabetes
No
Diabetes diagnosed ≤45 years and Yes

Testing for mitochondrial mutations
deafness/other neurological features
No
Permanent insulin within 3 months Yes

Probable Type 1 diabetes
of diagnosis and/or diabetic ketoacidosis
and/or positive β-cell antibodies
No No
≤30 years at diagnosis and/or C-peptide >0.2nmol/l outside

absence of insulin resistance and/or the honeymoon period
≥2 generations with young-onset diabetes β-cell antibody negative
Yes
Yes
No
Consider MODY genetic testing
Probable Type 2 diabetes
Fig. 13.1 Aetiological diagnosis in diabetes diagnosed <45 years.

Assessment of the newly

diagnosed patient
There are two issues to address in a patient with a new diagnosis of diabe-
tes: firstly, what the immediate management (inpatient vs outpatient, opti-
mal treatment) is and, secondly, what the underlying aetiology is. Assigning
aetiology is usually most challenging in those diagnosed in the second to
fourth decades of life where there is overlap of clinical features between
the common and rarer forms of diabetes. Reassessment over the first year
or so after diagnosis can be helpful. If in any doubt over whether this is
type 1 diabetes, be safe and commence insulin.
Fig. 13.1 suggests an algorithm for the investigation of young adults.
• History: acute or insidious onset, family history of diabetes, presence of
other autoimmune diseases, ethnic origin.
• Examination: BMI, acanthosis nigricans, vitiligo. Evaluation of
precipitating cause or infection.
• Investigations: HbA1c; renal, liver, and thyroid function; lipid profile.
Ketones (urine or blood) and venous bicarbonate to assess for DKA.
Test for B-cell antibodies in younger patients (<45 years at diagnosis).
Causes of diagnostic confusion
• Latent autoimmune diabetes of adulthood (LADA). This presents like
type 2 diabetes but is a form of type 1 diabetes with insidious onset,
defined by the presence of any B-cell antibody. Treat like type 2
diabetes, but progression to insulin is usually more rapid.
• Ketosis-prone diabetes (KPD). This presents with DKA or ketosis, but
insulin requirements decline over weeks l months, and insulin can
often be stopped. Most commonly seen in patients of African origin
who are antibody –ve. Patients should be advised that they may
develop ketosis again during illness and be given ketone-monitoring
equipment.
• Monogenic diabetes. b see p. 691.
ASSESSMENT OF THE NEWLY DIAGNOSED PATIENT 689
Genetics
Type 1 diabetes
The overall lifetime risk of developing type 1 diabetes in a Caucasian popu-
lation is currently 0.4%. This risk increases to:
• 1–2% if your mother has type 1 diabetes.
• 3–6% if your father has type 1 diabetes.
• 5–6% if a sibling has type 1 diabetes.
• Monozygotic twins have 750% concordance rate by age 40 years.
Early linkage studies identified the importance of the human leukocyte anti-
gen (HLA) genes of the major histocompatibility complex (MHC) in type 1
diabetes susceptibility. These variants account for half of the heritability of
type 1 diabetes. The HLA class II DR and DQ loci (respectively encoded
by genes DRB and DQB) account for almost all type 1 diabetes suscep-
tibility from this region. >90% of patients with type 1 diabetes carry at
least one copy of the DRB*301-DQB*201 or DRB*401-DQA*301-DQB*302
(allele numbers after asterisk).
Other susceptibility loci include variants in the gene encoding insulin
(INS) which confers a 2-fold increased risk. More recent genome-wide
association studies (GWAS) have increased the total number of loci asso-
ciated with type 1 diabetes to >40; however, these loci have much lower
effect size than the HLA or INS genes.
These genetic studies have confirmed that the pathogenesis of type 1
diabetes involves disordered immune regulation. Indeed, i levels of islet
cell antibodies (ICA), anti-glutamic acid decarboxylase (GAD) antibod-
ies, and anti-tyrosine phosphatase antibodies (anti-IA-2 antibodies) are
usually detected at diagnosis. The presence of all three antibodies give a
non-diabetic individual an 88% chance of developing type 1 diabetes over
the next 10 years.
Type 2 diabetes
The importance of genetic background in the aetiology of type 2 diabetes
is well established from family and twin studies (concordance between
monozygotic twins is 60–100%). Heritability of type 2 diabetes is estimated
at 725%.
• So far, >70 genetic susceptibility variants for type 2 diabetes have been
detected, largely through GWAS.
• TCF7L2 (encoding transcription factor 7-like 2 protein) in chromosome
10q is the susceptibility locus, with the largest effect on type 2 diabetes
risk, described to date, with a per-allele odds ratio of 71.4.
• Together, the genetic loci found so far only explain a small proportion
(710%) of the overall heritable risk for type 2 diabetes.
• Ongoing research is focused on identifying rare genetic variants which
might account for the missing heritability in type 2 diabetes.
• Potential areas of clinical translation include risk prediction,
prevention, pharmacogenetics, and development of novel
therapeutics.
GENETICS 691
Maturity onset diabetes of the young (MODY)

MODY, the commonest cause of monogenic B-cell dysfunction, is esti-
mated to be the underlying cause in 0.5–1% of all patients with diabetes.
A typical ‘MODY patient’ has young age of onset (<45 years, frequently
<25 years), autosomal dominant family history of diabetes, absence of
autoimmune markers, absence of insulin resistance and remains C-peptide
+ve, even if insulin-treated. Mutations in ten different genes have been
associated with the MODY phenotype; however, in clinical practice, the
vast majority of MODY cases are due to heterozygous mutations in genes
encoding the enzyme glucokinase (GCK) and the nuclear transcription
factors hepatocyte nuclear factor 1A (HNF1A), hepatocyte nuclear factor
4A (HNF4A), and hepatocyte nuclear factor 1B (HNF1B).
HNF1A-MODY (previous name MODY3)
• Accounts for 30–70% of MODY cases.
• Associated with a progressive defect of insulin secretion which can be
complicated by severe hyperglycaemia (1/3 patients eventually require
insulin therapy) and frequent microvascular complications.
• Low renal threshold for glucose.
• Importantly, these patients are exquisitely sensitive to sulfonylureas.
Low doses (e.g. gliclazide 40mg od) are recommended as first-line
pharmacological therapy, often maintaining excellent glycaemic control
for years. Insulin can be stopped in those who were assumed to have
type 1 diabetes at onset of diabetes.
• Low C-reactive protein (<0.5mg/L).
HNF4A-MODY (previous name MODY1)
• Clinical presentation similar to HNF1A-MODY (except normal renal
glucose threshold).
• Also sensitive to sulfonylureas (b see HNF1A-MODY above).
• Neonatal hyperinsulinaemia and hypoglycaemia associated with
macrosomia in affected neonates.
GCK-MODY (previous name MODY2)
• Results in a raised threshold for glucose-stimulated insulin secretion,
but importantly insulin secretion remains regulated.
• Lifelong, mild, stable fasting hyperglycaemia (fasting plasma glucose
5.5–8mmol/L and HbA1c <8%). Low increment of glucose rise
following a carbohydrate challenge.
• GCK-MODY can be diagnosed at any age. Patients are often
asymptomatic, with hyperglycaemia found during screening.
• Diabetes-related microvascular complications are not observed.
• Patients should be managed on diet alone (insulin is usually only
required during pregnancy if the fetus is macrosomic).
• Secondary care follow-up is not usually required.
HNF1B-MODY (previous name MODY5)
• Also known as renal cysts and diabetes (RCAD) syndrome.
• Accounts for 5–10% of cases of MODY.
• Clinical features include malformations of the genitourinary system

(commonly renal cysts and other renal developmental abnormalities),
pancreatic atrophy, and exocrine insufficiency.
• Patients or family members may present to renal physicians first.
• Not sensitive to sulfonylureas.
Management of MODY in pregnancy
Although MODY is an uncommon cause of GDM, women with MODY
often present with dysglycaemia in pregnancy. Most will be managed
according to routine guidelines, but for those known to have MODY prior
to pregnancy, specific advice on management can be sought from the
MODY UK diagnostic centre (M http://www.diabetesgenes.org).
For those with HNF1A/HNF4A-MODY already well controlled on
low-dose SU agents prior to pregnancy, there is a good argument for
using glibenclamide pre-conception (safe in type 2 diabetes) and continu-
ing as long as good control is maintained.
In HNF4A-MODY, an affected fetus can develop hyperinsulinaemia,
macrosomia, and neonatal hypoglycaemia. Seek specialist advice on fetal
monitoring.
In GCK-MODY, treatment (with insulin) is only recommended if mac-
rosomia is developing. Seek specialist advice.
Neonatal diabetes
• Affects 71 in 100,000–150,000 live births.
• Diabetes diagnosed before 6 months is likely to be one of the
monogenic subtypes of neonatal diabetes, rather than type 1 diabetes.
Refer those diagnosed before 6 months for genetic investigation, even if
many years later and attending adult clinics. Diagnosis could change
management.
• Transient neonatal diabetes (TNDM): diabetes usually remits within
3 months—chromosome 6q24 imprinting abnormalities (70% cases),
mutations in the KATP channel genes (20% cases).
• Permanent neonatal diabetes (PNDM): mutations in KCNJ11 and
ABCC8 genes, respectively encoding the Kir6.2 and SUR1 subunits of
the KATP channel (50% cases); insulin gene mutations (10–15% cases).
• Patients with KCNJ11 and ABCC8 mutations can be effectively treated
with high-dose sulfonylureas and insulin stopped.
• 720% cases with KATP channel gene mutations have additional
neurological features (DEND syndrome—developmental delay,
epilepsy, and neonatal diabetes).
• INS mutations should be treated with insulin sensitizers or insulin.
• Seek specialist advice for management (M http://www.diabetesgenes.org).
Mitochondrial diabetes
• Due to mutations in mitochondrial DNA (most common is an A-to-G
point mutation at position 3243 in the tRNA leucine gene).
• Maternal inheritance.
• Commonly associated with sensorineural deafness (MIDD: maternally
inherited diabetes and deafness).
GENETICS 693
• Clinical features include CNS disease, ophthalmic disease (e.g. macular

retinal dystrophy), myopathy, cardiac disease (e.g. LVH), and renal
disease—patients should have echos, and consider neurology referral.
• Clinical phenotype can be variable, even within the same family, due to
heteroplasmy.
• Patients should be referred to clinical genetics team for advice.
Genetic causes of severe insulin resistance
• Characterized by young onset of severe insulin resistance, e.g.
acanthosis nigricans, dyslipidaemia, hypertension, hepatic steatosis,
PCOS. This constellation of features, particularly in non-obese
patients, should raise suspicion of a genetic cause. Treatment can be
challenging. Exercise and insulin sensitizers are first line, then high-dose
insulin (concentrated U-500 insulin may be helpful).
• Lipodystrophies. Insulin resistance plus abnormal fat distribution, e.g.
loss of fat from limbs and increased central and ectopic fat. The
classic Dunnigan familial partial lipodystrophy is caused by mutations
in LMNA. Mutations in PPARG present with a similar phenotype. The
lipodystrophies are more readily diagnosed in female patients.
• Insulin receptor mutations. Present with a range of severities but, in
addition to severe insulin resistance, can present initially with fasting
hypoglycaemia and growth defects and hyperandrogenism in women.
Diagnostic genetic testing
Diagnostic testing is available for the MODY subtypes, neonatal diabetes,
mitochondrial mutations (particularly, the common A3243G variant), and
the lipodystrophies (LMNA/PPARG). Although testing can be expensive, a
clinical diagnosis is not a substitute for a definitive genetic test, especially
where treatment decisions, such as stopping insulin, might depend on the
outcome. Involve clinical genetics services to help with family screening.
In the UK, the Genetic Diabetes Nurses network can provide help and
expertise, and there is also an online MODY probability calculator; access
both through M http://www.diabetesgenes.org/.
Further reading
American Diabetes Association (2012). Diagnosis and classification of diabetes mellitus. Diabetes
Care 35(S1), S64–71.
Greeley SAW, Naylor RN, Philipson LH, Bell GI (2011). Neonatal diabetes: An expanding list of
genes allows for improved diagnosis and treatment. Curr Diab Rep 11, 519–32.
Murphy R, Turnbull DM, Walker M, Hattersley AT (2007). Clinical features, diagnosis and man-
agement of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G
mitochondrial point mutation. Diabet Med 25, 383–99.
Semple RK, Savage DB, Cochran EK, Gorden P, O’Rahilly S (2011). Genetic syndromes of severe
insulin resistance. Endocr Rev 32, 498–514.
Thanabalasingham G, Owen KR (2011). Diagnosis and management of maturity onset diabetes of
the young (MODY). BMJ 343, 837–42.
Visscher PM, Brown MA, McCarthy MI, Yang J (2012). Five years of GWAS discovery. Am J Hum
Genet 90, 7–24.
Expert management of type 1

diabetes
Background
This condition is characterized by absolute insulin deficiency secondary to
T-cell-mediated autoimmune destruction of the insulin-producing islets.
This is characterized by the presence of T1-associated autoantibodies to
glutamic acid decarboxylase (GAD), islet autoantigen (IA-2), and insu-
lin which can often be detected for a few years prior to diagnosis and
frequently declines from the time of diagnosis. They are often absent in
long-standing disease and are not thought to be pathogenic themselves.
80–95% of patients will have demonstrable autoantibodies at diagnosis.
Type 1 diabetes typically presents in children but can present much later
in life. Age at presentation is bimodal, with a peak around puberty and
another peak between 20–30 years of age. Incidence rates in those under
5 years have been rising sharply.
Some patients of Afro-Caribbean descent may present with diabetes
and ketones but are antibody –ve and have ketosis-prone type diabetes
(KPD, b see p. 688). Patients who develop type 1 diabetes later in life
frequently have a more insidious presentation, often termed latent auto-
immune diabetes in adults (LADA, b see p. 688).
Soon after diagnosis with type 1 diabetes, patients commonly go
through the ‘honeymoon period’ when insulin requirements reduce dra-
matically and patients can even come off insulin for a short duration. This
phase can last from a few weeks to a few years (longer with increasing
age), but it is important to monitor blood glucose carefully and reinstate
insulin treatment as soon as blood glucose starts to rise. At the time of
diagnosis, patients usually have between 10–20% of B-cell function left,
which can sustain the patient through this phase.
Management
In type 1 diabetes, insulin therapy is mandatory, along with dietary advice
and standard diabetes education. The aim of treatment is to mimic physi-
ological insulin production as far as possible, given limitations of current
insulin delivery. Physiological studies suggest normal insulin requirements
are around 0.5–0.6 units/kg/day, split equally between background (basal)
and mealtime (bolus) requirements.
An initial education package will include:
• An explanation as to what diabetes is and what it means to the patient.
• Aims of treatment, e.g. rationale of reducing complications and
suggested values to aim for (see Box 13.2).
• Self-monitoring, e.g. both the method(s) of doing this, the reasons for
doing it, and what to do with the results.
• Injection technique.
• Advice about hypoglycaemia detection and treatment.
• Dietary advice with information on carbohydrate counting.
• Information about annual screening (review) for complications of
diabetes, including referral to their local eye screening service.
EXPERT MANAGEMENT OF TYPE 1 DIABETES 695
Box 13.2 Suggested aims of treatment
Pre-meal blood glucose 4.5–7.5mmol/L

Post-meal blood glucose (at 2h) 8–10mmol/L
HbA1c 42–58mmol/mol (6.0–7.5%)
WITHOUT
Recurrent or debilitating hypoglycaemia
Blood pressure <130/80mmHg
Body mass index 20–25 ideally
Home monitoring Ideally required before each meal (to help
judge the dose of insulin required) and
pre-bed
• Advice regarding DVLA, insurance companies, and Diabetes UK.

• Advice regarding pregnancy (for women of childbearing age).
All patients with type 1 diabetes should be offered structured education
in flexible insulin therapy within their first year with diabetes. There are a
number of programmes available across the UK, the most widely available
is called DAFNE (Dose Adjustment For Normal Eating), but a variety of
local programmes offer training along similar principles.
Types of insulin
• Physiological insulin replacement depends on dividing the insulin into
basal (background) and bolus (mealtime/quick-acting) insulin.
• Background insulin is affected by weight, stress, exercise, alcohol.
• Quick-acting insulin is adjusted, according to carbohydrate intake and
exercise, and is used to correct high readings.
• Inhaled insulin. This was available briefly but was withdrawn in 2010.
Some newer preparations are under evaluation but are not currently
commercially available.
• Currently available insulins are listed in Box 13.3.
Insulin regimens
Basal bolus regimen
This is the most widely used regimen and the basis of most structured edu-
cation programmes for type 1 diabetes. Once or twice daily isophane or
analogue insulin is used to cover basal requirements, which can be adjusted
in response to exercise, alcohol, or illness. Ideally, the basal insulin is titrated
so that, if the patient did not eat, blood glucose would remain stable. This is
often done using carbohydrate-free days. Soluble or rapid-acting analogue
insulin is used to cover meals and also to correct high blood glucose read-
ings. This regimen, combined with patient education that trains patients to
adjust the doses in response to food, exercise, and illness, provides patients
with flexibility to be able to lead a more normal life.
Box 13.3 Summary of types of insulin available

Type of insulin Examples Peak activity (h) Duration of
action (h)
Bolus (quick-acting) insulin
Rapid-acting Humalog® 0–2 3–4
analogues (insulin lispro)
NovoRapid® 1–3 3–4
(insulin aspart)
Apidra® 1–3 3–4
(insulin glulisine)
Soluble Actrapid® 1–3 6–8
Humulin S® 1–3 6–8
Insuman Rapid® 1–4 7–9
Basal (background) insulin
Isophane (NPH) Insulatard® 2–8 10–16
Humulin I® 2–8 10–16
Insuman Basal® 3–4 11–20
Long-acting Levemir® Peakless 12–16
analogues (insulin detemir)
Lantus® (insulin glargine) Peakless 18–24
*Tresiba® (insulin degludec) Peakless 42
Mixed insulin
Isophane with Humulin M3®
soluble insulin
Insuman Comb 15®
Insuman Comb 25®
Insuman Comb 50®
Biphasic Humalog Mix 25®
analogue insulin
Novomix 30®
Animal insulin Display similar characteristics
to the human insulin above
Hypurin® Bovine Neutral
Hypurin® Porcine Neutral
Hypurin® Bovine Isophane
Hypurin® Porcine Isophane
Hypurin® Porcine 30/70 mix
* Available in standard U100 and U200 strength
Twice daily fixed mixture

These are pre-prepared mixtures of soluble and isophane insulin, most
commonly in the ratio of 30% soluble/70% isophane (e.g. Humulin M3®).
Insuman mixes are available in other ratios. Newer mixes with biphasic
analogue insulin are also available (e.g. Novomix 30®, Humalog Mix 25®).
These have the advantage of only two injections a day but offer less flex-
ibility in terms of ability to respond to changes in food, exercise, or illness.
These may be used in patients who are unable to inject more often or live
a very fixed lifestyle and are more commonly used in those with type 2
diabetes.
Twice daily free mixing
Historically, before insulin pens were available, this was a standard regi-
men, with patients drawing up insulin from vials in syringes. Usually, they
would use 2/3 isophane, 1/3 soluble, with 2/3 of the total daily dose given
pre-breakfast and 1/3 given pre-evening meal. This regime allows very lit-
tle flexibility in timing or quantity of meals and little ability to adjust for
changes in insulin requirements due to exercise or illness.
Insulin pump: continuous subcutaneous insulin infusion (CSII)
This involves continuous infusion of quick-acting insulin (usually
rapid-acting analogue insulin), using a small pager-sized pump through a
small subcutaneous cannula. The cannula is replaced by the patient every
2–3 days. The pump is programmed to deliver basal insulin, as required,
through the day and can be increased in response to illness or decreased/
suspended in response to exercise or alcohol. Most modern pumps have
in-built bolus calculators that use pre-programmed values for insulin: car-
bohydrate ratios, insulin sensitivity, and blood glucose targets to calculate
insulin doses. They can also store information on blood glucose readings
entered into the pump and insulin delivered for download and review.
This is discussed in more detail in the next section.
Structured education in flexible

insulin therapy
The Diabetes Control and Complications Trial (DCCT) demonstrated
that intensive control of blood glucose reduced the risks of microvas-
cular complications. However, in this study, this was associated with a
3-fold increase in severe hypoglycaemia (episodes requiring third-party
assistance). Subsequent studies in which patients were trained to adjust
their own insulin doses on the basis of their current blood glucose levels,
expected carbohydrate intake, and activity allowed them to achieve similar
blood glucose control, with a reduction in hypoglycaemia. There are a
number of similar programmes available (DAFNE, BERTIE, EXPERT, etc.)
which are based around the following key principles:
• Separation of meal (quick-acting) and background (basal) insulin.
• Adjustment of mealtime insulin, based on carbohydrate intake.
• Correction doses, based on a correction factor.
Basal insulin
Basal insulin is usually long-acting insulin, either regular (Insulatard® or
Humulin I®) or analogue (glargine or detemir). This replaces background
requirements and should produce stable glucose levels if the patient does
not eat carbohydrate. This should be adjusted in response to alcohol or
exercise. Commonly split into morning and evening doses if blood sugars
are seen to rise towards end of a 24h dose period.
Quick-acting insulin
This may be regular (Humulin S®, Insuman Rapid®) or analogue
(NovoRapid®, Humalog®, or Apidra®). This is adjusted, based on carbohy-
drate intake and current blood glucose levels.
Insulin-to-carbohydrate ratio
This is the amount of insulin required for a fixed amount of carbohydrate
(usually 10g). This is sometimes also expressed as number of grams of
carbohydrate required to neutralize 1 unit of insulin. A common starting
point for a normal weight adult would be 1 unit/10g.
Rule of 500. A simple rule to calculate insulin-to-carbohydrate ratio is
to divide 500 by the total daily dose (TDD).
For example, for a TDD of 50 units, insulin-to-carbohydrate ratio will
be 500/50 = 10g/unit. For a total daily dose of 80 units, insulin to carbohy-
drate ratio will be 500/80 = 6.25.
This can be tested by checking blood glucose levels 2h post-meal. If
these are above target (usually set for <10mmol/L), then this can be
increased.
Insulin sensitivity (correction factor)
This is the degree to which 1 unit of insulin will drop the blood glucose.
A common starting point for an adult is 1 unit to drop the glucose by
3mmol/L.
Rule of 100. 100/TDD = correction factor in mmol/L.
STRUCTURED EDUCATION IN FLEXIBLE INSULIN THERAPY 699
For example, for a TDD of 50 units, correction factor = 100/50 = 2.

(This is the ‘1800 rule’ when measuring glucose in mg/dL.)
Principles of dose adjustments
Patients are advised to test blood glucose before meals and before bed.
Reflect on blood glucose readings at regular intervals to look for patterns
over the previous 5–7 days. The only exception to waiting for a pattern
is when overnight or fasting hypoglycaemia occurs, when patients should
reduce their night-time background insulin by 10–20% the following night.
Some simple rules of adjustment are:
• Make one change at a time.
• Use carbohydrate-free days to adjust the daytime basal.
• Adjust the bedtime basal insulin, based on the fasting glucose.
• If a correction dose is required at the same time every day, consider
changing the insulin-to-carbohydrate ratio or basal insulin active at
that time.
• Reduce evening basal insulin after alcohol or exercise by 25–50%.
• Do not correct post-hypo highs.
• If high post-meal readings, increase insulin-to-carbohydrate ratio.
• Reduce bedtime basal insulin in response to recurrent unexplained
nocturnal hypoglycaemia.
Dawn phenomenon
Most people have a surge in insulin requirements 3–4h before waking up.
This is mainly due to increased amplitude and frequency of GH pulses but
also coincides with a natural rise in cortisol levels. In about 30% of people,
this causes >30% increase in insulin requirements. In patients on NPH
insulin, this coincides with a reduction in activity of the insulin, leading
to fasting hyperglycaemia. Increases in bedtime NPH lead to overnight
hypoglycaemia. This effect is less pronounced with analogue basal insulins,
which do not wane in function in the early hours. However, a large pro-
portion of patients with type 1 diabetes experience rising glucose between
4 and 8 a.m., leading to consistent fasting hyperglycaemia. These issues can
only be properly controlled by an insulin pump which can be programmed
to increase basal rates at the required time overnight.
Sick day rules

When unwell, patients become more insulin-resistant and can some-
times develop ketosis. If severe enough, this can progress to ketoacidosis.
A third of admissions for DKA are precipitated by illness, and some may
be avoided by appropriate use of ‘sick day rules’.
• Never stop basal insulin.
• Continue mealtime insulin with addition of extra insulin, as described
in the box on Minor illness and Severe illness below.
• Drink sugar-free fluids to remain hydrated—100mL/h.
Minor illness
KETONES urine –/+ OR blood <1.5mmol/L.
• If blood glucose >8mmol/L, increase all insulin doses by 10–20%.
• Check blood glucose and ketones every 4–6h.
• Take correction insulin (quick-acting insulin at usual correction
doses) every 4–6h, even if not eating.
Severe illness
KETONES urine ++/+++ OR blood >1.5mmol/L.
• Increase background insulin by 30–40%.
• KETONES 1.5–3mmol/L: take 10% of total daily insulin dose every 2h
as quick-acting insulin until ketones go away.
• KETONES >3mmol/L: take 20% of total daily insulin dose every 2h as
quick-acting insulin until ketones go away.
• If ketones do not fall after 2–4h, seek medical advice.
When ketones –ve/trace or <1.5mmol/L, carry on as for ‘minor illness’.
Try to eat 10–20g carbohydrate 4-hourly. Test frequently.
Calculation example
A patient has a standard regimen of basal insulin 12 units bd and 1
unit/10g CHO, giving an average TDD of 50 units.
• If unwell and hyperglycaemic but ketones <1.5mmol/L, increase basal
insulin to 13–14 units bd, and take regular correction doses.
• If blood ketones are 1.5–3mmol/L, take 10% of TDD = 5 units
2-hourly till ketone –ve.
• If blood ketones are >3mmol/L, take 10 units 2-hourly till
ketone –ve.
3 If ketones do not fall with these approaches and patients become more
ill or cannot take fluids due to nausea and vomiting, they should seek urgent
medical advice and will usually require admission.
SICK DAY RULES 701
Hypoglycaemia
Management of hypoglycaemia (b see p. 746)
Hypoglycaemia (low blood glucose) is defined as blood glucose below
3.9 mmol/L, resulting from an imbalance between glucose supply, glucose
utilization, and current insulin levels. This is characterized by typical symp-
toms (see Table 13.3).
Autonomic symptoms are associated with a release of catecholamines,
cortisol, glucagon, and growth hormone. They typically occur at a blood
glucose level of around 3.8mmol/L while neuroglycopenic symptoms
occur when glucose levels drop below 3mmol/L. In the elderly or those
with long diabetes duration, autonomic symptoms are less pronounced
and occur at lower blood glucose levels, often resulting in delay in detect-
ing hypoglycaemia. This can also result in neuroglycopenia and confusion,
causing failure of recognition of hypoglycaemia.
Risk factors and causes of hypoglycaemia are listed in Box 13.4.
Severe hypoglycaemia
• This is defined as an episode that requires assistance from another
person, or that requires hospitalization or parenteral glucose
administration or treatment with glucagon.
• This occurs when blood glucose drops to a level inadequate to
support consciousness, usually below 1.5mmol/L.
• It is thought that, in some cases, this is associated with seizures or
cardiac arrhythmias and can be associated with death. The term ‘dead
in bed’ describes the scenario seen in about 6% of deaths in young
people with type 1 diabetes where the patient is found dead in an
undisturbed bed. There is often a history of recent susceptibility to
nocturnal hypoglycaemia.
Impaired awareness of hypoglycaemia
Recurrent hypoglycaemia can reduce the hormonal and symptomatic
responses to subsequent hypoglycaemia, and, over time, after exposure to
multiple episodes, patients can lose the ability to recognize hypoglycaemia.
This is termed hypoglycaemia unawareness. Those with impaired aware-
ness of hypoglycaemia have a 3–5-fold greater risk of severe hypoglycae-
mia, compared to those with normal awareness. Often, other people will
recognize hypoglycaemia before the patient does.
A simple score to assess awareness of hypoglycaemia is called the
GOLD score (see Fig. 13.2).
HYPOGLYCAEMIA 703
Table 13.3 Typical symptoms of hypoglycaemia

Autonomic Neuroglycopenic General
Sweating Confusion Headache
Palpitations Drowsiness Nausea
Shaking Odd behaviour
Hunger Speech difficulty
Incoordination
Box 13.4 Hypoglycaemia: risk factors and causes

Risk factors Causes
• Impaired awareness of • Insulin doses are excessive, ill timed,
hypoglycaemia. or of the wrong type of insulin.
• Previous exposure to severe • Inadequate exogenous carbohydrate.
hypoglycaemia.
• Endogenous glucose production is
• Increasing age. decreased (e.g. alcohol ingestion).
• Increasing duration of diabetes. • Glucose utilization is increased.
• Strict glycaemic control. • Insulin clearance is decreased (e.g.
renal failure).
• Sleep.
• C-peptide negativity.
Ask patient: “How often are you aware of episodes of hypoglycaemia (cap-
illary blood glucose <3.5mmol/L)?”
Always Never
1 2 3 4 5 6 7
A score of 1 or 2 implies good awareness. A score of 3 denotes borderline

awareness, and a score of 4 or above denotes impaired awareness.
Fig. 13.2 GOLD score.
Insulin pump therapy

As per NICE guidance in the UK, insulin pump therapy is recommended
as a treatment option for adults and children 12 years and older with type
1 diabetes provided:
• Attempts to achieve target HbA1c with MDI result in disabling
hypoglycaemia, OR
• HbA1c remains above 69mmol/mol or 8.5%, despite a high level
of care.
CSII is also recommended for children younger than 12 years with type 1
diabetes provided:
• MDI therapy is considered impractical or inappropriate.
Following initiation of CSII, it should only be continued if it results in sus-
tained improvement in terms of improved HbA1c or reduced hypoglycae-
mia. CSII therapy in the UK is used by about 3.5% of patients with type 1
diabetes, compared to 20–35% in France, Germany, and the USA. NICE
guidance recommends that up to 15% of those in the UK would be eligible
under current guidance.
It is recommended that insulin pump therapy should only be started by
a trained team, comprising a physician, nurse, and dietitian with special
interest in pump therapy.
Key advantages of pump therapy are based around the ability to adjust or
alter basal insulin delivery through the day and to take recurrent boluses,
as required, to cover food intake. The pump uses rapid-acting insulin (usu-
ally an analogue) which is infused continuously through an infusion set.
The pump usually contains a disposable reservoir which is replaced every
2–3 days. The patient can deliver boluses to cover meals, using buttons on
the pump or on a remote handheld which communicates with the pump.
Pump start
This is often done in groups, and often patients are started on saline to
ensure that they can change sets and use the pumps safely before convert-
ing to insulin. Patients often require daily contact with the healthcare team
over the first few days as their basal rates are adjusted.
Starting doses can be calculated by a number of methods, but usually
total daily dose is reduced by 30%. Usually, patients will be started on one
or two basal rates through the day which will then be adjusted, according
to blood glucose levels.
Adjusting basal rates
Changes in basal rates take between 2 and 4h to produce a change in
plasma insulin levels. In clinical practice, it is common to adjust a basal rate
2h before the effect is desired, i.e. if a patient is often hypoglycaemic at
around 4 p.m., the basal rate would be lowered at 2 p.m.
To test if a basal rate is appropriate, it is common to perform
carbohydrate-free days where the patient takes no carbohydrate (they
may take other food) and tests blood glucose every 2–3h. Based on a rise
or fall in glucose, basal rates can be adjusted appropriately.
INSULIN PUMP THERAPY 705
Using downloads
All available insulin pumps allow all their data to be downloaded to a
computer. This allows the user and the healthcare professional to analyse
the information and look for patterns that may be associated with either
hyper- or hypoglycaemia.
Bolus calculators
All currently available pumps have in-built bolus calculators. These can be
programmed with insulin-to-carbohydrate ratio, insulin sensitivity, and tar-
get blood glucose values. The calculator then takes into account the effect
of any previous boluses that were administered that may still be having a
glucose-lowering effect and provides a recommendation for a bolus. This
prevents ‘stacking’ of insulin and reduces the risk of hypoglycaemia.
Advanced pumping
Temporary basal rates
These allow the patient to increase or decrease the basal rate for a limited
duration of time. For example, to avoid the risk of hypoglycaemia during
exercise, the patient can reduce the basal rate to 50% of usual during
exercise. Similarly, if stressed or unwell and blood glucose is running high,
the patient can increase the basal rate by 70% to bring them under control.
Altered wave boluses (see Box 13.5)
Pumps offer the ability to deliver the bolus over different time periods to
cover different types of food.
Square wave bolus: this delivers the bolus over a given period of time
and is useful if someone plans to eat gradually over a given time period,
e.g. grazing on popcorn during a movie.
Box 13.5 Types of bolus dose deliverable by pump

Type of bolus Diagrammatic Suggested use
representation
Normal wave Standard meals
Square (extended) Extended meals—benefits not proven

wave and the lack of early insulin action may
be problematic
Dual wave Variable amounts as normal bolus,
followed by the remainder as an
extended bolus—suggested, but not
proven, to improve postprandial
glucose excursions after high
carbohydrate, low glycaemic index, or
high-fat meals
Dealing with pump failure

Non-delivery of insulin from a pump is a major risk, and there have been a
few deaths with ketoacidosis due to this. Occasionally, if infusion sets are
not changed every 3 days, blood glucose levels rise due to non-delivery
of basal insulin. Patients should keep a supply of SC insulin for use in the
event of pump failure.
Pump manufacturers technical support helpline
• Medtronic: 01923 205 167.
• Roche: 0800 701 000.
• Animas: 0800 055 6606.
INSULIN PUMP THERAPY 707
Continuous glucose monitoring

Continuous glucose monitoring (CGM) systems consist of small sensors
inserted subcutaneously, usually on the abdominal wall, that measure glu-
cose in the interstitial fluid and display the value along with trend infor-
mation, and various alarms on the pump or a monitor. Interstitial fluid
glucose lags 6–15min behind blood glucose, and CGM need to be cali-
brated, using capillary glucose values 1–4 times/day.
Retrospective CGM systems are downloaded and analysed after wear-
ing and can be used to provide detailed information about glucose excur-
sions over a 6-day period. Combined with detailed information about
carbohydrate, insulin, and activity, they can be used to adjust therapy to
help improve glucose control or reduce hypoglycaemia.
CGM systems are increasingly used to provide a constant readout of
(interstitial) glucose and trends (e.g. rising or falling). In the UK, funding for
CGM is on an individual patient basis and varies between centres.
The JDRF-CGM study and STAR-3 have shown that CGM can help
reduce HbA1c by up to 0.5% in motivated patients without any increase in
hypoglycaemia. Results have been less robust in adolescents and children,
possibly reflecting the ease of use and ability to assimilate and utilize the
extra information.
Alarms
Low alarm
This is usually set somewhere between 3 and 5mmol/L. Given the delay
between blood glucose and sensor glucose, by the time sensor glucose
reads 3mmol/L, blood glucose is often below 2mmol/L. However, setting
the alarm too high leads to a high false +ve alarm rate, which can be intru-
sive. Many patients sleep through alarms, mainly at night.
High alarm
This alerts the patient when blood glucose is high and should trigger a
correction bolus delivered through the bolus calculator.
Predictive alarm
Predictive alarms alert the patient to impending hypoglycaemia. Often,
patients will have to respond to a predictive alarm when their sensor
glucose is >6mmol/L in order to prevent blood glucose dropping below
4mmol/L.
Low glucose suspend
One of the pump systems (Medtronic Paradigm Veo®) automatically sus-
pends insulin delivery for up to a maximum of 2h if the patient fails to
respond to a ‘low alarm’. Basal insulin can be manually restarted at any
point within the 2h. This should usually be set to kick in at a glucose of
3.5–4.5mmol/L and has been shown to significantly reduce the duration
of hypoglycaemia.
CONTINUOUS GLUCOSE MONITORING 709
Use of downloads
Most modern home blood glucose meters and all currently available insu-
lin pumps have the capability to download data to a computer. These
data can then be used to obtain statistics, such as mean glucose, standard
deviation, and number of hypo- or hyperglycaemic excursions. They can
also be used to look for trends or patterns that can be used to inform
changes to therapy.
Pump downloads can be used to evaluate total daily dose, frequency of
set changes, and number of boluses/day and, when combined with data
from a meter, can provide very useful data on patterns.
Patients can download their pumps and/or meters and send the informa-
tion electronically to their diabetes team, allowing remote consultations
and making it easier for the diabetes team to provide dose adjustment
advice.
Suggested use of downloads
• Look for mean tests/day.
• Look for mean boluses/day.
• Look for mean total daily dose and basal/bolus split.
• Pattern management:
• Look at different time periods (overnight/post-breakfast/post-lunch
and post-evening meal), and try to identify patterns.
• Look for low blood glucose readings, and use the download
to identify possible causes (high insulin-to-carbohydrate ratio,
correction bolus, basal rate too high).
• Look for very high blood glucose, and look for possible causes
(missed bolus, inadequate insulin-to-carbohydrate ratio,
overtreatment of hypo).
Emerging therapies
Closed-loop systems
The latest generation of sensor-augmented pumps can suspend insu-
lin delivery for up to 2h if the patient fails to respond to a hypoglycae-
mia alarm. This is particularly useful in preventing prolonged nocturnal
hypoglycaemia and has been shown to reduce the duration of nocturnal
hypoglycaemia in those most at risk. Currently, multiple groups are devel-
oping further generations of closed-loop systems, testing algorithms that
adjust insulin delivery through the pump, based on glucose data obtained
from CGM.
Immune modulation
Risk of type 1 diabetes can be predicted in siblings of patients with type 1
diabetes. Currently, immune modulation with anti-CD3 agents is in clini-
cal trials to try and stop the progression of the condition. To date, these
studies have produced small, but significant, protection of endogenous
insulin production and reduction in insulin doses, but the data do not cur-
rently justify clinical use outside of clinical trials. For more information on
trials on immune modulation in type 1 diabetes M http://www.bris.ac.uk/
trialnet-uk/index.html
ISLET CELL TRANSPLANTATION 711
Islet cell transplantation

Following the first reports of insulin independence following islet cell
transplant in 2000, this has become an established procedure for patients
with type 1 diabetes fulfilling any one of the following criteria:
• Recurrent disabling hypoglycaemia despite optimal medical therapy.
• Already on immunosuppression for a renal transplant.
• Progressive microvascular complications.
• Hypoglycaemia unawareness.
Patients must have type 1 diabetes, be aged 18–65 years, and must have
insulin requirements <0.6 units/kg, with body weight <85kg and BMI
<28kg/m2. Creatinine clearance must be >60mL/min.
Islets are separated from the donor pancreas and infused intraportally
into the liver. The patient requires immunosuppression. Outcomes include
improved glucose control, protection against hypoglycaemia, and slowing
down in deterioration of nephropathy. Latest data show 70% patients are
insulin-independent at 1 year, dropping to 50% at 4 years. For details on
islet transplantation in the UK M http://www.youngdiabetologists.org.uk/
etools/guidelines/islet
Pancreas transplantation
Pancreas transplantation is most commonly performed simultaneously
with renal transplant in patients with type 1 diabetes and renal failure.
Occasionally, it may be performed alone for similar indications as islet
cell transplant in whom islet cell transplantation is considered inappro-
priate. This procedure has a 4% operative mortality, with 10–15% risk
of re-laparotomy. At 1 year, 95% are insulin-independent, with between
65 and 70% insulin-independent at 5 years. The outcomes are better for
simultaneous pancreas kidney transplant (SPK) than pancreas transplant
alone (PTA) or pancreas after kidney (PAK). These procedures should
be carried out at centres with expertise in transplantation and diabetes
management following multidisciplinary assessment.
Further reading
American Diabetes Association (2005). Defining and reporting hypoglycemia in diabetes: a report
from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 28,
1245–9.
DAFNE Study Group (2003). Training in flexible, intensive insulin management to enable dietary
freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) rand-
omized controlled trial. Diabet Med 20 Suppl 3, 4–5.
Hovorka R, et al. (2010). Manual closed-loop insulin delivery in children and adolescents with type
1 diabetes: a phase 2 randomised crossover trial. Lancet 375, 743–51.
JDRF CGM Study Group (2008). Continuous glucose monitoring and intensive treatment of type 1
diabetes. N Engl J Med 359, 1464–76.
National Institute for Health and Clinical Excellence (2004). NICE Guidelines, type 1 diabetes in
adults. Available at: M http://guidance.nice.org.uk/CG15/Guidance//Adults.
National Insitute for Health and Clinical Excellence (2008). NICE Guidelines, diabetes insulin
pump therapy. Available at: M http://publications.nice.org.uk/continuous-subcutaneous-insulin-
infusion-for-the-treatment-of-diabetes-mellitus-ta151/guidance.
Effect of intensive therapy on the development and progression of diabetic nephropathy in the
Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT)
Research Group (1995). Kidney Int 47, 1703–20.
Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and
Complications Trial Research Group (1997). Diabetes 46, 271–86.
Pickup J, Mattock M, Kerry S (2002). Glycaemic control with continuous subcutaneous insulin infu-
sion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of
randomised controlled trials. BMJ 324, 705.
Shapiro AM, et al. (2006). International trial of the Edmonton protocol for islet transplantation.
N Engl J Med 355, 1318–30.
Expert management of type 2 diabetes

Background
Type 2 diabetes is associated with multiple vascular risk factors and a wide
range of complications such that its management draws on many areas
of primary and secondary healthcare. Treatment is, therefore, complex
and time-consuming. Patient education and self-care are crucial parts of
management. The NICE clinical guideline, focusing on the management of
type 2 diabetes, and its regular updates provide clear advice for healthcare
professionals on all aspects of care across the disease continuum, including
when to use specific diabetes therapies.
Key priorities of care
Offer a structured diabetes education programme (that meets the
Department of Health and Diabetes UK Patient Education Working
Group criteria) to every person and/or their carer at or around the time
of diagnosis, with annual review and reinforcement.
Provide individualized and ongoing culturally sensitive nutritional advice.
Set individualized target glycated haemoglobin (HbA1c) with the patient,
and provide a level of care to achieve and maintain that target.
Offer self-monitoring of blood glucose as an integral part of
self-management, and agree when it should be performed and how it
should be interpreted and acted upon. When starting insulin therapy,
employ a structured training programme with active dose titration.
Dietary/lifestyle advice
Encourage high-fibre, low glycaemic index sources of carbohydrate, such
as fruit, vegetables, wholegrains, and pulses; include low-fat dairy products
and oily fish; control the intake of foods containing saturated and trans
fatty acids. This should be integrated with other aspects of lifestyle modi-
fication, including physical activity and losing weight. For the overweight,
an initial weight loss target of 5–10% is advised whilst remembering any
weight loss is beneficial. Remember that alcohol is a significant source of
calories, and advise accordingly.
Glucose targets
Early intensive management of blood glucose has long-term benefits in
terms of reductions in all diabetes-related complications, including car-
diovascular disease. Whilst many patients will perform and should act
on self-monitored plasma glucose values (<7.0mmol/L pre-meal and
<8.5mmol/L post-meal), the HbA1c is generally used as the measure of
overall control and usually serves as the trigger for treatment change.
Although 48mmol/mol or 6.5% is recommended for people on single oral
therapy and/or diet and lifestyle, and 58mmol/mol or 7.5% for people on
more complex regimens, individualized targets should be agreed upon
with the patient, and pursuing highly intensive levels of less than 48mmol/
mol should be avoided. HbA1c may be increased in iron deficiency anae-
mia and decreased in haemolytic anaemia, secondary anaemia due to cir-
rhosis. Haemoglobinopathy may also affect it up or down.
Oral glucose control therapies

(See Table 13.4 for summary.)
Biguanides
Metformin is first-line therapy for the majority of patients, particu-
larly the obese or overweight. It is also used in some insulin-treated,
insulin-resistant, overweight subjects to reduce insulin requirements. The
UKPDS showed significantly better results from metformin for complica-
tions and mortality, compared to other therapies in the overweight patient
with type 2 diabetes. With long-term use, a 0.8–2.0% (or 9–22mmol/mol)
reduction in HbA1c can be expected.
Mode of action
Works by reducing hepatic gluconeogenesis and increasing muscle glucose
uptake/metabolism.
Side effects/contraindications
Contraindicated in patients with renal (creatinine >130nmol/L), hepatic,
or cardiac impairment, or who consume significant amounts of alcohol. GI
side effects occur in up to half of patients in the first 1–2 weeks of treat-
ment but are usually transient. If the starting dose is low (e.g. 500mg once
daily), most people develop tolerance and are able to take higher doses;
<5% are totally intolerant. Consider a trial of extended absorption met-
formin where GI tolerability prevents continued use. Rarely, skin rashes
and lactic acidosis occur.
Special precaution
Using radiological contrast media with metformin is associated with an
increased risk of lactic acidosis, and therapy should be stopped at the
time of, or prior to, such investigations and restarted 2 days after the test,
unless renal function has been affected by the procedure, in which case
delay until this has resolved.
Insulin secretagogues
Sulfonylureas include gliclazide, glipizide, glimepiride, glibenclamide, tolbu-
tamide, and chlorpropamide. Consider as first-line in non-obese patients,
those unable to tolerate metformin, or if a rapid response to therapy is
required because of hyperglycaemic symptoms. Can be used as second-line
agents when blood glucose control is inadequate with metformin.
Mode of action
Stimulate B-cell potassium ATP channel, closing the potassium channel
which leads to membrane depolarization, calcium influx, and subsequent
insulin release. A doubling of glucose-stimulated insulin secretion can be
expected. Results in a 1–2% (or 11–22mmol/mol) reduction in HbA1c
long term.
ORAL GLUCOSE CONTROL THERAPIES 715
Table 13.4 Oral hypoglycaemic agents: summary

Class Mechanism of Expected HbA1c Weight effect
action reduction
Biguanide Increase muscle 0.8–2.0% Neutral
glucose uptake 9–22mmol/mol
and metabolism,
decrease hepatic
gluconeogenesis
Sulfonylurea Stimulate insulin 1.0–2.0% Increase
secretion 11–22mmol/mol
Prandial glucose Stimulate insulin 0.6–2.0% Increase
regulator secretion 7–22mmol/mol
Alpha-glucosidase Inhibits digestive 0.4–0.7% Decrease
inhibitor enzyme 5–8mmol/mol
Thiazolidinedione Activate PPAR-G 0.6–1.5% Increase
receptor 7–17mmol/mol
DPP-4 inhibitor Inhibits enzymic 0.4–1.0% Neutral
degradation of 5–11mmol/mol ? decrease
incretin hormones
(GIP, GLP-1)
Side effects
Predominantly hypoglycaemia and weight gain. In the UKPDS, the mean
weight gain seen after 10 years of therapy was 2.3kg. Hypoglycaemia is
grossly under-reported with sulfonylurea therapies, with recent data sug-
gesting that up to 50% of patients experience at least one episode of low
blood sugar each year. The elderly are at particular risk. The longer-acting
agents, such as glibenclamide, should, if possible, be avoided.
Special precaution
Avoid in patients with porphyria.
Rapid-acting insulin secretagogues
These agents, whilst more commonly used in East Asian countries, are
not frequently prescribed in the UK. They include repaglinide, a carba-
moylmethyl benzoic acid derivative, and nateglinide, a D-phenylalanine
derivative, both of which stimulate insulin secretion with a short duration
of action. They are given 3 times a day and often referred to as prandial
glucose regulators. The short duration of action is associated with low
rates of hypoglycaemia, and they have been shown to reduce HbA1c by
0.6–2% (7–22mmol/mol). They should not be used in people with renal
and hepatic impairment.
Thiazolidinediones (glitazones)
Pioglitazone is generally only used as an alternative to insulin in peo-
ple suboptimally controlled on metformin and/or sulfonylurea because
of its side effects. Its indication does, however, vary around the world,
and, in the UK, it is also considered in combination with insulin. The
recent introduction of incretin-based therapies (b see Oral and inject-
able incretin-based therapies, Table 13.5) appears to have limited its use
even further. A reduction of 0.6–1.5% (7–17mmol/mol) in HbA1c can be
expected, with low rates of hypoglycaemia.
Mode of action
Insulin-sensitizing agents by activating the peroxisome proliferator acti-
vated receptor (PPAR-G) which stimulates gene transcription for glucose
transporter molecules, such as Glut 1 and Glut 4.
Side effects
Patients should be warned about the possibility of significant oedema and
weight gain. Pioglitazone should not be used in people with evidence of
heart failure and those at a higher risk of bone fracture and osteoporosis.
In contrast to troglitazone, improvements in liver function, especially with
non-alcoholic steatohepatitis (NASH), have been reported.
Special precaution
Troglitazone was withdrawn soon after its UK launch because of reports
of hepatotoxicity. The second of these agents, rosiglitazone, whilst not
associated with hepatotoxicity, was associated with other significant side
effects, including ischaemic heart disease and increased cardiovascular
morbidity, and was withdrawn in 2011.
Alpha-glucosidase inhibitors
Acarbose is generally only considered in patients unable to tolerate other
oral glucose-lowering agents. When taken with food, it reduces postpran-
dial glucose peaks by inhibiting the digestive enzyme A-glucosidase which
normally breaks carbohydrates into their monosaccharide components,
thus retarding glucose uptake. The passage of undigested carbohydrates
into the large intestine results in bacterial breakdown and the develop-
ment of common unpleasant GI side effects.
Oral and injectable incretin-based therapies
(See Table 13.5 for comparison.)
GLP-1 receptor analogues
Exenatide and liraglutide are licensed for the use in people with type 2 dia-
betes, in combination with other oral therapies and basal insulin, and are
available as subcutaneous injections. They are associated with an HbA1c
reduction of 1–2% or 11–22mmol/mol and are particularly attractive as
glucose-lowering agents because of low rates of hypoglycaemia and a
weight loss over 6 months of 73–4kg.
ORAL GLUCOSE CONTROL THERAPIES 717
Table 13.5 Comparison between the incretin-based therapies (GLP-1

receptor agonists and DPP-4 inhibitors)
Sitagliptin Vildagliptin Exenatide 10 Liraglutide
100mg od 50mg bd micrograms bd 1.2 or
1.8mg od
Administration Oral Oral SC injection SC injection
Reduction in 0.3–1.0% 0.4–0.7% 0.8–0.9% 1.0–1.5%
HbA1c
3–11mmol/mol 5–8mmol/mol 9–10mmol/mol 11–17mmol/
mol
Reduction 0.9–1.1 0.3–1.0 0.6–1.6 1.6
in fasting
plasma glucose
(mmol/L)
Change in –1.1 to +0.8 –0.23 to +1.3 73–4 73–4
weight (kg)
Hypoglycaemia Low Low Low Low
Mode of action
The incretin hormones glucagon-like polypeptide-1 (GLP-1) and gastric
intestinal polypeptide (GIP), released from the GI tract in response to
nutrient ingestion, stimulate insulin and suppress glucagon secretion in a
glucose-dependent manner. Their extrapancreatic effects include a slow-
ing of gastric emptying and central effects on the brain, leading to satiety
and reduced appetite.
Side effects
Mainly gastrointestinal, with generally mild and transient nausea, vomiting,
and diarrhoea. Headaches and dizziness are also reported. Increased risk
of hypoglycaemia when used with sulfonylureas.
Special precautions
Should not be used in people with a history of pancreatitis.
Dipeptidyl peptidase-4 (DPP-4) inhibitors
Oral therapies that are being used increasingly after metformin in many
patients. Sitagliptin has the broadest indication for use and can be used
with insulin. Lead to a 0.4–1.0% or 5–11mmol/mol reduction in HbA1c
over a 12-month period, with very low rates of hypoglycaemia, and are
weight-neutral (maybe even helping to reduce weight).
Mode of action
Inhibition of enzymic degradation of incretin hormones GLP-1 and GIP.
Side effects
Few major side effects reported. Skin rashes and nasopharyngitis.
Special precautions
Should not be used in people with history of pancreatitis. Liver function
test monitoring with vildagliptin.
Insulin therapy
The majority of patients with type 2 diabetes will require insulin injections
at some point in their lives. Most guidelines recommend the addition of
a basal insulin when other therapies are unable to achieve or maintain
adequate glycaemic control. When using a basal insulin, existing oral thera-
pies should be continued. The use of a sulfonylurea should be reviewed
if hypoglycaemia occurs. Many patients initiated on a basal insulin will
require further intensification within 12 months to either a basal bolus
regimen or twice daily pre-mix.
Insulin can also be initiated as twice daily pre-mix insulin, and sulfonylu-
reas are usually discontinued. Insulin can be used with sitagliptin and piogl-
itazone, although the latter should be discontinued if clinically significant
fluid retention develops.
The newer analogue insulins offer certain advantages over the older
human and animal insulins. They are, however, more expensive, and many
national and international guidelines suggest that their use in type 2 diabe-
tes should be restricted to people with difficulties on human and animal
insulin, in particular, hypoglycaemia.
For different insulin preparations in the management of type 1 diabetes,
b see Box 13.3, p. 696.
BARIATRIC SURGERY 719
Bariatric surgery
Gastric bypass appears to have significant, and usually persistent, effects
on the metabolic abnormalities of type 2 diabetes, including glucose tol-
erance, dyslipidaemia, and hypertension. Further randomized controlled
trials with predefined metabolic entry criteria and detailed follow-up are
required. (For a full discussion of bariatric surgery, b see Chapter 15,
Obesity p. 862.)
The delivery of diabetes care

The increasing global prevalence of diabetes is placing substantial pressures
on healthcare systems and economies, leading to reviews of how diabetes
care can be delivered in a most cost-effective manner. Although care has
traditionally been delivered from a diabetes centre and this model may still
be preferred in many developing countries with large rural communities,
there is an increasing move towards community-based service for routine
care (primary care), with only the more complex care being delivered in
hospitals by specialists (secondary care).
Chronic disease care models
In most European countries and the USA, diabetes care provision is
planned and based upon a system of insurance, with differing splits
between national and private schemes. Drugs are approved onto national
formularies and reimbursed.
Many countries are basing care on ‘chronic care models’ whose key
components are:
• Self-management.
• Decision support systems.
• Delivery system design.
• Clinical information systems.
• Healthcare organization and community resources.
Comprehensive, well-organized intensive diabetes management, incorpo-
rating planned diabetes visits, telephone contacts, and group education,
has been shown to reduce:
• Hospital admissions.
• Unplanned outpatient attendances.
• Healthcare costs.
A number of countries with limited diabetes care infrastructure have
worked with the World Diabetes Foundation to establish new strategic
national diabetes management projects.
In the UK, the template defining the important components of care
is the National Service Framework (NSF). To provide guidance on its
implementation, healthcare professionals and service users, as part of the
National Diabetes Support Team (NDST), have developed ‘The Levels of
Care’ approach to help with the service design process.
Levels of diabetes care
• Level 1: includes generic, essential components—‘the must haves’.
• Level 2: outlines core principles of level 1 components and important
quality standards, including, for example, those in NICE guidance.
• Level 3: covers how to design and organize local services.
• Level 4: focuses on care pathways.
Whilst levels 1 and 2 are considered national or generic, levels 3 and 4
describe activity at a local level and should be designed to make sure
that the patient is always seen by the most appropriate healthcare profes-
sional with the most appropriate level of training and skills at the most
THE DELIVERY OF DIABETES CARE 721
appropriate time and healthcare setting, including, when necessary, access

to secondary and tertiary care specialists.
Commissioning
To ensure a high-quality service for all patients which is best value for
money, the concept of commissioning is now being developed in many
countries, such as the UK. For the process to be effective, it should involve
collaboration between all interested parties, including healthcare profes-
sionals, patients, and local government.
Minimum requirements of the commissioning process should involve:
• Assessment of local needs.
• Design of specification to meet the needs.
• Procurement of local services.
• Proactive monitoring and audit of services.
The vast majority of routine diabetes care in the future will be delivered
in the community. Increasingly, both oral and injectable glucose-lowering
therapies are being initiated and intensified in the community, with the
involvement of specialist support, when needed and called upon by pri-
mary healthcare professionals. The management of other cardiovascular
risk factors, including weight, blood pressure, and lipids, and also the dif-
ferent components of the annual clinical and biochemical review can also
largely take place in the community.
Further reading
Drucker DJ, Sherman SI, Bergenstal RM, Buse JB (2011). The safety of incretin-based
therapies--review of the scientific evidence. J Clin Endocrinol Metab 96, 2027–31.
Farmer AJ (2012). Use of HbA1c in the diagnosis of diabetes. BMJ 345, 10.
Gerstein HC, Miller ME, Genuth S, et al. (2011). Long-term effects of intensive glucose lowering on
cardiovascular outcomes. ACCORD Study Group. N Engl J Med 364, 818–28.
Gough SC (2011). Organising a diabetes service. In: Stewart PM, Wass J (eds.) Oxford textbook of
endocrinology and diabetes, 2nd edn, pp. 2005–11. Oxford University Press, Oxford.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA (2008). 10-year follow-up of intensive
glucose control in type 2 diabetes. N Engl J Med 359, 1577–89.
Lebovitz HE (2011). Type 2 diabetes mellitus-current therapies and the emergence of surgical
options. Nat Rev Endocrinol 7, 408–19.
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B; American
Diabetes Association; European Association for Study of Diabetes (2009). Medical management
of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment
of therapy: a consensus statement of the American Diabetes Association and the European
Association for the Study of Diabetes. Diabetes Care 32, 193–203.
National Institute for Health and Clinical Excellence (2008). NICE Guidelines Type 2 diabetes.
Available at: M http://www.nice.org.uk/nicemedia/live/11983/40803/40803.pdf.
Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A (2011). Glucagon-like peptide ana-
logues for type 2 diabetes mellitus. Cochrane Database Syst Rev 10, CD006423.
Tahrani AA, Bailey CJ, Del Prato S, Barnett AH (2011). Management of type 2 diabetes: new and
future developments in treatment. Lancet 378, 182–97.
Zinman B (2011). Initial combination therapy for type 2 diabetes mellitus: is it ready for prime time?
Am J Med 124 (1 Suppl), S19–34.
Diabetes and life

Driving
Diabetes is said to influence the ability to drive safely because of hypogly-
caemia or complications, such as a reduction in visual acuity or fields. It has
been found to carry a similar risk of accidents to epilepsy, and restrictions
are placed on some drivers with diabetes. This can be a difficult subject for
people with diabetes, but the DVLA (Driver and Vehicle Licensing Agency)
in the UK sets legal requirements which must be met. If the DVLA is not
informed appropriately, a driving licence and insurance may be invalid.
Different standards apply for Northern Ireland and are administered by
the DVA (Driver and Vehicle Agency, M http://www.dvani.gov.uk).
Box 13.6 summarizes good practice for driving with diabetes.
Medical standards of fitness to drive
The guidance outlined here was produced by the DVLA Drivers Medical
Unit and came into effect from October 2011. Full details are available
on the DVLA website (M http://www.nidirect.gov.uk/index/information-
and-services/motoring/driver-licensing/telling-dva-about-a-condition.htm).
It is important to check for the latest information, as the standards are
reviewed every 6 months. Different standards apply for licensing to drive
group 1 vehicles (cars and motorcycles) and group 2 vehicles (large lorries
and buses).
2 Hypoglycaemia
Group 1
Hypoglycaemia is a significant risk factor for accidents while driving. For
group 1 licences, the following should be notified to the DVLA immedi-
ately if licensed. If any of these arise, revocation or refusal of a licence is
likely until the situation has been satisfactorily resolved:
• There has been >1 episode of hypoglycaemia requiring the assistance
of a third party in the previous 12 months.
• Awareness of hypoglycaemia becomes impaired.
• A driver suffers a disabling episode of hypoglycaemia while driving.
Group 2
The situation is similar, except there must not have been a single episode
of hypoglycaemia requiring third-party assistance in the previous 12 months.
Holding a group 1 licence (cars and motorcycles)
Those not treated with insulin
As long as there are no problems with hypoglycaemia and there are no
other contraindications to driving (e.g. from neuropathy/visual problems),
the DVLA does not need to be informed. Drivers on any treatment, other
than diet alone, need to be under regular medical review.
Those treated with insulin
Must inform the DVLA of their diabetes. As long as there are no problems
with hypoglycaemia, short-term (1–3 years) licences are issued under the
following conditions:
• Must perform appropriate blood glucose monitoring.
DIABETES AND LIFE 723
Box 13.6 Good practice for driving with diabetes

• Test blood glucose before driving, even short distances, and every 2h
during longer journeys if there is any possibility of hypoglycaemia.
• If blood glucose <4.0mmol, carbohydrate (CHO) should be taken
and driving delayed for at least 45min to allow any cognitive deficit
to recover.
• If glucose is <5mmol/L before driving, extra carbohydrate should be
strongly considered.
• Keep a source of rapid-acting CHO (e.g. glucose tablets) easily
available in the vehicle to treat symptoms of hypoglycaemia arising
while driving.
• Do not continue to drive once symptoms of hypoglycaemia develop.
• Move out of the driver’s seat to treat hypoglycaemia.
• Must not be regarded as a likely source of danger to the public whilst

driving.
• Must meet standards for visual acuity and visual field.
Temporary insulin treatment
The DVLA does not need to be informed initially as long as under medical
supervision and not advised to be at risk of disabling hypoglycaemia. The
DVLA must be informed if:
• Disabling hypoglycaemia develops.
• Treatment continues for longer than 3 months (3 months post-partum
in the case of gestational diabetes).
Holding a group 2 licence (large lorries and buses)
Those managed using agents carrying a risk of hypoglycaemia (including
insulin)
A recent change in the law means that this group will now be able to apply
for a group 2 licence as long as they meet the qualifying conditions. For
those on insulin, they must also undergo an independent medical examina-
tion and sign a commitment to follow medical advice. The procedure for
application is detailed on the DVLA website.
Qualifying conditions are:
• Has full awareness of hypoglycaemia.
• No episode of hypoglycaemia requiring the assistance of a third party
in the last 12 months.
• Demonstrates an understanding of the risk of hypoglycaemia.
• Tests appropriately (and, if on insulin, can produce results from the
last 3 months, using a meter with a memory function).
• There are no other debarring complications of diabetes.
Those using other treatment with no other contraindications
If on diet alone, the DVLA does not need to be informed. For other
treatment, drivers must be under regular medical review and test glucose
regularly. The DVLA must be informed but will usually issue a licence.
Sport and exercise and diabetes

The suggested amount of exercise is the same for those with diabetes
as for the general population (see Box 13.7). The health benefits, such
as d in blood pressure and lipids, may be particularly helpful in diabetes.
However, metabolic changes during exercise can make the management
of diabetes difficult. When encouraging people with diabetes to exer-
cise, it is important to take account of any complications. For example,
weight-bearing exercise is unlikely to be appropriate for an individual
with significant peripheral neuropathy. Cardiovascular risk should also be
assessed and formal assessment arranged, if appropriate.
For advice on sport and diabetes, see M http://www.runsweet.com/.
Type 1 diabetes
Lower intensity (aerobic) exercise
In those without diabetes, insulin levels d during exercise of lower inten-
sity and longer duration. The difficulty of achieving this with exogenous
insulin therapy means that the most common problem in diabetes is hypo-
glycaemia. Fear of hypoglycaemia is recognized as the most important
factor limiting people with type 1 diabetes for adopting a more active life-
style. Post-exercise hypoglycaemia is a real concern, particularly in young
men sleeping alone.
Higher intensity (anaerobic) and resistance exercise
In contrast, high intensity exercise and resistance exercise (particularly
involving the upper body) can cause significant i glucose through i
catecholamines. This is often unexpected and can cause confusion and
frustration.
General advice
• Avoid hypoglycaemia before exercise.
• Test blood glucose before, during, and after exercise where possible.
• Aim to keep blood glucose between 7 and 10mmol/L before and
during exercise.
• Ensure a supply of fast-acting CHO is freely available.
• Ensure safety—make sure those around are aware and can treat
hypoglycaemia. If alone, ensure somebody knows where you are
supposed to be and expected time of return.
Strategies for dealing with hypoglycaemia
• Avoid bolus insulin injection near exercising muscle (e.g. legs if
running/cycling).
• Adequate dietary energy consumption is important. This will vary with
factors, such as body weight and duration and intensity of exercise.
• If exercise is within 2h of a meal, bolus insulin dose with that meal
should be d by 25–75%.
• Extra rapid-acting CHO can be taken during exercise. Up to 1g/kg
body weight/h may be needed, although absorption of >60g/h can be
problematic. Ideally taken from around 15–20min into exercise and
gradually in small amounts thereafter.
SPORT AND EXERCISE AND DIABETES 725
Box 13.7 Physical activity recommendations for health

• At least 150min each week of moderate intensity physical activity in
blocks of at least 10min (e.g. 30min on at least 5 days each week),
75min of vigorous activity each week, or a combination of the two.
• At least two sessions of muscle strengthening activity each week.
These should not be on consecutive days.
• A post-exercise snack may be needed, with a reduced insulin bolus.

Insulin requirements with an evening meal post-exercise may also be
reduced.
• A d in basal insulin injection of 10–20% may be required on the night
after exercise to avoid nocturnal hypoglycaemia.
• CSII therapy can be very useful for exercise. Basal rate should be d
to 20–50% of normal around 30min before exercise and then ideally
returned to normal around 30min before the end. Insulin pumps
can be removed for exercise, although there is a significant risk of
hyperglycaemia 9 ketosis.
• Post-exercise CSII basal rate should be d by 20% from bedtime to
around 4 a.m.
Strategies for dealing with hyperglycaemia
• A small insulin bolus (often only 0.5–1 unit) may be needed
immediately before or after exercise. If given before, a snack may be
required afterwards.
Type 2 diabetes
Both aerobic and resistance exercise are beneficial in type 2 diabetes.
There is also a benefit in reducing the risk of ‘pre-diabetic’ states (IFG and
IGT) developing into diabetes.
The main benefits are:
• Improvement in glycaemic control.
• Insulin sensitivity i acutely with a single bout of exercise and
chronically with sustained exercise, leading to d insulin requirements.
• Cardiovascular risk factors improve.
• Help with weight control, both through better energy balance and a
reduction in insulin requirements.
• Improvements in general well-being and functional capacity.
Alcohol and diabetes

People with diabetes can continue to drink alcohol without problems
as long as they do so sensibly. Excess alcohol should be avoided (see
Box 13.8). It is best to avoid or limit sweet alcoholic drinks, such as sweet
wines and alcopops, and mixers should be of the ‘sugar-free’ or ‘diet’
varieties.
2 Alcohol increases the risk of hypoglycaemia, with larger amounts
increasing the risk. The risk can persist for up to 16h.
• Avoid drinking alcohol on an empty stomach—starchy snacks may be
helpful if drinking throughout an evening.
• Alcoholic drinks contain carbohydrate but should not be used to
replace meals or snacks.
• After consuming larger amounts of alcohol, ensure that some CHO is
eaten before going to bed (especially if treated with insulin). Healthy
snacks are better, but chips or pizza, for example, are an alternative.
Breakfast should be eaten the following morning.
• Alcohol intoxication may reduce hypoglycaemic symptoms. Remember
a hypo could be confused with drunkenness if alcohol is on the breath.
Box 13.8 Diabetes UK recommended alcohol limits

• ♀—no more than 2 units/day.
• ♂—no more than 3 units/day.
RECREATIONAL DRUG USE AND DIABETES 727
Recreational drug use and diabetes

In questionnaire surveys:
• 5–25% of those aged 12–20 and 29% of those aged 16–30 admitted to
recreational drug use during their lifetime.
• >50% of young people with DKA admitted into a tertiary centre over a
10-month period admitted to drug use, although only 20% volunteered
this on initial questioning.
The index of suspicion for drug use needs to be high, as drug use is sig-
nificantly associated with risk of death from acute diabetes-related events
(OR 5.7). In those where there is significant suspicion, urinary drug
screening should be considered. Box 13.9 lists some of the adverse effects
reported with recreational drugs in diabetes.
Mechanisms by which recreational drugs affect diabetes are variable:
• Effects on judgement and decision-making. For example:
• Missed insulin doses, resulting in hyperglycaemia/DKA.
• Alterations in food intake, resulting in hyper- or hypoglycaemia.
• Reduced ability to recognize hyper- or hypoglycaemia and treat
appropriately due to impaired perception.
• Catecholamine toxicity.
• Increased lipolysis.
• Altered renal handling of ketones and bicarbonate.
Advice about being as safe as possible when using recreational drugs
should be made available to people with diabetes. This may include:
• Being as well informed as possible about potential effects.
• Choosing as safe an environment as possible.
• Never experimenting the first time alone.
• Carrying something identifying you as having diabetes.
• Ensuring at least one person present knows you have diabetes and
ideally knows how to handle any emergency and remains capable of
providing assistance.
Box 13.9 Observed consequences of common

recreational drugs
• MDMA (ecstasy): diabetic ketoacidosis (DKA) and hyponatraemia.
• Ketamine: DKA (acidosis out of proportion to ketosis),
rhabdomyolysis.
• Heroin: hyperglycaemic hyperosmolar state (HHS), following heroin
OD; lethal levels of methadone in a patient who died of DKA.
• Cocaine: HHS and DKA (one study has shown cocaine use to be a
strong independent risk factor for recurrent DKA).
• Cannabis: direct effects minimal, although may lower blood glucose
in large amounts.
Travel and diabetes

People with diabetes need to plan ahead prior to travelling on holiday or
for business (see Box 13.10). If possible, take more medication (especially
insulin) than should be required in case there is a problem. When obtain-
ing insulin abroad, it is important to remember that not every country
uses U100 (i.e. 100 units/mL) insulin which is the standard in the UK. Some
countries use U40 or U80.
Crossing time zones can be complex. The day is longer travelling east to
west, and extra insulin doses may be required. Travelling west to east, the
day is shorter, so doses of basal insulin may overlap and require reduction.
Insulin requirements may alter when on holiday due to increased tem-
perature (d), unaccustomed exercise (d), and a change in diet (i or d).
Box 13.10 Travelling by plane with diabetes

• Contact the airport and airline well in advance.
• Have a letter from the healthcare team, explaining the need to carry
medication, delivery devices (including needles), and monitoring
equipment in hand luggage.
• Carry CHO-containing food for the journey.
• Ensure insulin does not travel in the hold—temperatures may cause
degradation, and there will be problems if luggage is lost.
• Inform airlines in advance of use of CSII/CGM technology.
• Wireless functionality may interfere with aircraft systems.
• Might need alternative insulin delivery for the journey.
• Should not go through X-ray machines or full body scanners.
RAMADAN AND DIABETES 729
Ramadan and diabetes

Fasting during Ramadan, the holy month of Islam, is a duty for all healthy
adult Muslims. Evidence from Islamic countries shows that 743% with
T1DM and 79% with T2DM fast, leading to an estimate of 50 million
worldwide. Many Muslims also fast for 1–2 days each week throughout
the year. Fasting includes omission of all oral intake, including liquids and
medications, during daylight hours. Fasting is not meant to create exces-
sive hardship, and advice should be sought from healthcare professionals
as to the risks. Healthcare providers must advise honestly, but be sensitive
to an individual’s spiritual views, with advice sought from religious leaders
where appropriate.
The main risks during Ramadan are:
• Hypoglycaemia.
• Hyperglycaemia.
• Diabetic ketoacidosis.
• Dehydration and thrombosis.
A pre-Ramadan medical assessment is helpful where advice can be given
about management of diabetes and fasting (see Box 13.11). Those with
problems with hypoglycaemia, insulin treatment, or complications of
diabetes may be at particularly high risk. Management strategies can be
suggested for those who do elect to fast. Ramadan-focused structured
education may helpful. The American Diabetes Association (ADA) has
published useful guidance for assessing the risks of fasting and appropri-
ate management of diabetes medication (b see Further reading, p. 731).
Box 13.11 Managing diabetes during Ramadan

• Blood glucose should be monitored more frequently.
• Insulin doses may need to be d.
• Type of insulin may need to be changed. Pre-mixed insulin is not
recommended during fasting.
• Consume more low glycaemic index (GI) food before the fast. Fruit,
vegetables, and salad should be included.
• Limit high GI and fatty foods when breaking the fast.
• Avoid dehydration—increase fluid intake during non-fasting hours.
• Break the fast in the event of hypoglycaemia (blood glucose
<3.9mmol/L) and significant hyperglycaemia (blood glucose
>16.7mmol/L).
• Avoid fasting on ‘sick days’.
Weight management with

insulin treatment
Treatment with insulin is often linked with i weight. As i weight often
results in i insulin requirements, this can become a vicious cycle. It is
helpful to warn patients of this, and the following strategies may be helpful
in its management:
• Control portion size, and monitor CHO intake.
• Do not miss meals—eat smaller ones.
• Keep physically active (see recommendations earlier in this chapter).
• Consider medications which may promote weight loss.
• Do not d insulin doses to promote weight loss.
ANNUAL REVIEW FOR PATIENTS WITH DIABETES 731
Annual review for patients

with diabetes
All patients with diabetes should have an annual medical check-up.
Diabetes UK defines ‘15 healthcare essentials’ which patients are entitled
to (M http://www.diabetes.org.uk).
These include:
• Assessment of glucose control: HbA1c, review of blood glucose
records, and adjustment of doses.
• Documentation of insulin doses and other medications.
• Assessment of complications, including:
• Diabetes retinal screening.
• Urine albumin/creatinine ratio.
• Foot examination (pedal pulses, monofilament sensation, vibration
sense, temperature sense).
• Biochemistry, including liver and renal function.
• Risk factor management:
• Blood pressure—target 130/80mmHg.
• Total cholesterol <4; LDL <2mmol/L.
• Weight loss to achieve normal BMI.
• Evaluation of hypoglycaemia: history of the number, severity,
and frequency of mild and severe hypoglycaemia. Evaluation of
hypoglycaemia awareness.
• Support to stop smoking.
• Pre-conception care.
• Emotional and psychological support.
• Access to specialist diabetes healthcare professionals, if required.
Further reading
The Diabetes UK website has useful information about all topics on diabetes and life. Available
at: M http://www.diabetes.org.uk.
Al-Arouj M, Assaad-Khalil S, Buse J, et al. (2010). Recommendations for management of diabetes
during Ramadan: update 2010. Diabetes Care 33, 1895–902.
Lee P, Greenfield JR, Campbell LV (2009). Managing young people with Type 1 diabetes in a 'rave' new
world: metabolic complications of substance abuse in Type 1 diabetes. Diabet Med 26, 328–33.
Lumb AN, Gallen IW (2009). Diabetes management for intense exercise. Curr Opin Endocrinol
Diabetes Obes 16, 150–5.
Hospital inpatient diabetes

management and diabetic
emergencies
Data from the National Diabetes Inpatient Audit suggest that the number
of hospital inpatients with diabetes ranges from 710 to 30%. This does not
mean that up to 1 in 3 inpatients are in hospital because of their diabetes
but happen to have diabetes, in addition to whatever other condition has
necessitated their admission. Whatever the reason for admission, patients
with diabetes often have longer lengths of hospital stay, and the presence
of diabetes remains an important comorbidity that must be dealt with by
staff who are competent and confident in its management.
Over the last few years, the Joint British Diabetes Societies Inpatient
Care Group has published several national guidelines on the management
of several aspects of inpatient diabetes care. The following guidelines are
largely derived from those, and full versions can be found on the internet
(M http://www.diabetologists-abcd.org.uk/JBDS/JBDS.htm).
HOSPITAL INPATIENT DIABETES MANAGEMENT 733
Diabetic hyperglycaemic emergencies

Diabetic ketoacidosis
The diagnosis of diabetic ketoacidosis (DKA) is dependent on the com-
bined presence of three biochemical abnormalities:
• Ketonaemia ≥3mmol/L or significant ketonuria (>2+).
• Blood glucose >11mmol/L or known diabetes mellitus.
• Bicarbonate (HCO3–) <15mmol/L and/or venous pH <7.3.
The presence of any of the following should prompt consideration of
admission to a level 2/HDU environment:
• Blood ketones >6mmol/L, bicarbonate level <5mmol/L, pH <7.1.
• Hypokalaemia (<3.5mmol/L).
• Abnormal GCS or AVPU score.
• Oxygen saturation <92% on air.
• Systolic BP <90mmHg, pulse >100 or <60bpm.
• Anion gap >16 (anion gap = (Na+ + K+) – (Cl– + HCO3–)).
The management of DKA
The resolution of DKA depends upon the suppression of ketonaemia,
and measurement of blood ketones now represents best practice in
monitoring the response to treatment. Bedside ketone monitors should
be used to measure the plasma ketone concentrations (in particular,
3B-hydroxybutyrate) because this is the direct marker of disease severity.
Where available, the specialist diabetes team should ideally be involved
as early as is practical after admission.
Monitor using venous blood gases (the differences in arterial and venous
pH, bicarbonate, and K+ are not great enough to alter management).
Plasma ketones, venous pH, and bicarbonate measurements should be
used as treatment markers (see Box 13.12).
Use a weight-based, fixed-rate intravenous insulin infusion (FRIII) at 0.1
units/kg/h, i.e. 7 units per hour for a 70kg individual. This enables rapid
blood ketone clearance. The fixed rate may be adjusted in insulin-resistant
states if the response is not fast enough. There is no need for a bolus dose
of insulin if the IV insulin infusion (IVII) is set up promptly.
Continue SC basal insulin analogues. They provide background insulin
when the IVII is discontinued. Short-acting insulin should be given before
discontinuing the IVII.
Bicarbonate should not be given because it may worsen intracellular
acidosis and it may precipitate cerebral oedema, particularly in children.
Box 13.12 Metabolic treatment targets in DKA

• Reduction in blood ketones by 0.5mmol/L/h.
• Increase in venous bicarbonate by 3mmol/L/h.
• Reduction in capillary blood glucose by 3mmol/L/h.
• Potassium maintained at 4.5–5.5mmol/L.
If these rates are not achieved, then the FRIII needs adjusting.
DIABETIC HYPERGLYCAEMIC EMERGENCIES 735
Initial actions (first hour of treatment)

• Rapid assessment and resuscitation of patient; commence IV fluids.
• Full clinical examination, with assessment of:
• Respiratory rate; temperature; blood pressure; pulse; O2 saturation.
• Assess GCS. Consider NG tube if GCS is <12.
• Initial investigations should include:
• Bedside capillary ketones and capillary glucose.
• Venous gases for glucose, U&Es, pH, HCO3–.
• FBC, blood cultures.
• ECG, CXR, MSU.
• Continuous cardiac monitoring and pulse oximetry.
• Low molecular weight heparin.
• Consider any precipitating causes, and treat appropriately.
Fluid resuscitation
If the systolic blood pressure is <90mmHg, consider causes other than
fluid depletion, such as heart failure, sepsis, etc. Give 500mL of 0.9%
sodium chloride (NaCl) solution over 10–15min, and repeat if necessary. If
there is no improvement in BP, consider the need for circulatory support.
If systolic BP is >90mmHg, use the rate of fluid replacement in Table 13.6.
Potassium replacement
Hypo- and hyperkalaemia are common in DKA. See Table 13.7.
Table 13.6 Fluid replacement rates

Fluid Volume
0.9% NaCl 1L 1000mL over first hour
0.9% NaCl 1L with KCl 1000mL 2-hourly × 3
0.9% NaCl 1L with KCl 1000mL 4-hourly × 2
Reassessment of cardiovascular status at 12h is mandatory; further fluid may be required.
Table 13.7 Potassium replacement for different levels

Potassium level in first Potassium replacement in mmol/L
24h (mmol/L) of infusion solution
Over 5.5 Nil
3.5–5.5 40mmol/L
Below 3.5 Additional potassium needed: either through
increased infusion rate or use of concentrated
potassium infusion (check local guidelines—may
require transfer to HDU)
Insulin infusion
• Start a continuous FRIII via an infusion pump. 50 units human soluble
insulin (Actrapid®, Humulin S®), made up to 50mL with 0.9% NaCl
solution.
• Infuse at a fixed rate of 0.1 unit/kg/h (i.e. 7mL/h if weight is 70kg).
Ongoing management of DKA after the first 60min is covered in detail in
the National Guidelines, available at: M http://www.diabetologists-abcd.
org.uk/JBDS/JBDS_IP_DKA_Adults.pdf.
This involves continual monitoring and reassessment of the patient to
ensure that metabolic targets are being achieved (see Box 13.12), stabiliza-
tion and treatment of precipitating factors, and that other medical inter-
ventions or monitoring (e.g NG tube, catheter) are not required.
Practice points
Infusion of large volumes of normal saline may lead to hyperchloraemic
acidosis; however, this is not a cause of significant morbidity or prolonga-
tion of inpatient stay.
Convert back to SC insulin when biochemically stable (blood ketones
<0.3, pH >7.3) and the patient is ready to eat and drink.
Involve the specialist diabetes team at an early stage. It is commonly said
that DKA is usually a failure of self-management, so assessing the reasons
behind admission and re-education to prevent recurrence are vital.
DIABETIC HYPERGLYCAEMIC EMERGENCIES 737
Hyperosmolar hyperglycaemic state

Whilst there is no formal definition of hyperosmolar hyperglycaemic state
(HHS; previous name HONK), the following criteria have been adopted
nationally across the UK:
• Hypovolaemia.
• Marked hyperglycaemia (30mmol/L or more).
• No significant ketonaemia (<3mmol/L) or acidosis (pH >7.3,
bicarbonate >15mmo/L).
• Osmolality usually ≥320mmol/kg.
(Calculated osmolality = 2 Na+ + glucose + urea)
NB A mixed picture of HHS and DKA may occur.
HHS typically occurs in the elderly, but, as type 2 diabetes is diag-
nosed in younger adults and teenagers, it is likely that HHS will present at
younger ages as well. Unlike DKA, which usually comes on over a matter
of hours, HHS comes on over many days, and consequently the dehydra-
tion and metabolic disturbances are more extreme.
Management of HHS
See M http://www.diabetologists-abcd.org.uk/JBDS/JBDS_IP_HHS_Adults.pdf.
Initial assessment
Hyperglycaemia results in an osmotic diuresis and renal losses of water in
excess of sodium and potassium. Fluid losses are estimated to be between
100 and 220mL/kg. Despite these severe electrolyte losses and total body
volume depletion, the typical patient with HHS may not look as dehy-
drated as they are because the hypertonicity leads to preservation of
intravascular volume.
The goals of treatment of HHS are to gradually and safely:
• Normalize the osmolality.
• Replace fluid and electrolyte losses.
• Normalize blood glucose.
• Treat the underlying cause.
• Prevent arterial or venous thrombosis.
• Prevent other potential complications, e.g. cerebral oedema/central
pontine myelinolysis.
• Prevent foot ulceration.
As with DKA, venous blood can be used to assess pH, bicarbonate, U&Es,
glucose, etc. in a blood gas analyser.
The presence of any of the following should prompt consideration of
admission to a level 2/HDU environment:
• Osmolality >350mOsm/kg, sodium >160mmol/L.
• Venous/arterial pH <7.1.
• Hypokalaemia (<3.5mm/L) or hyperkalaemia (>6mmol/L).
• Glasgow Coma Scale (GCS) <12 or abnormal AVPU score.
• Oxygen saturation <92% on air.
• Systolic blood pressure <90mmHg, pulse >100 or <60bpm.
• Hypothermia.
• Acute or serious comorbidity, e.g. MI, CCF, or CVA.
• Urine output <0.5mL/kg/h or other evidence of acute kidney injury.
HYPEROSMOLAR HYPERGLYCAEMIC STATE 739
Fluid replacement and changes in osmolality

The goal of the initial therapy is expansion of the intra- and extravascu-
lar volume and to restore peripheral perfusion. Replace fluid with 0.9%
sodium chloride. Measurement or calculation of osmolality should be
undertaken every hour initially and the rate of fluid replacement adjusted
to ensure a positive fluid balance sufficient to promote a gradual decline in
osmolality. Fluid replacement alone (without insulin) will lower BG which
will reduce osmolality, causing a shift of water into the intracellular space.
This inevitably results in a rise in serum sodium.
The aim of treatment should be to replace approximately 50% of esti-
mated fluid loss within the first 12h and the remainder in the following 12h,
although this will be determined by the initial severity, degree of renal impair-
ment, and associated comorbidities, which may limit the speed of correction.
A BG target of between 10 and 15mmol/L is a reasonable goal. Complete
normalization of electrolytes and osmolality may take up to 72h.
The role of insulin in HHS
If significant ketonaemia is present (3B-hydroxybutyrate is >1mmol/L),
this indicates relative hypoinsulinaemia, and insulin should be started at
time zero.
If significant ketonaemia is not present (3B-hydroxybutyrate <1mmol/L),
there is an argument for not starting insulin treatment immediately, as fluid
replacement alone will result in a falling blood glucose, and reducing this
too quickly may lead to lowering the osmolality precipitously. Insulin treat-
ment, prior to adequate fluid replacement, may result in cardiovascular
collapse, as water moves out of the intravascular space, with a resulting
decline in intravascular volume.
The recommended insulin dose is a fixed rate intravenous insulin infusion
(FRIII) given at 0.05 units/kg/h (e.g. 4 units/h in an 80kg person). A fall of
glucose at a rate of up to 5mmol/L/h is ideal, and once the blood glucose
has ceased to fall following initial fluid resuscitation, reassess fluid intake
and renal function. Insulin may be started at this point or, if already in place,
the infusion rate increased by 1 unit/h.
Potassium replacement
This is the same as DKA.
Anticoagulation
Because of the increased risk of arterial and venous thromboembolism,
all patients should receive prophylactic low molecular weight heparin
for the full duration of admission unless contraindicated. Full treatment
dose anticoagulation should only be considered in patients with suspected
thrombosis or acute coronary syndrome.
Other electrolytes
Hypophosphataemia and hypomagnesaemia are common in HHS; how-
ever, as with DKA, routine replacement is not recommended.
Foot protection
These patients are at high risk of pressure ulceration. An initial foot assess-
ment should be undertaken and heel protectors applied in those with
neuropathy, peripheral vascular disease, or lower limb deformity. The feet
should be re-examined daily.
Intravenous insulin infusions used

in hyperglycaemia
These can be either fixed-rate intravenous insulin infusions (FRIII) or vari-
able rate (VRIII).
Fixed-rate intravenous insulin infusions
These are used in the initial stages of DKA until ketones are <0.3mmol/L
and pH >7.3 and venous bicarbonate >18mmol/L, or in patients with HHS
once their blood glucose has stopped dropping at 5mmol/L/h with the
initial use of 0.9% sodium chloride. The starting doses are 0.1 unit/kg/h for
DKA, and 0.05 unit/kg/h for HHS.
Intravenous crystalloid solution must always be given with an FRIII. In
DKA, if the blood glucose levels are >14mmol/L, then this should be 0.9%
sodium chloride; if blood glucose levels are <14mmol/L, then 10% dex-
trose solution should be run alongside the saline infusion.
Variable-rate intravenous insulin infusions
The aim of the VRIII is to achieve and maintain normoglycaemia. It should
be made up in 50mL syringe with 0.9% sodium chloride—making a con-
centration of 1 unit per mL. See Table 13.8 for an example of how to
prescribe a VRIII.
Use of intravenous insulin infusion
• If the patient is already on a long-acting insulin analogue, these should
be continued.
• Monitor blood glucose hourly.
• If the blood glucose remains >12mmol/L for three consecutive
readings and is not dropping by 3mmol/L/h or more, the rate of insulin
infusion should be increased.
• If the blood glucose is <4.0mmol/L, the insulin infusion should be
reduced to 0.5 units per hour, and the low blood glucose should
be treated, irrespective of whether the patient has symptoms. If the
patient has continued on their basal insulin, then their VRII can be
switched off, but the regular blood glucose measurements need to
continue. Ensure basal insulin has been given before stopping VRII.
INTRAVENOUS INSULIN INFUSIONS USED IN HYPERGLYCAEMIA 741
Table 13.8 Prescribing a VRIII

Bedside capillary blood glucose Initial rate of insulin infusion
(mmol/L) (units per hour)
<4.0 0.5 (0 if basal insulin has been continued)
4.1–7.0 1
7.1–9.0 2
9.1–11.0 3
11.1–14.0 4
14.1–17.0 5
17.1–20 6
>20 Seek diabetes team or medical advice
of diabetes
Poor perioperative glycaemic control leads to poor outcomes in a vari-
ety of surgical specialities. There is detailed guidance available in the Joint
British Diabetes Societies guideline on the perioperative management of
adult patients with diabetes undergoing surgery or procedures (M http://
www.diabetologists-abcd.org.uk/JBDS/JBDS_IP_Surgery_Adults_Full.pdf).
There are several reasons why patients experience problems:
• Failure to identify patients with diabetes.
• Lack of institutional guidelines for management of diabetes.
• Poor knowledge of diabetes amongst staff delivering care.
• Complex polypharmacy and insulin-prescribing errors.
It is advocated that, whenever possible, the HbA1c should be below
69mmol/mol (8.5%) prior to surgery.
For most procedures where only one meal will be missed, hypogly-
caemic therapy can be adjusted, as outlined in Table 13.9 (OHA) and
Table 13.10 (insulin). The use of the VRIII (Table 13.8) should be limited to
those who will miss more than one consecutive meal, those who require
emergency surgery, and those for whom there was no time to optimize
their glycaemic control prior to surgery. The rate of insulin infusion is as
described in Table 13.8.
PERIOPERATIVE MANAGEMENT OF DIABETES 743
Table 13.9 Guideline for perioperative adjustment of non-insulin

medication (short starvation period—no more than ONE missed meal)
Tablet Day prior to Day of surgery
admission AM surgery PM surgery
Acarbose Take as normal Omit AM dose if NBM Give AM dose if
eating
Meglitinide Take as normal Omit AM dose if NBM Give AM dose if
(repaglinide or eating
nateglinide)
Metformin Take as normal Take as normal Take as normal
(procedure not
requiring use of
contrast media)*
Sulfonylurea Take as normal Once daily—AM omit Once daily—AM
omit
Twice daily—AM omit
Twice daily—
omit AM and PM
Pioglitazone Take as normal Take as normal Take as normal
DPP-IV inhibitor Take as normal Omit on day of surgery Omit on day of
surgery
GLP-1 analogue Take as normal Omit on day of surgery Omit on day of
surgery
NBM, nil by mouth; AM, morning; PM, afternoon.
* If contrast medium is to be used and eGFR less than 50mL/min/1.73m2, metformin should be
omitted on the day of the procedure and for the following 48h.
Table 13.10 Guideline for perioperative adjustment of insulin (short

starvation period—no more than ONE missed meal; in all cases, check
blood glucose on admission)
Insulins Day prior to Day of surgery
admission AM surgery PM surgery
Once daily basal No dose change* No dose change No dose change
(evening)
Once daily basal No dose change No dose change* No dose change*
(morning)
Twice daily No dose change Half AM dose Half AM dose
pre-mixed
PM—no change if PM—no change if
insulin or basal
eating eating
insulin
Twice daily No dose change Give half total Give half total
free-mixing AM dose as AM dose as
intermediate-acting intermediate-acting
PM dose—no PM dose—no
change if eating change if eating
Basal bolus No dose change Omit AM and Take usual AM
lunchtime insulin dose(s)
short-acting
Omit lunchtime
insulins
dose
Basal—no change
AM, morning; PM, afternoon.
* Some units would advocate reduction of usual dose of long-acting analogue by one-third.
This reduction should be considered for any patient who ‘grazes’ during the day. Warn the
patient that their blood glucose control may be erratic for a few days after the procedure.
PERIOPERATIVE MANAGEMENT OF DIABETES 745
(b see also Type 1 diabetes, p. 702.)
Hypoglycaemia is the commonest side effect of insulin and sulfonylurea
treatment. Hypoglycaemia should be excluded in any person with diabe-
tes who is acutely unwell, drowsy, unconscious, unable to cooperate, or
presenting with aggressive behaviour or seizures. The hospital environ-
ment presents additional obstacles to the maintenance of good glycaemic
control and the avoidance of hypoglycaemia.
Algorithm A: adults who are conscious, orientated, and able to swallow
Give 15–20g quick-acting carbohydrate of the patient’s choice:
• 5–7 Dextrosol® tablets (or 4–5 Glucotabs®).
• 90–120mL of original Lucozade® (preferable in renal patients).
• 150mL non-diet cola (a small can).
• 5 Jelly babies or fruit pastilles or 10 Jelly beans.
• 3–4 heaped teaspoons of sugar dissolved in water*.
• 150–200 mL pure fruit juice*.
*Some centres advocate ONLY glucose for the treatment of hypos.
Repeat capillary blood glucose measurement 10–15min later. If blood glu-
cose is less than 4.0mmol/L, repeat step 1 up to three times.
If blood glucose remains less than 4.0mmol/L after 45min or three
cycles, consider 1mg of glucagon IM (remembering that this may be less
effective in patients prescribed sulfonylurea therapy) or IV 10% glucose
infusion at 100mL/h.
Once the blood glucose is above 4.0mmol/L and the patient has recov-
ered, give 15g long-acting carbohydrate:
• Two biscuits.
• One slice of bread.
• 200–300mL glass of milk (not soya).
• Normal meal if due (must contain carbohydrate).
DO NOT omit insulin injection if due (a dose review may be required).
Relative hypoglycaemia
Adults who have poor glycaemic control may start to experience symp-
toms of hypoglycaemia above 4.0mmol/L. Adults who are experiencing
symptoms, but have a blood glucose level greater than 4.0mmol/L, should
consume a small carbohydrate snack only (e.g. one medium banana or a
slice of bread). All adults with a blood glucose level less than 4.0mmol/L,
with or without symptoms of hypoglycaemia, should be treated as out-
lined in Management of hypoglycaemia in the section above.
Algorithm B: adults who are conscious but confused, disorientated,
unable to cooperate, or aggressive but are able to swallow
• If patient is unable to follow algorithm A but is able to swallow, give
either 1.5–2 tubes GlucoGel®/Dextrogel®, squeezed into the mouth
between the teeth and gums, or (if ineffective) give glucagon 1mg IM.
MANAGEMENT OF HYPOGLYCAEMIA 747
• Monitor blood glucose levels after 15min. If still less than 4.0mmol/L,
repeat steps 1 and 2 up to three times.
• If blood glucose level remains less than 4.0mmol/L after 45min, give IV
10% glucose infusion at 100mL/h.
• Once blood glucose is above 4.0mmol/L and the patient has
recovered, give a long-acting carbohydrate, as outlined in Management
of hypoglycaemia, see b p. 746.
• DO NOT omit insulin injection if due (a dose review may be
required).
• NB Patients given glucagon require a larger portion of long-acting
carbohydrate to replenish glycogen stores (double the suggested
amount above).
Algorithm C: adults who are unconscious and/or having seizures and/or
are very aggressive OR patients who are nil by mouth
• Assess patient.
• If the patient has an insulin infusion in situ, stop it immediately.
• The following two options are both appropriate:
• Glucagon 1mg IM (remembering that this may be less effective in
patients prescribed sulfonylurea therapy and may take up to 15min
to work).
• If IV access available, give 75mL of 20% glucose or 150mL of
10% glucose over 12–15min. Repeat capillary blood glucose
measurement 10min later. If blood glucose less than 4.0mmol/L,
repeat.
• Once blood glucose is greater than 4.0mmol/L and the patient has
recovered, give a long-acting carbohydrate, as outlined in Management
of hypoglycaemia, see b p. 746.
• DO NOT omit insulin injection if due (dose review may be required).
• If the patient was on IV insulin, continue to check blood glucose every
30min until it is above 3.5mmol/L, then restart IV insulin after review
of dose regimen.
The management of stroke patients

with diabetes
See M http://www.diabetologists-abcd.org.uk/JBDS/JBDS_IP_Enteral_
Feeding_Stroke.pdf. Also see Fig. 13.3.
Diagnosis of CVA
If blood glucose raised, does patient already have diagnosis of diabetes?

Type 1 or type 2 diabetes?
If type 1 diabetes continue subcutaneous basal insulin
MDT decision to feed via nasogastric tube (NGT)
Refer to dietitian and diabetes team/diabetes inpatient specialist nurse.

Dietitian to prescribe appropriate feed regimen for patient.
Diabetes team to match insulin regimen/dose to feed regimen
Type 2 diabetes with well-

Type 1 diabetes continue basal
controlled BG - consider
insulin initially.
metformin powder via NGT.
Commence feed and start subcutaneous insulin. First-line insulin

options are NPH insulin at start of feed or mixed insulin at start and
middle of feed. BG target 6–12mmol/L. Diabetes team review
24–48hrly. Utilise VRIII for minimal possible period. Check BG hourly
on VRIII (Table 13.8 page 741)
Treat hypoglycaemia If feed stopped for longer If BG >12mmol/L, increase

promptly as per than 2 hours consider insulin doses by 2–4 units
guidelines. Alter starting IV 10% glucose if or 10–20% per dosage
treatment if insulin already administered adjustment. If ketones, assess
hypoglycaemia persists to avoid hypoglycaemia for DKA and consider
VRIII/FRIII.
Fig. 13.3 Algorithm for managing diabetes in patient with a stroke and swallowing
difficulties.
THE MANAGEMENT OF STROKE PATIENTS WITH DIABETES 749
The critically ill patient

There is controversy regarding the best way to treat hyperglycaemia in
critically ill patients. There have been a number of studies done in this
population, although the vast majority have been done on patients in
intensive care or cardiac surgical patients. The results have not been con-
sistent, with some studies showing benefit and others showing potential
harm. In addition, there is currently little consensus on the best way to
treat hyperglycaemia-associated poor outcomes following an episode of
acute coronary syndrome; however, studies to assess this are ongoing. If
one accepts the premise that high blood glucose levels are associated with
harm, then a pragmatic approach is to keep the blood glucose between 6
and 10mmol/L using whatever means necessary—oral medication, where
appropriate, or a VRIII (Table 13.8 b p. 741). Local guidelines should be
followed and guidance sought from diabetes specialist teams.
Further reading
Dhatariya K, Flanagan D, Hilton L, et al. (2011). Management of adults with diabetes undergoing
surgery and elective procedures: improving standards. London. Joint British Diabetes Societies
Inpatient Care Group for NHS Diabetes. Available at: M http://www.diabetologists-abcd.org.
uk/JBDS/JBDS_IP_Surgery_Adults_Full.pdf
Furnary AP, Zerr KJ, Grunkemeier GL, Starr A (1999). Continuous intravenous insulin infusion
reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical
procedures. Ann Thorac Surg 67, 352–62.
Gandhi GY, Nuttall GA, Abel MD, et al. (2007). Intensive intraoperative insulin therapy versus
conventional glucose management during cardiac surgery: a randomized trial. Ann Intern Med
146, 233–43.
Savage MW, Dhatariya KK, Kilvert A, et al. (2011). Joint British Diabetes Societies guideline for the
management of diabetic ketoacidosis. Diabet Med 28, 508–15.
Stanisstreet D, Walden E, Jones C, et al. (2010). The hospital management of hypoglycaemia in
adults with diabetes mellitus. London, Joint British Diabetes Societies Inpatient Care Group
for NHS Diabetes. Available at: M http://www.diabetologists-abcd.org.uk/JBDS/JBDS_IP_Hypo_
Adults.pdf
The NICE-SUGAR Study Investigators (2009). Intensive versus conventional glucose control in
critically ill patients. N Engl J Med 360, 1283–97.
Van den Berghe G, Wouters P, Weekers F, et al. (2001). Intensive insulin therapy in the surgical
intensive care unit. N Engl J Med 345, 1359–67.
THE CRITICALLY ILL PATIENT 751
Diabetes and pregnancy

Background
Diabetes is the most common medical complication of pregnancy, affect-
ing approximately 1 in 250 pregnancies. Of the 650,000 women giving birth
in England and Wales each year, 2–5% will involve women with diabetes.
Approximately 87.5% of pregnancies complicated by diabetes are due to
gestational diabetes (which may, or may not, resolve after pregnancy),
with 7.5% being due to type 1 diabetes and the remaining 5% being due to
type 2 diabetes. In both cases, there are risks both to the mother and the
fetus, with a congenital malformation rate of up to 10% or 4–5 times that
of the background population in women with very poor glycaemic control
(periconception HbA1c >86mmol/mol or 10%). The risk can be reduced,
but not entirely eliminated, by optimal pre-conception glycaemic control
(HbA1c <53mmol/mol or 7% or lower if achieved without hypoglycae-
mia.) and 5mg folic acid supplementation (see Box 13.13).
Risks
Fetal
• Macrosomia (birthweight above the 90th percentile) remains the
commonest complication of diabetic pregnancy, affecting 40–50% of
offspring born to mothers with type 1 and type 2 diabetes. As well as
causing birth trauma and delivery complications, macrosomic infants
have increased longer-term risks of insulin resistance, obesity, and type
2 diabetes. Fetal hyperinsulinaemia causes growth of insulin-sensitive
tissues, with increased abdominal circumference, due to hypertrophy
of the fetal pancreatic cells, liver, and heart.
• Preterm delivery (before 37 weeks’ gestation) occurs in approximately
37% of pregnancies, with resulting complications of hypoglycaemia
(30–50% preterm infants), jaundice, and polycythaemia.
• Neonatal care admission: approximately 40% infants born to mothers
with diabetes require additional neonatal care, most typically for
complications of prematurity or macrosomia.
• Congenital malformation: cardiac, renal, and neural tube defects occur
during the first 5–6 embryonic weeks, stressing the importance of
optimizing glycaemic control before conception. The risk of having
an infant with a major congenital malformation is comparable for
women with type 1 and type 2 diabetes (2–4%) and twice that of the
background population (1–2%). The contributions of hyperglycaemia
and maternal obesity to the pathogenesis of congenital malformation
are well recognized. Alterations in oxygen free radicals, myoinositol,
arachidonic acid, and zinc metabolism have also been implicated.
• Fetal mortality (up to 2.2% of births in mothers with type 1 and type 2
diabetes).
• Stillbirth (increased risk if poor glycaemic control and after 38 weeks’
gestation).
DIABETES AND PREGNANCY 753
Box 13.13 Pre-conception management

• Pre-conception glycaemic control optimized, aiming for HbAlc
<43mmol/mol (6.1%) if safely achievable without severe
hypoglycaemia.
• High-dose folic acid supplements (5mg/day).
• Reviewing potentially teratogenic drugs, including ACE inhibitors,
statins.
• Advice on losing weight for all women with BMI >27kg/m2.
• Advice on stopping smoking, reducing alcohol intake, avoiding
unpasteurized dairy products.
• Screening for retinopathy and nephropathy.
• Metformin may be used as an adjunct or alternative to insulin.
All other oral hypoglycaemic agents should be discontinued and
replaced with insulin. In HNF1A/4A-MODY already well controlled
on low-dose SU glibenclamide can be substituted—b see p. 692).
Maternal
• Increased risk of severe hypoglycaemia (SH), particularly during early
pregnancy. Historically, the prevalence of SH was as high as 30–40% in
type 1 diabetes but may now be declining with increased use of insulin
analogues and pump therapy.
• Increased risk of pre-eclampsia, which is related to glycaemic control
and complicates approximately 15% diabetic pregnancies.
• Worsening of diabetic nephropathy and progression of
retinopathy: renal and retinal screening is recommended before
pregnancy and during each trimester.
• Increased risk of diabetic ketoacidosis (DKA). Although rare, affecting
<1% of pregnancies, DKA is associated with fetal loss in up to 20% of
episodes. Women with suspected DKA should be admitted to level 2
critical care for immediate medical and obstetric care.
• Increased delivery by Caesarean section (66% in type 1 diabetes).
• Thromboembolic disease, while rare, is responsible for a third of all
maternal deaths. All women with risk factors (age >35, BMI >30kg/m2,
proteinuria >5g/day) and/or other comorbidities should receive
prophylactic low molecular weight heparin throughout pregnancy.
• Thyroid dysfunction is three times more common in type 1 diabetes
pregnancy and should be assessed during pregnancy and post-partum.
Type 1 and type 2 diabetes
• Most women (95%) deliver normal healthy babies. The congenital
malformation and spontaneous abortion rates are higher when the
HbA1c is elevated (>6.1%; 43mmol/mol).
• Pregnancy is not recommended in women with HbA1c >86mmol/
mol (10%).
Management during pregnancy

All pregnant women should be managed in a multidisciplinary clinic
and reviewed every 1–2 weeks. A checklist for the clinic visit is listed in
Box 13.14.
Maintain good glycaemic control
Good glycaemic control reduces the risk of DKA, fetal macrosomia, fetal
loss, and congenital malformation. However, even with near perfect con-
trol, there is a small, but significant, risk of major congenital malformations
and an unexplained risk of late stillbirths.
A basal bolus regimen is used to achieve the tight postprandial glu-
cose targets. Fast-acting insulin analogues (aspart and lispro) are preferred
and safe for use in pregnancy. Levemir® (not yet Lantus®) is licensed by
the FDA for pregnancy while basal insulin analogues are not licensed in
Europe at the time of writing. However, both Lantus® and Levemir® are
increasingly used in type 1 diabetes in pregnancy to reduce the risk of
hypoglycaemia.
Insulin pump therapy (CSII) is indicated for women with type 1 diabetes
who cannot achieve optimal glycaemic control on multiple daily injections
without disabling hypoglycaemia.
Insulin therapy
In type 1 diabetes, insulin requirements often fall in the first trimester,
increase slightly in the second, and then continue to rise until about
36 weeks, falling back to pre-pregnancy levels after delivery.
Women with type 1 diabetes should be advised about the increased risk
of severe hypoglycaemia and that hypoglycaemia awareness may decrease.
Advice regarding care with driving (do not drive below 5mmol/L) is essen-
tial. Partners should be instructed how and when to administer glucagon.
In type 2 diabetes, insulin requirements vary considerably; approxi-
mately 1.0 units/kg per day initially and up to 2.0 units/kg per day later in
the pregnancy.
Monitoring of diabetic complications during pregnancy
Screening for nephropathy and retinopathy is advised at the first antenatal
appointment and repeated at 28 weeks. Diabetic retinopathy should not
be considered a contraindication to rapid optimization of glucose control.
If serum creatinine is abnormal (120micromol/L or more) or the estimated
glomerular filtration rate (eGFR) is <45mL/min/1.73m2, referral to a neph-
rologist is indicated.
Fetal monitoring
• Scanning of the fetus at 10–12 weeks to confirm dates, looking for
congenital abnormalities.
• Screening for congenital malformations at 18–20 weeks.
• Fetal growth assessments at 28, 32, and 36 weeks.
Management of delivery and after delivery
• Women should be offered elective birth through induction of labour
or by elective Caesarean section after 38 completed weeks.
DIABETES AND PREGNANCY 755
Box 13.14 Checklist for type 1/type 2 diabetes in

pregnancy during clinic visit
• Capillary blood glucose monitoring before and 1h after meals and
before bed, i.e. 7–8 tests per day.
• Fasting glucose of <5.9mmol/L.
• 1h postprandial glucose of <7.8mmol/L.
• HbA1c <43mmol/mol (6.1%).
• Insulin therapy—basal bolus or insulin pump therapy. Metformin and/
or glibenclamide may be continued.
• Reinforce risk of hypoglycaemia during first trimester (e.g.
education on driving, glucagon injection) and DKA (e.g. ketone
testing during illness).
• Monitoring of maternal weight, BP, and urinalysis.
• Reinforce dietary advice throughout pregnancy.
• Physical activity (at least 30min daily), with advice on monitoring
BGs and adjusting diet and/or insulin.
• Assessment for nephropathy and retinopathy at first antenatal
visit and at 28 weeks.
• Screening for thyroid disorders.
• Fetal monitoring.
• Scanning at 18–20 weeks for congenital abnormalities.
• Growth scanning at 28, 32, and 36 weeks.
• Review 1–2-weekly.
• At 36 weeks’ clinic visit, discuss and document.
• Mode and timing of delivery.
• BG management and insulin infusion rate for delivery.
• Benefits of breastfeeding (mother and baby).
• Options for safe, effective post-partum contraception.
• Induction of labour or elective Caesarean section is usually advised
at or around 38 completed weeks.
• During labour, capillary blood glucose should be monitored on an

hourly basis and maintained between 4 and 7mmol/L.
• Intravenous dextrose and insulin infusion is recommended during
labour and birth for women if blood glucose is not 4–7mmol/L.
• Blood glucose testing should be carried out routinely in babies of
women with diabetes at 2–4h after birth.
• Women should commence pre-conception insulin doses or reduce
late pregnancy doses by at least 50% as soon as possible after birth.
The potential for hypoglycaemia in mothers who are breastfeeding should
be discussed. Extra carbohydrate snacks for the mother are often needed
(10–15g CHO per feed), along with further reductions in pre-conception
insulin requirements. One day’s worth of breast milk contains about 50g
of carbohydrate.
Gestational diabetes
Epidemiology
Pregnancy induces a state of insulin resistance, with increases in the lev-
els of growth hormone, progesterone, placental lactogen, and cortisol,
resulting in impaired glucose disposal. Hyperglycaemia during pregnancy
occurs in up to 2–5% of women and is associated with increased risk of
subsequent type 2 diabetes in up to 50% women over the next 5–10 years.
The risk of subsequent type 2 diabetes is significantly reduced by diet and
lifestyle and by metformin.
There is a clear association with increasing hyperglycaemia and poorer
maternal and fetal outcomes. Intensive treatment with diet, metformin,
and insulin (required in 10–20% women) reduces the risk of serious
perinatal morbidity (death, macrosomia with associated complications of
shoulder dystocia, bone fracture, and nerve palsy), Caesarean delivery,
and maternal hypertensive disorders.
Diagnostic criteria for GDM are listed in Table 13.11.
High-risk groups
Most women with gestational diabetes are detected on routine screening
at 24–28 weeks, but certain high-risk groups should be screened earlier.
These risk factors include:
• Previous gestational diabetes.
• A large baby in their last pregnancy, e.g. >4.5kg.
• A previous unexplained stillbirth/perinatal death.
• Maternal obesity (BMI above 30kg/m2).
• Family history of diabetes (first-degree relatives).
• Family origin with a high prevalence of type 2 diabetes:
• South Asian.
• Black Caribbean.
• Middle Eastern.
• Polyhydramnios.
Screening
Screening is recommended at 16 weeks if previous gestational diabetes
and, if normal, should be repeated at 24–28 weeks in high-risk groups.
Box 13.15 details methods of screening.
Table 13.11 Diagnosis of gestational diabetes, according to the

current WHO and proposed IADPSG diagnostic criteria
Plasma glucose (mmol/L)
WHO Fasting >7.0mmol/L Postprandial level ≥7.8mmol/L at 2h
IADPSG ≥5.1mmol/L ≥10.1mmol/L at 1h or ≥8.5mmol/L at 2h
NICE guidelines currently recommend WHO diagnostic criteria. Use of the IADPSG
(International Association of Diabetes and Pregnancy Study Group) criteria is an attempt to
standardize the diagnosis, based on the Hyperglycaemia and Adverse Pregnancy Outcome
(HAPO) study.
GESTATIONAL DIABETES 757
Box 13.15 Methods of screening

• The NICE guidelines for GDM screening are currently under review.
At present, screening is recommended only in high-risk groups.
• The 2h 75g oral glucose tolerance test (OGTT) should be used at
24–28 weeks, with earlier testing (16–18 weeks) and/or capillary
glucose testing indicated in women with previous GDM.
• Fasting plasma glucose, random blood glucose, glucose challenge
test, and urinalysis should not be undertaken.
Treatment
• Initial treatment is with dietary advice and exercise. There is an
emphasis on watching the quantity of carbohydrate (especially
at breakfast) and choosing carbohydrates from low glycaemic
index sources, lean proteins, including oily fish, and a balance of
polyunsaturated fats and monounsaturated fats.
• 30min of daily physical activity is recommended.
• Women with pre-pregnancy BMI ≥27kg/m2 should also be advised to
restrict calorie intake (to 25kcal/kg/day or less).
Oral hypoglycaemic therapy
Oral hypoglycaemic treatment is recommended if diet and exercise fail to
maintain blood glucose levels in the target range (3.5–7.8mmol/L) and/or
the growth scans suggest incipient macrosomia (abdominal circumference
>70th percentile).
Metformin and/or glibenclamide are not licensed for use in pregnancy
but are commonly used. Informed consent should be obtained.
Insulin therapy
• Required in 10–20% gestational diabetes pregnancies to maintain
fasting blood glucose 3.5–5.9mmol/L and 1h postprandial <7.8mmol/L.
• Used in conjunction with diet and exercise or in addition to
metformin.
• Regimen should be tailored to glycaemic profile and patient
acceptability: boluses alone, basal alone, mixed or basal bolus.
• Most (but not all) women can stop insulin and/or oral hypoglycaemic
treatments immediately after birth.
Post-partum follow-up
• Women with gestational diabetes should be offered lifestyle advice
(including weight control, diet, and exercise) and a fasting plasma
glucose measurement at the 6-week post-natal check and annually
thereafter.
• NICE do not recommend a post-partum OGTT, but this is often used
in high-risk multiethnic groups at increased risk of type 2 diabetes.
See Box 13.16 for a checklist for GDM during clinic visit.
Box 13.16 Checklist for gestational diabetes during

clinic visit
• Monitoring BG, aim:
• Fasting BG <5.9mmol/L.
• 1h postprandial BG <7.8mmol/L (some advocate lower BG
targets for obese women, e.g. <5.1 fasting and <7.0 after meals).
• Monitor maternal weight, BP, and urinalysis.
• Monitor fetal size (abdominal circumference)—increase treatment if
abdominal circumference ≥70th percentile.
• Treatment:
• Diet and lifestyle advice.
• Oral hypoglycaemic agents if diet and exercise inadequate or
incipient macrosomia: metformin/glibenclamide; insulin therapy—
NPH and/or rapid-acting insulin analogues (aspart and lispro).
• Reinforce dietary advice throughout pregnancy.
• Advice on physical activity (at least 30min daily).
• At 36 weeks’ clinic visit, discuss and document:
• Mode and timing of delivery.
• BG management and insulin infusion rate for delivery.
• Increased risk of type 2 diabetes and evidence for delaying and
prevention (diet and lifestyle or metformin).
• Benefits of breastfeeding (mother and baby).
• Options for safe, effective post-partum contraception.
• Post-partum follow-up—fasting glucose or OGTT 6 weeks
post-delivery.
Further reading
Crowther CA, et al. (2005). Effect of treatment of gestational diabetes mellitus on pregnancy
outcomes. N Engl J Med 352, 2477–86.
International Association of Diabetes and Pregnancy Study Groups Consensus Panel (2010).
International Association of Diabetes and Pregnancy Study Groups recommendations on the
diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 33, 676–82.
Landon MB, et al. (2009). A multicenter, randomized trial of treatment for mild gestational diabetes.
N Engl J Med 361, 1339–48.
Macintosh MC, et al. (2006). Perinatal mortality and congenital anomalies in babies of women with
type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population based study.
BMJ 333, 177.
Metzger BE, et al. (2008). Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 358,
1991–2002.
National Institute for Health and Clinical Excellence (2008). NICE guideline 63: Diabetes in Pregnancy:
Management of diabetes and its complications in pregnancy from the pre-conception to the post-
natal period. Available at: M http://publications.nice.org.uk/diabetes-in-pregnancy-cg63/guidance.
Ratner RE, et al. (2008). Prevention of diabetes in women with a history of gestational diabetes:
effects of metformin and lifestyle interventions. J Clin Endocrinol Metab 93, 4774–9.
Rowan JA, et al. (2008). Metformin versus insulin for the treatment of gestational diabetes. N Engl
J Med 358, 2003–15.
GESTATIONAL DIABETES 759
Contraception and diabetes

Oral contraceptives
Standard advice regarding the pill should be given, with extra caution in
at-risk groups, such as overweight smokers with a family history of throm-
boembolism and coronary heart disease. It is important to balance the
risks and benefits of safe effective contraception with the consequences
of unplanned pregnancy.
In those with microvascular disease or coronary risk factors, the
progesterone-only ‘mini-pill’ (POP) is safer than the combined OCP,
as it has no significant adverse effects on lipid metabolism, clotting,
platelet aggregation, or fibrinolytic activity. It has been suggested that
levonorgestrel- and norethisterone-containing POPs may reduce HDL2
cholesterol subfractions.
Barrier methods
These are less effective forms of contraception, with failure rate of
0.7–3.6/100 couple years, compared to nearly 0.2/100 with the combined
OCP. As unplanned pregnancy carries significant risks, safer forms of con-
traception are recommended.
Intrauterine contraceptive devices (lUD)
There were historical concerns that diabetes might make a pelvic infection
associated with an IUD more severe, but these are unconfirmed.
Implantable contraceptive
Etonogestrel (Nexplanon®) is a matchstick-sized progestin-only contra-
ceptive, inserted under the skin of the inner upper arm, that offers safe,
effective contraception for up to 3 years. It is a popular option for women
who cannot, or do not want to, use the combined OCP.
CONTRACEPTION AND DIABETES 761
Paediatric and transition diabetes

Diabetes is the third commonest chronic condition in childhood.
• Prevalence—there are 23,000 children and young people under 18
with diabetes in England; 97% type 1, 1.5% type 2, and 1.5% other
types. The others are made up of secondary diabetes, e.g. cystic
fibrosis, as well as single gene abnormalities.
• Incidence is currently around 26:100,000 children per year. This is
rising at around 4% per year in most developed countries, and even
faster in some developing nations.
Type 1 diabetes
Epidemiology
• Age of onset can be anything from 6 months onwards.
• There are typically two peaks of onset—at around ages 5–6 and
12–13 years. It is thought that this suggests viral infections as a cause.
• The environmental trigger is, however, unknown in most cases, and
various pancreatic antibodies can be present months or years before
the diagnosis is made.
Diagnosis
• Onset generally with polyuria and polydipsia in older children.
• 50–90% have new-onset bedwetting, having been dry previously.
• Younger children, including babies and toddlers, may have less easily
recognized symptoms—constipation, lethargy, thrush, poor feeding.
• 30–40% under age 5 are in DKA at diagnosis, compared with 20–25%
of older children.
• Symptoms of DKA in children can be abdominal pain, breathing
difficulties, vomiting, dehydration, and shock.
The diagnosis should be made at the first presentation by doing a capillary
BG measurement, rather than waiting for a urine sample or fasting BG
sample. Management in children is highly specialized and is only done in
secondary care centres with an appropriate MDT with training in diabetes
in children. If BG greater than 11mmol/L, the child should be referred that
same day to such a centre.
Type 2 diabetes
Increasing in Europe but not to the same extent as in the USA where half
of children diagnosed with diabetes now have type 2. Associated with
obesity but also in particular ethnic groups with a high genetic susceptibil-
ity. Children often have a family history and may have acanthosis nigricans,
indicative of insulin resistance. At present, in the UK, only 1.5% of all chil-
dren with diabetes have type 2. Therefore, only a few centres have a lot
of experience, and adult diabetologists may be asked to assist with the
management.
PAEDIATRIC AND TRANSITION DIABETES 763
Other types of diabetes

Neonatal diabetes
Diabetes presenting before the age of 6 months is very rare and unlikely
to be autoimmune in aetiology. This can be transient or permanent and
is usually due to single gene abnormalities. Many of these babies require
tiny doses of insulin, particularly if also of low birthweight, and this is best
given using an insulin infusion pump. This should only be done in specialist
centres.
Monogenic diabetes
Various single gene disorders can present in childhood.
Making a correct genetic diagnosis of neonatal diabetes or MODY is
important, as insulin treatment may not be required (b see p. 691).
Secondary forms of diabetes
• Most common is cystic fibrosis (CF-related diabetes; CFRD).
• Weight loss and frequent infections are signs of possible CFRD.
• CGM may be the best way of diagnosing subtle changes in glucose
tolerance.
• All teenagers with CF should be screened.
• Management is with insulin.
Management of children
with diabetes
In the UK, standards for best practice in caring for children with diabetes
have been linked to payment of a ‘best practice tariff’—a set amount of
money paid for each young person cared for (up to their 19th birthday).
To qualify for this, the following must apply:
• Every child or young person with diabetes will be cared for by a
specialist team of healthcare professionals (consisting of a doctor,
a nurse, and a dietician as a minimum) who have specific training in
paediatric diabetes. DSN caseload 70–100 patients.
• For new diagnoses: the case must be discussed with the specialist team
within 24h of the diagnosis and seen on the next working day.
• An age-appropriate structured education programme offered at
diagnosis and with updates, as needed.
• Four clinic appointments with HbA1c check.
• Annual dietician contact.
• At least eight additional contacts per year from members of the
specialist team (not all face-to-face) are recommended.
• Annual review with BP and retinopathy/renal screening from age 12.
• Annual psychology assessment and access to psychology services.
• 24h emergency phone advice for families/other health professionals.
• Involvement in the National Paediatric Diabetes Audit and Paediatric
Diabetes Network.
• Policy for transition to adult services.
• Policy on managing high HbA1c and infrequent clinic attendance.
Type 1 diabetes in children
Insulin
Insulin is started at a total daily dose of 0.5 units/kg body weight in children.
In puberty, the starting dose is 0.7 units/kg body weight.
Insulin regimens are the same as in adults, varying from centre to centre,
with very little evidence base for one being superior. In toddlers, basal
insulin tends to be given in the morning, moving to the evening in children
aged >5 years. It is often used twice daily in puberty. Prandial insulin doses
for food can be anything from 0.5 units for 40g of CHO in babies to 3–4
units for 10g in pubertal boys.
Continuous subcutaneous insulin infusion (CSII) pumps (b p. 704)
NICE guidelines allow for pumps to be funded in children under the age
of 12 in whom multiple insulin injections are considered to be impractical
or inappropriate. Over 12s have the same funding restrictions as adults.
Education
As in adults, this is the mainstay of management to allow parents and then
children to self-manage their own condition.
• Carbohydrate counting. This may be taught at any stage but is better if
done soon after diagnosis so that it becomes routine for the family.
• Multiple carers. One of the main differences between children and
adults with diabetes is the need to teach many family members about
the condition, including grandparents and childminders.
MANAGEMENT OF CHILDREN WITH DIABETES 765
• Blood testing. Before every meal and at other times to work out
whether mealtime doses are correct, as well as at other times for
troubleshooting. Many children require 6–8 blood tests per day, and
so there is much interest currently in continuous subcutaneous glucose
sensing.
• Exercise. Children’s exercise levels vary enormously from one day to
the next. Therefore, advice about how to cope with the BG variability
is essential and built into most structured education programmes.
• Management at school and nursery:
• Children spend around a third to half of waking hours at school.
• Schools need to support intensive management of diabetes.
• This works best when volunteers at primary school are taught
diabetes management. This includes either supervising or doing the
BG testing, insulin injections, or pump boluses, and, in some places,
the use of algorithms to calculate insulin doses for food and BG
correction. This involves a lot of education, usually by the DSN.
• All school staff (primary and secondary) should be aware of the
symptoms of hypoglycaemia in a particular child and should know
how to treat hypoglycaemia.
Acute complications are mainly treated as in adults (b see Expert man-
agement of type 1 diabetes, p. 694; Diabetes and life, p. 722; Hospital
inpatient diabetes management and diabetic emergencies, p. 732). Specific
points relevant to children are described in the following sections.
Hypoglycaemia
• Parents and carers should look out for symptoms, as children may not
recognize them reliably until around 10 years old.
• Dose of glucagon for severe lows with fits or unconsciousness: 0.5mg
if under 8 years old and 1.0mg if older.
Diabetic ketoacidosis
Management in those <18 years should be according to the British Society
of Paediatric Endocrinology and Diabetes guidelines (M http://www.
bsped.org.uk/clinical/clinical_endorsedguidelines.html). Key features which
are different from the new adult guidelines are:
• Lower volumes of fluid than in adults because of the risk of cerebral
oedema.
• Fixed-rate insulin infusion at 0.1 units/kg/h.
• Delay in insulin administration until after 1h of fluids for the same reason.
Complications and associated conditions
Annual review should include:
• Blood pressure at all ages.
• Microalbuminuria and retinopathy screening: annually when >12 years.
• Examine feet to instil good practices.
• 3-yearly screening for coeliac disease (6–8% patients have condition).
• Annual thyroid function tests.
• Addison’s disease—no screening, but consider if recurrent
hypoglycaemia and lethargy.
Puberty and diabetes

• Insulin requirements rise from 70.7 units/kg/day to up to
2.0 units/kg/day in early puberty in girls and late puberty in boys (timed
with the growth spurt) because of the insulin resistance of puberty.
• Puberty can make the management of a chronic condition difficult as
the teenager wishes, most of all, to be accepted into a peer group, and
feeling different in any way makes this hard.
• Therefore, some young people will stop doing BG testing or miss
insulin doses, particularly when out with friends.
• Supportive management with short-term goal-setting and counselling is
important.
• Young people often need to be seen more frequently, rather than less,
during this time.
Transition from paediatric to adult services
During the teenage years, there is a gradual change from parental man-
agement of the diabetes to the young person themselves being responsi-
ble for their own diabetes. Many parents think that as soon as the child
reaches the age of 14–15, they can take care of their own diabetes and
should be left to get on with it. This is NOT true. HbA1c levels continue
to increase until the age of around 20, and it is only when young people
settle down in their early 20s that diabetes becomes more stable.
Good research evidence shows that the longer the parents remain
involved, the better the outcomes in terms of HbA1c and quality of life.
Therefore, young people should be seen with their parents as long as they
wish to, even in an adult clinic. Seeing them alone at the start of the con-
sultation may help to uncover their own management style, but parental
involvement should still be encouraged.
How a transition service should work
• The service should have a transition protocol, which should include
agreeing the timing of transfer with the young person, discussed well in
advance.
• Transfer should be to a service with a young adult clinic, rather than
to general practitioners, as they do not generally have the expertise to
manage young people with type 1 diabetes.
• Some evidence suggests that transition is more successful if there is a
joint clinic between the paediatric MDT and the adult MDT.
• A dedicated transition service DSN should keep in contact with young
people in the community when they default from clinics.
• There is evidence that defaulters have higher HbA1c levels, and so
they do need to be followed up in specialist care.
Educational aspects of transition
It is helpful to have leaflets on all of the following issues available at each
contact with young people. Advice should be non-judgemental, be offered
from early teenage years, and take place with parents absent.
• Alcohol.
• Driving: a doctor is required to sign the provisional driving licence
application form. The usual DVLA rules apply.
PUBERTY AND DIABETES 767
• Smoking.
• Recreational drugs.
• Contraception and pre-conception care.
• Sick day rules—to take account of living alone for the first time.
• Eating disorders:
• Mild forms are common, especially, but not exclusively, in girls.
Discussion should be towards helping the young person recognize
the link between thoughts, feelings, and behaviour and to try to find
alternative behaviours. Missed insulin injections are often a way of
controlling weight.
• Higher education:
• Often secondary specialist care is kept at home for appointments
during the holidays, with local GP registration with the university/
college student health system. Young people on insulin need a
fridge to be provided in their University accommodation and to let
people on their corridor know about diabetes. A discussion about
how they will manage ‘fresher’s week’, especially with alcohol, and
other issues is helpful.
• Separation from parents:
• The paediatric team will usually have spent many years
communicating more with the parents than the children. However,
now the young person may need to be helped to understand their
diabetes for themselves, often requiring a new process of education
from basics onwards.
Diabetic eye disease

Epidemiology
Diabetic retinopathy (DR) is a complication of diabetes, resulting from
damage to the small blood vessels, generally occurring 10 years after dia-
betes onset (which may be some years before the diagnosis of type 2 dia-
betes). DR is the leading cause of blindness in the working age population.
Cataracts are also more common in people with diabetes.
DR is extremely common with long durations of diabetes. A recent
study of global prevalence of DR showed a prevalence of 35% for any DR,
7% had proliferative diabetic retinopathy (PDR), 7% had macular oedema,
and 10% had sight-threatening diabetic eye disease (STED).
Recent studies have shown that, since 1985, people with diabetes have
experienced lower rates of progression to proliferative DR and severe
visual loss, probably reflecting improvements in diabetes care.
Some studies have suggested that non-White ethnic groups have higher
prevalences of DR. However, this has been difficult to separate from con-
founding risk factors, such as age, duration of diagnosed diabetes, HbA1c,
and blood pressure.
See Box 13.17 for classification of DR.
DIABETIC EYE DISEASE 769
Box 13.17 Classification and features of diabetic

retinopathy
• Background retinopathy (graded as R1 by the National Screening
Committee—NSC):
• Microaneurysms.
• Haemorrhages—dot and flame-shaped.
• Hard exudates.
• Soft exudates/cotton wool spots.
• Pre-proliferative retinopathy (graded as R2):
• Multiple blot haemorrhages.
• Intraretinal microvascular abnormalities (IRMAs).
• Venous beading.
• Venous reduplication.
• Proliferative retinopathy (graded as R3):
• New vessels on the disc (NVD) or within 1 disc diameter of it.
• New vessels elsewhere (NVE).
• Fibrovascular proliferation 9 tractional retinal detachment.
• Pre-retinal or vitreous haemorrhage.
• Rubeosis iridis (9 neovascular glaucoma).
• Maculopathy (graded as M0 if none and M1 if present):
• Exudate within 1 disc diameter (DD) of the centre of the fovea.
• Group of exudates within the macula.
• Any microaneurysm or haemorrhage within 1 DD of the centre
of the fovea only if associated with a best VA of ≤6/12 (if no
stereo).
• Retinal thickening within 1 DD of the centre of the fovea (if
stereo available).
Other NSC grades
• R0—no retinopathy.
• O—other non-diabetic lesions seen (e.g. drusen and macular
degeneration).
• P—evidence of previous laser therapy/retinal photocoagulation.
• U—unclassifiable, often due to cataracts.
Clinical and histological features

of diabetic eye disease
The classification of diabetic retinopathy is based on clinical examination
or on grading of retinal photographs, but changes in the pathophysiology
may explain some of the clinical findings.
One of the first histological changes seen is thickening of the base-
ment membrane and loss of pericytes embedded within it, forming acel-
lular capillaries. Breakdown in endothelial cell tight junctions leads to
increased capillary permeability. The microaneurysm is the hallmark of
retinal microvascular disease in diabetes. Microaneurysms may be asym-
metrical dilatations of the capillary wall where it is weakened or damaged,
following the loss of the supporting pericytes and localized increases in
hydrostatic pressure. Smooth muscle cell death, capillary weakening
and closure, with the occurrence of intraretinal microvascular abnor-
malities (IRMA), and impaired autoregulation are all features of diabetic
retinopathy.
The natural progression, with increasing retinal ischaemia, is from
background to pre-proliferative to proliferative DR and ultimately to
sight-threatening DR. Maculopathy can occur at any of these stages but
does occur more frequently with more advanced disease.
Background retinopathy
Capillary microaneurysms are the earliest feature seen clinically as red
‘dots’. Dot haemorrhages also occur, and these can be difficult to dis-
tinguish from microaneurysms and are collectively, referred to as HMA.
Small intraretinal haemorrhages or ‘blots’ also occur, as can haemorrhage
into the nerve fibre layer, which are often more flame-shaped. With i
capillary leakage, hard exudates, which are lipid deposits, can also be seen.
A cotton wool spot is a delay in transmission along the axoplasm of the
nerve fibre layer of the retina, caused by ischaemia. It used to be con-
sidered a pre-proliferative feature, but, because it is not a good indica-
tor of progression to proliferative retinopathy, it is now included in the
background R1 category in the English national DR screening programme.
Pre-proliferative retinopathy
With increasing ischaemia, the retina shows signs of increasing numbers of
blot haemorrhages, which are usually in a deeper layer of the retina than
dot or flame-shaped haemorrhages.
Intraretinal microvascular abnormalities (IRMA) are tortuous intrareti-
nal vascular segments varying in calibre. They derive from remodelling of
the retinal capillaries and small collateral vessels in areas of microvascular
occlusion.
Venous beading is a localized increase in calibre of the vein, and the
severity is dependent on the increase in calibre and the length of vein
involved.
Venous reduplication is dilation of a pre-existing channel or prolifera-
tion of a new channel adjacent to, and approximately the same calibre as,
the original vein.
CLINICAL & HISTOLOGICAL FEATURES OF DIABETIC EYE DISEASE 771
The Early Treatment of Diabetic Retinopathy Study (ETDRS) provided

evidence that certain features were more indicative of progression to pro-
liferative DR and suggested a ‘4–2–1’ rule:
• 4 quadrants of severe haemorrhages or microaneurysms.
• 2 quadrants of IRMAs.
• 1 quadrant with venous beading.
If you have one of these features, there is a 15% risk of developing prolif-
erative diabetic retinopathy within the next year; if two are present, the
risk rises to 45%.
Proliferative retinopathy
(See Fig. 13.4.)
New vessels developing in diabetic retinopathy are characterized
according to whether they develop at or near the optic disc (NVD) or
elsewhere in the retina (NVE). They usually develop from the venous cir-
culation and grow forwards in the vitreous gel, but they can also develop
from the arterial circulation.
Fig. 13.4 This photograph shows new vessels at the disc (NVD) and haemorrhage
from these new vessels in front of the inferior temporal arcade.
New vessels on the disc (NVD) are defined as any new vessel devel-
oping at the optic disc or within 1 disc diameter of the edge of the
optic disc.
New vessels elsewhere (NVE) are defined as any new vessel developing
more than 1 disc diameter away from the edge of the optic disc.
Both give no symptoms but cause the problems of advanced retinopa-
thy, such as haemorrhage, scar tissue formation, traction on the retina, and
retinal detachment which actually results in loss of vision.
The Diabetic Retinopathy Study (DRS) recommended prompt treat-
ment with panretinal photocoagulation in the presence of DRS high-risk
characteristics, which reduced the 2-year risk of severe visual loss by 50%
or more and were defined by:
• The presence of pre-retinal or vitreous haemorrhage.
• Eyes with NVD equalling or exceeding 1/4 to 1/3 disc area in extent
with no haemorrhage.
• NVE equalling >1/2 disc area with haemorrhage (from the NVE).
Untreated, eyes with high-risk characteristics had between 25.6% and
36.9% chance of severe visual loss within 2 years.
Proliferative eyes without high-risk characteristics had the following
risks of severe visual loss:
• Untreated—2 years 7.0%, 4 years 20.9%.
• Treated—2 years 3.2% 4 years 7.4%.
Because the side effects of modern laser treatment are considerably less
than the early lasers, most ophthalmologists treat eyes that develop new
vessels of either the high- or low-risk categories.
Diabetic macular oedema
Diabetic macular oedema or maculopathy may be classified into focal,
diffuse, and ischaemic types.
In focal maculopathy, focal leakage tends to occur from microaneu-
rysms, often with a circinate pattern of exudates around the focal leakage.
In the diffuse variety, there is a generalized breakdown of the blood–
retina barrier and profuse early leakage from the entire capillary bed of
the posterior pole, sometimes accompanied by cystoid macular changes.
In ischaemic maculopathy, enlargement of the foveal avascular zone
(FAZ) due to capillary closure is found with variable degrees of visual loss.
The Early Treatment Diabetic Retinopathy Study (ETDRS) reported
that focal photocoagulation of ‘clinically significant’ diabetic macular
oedema (CSMO) substantially reduced the risk of visual loss, CSMO being
defined as:
• Thickening of the retina at or within 500 microns of the centre of the
macula.
• Hard exudates at or within 500 microns of the centre of the fovea,
if associated with thickening of the adjacent retina (no residual hard
exudates remaining after disappearance of retinal thickening).
• A zone or zones of retinal thickening 1 disc area or larger, any part of
which is within 1 disc diameter of the centre of the macula.
CLINICAL & HISTOLOGICAL FEATURES OF DIABETIC EYE DISEASE 773
Eye screening
National screening programmes
The development of screening in Europe was first encouraged by the
St. Vincent Declaration which, in 1989, set a target for the reduction of
new blindness by one-third in the following 5 years.
National screening programmes, with consensus grading protocols,
were introduced in the UK in 2002–2004. The National Institute for
Health and Clinical Excellence (NICE) recommends that those with type 1
and type 2 diabetes have their eyes screened at the time of diagnosis and
at least annually thereafter. There are differences in the protocols used
globally in screening programmes. In England, the method used is two-field
mydriatic digital photography, with screening performed by technician
screeners or optometrists. Fixed locations and mobile units are both used.
Monitoring of programme performance is via Quality Assurance Standards
and Key Performance Indicators against which individual screening pro-
grammes are assessed.
Ad hoc eye examinations
It is important to remember that the patients who are most at risk of
developing sight-threatening diabetic retinopathy and visual loss are the
regular non-attenders for screening. Hence, it is important to examine
the eyes of patients who have not attended for routine screening using
the following method:
Visual acuity
Use a standard Snellen chart for distance, and check each eye separately.
Let the patient wear their glasses for the test, and if vision is worse
than 6/9, also check with a pinhole, as this will correct for any refractive
(glasses) error. If it does not correct to 6/9 or better, consider more
careful review; some maculopathy changes cannot be seen easily with a
handheld ophthalmoscope, and an ophthalmology review may be needed.
Cataracts are a more likely cause, so look carefully at the red reflex.
High blood glucose readings can lead to myopia and low blood glucose
to hypermetropia. In both these circumstances, one would expect the
vision to improve with a pinhole.
Eye examination
• Dilate the pupil before looking into the eye.
• Use tropicamide 1%—dilates the pupil adequately in 15–20min and
lasts only 2–3h.
• In those with a dark iris, you may also need phenylephrine (2.5%),
added soon after the tropicamide, to give adequate views.
• The main reasons not to dilate are closed angle glaucoma and
recent eye surgery, but as such patients are usually under an eye
clinic already, most people are suitable for dilatation.
• Once the pupil is dilated, look at the red reflex to check for lens
opacities. Examine the anterior chamber, as, although rare, rubeosis
iridis is important to pick up. The vitreous is examined before
EYE SCREENING 775
examining the retina. When examining the retina, use the optic disc
as a landmark; follow all four arcades of vessels out from it; examine
the periphery, and at the end, examine the macula, as this can be
uncomfortably bright through a dilated pupil, and if done at the start, it
makes it difficult for anyone to keep their eye still enough to complete
the examination adequately. It is usually much easier for the patient
to look directly at the light if a smaller spot size or a target on a green
background are chosen for this aspect of the examination.
When to refer
Referral will depend on local preferences but are based on NSC manage-
ment guidelines, as outlined in Box 13.18.
Box 13.18 Reasons for and timing of referral to

ophthalmologist
• Immediate referral:
• Rubeosis iridis/neovascular glaucoma.
• Vitreous haemorrhage.
• Advanced retinopathy with retinal detachment.
• Urgent referral (<2 weeks):
• R3/proliferative retinopathy, as untreated NVD carries a 40% risk
of blindness in <2 years and laser treatment reduces this.
• Routine referral (<13 weeks):
• R2/pre-proliferative changes.
• M1/maculopathy.
• Routine non-DR referral:
• Cataracts.
• Other categories:
• R0/no retinopathy—annual screening.
• R1/background retinopathy—annual screening and inform
diabetes care team.
Medical treatment for diabetic

eye disease
Box 13.19 shows the risk factors for worsening retinopathy.
Glycaemic control
The DCCT and UKPDS confirmed the link between glycaemic control and
the onset and progression of diabetic eye disease.
Worsening of DR can occur when glycaemic control improves rapidly,
so careful monitoring of diabetic retinopathy is needed during this period
(e.g. pregnancy). However, the long-term benefits of improved glycaemic
control greatly outweigh the risks of early worsening.
Blood pressure control/therapy
UKPDS also showed that good blood pressure control is vital to reduce
the onset and progression of DR.
Lipid control/therapy
Evidence that elevated serum lipids are associated with macular exudates
and moderate visual loss and that partial regression of hard exudates may
be possible by reducing elevated lipid levels comes from several studies.
The FIELD study suggested that the use of fenofibrate in type 2 diabetes
might reduce the need for laser treatment of diabetic retinopathy over a
5-year period. However, caution is needed with this interpretation, as the
numbers of events were small.
Antiplatelet therapy
These agents have been tried in patients with diabetes, but the results
are variable.
Lifestyle advice
Stopping smoking may reduce the risk of DR in type 1 diabetes. Changes
to alcohol consumption or physical activity show no consistent effect.
Box 13.19 Risk factors for developing/worsening of

diabetic retinopathy
Modifiable risk factors for DR:
• Glucose control.
• Systemic hypertension.
• Blood lipids.
• Smoking in type 1 diabetes.
Non-modifiable risk factors for DR:
• Duration of diabetes.
• Age.
• Genetic predisposition.
• Ethnicity.
• Pregnancy.
MEDICAL TREATMENT FOR DIABETIC EYE DISEASE 777
Surgical treatment for diabetic

eye disease
Laser treatment
• The ETDRS protocol for panretinal photocoagulation recommends
1,200–1,600 argon laser burns of 500 micron spot size, with the
treatment performed in two or more episodes, no more than 2 weeks
apart, and that no more than 900 burns should be applied in one session.
• Laser therapy is usually performed as two sessions of outpatient
treatment on conscious patients. Topical local anaesthetic drops
allow a contact lens to be placed on the cornea for application of the
laser through the contact lens. Modern multispot laser machines with
reduced duration of the burn and the ability to apply predetermined
pattern types, which can administer up to 25 spots at a time, have
reduced the time taken and the discomfort of panretinal laser
treatment. Hence, panretinal photocoagulation can usually be applied
with local anaesthetic drops.
• The laser energy is absorbed by the choroid and the pigment epithelium.
• Laser treatment for clinically significant macular oedema reduces visual
loss by >50%.
• Laser treatment aims to prevent further visual loss, especially in
maculopathy, not to restore vision, and the distinction must be
emphasized to all patients requiring treatment. The benefits from laser
therapy currently outweigh the risks, which include accidental burns to
the fovea if the eye moves during therapy, a reduction in night vision,
and, in a small number, interference with visual field severe enough to
affect the ability to drive. Most patients, however, retain the minimum
field for driving.
Vitrectomy
The surgical techniques of vitrectomy for advanced diabetic retinopathy
have improved over the last 30 years, which has been demonstrated by
the improved surgical results during this period. Most modern systems
employ three small (20–25 gauge) entry ‘ports’ into the eye, and a cutting/
suction device, an intraocular light source, and an infusion cannula are
inserted through these trans-scleral incisions.
The reasons why vitrectomy may be required are:
• Non-clearing vitreous haemorrhage.
• A large subhyaloid macular haemorrhage.
• Tractional retinal detachment.
• Combined rhegmatogenous (due to retinal tear)/tractional retinal
detachment.
• Progressive severe fibrovascular proliferation.
• Taut posterior hyaloid in diabetic macular oedema.
SURGICAL TREATMENT FOR DIABETIC EYE DISEASE 779
Alternative surgical treatment—the use of intravitreal

VEGF inhibitors
Ocular neovascularization (angiogenesis) and increased vascular perme-
ability have been associated with Vascular Endothelial Growth Factor
(VEGF), which does also have a neuroprotective effect.
There are three potential VEGF inhibitors: pegaptanib, ranibizumab, and
bevacizumab. Ranibizumab is an antibody fragment derived from beva-
cizumab, which is a full-length humanized monoclonal antibody against
human VEGF.
The Diabetic Retinopathy Clinical Research Network reported the
results of a multicentre, randomized clinical trial of 854 eyes in 691 par-
ticipants that evaluated ranibizumab plus prompt or deferred laser or tri-
amcinolone plus prompt laser for diabetic macular oedema. Intravitreal
ranibizumab with prompt or deferred laser was more effective through at
least 1 year, compared with prompt laser alone for the treatment of DME
involving the central macula. The expense of these agents has led to some
limitation in their use in diabetic eye disease, but a NICE appraisal in 2013
has now recommended the use of ranibizumab in certain cases of diabetic
macular oedema.
Favourable results have been reported with some regression of neo-
vascularization and reduction in fluorescein leakage in some studies using
bevacizumab and pegaptanib, but the effect is only transient (2–11 weeks).
Intravitreal injection is an effective means of delivering anti-VEGF drugs
to the retina but has the potential complications of endophthalmitis and
retinal detachment. Randomized controlled trials utilizing varying doses
of the VEGF inhibitors are required to assess the long-term efficacy and
safety and to define optimum treatment regimens. Cost effectiveness
studies are also needed.
Cataract extraction
This is a common procedure, with a slightly higher complication rate than
in the non-diabetic population. Although diabetes is a risk factor for the
development of cataracts and studies have shown an increased risk of ocu-
lar complications in people with diabetes after cataract surgery, modern
surgical techniques and appropriate preoperative laser treatment have led
to an overall good visual outcome in the majority of patients.
Further reading
Elman MJ, Aiello LP, Beck RW, et al. (2010). Randomized trial evaluating ranibizumab plus prompt
or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology
117, 1064–77.
Keech AC, Mitchell P, Summanen PA, et al. (2007). Effect of fenofibrate on the need for laser treat-
ment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 370, 1687–97.
Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE (2008). The Wisconsin Epidemiologic Study
of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with
type 1 diabetes. Ophthalmology 115, 1859–68.
National Institute for Health and Clinical Excellence (2013). NICE appraisal: Ranibizumab for the
treatment of diabetic macular oedema. Available at: M http://www.nice.org.uk/nicemedia/
live/14082/62873/62873.pdf.
No authors listed (1985). Photocoagulation for diabetic macular edema. Early Treatment Diabetic
Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research
group. Arch Ophthalmol 103, 1796–806.
No authors listed (1987). Indications for photocoagulation treatment of diabetic retinopa-
thy: Diabetic Retinopathy Study Report no. 14. The Diabetic Retinopathy Study Research
Group. Int Ophthalmol Clin 27, 239–53.
No authors listed (1991). Grading diabetic retinopathy from stereoscopic color fundus
photographs--an extension of the modified Airlie House classification. ETDRS report number
10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 98(5 Suppl),
786–806.
Raymond NT, Varadhan L, Reynold DR, et al. (2009). Higher prevalence of retinopathy in dia-
betic patients of South Asian ethnicity compared with white Europeans in the community: a
cross-sectional study. Diabetes Care 32, 410–15.
Wong TY, Mwamburi M, Klein R, et al. (2009). Rates of progression in diabetic retinopathy during
different time periods: a systematic review and meta-analysis. Diabetes Care 32, 2307–13.
Yau JW, Rogers SL, Kawasaki R, et al. (2012). Global prevalence and major risk factors of diabetic
retinopathy. Diabetes Care 35, 556–64.
SURGICAL TREATMENT FOR DIABETIC EYE DISEASE 781
Diabetic renal disease

Background
Diabetic nephropathy is now the major cause of end-stage renal disease
(ESRD) worldwide, representing over 50% of patients on renal replace-
ment therapy in many Middle and Far Eastern countries (>20% in the UK),
the majority having type 2 diabetes. Cardiovascular morbidity and mortal-
ity is much greater in diabetic patients with nephropathy, and many will
die before reaching ESRD.
Definition
Diabetic nephropathy is defined by the presence of dipstick +ve proteinu-
ria in a person with diabetes. This equates to an albumin concentration of
300mg/L (total protein 0.5g/L). Most patients will also have hypertension
and retinopathy, and many will have renal impairment. Research studies
use timed urine collections, with a diagnostic level of >300mg/day (about
200 micrograms/min). This level of albuminuria is termed overt or clinical
nephropathy. Excretion rates between 20 and 200 micrograms/min are
called microalbuminuria or incipient nephropathy and indicate a high risk
for future ESRD, although as many as 30% may spontaneously revert to
normal (see Table 13.12).
Chronic kidney disease (CKD) has been classified into stages, according
to an estimated glomerular filtration rate (eGFR) derived from serum cre-
atinine concentrations. Stages 1 and 2 (eGFR >90 and 60–89mL/min/1.73m2,
respectively) also require the presence of albuminuria or renal structural
abnormality, but stages 3–5 (eGFR 30–59, 15–29, and <15mL/min/1.73m2,
respectively) do not (see Table 13.13). The problem is that this classifica-
tion does not map easily to the classical definition of incipient and overt
nephropathy. Moreover, not all CKD is due to diabetic glomeruloscle-
rosis, particularly in the older person with type 2 diabetes, although the
presence of retinopathy makes the likelihood of diabetic glomeruloscle-
rosis >80%. Table 13.13 attempts to reconcile these diagnostic difficulties.
Epidemiology
The duration of diabetes is a major risk for the development of nephropa-
thy, so point prevalence studies are hard to interpret. In addition, the
incidence appears to be declining, at least in type 1 diabetes, so historical
prevalence rates may be misleading. In an inception cohort of 277 type 1
patients from Denmark studied from 1979 to 2004, the cumulative inci-
dence of microalbuminuria was 34% and for clinical nephropathy 15% after
20 years. For ESRD, rates of 2.2% and 7.8% have recently been reported
from Finland after 20 and 30 years’ duration, respectively.
Because the true date of onset of type 2 diabetes is hard to determine,
cumulative incidence data are less reliable. However, the annual incidence
of microalbuminuria was around 2% in the United Kingdom Prospective
Diabetes Study (UKPDS), which is slightly more than that seen in type
1, and 3% per annum for clinical nephropathy in those with established
microalbuminuria. Rates of ESRD are very dependent upon background
ethnicity. In the UKPDS population of mainly white Europid patients, ESRD
occurred in 0.6% after 10 years. Prevalence is equal in men and women.
The rates are at least double for those of South Asian background.
DIABETIC RENAL DISEASE 783
Table 13.12 Definitions of nephropathy, based upon albuminuria

Urine specimen Microalbuminuria Clinical nephropathy
Overnight collection 20–199 micrograms/min >200 micrograms/min
24h collection 30–299mg/day ≥300mg/day
Albumin concentration 20–300mg/L >300mg/L
Albumin:creatinine ratio ♂ 2.5–30mg/mmol ♂ >30mg/mmol
(ACR, Europe) ♀ 3.5–30mg/mmol ♀ >30mg/mmol
ACR (USA) Both 30–300mg/g >300mg/g
Table 13.13 Relative likelihood of diabetic kidney disease (DKD) by

CKD stage and albuminuria
Stage GFR (mL/min) Diabetes
Normoalbuminuria Microalbuminuria Clinical
nephropathy
1 >90 At risk for DKD Probable DKD DKD
(T1DM)
Possible DKD
(T2DM)
2 60–89 At risk for DKD Probable DKD DKD
(T1DM)
Possible DKD
(T2DM)
3 30–59 Probable DKD DKD (T1DM) DKD
(T1DM)
Probable DKD
Possible DKD (T2DM)
(T2DM)
4 15–29 Probable DKD DKD DKD
5 <15 Probable DKD DKD DKD
NB Likelihood >80% if concomitant retinopathy.
Making the diagnosis of diabetic

renal disease
Timed urine collections are too cumbersome for routine clinical care, so
spot samples (preferably first morning void specimens) are used, and, in
order to allow for urine concentration, the albumin content is corrected
for creatinine, giving an albumin:creatinine ratio or ACR. A +ve dipstick
test or ACR on two or more occasions over 6 months is usually enough to
confirm the diagnosis. Remember to exclude potential confounding causes
of a +ve test (see Box 13.20).
An increased ACR in a person with type 1 diabetes is almost always
due to diabetic kidney disease, but up to 15% of type 2 patients with
microalbuminuria have atypical appearances on renal biopsy. The pres-
ence of retinopathy makes diabetic glomerulosclerosis much more likely.
Nephrosclerosis and tubulointerstitial changes are the most commonly
seen non-diabetic changes.
Rapidly developing nephrotic-range proteinuria, an accelerated loss of
GFR (>5mL/min/year), the presence of features of other systemic disease
(such as connective tissue disorders or myeloma), or accelerated hyper-
tension should prompt investigation, as these features may suggest alter-
native, potentially treatable conditions. An increase in serum creatinine
of >30% after initiation of ACE inhibitor therapy suggests possible renal
artery stenosis.
Pathology
The earliest pathological feature in type 1 patients is kidney enlargement,
mostly due to tubular hypertrophy and hyperplasia in response to glyco-
suria. These changes are not completely reversible with glycaemic correc-
tion in man, and their link to later nephropathy is uncertain. GFR is also
increased in newly diagnosed patients (termed hyperfiltration), but this
usually returns to normal with glycaemic correction.
Within 5 years of type 1 diabetes, small, but significant, increases in
glomerular capillary basement membrane (GBM) thickness are seen due
to an accumulation of matrix material, and recent studies have linked this
to hyperfiltration. As nephropathy progresses, GBM width continues to
increase, and matrix accumulation occurs in the glomerular mesangium
(diffuse glomerulosclerosis). In advanced nephropathy, these accumula-
tions can form large acellular (Kimmelstiel–Wilson) nodules (nodular glo-
merulosclerosis). Ultimately, the glomerular capillaries are obliterated by
matrix material and become sclerosed and non-functioning. The increase
in GBM width leads to increased passage of albumin into the filtrate. At
the same time, there is a detachment and loss of podocytes on the epi-
thelial side of the GBM, reducing the integrity of the filtration barrier to
circulating proteins, thus leading to increasing proteinuria. These changes
are also seen in type 2 diabetes, although this has been less well studied,
and pathological appearances are often confounded by coexisting hyper-
tension and ischaemia.
Tubulointerstitial changes are also seen, particularly in advanced
nephropathy and in type 2 diabetes, and are due to a combination of
MAKING THE DIAGNOSIS OF DIABETIC RENAL DISEASE 785
Box 13.20 Causes of a false positive test for albuminuria

• Vigorous exercise.
• Urinary tract infection.
• Presence of blood, e.g. menses.
• Concentrated urine (less likely using ACR).
Causes of a false negative test for albuminuria
• Dilute urine (less likely using ACR).
nephron loss secondary to global glomerulosclerosis and direct disease,

perhaps secondary to increasing proteinuria. The combination of glomeru-
lar capillary loss and tubulointerstitial disease results in a progressive loss
of GFR toward ESRD.
Pathogenesis
Hyperglycaemia
Experimental studies suggest that an interaction between metabolic and
haemodynamic changes secondary to hyperglycaemia are the drivers for
nephropathy. Hyperglycaemia results in glycation of structural proteins
(such as collagen), making them less easy to metabolize and altering their
function. Increased levels of circulating and tissue advanced glycation
end-products (AGEs) have been linked to microvascular and macrovas-
cular complications.
Hyperglycaemia also induces the polyol (sorbitol) and hexosamine path-
ways and also results in the activation of protein kinase C which increases
flux through glycolysis. In experimental studies, these changes can cause
increased oxidative stress, increased thrombosis, and alterations in blood
flow which can result in microvascular damage.
In human diabetes, epidemiological studies have shown that both dura-
tion and severity of hyperglycaemia are strong determinants of nephropa-
thy risk. Moreover, cross-sectional studies have largely supported a role
for these mechanisms.
Haemodynamic alterations
The raised GFR in people with newly diagnosed type 1 (and to a lesser
extent type 2) diabetes has been shown in experimental studies to be
due to dilatation of the afferent glomerular arteriole. This leads to an
increase in glomerular capillary pressure which drives increased filtra-
tion (hyperfiltration). The increased pressure results in mechanical
stress in the GBM which, in turn, is thought to stimulate matrix pro-
duction and thickening via production of pro-fibrotic cytokines, such as
transforming growth factor-B (TGF-B). Angiotensin II is thought to be a
key mediator of these changes. Hyperfiltration has been associated with
later nephropathy development in type 1 diabetes, but the link was no
longer significant when corrected for hyperglycaemia. Its role in type 2
is much less certain.
Systemic hypertension is known to accelerate nephropathy develop-
ment and loss of GFR, probably through similar mechanisms and mediators.
Genetic predisposition and ethnicity

Studies in families with multiple siblings with type 1 diabetes have shown
concordance for nephropathy development, but it is not possible to com-
pletely exclude confounding factors. Over 20 different genetic polymor-
phisms have been linked to nephropathy; those linked to the ACE gene
appear to be the strongest. No major gene effect has yet been identified.
Nephropathy rates are much higher in certain ethnic subgroups, nota-
bly the Pima and other Native American communities, Pacific Islanders,
Australian Aborigines, and non-Ashkenazi Jews. Rates are also higher in
those from Afro-Caribbean and Asian populations, compared to White
Europid age- and duration-matched cohorts in the UK. The reasons are
unclear but may be related to greater insulin resistance in the Asian
population.
Smoking and other factors
A consistent link between cigarette smoking and nephropathy has been
known for some time, but an aetiological mechanism is not yet known.
Dietary protein (particularly animal) intake has also been linked to
nephropathy in some epidemiological studies.
Natural history
This can be best described in terms of changes to the main clinical features
of nephropathy—GFR, albuminuria, blood pressure, and cardiovascular
disease.
GFR
The hyperglycaemia-driven GFR increases in early diabetes mostly resolve
with glycaemic correction. Thereafter, GFR remains stable until other
features of nephropathy are present, notably albuminuria and hyperten-
sion. Historically, GFR declined at a rate of 10mL/min/year once patients
developed overt nephropathy, but this rate is now 2–4mL/min/year with
effective blood pressure control. Rates of decline greater than this should
prompt clinical review. The MDRD GFR equation (estimates GFR based
on creatinine, age, sex and race) www.renal.org/egfrcalc is not very pre-
cise at GFR levels >90mL/min/1.73m2, so it is hard to detect changes in
early diabetes prior to the development of albuminuria.
Older people with type 2 diabetes may have CKD due to other
non-diabetic causes, such as hypertension or renovascular disease. They
often have a more benign course and stable renal function for many years.
Albuminuria
The development of albuminuria is usually the first clinical sign of nephrop-
athy and is associated with a gradual loss of GFR. The rate of increase of
albuminuria is heavily influenced by systemic blood pressure and dietary
protein but is around 2% per year. Albuminuria fluctuates greatly on a daily
basis as a result of glycaemic variation, diet and exercise, and antihyperten-
sive therapy. Around 30% of patients with microalbuminuria can regress
to normal; some of these will revert, but others will be normoalbuminu-
ric for many years. It is unclear whether these patients with intermittent
albuminuria will have progressive nephropathy. Once albuminuria exceeds
an ACR of 10mg/mmol (7100mg/g), it is usually persistent and represents
established nephropathy.
MAKING THE DIAGNOSIS OF DIABETIC RENAL DISEASE 787
Blood pressure
Blood pressure is normal, or even low, at the onset of type 1 diabetes.
It increases with albuminuria such that over 50% of patients are on anti-
hypertensive therapy or have values >130/80mmHg by the time they
develop persistent microalbuminuria. In contrast, over 35% of newly diag-
nosed patients with type 2 diabetes in the UKPDS had a blood pressure
>160/90mmHg or were on treatment. More than 80% of patients with
overt nephropathy will be on antihypertensive therapy, irrespective of
their type of diabetes. Thus, blood pressure increases are a concomitant
factor of nephropathy in type 1 patients but may be more of a causa-
tive factor in type 2 diabetes. What is certain is that high blood pressure
drives nephropathy progression (increases in albuminuria and rate of loss
of GFR), and its management is critical in the prevention of ESRD.
Cardiovascular disease
Patients with nephropathy have a greatly increased risk of cardiovascular
disease partly because of increases in blood pressure, but also partly due
to increased insulin resistance and serum lipid abnormalities. Mortality
is increased at least 2-fold for patients with microalbuminuria. Recent
data in people with type 1 diabetes from Finland suggest that mortality
is increased only in those with increased albuminuria. The UKPDS cohort
had an annual mortality of 2–4% for those with microalbuminuria, but this
increased to nearly 20% in those with a serum creatinine >175micromol/L
and/or renal replacement therapy (RRT). This explains why many patients
fail to survive to RRT. Intensive management of modifiable cardiovascular
risk factors has been shown to improve both morbidity and survival in
people with type 2 diabetes and microalbuminuria, and the SHARP trial
has established the effectiveness of lipid-lowering therapy in preventing
cardiovascular events in patients with CKD stage 3 or worse.
Treatment for diabetic renal disease

Treatments can usefully be considered under the headings of glycaemia
(and other metabolic corrections), blood pressure, cardiovascular risk fac-
tors, and diet.
Glycaemia
Both the DCCT/EDIC and the UKPDS studies confirmed that good gly-
caemic control can prevent the development of microalbuminuria. There
are conflicting data on the role of glycaemic control in the progression of
established nephropathy, although, as a rule, patients with worse control
do less well and have a greater incidence of concomitant complications,
such as retinopathy and neuropathy.
As GFR declines, insulin clearance by the kidneys is reduced, so doses
may need adjustment. In addition, as most patients with overt nephropa-
thy will also have a long duration of diabetes, they will be at greater risk
of hypoglycaemic unawareness. These two factors make hypoglycaemia a
real risk, so target HbA1c may need to be higher than for those without
nephropathy.
A small study of pancreas transplantation in type 1 patients with estab-
lished nephropathy and glomerulosclerosis showed that prolonged nor-
moglycaemia for >10 years resulted in a reversal of matrix accumulation
and GBM thickening. This demonstrates that the pathology may take as
long to reverse as it does to develop and that nothing short of normogly-
caemia may suffice for the resolution of established disease.
Blood pressure
There are no data supporting a role of antihypertensive therapies (specifi-
cally agents which block the renin–angiotensin system RAS) in the pre-
vention of nephropathy in normoalbuminuric, normotensive people with
type 1 or type 2 diabetes. Once blood pressure rises above 140/90mmHg
in type 1 and 160/90mmHg in type 2, there are trial data showing that
RAS-blocking agents can prevent the development of microalbuminuria
and overt nephropathy. These studies have not been of a sufficient dura-
tion to demonstrate any impact on ESRD rates. Once overt nephropathy
has developed, ACE inhibitors in type 1 and angiotensin II receptor block-
ers (ARBs) in type 2 diabetes have been shown to reduce the numbers
developing ESRD, more so than other antihypertensive therapies. These
drugs remain the cornerstone of treatment of blood pressure in nephrop-
athy. Diabetes and renal guidelines suggest a target blood pressure of
<130/80mmHg in patients with nephropathy.
Cardiovascular risk factors
The high rates of CV disease and the unfavourable lipid profiles seen
in people with nephropathy make these attractive targets. In the Heart
Protection Study (mainly type 2 patients), there was a reduction in CV
events by around 25%, but few had nephropathy. Recently, the SHARP
TREATMENT FOR DIABETIC RENAL DISEASE 789
trial reported a significant reduction in risk for CV events of 17% in over

6,000 people with pre-dialysis CKD randomized to simvastatin/ezetimibe
vs placebo. Lipid-lowering to a target LDL cholesterol of <2mmol/L should
be undertaken in all people with diabetes and CKD. No consistent effect of
lipid-lowering has been shown on the rate of loss of GFR or albuminuria.
Smoking rates are higher in those with nephropathy, compared to those
without, and there are some data that cessation can help preserve renal
function as well as CV risk.
Multifactorial intervention (including glycaemic control, ACE inhibitors,
aspirin, lipid-lowering, smoking cessation, weight reduction, exercise, and
antioxidant therapy—the Steno 2 trial) has been shown to reduce CV
morbidity and mortality in 80 people with type 2 diabetes and micro-
albuminuria. Thus, a broad clinical approach to management should be
undertaken in all with diabetes and CKD.
Diet
High dietary protein has been shown to damage the kidney in experimen-
tal diabetes. In type 1 diabetes, protein restriction can reduce rate of loss
of GFR, albuminuria, and mortality in people with established nephropa-
thy. The data are less strong in type 2 diabetes. A dietary protein content
<0.8g/kg is suggested, but patients find long-term adherence to be difficult.
As with all patients with CKD, people with diabetes may develop anae-
mia, hyperphosphataemia, vitamin D deficiency, and hyperkalaemia, par-
ticularly in stage 4. All of these may require expert dietary and nephrology
input and should prompt referral.
When to refer to nephrology
Current CKD guidance from NICE suggests referral of all patients with
CKD stage 4 or worse (GFR <30mL/min/1.73m2). All those with a rate
of progression that suggests that they will develop ESRD within 2 years
should be referred for preparation for RRT, as there is good evidence
that survival is better with careful planning. Those with stable CKD, no
significant albuminuria, and well-controlled blood pressure and glycaemia
may not need referral.
Complications of CKD, such as anaemia and secondary hyperparathy-
roidism, or unusual features suggestive of non-diabetic CKD, such as
nephrotic-range proteinuria, the presence of signs of non-diabetic sys-
temic disease, or a rapidly declining GFR, should also prompt referral.
Survival in those requiring RRT is best for those who receive a renal
transplant although remains less good than for those with non-diabetic
renal disease. Simultaneous pancreas transplantation has not been shown
to improve survival, although there are some data suggesting an improved
quality of life in those achieving normoglycaemia. See Box 13.21.
Box 13.21 Criteria for referral for specialist review (take

into account patient’s wishes, serious comorbidities,
and age)
• CKD stage 4 or 5 (eGFR <30mL/min/1.73m2).
• Rapid decline of GFR (eGFR decline >5mL/min/1.73m2/year or
>10mL/min/1.73m2/5 years).
• Microscopic or macroscopic haematuria and/or active urinary
sediment.
• Signs of other systemic disease, such as SLE or systemic sclerosis.
• Blood pressure outside target despite four or more drugs at
optimum titration.
• Heavy proteinuria (>1g/day or protein:creatinine ratio >100mg/
mmol or ACR >70mg/mmol).
• Family history of genetic causes of kidney disease (e.g. polycystic
kidneys).
• Suspected renal artery stenosis.
For further details, see M http://www.renal.org.
Further reading
Bilous R (2008). Microvascular disease: what does the UKPDS tell us about diabetic nephropathy?
Diabet Med Suppl 2, 25–9.
Bilous R, Chaturvedi N, Sjolie AK, et al. (2009). Effect of candesartan on microalbuminuria and
albumin excretion rate in diabetes: 3 randomised trials. Ann Intern Med 151, 11–20.
DCCT/EDIC Research Group (2003). Sustained effect of intensive treatment of type 1 diabetes
mellitus on development and progression of diabetic nephropathy. JAMA 290, 2159–67.
De Boer I, Rue T C, Cleary PA, et al. (2011). Long-term outcomes of patients with type 1 diabetes
mellitus and microalbuminuria. Arch Int Med 171, 412–20.
Forbes JM, Coughlan MT, Cooper ME (2008). Oxidative stress as a major culprit in kidney disease
in diabetes. Diabetes 57, 1446–54.
Gaede P, Lund-Andersen H, Parving H-H, Pedersen O (2008). Effect of multifactorial interventions
on mortality in type 2 diabetes. N Engl J Med 358, 580–91.
Joint Specialty Committee on Renal Medicine of the Royal College of Physicians and the Renal
Association, and the Royal College of General Practitioners (2006). Chronic Kidney Disease
in Adults: UK Guidelines for identification, management and referral. London: Royal College
of Physicians.
KDOQI (2007). KDOQI Clinical Practice Guidelines in Clinical Practice Recommendations for
Diabetes and Chronic Kidney Disease. Am J Kidney Dis 49(Suppl 2), S1–180.
Levey AS, Coresh J (2012). Chronic kidney disease. Lancet 379, 165–80.
National Collaborating Centre for Chronic Conditions (2008). Clinical guidance 73. Chronic Kidney
Disease. Early identification and management of chronic kidney disease in adults in primary and
secondary care. Available at: M http://guidance.nice.org.uk/CG73/QuickRefGuide/pdf/English.
Prigent A (2008). Monitoring renal function and limitation of renal function tests. Semin Nucl Med
38, 32–46.
TREATMENT FOR DIABETIC RENAL DISEASE 791
Diabetic neuropathy
Definition
Involvement of cranial, peripheral, and autonomic nerves may be found in
patients with diabetes and termed diabetic neuropathy; this usually sug-
gests a diffuse, predominantly sensory peripheral neuropathy. The effects
on nerve function can be both acute or chronic as well as being transient
or permanent. The commonest clinical consequences of neuropathy are:
• Altered sensation (both pain and i sensitivity to normal sensation).
• Neuropathic ulcers, usually on the feet.
• Erectile dysfunction (with autonomic neuropathy).
• Charcot arthropathy.
See Box 13.22 for classification.
Pathology
Diabetic neuropathy is one of the microvascular complications of diabetes.
Pathologically, distal axonal loss occurs with focal demyelination and
attempts at nerve regeneration. The vasa nervorum often shows base-
ment membrane thickening, endothelial cell changes, and some occlusion
of its lumen. This results in slowing of nerve conduction velocities or a
complete loss of nerve function. Both metabolic and vascular changes have
been implicated in its aetiology.
Pathogenesis
Hyperglycaemia is probably the major underlying cause of the histological
and functional changes, although vascular risk factors, such as hypertension
and hyperlipidaemia, may also have a role. Several possible mechanisms
have been suggested:
• Overloading of the normal pathways for glucose metabolism, resulting
in i use of the polyol pathway which leads to i levels of sorbitol
and fructose and d levels of myoinositol and glutathione. This may
result in more free radical damage and also lowers nitric oxide levels,
thus altering nerve blood flow. Experimental models, using aldose
reductase inhibitors which can improve aspects of diabetic neuropathy,
support this theory.
• Accumulation of AGE (via non-enzymatic glycation) may contribute.
• In the more acute neuropathies, acute ischaemia of the nerves due to
vascular abnormalities has been suggested as the cause. The underlying
reason for this is still unclear. Insulin-induced ‘neuritis’ may occur when
insulin therapy is started and blood glucose levels fall.
• Other potential aetiological factors include changes in local growth
factor production and oxidative stress.
Further work is needed to clarify the exact role of each of the above
mechanisms. In the meantime, studies showing improvements in neuropa-
thy associated with good diabetic control strengthen the argument for the
role of hyperglycaemia and offer us a treatment option.
DIABETIC NEUROPATHY 793
Box 13.22 Classification of diabetic neuropathies

• Sensory neuropathy:
• Acute.
• Chronic.
• Autonomic neuropathy:
• Gastroparesis.
• Postural hypotension.
• Mononeuropathy:
• Entrapment neuropathy.
• External pressure palsies.
• Spontaneous mononeuropathy.
• Proximal motor neuropathy (diabetic amyotrophy).
Peripheral sensorimotor neuropathy

(See Box 13.23.)
Although hyperglycaemia can alter nerve function and often gives some
sensory symptoms at diagnosis, correcting the hyperglycaemia can often
resolve these. Chronic sensorimotor neuropathy is the most common fea-
ture of peripheral nerve involvement seen in patients with diabetes. The
exact prevalence of diabetic neuropathy varies in most studies because
of the different definitions and examination techniques used. For exam-
ple, sensitive nerve conduction studies can show up to 80% of patients
have abnormal results. In more normal practice, however, around 30% of
patients have either symptomatic neuropathy or abnormalities on exami-
nation which are clinically significant. But at least 50% of these patients are
asymptomatic. Prevalence increases with increasing duration of diabetes,
so although 7–8% of type 2 patients have abnormalities at diagnosis, 50%
can be expected to have them 25 years later.
Box 13.23 Features of peripheral sensorimotor

neuropathy
• Usually insidious onset with numbness or paraesthesiae, often found
on screening rather than as a presenting problem.
• Starts in the toes and on the soles of the feet, then spreads up to
midshin level in a symmetrical fashion. Less often, in more severe
cases, it also involves the fingers and hands.
• Affects all sensory modalities and results in reduced vibration
perception thresholds, pinprick, fine touch, and temperature
sensations.
• d vibration sensation and absent ankle reflexes are often the first
features found. Another risk factor for ulceration is the inability to
feel a 10g monofilament.
• Less often, the skin is tender/sensitive to touch (allodynia) or frank
pain can occur.
• Painful neuropathy affects up to 20% of a general clinic population.
This pain may be sharp, stabbing, or burning in nature and at times
very severe. This is also associated with sleep disturbance, mood
disorders, and loss of quality of life.
• There may also be some wasting of the intrinsic muscles of the foot
with clawing of the toes.
MONONEUROPATHIES 795
Mononeuropathies
Peripheral mononeuropathies and cranial mononeuropathies are not
uncommon. These may be spontaneous or may be due to entrapment
or external pressure. Of the peripheral mononeuropathies, median nerve
involvement and carpal tunnel syndrome may be found in up to 10% of
patients and require nerve conduction studies and then surgical decom-
pression. Entrapment of the lateral cutaneous nerve of the thigh is also
seen more commonly in those with diabetes, giving pain over the lateral
aspect of the thigh. Common peroneal nerve involvement, causing foot
drop and tarsal tunnel syndrome, is also recognized but less common.
Cranial mononeuropathies usually occur suddenly and have a good
prognosis. Palsies of cranial nerves III and VI are most commonly seen
(but still infrequent). In the IIIrd nerve palsy, sparing of the pupillary
responses is usual. Spontaneous recovery is slow over several months,
and no treatment, apart from symptomatic help such as an eye patch, is
needed. Unlike entrapment neuropathies where decompression may help,
no effective treatment is currently available in most cases of spontaneous
mononeuropathy.
Proximal motor neuropathy

(diabetic amyotrophy)
This is an uncommon, but disturbing, condition to have, mostly affecting
♂ in their 50s with type 2 diabetes. It presents with severe pain and par-
aesthesiae in the upper legs and is felt as a deep aching pain which may be
burning in nature and can keep patients awake at night and cause anorexia,
resulting in marked cachexia. This, with proximal muscle weakness and
wasting of the quadriceps, in particular, can be very debilitating. The lum-
bar sacral plexus lower motor neurons are affected, and improvement is
usually spontaneous over 3–4 months. Before making this diagnosis, how-
ever, consider other causes, such as malignancies and lumbar disc disease.
An MRI scan of the lumbar sacral spine is advisable.
Oral antidiabetic agents may play a part in the aetiology of this problem,
and conversion to insulin therapy is advised, although the anorexia expe-
rienced when the pain is severe can make this difficult. Although recovery
happens over many months, only 50% recover fully, but no other treat-
ment is currently known to improve on this.
PROXIMAL MOTOR NEUROPATHY (DIABETIC AMYOTROPHY) 797
Foot examination for diabetic

neuropathy
• Mandatory at diagnosis and at least yearly in all asymptomatic patients.
• Test vibration, fine touch (with a 10g monofilament), and reflexes as a
minimum. Using a neurothesiometer or biosthesiometer gives a more
quantitative measure of vibration than a 128Hz tuning fork. Inability
to feel the vibrating head at >25V in the toes is associated with a
significant risk of neuropathic ulceration and should be considered a
sign of ‘at-risk’ feet.
Differential diagnoses of peripheral neuropathy
• Uraemia.
• Vitamin B12 deficiency.
• Infections (e.g. HIV and leprosy).
• Toxins (e.g. alcohol, lead, mercury).
• Drugs (chemotherapeutic agents).
• Malignancy.
Treatment
(See Box 13.24.)
For all patients
Review by a podiatrist and, if indicated, an orthotist to give education on
foot care and suitable footwear. If followed by regular podiatry review,
this can help to prevent some problems developing.
Asymptomatic patients
Apart from good glycaemic control, no drugs are yet available.
Painful diabetic neuropathy (painful DN)
Pharmacological treatment of painful DN is not entirely satisfactory, as
currently available drugs are often ineffective and complicated by side
effects.
• Tricyclic compounds (TCAs) have been used as first-line agents for
many years, but many patients fail to respond to them and side effects
are frequent. Amitriptyline or imipramine 10mg taken at night may be
started. Depending on side effects, the dose can be gradually increased
up to 75mg/day.
• Duloxetine, a selective serotonin noradrenaline reuptake inhibitor
(SNRI), is a first-line treatment for painful DN. It relieves pain by
increasing synaptic availability of 5-HT and noradrenaline in the
descending pathways that inhibit pain impulses. Duloxetine for painful
DN has been investigated in three identical trials, and pooled data
from these shows that 60–120mg/day doses are effective in relieving
symptoms, starting within a week and lasting the full treatment
period of 12 weeks. The main side effect is nausea, but this is often
self-limiting. It is advisable to start at 30mg/day taken with food for a
few days.
• The anticonvulsant gabapentin, gradually titrated from 100mg bd to
1,800mg/day, is also effective. Doses up to 3,600mg/day can be used.
FOOT EXAMINATION FOR DIABETIC NEUROPATHY 799
Box 13.24 Pharmacological treatment of painful DN

Only two (duloxetine and pregabalin) have been formally approved by
the EMA and FDA for the treatment of painful DN.
• Tricyclic antidepressants (TCAs):
• Amitriptyline 25–75mg/day.
• Imipramine 25–75mg/day.
• Serotonin noradrenaline reuptake inhibitors (SNRIs):
• Duloxetine 60–120mg/day.
• Anticonvulsants:
• Gabapentin 300–3,600mg/day.
• Pregabalin 300–600mg/day.
• Opiates:
• Tramadol 200–400mg/day.
• Oxycodone 20–80mg/day.
• Morphine sulphate SR 20–80mg/day.
• Capsaicin cream (0.075%)—applied sparingly 3–4 times per day.
• IV lidocaine (for refractory painful neuropathy)—5mg/kg, given IV
over 1h with ECG monitoring.
• Pregabalin has been shown in seven clinical trials to be effective in the

management of painful DN. Starting dose is 75mg bd, increased to a
150mg bd maintainance dose, with a maximum dose of 600mg/day.
• Other drugs include other anticonvulsants, in particular carbamazepine,
opiates, such as tramadol and oxycodone, and, for refractory cases,
intravenous lidocaine. The antioxidant alpha-lipoic acid is also an
effective treatment and is widely used in Germany, Eastern Europe,
and China. Topical capsaicin, a substance P depleter, is also used; local
discomfort at the site of application initially means many patients do
not persevere with treatment to see a favourable outcome.
Despite these treatments, however, many sufferers have suboptimal pain
relief. Non-pharmacological treatments, such as acupuncture, TENS, and,
for severe resistant cases, electrical spinal cord stimulation, may be used.
A recent consensus panel evaluated all published clinical trial data and
recommended that first-line therapies for painful DN to be a TCA, the
SNRI duloxetine or the anticonvulsants pregabalin or gabapentin, taking
into account patient comorbidities and cost.
General treatments
Specific treatments for each form of neuropathy have already been dis-
cussed, but there is some evidence for more general therapies.
• Poor diabetic control appears to be associated with worsening
neuropathy, and improving glycaemic control is advocated in any
patient, especially if neuropathy is present.
• Cardiovascular risk factors, such as hypertension, smoking, obesity, and
hyperlipidaemia (especially hypertryglyceridaemia), are risk factors for
peripheral neuropathy. Clinical trials are now required to test whether
CV risk reduction improves neuropathy outcomes.
Autonomic neuropathy
The commonest effect of autonomic neuropathy is erectile dysfunction
which affects 40% of ♂ with diabetes (although this is multifactorial).
The recent interest in sildenafil has highlighted this. Only a small number
develop severe GI, cardiac, or bladder dysfunction. Abnormal autonomic
function tests can be expected in 20–40% of a general diabetic clinic popu-
lation. The i problems during surgery from cardiac involvement should
be remembered.
Clinical features
• Postural hypotension—giving dizziness and syncope in up to 12%.
• Resting tachycardia or fixed heart rate/loss of sinus arrhythmia—in up
to 20%.
• Gustatory sweating—sweating after tasting food.
• Delayed gastric emptying, nausea/vomiting, abdominal fullness.
• Constipation/diarrhoea.
• Urinary retention/overflow incontinence.
• Anhidrosis—absent sweating on the feet is especially problematic, as it
increases the risk of ulceration.
• Abnormal pupillary reflexes.
Assessment
If AN is suspected, check:
• Lying and standing BP (measure systolic BP after 2min standing; normal
is <10mmHg drop; >30mmHg is abnormal).
• Pupillary responses to light.
Other less commonly performed tests to consider if the diagnosis is
uncertain or in high-risk patients include:
• Loss of sinus arrhythmia. Measure inspiratory and expiratory heart rates
after 5s of each (<10 beats/min difference is abnormal; >15 is normal).
• Loss of heart rate response to Valsalva manoeuvre. Look at the ratio
of the shortest R–R interval during forced expiration against a
closed glottis, compared to the longest R–R interval after it (<1.2 is
abnormal).
• BP response to sustained hand grip. Diastolic BP prior to the test is
compared to diastolic BP after 5min of sustaining a grip equivalent
to 30% of maximal grip. A diastolic BP rise >16mmHg is normal;
<10mmHg is abnormal. A rolled-up BP cuff to achieve the required
hand grip may be used.
• For gastroparesis, consider a radioisotope test meal to look for
delayed gastric emptying. Blood glucose should be <10mmol/L, as
hyperglycaemia exacerbates delayed gastric emptying.
Treatment
This is based on the specific symptom and is usually symptomatic only.
In all patients, improvement in diabetic control is advocated in case any
of it is reversible, but this is not usually very helpful or effective.
AUTONOMIC NEUROPATHY 801
Postural hypotension
Stopping drugs that may result in, or exacerbate, postural hypotension,
including diuretics, B-blockers, anti-anginal agents, tricyclic agents, etc.
• Advising patients to get up from the sitting or lying position slowly and
crossing the legs.
• Increasing sodium intake up to 10g (185mmol) per day and fluid intake
to 2.0–2.5L per day (caution in elderly patients with heart failure).
• Raising the head of the bed by 10–20°, as this stimulates the renin–
angiotensin–aldosterone system and results in a decrease in the
nocturnal diuresis.
• Drinking approximately 500mL of water, which stimulates a significant
pressor response and improves symptoms of postural hypotension.
• Using custom-fitted elastic stockings extending to the waist.
• Pharmacological treatment with fludrocortisone, starting at
100 micrograms per day, whilst carefully monitoring for supine
hypertension, ankle oedema, and hypokalaemia. Potassium
supplementation may be required when higher doses are used, and it
is important to monitor urea and electrolytes.
• In severe cases, the following drugs: alpha-1 adrenal receptor agonist
midodrine (2.5–10.0mg tds), sympathomimetic ephedrine (25mg tds),
and occasionally octreotide and erythropoietin (25–75U per kg three
times a week until a haematocrit level approaching normal is achieved),
may be tried.
Erectile dysfunction
Libido is not normally affected and pain is also unusual, so look for hypog-
onadism and Peyronie’s if they are present. Autonomic neuropathy is the
likely cause, but many drugs, especially thiazides and B-blockers, can also
cause it, as can alcohol, tobacco, cannabis, and stress. These should be
assessed by direct questioning. Examination should include:
• Genitalia and s sexual characteristics.
• Peripheral pulses—as vascular insufficiency may play a part.
• Lower limb reflexes and vibration thresholds—to confirm that
neuropathy is present.
Biochemical screening should at least include:
• Prolactin.
• Testosterone.
• Gonadotrophins (LH/FSH).
Exacerbating factors, such as alcohol and antihypertensive drugs, should
be modified. The main therapies are:
• Oral therapies include: sildenafil (start at 25–50mg, i to 100mg if
needed, and taken 1h prior to sexual intercourse), vardenafil (start
at 10mg, i to 20mg if needed, and taken 25–60min prior to sexual
intercourse), tadalafil (start at 10mg, i to 20mg if needed, and taken
30min to 12h prior to sexual intercourse).
• Intraurethral alprostadil (start at 125 micrograms, i to 250 or 500
micrograms if needed).
• Intracavernosal alprostadil (trial dose is 2.5 micrograms; treatment is
5–40 micrograms).
• Vacuum devices.
None of these is ideal. Sildenafil, although an oral therapy, is effective in

only 60% of those with diabetes and is contraindicated with severe heart
disease and those on nitrates, which rules many out.
Gastroparesis
Management of diabetic gastroparesis includes:
• Optimization of glycaemic control, as hyperglycaemia can delay gastric
emptying. Insulin pump therapy is commonly used.
• Stopping drugs that can delay gastric emptying, such as calcium
channel blockers, GLP-1 analogues, and anticholinergic agents, such as
antidepressants, etc.
• Antiemetics (metoclopramide and domperidone).
• Erythromycin which may enhance activity of the gut peptide motilin.
• Gastric electrical stimulation (‘pacing’) is a treatment option in patients
with drug-refractory gastroparesis and can increase the quality of life
and decrease hospital admissions by alleviating nausea and vomiting.
Severe gastroparesis, causing recurrent vomiting, is associated with dehy-
dration, swings in blood sugar, and weight loss and is, therefore, an indica-
tion for hospital admission. The patient should be adequately hydrated
with intravenous fluids, and blood sugar should be stabilized by intrave-
nous insulin; antiemetics could be given intravenously, and if the course
of the gastroparesis is prolonged, total parenteral nutrition or feeding
through a gastrostomy tube may be required.
Autonomic diarrhoea
The patient may present with diarrhoea which tends to be worse at night,
or alternatively some may present with constipation. Both the diarrhoea
and constipation respond to conventional treatment.
• Diarrhoea associated with bacterial overgrowth may respond to
treatment with a broad-spectrum antibiotic, such as erythromycin
250mg qds for 7 days or tetracycline 250mg bd for 7 days.
• Bile acid malabsorption may be treated with colestyramine.
• The antidiarrhoeal synthetic opioids (e.g. loperamide 2mg qds) and
codeine phosphate (30mg qds) can improve symptoms by decreasing
peristalsis and increasing rectal sphincter tone.
• Refractory diarrhoea may be treated with the A2-adrenergic
receptor agonist clonidine and the somatostatin analogue octreotide.
Octreotide suppresses gastrointestinal motility and inhibits the
release of motilin, serotonin, and gastrin but may result in recurrent
hypoglycaemia due to impaired counter-regulation.
Neuropathic bladder
• Bladder dysfunction is a rare complication of autonomic neuropathy,
involving the sacral nerves. The patient presents with hesitancy of
micturition, increased frequency of micturition, and, in serious cases,
with urinary retention associated with overflow incontinence.
• Patients are prone to urinary tract infections. Ultrasound scan of the
urinary tract, intravenous urography, and urodynamic studies may be
required.
AUTONOMIC NEUROPATHY 803
• Treatment manoeuvres include mechanical methods of bladder

emptying by applying suprapubic pressure or the use of intermittent
self-catheterization.
• Anti-cholinesterase drugs, such as neostigmine or pyridostigmine, may
be useful.
• Long-term indwelling catheterization may be required in some, but this
unfortunately predisposes the patient to urinary tract infections and
long-term antibiotic prophylaxis may be required.
Anhidrosis
Dry feet can cause cracks in the skin and act as a site for infection. Emollient
creams may help prevent this.
Gustatory sweating
Increased sweating, usually affecting the face and often brought about by
eating (gustatory sweating), can be very embarrassing to patients and dif-
ficult to treat.
• Oral anticholinergic agents, including oxybutynin, propantheline, and
glycopyrronium bromide, may improve symptoms; however, adverse
reactions, including dry mouth, constipation, potential worsening of
gastroparesis, and confusion, limit their use.
• Clonidine has been used with some success but is also limited by side
effects, including hypotension and dry mouth.
• Systemic side effects have led to the investigation of non-systemic
approaches. Topical glycopyrronium bromide, a quaternary ammonium
antimuscarinic compound, has been shown to significantly decrease
the incidence, severity, and frequency of sweating with eating and is
tolerated well.
• Botulinum toxin has been used for gustatory sweating, though, in most
literature, it is limited to use in unilateral, surgically related cases.
Further reading
Tesfaye S, Boulton AJ (eds) (2009). Diabetic neuropathy. Oxford: Oxford University Press.
Tesfaye S, et al. on behalf of the Toronto Expert Panel on Diabetic Neuropathy (2011). Painful
Diabetic Peripheral Neuropathy: Consensus Recommendations on Diagnosis, Assessment and
Management. Diabetes Metab Res Rev [Epub ahead of print].
Vinik AI, Ziegler D (2007). Diabetic cardiovascular autonomic neuropathy. Circulation 115, 387–97.
The diabetic foot

Diabetic foot problems are a leading cause of morbidity. Box 13.25 illus-
trates the burden of diabetic foot ulceration in the UK.
See Box 13.26 for clinical features and Box 13.27 for Wagner’s classifica-
tion of diabetic foot lesions.
Risk factors for foot ulcer development
Several factors predispose to ulcer formation, and awareness of these
should highlight ‘at-risk’ patients for education and other preventive strat-
egies. Ulcers can occur anywhere on the foot, but the tips of claw/ham-
mer toes and over the metatarsal heads are the most frequent sites. Risk
factors include:
• Peripheral neuropathy (seen in up to 80% of diabetic patients with foot
ulcers) reduces awareness of pain and trauma caused by footwear
and foreign bodies in shoes. Look for reduced sensation on 10g
monofilament and reduced vibration perception thresholds (e.g.
reduced sensation to a 128Hz tuning fork for <10s or >25V with a
biosthesiometer).
• Autonomic neuropathy, leading to anhidrosis, can dry out the skin and
cause it to crack, so allowing a portal of entry for infection. These feet
are often warm and dry, with distended veins.
• Motor neuropathy can result in altered foot muscle tone, wasting of
small muscles, raising of the medial longitudinal arch, and clawing of
the toes. This puts more pressure through the metatarsal heads and
heels, predisposing to callus and ulcer formation. Electrophysiology can
help examine this but is not in widespread routine use.
• Peripheral vascular disease (seen in up to 10% of patients) and
microvascular circulatory disease lead to local ischaemia, i the potential
for ulcer formation and delaying wound healing. Always examine
peripheral pulses, and consider Doppler studies if abnormal. An
ankle:brachial artery ratio of >1.1 suggests arterial disease (the ratio of
the BP in the ankle and the arm measured while at rest).
• Duration of diabetes is an independent risk factor, as is i age.
Remember type 2 diabetes may be present and undiagnosed for
some time.
• The presence of other microvascular complications, such as nephropathy
and retinopathy, is also a risk factor for foot ulcer development.
• Previous ulceration is an important risk factor, and anyone with previous
problems needs very careful monitoring/follow-up.
• Lack of diabetes monitoring and lack of previous examinations of the
feet are also recognized risk factors.
• Mechanical, chemical, or thermal trauma/injury is often the predisposing
factor, and any profession or pastime that increases the risk of these is
a risk factor.
THE DIABETIC FOOT 805
Box 13.25 Epidemiology of foot ulceration in the UK

Prevalence of foot ulceration 5–10%
Number of people with diabetes with foot ulcers 61,000
Proportion of people with diabetes undergoing lower 0.2%
limb amputation each year
Number of people with diabetes undergoing lower 6,000
limb amputation per year
Annual NHS expenditure on diabetes foot-related 7£650 million
care
Box 13.26 Clinical features of diabetic feet

Neuropathic feet Ischaemic feet
• Warm. • Cold/cool.
• Dry skin. • Atrophic/often hairless.
• Palpable foot pulses. • No palpable foot pulses
• No discomfort with ulcer. • More often tender/painful.
• Callus present. • Claudication/rest pain.
• Skin blanches on elevation and
reddens on dependency.
Box 13.27 Wagner’s classification of diabetic foot lesions

• Grade 0—high-risk foot, no ulcer present.
• Grade 1—superficial ulcer, not infected.
• Grade 2—deep ulcer, with or without cellulitis, but no abscess or
bone involvement.
• Grade 3—deep ulcer with bone involvement or abscess formation.
• Grade 4—localized gangrene (toe, forefoot, heel).
• Grade 5—gangrene of the whole foot.
Treatment of the diabetic foot

This is a multidisciplinary problem, requiring collaboration between dia-
betologists, diabetes nurse specialists, podiatrists, orthotists, vascular sur-
geons, plastic surgeons, and orthopaedic surgeons. Treatment is aimed at
several distinct areas, namely:
• At-risk feet with no current ulceration.
• Treating existing ulcers.
• Treating infected ulcers.
• Treating osteomyelitis.
• Treating vascular insufficiency.
The typical clinical features of diabetic feet are listed in Box 13.26.
At-risk feet with no current ulceration
When at-risk feet are identified in any patient with diabetes, standard
advice should be given, and this will need to be repeated/reinforced regu-
larly. This advice would usually include:
• General advice on nail care, hygiene, and care with footwear—often
best from the podiatrist.
• Reinforce the need for regular daily examination of the feet by the
patient or carer.
• Consider regular podiatry review as well as self-monitoring. Also
reinforce the need for urgent review if the patient discovers problems.
• Consider the need for modification of footwear or special footwear if
there are abnormalities with foot posture or problems with pressure
loading on certain parts of the foot. Padded socks can also reduce
trauma. Advise the patient to examine shoes before putting them
on, wear lace-ups or shoes with lots of room for the toes, and avoid
ill-fitting fashion shoes. In some people, protective toecaps can be
useful.
• Avoid walking barefoot.
At the moment, no other therapy is advocated in this group of patients,
but, as discussed in the neuropathy section, good diabetic control is
important and other agents may be useful in the future, such as aldose
reductase inhibitors, inhibitors of non-enzymatic glycation, and various
growth factors.
Existing ulcers
All ulcers should be considered deep/involving bone until proved otherwise.
Box 13.27 shows one classification of diabetic foot lesions.
Management
• Optimize diabetic control.
• Reduction of oedema is important to aid healing.
• Regular debridement of callus and dead tissue/skin is important for
both neuropathic and ischaemic ulcers. Debridement is usually best
with a scalpel and forceps, although chemical agents can occasionally
help. But, as these agents can also damage healthy tissue, use under
careful supervision. More recently, the use of sterile maggots has
TREATMENT OF THE DIABETIC FOOT 807
been shown to be effective. After debridement, apply dressings, but

change these regularly. Be careful that dressings do not impair a poor
circulation or cause further skin trauma or pressure effects.
• Infection control. Infection may be localized, but any evidence of deeper
infection or sinus formation raises the possibility of osteomyelitis.
Systemic symptoms of an infection may be minimal as may pain/
tenderness in the foot itself, so be suspicious of more severe infection
than you can see. The organisms may be ordinary skin commensals
given a port of entry, but send swabs for culture and think of
Staphylococcus aureus or streptococci as likely organisms.
• If a sinus is present, probe it, and, if down to bone, assume there is
osteomyelitis. Culture anything you get out. Plain radiographs may
show bone erosion or destruction with osteomyelitis; radioisotope
scans using technetium can show i uptake in both infection and
Charcot arthropathy. The use of MRI scanning can be useful to
differentiate in this situation.
• If infection is present, use antibiotics according to local
microbiology guidelines and culture results. Commonly: ‘triple
therapy’ with flucloxacillin (500mg qds), ampicillin/amoxicillin (500mg
tds), and metronidazole (200mg tds); or co-amoxiclav (amoxicillin/
clavulanic acid, 250/125mg tds) or ciprofloxacin (500–750mg bd) and
clindamycin (300–450mg bd). IV treatment initially if the infection is
severe, and, for the deeper infections, several months of therapy
may be needed. For osteomyelitis, again follow local guidelines, but
agents, such as ciprofloxacin or sodium fusidate which have better
bone penetration, can be used, again for several months. Linezolid
is also a useful therapy as a second- or third-line agent, but care
with hepatic and renal impairment, and the need to monitor for
potential thrombocytopenia, anaemia, or pancytopenia may limit
its use.
• In some patients, this approach fails to control osteomyelitis
adequately, and resection/amputation is required, so regular
surgical liaison is imperative.
• Reducing trauma and pressure relief in neuropathic ulcers. Padded
socks can reduce shear stress and trauma. Suitable shoes and insoles
can help to relieve pressure to allow healing to occur as long as
unnecessary walking is minimized. If this is not enough, a pneumatic
boot/Aircast boot or a total contact cast may be needed. These allow
the patient to be mobile but take the weight away from the ulcerated
area or foot and put through to the calf instead. The involvement of
both podiatrists and orthotists is essential.
• Revascularization. Always consider coexistent vascular disease. Vascular
bypass grafting/reconstruction or angioplasty can give excellent results,
with a 70–95% limb salvage rate often quoted. The improved blood
supply will also help healing of existing ulcers and may negate the need
for amputation or allow the area requiring resection to be minimized.
If vascular intervention is unsuccessful or not possible, then amputation
is required, preferably as a below-knee procedure to give a better
mobilization potential post-operatively.
The Charcot foot

Epidemiology
This is a relatively rare complication of diabetes: an average district general
hospital clinic will have 3–10 patients with this problem.
Pathogenesis
It is suggested that blood flow increases due to sympathetic nerve loss.
This causes osteoclast activity and bone turnover to increase, so making
the bones of the foot more susceptible to damage. Even minor trauma
can, therefore, result in destructive changes in this susceptible bone.
Clinical features
The most likely site is the tarsal–metatarsal region or the metatar-
sophalangeal joints. Initially, it gives a warm/hot, swollen, and often
uncomfortable foot, which may be indistinguishable from cellulitis and
gout. Peripheral pulses are invariably present, and peripheral neuropathy
is evident clinically.
Plain radiographs will be normal initially and later show fractures with
osteolysis and joint reorganization with subluxation of the metatar-
sophalangeal joints and dislocation of the large joints of the foot. Isotope
scans with technetium are abnormal from early on, but differentiation
from infective or other inflammatory causes can be difficult. MRI scanning
may prove more useful for this in the future, as may 111indium-labelled
white cell studies if infection is suspected.
Eventually, in the untreated patient, two classic deformities are seen:
• A ‘rocker bottom’ deformity due to displacement and subluxation of
the tarsus downwards.
• Medial convexity due to displacement of the talonavicular joint or
tarsometatarsal dislocation.
Management
If diagnosed early, immobilization may help to prevent joint destruction.
Exactly how best to do this is not agreed, but using a non-walking plaster
cast or an Aircast type of boot is needed for at least 2–3 months while
bone repair/remodelling is going on. Some advocate immobilization for
anything up to a year.
The use of bisphosphonates does not seem to alter outcomes.
Further reading
National Institute for Health and Clinical Excellence (2004). Type 2 diabetes—footcare. Available
at: M http://www.nice.org.uk/CG10.
National Institute for Health and Clinical Excellence (2011). Diabetic foot problems—inpatient
management. Available at: M http://www.nice.org.uk/guidance/CG119.
Rogers LC, et al. (2011). The Charcot foot in diabetes. Diabetes Care 34, 2123–9.
THE CHARCOT FOOT 809
Macrovascular disease
People with diabetes have a significantly greater risk of macrovascu-
lar complications (coronary heart disease, cerebrovascular disease, and
peripheral vascular disease) than the non-diabetic population. Around
three-quarters of people with diabetes will die as a result of macrovascular
disease, and a diagnosis of type 2 diabetes equates to a cardiovascular risk
equivalent of ageing 10–15 years.
Epidemiology
The exact prevalence and incidence of macrovascular disease and its out-
comes will vary, depending on the age, gender, and ethnic mix of the
patients being assessed. The previous belief that cardiovascular disease is
less common in type 1 diabetes has been proven wrong, and, in general,
vascular complications account for around three-quarters of deaths in
both type 1 and type 2 diabetes. Although the atheroma seen is histologi-
cally the same as in a non-diabetic population, it tends to be more diffuse
and progresses more rapidly. It also occurs at an earlier age, and women
with diabetes lose the cardiovascular protection seen in the non-diabetic
population.
• Overall, peripheral vascular disease occurs in up to 10% of patients,
and they have up to 15-fold greater risk of needing a non-traumatic
amputation than the non-diabetic population.
• Thromboembolic cerebrovascular events increase in individuals with
diabetes, compared to the non-diabetic population.
• The risk of having a myocardial infarction is also increased 2–4 times in
individuals with diabetes.
Secondary prevention
• Stop smoking.
• Strict control of blood pressure.
• Lipid-lowering drugs.
• Early control of blood glucose.
• Aspirin: this is no longer recommended for primary cardiovascular
protection in subjects with diabetes.
Pathogenesis
The risk factors for atherosclerosis, such as smoking and family history, still
apply in a diabetic population. Some factors, however, are more common
in those with diabetes and may also confer a greater risk to the diabetic
population. These include:
• Glycaemic control. Short-term studies, such as ACCORD, VADT, and
ADVANCE, investigating the effects of tight glycaemic control on the
development of macrovascular disease have been disappointing. These
showed that optimizing glucose control has no value in preventing
vascular ischaemic events. However, longer-term studies, such as
DCCT-EDIC in type 1 diabetes and UKPDS in type 2 diabetes, have
clearly demonstrated that early glycaemic control is key for the
prevention of cardiovascular disease later in life. However, strict
MACROVASCULAR DISEASE 811
glycaemic control should not occur at the expense of increased

hypoglycaemia, which can be life-threatening.
• Hypertension. More common in both type 1 and type 2 patients and
results in vascular endothelial injury, so predisposing to atheroma
formation. The UKPDS suggests BP control is a more important
individual risk factor for CVD than glycaemic control. Therefore, there
are strict criteria to control BP in patients with diabetes, particularly in
the presence of microvascular complications.
• Hyperlipidaemia. Common, e.g. hyperinsulinaemia in insulin-resistant
type 2 patients causes reduced HDL cholesterol, elevated triglycerides
(and VLDL), and smaller denser, and therefore, more atherogenic LDL
cholesterol. Results from the FIELD study, investigating the effects of
lowering triglyceride levels with fibrate treatment in diabetes, failed
to show a beneficial effect on vascular complications, which may have
been partially related to study design. On the other hand, the use of
statins in diabetes has been shown to reduce cardiovascular events in
a number of studies, and this is now routine practice for both primary
and secondary cardiovascular protection in diabetes.
• Obesity. An independent risk factor, more common in type 2 patients.
Central obesity, in particular, is more atherogenic.
• Insulin resistance or elevated circulating insulin/proinsulin-like molecule
levels are known to increase the risk of atherosclerosis in both
diabetic and non-diabetic populations. This may be linked to impaired
endothelial function.
• Altered coagulability. Circulating fibrinogen, plasminogen activator
inhibitor (PAI)-1, and von Willebrand factor levels are altered
in diabetes, whereas platelet activity is enhanced. Antiplatelet
agents, mainly aspirin, were previously recommended for primary
cardiovascular protection, but recent evidence (e.g. POPADAD study)
does not support such practice. ASCEND, running till 2017, is a large
study that will address the role of asprin in primary prevention in
diabetes further. However, aspirin continues to be used for secondary
cardiovascular protection in diabetes. No specific treatment exists at
present to address changes in level/activity of coagulation factors.
The UKPDS has shown the major risk factors for coronary heart disease
in type 2 patients to be elevated LDL cholesterol, decreased HDL choles-
terol, hypertension, hyperglycaemia, and smoking.
See Box 13.28 for the management of myocardial infarction in those
with diabetes.
Box 13.28 Management of acute myocardial infarction

Patients with diabetes are more likely to have a myocardial infarction
and more likely to die from it than the non-diabetic population. This
may be due to a greater likelihood of myocardial pump failure. Several
studies highlight this (see Table 13.14).
Up to 20–40% of patients admitted to hospital with a myocardial
infarction will have hyperglycaemia, many of whom will not have been
previously diagnosed with diabetes.
As in the non-diabetic population, streptokinase, aspirin, and acute
angioplasty have proven benefits. The previous contraindication for
thrombolysis in those with proliferative diabetic retinopathy has been
questioned by many, although this is less an issue these days as primary
angioplasty is used, rather than thrombolytic therapy, in most centres.
Tight glycaemic control (blood glucose 7–10mmol/L) using IV glucose
and insulin for at least 24h followed by SC insulin, as used in the DIGAMI
study, also has benefits. In this study, patients with an admission blood
glucose >11.0mmol/L who were treated with this regimen had a 7.5%
absolute risk reduction in mortality at 1 year and an 11% risk reduction
at 3.5 years, compared to the control group (i.e. 33% mortality with
treatment vs 44% in controls at 3.5 years). This equates to one life saved
for every nine treated with this regimen. The exact reason for this is
unclear. However, DIGAMI 2 study failed to show a benefit for insulin
therapy post-MI, but the various groups had similar glycaemic control,
making results interpretation from this trial problematic.
• It is suggested that all patients with a blood glucose >11mmol/L
benefit from glucose-lowering therapy, whether previously known
to have diabetes or not. Using an admission HbA1c to detect
those with undiagnosed or stress-related hyperglycaemia can be
useful but should not result in withholding the acute treatment
of this hyperglycaemia in such patients. It may, however, help to
identify those who may be troubled by hypoglycaemia and may
not, therefore, be suitable for SC insulin or sulfonylureas in the
intermediate or long term.
• Using ACEIs early after myocardial infarction gives a 0.5% absolute
risk reduction in 30-day mortality and a 4–8% risk reduction over
15–50 months in a general population. Analysis of the diabetic
subgroup in the GISSI-3 study showed a 30% relative risk reduction
in 6-week mortality for the diabetic subgroup (8.7% vs 12.4%),
compared to a 5% reduction for non-diabetics. In view of the greater
proportion of diabetics with poor left ventricular function after
myocardial infarction compared to the non-diabetic population, this
difference is very important.
MACROVASCULAR DISEASE 813
Table 13.14 Studies of patients with myocardial infarction

Trial and outcome examined Non-diabetic Diabetic
subgroup (%) subgroup (%)
ISSI-2: non-streptokinase 4-year 27 41
mortality
GUSTO: in-hospital mortality 6.2 10.6
GISSI-2: re-infarction rates 14 30
Lipid abnormalities found in

patients with diabetes
Hyperlipidaemia in a patient with diabetes, at any level of cholesterol,
is associated with a greater risk of macrovascular disease than in a
non-diabetic individual. Patients with diabetes may have altered activity
of insulin-dependent enzymes, such as lipoprotein lipase, which results in
delayed systemic clearance of certain lipids. This, combined with altered
hepatic production of apoprotein B-containing lipoproteins, gives a more
atherogenic profile.
Usual findings are of increased triglyceride-containing lipoproteins, chy-
lomicrons, and VLDL. Although more common in the insulin-resistant type
2 patients, this can also be seen in type 1 patients, particularly in those
with poor glycaemic control. Another abnormality is low HDL choles-
terol (HDL2 especially), commonly seen in type 2 diabetes patients and
individuals with insulin resistance. Other atherogenic changes include a
tendency to develop small dense LDL cholesterol particles and a greater
tendency to oxidative damage which renders them even more athero-
genic. Lipoprotein a (Lpa) levels, which are thought to contribute to the
atherothrombotic process, are also often raised.
Other causes of lipid abnormalities should be kept in mind when assess-
ing individuals with diabetes, such as familial hypercholesterolaemia or
familial combined hyperlipidaemia (b see Chapter 14, p. 828). Screening
for secondary causes of hyperlipidaemia, such as hypothyroidism, obstruc-
tive liver disease, nephrotic syndrome, and alcohol abuse, should also be
performed.
Evidence from trials
The diabetic subgroups from the major lipid-lowering trials (see
Table 13.15), such as the 4S study (Scandinavian Simvastatin Survival
Study), CARE (Cholesterol and Recurrent Events Trial), LIPID (Long-term
Intervention with Pravastatin in Ischaemic Disease), and WOSCOPS (West
of Scotland Coronary Prevention Study), show impressive reductions in
mortality, re-infarction, and stroke, although the numbers in each were rel-
atively small (see Table 13.15). In 4S, for example, the simvastatin-treated
diabetic subgroup had a 23% rate of major coronary events, compared
to 45% in the diabetic placebo group, while the non-diabetic simvastatin
group had 19% major coronary events and the placebo non-diabetic group
had 27%. On the basis of this, it is suggested that if 100 patients with
diabetes who have angina or are post-MI are treated with simvastatin for
6 years, 24 of the 46 expected coronary deaths and non-fatal myocardial
infarctions can be prevented.
More recent lipid-lowering trials in individuals with diabetes, such
as CARDS (Collaborative Atorvastatin Diabetes Study), showed sig-
nificant benefit of statin treatment in this population. However, ASPEN
(Atorvastatin Study for the Prevention of Endpoints in Non-insulin
dependent diabetes) demonstrated no effects, but this may have been due
to study design and protocol changes during the study.
LIPID ABNORMALITIES FOUND IN PATIENTS WITH DIABETES 815
Table 13.15 Important lipid-lowering studies

Study 4S WOSCOP CARE LIPID
Type of study s prevention p prevention s prevention s
of CHD of CHD of CHD prevention
of CHD
Duration of 6 5 5 6
study (years)
Number 4,444 6,595 4,159 9,014
studied
Mean total 6.8 7.0 5.4 5.6
cholesterol (5.5–8.0) (>6.5) (<6.2) (4.0–7.0)
(mmol/L)
(cholesterol at
inclusion)
Age range 35–70 45–64 21–75 31–75
(years)
% men 81 100 86 83
% with 4.5 1 17 8.6
diabetes
Treatment Simvastatin Pravastatin Pravastatin Pravastatin
20–40mg daily 40mg daily 40mg daily 40mg daily
Event 34% for 31% overall 23% for 23% overall
reduction for non-diabetics non-diabetics
55% for diabetics 25% for diabetics
Management
Patients with diabetes are given dietary advice to help control blood glu-
cose, which also contributes to improving lipid profile. In a patient who is
already following a good ‘diabetic diet’, however, there is often not much
room for improvement.
Other standard advice should also be given:
• Stop smoking—reduces risk of death by about 50% over a 15-year
period.
• Reduce weight if overweight/obese.
• Increase physical activity.
Lipid-lowering therapy
The use of general cardiovascular risk stratification tables is not recom-
mended for individuals with diabetes. NICE guidelines recommend for
those with type 1 diabetes, statin treatment is used in those with raised
albumin excretion rate or ≥2 features of metabolic syndrome or other
risk factors (e.g. age >35 years or high-risk ethnic group). For those with
type 2 diabetes, statin treatment is recommended in all those >40 years
old, unless their CV risk is low (<20% over 10 years, using the UKPDS risk
engine), and in those under 40 years with multiple CV risk factors.
Treatment aims for lipids

• Total cholesterol <4.0mmol/L.
• LDL cholesterol <2.0mmol/L.
• HDL >1.0 mmol/L.
• Triglycerides <2.3mmol/L.
Pharmacological interventions to increase HDL levels have not been shown
to improve clinical outcome. HDL can be raised non-pharmacologically
using lifestyle measures (weight loss, exercise, and stopping smoking).
Remember that a fit patient with diabetes has a similar risk when com-
pared to a non-diabetic of the same age and gender who has also had a
coronary event. More strict lipid targets are advocated by many, espe-
cially for those patients who are post-coronary artery bypass grafting or
post-angioplasty.
In those with mixed hyperlipidaemia, consider a fibrate or a statin
licensed for this indication. A fibrate will reduce triglycerides by 30–40%
and LDL cholesterol by 20% while a statin would reduce triglycer-
ides slightly less (10–15%) and LDL cholesterol slightly more (25–35%).
Fibrates also alter the LDL cholesterol to its less atherogenic form. The
choice of agent must be tailored to the individual patient. For hypercho-
lesterolaemia alone, a statin is first-choice, as in the non-diabetic patient,
and, in severely resistant patients, combination therapy with statins and
ezetimibe or statin and fibrates may be required. Combination of statin
and ezetimibe may reduce LDL more effectively than increasing the statin
dose alone, although there is no evidence that such combination therapy
is translated into better clinical outcome, compared to monotherapy with
higher-dose statin.
LIPID ABNORMALITIES FOUND IN PATIENTS WITH DIABETES 817
Hypertension
Epidemiology
Hypertension is twice as common in the diabetic population as in the
non-diabetic population, and standard ethnic differences in the prevalence
of hypertension still hold true. It is known that hypertension worsens
the severity and increases the risk of developing both microvascular and
macrovascular disease. Using a cut-off of >160/90mmHg, hypertension
occurs in:
• 10–30% of patients with type 1 diabetes.
• 20–30% of microalbuminuric type 1 patients.
• 80–90% of macroalbuminuric type 1 patients.
• 30–50% of Caucasians with type 2 diabetes.
Using the UKPDS suggested target of 140/80, hypertension is even more
common.
Pathogenesis
• Type 1 patients. Hypertension is strongly associated with diabetic
nephropathy and microalbuminuria and occurs at an earlier stage than
that seen in many other causes of renal disease.
• Type 2 patients. Hypertension is associated with insulin resistance and
hyperinsulinaemia. Hyperinsulinaemia can directly cause hypertension
by increased sympathetic nervous system activity, enhanced proximal
tubule sodium reabsorption, and stimulation of vascular smooth
muscle cell proliferation.
HYPERTENSION 819
Management of hypertension
Treatment aim
NICE guidelines recommend all patients with diabetes should have a blood
pressure <140/80mmHg or 130/80 in the presence of diabetic complications.
The hypertension study in the UKPDS highlights the benefits for type 2
patients of such a treatment level on mortality, diabetes-related endpoints,
and microvascular endpoints. In this study, a 10/5mmHg difference in BP
was associated with a 34% risk reduction in macrovascular endpoints, a
37% risk reduction in microvascular endpoints, and a 44% risk reduction
in stroke. The Hypertension Optimal Treatment (HOT) study supports
these targets.
Predisposing conditions
Other conditions causing both hypertension and hyperglycaemia should be
considered, e.g. Cushing’s syndrome, acromegaly, and phaeochromocytoma.
End-organ damage
Assess evidence of end-organ damage (eyes, heart, kidneys, and peripheral
vascular tree, in particular).
Assessment of cardiac risk factors
Treat associated risk factors for coronary heart disease.
Treatment
General
Modify other risk factors, such as glycaemic control, smoking, and dyslipi-
daemia. Then consider:
• Weight reduction if obese.
• Reduced salt intake (<6g/day).
• Reduced alcohol intake (<21 units/week in ♂, <14 in ♀).
• Exercise (20–40min of moderate exertion 3–5 times/week).
Pharmacological
Most agents currently available will drop systolic BP by no more than
20mmHg at most. In the UKPDS BP study, one-third of those achieving
the current BP targets required three or more drugs. Recently, the NICE
guidelines for BP treatment were updated and now advocate an ‘A/CD’
approach. That is starting with ‘A’, an ACEI (or an angiotensin II recep-
tor blocker/antagonist if the ACEI is not tolerated), and then adding in
either a ‘C’/calcium channel blocker or a ‘D’/thiazide-type diuretic, with an
A-blocker, a B-blocker, or further diuretic therapy then added if this fails
to reduce BP adequately.
• In the presence of microalbuminuria or frank proteinuria, an ACEI is
first-line, or an angiotensin II receptor antagonist if not tolerated.
• In Afro-Caribbean patients, ACEI and B-blockers are less effective than
calcium channel blockers and diuretics. A diuretic may be needed to
improve the efficacy of the ACEI in these patients.
• Several agents, such as high-dose thiazides and B-blockers, can worsen
diabetic control and exacerbate dyslipidaemia, so tailor the drugs
MANAGEMENT OF HYPERTENSION 821
chosen to each patient. Interestingly, a recent review of data from the

Nurses Health Study and the Health Professionals Follow-up study
(HPFS) suggested that, while these agents may increase the risk of
developing diabetes, it may not be associated with an increased risk of
cardiovascular or total mortality.
• In those with angina, a B-blocker has added benefits.
• In those with PVD, consider vasodilators, e.g. calcium channel blockers.
In summary, to reduce the risk of macrovascular complications in diabetes,
we should ensure:
• Early glycaemic control: strict glycaemic control to achieve HbA1c
of 6.5% or less, with avoidance of hypoglycaemia. In individuals with
long-standing diabetes and advanced arterial disease, strict glucose
control is probably less effective at reducing cardiovascular events.
• Strict blood pressure control: aiming for BP <140/80mmHg or
<130/80mmHg for those with micro- or macrovascular complications.
• Treatment of dyslipidaemia, aiming for total cholesterol of
<4.0mmol/L, LDL <2.0mmol/L, HDL >1.0mmol/L, and triglyceride
<2.3mmol/L.
• Patient should be encouraged to lose weight through healthy diet and
regular exercise.
• Aspirin therapy has currently no role in primary cardiovascular
protection but continues to be used for secondary prevention.
Further reading
Ajjan RA, Grant PJ (2011). The role of antiplatelets in hypertension and diabetes mellitus. J Clin
Hypertens 13, 305–13.
Betteridge DJ (2011). Lipid control in patients with diabetes mellitus. Nat Rev Cardiol 8, 278–-90.
Chrysant SG, Chrysant GS (2011). Current status of aggressive blood glucose and blood pressure
control in diabetic hypertensive subjects. Am J Cardiol 107, 1856–61.
Hill D, Fisher M (2010). The effect of intensive glycaemic control on cardiovascular outcomes.
Diabetes Obes Metab 12, 641–7.
Malmberg K for the DIGAMI (DM, Insulin Glucose Infusion in Acute Myocardial) study group
(1997). Prospective randomized study of intensive insulin treatment on long term survival after
acute myocardial infarction in patients with DM. BMJ 314, 1512–15.
National Institute for Health and Clinical Excellence (2006). Hypertension: management of hyper-
tension in adults in primary care. NICE clinical guidelines 34 (partial update of NICE clinical
guideline 18), June 2006. NICE: London. Available at: M http://www.nice.org.uk/nicemedia/pdf/
cg034niceguideline.pdf
National Institute for Health and Clinical Excellence (2008). Type 2 diabetes: the management of
type 2 diabetes. Management of blood pressure and lipids. NICE Clinical Guideline CG 66 (May,
2008). Available at: M http://www.nice.org.uk/nicemedia/live/11983/40803/40803.pdf.
UKPDS Group (1998). Tight blood pressure control and risk of macrovascular and microvascular
complications in type 2 diabetes: UKPDS 38. BMJ 317, 703–13.
Zuanetti G, Latini R, Maggioni AP, et al. (1997). Effect of the ACE inhibitor lisinopril in diabetic
patients with acute myocardial infarction. Data from GISSI-3 Study. Circulation 96, 4239–45.
Chapter 14 823
Lipids and
hyperlipidaemia
Lipids and coronary heart disease 824

Assessment of CVD risk 826
Primary hyperlipidaemias 828
Polygenic hypercholesterolaemia 829
Familial hypercholesterolaemia (FH) 830
Familial combined hyperlipidaemia (FCHL) 832
Familial hypertriglyceridaemia 832
Rare genetic hypertriglyceridaemias 833
Familial dysbetalipoproteinaemia 833
Elevation of Lp(a) 834
Rare familial mixed dyslipidaemias 835
Secondary hyperlipidaemias 836
Management of dyslipidaemia 838
Drug therapy 840
824 CHAPTER 14 Lipids and hyperlipidaemia
Lipids and coronary heart disease

Physiology
The two main circulating lipids triglycerides and cholesterol are bound
with phospholipid and apolipoproteins to make them more water-soluble
for transportation throughout the body. The apolipoproteins on the sur-
face of these soluble complexes have functional characteristics and are
specific for each lipoprotein:
• Chylomicrons. Contain 85% triglycerides and 4% cholesterol and can be up
to 0.001mm in diameter (light-scattering and presence, therefore, gives a
milky appearance to plasma). Main transport vehicle of fat (50–150g/day)
from intestine, and assembled and secreted by the mucosa of the small
intestine and after fat ingestion. Their triglyceride content is broken down
in peripheral tissues by lipoprotein lipase. Initially, they contain apoprotein
B-48 (apo B-48) and acquire apo E and apo C-II from circulating HDL.
Following the triglyceride removal in the capillary bed, the chylomicron
remnants are removed by specific apo B and apo E receptors in the liver.
• Very low density lipoproteins (VLDLs). Contain 50% triglyceride, 15%
cholesterol, and 18% phospholipid. They are the main carrier of
triglycerides from the liver (approximately 50g/day). The VLDL contain
apo B-100 and apo E. VLDL triglycerides are also broken down by
lipoprotein lipase in peripheral tissue to generate IDLs or other
remnants (LDL) which are removed by the liver.
• Intermediate density lipoproteins (IDLs). These VLDL remnants contain
mostly cholesterol and phospholipid and are either removed by the
liver or metabolized to form LDLs.
• Low density lipoproteins (LDLs). Contain 45% cholesterol, 10% triglycerides,
and 20% phospholipid. LDL has apo B-100 on its surface and is the
predominant cholesterol transport vehicle in the circulation. The liver has
specific LDL receptors to extract it from the circulation. Half of the body’s
circulating LDL is removed from the plasma each day, mostly by the liver.
Small, dense LDL (5–50% of the LDL pool) is easily oxidized. This is likely
to occur whilst the LDL particle has been retained in the vascular wall.
Modified LDL is taken by macrophages, and an extensive uptake will be
the basis of foam cell formation in the atheromatous plaque.
• High density lipoproteins (HDLs). Made in the liver and gut; contain 17%
cholesterol, 4% triglycerides, and 24% phospholipid. HDL transports
20–50% of circulating cholesterol. The main apoprotein is apo AI which
attracts free cholesterol from peripheral tissues to form the first step
of ‘reverse cholesterol transport’.
In practice, patients are managed by their levels of cholesterol (total, LDL,
HDL) and triglycerides. Elevated total or LDL cholesterol with normal tri-
glycerides is hypercholesterolaemia. Isolated elevation of triglyceride is hyper-
triglyceridaemia, and both together is combined or mixed hyperlipidaemia.
There is an exponential relationship between hypercholesterolaemia
and coronary heart disease (CHD). A man with a TC of 6.5mmol/L has
double the risk of CHD of a man with a TC of 5.2mmol/L, and half the risk
of a man with a cholesterol of 7.8mmol/L. Intervention studies show that
reductions in total and LDL cholesterol reduce coronary and cerebrovas-
cular events as well as mortality.
LIPIDS AND CORONARY HEART DISEASE 825
HDL cholesterol has an inverse relationship with CHD, i.e. increased

levels appear protective. Low HDL cholesterol concentrations may be
due to lack of physical exercise, obesity, or the presence of hypertriglyc-
eridaemia and occurs in smokers.
A low HDL is very often seen in the presence of hypertriglyceridaemia.
Although much debated over the past decades, recent evidence sug-
gests that hypertriglyceridaemia is directly related to CHD. Combined
hyperlipidaemia carries a substantial excessive CHD risk.
The specific role of low HDL is less clear, as the monogenic ‘low HDL
syndromes’ often do not carry an excessive CHD risk.
A novel and useful way of quantifying the presence of potentially ath-
erogenic lipoprotein concentrations in plasma is to use apo B which is a
marker of lipoprotein particle number.
Pathogenesis
Hyperlipidaemia is due to a combination of genetic and environmental
factors. Obesity is one of the strongest s factors. It is a major risk factor
for atherosclerosis.
• p hyperlipidaemias—usually genetically determined.
• s hyperlipidaemias—due to a combination of other conditions, drugs,
and dietary anomalies.
Atherosclerosis
In atherosclerosis, subintimal plaques start in medium-sized blood ves-
sel walls when cholesterol from LDL accumulates. A cholesterol-rich
necrotic core, surrounded by smooth muscle cells and fibrous tissue, then
develops. These plaques can calcify. If the surface of the plaques ulcerates,
thrombosis occurs which can obliterate the lumen of a blood vessel.
Plaques may result from diffusion of elevated LDL cholesterol, a qualita-
tive abnormality of LDL cholesterol, endothelial cell damage, or a combi-
nation of these. Endothelial cell damage may be due to:
• Physical trauma, e.g. with hypertension.
• Toxins, e.g. tobacco or alcohol.
• Low-grade infection or inflammation, e.g. Chlamydia.
• Immune complex damage.
CHD/atherosclerosis risk factors
♂ gender, i age, and a +ve family history are all linked with a greater risk
for atherosclerosis. There are also several modifiable risk factors:
• Cigarette smoking. >10 cigarettes/day increase the CHD odds ratio by
6.7-fold while stopping smoking reduces risk of myocardial infarct (MI)
by 50–70% within 5 years.
• Hypertension. Increases the CHD odds ratio by 2.7-fold. Each 1mmHg
drop in diastolic blood pressure reduces the MI risk by 2–3%. But
remember, aspirin reduces MI risk by 33%.
• Hyperlipidaemia. A 10% fall in total cholesterol (TC) results in a 25%
decrease in CHD risk, and plaque regression with reducing lipids is
well documented.
• Other. Less strongly associated factors include type A personality and
hyperuricaemia.
Assessment of CVD risk

Risk assessment tables/calculators for CVD or CHD are now available,
such as the Sheffield tables, the New Zealand tables, the Joint British
Societies Coronary Risk Prediction Chart, and QRISK. These calculate the
likelihood of the patient’s absolute risk of CVD over a period of years
and/or the individual’s relative risk, assuming CVD is not present at this
time. The data used for assessment include sex, age, blood pressure, pres-
ence of left ventricular hypertrophy, smoking, diabetes mellitus, and the
measured values of total cholesterol (TC), HDL cholesterol, or the ratio
of TC:HDL cholesterol. The tables give a prediction which is useful for
estimating the need for treatment.
Risk assessment tables/calculators can be accessed online or down-
loaded to clinic room computers.
Joint British Society Coronary Risk Prevention Score
Available at: M http://www.bhsoc.org/index.php?cID=269.
This chart was updated in 2009 to include older patients aged >70 years
and to show risk thresholds of <10%, 10–20%, and >20% over 10 years (in
line with NICE guidance for statin use).
QRISK
Available at: M http://www.qrisk.org/.
QRISK, which uses data from British subjects, appears to be better
at predicting outcome. The other risk assessment tables are calculated,
based on data from the Framingham study which appears to overestimate
the risk in the UK. QRISK also takes ethnicity into account and allows UK
postcode entry to calculate the effects of deprivation.
UKPDS risk engine
Available at: M http://www.dtu.ox.ac.uk/riskengine/index.php.
The UKPDS risk engine provides risk calculation in patients with type 2
diabetes.
General cautions when interpreting calculated risk
• CVD risk may be higher than indicated in the charts for:
• Those with a family history of premature CVD (♂ <55 years and
♀ <65 years). This is accounted for in QRISK.
• Those with raised triglyceride levels.
• Those who are not diabetic but have impaired glucose tolerance.
• Women with premature menopause.
• As the person approaches the next age category. As risk increases
exponentially with age, the risk will be closer to the higher
decennium for the last 4 years of each decade.
• The estimates of CVD risk from the chart are based on groups of
people, and in managing an individual, the physician also has to use
clinical judgement in deciding how intensively to intervene on lifestyle
and whether or not to use drug therapies.
ASSESSMENT OF CVD RISK 827
• An individual can be shown on the chart (or by using the calculator

in QIntervention M http://qintervention.org/) the direction in which
the risk of CVD can be reduced by changing smoking status, BP, or
cholesterol.
Individuals at risk of hyperlipidaemia
• Those with premature CHD (<55 years in ♂, <65 years in ♀).
• Those with signs of other atherosclerotic disease (e.g. PVD, ischaemic
cerebrovascular disease).
• Those with diabetes mellitus.
• Those with signs of insulin resistance, such as acanthosis nigricans.
• Post-menopausal ♀ not on HRT.
• Those with a high alcohol intake (♀ >14 units/week, ♂ >21).
• Those with a family history of hyperlipidaemia.
• Those with a family history of early CHD or other atherosclerotic
disease.
• Those with known s causes of hyperlipidaemia (b see p. 836).
Lipid measurements
Measurements should not be taken during an acute illness or during
periods of rapid weight loss, as these artificially lower the results. This
is particularly important from 24h after an MI for up to 6 weeks (less if
thrombolysed), as during this time, the levels of TC and LDL cholesterol
may be falsely reduced.
Pregnancy or recent weight gain will increase lipid levels. Following
rapid weight gain or weight loss, leave at least 1 month before reassessing
lipid levels.
Full lipid profile
Measures TC, HDL cholesterol, LDL cholesterol, and triglycerides.
This needs to be a fasting sample. If non-fasting, only TC and HDL cho-
lesterol measurements are accurate. Triglycerides rise postprandially, and
LDL is usually calculated with the formula below so is inaccurate if not
fasting. It is also invalid if triglycerides are >4.5mmol/L:
LDL (in mmol/L) = TC – HDL – 0.45 (triglycerides)
The use of TC alone can be misleading, as isolated HDL elevation can
increase the value. Use of a TC:HDL or an LDL:HDL ratio is preferred,
especially in ♀ and people with diabetes mellitus. Most risk calculation
tables now use these ratios, rather than total values alone.
Variations between assay method and different samples should not lead
to >3% variation, but more than one measurement should be used to
decide on initial pharmacological intervention.
ApoB
ApoB is the carrier protein of LDL and VLDL. As there is one molecule
of apoB per lipoprotein particle, measuring apoB in plasma gives insight
to the total number of potentially atherogenic lipoprotein particles. Some
studies suggest that apoB is a more accurate CVD risk indicator than LDL
cholesterol or non-HDL cholesterol and may, therefore, serve as a useful
CVD risk indicator. ApoB concentration is largely independent of fasting.
Primary hyperlipidaemias
Background
A primary hyperlipidaemia is defined by a knowledge of a monogenic or
polygenic cause. Although the clinical features of p hyperlipidaemia are
driven by a specific defect, the phenotype is also susceptible to environ-
mental pressure. Some of the primary hyperlipidaemias are very aggressive
and need strict clinical attention. At present, the family history and the
phenotypic findings in other family members are used as a surrogate for
a genetic diagnosis. DNA-based diagnosis is established for type III hyper-
lipidaemia and is being implemented for familial hypercholesterolaemia.
The latter can be useful not just for initial diagnosis, but also for family
screening.
Severe isolated hypertriglyceridaemias are classically recessive, and
genetic diagnosis is of little help or unavailable in clinical routine.
POLYGENIC HYPERCHOLESTEROLAEMIA 829
Polygenic hypercholesterolaemia
This is the most common cause of isolated hypercholesterolaemia. LDL
clearance appears to be reduced by a variety of mechanisms, and the E4
allele of apo E is a common association. Patients do not have the charac-
teristic xanthelasmata or extensor tendon deposits (xanthomata) seen in
familial hyperlipidaemia, and occasionally it can be difficult to distinguish
from familial hypercholesterolaemia. If young offspring of cases with poly-
genic hypercholesterolaemia are tested, it would be unsurprising if they
have normal cholesterol concentrations, which is in contrast to children
of those with familial hypercholesterolaemia.
Familial hypercholesterolaemia (FH)

FH is an autosomal dominant disorder. Its gene frequency is thought to be
1 in 500 in Western Europe and North America. In FH, hypercholesterol-
aemia is mainly (>95%) due to an increase in LDL cholesterol, caused by
LDL receptor mutations (on the short arm of chromosome 19) reducing
the number of high-affinity LDL receptors by up to 50%, so reducing LDL
clearance and thus prolonging the circulating time before catabolism from
the normal 2.5 days to >4.5 days. More than 1,000 different mutations
have, so far, been described. Less commonly, FH is due to familial defec-
tive apolipoprotein B-100 (3–4%) and proprotein convertase subtilisin/
kexin 9 gene (PCSK9) mutation (<1%). These can lead to several situations,
causing elevation of circulating LDL cholesterol by:
• Not producing any LDL receptors.
• Failure of LDL receptors to move to the cell surface.
• Abnormal binding of the receptor to LDL.
• Inability to adequately internalize LDL for metabolism.
Patients with untreated FH have a very high risk of premature CHD.
See Box 14.1 for clinical features.
Pharmacological treatment of FH
Treatment is with high-dose statins and ezetimibe, with bile acid seques-
trants, fibrates, and nicotinic acid as next-line treatments. Aim to reduce
LDL-C by >50%. Children should be treated by age 10. Homozygote FH
should be treated in a specialist lipid clinic.
It is estimated that >50% of heterozygous FH patients will die from
CHD before 60 years of age if left untreated. One in 20 patients under
60 years old surviving an MI are FH heterozygotes. Homozygous FH may
need non-pharmacological therapies, such as plasmapheresis, or surgical
procedures, such as ileal bypass, portocaval shunts, or liver transplanta-
tion. These treatments are not readily available and, along with pharma-
cological treatments, may be superseded by gene therapy in the future.
Clinical diagnosis is made by measurement of blood lipids, searching
for clinical stigmata, and noting the family history. DNA sequencing can
sometimes be used for specific diagnosis. Once an index case is detected,
further testing should involve immediate family members and can be done
at any age, using so-called ‘cascade screening’. In neonates, LDL can be
measured in cord blood, although this screening method may be unreli-
able in heterozygote FH. Screening children is best carried out before
10 years of age (at this age, a total cholesterol of above 5.5mmol/L is
highly indicative of FH) and then again at adolescence and early adulthood.
Typically, between the ages of 1 and 16 years, heterozygotes will have a
2-fold higher cholesterol level than unaffected siblings, so standard lipid
profiles can be used. Over 16 years of age, use a full fasting lipid profile
and clinical examination.
FAMILIAL HYPERCHOLESTEROLAEMIA (FH) 831
Box 14.1 Clinical features of FH

• TC >7.8mmol/L (>12.5mmol/L in homozygotes), LDL high
from birth.
• Normal triglycerides.
• Clinical stigmata: xanthelasmic deposits around the eyes and on the
tendons (i.e. fingers, hands, elbow, knee, and the Achilles tendon).
Tendon xanthoma is more specific for FH than corneal arcus or
xanthelasma. 7% of heterozygote FH (aged >19 years) and 75% of
homozygotes have tendon xanthomas (but may not be present until
age >40 years).
• Onset of a corneal arcus aged 30–40 years.
• Achilles tendonitis in childhood.
• Homozygotes can have CHD presenting in childhood and certainly
before the age of 30.
• Heterozygotes usually present after 30 years of age.
• FH may occur without clinical stigmata but with strong family history
of early-onset CHD, e.g. <50 years.
Familial combined
hyperlipidaemia (FCHL)
• FCHL is a high-risk syndrome for CHD.
• Population frequency has been estimated to 1/200.
• The aetiology is not yet known. Despite its seemingly dominant
appearance, the risk is clearly conveyed by a number of different
unknown genes.
• It is the most common type of inherited dyslipidaemia, estimated to
cause 10% of cases of premature CHD.
• It has no unique clinical manifestations, and the diagnosis is based on
raised lipids (>95th centile for age) and a family history of premature
CHD in first-degree relatives. In contrast to FH, tendon xanthomata
should not be present.
• The lipid phenotype can vary within individuals and family members
such that combined hyperlipidaemia, isolated hypercholesterolaemia,
and isolated hypertriglyceridaemia can be seen within the same
individual at different times and in different family members.
• Very likely to have raised Apo B concentrations.
• Should be treated aggressively and very often needs the combination
of several different pharmacological agents.
Familial hypertriglyceridaemia
• Is defined as a subentity of FCHL, but clearly less common, perhaps
with a frequency of 1/1,000, often as an autosomal dominant trait with
elevated VLDL levels, and is frequently accompanied by a moderate
hypercholesterolaemia. Triglyceride concentrations are rarely higher
than 10mmol/L.
• Suspect this condition where there is a subtle hypertriglyceridaemia
without any obvious causes (obesity, type 2 diabetes, etc.), together
with a positive CHD or stroke family history.
• The condition can sometimes be surprisingly responsive to statins.
FAMILIAL DYSBETALIPOPROTEINAEMIA 833
Rare genetic hypertriglyceridaemias

Two rare, but important, familial causes of severe hypertriglyceridaemia
are lipoprotein lipase deficiency and apolipoprotein C-II deficiency. Both are
autosomal recessive conditions which present in childhood and are char-
acterized by the presence of hyperchylomicronaemia.
• Lipoprotein lipase (LPL) is the enzyme needed to metabolize
chylomicron triglycerides; complete absence of this enzyme or
production of an inactive form are both recognized defects. Some
cases of apo C-II (the apolipoprotein-activating LPL) deficiency
have been described. Heterozygous LPL deficiency has a mild
phenotype. Recently, additional causes have been described in
cases with mutations in the protein-binding LPL to the endothelium
(GP1-HDLBP) and also with mutations in Apo AV. The overwhelming
clinical concern is pancreatitis. At present, the only useful treatment is
an extremely low fat diet.
• Pseudohypertriglyceridaemia should be suspected when a very stable
hypertriglyceridaemia (typically around 5mmol/L) is seen in someone
without any obvious secondary causes (obesity, type 2 diabetes, etc.).
The condition is X-linked (essentially restricted to ♂) and caused
by glycerol kinase (GK) deficiency. Typically, upon inspection of a
fasting plasma sample, it is clear (hypertriglyceridaemia in the range of
5mmol/L always show some opalescence). Test for free glycerol. This
is a harmless condition that should be left untreated.
Familial dysbetalipoproteinaemia
• Also known as type III hyperlipidaemia or broad beta disease.
• It is associated with early-onset CHD.
• It is an uncommon disorder affecting 1/10, or less, of people with the
Apo E2/E2 genetic background (which is 1/100 in most populations).
• The condition leads to specific elevation of IDL and chylomicron
remnants which are both cholesterol- and triglyceride-rich. Typically,
the rise of cholesterol and triglycerides is equimolar, and very high
concentrations can be seen (15mmol/L of TG and 15mmol/L of
cholesterol).
• Diagnosis is confirmed by genetic testing.
• A characteristic clinical feature is the presence of palmar striae
xanthoma; tubero-eruptive xanthomata, found over the tuberosities of
the elbows and knees, may also be present.
• Due to the recessive nature of the apo E2 genotype and the required
additional environmental pressure, family history is rarely revealing.
• Apo E2/E2 genetic background is not enough to precipitate the
syndrome; an additional factor is needed. This is typically obesity, type
2 diabetes, hypothyroidism, B-blocker, or thiazide diuretic medication.
The oral contraceptive pill can also elicit type III hyperlipidaemia.
Elevation of Lp(a)
• Lp(a) is an LDL-like lipoprotein particle, but it is not cleared via the
LDL receptors. Less than 5% of the population have raised Lp(a),
and the distribution is very skewed. Synthesis appears to be highly
genetically driven. Recent evidence suggests this is a highly atherogenic
lipoprotein particle. Raised Lp(a) should be suspected in someone
with early presentation of CHD, stroke, or peripheral vascular disease,
with moderately elevated cholesterol that is seemingly resistant to
statin therapy. At present, the only available pharmacological means by
which lowering of Lp(a) can be achieved is with niacin. However, there
is no formal evidence to suggest that niacin reduces cardiovascular
events in people with raised Lp(a).
RARE FAMILIAL MIXED DYSLIPIDAEMIAS 835
Rare familial mixed dyslipidaemias

These should be considered in any patient with unexplained neurology,
organomegaly, or corneal opacities.
• Familial lecithin:cholesterol acyltransferase (LCAT) deficiency. In this
recessively inherited disorder, an enzyme necessary for intravascular
lipoprotein metabolism is deficient, resulting in elevated cholesterol
and triglycerides. Clinically, corneal lipid deposits result in visual
disturbances and renal deposits in glomerular damage, proteinuria, and
often renal failure. Red blood cell morphology.
• Tangier disease (analphalipoproteinaemia or familial alphalipoprotein
deficiency). In this autosomal recessive condition, apo A-I, which
is found on HDL, is deficient. HDL level is low, as is TC while
triglycerides are normal or high. Cholesterol accumulation
gives enlarged orange-coloured tonsils, hepatosplenomegaly,
polyneuropathy, and corneal opacities.
• Fish eye disease. A rare disorder from northern Sweden, with high
VLDL levels, low HDL, and a triglyceride-rich LDL. As well as
hypertriglyceridaemia, dense corneal opacities occur, giving visual
impairment.
• Abetalipoproteinaemia. Results in intestinal fat accumulation due to
failure of secreting chylomicrons. Cholesterol levels are low, with
no LDL and VLDL in many cases, which results in fat accumulation
in the gut and nerves. Vitamin E injections may prevent some of the
neurological abnormalities observed (ataxia, nystagmus, dysarthria,
and motor plus sensory neuropathies) but usually not the retinitis
pigmentosa and acanthocytes which also feature.
• Hypobetalipoproteinaemia. This autosomal dominantly inherited
condition gives a TC of 1–4mmol/L and can be associated with
organomegaly and neurological changes in middle age due to fat
deposition and abnormal red cell morphology. The homozygous state
is similar to abetalipoproteinaemia.
• Hyperalphalipoproteinaemia or HDL hyperlipoproteinaemia. Results
in mildly elevated HDL and TC and may be beneficial. If very high
HDL is seen together with a type III-like pattern, hepatic lipase
deficiency could be suspected. Raised HDL can also occur with
exercise, exogenous oestrogen, phenytoin and phenobarbital use,
or from alcohol. Very high consumption of alcohol is one of the
few circumstances when high HDL is seen together with raised
triglycerides.
Secondary hyperlipidaemias
Background
Secondary hyperlipidaemias are common, and the predominant precipitat-
ing factors are obesity and type 2 diabetes They may consist of isolated
elevations of cholesterol or triglycerides or be combined. Treatment is
based upon managing the primary disorder disease before making a fur-
ther decision on the raised lipids. Not infrequently, more than one cause
is apparent in secondary hyperlipidaemias.
Causes
(Summarized in Table 14.1.)
• Obesity (b see Consequences of obesity, p. 857).
• Diabetes mellitus (b see Lipid abnormalities found in patients with
diabetes, p. 814).
• Fatty liver disease. Almost invariably associated with elevated TG.
• Diet. Excessive consumption of saturated fats, carbohydrate, sugary
drinks, and alcohol. Raised triglycerides by alcohol are normally
only seen after excessive consumption. Occasionally, the unusual
combination of elevated HDL cholesterol with raised triglycerides
is seen.
• Hypothyroidism. Estimated to occur in 4% of those with
hyperlipidaemia, and compensated (subclinical) hypothyroidism in a
further 10%. Usually resulting in hypercholesterolaemia with a TC of
7–12mmol/L. It also worsens primary hypercholesterolaemias due to d
synthesis of hepatic LDL receptors.
• Chronic renal disease.d creatinine clearance is accompanied by
hypertriglyceridaemia and d HDL cholesterol. Proteinuria, in the
nephrotic syndrome, is associated with hypercholesterolaemia.
It also raises Lp(a). After kidney transplantation, ciclosporin may
increase LDL.
• Liver disease. Especially with cholestasis, resulting in abnormal LDL
cholesterol. Primary biliary cirrhosis often results in TC >12mmol/L,
which is close to treatment resistance. The accumulating cholesterol
is contained in a fraction called LpX, absent in healthy humans. These
are large aggregates of phospholipids and free cholesterol and do not
resemble conventional lipoproteins. However, severe hepatocellular
damage may also lower LDL cholesterol by d production of its
component parts and the enzymes which metabolize it.
• Cushing’s syndrome. Glucocorticoids increase VLDL production,
thus hypertriglyceridaemia. The associated weight gain and glucose
intolerance can make this effect more pronounced.
• Lipodystrophies. A very rare group of disorders, hallmark of
which is regional, partial, or generalized fat loss, associated with
hyperlipidaemia, especially unusually raised triglycerides. Also
associated with glucose intolerance. See b Genetic causes of severe
insulin resistance, p. 693.
SECONDARY HYPERLIPIDAEMIAS 837
• Drugs. Medications commonly implicated are:

• B-blockers, especially the non-cardioselective ones.
• Thiazide diuretics.
• Exogenous oestrogens.
• Anabolic steroids.
• Glucocorticoids.
• Isotretinoin.
• Protease inhibitors (said to cause hyperlipidaemia in 50% after
10 months of treatment).
• Pregnancy. Cholesterol rises throughout pregnancy, mostly in the
second trimester. Triglycerides also rise but in the final trimester and
mostly in those with underlying genetic abnormalities. Both return to
normal by 6 weeks post-partum.
Table 14.1 Secondary causes of dyslipidaemia

Elevated LDL cholesterol Elevated triglycerides Reduced HDL cholesterol
Diet Diet Diet
(high saturated fats, high (weight gain + excess (some low-fat diets)
calories) of sugary drinks and
alcohol)
Drugs Drugs Drugs
(glucocorticoids, thiazide + (glucocorticoids, (anabolic steroids,
loop diuretics, ciclosporin) B-blockers, oestrogens, tobacco, B-adrenergic
isotretinoin) blockers)
Hypothyroidism Hypothyroidism Type 2 diabetes
Nephrotic syndrome Type 2 diabetes Insulin resistance
syndromes/obesity
Chronic liver disease Insulin resistance Chronic renal failure
syndromes
Cholestasis + biliary Cushing’s syndrome
obstruction
Pregnancy Chronic renal failure
Peritoneal dialysis
Pregnancy
Management of dyslipidaemia
Background
Hyperlipidaemias are common, and a decision to use pharmacological
means to lower hyperlipidaemias should depend on estimated cardiovas-
cular risk. For this purpose, useful risk scoring systems have been devel-
oped, but it is important to use these wisely. Importantly, they should
not be used for certain primary and familial conditions with very high
cardiovascular risk.
It can be a challenge to the physician to describe benefits of the medica-
tion or the necessary change in lifestyle to the patient, as treatment rarely
comes with an obvious ‘reward’ and the true effect may only be described
as a certain CHD risk reduction noticeable a decade or more ahead.
Overall, the use of statins has an extremely good evidence base, whereas
most alternative or complementary options have less solid evidence.
Primary and secondary prevention
It is universally accepted that lowering hypercholesterolaemia using statins
in secondary prevention reduces future cardiovascular events and overall
mortality. It is estimated that a 10% fall in TC results in a 25% decrease
in CHD risk. Regression and remodelling of atheromatous lesions have
also been clearly demonstrated. The presence of type 2 diabetes mellitus
puts the patient in the category for secondary prevention. Acute coronary
syndrome should be treated aggressively (high-dose atorvastatin 80mg),
which shows early benefit with statin treatment. In post-MI patients,
omega-3 fatty acids are recommended, as it reduces the incidence of sud-
den death due to arrhythmias.
A decision to reduce cholesterol primary prevention is much depend-
ent on the overall cardiovascular risk (b see p. 826). The reduction
in absolute risk is marginal in patients with few other risk factors and
should be evaluated critically. An estimated risk of CHD >2% per annum
has unquestionable support for initiation of pharmacological treatment.
However, even young patients with primary and familial conditions should
be treated aggressively without applying risk scoring systems.
Specific interventions
Dietary advice
Current recommendations are that fats should constitute <30% of energy
consumed and saturated fats must be <30% of the total fat content. To
achieve this, vegetable and marine mono- and polyunsaturated fats should
be high in the diet, whereas animal and dairy fat should be low. Total
dietary cholesterol should not exceed 300mg per day. Foods advocated
include fresh fruit and vegetables, which are also important sources of
antioxidants. A high fibre content is cholesterol-lowering. Four months
should be given to see if dietary manipulation will work in patients with
low-to-moderate risk. It is unusual to see more than a 15% fall in choles-
terol from dietary measures, but certain individuals can respond better.
Alcohol should be <14 units/week for a ♀ and <21 units/week for a ♂.
MANAGEMENT OF DYSLIPIDAEMIA 839
Plant sterols and stanols, 2–3g daily, can reduce blood cholesterol by
10–15%. They are available commercially in enriched margarine spreads,
yoghurt, and milky drinks.
Weight control
All overweight patients must be encouraged to lose weight. Weight
reduction is closely attuned to dietary advice and physical exercise. Most
weight is lost in the first 4 months of a regimen. A 10kg weight loss in
an obese subject can reduce LDL cholesterol by 7% and increases HDL
cholesterol by 13%. The effect on raised triglycerides can be much greater
and clinically very useful.
Physical activity
Physical activity, especially aerobic exercise, is recommended. This should
be realistic and adapted to the individual’s capacity. Although exercise
levels in the range of 70% of VO2max for 30–40min at least 3–5 times per
week is extremely useful, it is often unrealistic, and very good effects are
seen by walking, etc. Acute exercise will transiently change lipoprotein
levels and increase lipoprotein lipase activity. These effects become more
permanent with regular training. Triglyceride levels fall, HDL cholesterol
levels rise, especially the HDL2 subfraction with more vigorous exercise,
and the LDL cholesterol is of the less dense variety which is not so ath-
erogenic. The changes are dose-dependent with i exercise, and a 20%
alteration in each variable is achievable after 6 weeks. Particularly good
effects are seen in type 2 diabetes mellitus.
Modification of other risk factors
Other risk factors, such as hypertension, smoking, and diabetes mellitus,
must be addressed.
Drug therapy
Numerous agents can be used for both p and s prevention in patients in
whom non-pharmacological approaches have either been unsuccessful or
deemed insufficent.
HMG CoA reductase inhibitors (statins)
Table 14.2 shows the comparative potency of common statins.
Indications
Raised LDL, heterozygous + homozygous FH, mixed hyperlipidaemia. Not
all these medications are licensed for use in children and should be used
with caution in ♀ of childbearing age because of potential teratogenicity.
The medication should be stopped for at least 3 months before pregnancy
is planned. Women of childbearing age must ensure effective contracep-
tion when on these drugs.
Mechanism of action
Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) which
is the rate-limiting enzyme in cholesterol synthesis. Its activation increases
hepatocyte LDL receptor numbers which leads to increased clearance of
LDL and VLDL remnants. See Table 14.2 for comparative lipid-lowering
profile and Table 14.3 for dosage.
Side effects
Statins are usually very well tolerated. The most common side effect is
muscle ache which, in extremely rare cases, also develops into myositis.
Hepatotoxicity is not common but does exist. LFTs and creatine kinase
should be measured before they are prescribed and used with caution in
those with an excessive alcohol intake. It is recommended that the medi-
cations should be discontinued if the liver enzymes aspartate transami-
nase (AST) and/or alanine transaminase (ALT) show more than a 2–3-fold
elevation above the upper limit of normal. LFTs should, therefore, be
checked within 3–4 months of treatment and, at most, annually in the long
term if the patient is without symptoms. Myositis is rare, but the frequency
increases with concomitant medications, e.g. ciclosporin, fibrates, or when
renal impairment or untreated hypothyroidism are present. Clinically,
there is a picture of swollen tender muscles and creatine kinase being
>10× the upper limit of normal. Rhabdomyolysis is even rarer.
Interactions
Several statins are metabolized through CYP3A4. Grapefruit juice should
be avoided. Statins can interact with ciclosporin. There is an interaction
with warfarin for atorvastatin, simvastatin, and rosuvastatin, but it is often
not clinically significant and would only lead to small adjustments of the
warfarin dose. Erythromycin interacts with all statins. Digoxin interacts
with atorvastatin and simvastatin. Rifampicin interacts with fluvastatin and
pravastatin. Atorvastatin and rosuvastatin may also interact with the oral
contraceptive pill, antacids, and some antifungals.
DRUG THERAPY 841
Table 14.2 Comparative lipid-lowering profile of statins

Statin % fall in LDL-C % fall in triglycerides % rise in HDL-C
Atorvastatin 38–54 13–32 3–7
Fluvastatin 17–34 8–12 3–6
Pravastatin 18–34 5–13 5–8
Rosuvastatin 50–63 10–28 3–14
Simvastatin 26–48 12–38 8–12
Management of statin intolerance

Muscle problems after start of statin treatment is common. Although
it has been demonstrated that Q10 is reduced in muscle samples after
statin treatment, there is no evidence from randomized controlled trials
that supplementation of Q10 is of any benefit. The two main strategies
are to change statin or to reduce the dose. The first option normally
involves switching from simvastatin or atorvastatin to a low dose of
pravastatin (10 or 20mg). The second option involves a very low dose
of a second-generation statin, e.g. rosuvastatin 5mg every second day.
Non-statin agents are possible but should be used with caution, as the evi-
dence base for cardiovascular benefits is low (i.e. fibrate alone, ezetimibe
alone, etc.).
Fibrates
Indications
Raised plasma triglycerides or IDL, i.e. mixed hyperlipidaemias which have
not responded adequately to diet or other therapies. Fibrates should
normally be seen as add-on therapy beyond statins. However, fibrates
constitute first-line therapy in type III hyperlipidaemia. These medications
are less effective than statins at lowering cholesterol but better at i HDL
cholesterol and more effective in lowering triglycerides. Reduce triglyc-
erides by 20–60%, increase HDL by 5–20%, and reduce LDL by 5–25%.
Mechanism of action
Increases VLDL triglyceride clearance by i lipoprotein lipase activity and
LDL receptor-mediated LDL clearance while i HDL synthesis. The effect
on LDL cholesterol may vary in isolated hypertriglyceridaemia, and an
increase in LDL cholesterol can be seen in type IV hyperlipidaemia. See
Table 14.3 for dosages.
Side effects
Occasionally cause nausea, anorexia, or diarrhoea and precipitate gall-
stones. They should not be used in patients with severe liver disease
(AST/ALT >2–3× upper limit of normal) and renal dysfunction (creatinine
>150micromol/L), as they are conjugated in the liver prior to excretion by
the kidney. Myopathy, although rare, is the main concern, and the risk of
this increases if used with statins.
Interactions
Use with caution in combination with statins. Can enhance the effects of
warfarin and antidiabetic agents and is contraindicated in those on orlistat.
Anion exchange resins (bile acid sequestrants)
Indications
High LDL, i.e. hypercholesterolaemia. Largely superseded by statins, these
are now best used as adjuncts when LDL has not fallen enough with a
statin alone. They are also the only drug licensed for use during pregnancy.
Mechanism of action
Bind to bile acids in the gut, so reducing their enterohepatic circulation
and i bile acid excretion. This increases hepatocyte cholesterol require-
ments which increases LDL receptor production, so reducing circulating
LDL levels. Under optimum conditions, LDL cholesterol can be reduced
by 20–30%; triglycerides rise by 10–17%, and HDL increases by 3–5%.
Side effects
These agents remain in the gut, so constipation, bloating, nausea, and
abdominal discomfort are not uncommon. Constipation, found in 35–40%
of those on these agents, can be helped with bulking laxatives. Less often,
a bleeding tendency due to vitamin K malabsorption can be seen. These
agents can also exacerbate hypertriglyceridaemia, but HDL cholesterol
is often i slightly. To reduce the side effects, start with low doses and
build up gradually over the next 3–4 weeks while maintaining a good fluid
intake.
Interactions
These agents can reduce the absorption of warfarin, digoxin, β-blockers,
pravastatin, fluvastatin, and hydrochlorothiazide. Many other agents, such as
simvastatin, have not been checked, so to avoid any potential interaction,
advise patients to take all other drugs 1–3h before or 4–6h after the resin.
Nicotinic acid and acipimox
Indication
High LDL, VLDL, IDL, or triglycerides. Nicotinic acid is the most effective
medication for i HDL cholesterol. In practice, however, their use is lim-
ited by the side effect profile, especially flushing.
Mechanism of action
Work by inhibiting lipolysis in adipocytes, so altering fatty acid flux and
reducing VLDL synthesis and HDL clearance, or by inhibiting VLDL tri-
glyceride synthesis. Plasma triglycerides fall by 20–50%, and LDL by 5–25%
while HDL levels rise (by 10–50%).
Side effects
Common, with 30% unable to tolerate these agents. Vasodilatation, giving
cutaneous/facial flushing, occurs in most patients but tends to improve
after 2–3 weeks of therapy. Pruritus and dry, burning sensation in the skin
can be seen. High doses of aspirin were previously given to reduce this
effect, but this is now rarely practised due to the side effects of high-dose
DRUG THERAPY 843
aspirin. Patients should also be instructed to avoid hot drinks and spicy
food. Gastritis is also a common side effect, whereas liver side effects
are rare. Raises uric acid almost invariably, and exacerbation of gout can
be seen. Rarely, precipitation of acanthosis nigricans and retinal oedema
are also recognized side effects. Nicotinic acid can adversely affect glucose
control in prediabetic states and in diabetes mellitus. Acipimox, a nicotinic
acid analogue, seems to be less problematic but is also less potent. In 2013
following the results of the HPS2-THRIVE study, the European Medicines
Agency suspended licences for nicotinic acid preparations on the grounds
that they were ineffective and associated with adverse effects. Acipimox
remains available.
Omega-3 fatty acids (Omacor®, Maxepa®)
Indications
Hypertriglyceridaemia.
Mechanism of action
Inhibit the secretion of VLDL due to i intracellular apo B-100 destruc-
tion. Normal patients see both a fall in VLDL and LDL, but LDL may rise
in the hypertriglyceridaemic individual. Should be seen as add-on therapy
to statins. Lower doses (1g per day) have demonstrated positive effects
on cardiovascular prevention, but the mechanism of action is likely to be
through an antiplatelet effect.
Side effects
As high doses are needed, this is a high calorie load and may increase
obesity. More commonly, gives nausea and belching. Omacor® produces
fewer unwanted effects and is less calorific, as it is used in a smaller dose.
Interactions
None significant.
Cholesterol absorption blocker
Ezetimibe is the only available compound. Should be used as second-line
treatment after a statin.
Indications
LDL cholesterol-lowering in patients who are intolerant of statins or in
combination with a statin in those that are not adequately controlled with
a statin alone. Also in the very rare condition of sitosterolaemia where
there is an i absorption of plant sterols.
Mechanism of action
Dietary and biliary cholesterol absorption is selectively inhibited.
Ezetimibe (10mg) monotherapy produces an 18% fall in LDL cholesterol
and an increase in HDL cholesterol of 1–3%, and triglycerides are not
affected. In combination therapy with a statin, ezetimibe reduces levels by
an additional 22% to that obtained by statin alone.
Interactions
None significant.
Which drug to use when (for diet-resistant

dyslipidaemias)
Elevated LDL cholesterol only
• First choice:
• Statins.
• Second choice:
• Cholesterol absorption blocker.
• Then:
• Fibrates.
• Nicotinic acid (not available in Europe).
• Bile acid sequestrants.
Elevated triglycerides only
• First choice:
• Fibrates.
• Second choice:
• Omega-3 fatty acids or nicotinic acid.
All three groups can occasionally be used together if one or two of the
above groups are insufficient.
Mixed hyperlipidaemia
• First choice:
• Statin.
• Second choice:
• Statin + fibrate (but needs close monitoring).
• Statin + fibrate + nicotinic acid (but needs close monitoring).
As with elevated LDL alone, combination therapy may sometimes be use-
ful, with emphasis on avoiding side effects and interactions as above.
The relative doses of lipid-lowering drugs are shown in Table 14.3.
Aims of treatment
Primary prevention:
• TC <5.2mmol/L.
• LDL cholesterol <4mmol/L.
• HDL cholesterol >1mmol/L in ♂; >1.2 in ♀ (TC:HDL ratio <6).
Secondary prevention. For patients with CHD or post-MI (s prevention)
and diabetes mellitus, the target should be:
• TC <4mmol/L.
• LDL cholesterol <2mmol/L.
• HDL cholesterol >1.0mmol/L in ♂; >1.2mmol/L in ♀.
• Apo B <1g/L.
If these optimal levels are not achievable, at least a 25% fall from pretreat-
ment serum TC concentration or 30% reduction in LDL cholesterol is
acceptable, whichever gets to the lowest.
DRUG THERAPY 845
Table 14.3 Dosage of lipid-lowering drugs

Drug Dose/day
Statins
Atorvastatin 10–80mg
Fluvastatin 20–80mg
Pravastatin 10–40mg
Rosuvastatin 10–40mg (5–20mg in patient of Asian
origin)
Simvastatin 10–40mg
Fibrates
Bezafibrate 400–600mg
Ciprofibrate 100mg
Fenofibrate 67–267mg
Gemfibrozil 0.9–1.2g
Anion exchange resins
Colestyramine 12–36g (in single dose or up to 4×/day)
Colestipol hydrochloride 5g 1–2×/day (max 30g/day)
Colesevelam 1–2g 2×/day
Nicotinic acid group
Acipimox 500–750mg in divided doses
Nicotinic acid MR 375–2,000mg
Nicotinic acid 300mg–6g in divided doses
Nicotinic acid with laropriprant 1,000–2,000mg
Omega-3 fatty acids
Omacor® 1–4g
Cholesterol absorption blocker
Ezetimibe 10mg
Further reading
Bhatnagar D, Soran H, Durrington PN (2008). Hypercholesterolaemia and its management. BMJ
337, a993.
Chapman MJ, Ginsberg HN, Amarenco P (2011). European Atherosclerosis Society Consensus
Panel. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high
risk of cardioivascular disease: evidence and guidance for management. Eur Heart J 32, 1345–61.
Graham I, Atar D, Borch-Johnsen K, et al. (2007). European guidelines on cardiovascular disease
prevention in clinical practice: full text. Fourth Joint Task Force of the European Society of
Cardiology and other societies on cardiovascular disease prevention in clinical practice (consti-
tuted by representatives of nine societies and by invited experts). Eur J Cardiovasc Prev Rehabil
14 Suppl 2, S1–113.
Watts GF, Karpe F (2011). Triglycerides and atherogenic dyslipidaemia: extending treatment
beyond statins in the high-risk cardiovascular patient. Heart 97, 350–6.
Hippisley-Cox J, Coupland C, Vinogradova Y, et al. (2008). Predicting cardiovascular risk in England
and Wales: prospective derivation and validation of QRISK2. BMJ 336, 1475–82.
The National Institute for Clinical Excellence guidelines on lipid modification. Available at: M
http://guidance.nice.org.uk/CG67.
The National Institute for Clinical Excellence guidelines: identification and management of familial
hypercholesterolaemia. Available at: M http://www.nice.org.uk/CG71.
The online access to metabolic and molecular basis of inherited disease. Available at: M http://
www.ommbid.com/OMMBID/the online metabolic and molecular bases of inherited disease/b/
parttoc/part 12.
Chapter 15 847
Obesity
Definition of obesity 848

Epidemiology of obesity 850
Aetiology of obesity 852
Pathophysiology of obesity 854
Consequences of obesity 857
Management of an obese patient 858
Bariatric surgery 862
848 CHAPTER 15 Obesity
Definition of obesity
Obesity is defined as an excess of body fat sufficient to adversely affect
health. Body mass index (BMI) and waist circumference, as a measure of
fat distribution, are the most commonly used measures, but a clinical stag-
ing system is increasingly used to determine risk and management (see
Box 15.1). BMI is an imprecise measure of adiposity and does not account
for fat distribution, which may better determine metabolic and cardiovas-
cular risk at lower BMI.
Lower cut-off values for BMI and waist circumference are applicable to
non-Caucasian ethnic groups: cut-off points for increased risk varies from
22kg/m2 to 25kg/m2 in different Asian populations, and for high risk from
26kg/m2 to 31kg/m2.
Central obesity may reflect increased visceral (intra-abdominal fat)
stores and/or ‘ectopic’ fat (fat stored in liver, muscle, pancreas, and epicar-
dium) more directly linked to pathophysiology, such as insulin resistance.
Assess overall clinical status, using BMI, waist circumference, and stage
(see Box 15.1).
Obesity is associated with increased secretion of adipose tissue prod-
ucts, including hormones, cytokines (adipocytokines), and growth factors
such that it is now regarded as a disease of chronic low-grade systemic
inflammation. Many of its adverse sequelae relate to this pathology.
DEFINITION OF OBESITY 849
Box 15.1 Edmonton Obesity Staging System (EOSS)

Stage 0
• No apparent obesity-related risk factors, physical symptoms,
psychopathology, functional limitations, and/or impairment of
well-being.
Stage 1
• Obesity-related subclinical risk factor(s) (borderline hypertension,
impaired fasting glucose, elevated liver enzymes, etc.), mild physical
symptoms (e.g. dyspnoea on moderate exertion), psychopathology,
functional limitations, and/or impairment of well-being.
Stage 2
• Established obesity-related chronic disease(s) (hypertension, type 2
diabetes, sleep apnoea, osteoarthritis, reflux disease, polycystic ovary
syndrome, anxiety disorder), moderate limitations in activities of
daily living, and/or well-being.
Stage 3
• Established end-organ damage (myocardial infarction, heart failure,
diabetes complications, incapacitating osteoarthritis), significant
psychopathology, functional limitation(s), and/or impairment of
well-being.
Stage 4
• Severe (potentially end-stage) disability/ies from obesity-related
chronic diseases, disabling psychopathology, functional limitation(s),
and/or impairment of well-being.
Epidemiology of obesity
Overweight and obesity are rapidly increasing globally; the highest rates
of obesity (>30%) are seen in the USA, Mexico, and the Middle East. One
billion adults are currently overweight (BMI 25–29.9kg/m2), and a further
475 million are obese. When Asian-specific cut-off points for the definition
of obesity are taken into account, the number of adults considered obese
globally is over 600 million.
In the UK, prevalence has doubled in 25 years: 26.1% of adults (aged
16 years and over) were obese in 2010, and 55% of the population is either
overweight or obese.
Global estimates of childhood obesity suggest 200 million school-aged
children are either overweight or obese, of whom 40 million are obese.
In the UK, 10.1% of boys and 8.8% of girls aged 4–5 years and 20.6% of
boys and 17.4% of girls aged 10–11 years are obese
Prevalence of obesity varies with age (peak prevalence at 50–70 years),
socio-economic class (15% women and 21% men in social class I; 34% and
30% in social class V) and social deprivation in women (22% least to 31%
most deprived).
EPIDEMIOLOGY OF OBESITY 851
Aetiology of obesity
Overweight and obesity results from a complex interaction between envi-
ronmental pressures and risks and genetic susceptibility. Heritability of
obesity is about 60%, but the rapid increase in obesity prevalence over
the past 30 years argues in favour of predominantly environmental drivers.
However, there is increasing interest in the possibility of epigenetic influ-
ences on obesity related to maternal obesity, diet, gestational diabetes,
and even possibly environmental pollutants, such as polyfluorinated com-
pounds and polycyclic aromatic hydrocarbons.
Genetic factors
Monogenic obesity
Mutations in genes (usually related to appetite control within the hypo-
thalamus) are associated with obesity of early childhood onset, usually
with hyperphagia. However, only about 5% of all severe childhood and
2% of adult obesity are associated with identified genetic causes. Of these,
mutations in the melanocortin 4 receptor (MC4R) are the most frequent
and are associated with increased linear growth, fat and lean mass, hyper-
phagia (moderate) and severe hyperinsulinaemia, but normal puberty and
fertility.
An increasing number of genes associated with the development of obe-
sity have been identified through genome-wide association studies. The
FTO ‘fat mass and obesity associated’ gene was originally linked to type 2
diabetes; the association was actually found to be due to the higher BMI of
diabetic cases in comparison to non-diabetic controls; common variants in
the first intron result in a +0.4kg/m2 elevation in BMI per risk allele. Similar
to the situation with type 2 diabetes, possession of ‘risk’ single nucleotide
polymorphisms (SNPs) only accounts for a small increase in susceptibility
to obesity or adult BMI.
Environmental factors
The drivers of obesity can be considered under two main head-
ings: increased energy (food) intake or decreased energy expenditure due
to physical inactivity, as the major determinants of obesity in genetically
susceptible individuals. Societal changes, e.g. increased availability of high
caloric density foods and sedentary lifestyle, have been one of the main
causes of changes in this balance.
Secondary causes
These are uncommon because, even when linked to weight gain, the dis-
ease usually manifests itself from its particular pathophysiology.
• Hypothyroidism: an important cause to exclude in children but rarely
presents simply with weight gain in adults.
• Cushing’s disease/syndrome: rare, but an important cause to exclude in
obese patients presenting with ‘overlap’ signs and symptoms which can
include striae, depression, and hypertension.
AETIOLOGY OF OBESITY 853
• Hypothalamic lesions: gonadal failure, visual disturbances, headache,

or raised intracranial pressure often predominate as presenting signs,
rather than weight gain and hyperphagia.
• Polycystic ovary syndrome (PCOS): strongly linked to overweight and
obesity but mechanism unclear. Features of hyperandrogenism and
oligomenorrhoea may result from obesity itself.
• Iatrogenic: drugs, e.g. antipsychotic medication, hypoglycaemics
(including insulin) glucocorticoids. Also recreational drugs, e.g.
cannabis.
Pathophysiology of obesity
Energy balance and body weight are regulated, but the main drive of this
allostatic physiology is towards energy acquisition (and thus fat deposition)
and defence against weight loss. Although physiology can be ‘overridden’
by cognitive and behavioural control (e.g. diet, exercise) long-term, these
mechanisms (within our obesogenic environment) usually prove insuffi-
cient in the long-term either to protect against or reverse weight gain.
Long-term signals associated with body fat stores are provided by leptin
and insulin. In human obesity, leptin levels are high, rather than low, cor-
relating with fat mass, suggesting either that leptin ‘resistance’ is present
or that leptin is a starvation, rather than obesity, signal (see Box 15.2 and
Table 15.1).
Gut peptide hormones released after food intake provide acute signals
of hunger, satiety, and fullness (see Box 15.3). Although originally thought
to be short-term signals, the importance of the gut–brain axis as a regu-
lator of body weight in humans has become increasingly apparent from
the effects of bariatric surgery. Ghrelin, a hunger hormone, rises before,
and probably is involved with, initiation of food intake. Satiety hormones
released after food include glucagon-like peptide-1 (GLP-1), an incretin
hormone secreted by ileal L-cells in the distal intestine that stimulates
insulin secretion, and peptide YY secreted from the ileum and colon.
Oxyntomodulin (also derived from preproglucagon) reduces food intake
and increases energy expenditure after systemic administration.
Weight is gained or lost usually in the proportion of 70% fat and 30%
lean tissue, implying that approximately 30MJ (7,000kcal) surplus or deficit
is needed to gain or lose 1 kg in body mass. During the first days of a very
low energy or ketogenic diet, liver glycogen may be the primary source
of stored energy to meet metabolic needs; since it provides about 8MJ/kg,
initial weight loss is more rapid than with less severe energy restriction.
PATHOPHYSIOLOGY OF OBESITY 855
Box 15.2 Leptin

• Synthesized in, and secreted by, adipose tissue (subcut > visceral).
• Encoded by LEP gene (chromosome 7q31.3).
• Hypothalamic receptors, activated through entry via arcuate nucleus
(exposed to peripheral circulation), decrease food intake and
increase energy expenditure (by sympathetic activation).
• Stimulated by glucocorticoids.
• Human obesity persists, despite high circulating levels of leptin
(proportional to fat mass), suggesting resistance to effects or that,
in human physiology, leptin signals low body fat stores, such as in
starvation.
• Mutations in LEP lead to a rare syndrome of hyperphagia, obesity,
hypogonadism, and impaired immunity. Features are reversed by
recombinant leptin replacement.
• In conditions of selective decrease in adipose tissue mass
(lipodystrophy, HIV or HIV therapy-associated lipoatrophy, severe
anorexia nervosa), leptin replacement therapy reverses insulin
resistance.
• In response to fasting, leptin levels fall rapidly before, and out of
proportion to, changes in fat mass, triggering the neuroendocrine
response to acute energy deprivation.
• Trials of leptin augmentation in common obesity do not lead to
weight loss or maintenance of weight loss.
Table 15.1 Leptin deficiency

Type Frequency Features
Complete congenital Rare hyperphagia
hypogonadotrophic
advanced bone age
hyperinsulinaemic
immune dysfunction
Heterozygous 5–6 %
Leptin resistant gene Rare hypogonadotrophic
mutations abnormal GH and TSH secretion
POMC mutation Rare ACTH d red hair, pale skin
MCR 4 mutation Rare i growth
i bone mineral density
Box 15.3 Gut peptide hormones linked to weight

regulation
Ghrelin
• The only known ‘hunger’ hormone.
• Derived from preproghrelin secreted in the stomach, cleaved to
active form acyl ghrelin (28 amino acid peptide) and obestatin.
• Acts on hypothalamic GH secretagogue receptors (GHSR1a) to
increase the release of GH from the pituitary.
• Peripherally injected ghrelin increases food intake through the
stimulation of ghrelin receptors on hypothalamic neuropeptide
Y-expressing neurons and agouti-related protein-expressing neurons.
• Levels in obesity not consistently elevated but are markedly reduced
by bariatric surgery (sleeve gastrectomy and gastric bypass).
• Circulating ghrelin increases preprandially and decreases
postprandially and is thought to regulate premeal hunger and meal
initiation.
• GHSR1a is also expressed in other brain areas, linking to the
mesolimbic reward neuropathway and to central pathways of energy
balance.
• Ghrelin is also involved in modulating reward and motivation in
enhancing the hedonic and incentive response to food-related cues.
Glucagon-like peptide-1 (GLP-1)
• Secreted by L-cells in the distal intestine.
• Stimulates insulin secretion and (in animals) islet cell differentiation
and proliferation.
• Inhibits glucagon secretion; inhibits gastric emptying.
• Unlike GIP, levels of GLP-1 are reduced in patients with diabetes.
• Levels raised preferentially by protein, accounting, in part, of
protein’s higher satiating effects compared to other macronutrients.
• GLP-1 analogues (exenatide and liraglutide) are associated with 75%
weight loss.
• Liraglutide (see b p. 716), in higher doses than used for diabetes
treatment, produces sustained weight loss >10% in non-diabetic
subjects.
• Levels markedly elevated after bariatric surgery.
Peptide YY
• 36 amino acid peptide synthesized and released in L-cells in distal
GI tract.
• Conversion of PYY1-36 to active PYY3-36 by dipeptidyl peptidase IV
(DPP-IV).
• PYY3-36 shows affinity for hypothalamic neuropeptide Y neurones.
• PYY levels are low in the fasting state, rapidly increase in response
to food intake, peak at 1–2h after a meal, and remain elevated for
several hours.
• In addition to regulating food intake, PYY3-36 has additional
metabolic beneficial effects on energy expenditure and fuel
partitioning.
CONSEQUENCES OF OBESITY 857
Consequences of obesity
Most metabolic, physiological, and organ systems are affected by obe-
sity and can be considered under the ‘4 M’ headings: mental, metabolic,
mechanical, and monetary (see Box 15.4).
• Mortality rates rise steadily at BMI >5kg/m2. Obesity and physical
inactivity have both independent and dependent effects on all-cause
mortality.
• Loss of life expectancy: BMI >35kg/m2—5–7 years at age 45.
• Type 2 diabetes: elevation in BMI, the dominant risk factor for
development of diabetes. Relative risk (RR) in overweight men 2.4,
women 12.4; at BMI 30kg/m2 >10; increased to 50–90-fold at BMI >35.
• Hypertension: RR for overweight men 1.8, women 2.4.
• Dyslipidaemia: moderate relationship with total cholesterol, closer
relationship with triglycerides, HDL cholesterol.
• Stroke: RR 1.2 for overweight and 1.5 for obese men and women.
• Asthma: obese 2 ×, overweight 1.4 × more likely to develop asthma.
Box 15.4 Obesity associations and consequences

‘Mental’ ‘Mechanical’ ‘Metabolic’ ‘Monetary’
Depression Sleep apnoea Type 2 diabetes Lower educational
Low self-esteem Hypoventilation Dyslipidaemia achievement
Attention deficit Osteoarthritis Hypertension Employment
disorder Chronic pain IHD discrimination
Eating disorder Gastro-oesophageal Gout Lower income
Cognitive reflux NAFLD and Chronic disability
impairment Incontinence NASH Increased healthcare
Thrombosis Cancer costs
Intertrigo
Management of an obese patient

The use of a structured approach, modified from management of other
chronic diseases, consists of Ask, Assess, Advise, Agree, and Assist (5 As).
Ask permission to discuss weight
A non-judgemental approach, using motivational interviewing techniques,
that also explores the patient’s readiness to change is recommended.
Assess ‘root causes’ of obesity and obesity-related risk
History
• Weight history from birth onwards (early onset may suggest genetic
syndromes).
• Previous treatment/management strategies and their success.
• Current eating habits and triggers for eating/activity levels.
• Family history of obesity and obesity-related disease.
• Symptoms or previous diagnosis of obesity-related diseases, including
CVD, diabetes, psychological issues (eating disorder, depression, low
self-esteem), OA, obstructive sleep apnoea, PCOS.
• Symptoms of reflux.
• Other risks, such as smoking and alcohol intake.
• Drugs that might exacerbate weight gain.
• Patient’s beliefs and expectations.
• Optimal management of other diseases, obesity-related or not.
Examination
• Height, weight, fat distribution.
• General: evidence for syndrome (e.g. small hands and facies in Prader–
Willi syndrome), mood.
• Skin: acanthosis nigricans and skin tags (insulin resistance), intertrigo,
fat distribution (partial lipodystrophy).
• Cardiovascular: hypertension, heart failure, and other causes for
breathlessness.
• Respiratory: airway, obstructive sleep apnoea (somnolence), pulmonary
hypertension, cardiopulmonary fitness (consider 6-minute walk test).
• GI: hepatomegaly, herniae (may influence bariatric surgery).
• Musculoskeletal: mobility.
• Consider other diagnoses: hypothyroidism, Cushing’s syndrome,
haemochromatosis.
Investigations
• Blood count and iron studies (iron deficiency anaemia from reflux or
GI bleeding; polycythaemia from hypoventilation).
• Renal function.
• Liver function (non-alcoholic steatohepatitis).
• Glucose, HbA1c, and possibly insulin (prediabetes, diabetes).
• Fasting lipid profile (raised triglycerides, total and LDL cholesterol,
lowered HDL cholesterol).
• Vitamin D (often deficient in the obese).
• Thyroid function (hypothyroidism).
• ECG (atrial fibrillation, left ventricular hypertrophy).
MANAGEMENT OF AN OBESE PATIENT 859
Additional tests
• Liver ultrasound if abnormal liver function to confirm NAFLD.
• Echocardiogram if heart failure suspected.
• Pharmacological stress testing if ischaemic heart disease suspected
(subject may be unable to undertake exercise test).
• Endoscopy if anaemia—gastroscopy if reflux disease, colonoscopy if
colon cancer suspected.
• Gynaecological referral if post-menopausal bleeding (high incidence of
endometrial cancer in obese women).
• Dexamethasone suppression (overnight or low-dose) if Cushing’s
disease suspected.
• Transferrin, then genetic testing for haemochromatosis in patients with
type 2 diabetes and abnormal liver function.
Advise on risks of obesity, benefits of weight loss and treatment options,
and the need for a long-term strategy. Treatment options include:
• Stress management and self-assertiveness training.
• Dietary intervention.
• Physical activity.
• Psychological counselling.
• Anti-obesity medication.
• Bariatric surgery.
Agree on:
• Weight loss goals.
• Behavioural goals and health outcomes.
• Management plan.
Assist in addressing drivers and barriers to weight management; offer
referral to appropriate provider (primary care for diet and lifestyle pro-
grammes, psychology services if binge eating disorder or severe depres-
sion, secondary care if obesity severe or complex).
General principles
Dietary energy restriction produces greater weight loss than exercise.
Increased physical activity and exercise predicts weight loss maintenance.
Patients’ expectations frequently exceed realistic goals or need.
A weight loss of 5–10% of the initial body weight reduces many
of the health risks associated with obesity and reduces cancer and
diabetes-related mortality; a 5kg loss in adults with prediabetes reduces
progression to diabetes by 60%, maintained even if weight regain occurs. In
patients with a BMI >35kg/m2, greater weight loss (>10kg or 15%) is likely
to be needed to produce a sustained improvement in comorbid diseases;
10–15% may be needed.
Diet, physical activity, and behavioural therapy
• Dietary advice should aim to reduce energy intake to produce a 2.5MJ
(600kcal)/day deficit (calculated from standard equations of resting
energy expenditure and assuming a physical activity level (PAL) of
1.3). Both low carbohydrate (<30g/day) and low fat (<30% total daily
energy) produce equivalent weight loss (4–5kg) at 1 year. High-protein
diets may be more satiating.
• Commercial providers (e.g. Weight Watchers, Rosemary Conley) can

achieve equivalent, or better, results than GPs or pharmacists.
• Low (3.4–5MJ; 800–1,200kcal/day) and very low (<3.5MJ, 800kcal/day)
diets produce more rapid initial weight loss and, in combination with
behaviour therapy and pharmacotherapy, produce sustained weight
loss greater than that achieved with conventional diets.
• Regular exercise induces cardiorespiratory fitness and leads to a
beneficial effect on other risk factors, with a reduction in blood
pressure and improvement in lipid profile.
• The PAR-Q physical activity readiness questionnaire provides a quick
and validated screening tool to risk-assess patients before they start an
exercise programme.
• 225–300min/week of moderate intensity exercise (equivalent to
7.5–10.5MJ, 1,800–2,500kcal) is recommended for weight loss
maintenance.
• Behavioural interventions may include self-monitoring of behaviour
and progress, stimulus control, goal-setting, problem-solving and
assertiveness training, relapse prevention and management but has
only been shown to provide modest benefit in terms of weight
outcomes
Anti-obesity drugs
In Europe, only orlistat is licensed; elsewhere, phentermine is widely
prescribed. Several new drugs (lorcaserin, a 5HT2c agonist; Qnexa®, a
combination of phentermine and topiramate; Contrave®, a combination of
naltrexone and bupropion) are currently under review by the US licens-
ing authorities. The GLP-1 agonist liraglutide is in phase 3 trials, at higher
doses than used for treating diabetes, as a weight loss drug in non-diabetic
patients. Off-label use of drugs is not recommended: the history of
anti-obesity pharmacotherapy has seen many adverse effects emerge, even
with well-investigated and developed drugs, such as sibutramine (with-
drawn in 2010 due to adverse cardiovascular outcomes) and rimonabant
(withdrawn in 2009 due to depression and suicide risk).
Orlistat
• Intestinal pancreatic lipase inhibitor; reduces fat absorption.
• Increases dietary fat loss to 30% (compared to <5% on placebo).
• Best used in those at medical risk from obesity: BMI >30kg/m2 or
BMI >27 with established comorbidities (e.g. diabetes, heart disease,
dyslipidaemia).
• May have modest insulin-sensitizing effects over and above weight loss
(reduced portal triglyceride levels).
• Only use in patients who achieve at least 2.5kg weight loss in 4 weeks
using a dietary programme alone (NICE guidelines). This ensures
adequate dietary compliance with a low-fat diet (ideally <50g/day) and
minimizes GI side effects.
• Average weight loss of 8% at 1 year.
• NICE guidelines:
• At 3 months, stop if <5% weight loss.
• At 6 months, stop if <10% weight loss (of initial weight).
MANAGEMENT OF AN OBESE PATIENT 861
• Contraindications: cholestasis, hepatic dysfunction, malabsorption,

pregnancy, breastfeeding, concomitant use of fibrate, acarbose, renal
impairment (creatinine >150micromol/L), anticoagulation (possible
d vitamin K absorption with orlistat).
• Consider vitamin supplementation (especially vitamin D) if used
beyond 1 year.
• Side effects (must warn patient): flatus (24%), oily rectal discharge,
fatty stool (20%), faecal urgency (22%), fat-soluble vitamin deficiency,
incontinence (8%). Limited by dietary fat reduction (to <35% of
energy).
Bariatric surgery
Three types of surgery are commonly performed—all usually done lapa-
roscopically. The most compelling data for the success of bariatric surgery
at producing weight loss and improving the clinical outcomes for obese
patients come from the 20-year follow-up data of the Swedish Obese
Subjects study (a case control study started at a time when surgical tech-
niques were not as advanced as nowadays). The persistent weight loss in
the surgical groups was associated with a much reduced mortality: the
unadjusted overall hazard ratio was 0.76 in the surgery group (P = 0.04),
compared with the control group, and the hazard ratio adjusted for sex,
age, and risk factors was 0.71 (P = 0.01). Other studies have confirmed
that bariatric surgery is associated with reduced all-cause mortality, includ-
ing deaths from CVD, diabetes, and cancer.
In patients with type 2 diabetes, benefit extends beyond weight loss. Up
to 80% of people with type 2 diabetes may experience remission of their
diabetes (normoglycaemia without the need for hypoglycaemic medica-
tion), the exact remission rate being determined by the type of surgery
and the duration of diabetes prior to surgery.
Gastric bypass (see Fig. 15.1)
Patients will lose approximately 50–75% of their excess weight (30–40%
absolute weight loss) within 12–18 months of surgery. The large majority
(>80%) of patients will have a significant improvement or resolution of
their weight-related illnesses, and most patients report dramatic changes
to their quality of life. Routine supplementation of vitamins, minerals, and
vitamin B12 is required.
The gastric bypass works in the following way:
• There is a restriction in food intake, as the stomach is reduced to the
size of a large egg.
• Food bypasses digestive secretions, causing some malabsorption.
• Profound changes are seen in gut hormones that control hunger,
satiety, and glucose metabolism (reduced ghrelin, increased and earlier
release of GLP-1 and PYY).
• Other mechanisms, involving changes in gut flora and bile salt
metabolism that affect appetite and CV risk, are also postulated.
Sleeve gastrectomy (see Fig. 15.2)
Patients will lose approximately 50–75% (30–40% absolute weight loss)
of their excess weight within 12–18 months of surgery. Again, >80% have
a significant improvement in weight-related illnesses and improved QoL.
Routine supplementation of vitamins is required for the first year.
The sleeve gastrectomy works in the following way:
• 75% of the stomach is removed, restricting the volume of food patients
are able to eat in one sitting.
• Gastric emptying is faster which alters gut hormone profiles, resulting
in satiety (reduced ghrelin, increased and earlier release of GLP-1
and PYY).
Gastric Bypass
Fig. 15.1 Gastric bypass.
Sleeve Gastrectomy
Fig. 15.2 Sleeve gastrectomy.

Adjustable gastric banding (see Fig. 15.3)

Patients will lose approximately 50% of their excess weight (30% absolute
weight loss) within 2–3 years of surgery. Routine supplementation of vita-
mins, minerals, and vitamin B12 is not usually needed beyond the first year.
The gastric band works in the following way:
• Gastric restriction is achieved by placing an adjustable silastic band
around the upper gastric cardia that can be tightened or loosened by
injecting saline into a tube that connects to a port under the skin. The
restriction slows the speed of eating.
• Patients are required to attend clinic for band consultations every
2–3 months until the right degree of band adjustment is achieved.
Pre- and post-operative care needs to be provided by specialist
multidisciplinary teams.
Bariatric surgery and diabetes
In 2011, the International Diabetes Federation recommended that bari-
atric surgery:
• Constitutes a powerful option to ameliorate diabetes in severely obese
patients, often normalizing blood glucose levels, reducing or avoiding
the need for medications, and providing a potentially cost-effective
approach to treating the disease.
• Is an appropriate treatment for people with type 2 diabetes and
obesity not achieving recommended treatment targets with medical
therapies.
Adjustable Gastric Band
Fig. 15.3 Adjustable gastric banding.

• Should be an accepted option in people who have type 2 diabetes

and a BMI >35 and even an alternative treatment option in patients
with a BMI between 30 and 35 when diabetes cannot be adequately
controlled by optimal medical regimen, especially in the presence of
other major cardiovascular disease risk factors.
Further reading
Chandarana K, Gelegen C, Karra E, et al. (2011). Diet and gastrointestinal bypass–induced weight
loss. The roles of ghrelin and peptide YY. Diabetes 60, 810–18.
Hinney A, Vogel CIG, Hebebrand J (2010). From monogenic to polygenic obesity: recent advances.
Eur Child Adolesc Psychiatry 19, 297–310.
Kelesedis T, Kelesidis I, Chou S, et al. (2010). Narrative review: the role of leptin in human physiol-
ogy: emerging clinical applications. Ann Intern Med 152, 93–100.
National Institute for Health and Clinical Excellence (NICE) Clinical guideline 43: obesity guidance on
the prevention, identification, assessment, and management of overweight and obesity in adults
and children. Available at: M http://www.nice.org.uk/nicemedia/live/11000/30365/30365.pdf.
Ramachandran S, Farooqi IS (2011). Genetic approaches to understanding human obesity. J Clin
Invest 121, 2080–6.
Rucher D, Padwal R, Li SK, et al. (2007). Long term pharmacotherapy for obesity and over-
weight: updated meta-analysis. BMJ 335, 1194–9.
Scottish Intercollegiate Guidelines Network (2010). Management of obesity: a national clinical
guideline. Edinburgh. Available at: M http://www.sign.ac.uk.
Sharma AM, Kushner AF (2009). A proposed clinical staging system for obesity. Int J Obes (Lond)
33, 289–95.
Sjöström L, Peltonen M, Jacobsen P, et al. (2012). Bariatric surgery and long-term cardiovascular
events. JAMA 307, 56–65.
Tsigos C, Hainer V, Basdevant A, et al. (2008). Management of obesity in adults: European clinical
practice guidelines. Obesity facts 1, 106–16.
Appendix 1 867
Pitfalls in laboratory
endocrinology
Introduction 868
Analytical factors 870
Post-analytical factors 872
868 APPENDIX 1
Introduction
As with all biochemical investigations, their usefulness lies in careful and
appropriate selection, combined with discerning interpretation. Where
neither is possible nor simple, the chemical pathologist, or other members
of the analysing laboratory, would always be happy to help.
The results obtained by the wide variety of analytical techniques can
be altered by many factors, some associated with an underlying pathol-
ogy and others not. A brief consideration of potential confounding factors
seems relevant here.
Box A1.1 Factors influencing laboratory investigations

• Pre-analytical factors:
• Sample timing—in relation to dose, stimulation, suppression,
diurnal variation, etc.
• Which tube, preservative, order of blood collection into a variety
of different tubes?
• Rapidity and temperature of transport required to maintain
sample stability, or when to centrifuge and separate.
• Biological variation—within-person variation (see Box A1.2).
• Which stimulation/suppression test?
• Analytical factors:
• Assay specificity, sensitivity, and overall performance.
• Assay standardization—quality control, quality assurance.
• Analytical performance—precision, accuracy, robustness, etc.
• Hook effects (e.g. prolactin) in very high concentrations, requiring
dilution and re-measurement to exclude as a confounding factor.
• Sample interference—haemolysis, lipaemia, or icteric/elevated
bilirubin levels. Most analysers have automatic detection levels of
each interference.
• Antibody interference—heterophilic antibodies can increase
assayed, but not biologically active, measurements.
• Particularly problematic assays—very low concentrations, poorly
specific antibodies, commonly occurring interferences, etc.
• Post-analytical factors:
• Reference interval.
• Units of standardization.
• Interpretation in the specific clinical setting and dynamic function
test—complicated results are often best addressed by joint
endocrinologist’s and chemical pathologist’s input in MDT
meetings.
APPENDIX 1 869
Box A1.2 Examples of within-person (biological) variation

• Aldosterone, 29%
• Androstenedione, 16%
• CA125, 36%
• CA153, 5.7%
• CEA, 10.6%
• DHAS, 3.4%
• Prolactin, 24%
• SHBG, 9%
• Testosterone (♂), 10%
• TSH, 20%
Variation expressed as cv (%) (Coefficient of variation = (standard
deviation/mean) × 100).
870 APPENDIX 1
Analytical factors
Most endocrine assays are immunoassays which rely on binding of an
analyte by a diagnostic antibody. The binding specificity will depend on
the care and attention with which the manufacturer has chosen the rea-
gents. Typical interferences in small molecules are due to slightly differ-
ent molecular forms and typically occur with steroid and digoxin assays.
Peptide hormones are more complex because so many differently glyco-
sylated forms of those peptides exist.
Standards for pituitary hormones are generally derived from purified
pituitary extracts which contain a mixture of peptides. This leads to differ-
ent assays having quite marked biases between each other due to different
binding affinities of the antibodies to the different isoforms. A similar situ-
ation exists with hCG for which many multiple molecular forms co-exist.
Attempts to find international consensus for standards which can be used
in diagnostic systems are being made, particularly for growth hormone and
glycated haemoglobin at the present time.
Analytical performance or assay reproducibility is important in deter-
mining the critical differences between patient samples. A significant dif-
ference between consecutive samples at 95% confidence will require a
difference of 1.96 x the method standard deviation at the appropriate
concentration.
The hook effect occurs when very high analyte concentrations flood
the available antibody in vitro and this leads to artefactually low results.
It is less common nowadays as assays have large dynamic ranges but new
cases continue to be reported, and there are published case reports for all
hormones and tumour markers.
Antibody interference is a widespread problem that affects approxi-
mately 1% of immunoassays. It is insidious and is due to endogenous
antibodies which interfere with analyte binding in vitro. Most importantly,
they cannot be detected by usual quality control mechanisms. There are
a number of laboratory techniques that can be used to clarify whether
such interference is present but it is inherent on the clinician to alert the
laboratory to a potential clinical mismatch.
Some assays can only be classified as problem assays. These include
thyroglobulin and low concentrations of oestradiol (<300pmol/L) and
testosterone (<5nmol/L). The former is due to the high prevalence of
endogenous anti-thyroglobulin antibodies which are particularly prevalent
in patients with thyroid disease. The latter are due to antibody specificity;
however, it is hoped that this will be resolved with the introduction of
mass spectrometry into routine clinical practice.
APPENDIX 1 871
Post-analytical factors
Interpretation of assay results is made in relation to reference ranges
provided by the laboratory. These usually represent the 95th centiles of
a population of healthy individuals. However, the definition of normal-
ity is subjective and reference ranges are affected by such factors as age,
gender, and in some cases by ethnicity. Moreover, for hormones, time of
day, month, and season will be important. For some analytes, it is diffi cult
to obtain appropriate samples to construct ranges such as in children and
circumstances that are difficult to obtain in health e.g. following pharma-
cological stimulation or samples of CSF.
If the central 95th centile reference ranges are used, there is a 5% chance
that a result will be out-of-range due to chance. As the number of tests
taken are i, so will the risk of a chance abnormality. The increase will be
x% (where x = 1 – 0.95a and a is the number of tests performed).
Literature from the USA and European journals may use different
units—beware! SI units use molar or mass (g) and volumes reported in
litres.
Most assays are standardized with international preparations. These
are usually the molecular forms that are most prevalent when basal sam-
ples are taken. However, following stimulation non-standard molecules
are released into the circulation which have different clearance rates and
different binding characteristics to the diagnostic antibodies in vitro. This
can lead to marked differences between methods. For example, following
stimulation by ACTH corticosteroid precursors are released which will
compete with cortisol for binding in the assay; similarly following stimula-
tion of GH release different isoforms of GH are secreted and the most
abundant 20 and 22kDa isoforms clear at different rates leading to varia-
tions in recognition by the diagnostic antibodies at different times during
the test.
Box A1.3 Disastrous outcomes

• Assay interference: a series of patients has been described in whom
aggressive therapy for chorioncarcinoma was instituted for diagnoses
that were based on assays affected by in vitro artefacts.
• Antibody specificity: a patient has been described who had prolactin
measured by 3 different assays giving 3 different answers. The
solution awaited a clinical answer when the hyperprolactinaemia
resolved after stopping the offending medication.
• Interference by insulin auto-antibodies: a patient has been described
with recurrent hypoglycaemia due to insulin auto antibodies caused
by myeloma. This patient demonstrated in vivo interference by
endogenous antibodies as well as in vitro interference.
• Hook effect: a patient presents with a large pituitary tumour that
appears to be non-functioning as the prolactin is normal and the
patient is treated surgically. The following day the blood sample is
reassayed after dilution and the high prolactin is uncovered when the
antibody is no longer flooded by excess prolactin.
Appendix 2 873
Reference intervals
874 APPENDIX 2
Introduction
All values are for serum unless specified otherwise.
Box A2.1 Definitions

• Serum. A serum sample is collected in a plain tube, left to permit
clotting, then centrifuged and separated.
• Plasma. A plasma specimen is collected in a tube containing EDTA or
lithium heparin, centrifuged immediately, and separated.
Box A2.2 Table notes

a
EDTA tube cold spun immediately and frozen on separation.
b
Serum, cold spun, flash frozen.
c
Fasting sample collected into 2 × EDTA tubes, cold spun, and flash
frozen.
d
Acid-containing container (20mL 6M HCl).
Table A2.1 Thyroid function

Analyte SI units Traditional units Conversion factor
TSH 0.35–5.50mU/L 0.35–5.50mU/L 1
Free T4 10.5–20pmol/L 0.8–1.6ng/dL 12.9
Total T3 0.9–2.8nmol/L 60–190ng/dL 0.015
Free T3 3.5–6.5pmol/L 2.3–4.3pg/mL 1.54
Thyroid-binding 13–28ng/L
globulin
Thyroid-stimulating <7U/L
hormone receptor
antibodies
Antithyroid <50IU/mL
peroxidase antibodies
APPENDIX 2 875
Table A2.2 Adrenal and gonadal function

Analyte SI units Traditional Conversion
units factor
Cortisol 180–620nmol/L 6.5–22.5ng/dL 27.6
(9 a.m.)
Aldosterone Random 100–800pmol/L 3.6–28.9ng/dL 27.7
(Charing Cross) Supine 100–450pmol/L 3.6–16.2ng/dL 27.7
Plasma renin Random 0.5–3.1pmol/mL/h N/A*
activity Supine 1.1–2.7pmol/mL/h N/A
(Charing Cross) Ambulant 2.8–4.5pmol/mL/h N/A
(30min)
Serum 24–46nmol/L
11-deoxycortisol
DHEAS ♀ 1.9–9.4micromol/L 5.1–25.4pg/mL 0.0027
♂ 2.8–12micromol/L 7.6–32.4pg/mL 0.0027
Androstenedione ♀ 3.0–8.0nmol/L 10.5–27.5 3.49
micrograms/L
♂ 3.0–8.0nmol/L 10.5–27.5 3.49
micrograms/L
17-hydroxy- ♀
progesterone Follicular 1–8.7nmol/L 3.3–28.7 3.3
(Barts) micrograms/L
Luteal <18nmol/L <59.4
micrograms/L
♂ 1–8.7nmol/L 3.3–28.7 3.3
micrograms/L
Neonatal 20nmol/L <66
micrograms/L
Oestradiol ♀ Follicular 69–905pmol/L 248–325pg/mL 3.6
Midcycle 130–2095pmol/L 468–7542pg/mL 3.6
Luteal 82–940pmol/L 295–3384pg/mL 3.6
♂ 43–151pmol/L 155–544pg/mL 3.6
Progesterone ♀ 0–90nmol/L 0–288ng/mL 3.2
♂ 0–10nmol/L 0–32ng/mL 3.2
Testosterone ♀ 0.5–2.6nmol/L 1.7–9ng/mL 3.5
♂ 8.4–28.7nmol/L 29–100ng/mL 3.5
DHT (Barts) ♀ 0.1–0.8nmol/L 2.9–23ng/dL 0.034
♂ 1–2.9nmol/L 29–85ng/dL 0.034
SHBG ♀ 18–114nmol/L 18–114nmol/L 1
♂ 13–71nmol/L 13–71nmol/L 1
Adrenaline (after 0.03–1.31nmol/L
30min resting)
Noradrenaline 0.47–4.14nmol/L
(after 30min
resting)
* A variety of different units are used by non-UN labs.
876 APPENDIX 2
Table A2.3 Pituitary hormones

Analyte SI units Traditional Conversion
units factor
FSH ♀ Follicular 2.5–10.2U/L 2.5–10.2mU/mL 1
Midcycle 3.4–33.4U/L 3.4–33.4mU/mL 1
Luteal 1.5–9.1U/L 1.5–9.1mU/mL 1
Post-menopausal 23–116U/L 23-116mU/mL 1
♂ 1.4–18.1U/L 1.4–18.1mU/mL 1
LH ♀ Follicular 1.9–12.5U/L 1.9–12.5mU/mL 1
Midcycle 8.7–76.3U/L 8.7–76.3mU/mL 1
Luteal 0.5–16.9U/L 0.5–16.9mU/mL 1
Post-menopausal 15.9–54U/L 15.9–54mU/mL 1
♂ 1.5–9.3U/L 1.5–9.3mU/mL 1
Prolactin ♀ 60–620mU/L 3–31ng/mL 20
♂ 45–375mU/L 2.2–19ng/mL 20
IGF-1 20 years 16–118nmol/L 120–885ng/mL 7.5
40 years 14–47nmol/L 105–353ng/mL
60 years 10.5–35nmol/L 79–263ng/mL
>60 years 7.0–28nmol/L 52–210ng/mL
IGF-1:IGF-2 >10
ratio
ACTHa 2.2–17.6pmol/L 10–80ng/L 0.22
Inhibin B 80–150pg/mL
(Charing
Cross)
a
APPENDIX 2 877
Table A2.4 Bone biochemistry

Parathyroid 1.3–7.6pmol/L 13–73pg/mL 0.1
hormoneb
Total 25-hydroxy- 25–125nmol/L 10–50ng/mL 2.5
colecalciferolb
25-hydroxycalcitriol 2.4
Deficiency <30nmol/L <12.5ng/mL
Insufficiency 30–79nmol/L 12.5–33ng/mL
Sufficiency 80–150nmol/L 33–63ng/mL
1,25-dihydroxy- 43–144pmol/L 18–60pg/mL 2.4
colecalciferolb
(Liverpool)
Calcitonina <0.10ng/L
P1NPb procollagen 20–60
extension peptide micrograms/L
a
b
Serum, cold spun, flash frozen.
Table A2.5 Plasma gastrointestinal and pancreatic hormones

Insulin (fasting) 18–77pmol/L 2.6–11.1mU/L 6.9
C-peptide (fasting) 0.27–1.28nmol/L 0.8–3.88ng/mL 0.33
Gastrinc 0–40pmol/L 0–89pg/mL 0.45
Glucagonc 0–50 pmol/L 0–179pg/mL 0.28
Vasoactive 0–30pmol/L 0–71pg/mL 0.42
intestinal
polypeptide (VIP)c
Pancreatic 0–300pmol/L 0–1250pg/mL 0.24
polypeptidec
Somatostatinc 0–150pmol/L
Chromogranin Ac 0–60pmol/L
Chromogranin Bc 0–150pmol/L
Neurotensinc 0–100pmol/L
c
2× EDTA tubes cold spun and flash frozen.
878 APPENDIX 2
Table A2.6 Tumour markers

Analyte SI units
B-hCG 0–4U/L
Carcinoembryonic antigen (CEA) 0–3U/L
Prostate-specific antigen (PSA) 0–4 micrograms/L
Alpha fetoprotein 0–7IU/mL
Table A2.7 Urinary collections (1)

Analyte ♀ SI units ♂ SI units
(micromol/24h) (micromol/24h)
Normetadrenalined
20–40 years 3.0 3.6
40–60 years 3.45 4.25
60–80 years 3.65 4.5
Metadrenalined
20–40 years 1.4 1.9
40–60 years 1.4 1.9
60–80 years 1.4 1.9
3-methoxytyramined
20–40 years 2.75 3.3
40–60 years 2.55 3.1
60–80 years 2.3 2.8
d
Table A2.8 Urinary collections (2)

Urinary SI units Traditional SI units Conversion
analyte (mmol/L) units (mmol/24h) factor
Cortisol 0–560
Calcium 1.25–3.75 50–150mg/L 2.5–7.5 0.025
Phosphate 7.5–25 0.2–0.8mg/L 12.9–42 32.3
Potassium 20–60 20–60mmol/L ♀: 34–103 1.0
♂: 37–139
Sodium 50–125 50–125mmol/L ♀: 61–214 1.0
♂: 83–287
5-hydroxyin- 1.9–7.7mg/24h 10–40Umol/L/24h 5.2
doleacetic acidd
Aldosterone 14–53nmol/L
d
APPENDIX 2 879
Table A2.9 Table of analyses

Analyte SI Units Other Units Conversion factor
Fasting Glucose1
Normal ≤6.0 mmol/l ≤108mg/dl
Impaired fasting ≥6.1<7.0 ≥11<126mg/dl
glycaemia mmol/l
Diabetes ≥7.0 mmol/l ≥126mg/dl
2-hour glucose in 18
75g OGTT:
Normal <7.8 mmol/l <140 mg/dl
Impaired glucose ≥7.8 <11.1 ≥140<200mg/dl
tolerance mmol/l
Diabetes ≥11.1 mmol/ ≥200mg/dl
HbA1c < 48 mmol/ <6.5 mmol/mol value =
(non-diabetic mol (% value x 10.93) – 23.5
range) % value=(0.0915 x mmol/
mol value) + 2.152
Total Cholesterol3 ≤ 6.5 mmol/l 195 mg/dl
HDL-Cholesterol3 >1.5 mmol/ >60 mg/dl 38.6
LDL-Cholesterol3 ≤4 115 mg/dl
Fasting 0.55–1.9 49–168 mg/dl 88.5
triglycerides mmol/l
Adiponectin N/A Males Females N/A
Inversely µg/ml µg/ml
correlated with 5–25 5–35
body % fat
Leptin N/A Males Females N/A
Correlated with ng/ml ng/ml
% body fat 1–10 4–25
1.
Figures quoted are World Health Organisation definitions. The American Diabetes
Association have a lower cut off for normal fasting glucose of 5.6 mmol/l or 100mg/dl
2.
Not straightforward, best to download a converter to your smartphone or print out a chart
for the clinic wall.
3.
The appropriate cholesterol level for an individual depends on cardiovascular risk, presence
of diabetes and whether primary or secondary prevention. The figures quoted would be
appropriate for primary prevention. See also b pp. 810, 824.
Appendix 3 881
Patient support groups

and other endocrine
organizations
882 APPENDIX 3
Addison’s Disease Self-Help Group

Conditions: Addison’s disease
Web: http://www.adshg.org.uk/
ALDLIFE
Conditions: Adrenoleukodystrophy and adrenomyeloneuropathy
Phone: 0208 473 7493
Email: [email protected]
Web: http://aldlife.org/
Androgen Insensitivity Syndrome Support Group
Conditions: Complete and partial androgen insensitivity syndrome and
related conditions (e.g. Swyer’s syndrome, 5 alpha-reductase deficiency,
Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome)
Web: http://www.aissg.org/
Anorchidism Support Group
Conditions: Anorchidism
Helpline: 01708 372597
Web: http://www.asg4u.org/
Association for Multiple Endocrine Neoplasia Disorders
Conditions: Multiple endocrine neoplasia disorders and associated endocrine
growths.
Phone: 01892 516076
Web: http://www.amend.org.uk/
British Thyroid Foundation
Conditions: Disorders of the thyroid gland
Phone: 01423 709707
Email: Via form on website
Web: http://www.btf-thyroid.org/
British Thyroid Association
Web: www.british-thyroid-association.org
Butterfly Thyroid Cancer Trust
Conditions: Thyroid cancer
Phone: 01207 545469
Web: http://www.butterfly.org.uk/
Child Growth Foundation
Conditions: Growth related conditions including Turner syndrome, growth
hormone deficiency and premature sexual maturity
Phone: 0208 995 0257
Web: http://www.childgrowthfoundation.org/
APPENDIX 3 883
CLIMB (Children Living with Inherited Metabolic

Conditions)
Conditions: Inherited metabolic diseases
Phone: 0800 652 3181
Web: http://www.climb.org.uk/
Living with CAH – Congenital Adrenal Hyperplasia Support
Group
Conditions: Congenital Adrenal Hyperplasia
Phone: 01525 717536
Web: http://www.livingwithcah.com/
Daisy Network
Conditions: Premature menopause
Web: http//www.daisynetwork.org.uk/
Diabetes UK
Conditions: Diabetes mellitus
Phone: 0845 120 2960
Web: http://www.diabetes.org.uk/
dsdfamilies
Conditions: Disorders of sex development
Web: http://www.dsdfamilies.org/
FIPA Patients
Conditions: Familial isolated pituitary adenoma
Web: http://www.geneticalliance.org.uk/
The Gender Trust
Web: www.gendertrust.org.uk
Genetic Alliance UK
Conditions: All genetic disorders
Web: http://www.geneticalliance.org.uk/
Hypoparathyroidism UK
Conditions: Hypoparathyroidism and other parathyroid conditions
Web: http://www.hypoparathyroidism.orn.uk/
Infertility Network UK
Conditions: All conditions related to male and female fertility
Phone: 0800 008 7464
Web: http://www.infertilitynetworkuk.com/
884 APPENDIX 3
Kallman Syndrome Organisation

Conditions: Kallman’s syndrome
Web: http://www.kallmanns.org
Klinefelter’s Organisation
Web: http://www.klinefelter.org.uk/
Klinefelte’s Syndrome Association
Conditions: Klinefelter’s syndrome
Phone: 0845 230 0047
Web: http://www.ksa-uk.co.uk/
Men’s Health Forum’s
Conditions: General information on male health
Web: http://www.menshealthforum.org.uk/
National Association for Premenstrual Syndrome (NAPS)
Conditions: Premenstrual syndrome
Phone: 0844 815 7311
Web: http://www.pms.org.uk/
National Osteoporosis Society
Conditions: Osteoporosis
Phone: 0845 450 0230
Web: http://www.nos.org.uk/
NET Patient Foundation
Conditions: Neuroendocrine tumours
Phone: 0800 434 6476
Web: http://www.netpatientfoundation.com/
Paget’s Association
Conditions: Paget’s syndrome
Phone:
Email:
Web: http://www.pagets.org.uk/
Pituitary Foundation
Conditions: Disorders of the pituitary gland
Phone: 0845 450 0375
Web: http://www.pituitary.org.uk/
APPENDIX 3 885
Prader-Willi Syndrome Association UK

Conditions: Prader-Willi syndrome
Phone: 01332 365 676
Web: http://pwsa.co.uk
Restricted Growth Association
Conditions: Conditions which cause restricted growth
Phone: 0300 111 1970
Web: http://www.restrictedgrowth.co.uk/
Sexual Advice Association
Conditions: Male and female sexual disorders
Phone: 020 7486 7262
Web: http://www.sda.uk.net/
The Gender Trust
Conditions: Gender identity
Web: http://www.gendertrust.org.uk/
Thyroid Eye Disease Charitable Trust
Conditions: Thyroid eye disease
Phone: 0844 800 8133
Web: http://www.tedct.co.uk/
Turner Syndrome Support Society
Conditions: Turner syndrome
Phone: 0300 111 7520
Web: http://www.tss.org.uk/
Unique
Conditions: Conditions caused by rare chromosome disorders
Phone: 01883 330766
Web: http://www.rarechromo.org/
Verity (PCOS)
Conditions: Polycystic ovary syndrome
Web: http://www.verity-pcos.org.uk/
Weight Concern
Conditions: Obesity
Web: http://www.weightconcern.org.uk/
886 APPENDIX 3
Women’s Health Concern

Conditions: General information on female health
Web: http://www.womens-health-concern.org/
You & Your Hormones
Conditions: General information on endocrine conditions
Web: http://www.yourhormones.info
BMI ready reckoner
BODY MASS INDEX READY RECKONER FOR ADULTS
Height (m)
1.38 1.42 1.46 1.50 1.54 1.58 1.62 1.66 1.70 1.74 1.78 1.82 1.86 1.90 1.94 1.98
150 79 74 70 67 63 60 57 54 52 50 47 45 43 42 40 38 23st 8
148 78 73 69 66 62 59 56 54 51 49 47 45 43 41 39 38 23st 3
146 77 72 68 65 62 58 56 53 51 48 46 44 42 40 39 37 22st 13
144 76 71 68 64 61 58 55 52 50 48 45 43 42 40 38 37 22st 9
142 75 70 67 63 60 57 54 52 49 47 45 43 41 39 38 36 22st 4
140 74 69 66 62 59 56 53 51 48 46 44 42 40 39 37 36 22st
138 72 68 65 61 58 55 53 50 48 46 44 42 40 38 37 35 21st 10
136 71 67 64 60 57 54 52 49 47 45 43 41 39 38 36 35 21st 5
134 70 66 63 60 57 54 51 49 46 44 42 40 39 37 36 34 21st 1
132 69 65 62 59 56 53 50 48 46 44 42 40 38 37 35 34 20st 10
130 68 64 61 58 55 52 50 47 45 43 41 39 38 36 35 33 20st 6
128 67 63 60 57 54 51 49 46 44 42 40 39 37 35 34 33 20st 2
126 66 62 59 56 53 50 48 46 44 42 40 38 36 35 33 32 19st 12
124 65 61 58 55 52 50 47 45 43 41 39 37 36 34 33 32 19st 7
122 64 61 57 54 51 49 46 44 42 40 39 37 35 34 32 31 19st 3
120 63 60 56 53 51 48 46 44 42 40 38 36 35 33 32 31 18st 13
118 62 59 55 52 50 47 45 43 41 39 37 36 34 33 31 30 18st 8
116 61 58 54 52 49 46 44 42 40 38 37 35 34 32 31 30 18st 4
114 60 57 53 51 48 46 43 41 39 38 36 34 33 32 30 29 17st 13
112 59 56 53 50 47 45 43 41 39 37 35 34 32 31 30 29 17st 9
110 58 55 52 49 46 44 42 40 38 36 35 33 32 30 29 28 17st 5
108 57 54 51 48 46 43 41 39 37 36 34 33 31 30 29 28 17st
106 56 53 50 47 45 42 40 38 37 35 33 32 31 29 28 27 16st 10
104 55 52 49 46 44 42 40 38 36 34 33 31 30 29 28 27 16st 5
102 54 51 48 45 43 41 39 37 35 34 32 31 29 28 27 26 16st 1
100 53 50 47 44 42 40 38 36 35 33 32 30 29 28 27 26 15st 10
weight (st / lbs)

98 51 49 46 44 41 39 37 36 34 32 31 30 28 27 26 25 15st 6
weight (kg)
96 50 48 45 43 40 38 37 35 33 32 30 29 28 27 26 24 15st 2
94 49 47 44 42 40 38 36 34 33 31 30 28 27 26 25 24 14st 11
92 48 46 43 41 39 37 35 33 32 30 29 28 27 25 24 23 14st 7
90 47 45 42 40 38 36 34 33 31 30 28 27 26 25 24 23 14st 2
88 46 44 41 39 37 35 34 32 30 29 28 27 25 24 23 22 13st 12
86 45 43 40 38 36 34 33 31 30 28 27 26 25 24 23 22 13st 8
84 44 42 39 37 35 34 32 30 29 28 27 25 24 23 22 21 13st 3
82 43 41 38 36 35 33 31 30 28 27 26 25 24 23 22 21 12st 13
80 42 40 38 36 34 32 30 29 28 26 25 24 23 22 21 20 12st 8
78 41 39 37 35 33 31 30 28 27 26 25 24 23 22 21 20 12st 4
76 40 38 36 34 32 30 29 28 26 25 24 23 22 21 20 19 12st
74 39 37 35 33 31 30 28 27 26 24 23 22 21 20 20 19 11st 9
72 38 36 34 32 30 29 27 26 25 24 23 22 21 20 19 18 11st 5
70 37 35 33 31 30 28 27 25 24 23 22 21 20 19 19 18 11st
68 36 34 32 30 29 27 26 25 24 22 21 21 20 19 18 17 10st 10
66 35 33 31 29 28 26 25 24 23 22 21 20 19 18 18 17 10st 6
64 34 32 30 28 27 26 24 23 22 21 20 19 18 18 17 16 10st 1
62 33 31 29 28 26 25 24 22 21 20 20 19 18 17 16 16 9st 11
60 32 30 28 27 25 24 23 22 21 20 19 18 17 17 16 15 9st 6
58 30 29 27 26 24 23 22 21 20 19 18 18 17 16 15 15 9st 2
56 29 28 26 25 24 22 21 20 19 18 18 17 16 16 15 14 8st 11
54 28 27 25 24 23 22 21 20 19 17 17 16 16 15 14 14 8st 7
52 27 26 24 23 22 21 20 19 18 17 16 16 15 14 14 13 8st 3
50 26 25 23 22 21 20 19 18 17 17 16 15 14 14 13 13 7st 12
48 25 24 23 21 20 19 18 17 17 16 15 14 14 13 13 12 7st 8
46 24 23 22 20 19 18 18 17 16 15 15 14 13 13 12 12 7st 3
44 23 22 21 20 19 18 17 16 15 15 14 13 13 12 12 11 6st 13
42 22 21 20 19 18 17 16 15 15 14 13 13 12 12 11 11 6st 9
40 21 20 19 18 17 16 15 15 14 13 13 12 12 11 10 10 6st 4
38 20 19 18 17 16 15 14 14 13 13 12 11 11 11 10 10 6st
36 19 18 17 16 15 14 14 13 12 12 11 11 10 10 9 9 5st 9
4' 61/2 4' 8 4' 91/2 4' 11 5' 1/2 5' 2 5' 4 5' 51/2 5' 7 5' 81/2 5' 10 5' 111/2 6' 1 6' 3 6' 41/2 6' 6
Height (ft/in)
To Calculate BMI: Weight (kg)

Height (m) x Height (m)
Key:
BMI <20 BMI 20-25 BMI 25-30 BMI 30-35 BMI 35-40 BMI >40
Underweight (19-23 for S Asian) (23-28 for S Asian) (>28 for S Asian) Obese Morbidly
Desirable Overweight Obese (Class I) (Class II) Obese
CLASSIFICATION OF OVERWEIGHT AND OBESITY IN CHILDREN

RCPCH [Royal College of Paediatrics & Child Health] UK 2–20yrs Body Mass Index chart should be used
to identify overweight and obese children:
Overweight: BMI >/= 91st centile
Obese: BMI >/= 98th centile
Approximate height conversions
m ft and in m ft and in
1.22 4'0" 1.69 5'6½"
1.23 4'½" 1.7 5'7"
1.24 4'1" 1.71 5'7½"
1.26 4'1½" 1.73 5'8"
1.27 4'2" 1.74 5'8½"
1.28 4'2½" 1.75 5'9"
1.29 4'3" 1.76 5'9½"
1.31 4'3½" 1.78 5'10"
1.32 4'4" 1.79 5'10½"
1.33 4'4½" 1.8 5'11"
1.35 4'5" 1.82 5'11½"
1.36 4'5½"
1.37 4'6" 1.83 6'0"
1.38 4'6½" 1.84 6'½"
1.4 4'7" 1.85 6'1"
1.41 4'7½" 1.87 6'1½"
1.42 4'8" 1.88 6'2"
1.43 4'8½" 1.89 6'2½"
1.45 4'9" 1.9 6'3"
1.46 4'9½" 1.92 6'3½"
1.47 4'10" 1.93 6'4"
1.49 4'10½" 1.94 6'4½"
1.5 4'11" 1.96 6'5"
1.51 4'11½" 1.97 6'5½"
1.98 6'6"
1.52 5'0" 1.99 6'6½"
1.54 5'½" 2.01 6'7"
1.55 5'1" 2.02 6'7½"
1.56 5'1½" 2.03 6'8"
1.57 5'2" 2.04 6'8½"
1.59 5'2½" 2.06 6'9"
1.6 5'3" 2.07 6'9½"
1.61 5'3½" 2.08 6'10"
1.63 5'4" 2.10 6'10½"
1.64 5'4½" 2.11 6'11"
1.65 5'5" 2.12 6'11½"
1.66 5'5½" 2.13 7'0"
1.68 5'6"
Adapted with permission from Webster-Gandy J, Madden A, and Holdsworth M (2006).
Oxford Handbook of Nutrition. Oxford University Press: Oxford.
Approximate weight conversions
kg st lb kg st lb kg st lb
0.5 1 40 6 3 75 11 11
1 2 41 6 7 76 12 0
1.5 3 42 6 8 77 12 1
2 4 43 6 11 78 12 5
2.5 6 44 6 13 79 12 6
3 7 45 7 1 80 12 8
3.5 8 46 7 3 81 12 10
4 9 47 7 6 82 12 13
4.5 10 48 7 8 83 13 1
5 11 49 7 10 84 13 3
5.5 12 50 7 13 85 13 6
6 13 51 8 0 86 13 7
52 8 3 87 13 10
10 1 8 53 8 4 88 13 11
15 2 6 54 8 7 89 14 0
20 3 1 55 8 10 90 14 3
21 3 4 56 8 11 91 14 4
22 3 7 57 9 0 92 14 7
23 3 8 58 9 1 93 14 8
24 3 11 59 9 4 94 14 11
25 3 13 60 9 6 95 14 13
26 4 1 61 9 8 96 15 1
27 4 3 62 9 11 97 15 4
28 4 6 63 9 13 98 15 6
29 4 8 64 10 1 99 15 8
30 4 10 65 10 3 100 15 10
31 4 13 66 10 6 101 15 13
32 5 0 67 10 7 102 16 1
33 5 3 68 10 10 103 16 3
34 5 6 69 10 13 104 16 6
35 5 7 70 11 0 105 16 7
36 5 10 71 11 3 106 16 10
37 5 11 72 11 4 107 16 11
38 6 0 73 11 7 108 17 0
39 6 1 74 11 8 109 17 3
Adapted with permission from Webster-Gandy J, Madden A, and Holdsworth M (2006).
Oxford Handbook of Nutrition. Oxford University Press: Oxford
kg st lb kg st lb kg st lb
110 17 5 141 22 3 172 27 1
111 17 7 142 22 5 173 27 3
112 17 8 143 22 7 174 27 6
113 17 11 144 22 10 175 27 8
114 17 13 145 22 11 176 27 10
115 18 1 146 23 0 177 27 12
116 18 5 147 23 1 178 28 0
117 18 6 148 23 5 179 28 3
118 18 8 149 23 6 180 28 5
119 18 10 150 23 8 181 28 7
120 18 13 151 23 11 182 28 9
121 19 0 152 23 13 183 28 11
122 19 3 153 24 1 184 28 14
123 19 6 154 24 3 185 29 2
124 19 7 155 24 6 186 29 4
125 19 10 156 24 7 187 29 6
126 19 11 157 24 10 188 29 8
127 20 0 158 25 13 189 29 11
128 20 1 159 28 0 190 29 13
129 20 5 160 25 3 191 30 1
130 20 7 161 25 5 192 30 3
131 20 8 162 25 7 193 30 5
132 20 11 163 25 9 194 30 8
133 20 13 164 25 12 195 30 10
134 21 1 165 25 14 196 30 12
135 21 3 166 26 2 197 31 0
136 21 6 167 26 4 198 31 3
137 21 8 168 26 6 199 31 5
138 21 10 169 26 9 200 31 7
139 21 13 170 26 11
140 22 0 171 26 13
887
Index
A adrenal disorders
Addison’s disease
MEN-1 587
paraganglioma
abetalipoproteinaemia 835 266–7, 445 284–7, 288–91
acarbose 716, 743 adrenal insufficiency see phaeochromocytoma see
achondroplasia 530 adrenal insufficiency phaeochromocytoma
acipimox 842–3 apparent mineralocorti- staging 253
dose 845 coid excess (AME) 248 adrenal venous sampling 233
acne, PCOS 317–18 autoimmune hyperaldosteronism 244
acromegaly 136, 647 adrenalitis 268–9 adrenalectomy 168, 256, 257
associations 150 autoimmune polyglandular bilateral 611
causes 149, 150 syndrome 270, 271 adrenaline 878
clinical features 151 Cushing’s disease adrenarche, premature 541
and colonic polyps 155–6 250–1, 252–4 adrenocorticotrophic hor-
definition 148 HIV/AIDS 654 mone see ACTH
epidemiology 148 hyperaldosteronism see adrenoleukodystrophy 262
investigations 152–3 hyperaldosteronism age and ageing 613–26
MEN-1 587 hyperplasia see adrenal adrenal function 622
mortality 157 hyperplasia bone disease 616
pregnancy 441 liver disease 659 endocrinology 614–15
treatment 154–7, 155 pregnancy 444 gonadal function 620–1
definition of cure 154 Addison’s disease 445 growth hormone 618
radiotherapy 154 adrenal insufficiency IGF-1 618
surgery 154 277, 445 thyroid disorders 624–6
ACTH 109, 110 CAH 324, 325, 446 Albright’s hereditary
CAH 322 phaeochromocytoma osteodystrophy 476
contraindication in phaeo- 447, 448 albuminuria
chromocytoma 295 renal disease 661 diabetic nephropathy 786
critical illness 662, 663 tumours see adrenal false positive 785
Cushing’s disease 163, tumours alcohol, and diabetes
164, 165 adrenal function 878 mellitus 726
deficiency 123, 265 adrenal hormones 230 aldosterone 229
ectopic ACTH syndrome biosynthesis 321 deficiency see
249, 652–3 older patients 622 hypoaldosteronism
pregnancy 436 see also individual excess see
resistance 664–5 hormones hyperaldosteronism
response to 272 adrenal hyperplasia plasma 878
serum 272, 879 bilateral 239, 254 production 230
ACTH stimulation test congenital see congenital urinary 882
117, 322 adrenal hyperplasia aldosterone-producing
Addison’s disease 266–7 macronodular 653 carcinoma 237
emergency pack 278 adrenal hypoplasia congen- aldosteronoma see Conn’s
pregnancy 445 ita 262, 363 syndrome
see also adrenal X-linked 368 alendronic acid 497
insufficiency adrenal insufficiency alfalfa (Medicago sativa) 678
adolescents 262, 264–5 alkaline phosphatase
diabetes mellitus 762–3 acute 273, 274 as bone turnover
management 764–5 cause 273 marker 452
transition to adult HIV/AIDS 654 thyrotoxicosis 24
services 766–7 investigations 272–4 alpha fetoprotein 881
see also children pregnancy 277 alpha-glucosidase inhibitors
adrenals 227–296 treatment 274, 276–8 715, 716
anatomy 228 adrenal tumours alpha-lipoic acid 677
imaging 232–3 adenoma 252 alprostadil 392
older patients 622 androgen-secreting 328 Alzheimer’s disease, HRT 349
physiology 230 carcinoma 237, 241, 252 ambiguous genitalia 545
pregnancy 444 incidentaloma 282–3 sex assignment 548
888 INDEX
amenorrhoea antithyroid peroxidase sleeve gastrectomy

causes 331, 333 antibodies 877 862, 863
definition 330 Antley-Bixler skeletal type 2 diabetes 719, 864–5
hypothalamic 333 dysplasia 551 Bartter’s syndrome 258, 259
investigations 334 apolipoprotein B 827 Beckwith-Wiedemann
with normal apolipoprotein C-II syndrome 150
gonadotrophins 335 deficiency 833 benzoyl peroxide 317
PCOS 316, 333 apoplexy 123 berberine 676
treatment 335 arginine test 118 Berutti regimen 253
WHO categorization 330 ART see assisted reproduc- bevacizumab 779
amiloride 246 tive techniques bezafibrate 845
aminoglutethimide 171 arterial thrombosis, biguanides 714
amiodarone-induced COCP 358 bile acid sequestrants
thyrotoxicosis assisted reproductive tech- 842, 845
86–90, 87, 89 niques (ART) 407 bisphosphonates 497, 502
treatment 89 gamete intrafallopian bitter melon (Momordica
amitriptyline 295, 799 transfer (GIFT) 407 charantia) 676
anastrozole 386 Human Fertilisation black cohosh (Actaea
androgen insensitivity and Embryology Act racemosa) 679
syndrome 416, 546 (UK) 412 bladder, neuropathic
androgen receptor intracytoplasmic sperm 802–3
blockers 315–16 injection (ICSI) 407 blood pressure, diabetic
androgen replacement intrauterine insemination nephropathy 787
therapy 353, 354, 378–9 (IUI) 407 bone 449–511
contraindications 379 in vitro fertilization (IVF) biochemistry 880
erectile dysfunction 392 317, 407 biopsy 455
follow-up 379 atherosclerosis 825 exercise effects 672
risks and side effects 380 risk factors 825 imaging 453
androgen-dependent atorvastatin 841 investigations 452
hirsutism 306 dose 845 physiology 450
androgen-secreting tumours atrial fibrillation, bone age 515, 552
328–9, 329 thyrotoxicosis 31 bone densitometry 496
androgens 230 atrophic thyroiditis 70 bone disorders
actions of 302 auscultation, thyroid 3 hypercalcaemia see
CAH 322 autoimmune hypercalcaemia
hyperandrogenism adrenalitis 268–9 inherited 510–11
308, 328 autoimmune polyglandular older patients 616
ovarian, suppression 315 syndrome 270, 271 osteomalacia and
synthesis defects 546 autoimmune thyroid rickets 480–2
women 304, 305 disease 26 osteoporosis see
androstenedione see also autoimmune osteoporosis
normal values 878 thyroiditis; Graves’ Paget’s disease 506–9
PCOS 313 disease bone mass 450
anhidrosis 803 autoimmune lifestyle factors
anion exchange resins thyroiditis 68, 70 affecting 492
842, 845 autonomic loss of see osteoporosis
anorexia nervosa 222 neuropathy 800–3 measurement 454
anovulation 406 assessment 800 peak 492
anti-Müllerian clinical features 800 bone mineral density,
hormone deficiency/ treatment 800–2 increased 493, 503
insensitivity 547 azoospermia, bone turnover 450
anti-obesity drugs 860–1 obstructive 408 markers 452
antibodies, thyroid 15 brain tumours 524
anticoagulation, in hyperos- breast cancer
molar hyperglycaemic B COCP 358
state 739 banaba (Lagerstroemia HRT 346, 348
antidiuretic hormone, speciosa) 676 breastfeeding,
deficiency 123 bariatric surgery prolactinoma 438
antithyroid drugs 30, 65 gastric banding 864 bromocriptine 204
side effects 31 gastric bypass 862, 863 pregnancy 205, 437
thyrotrophinoma 181 obesity 862–5 bulimia 222
INDEX 889
C hyperlipidaemia 824–5
risk factors 825, 826–7
chlorpromazine 295
cholesterol absorption
C-peptide 880 testosterone replacement blocker 843
C-peptide suppression therapy 380 chromium 676
test 632 Carney complex 150, chromogranin A 880
cabergoline 144, 204 250, 583 chromogranin B 880
and cardiac cassia cinnamon chronic fibrosing thyroiditis
valvulopathy 145 (Cinnamomum see Riedel’s thyroiditis
pregnancy 437 aromaticum) 676 Chvostek’s sign 474
café-au-lait spots 540, 576 cataracts, diabetic eye chylomicrons 824
CAH see congenital adrenal disease 779 ciprofibrate 845
hyperplasia catecholamines, hypersecre- citalopram 347
calcitonin 458 tion 288, 289 clivus chordoma 190
complications of cerebral salt wasting 198 clomifene citrate 317,
therapy 502 cerebrovascular disease, 386, 410–11
normal values 880 HRT 348 clomifene test 119, 120
osteoporosis 497 cervical cancer, COCP 358 clonidine 347
calcitriol 497 Charcot foot 808 clonidine suppression test
renal disease 660 CHARGE syndrome 367 290, 291
calcium 451 chemotherapy sensitivity and
circulating 451 endocrine effects 640 specificity 289
serum levels 152, 456 hypogonadism coagulation factors, in
hormonal regulation 458 induced by 373 diabetes mellitus 811
hypercalcaemia see neuroendocrine cocaine 295
hypercalcaemia neoplasias 559 coeliac disease 530
hypocalcaemia see children 513–52 colesevelam 845
hypocalcaemia adrenal disorders, colestipol hydrochloride 845
metabolism 449 Cushing’s disease 173 colestyramine 845
roles of 451 CAH 550–2 collagen crosslinks 452
supplements 502, 609 coeliac disease 530 colonic polyps, and
osteoporosis 680 diabetes mellitus 762–3 acromegaly 155–6
urinary 457, 882 management 764–5 colorectal cancer, HRT
see also bone puberty 766–7 346
calcium/creatinine excretion endocrine effects of combined oral contra-
ratio 457 cancer 642–5 ceptive pill (COCP)
cancer growth 514–17 315, 356–9
childhood, endo- constitutional benefits 356
crine effects in delay 520–1 contraindications 357
survivors 642–5 GH deficiency 522, 524 arterial thrombosis 358
endocrine effects 640 GH resistance 528 venous thromboembo-
see also individual systems rapid 534–5 lism 358
and tumours short stature 518–19 practical issues 359
cannabinoids 677 tall stature 534–5 preparations 357
capecitabine 559 intrauterine growth side effects 356
capsaicin 799 restriction 531 complementary and alterna-
carbimazole 30 puberty 536–7, 537 tive therapy 674
dose 30 delayed 520–1 DHEA 682
side effects 31 delayed/absent diabetes mellitus 676–7
treatment regimen 32 542–3, 543 iodine supplements 682
carbohydrate absorption precocious 538–41 menopause 678–9
inhibitors 677 sexual development osteoporosis 680–1
carcinoembryonic disorders 546–8 computed
antigen 881 sexual differentiation 544 tomography see CT
carcinoid crisis 560 ambiguous genitalia 545 congenital adrenal
carcinoid heart disease skeletal dysplasias 530 hyperplasia
560 small for gestational age 531 adults 320–1, 321
carcinoid tumours, thyroid disorders follow-up 326
MEN-1 587 cancer 102 investigations 322–3
cardiovascular disease hyperthyroidism 48 prognosis 326
diabetes mellitus 810–13 hypothyroidism 7, treatment 324–5
diabetic nephropathy 787 84–5, 529 children 550–2
HRT 349 Turner’s syndrome 532–3 enzyme deficiencies 323
890 INDEX
congenital adrenal children 173 diabetes insipidus

hyperplasia (Cont’d) clinical features 160 186, 210–11
lipoid 262 cyclical 163 causes 211
non-classic 321, 324 definition 158 definition 210
pregnancy 324, 325, 446 ectopic ACTH investigations 212–13, 213
congenital adrenal hypo- syndrome 652–3 nephrogenic 214
plasia 262, 363 epidemiology 158 treatment 214
X-linked 368 follow-up 172 diabetes mellitus 683–821
congenital hypothyroidism and hyperlipidaemia 836 annual review 731
7, 84–5 investigations 162–7 assessment 688
Conn’s syndrome 237, 238 MEN-1 587 care delivery 720–1
pregnancy 448 pathophysiology 159 children and
contraception 355 pregnancy 439, 440 adolescents 762–3
COCP 315, 356–9 prognosis 172 management 764–5
diabetes mellitus 760 screening tests 164 puberty 766–7
emergency 360 steroid replacement classification 685
corticotrophin-releasing therapy 281 complementary and alter-
hormone test 164, 166 subclinical 254 native therapy 676–7
cortisol treatment 168–71, carbohydrate absorption
critical illness 662, 663 252–4, 440 inhibitors 677
hypercortisolism 654 adrenalectomy 168 hypoglycaemic
midnight 162 pharmacological agents 676
older patients 622 170–1, 171 insulin sensitizers 676–7
pregnancy 436 radiotherapy 168 contraception 760
production 230 surgery 168 critical illness 750
resistance 663 cyproterone acetate 316 diagnosis 684, 687
serum 272, 878 cysts emergencies 732
urinary 162, 882 perisellar 188 hyperglycaemia 740–1
cortisone acetate, equiva- Rathke’s cleft 189 hyperosmolar hypergly-
lent dose 281 thyroglossal 7 caemic state 738–9
Cowden syndrome 584 ketoacidosis 734–6
cranial irradiation 524 eye disease
craniopharyngioma 113, 188 D diabetic retinopathy see
treatment 189 dacarbazine 559 diabetic retinopathy
craniotomy 602–4 danazol 386 macular oedema 772
transfrontal 199 de Quervain’s thyroiditis screening for 774–5
see also transsphenoidal 1_130,29, 68 treatment 776, 778–9
surgery dehydration, older genetic background 690
creatinine kinase, patients 615 genetic testing 693
hypothyroidism 24 dehydroepiandrosterone glycaemic control
critical illness 662–3, 663 (DHEA) 230 708–9, 810–11
ACTH 662 anti-ageing effects 682 hyperlipidaemia
cortisol 662 normal values 878 811, 814–16
diabetes mellitus 750 older patients 622 hypertension 811,
growth hormone PCOS 313 818, 820–1
(GH) 663 replacement therapy 276 hypoglycaemia see
metabolism 662 dementia 342 hypoglycaemia
sex steroids 662 denosumab 497, 503 inpatient management 732
thyroid stimulating Dent’s disease 598 ketosis-prone 688
hormone 662 11-deoxycorticosterol 878 latent autoimmune of
cryptorchidism 372 deoxycorticosterone adulthood (LADA) 688
CT excess 249 lifestyle factors
adrenals 232 desmopressin 214 alcohol 726
bone mass 454 dexamethasone 128, 246 driving 722–3
hyperaldosteronism 244 CAH 325 Ramadan (fasting) 729
thyroid 22 contraindication in phaeo- recreational drug
Cushing’s disease/syndrome chromocytoma 295 use 727
136, 647 equivalent dose 281 sport and exercise 722–3
ACTH-dependent 163, dexamethasone suppression travel 728
164, 165 test 162, 163 weight management 730
adrenal 250–1, 252–4 DHEA see macrovascular
causes 159, 163 dehydroepiandrosterone disease 810–13
INDEX 891
maturity onset of the foot examination 798–9 see also individual hor-
young (MODY) 691–2 mononeuropathies 795 mones and conditions
mitochondrial 692–3 peripheral sensorimotor Edmonton Obesity Staging
neonatal 692, 763 neuropathy 794 System 849
perioperative management proximal motor eflornithine 316
742, 743, 744 neuropathy 796 electrolyte balance, older
pregnancy 752–5 treatment 799 patients 614
fetal monitoring 754 diabetic retinopathy 768–9 emergency contraception 360
gestational background 770 empty sella syndrome 123
diabetes 756–8 classification 769 endometrial cancer
glycaemic control 754 clinical and histological HRT 348
MODY 692 features 770–2 and PCOS 311
pre-conception pre-proliferative 770–1 endometriosis
management 753 proliferative 771–2 HRT 349
renal disease see diabetic risk factors 776 and infertility 406
nephropathy treatment 788–90 ependymoma 190
secondary 763 blood pressure 788 ephedrine 295
sick day rules 700 cardiovascular risk eplerenone 246
stroke patients 748 factors 788–9 erectile dysfunction 388
type 1 686 diet 789 in autonomic
children and adolescents glycaemia 788 neuropathy 801–2
762, 764–5 referral 789, 790 causes 391
genetics 690 diarrhoea, autonomic 802 definition 388
immune modulation diet evaluation 390–1
therapy 710 diabetes mellitus 713 in older age 621
insulin therapy see diabetic retinopathy 789 treatment 392–4
insulin hyperlipidaemia 838–9 etidronate 497
islet cell obesity 859–60 etomidate 171
transplantation 711 differential diagno- everolimus 559
pancreas sis of endocrine exenatide 716, 717
transplantation 712 disorders 666–9 exercise 672–3
sport and exercise 724–5 dihydrotestosterone 878 bone health 672
type 2 686, 713 dipeptidyl peptidase-4 doping 673
bariatric surgery inhibitors 715, 717 female athlete triad 673
719, 864–5 dong quai (Angelica hypothalamo-pituitary
children and sinensis) 679 axis 672
adolescents 762 dopamine agonists 205 eye examination in diabetes
dietary/lifestyle acromegaly 156 mellitus 774–5
advice 713 pituitary tumours 144, ezetimibe 843
genetics 690 204 dose 845
insulin therapy see insulin resistance 145, 146
oral hypoglycaemics side effects 204
714–17, 715 Down’s syndrome 150 F
and PCOS 311 driving, diabetes familial combined
sport and exercise 725 mellitus 722–3 hyperlipidaemia 832
diabetic amyotrophy 796 drug-induced conditions, familial dysbetalipopro-
diabetic foot 804–5 thyroiditis 73 teinaemia 833
clinical features 805 DSD see sexual differention familial hypercholesterolaemia
epidemiology 805 disorders 830–1
foot examination 798–9 dual-energy absorptiometry familial
protection 739 (DXA) 454 hypertriglyceridaemia 832
risk factors 804 duloxetine 799 familial hypocalciuric
treatment 806–7 dyslipidaemias see hypercalcaemia 470,
Wagner’s classification 805 hyperlipidaemias 471–2, 598
diabetic nephropathy 782–3 familial isolated
definition 782, 783 hyperparathyroidism 596
diagnosis 784–7 E familial mixed
relative risk 783 eating disorders 222 dyslipidaemias 835
diabetic neuropathy ectopic hormone Fanconi syndrome 485
792–3, 793 production 646–7 fasting (Ramadan), diabetes
autonomic ACTH 249, 652–3 mellitus 729
neuropathy 800–3 growth hormone 149 fatigue 667
892 INDEX
female athlete triad 673 gastric banding 864 glucocorticoid-suppressible

fenofibrate 845 gastric bypass 862, 863 hyperaldosteronism
fenugreek (Trigonella gastrin 880 237, 240
foenum-gracum) 676 gastrinoma 565 glucose monitoring 708–9
Ferriman-Gallwey score 306 MEN-1 587, 588 GnRH 300
fertile eunuch syndrome 363 prognosis 567 pulsatile 412
fertility, POI 340 treatment 567 GnRH analogues 315
fetus Zollinger-Ellison goitre
thyroid disorders 429–30 syndrome 566 aetiology 66
thyroid function 426 gastrointestinal multinodular 29, 64–7
fibrates 841–2, 845 hormones 880 older patients 625
finasteride 316 gastroparesis 802 goitrogens 4
fine needle aspiration gemfibrozil 845 gonadal development 544
cytology (FNAC), gender dysphoria 420 gonadal function 878
thyroid 20, 21 gender reassignment childhood cancer
fish eye disease 835 surgery 422–3 survivors 645
fistulae, thyroglossal 7 gender reconstructive HIV/AIDS 655
fludrocortisone suppression surgery 418 liver disease 658, 659
test 242 genitalia older patients 620–1
fluid balance ambiguous 545 regulation of 300–1
older patients 614 external 544 renal disease 661
post-operative 197 internal 544 gonadectomy 418
fluid deprivation test 213 see also sexual gonadotrophin releasing
fluid replacement differentiation hormone see GnRH
hyperosmolar hypergly- germ cell tumours gonadotrophinoma 178
caemic state 739 non-seminoma 387 gonadotrophins 375
ketoacidosis 735 pineal 224 critical illness 662
fluoride supplements in germ cells 298 deficiency 542, 547
osteoporosis 680 gestational diabetes 756–8 ovulation
fluoxetine 295 checklist 758 induction 411–12
flushing 668–9 diagnostic criteria 756 see also individual
flutamide 316 screening 756, 757 hormones
fluvastatin 841 GH see growth hormone gonads 300
dose 845 ghrelin 856 Graafian follicle 298
FNAC see fine needle aspi- GHRH 149, 152 granulosa cells 298
ration cytology ginseng 677, 678 Graves’ dermopathy 62
follicle stimulating hormone Gitelman’s syndrome Graves’ disease 15, 17,
(FSH) 108, 110, 300 258, 260 28–9, 29
critical illness 663 glomerular filtra- conditions associated
deficiency 123 tion rate, diabetic with 29
liver disease 659 nephropathy 786 pregnancy 44, 45, 428–9
male infertility 404 GLP-1 receptor scintiscanning 17
normal values 879 analogues 716 treatment regimen 32
perimenopausal glucagon 295 see also thyrotoxicosis
changes 343 normal values 880 Graves’ ophthalmopathy 34,
pregnancy 436 glucagon test 116 54–6, 55
follicular thyroid glucagon-like peptide-1 856 radioiodine
carcinoma 99 glucagonoma 568–9, 569 contraindication 34
follow-up 100–2, 102 MEN-1 587 treatment 61
foot glucocorticoids 228, 230 drugs 58
Charcot 808 long-term administration surgery 60
diabetic see diabetic foot 280–1, 281 growth 514–17
osteoporosis induced by assessment 514–15
498, 500 bone age 515
G resistance 664 mid-parental height 515
gabapentin 347, 799 steroid equivalents 281 constitutional delay 520–1
gallstones glucocorticoid replacement final height 514, 515
COCP 358 therapy 128–9, 276 rapid 534–5
HRT 349 monitoring 128 regulation of 514
gamete intrafallopian trans- safety 128 secular trends 516
fer (GIFT) 407 steroid equivalents sex differences 514
gametogenesis 300–1 128, 281 short stature 518–19
INDEX 893
tall stature 534–5 Ferriman-Gallwey Human Fertilisation

tempo 514 score 306 and Embryology Act
growth charts 515, 516, 517 treatment 314, 315 (UK) 412
growth hormone (GH) HIV/AIDS, endocrine hydrocortisone 127, 128
108, 110 dysfunction 654–7 adrenal insufficiency 274
assessment 521 adrenal 654 CAH 551
critical illness 663 gonads 655 day curve 129
day curve 153 hypercalcaemia 655 equivalent dose 281
deficiency 123, 132 hypocalcaemia 655 pregnancy 442
childhood cancer hyponatraemia 655 25-hydroxycolecalciferol
survivors 642–3 lipodystrophy 657 880
primary 522 pituitary 656 5-hydroxyindoleacetic acid,
secondary 524, 525 thyroid 656 urinary 882
treatment 526, 527 wasting syndrome 656–7 17α-hydroxylase deficiency
ectopic secretion 149 HMG CoA reductase 323, 551
elevation 153 inhibitors see statins 21α-hydroxylase deficiency
pregnancy 436, 443 Hook effect 142 323, 550
provocation tests 519 hops (Humulus lupulus) 678 3β-hydroxylase
renal disease 661 hormones deficiency 323
replacement therapy 127, ectopic production see 11β-hydroxylase deficiency
130–1, 134–5, 135, ectopic hormone 323, 550
526, 527 production 17-hydroxyprogesterone
dose 526 resistance to 664–5 878
side effects 526 see also individual 3β-hydroxysteroid dehydro-
resistance 528 hormones genase deficiency 551
stress effects 670 hormone replacement hyperaldosteronism
testing 152 therapy (HRT) diagnosis 244
growth hormone receptor alternatives to 347 glucocorticoid-suppressible
antagonists 156, 206 benefits 346, 351 237, 240
growth hormone releasing complications 502 idiopathic 237, 239
hormone see GHRH contraindications 347 primary 234, 236, 237
growth hormone-secreting menopause 346–51 pseudoaldosteronism
tumours 205 osteoporosis 346, 497 234, 262
gustatory sweating 803 POI 340, 341 screening 242–3, 243
gymnema (Gymnema risks 346, 351 secondary 234
sylvestre) 676 breast cancer 346, 348 treatment 246–7
gynaecomastia 24, cerebrovascular hyperalphalipoproteinae-
380, 382–3 disease 348 mia 835
causes 383 endometrial cancer 348 hyperandrogenism 308, 328
definition 382 endometriosis and hypercalcaemia 460–1
evaluation 384–5, 385 fibroids 349 causes 460, 461
hormonal influences 382 gallstones 349 clinical features 460, 461
treatment 386 liver disease 349 familial hypocalciuric
migraine 349 470, 471–2
ovarian cancer 348 HIV/AIDS 655
H venous hyperparathyroidism
haemochromatosis 365 thromboembolism 462–4
hair growth 304 348 of malignancy 469,
androgen-independent 306 sexual differentiation 646, 650
see also hirsutism disorders 419 sarcoidosis 472
hamartoma 190 side effects 350 thyrotoxicosis 24
Hashimoto’s thyroiditis see treatment regimens vitamin D intoxication 472
autoimmune thyroiditis 352–4 hypercalciuria
β-hCG 881 uncertainties 349 causes 600
hCG test 120 see also individual thyrotoxicosis 24
high density lipoproteins hormones hypercholesterolaemia
(HDLs) 824 hot flushes 344, 346 familial 830–1
hirsutism 304 Houssay phenomenon 122 polygenic 829
androgen-dependent 306 HRT see hormone hypercortisolism 654
causes 305 replacement therapy hyperemesis gravidarum 25,
definition 304 huangqi (Radix astragali) 29, 44–5, 430
evaluation 306–7 677 hypergastrinaemia 566
894 INDEX
hyperglycaemia 740–1 diabetic nephropathy 785 hypoglycaemic agents see

and diabetic treatment 820–1 oral hypoglycaemics
nephropathy 785 hyperthyroidism 5, 28 hypogonadism
see also diabetes mellitus aetiology 27 clinical assessment 374–6
hypergonadotrophic cancer survivors 643 hypergonadotrophic 542
hypogonadism 542 children 48 hypogonadotrophic 366–8
hyperinsulinaemia, definition 26 male 361, 371
PCOS 310 fetal 429 primary 370–3
hyperlipidaemias investigations 28 secondary 362–5, 363
cardiovascular older patients 625 liver disease 658, 659
disease 824–5 post-partum 432 renal disease 661
risk factors 826–7 pregnancy 428–31 systemic illness
diabetes mellitus radioiodine therapy 34 causing 368
811, 814–16 secondary 50–1 WHO categorization 330
familial combined 832 subclinical 42–3 see also specific conditions
familial dysbetalipopro- symptoms and signs 28 hypogonadotrophic
teinaemia 833 treatment 30 hypogonadism 366–8
familial mixed see also thyrotoxicosis causes 367
dyslipidaemias 835 hypertriglyceridaemia childhood cancer
hypercholesterolaemia familial 832 survivors 644
familial 830–1 genetic 833 idiopathic 363, 366
polygenic 829 hypoaldosteronism, infertility 408
hypertriglyceridaemia hyporeninaemic 262 hypomagnesaemia 488–9
familial 832 hypobetalipoproteinae- causes 489
genetic 833 mia 835 hyponatraemia 216–19
Lp(a) elevation 834 hypocalcaemia 474–6 causes 216
management 838–9 acute 479 HIV/AIDS 655
dietary advice 838–9 Albright’s hereditary investigations 217, 218
drug therapy 840–4 osteodystrophy 476 neurosurgical 219
exercise 839 autosomal dominant 479 older patients 615
weight control 839 causes 474, 475 SIADH 220–1, 648
pathogenesis 825 chronic 478 thyrotoxicosis 24
and PCOS 311 clinical features 474 treatment 218
prevention 838 HIV/AIDS 655 hypoparathyroidism 478
primary 828 post-parathyroidectomy pregnancy 434
secondary 836–7, 837 608, 609 hypophosphataemia
hypernatraemia in older pseudohypoparathy- 480–2, 486–7
patients 615 roidism 475 causes 487
hyperosmolar hyperglycae- treatment 478–9 treatment 486
mic state 738–9 hypochondroplasia 530 X-linked 484–5
hyperparathyroidism 462–4 hypoglycaemia 628–9, 702–3 hypopituitarism 122–4, 123,
diagnosis 463 acute 634 174, 547
end-organ damage 463 causes 629, 703 investigations 125
familial isolated 596 children 765 post-radiotherapy 202
inherited 596 and driving 722 pregnancy 442–3
MEN-1 588 factitious 633 treatment 126
MEN-2 593, 594 impaired awareness hypothalamic syndrome 223
older patients 616 702, 703 hypothalamo-pituitary-
pregnancy 434 inpatient adrenal (HPA) axis
treatment 466–7 management 746–7 exercise effects 672
hyperparathyroidism-jaw investigations 632–3 in hypothyroidism 24
tumour (syndrome) 596 non-islet cell 647 stress effects 670
hyperprolactinaemia 140 pathology 628 hypothalamo-pituitary-
drug-induced 143 postprandial thyroid (HPT) axis 4, 5
idiopathic 143 reactive 636–7 exercise effects 672
PCOS 313 recurrent chronic 634 fetal 46
treatment, dopamine risk factors 703 stress effects 670
agonists 205 severe 702 hypothalamus 223
hypertension sport and exercise 724 gonadal function
COCP 358 symptoms 630, 703 regulation 300
diabetes mellitus 811, treatment 634, 702 hypothyroidism 5, 74–6
818, 820–1 Whipple’s triad 628 autoimmune 15
INDEX 895
causes 75
childhood cancer
sensitivity 698–9
type 2 diabetes 718
K
survivors 643 types of 695, 696 Kallman’s syndrome 362,
congenital 7, 84–5, 529 basal 698 366, 547
fetal 429 quick-acting 698 ketoacidosis 734–6
and hyperlipidaemia 836 insulin growth factor bind- children 765
older patients 624 ing protein-3 (IGFBP-3), ketoconazole 171, 196
post-partum 432 liver disease 659 ketosis-prone diabetes 688
post-radioiodine 35 insulin growth factor-1 Klinefelter’s syndrome
subclinical 78–9 (IGF-1) 132, 152 361, 370
treatment 80–3, 81, 83 critical illness 663 kudzu (Pueraria lobata) 678
generation test 521
liver disease 659
I normal values 879 L
ibandronic acid 497 pregnancy 436 laboratory investigations
IGF-1 see insulin growth insulin pumps 697, autoimmune
factor-1 704–6, 705 adrenalitis 269
imaging see individual modes children 764 factors influencing868–9
imipramine 295, 799 closed-loop systems 710 thyroid disorders 24
immune response in critical insulin secretagogues see also specific conditions
illness 663 714–15, 743 Langerhans cell
in vitro fertilization (IVF) rapid-acting 715 histiocytosis 192
317, 407 insulin sensitizers 676–7 lanreotide 204
incidentaloma insulin tolerance test Laron syndrome 528
adrenal 282–3 114–15 laser treatment, diabetic eye
pituitary 182–3 insulin-to-carbohydrate disease 778
incretin-based therapies ratio 698 latent autoimmune dia-
716–17, 717 insulinoma 562 betes of adulthood
inferior petrosal sinus sam- biochemical features 633 (LADA) 688
pling 164, 167 MEN-1 587 Laurence-Moon-Biedl
infertility 396–7 prognosis 564 syndrome 364, 367
ART 407 treatment 564 lecithin:cholesterol
definition 396 tumour localization 563 acyltransferase (LCAT)
female 396, 398–400, 400 interferon α, neuroendo- deficiency 835
treatment 406–7, 407 crine neoplasias 559 leptin 855
male 397, 402–3, 403 intermediate density lipo- levothyroxine 81
age-related 621 proteins (IDLs) 824 Leydig cells 298
treatment 408–9 interstitial cells 298 licorice (Glycyrrhiza
ovulation intracytoplasmic sperm glabra) 678
induction 410–13 injection (ICSI) 407 Liddle’s syndrome 258
PCOS 317 intrauterine growth restric- lipids 824–5
inherited endocrine tion (IUGR) 531 measurements 827
syndromes 575–600 intrauterine insemination see also hyperlipidaemia
see also specific syndromes (IUI) 407 lipid-lowering drugs 815–16,
inhibin B 376 123iodine- 840–4, 845
normal values 879 metaiodobenzylguanidine acipimox 842–3
insulin see MIBG aims of treatment 844
children 764 ischaemic heart disease, anion exchange resins 842
dawn phenomenon 699 post-menopausal 342 choice of 844
dose adjustments 699 islet cell transplantation 711 cholesterol absorption
in hyperglycaemia 740–1 isoflavones 680 blocker 843
hyperinsulinaemia 310 isotope bone scanning 453 fibrates 841–2
in hyperosmolar hypergly- isotretinoin 318 nicotinic acid 842–3
caemic state 739 omega-3 fatty acids 843
in ketoacidosis 736 statins 815, 840–1, 841
normal values 880 J lipodystrophy 836
perioperative jet lag 224 HIV/AIDS-related 657
management 744 Jod-Basedow lipoma, MEN-1 587
in pregnancy 754 phenomenon 86 lipoprotein A, elevated 834
gestational diabetes 757 Joint British Society lipoprotein lipase
regimens 695–7 Coronary Risk deficiency 833
resistance 663, 693, 811 Prevention Score 826 liquorice ingestion 249
896 INDEX
liraglutide 716, 717 feminization 647 phaeochromocytoma 290

lisuride 204 gonadal function drugs interfering with
liver disease 658–9 childhood cancer uptake 293
adrenal function 659 survivors 645 sensitivity 289
COCP 358 HIV/AIDS 655 specificity 289
gonadal function liver disease 658, 659 mifepristone 171
men 658, 659 in older age 620–1 migraine, HRT 349
women 658, 659 hypogonadism 361, 371 mineralocorticoids 228, 230
HRT 349 infertility 397, 402–3, 403 apparent excess
and hyperlipidaemia 836 treatment 408–9 (AME) 248
thyroid function 658, 659 osteoporosis 504 deficiency 262–3
low density lipoproteins sexual function 388 excess 234
(LDLs) 824 MEN-1 150, 586–7 replacement therapy 276
luteinizing hormone (LH) clinical features 586, resistance 665
108, 110, 300 587, 587 mitochondrial
critical illness 663 genetics 586, 589 diabetes 692–3
deficiency 123 prognosis 590 mitotane 171
liver disease 659 screening 589, 590 mixed gonadal dysgenesis
male infertility 404 treatment 588–90 (XX/XO) 371
normal values 879 MEN-2 285, 592–3 molecular therapies,
pregnancy 436 classification 593 neuroendocrine
lymphocytic hypophysitis clinical features 592, 593 neoplasias 559
194–5, 195 genetics 592, 595 mononeuropathies 795
pregnancy 442 prognosis 595 mood changes, HRT 349
lymphoma, thyroid 105 screening 292, 595 morphine 799
lysine vasopressin 214 treatment 594–5 MRI
meningioma 190 adrenal glands 232
menopause 342–3, 620 pituitary 112, 113, 166
M clinical features 344 acromegaly 152
McCune-Albright syndrome definition 342 prolactinoma 142
150, 251, 576–7 evaluation 345 mTOR 559
clinical features 576, 577 hormonal changes 343 multiple neuroendocrine
genetics 576 physiology 342 neoplasia see MEN
precocious puberty treatment MYC associated
540, 577 complementary factor X 285
prognosis 577 and alternative myocardial infarction
macroglossia 150 therapy 678–9 812, 813
macroprolactinoma 142 HRT 346–51 myxoedema 74
macular oedema, phytoestrogens 350 see also hypothyroidism
diabetic 772 menstrual cycle 301 myxoedema coma 82
magnesium menstrual disorders
hypomagnesaemia 488–9 amenorrhoea see
serum levels 456 amenorrhoea N
supplements, assessment 330–1 Nelson’s syndrome 169
osteoporosis 680 causes 331 see also Cushing’s disease/
magnetic resonance imaging clinical evaluation 332–3 syndrome
see MRI investigations 334 neonatal diabetes 692, 763
Marcus Gunn pupil 56 metabolism neuroendocrine
mastocytosis 638–9, 639 in critical illness 662 disorders 553–71
maturity onset diabetes of stress effects 671 see also specific disorders
the young (MODY) 691–2 metadrenaline, urinary 881 neuroendocrine
Maxepa® 843 metaiodobenzylguanidine neoplasias (NENs)
medullary thyroid see MIBG biochemical
carcinoma 103 metformin 314, 317, 714, 743 investigations 557
MEN-2 592, 594 3-methoxytyramine, classification 556
treatment 594 urinary 881 clinical features 556
megestrol acetate 347 metoclopramide 295 imaging 557
meglitinide 743 metyrapone 196 non-functioning
melanoma, MEN-1 587 Cushing’s disease 171 pancreatic 559
men MIBG 233 pathology 557
erectile dysfunction 388, neuroendocrine treatment 558–61
390–1, 392–4 neoplasias 560 ablative therapies 558
INDEX 897
medical 558–60 oocyte ovarian diathermy 411

surgery 558 cryopreservation 412 ovarian insufficiency,
neuroendocrine system ophthalmoplegia 56 premature 336–8
554 optic neuropathy 56 autoimmune-mediated 338
neurofibromatosis 578–9 oral contraceptives, causes 336
phaeochromocytoma 285 diabetes mellitus 760 investigations 339
screening 292 oral glucose tolerance test karyotype 337, 339
type 1 578, 579 (OGTT) 152, 633, 636 pathogenesis 336
neurophysin 208 oral hypoglycaemics prognosis 341
neurosarcoidosis 192 714–17, 715 treatment 340–1, 341
neurotensin 880 alpha-glucosidase Turner’s syndrome 337
nicotinic acid 842–3 inhibitors 716 ovarian tumours,
dose 845 biguanides 714 androgen-secreting 328
Noonan’s syndrome 371–2 complementary and ovotesticular DSD 417
noradrenaline 878 alternative therapy 676 ovulation induction 410–13
normetadrenaline, gestational diabetes 757 oxandrolone 520
urinary 881 incretin-based therapies oxycodone 799
716–17, 717 oxytocin 208
insulin
O secretagogues 714–15
obesity 847–65 rapid-acting 715 P
aetiology 852–3 thiazolidinediones P1NP procollagen extension
bariatric surgery 862–5 (glitazones) 716 peptide 452
childhood cancer orchitis 372 normal values 880
survivors 645 orlistat 860–1 paediatrics see children
consequences 857 orphan Annie eyes 96 Paget’s disease 506–9
definition 848 osteoblasts 450 aetiology 506
and diabetes mellitus 811 osteocalcin 452 clinical features 507
Edmonton Obesity Staging osteoclasts 450 complications 508
System 849 osteocytes 450 epidemiology 507
epidemiology 850 osteodystrophy, renal 660 follow-up 509
management 858–61 osteogenesis investigation 507
pathophysiology 854, imperfecta 510–11 pathology 506
855, 856 classification 511 treatment 508, 509
octreotide 204 osteomalacia 480–2 palpation, thyroid 3
oestradiol 375 causes 482 palpitations 667
critical illness 663 clinical features 480 pancreas transplantation 712
liver disease 659 definition 480 pancreatic hormones 880
normal values 878 oncogenic 485, 647 pancreatic polypeptide 880
perimenopausal osteoporosis 342, 347, pancreatic tumours, MEN-1
changes 343 490–1, 616 587, 588
oestrogens causes 490–1 papillary thyroid carcinoma
actions of 302 childhood cancer 91, 96–8
COCP 356 survivors 645 follow-up 100–2, 102
elevated 375 clinical presentation 495 papillary thyroid
liver disease 659 definition 493 microcarcinoma 93–4
oestrogen replacement epidemiology 494 paraganglioma 284–7
therapy 127 glucocorticoid-induced imaging 290–1
delayed puberty 543 498 investigations 288–91, 289
POI 341 investigations 494–5, 496 parasellar
prolactinoma 144 men 504 inflammation 192–3
treatment regimen pathology 492–3 parasellar tumours 190
352, 353 premenopausal parathyroid disorders
oligomenorrhoea women 504 hyperparathyroidism
definition 330 treatment 497, 498, 499 462–4
perimenopausal 344 complementary hypoparathyroidism
Omacor® 843 and alternative 434, 478
dose 845 therapy 680–1 pregnancy 434
omega-3 fatty acids 843 complications 502–5 parathyroid hormone 458
dose 845 HRT 346, 497, 502 normal values 880
oncogenes 138 see also bone mass recombinant human 497
oncogenic osteomalacia 485 ovarian cancer, HRT 348 renal disease 660
898 INDEX
parathyroid anterior 110, 222–3 pregnancy 441

hormone-related pep- gonadal function parasellar 190
tide (PTHrP) 458, 650 regulation 300 pathogenesis 138
parathyroidectomy 466, imaging 112–13 prolactinoma see
466–7, 467, 608–9 MRI 112, 113 prolactinoma
complications 468 physiology 108–9, 110 thyrotrophinoma 180–1
paroxetine 295 posterior 208 treatment
pasireotide 171 pregnancy 436 pharmacological 204–6
patient support pituitary disorders radiotherapy
groups884–6 acromegaly see 200–1, 202–3
PCOS see polycystic ovary acromegaly surgery 175, 196–8, 197
syndrome Cushing’s disease see POEMS syndrome 585
pegaptanib 779 Cushing’s disease/ POI see ovarian insuffi-
pegvisomant 156, 206 syndrome ciency, premature
Pemberton’s sign 64 diabetes insipidus see dia- polycystic ovary syndrome
Pendred’s syndrome 84 betes insipidus (PCOS) 308–11
penile prosthesis 394 HIV/AIDS 656 causes 309
peptide receptor radioligand hyponatraemia 216–19 complications 313
therapy 560 hypopituitarism see definition 308, 309
peptide YY 856 hypopituitarism epidemiology 308
percussion, thyroid 3 lymphocytic hypophysitis hormone secretion
pergolide 204 194–5, 195 abnormalities 309
peripheral sensorimotor parasellar investigations 312–13
neuropathy 794 inflammation 192–3 pathogenesis 308
perisellar cysts 188 pregnancy 436 risks 311
PET acromegaly 441 treatment 314–18
adrenals 233 Cushing’s disease/syn- see also hirsutism
phaeochromocytoma 291 drome 439, 440 polycythaemia 380
thyroid 23 hypopituitarism 442–3 polydipsia 210
phaeochromocytoma 284–7 prolactinoma 437, 438 see also diabetes insipidus
follow-up 295 tumours see pituitary polydipsic polyuria 214
imaging 290–1 tumours polygenic hypercholesterol-
interference with MIBG pituitary function tests aemia 829
uptake 293 acromegaly 152 polyostotic fibrous dysplasia
investigations 288–91, 289 ACTH stimulation 576, 577
malignancy 295 test 117 positron emission tomogra-
MEN-1 587 arginine test 118 phy see PET
MEN-2 592, 594 clomiphene test 119, 120 post-partum thyroiditis
pregnancy 447, 448, 611 glucagon test 116 46, 68, 72
prognosis 296 hCG test 120 postprandial reactive
screening 286 insulin tolerance hypoglycaemia 636–7
associated test 114–15 postural hypotension 801
conditions 292–3 TRH test 121 potassium
syndromes associated pituitary gigantism 148 Cushing’s disease 163
with 285 pituitary hormones 879 replacement therapy 735
treatment 294–6, 448, 594 anterior 110, 222–3 PPoma 587
medical 294, 295 replacement 127 Prader-Willi syndrome
surgical 294, 610–11 posterior 208 364, 367
phosphate see also individual pravastatin 815, 841
hypophosphataemia hormones dose 845
480–2, 484–5, 486–7 pituitary tumours 136–7 precocious puberty 538–41
serum levels 456 adenoma 112 central 539
urinary 457, 882 acromegaly see childhood cancer
phosphodiesterase inhibi- acromegaly survivors 644
tors 392, 393 familial isolated 150 definition 538
contraindications and carcinoma 184–5, 185 gonadotrophin-
cautions 393 gonadotrophinoma 178 independent 539–40
phytoestrogens 350, 678 incidentaloma 182–3 prednisolone 127, 128
pineal gland 224–5 MEN-1 587, 588 CAH 324
pioglitazone 716, 743 metastases 186 equivalent dose 281
pituitary 107–225 non-functioning pregabalin 799
anatomy 108, 109 174–6, 177 pregnancy 425–48
INDEX 899
adrenal disorders 444 prognosis 146 pituitary disorders 175,

Addison’s disease 445 treatment 144–7, 438 200–1, 201
adrenal insufficiency propranolol acromegaly 154
277, 445 phaeochromocytoma, carcinoma 184–5
CAH 324, 325, 446 contraindication 295 complications 202–3
phaeochromocytoma thyrotoxicosis 31 Cushing’s disease 168
447, 448, 611 proptosis 55 indications 200
diabetes mellitus 752–5 propylthiouracil 30 prolactinoma 145–6
fetal monitoring 754 side effects 31 recurrence rates
gestational treatment regimen 32 201, 203
diabetes 756–8 prostate-specific antigen 881 thyrotrophinoma 181
glycaemic control 754 prostatic disease 380 side effects 640
MODY 692 proximal motor hypogonadism 373
pre-conception neuropathy 796 oncogenesis 92, 202
management 753 psammoma bodies 96 thyroiditis 68
hyperlipidaemia 837 pseudo-Cushing’s raloxifene 497, 502
parathyroid disorders 434 disease 162 ranibizumab 779
pituitary disorders 436 pseudoaldosteronism Rathke’s cleft cysts 189
acromegaly 441 234, 262 recreational drug use,
Cushing’s disease/ pseudohypertriglyceridae- diabetes mellitus 727
syndrome 439, 440 mia 833 5α-reductase inhibitors 316
hypopituitarism 442–3 pseudohypoparathy- renal calculi
non-functioning pituitary roidism 475 causes 599
tumours 441 treatment 478 definition 598
prolactinoma 437, 438 psychosocial deprivation genetics 598, 599
thyroid disorders 426 524, 525 inherited 598–600
cancer 101 pubarche, premature 541 investigations 599
Graves’ disease 44, puberty 536–7 treatment 599
45, 428–9 childhood cancer renal disease 660–1
hyperemesis gravidarum survivors 644 adrenal function 661
25, 29, 44–5, 430 delayed 520–1 calcitriol 660
hyperthyroidism 428–31 delayed/absent 542–3, 543 calculi see renal calculi
nodules 67 precocious 538–41, 644 in diabetes mellitus see
post-partum thyroid Tanner stages 537 diabetic nephropathy
dysfunction 432 pyogenic thyroiditis 68, 72 gonadal function 661
thyrotoxicosis 44–7, 47 growth hormone 661
pretibial myxoedema 62 and hyperlipidaemia 836
prickly pear cactus (Opuntia Q parathyroid hormone 660
ficus-indica) 677 QRISK 826 prolactin 661
progestagens, COCP 356 quinagolide 204 thyroid function 661
progestagen replacement pregnancy 437 renal osteodystrophy 660
therapy renal tubular abnormalities
POI 341 258, 260
treatment regimen R Bartter’s syndrome
352, 353 radiation side effects see 258, 259
progesterone 878 radiotherapy, side effects Gitelman’s syndrome
sensitivity 335 radioiodine therapy 258, 260
17OH-progesterone 34–6, 35, 37 Liddle’s syndrome 258
CAH 322 non-toxic multinodular renin
PCOS 313 goitre 66 CAH 322
prolactin 108, 110 papillary thyroid plasma levels 272, 878
deficiency 123 carcinoma 96–7 reproductive endocrinology
liver disease 659 toxic multinodular 297–423
pregnancy 436 goitre 66 stress effects 670
renal disease 661 radiology, skeletal 453 see also specific conditions
serum levels 142, 879 radionuclide imaging reproductive physiology 298
prolactinoma 140–1 adrenals 233 anatomy 298
breastfeeding 438 hyperaldosteronism 244 gonadal function
causes 141 phaeochromocytoma 290 regulation 300–1, 302
investigations 142 isotope bone scanning 453 sex steroids see sex
MEN-1 587 radiotherapy steroids
pregnancy 437, 438 orbital 59 resveratrol 677
900 INDEX
retinoids, topical 318 definition 518 adrenalectomy 168, 256,

retinopathy, diabetic see genetic 519 257, 611
diabetic retinopathy psychosocial deprivation hyperaldosteronism 246
rickets 480–2 524, 525 phaeochromocytoma
causes 482 SIADH 220–1, 646, 648 294, 610–11
clinical features 480 causes 221 diabetic eye disease 778–9
definition 480 diagnosis 648 neuroendocrine
Riedel’s thyroiditis 68, 72 treatment 648–9 neoplasias 558
risedronate 497 sildenafil 392, 393 parathyroidectomy 466–7,
rosiglitazone 716 silent thyroiditis 72 467, 468, 608–9
rosuvastatin 841 Simpson-Golabi-Behmel complications 468
dose 845 syndrome 150 pituitary disorders 175,
RU486 see mifepristone simvastatin 815, 841 196–8, 197
dose 845 acromegaly 154
sitagliptin 717 Cushing’s disease 168
S skeletal dysplasias 530 prolactinoma 144–5
salbutamol 295 Antley-Bixler 551 thyrotrophinoma 181
saline infusion test 242 skeletal radiology 453 see also specific
sarcoidosis 472 sleeve gastrectomy 862, 863 procedures
scintiscanning 16, 17 small for gestational age thyroid disease 38, 39
screening (SGA) 531 Graves’
Cushing’s disease/ sodium, urinary 882 ophthalmopathy 60
syndrome 164 sodium loading test 243 thyroid masses 66
hyperaldosteronism somatostatin 880 thyroidectomy 38, 606–7
242–3, 243 somatostatin analogues 205 transsphenoidal
phaeochromocytoma 286 acromegaly 156 196–7, 602–4
associated neuroendocrine acromegaly 154
conditions 292–3 neoplasias 558 complications 198
thyroid disorders 15 pituitary tumours Cushing’s disease
selenium 59 181, 204–6 168, 169
semen analysis 402, 403 side effects 206 suxamethonium 295
seminiferous tubules 298 somatostatinoma 572–3, 573 sweating 666
seminoma 387 spironolactone 246, 315 gustatory 803
Sertoli cells 298 statins 815, 840–1, 841 Synacthen® test
sex hormone-binding dosage 845 long 272
globulin (SHBG) 375 indications 840 short 272
liver disease 659 interactions 840 syndrome of inappropriate
male infertility 404 intolerance to 841 ADH see SIADH
normal values 878 mechanism of action 840
sex steroids side effects 840
biosynthesis 299 steroid acute regulatory T
critical illness 662 protein (STAR) 551 tadalafil 392, 393
liver disease 658, 659 steroid equivalents 281 tall stature 534–5
metabolism 302 Stevia rebaudiana 677 causes 535
peripheral secretion 540 streptozotocin 559 tamoxifen 386
replacement 127 stress 670–1 Tangier disease 835
transport 302 definition 670 Tanner stages 537
see also individual endocrine effects 670–1 tea, in osteoporosis 681
hormones stroke, and diabetes temozolamide 155, 559
sexual development mellitus 748 teriparatide 497, 503
disorders 546–8 stromal tumour 387 testes
sexual differentiation 544 strontium ranelate 497, 503 choriocarcinoma 25
ambiguous genitalia 545 struma ovarii 25, 29 developmental
disorders of 414–15, 415 succinate dehydrogenase disorders 546
androgen insensitivity mutations 285 dysfunction 361, 371
syndrome 416 screening 292 hormonal evaluation of
ovotesticular DSD 417 sulfonylureas see insulin function 374–5
sexual differentiation disor- secretagogues trauma 373
ders, treatment 418–19 sulpiride 295 testicular tumours 387
Sheehan’s syndrome 124 sunitinib 559 MEN-1 587
pregnancy 443 surgery 601–11 testolactone 386
short stature 518–19 adrenal disorders testosterone 374
INDEX 901
liver disease 659 papillary 91, 96–8, thyroid hormone

male infertility 404 100–2, 102 dysgenesis 84
normal values 878 microcarcinoma 93–4 thyroid releasing hormone
testosterone replacement pregnancy 101 (TRH) test 121
therapy 127, 381, 621 scintiscanning 17 thyroid stimulating hormone
delayed puberty 543 staging 93 (TSH) 10, 11, 108, 110
POI 341 thyroid disorders 5 critical illness 662, 663
testoxicosis 540 autoimmune 26 deficiency 123
theca cells 298 cancer see thyroid cancer normal values 877
thelarche childhood cancer persistent elevation 82, 83
premature 540 survivors 643–4 pituitary tumours
variant 540 children secreting 50
thiazolidinediones (glita- cancer 102 pregnancy 426
zones) 715, 716 hyperthyroidism 48 recombinant 98
thyroglobulin 97 hypothyroidism 7, thyroid storm 40–1
pregnancy 426 84–5, 529 thyroid-binding globulin 877
thyroglossal cysts 7 HIV/AIDS 656 thyroid-stimulating hormone
thyroglossal fistula 7 hyperthyroidism see receptor antibodies 877
thyroid 1–105 hyperthyroidism; thyroidectomy 38, 606–7
anatomy 2 thyrotoxicosis thyroiditis 17, 68, 72
antibodies 15 hypothyroidism see atrophic 70
atypical clinical hypothyroidism autoimmune see
situations 25 liver disease 658, 659 autoimmune thyroiditis
development 2, 7 older patients 624–6 causes and
examination 2–3 pregnancy 426 characteristics 68
fetus 426 hyperemesis gravidarum clinical presentation 68
FNAC 20, 21 25, 29, 44–5, 430 de Quervain’s
histology 2 hyperthyroidism 428–31 1_130,29, 68
imaging nodules 67 drug-induced 73
CT 22 post-partum thyroid Hashimoto’s see autoim-
PET 23 dysfunction 432 mune thyroiditis
scintiscanning 16, 17 thyrotoxicosis 44–7, 47 post-partum 46, 68, 72
ultrasound 18 renal disease 661 pyogenic 72
laboratory scintiscanning 17 Riedel’s 68, 72
investigations 24 screening 15 scintiscanning 17
lingual 7 treatment silent 72
non-thyroidal illness 24 drugs 30 thyrotoxic hypokalaemia
physiology 4–5, 426 radioiodine therapy periodic paralysis 43
pregnancy 426 34–6, 35, 37 thyrotoxicosis
status 3 surgery 38, 39 aetiology 26, 27
thyroid acropachy 63 thyroid function tests 8, 877 amiodarone-induced
thyroid adenoma 17, adrenal insufficiency 273 86–90, 87
64–7, 65 atypical 12 causes 29
thyroid binding globulin effect of drugs on 11 definition 26
(TBG) 4, 5 non-thyroidal illness 76 neonatal 430
pregnancy 426 older patients 624, 625 pregnancy 44–7, 47
thyroid cancer post-amiodarone treatment
aetiology 92–4 administration 87 pharmacological 30
anaplastic (undifferenti- prolactinoma 142 radioiodine therapy
ated) 91, 104 thyroid hormones 4–5, 5 34–6, 35, 37
children 102 concentration 8 see also hyperthyroidism
cancer survivors 644 critical illness 662 thyrotoxicosis factitia
classification 91 disorders of metabolism 14 17, 25, 29
epidemiology 91 homeostatic control 10, 11 scintiscanning 17
evaluation 64, 65 liver disease 659 thyrotrophinoma 180–1
follicular 91, 99, molecular action 6 thyroxine (T4) see thyroid
100–2, 102 normal values 877 hormones
follow-up 93 pregnancy 426, 443 tibolone 352
lymphoma 105 replacement 80–3, 81, TMEM127 285
medullary 103 83, 127 toxic multinodular goitre
MEN-2 592, 594 resistance 10, 50, 51 29, 64–7
older patients 626 stress effects 670 treatment 65
902 INDEX
tramadol 799 urine phaeochromocytoma 285

transfrontal craniotomy 199 collections 881, 882 prognosis 582
transsexualism 420–3 free cortisol 162 screening 292
definition 420 osmolality 213 surveillance 581
female to male 422 uterine bleeding 351
gender reassignment uterine fibroids, HRT 349
surgery 422–3 W
hormone manipulation wasting syndrome, HIV/
421, 421 V AIDS-related 656–7
maintenance hormone vaginal atrophy 346 websites 887
regimens 423 vanadium 676 Wegener’s
male to female 421–2 vardenafil 392, 393 granulomatosis 192
prognosis 423 varicocele 408 weight management
transsphenoidal surgery vascular endothelial growth diabetes mellitus 730
196–7, 602–4 factor inhibitors 779 PCOS 314
acromegaly 154 vasoactive intestinal wild yam 681
complications 198 polypeptide 880 Wolff-Chaikov effect 86
Cushing’s disease 168, vasopressin 208 women
169 ectopic production androgen production in
post-operative care 603–4 see SIADH 304, 305
preoperative older patients 614 female athlete triad 673
assessment 602 pregnancy 443 gonadal function
traumatic brain injury 123 venlafaxine 347 childhood cancer
travel, diabetes mellitus 728 venous thromboembolism survivors 645
triamterene 246 COCP 358 HIV/AIDS 655
triiodothyronine (T3) see HRT 348 liver disease 658, 659
thyroid hormones vertebroplasty 499 in older age 620
troglitazone 716 very low density lipopro- infertility 396, 398–400
trophoblastic tumour 29 teins (VLDLs) 824 treatment 406–7, 407
Trousseau’s sign 474 vildagliptin 717 menstrual disorders see
TSH see thyroid stimulating VIPoma 570–1, 571 menstrual disorders
hormone MEN-1 587 premenopausal,
TSHoma 51 virilization 305 osteoporosis 504
tubal infertility 406 androgen-secreting
tuberculoma 193 tumours 328
tubocurarine 295 visual impairment, X
tumour markers 881 post-radiotherapy 202 X-linked adrenal hypoplasia
tumour suppressor vitamin D congenita 368
genes 138 abnormal metabolism 481 XX males 371
tumours see specific systems calcium regulation 458 46XX DSD 546, 547
and tumours deficiency 478, 484–5, 46XY DSD 546, 547
Turner’s syndrome 337 616 XYY syndrome 371
children 532–3, 533 intoxication 472
treatment 532 resistance 481
tyrosine kinase supplements 502 Y
inhibitors 97–8 osteoporosis 680 Y chromosome
vitamin D analogues 609 microdeletions 371
vitrectomy 778
U von Hipple-Lindau
UKPDS risk engine 826 syndrome 580–2 Z
ultrasound clinical features 577, 581–2 zoledronic acid 497
adrenal glands 232 definitions 580 Zollinger-Ellison syndrome
thyroid 18 genetics 580 566

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OXFORD MEDICAL PUBLICATIONS

Introduction to the Handbook of Endocrinology

John Wass and Katharine Owen

Ramzi Ajjan Ketan Dhatariya

Fredrik Karpe Peter Scanlon

aFP alpha fetoprotein

ETDRS Early Treatment of Diabetic Retinopathy Study

GI gastrointestinal; glycaemic index

HRT hormone replacement therapy

od omne in die (once daily)

PRTH pituitary resistance to thyroid hormone

Palpation (usually from behind)

Table 1.1 Disordered thyroid hormone–protein interactions

Table 1.2 Circumstances associated with altered

Molecular action of thyroid

Tests of hormone concentration

Tests of homeostatic control

Box 1.1 Thyroid hormone resistance (RTH) (b see also

Table 1.3 Thyroid hormone concentrations in various thyroid

Table 1.4 Influence of drugs on thyroid function tests

Table 1.5 Atypical thyroid function tests1

Rare genetic disorders of thyroid

Table 1.6 Antithyroid antibodies and thyroid disease

Table 1.7 Radioisotope scans

Half-life Short Short

Table 1.8 Radionuclide scanning (scintigram) in thyroid disease

Ultrasound (US) scanning

Fine needle aspiration

Table 1.9 Diagnostic features of FNAC

Table 1.10 Diagnostic categories from FNAC

Computed tomography (CT)

Positron emission tomography (PET)

Additional laboratory investigations

Non-thyroidal illness (sick euthyroid

Atypical clinical situations

Table 1.11 Classification of the aetiology of thyrotoxicosis

Box 1.2 Manifestations of hyperthyroidism (all forms)

Table 1.12 Tests which help to differentiate different causes of

• Localized dermopathy (pretibial myxoedema, b see Graves’s

concentrations of thyrotropin receptor antibody at the time of

Table 1.13 Recommended activity of radioiodine

Hypothyroidism after radioiodine

Instructions to patients before treatment

Table 1.14 Number of days to apply caution after radioiodine

Box 1.3 Complications of thyroidectomy

Thyroid crisis (storm)

Box 1.4 Clinical signs suggestive of a thyroid storm

Box 1.5 Indications to treat subclinical hyperthyroidism

• The i risk of fracture reported in older ♀ taking thyroid hormone

Thyrotoxic hypokalaemic periodic paralysis

• Serum free T4 concentration may be i and the TSH levels suppressed

• Antithyroid medication requirements usually decrease during gestation;

Box 1.6 Potential maternal and fetal complications in

occurring in the first 3 months post-partum, followed by a hypothyroid

• About 85% of thyroid hormone resistance syndromes result from

Table 1.15 Tests useful in the differential diagnosis of TSHomas,

Box 1.7 Assessment of severity of Graves’s

• Documentation using a Hertel exophthalmometer. The feet of the

Medical treatment of Graves’s

Surgical treatment of Graves’s