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Essential Endocrinology
and Diabetes

Essential
Endocrinology
and Diabetes
Richard IG Holt
Professor in Diabetes and Endocrinology
Faculty of Medicine
University of Southampton
Neil A Hanley
Professor of Medicine
Faculty of Medical & Human Sciences
University of Manchester
Sixth edition
A John Wiley & Sons, Ltd., Publication
This edition first published 2012 © 2012 by Richard IG Holt and Neil A Hanley
Fifth edition © 2007 Richard Holt and Neil Hanley
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Library of Congress Cataloging-in-Publication Data
Holt, Richard I. G.
Essential endocrinology and diabetes. – 6th ed. / Richard I.G. Holt, Neil A. Hanley.
p. ; cm. – (Essentials)
Includes bibliographical references and index.
ISBN-13: 978-1-4443-3004-5 (pbk. : alk. paper)
ISBN-10: 1-4443-3004-7 (pbk. : alk. paper) 1. Endocrinology–Case studies. 2. Diabetes–Case studies. I. Hanley,
Neil A. II. Title. III. Series: Essentials (Wiley-Blackwell)

[DNLM: 1. Endocrine Glands–physiology. 2. Diabetes Mellitus. 3. Endocrine System Diseases. 4. Hormones–
physiology. WK 100]
RC648.H65 2012
616.4–dc23
2011024249
A catalogue record for this book is available from the British Library.
Set in 10 on 12 pt Adobe Garamond Pro by Toppan Best-set Premedia Limited
1 2012
Contents
Preface vii
List of abbreviations x
How to get the best out of your textbook xii
PART 1: Foundations of Endocrinology 1
1 Overview of endocrinology 3
2 Cell biology and hormone synthesis 14
3 Molecular basis of hormone action 27
4 Investigations in endocrinology and diabetes 48
PART 2: Endocrinology – Biology to Clinical Practice 63
5 The hypothalamus and pituitary gland 65
6 The adrenal gland 99
7 Reproductive endocrinology 127
8 The thyroid gland 165
9 Calcium and metabolic bone disorders 190
10 Pancreatic and gastrointestinal endocrinology and
endocrine neoplasia 213
PART 3: Diabetes and Obesity 233
11 Overview of diabetes 235
12 Type 1 diabetes 257
13 Type 2 diabetes 285
14 Complications of diabetes 311

15 Obesity 343
Index 360

Preface
There have been significant advances and developments in the 4 years since we wrote
the last edition. Consequently, many areas of the book have required substantial updating
and extensive re-writing. Nevertheless, the structure of the book has remained similar
to the last edition, which seemed popular around the world.
The first part strives to create a knowledgeable reader prepared for the clinical sec-
tions. Recognizing that many students now come to medicine from non-scientific
backgrounds, we have tried to limit assumptions on prior knowledge. For instance, the
concept of negative feedback regulation, covered in Chapter 1, is mandatory for under-
standing almost all endocrine physiology and is vital for the interpretation of many
clinical tests. Similarly, molecular diagnostics has advanced far beyond the historical
development of immunoassays. New modalities, such as molecular genetics, mass spec-
trometry and sophisticated imaging, are already standard practice and it is important
that aspiring clinicians, as well as scientists, appreciate their methodology, application
and limitations. The second part retains a largely organ-based approach. The introduc-
tory basic science in these chapters aims to be concise yet sufficient to understand,
diagnose and manage the associated clinical disorders. The chapter on endocrine neo-
plasia, including hormone-secreting tumours of the gut, has been expanded in recogni-
tion of the increasing array of hormones discovered from the pancreas and gastrointestinal
tract. In previous editions these hormones have lacked attention. However, many of
them are now emerging as key regulators that are exploited in new therapies. For
instance, augmentation of glucagon-like peptide 1 signalling is an effective treatment for
diabetes. The third part on diabetes and obesity was entirely new in the last edition and
these chapters have undergone the greatest change here. Over the last 4 years we have
seen significant advances in the treatment of type 2 diabetes such as the new incretin-
based therapies and the withdrawal of other treatments due to safety concerns. Clinical
algorithms have also changed and these have been updated.

The textbook aims to bridge the gap from basic science training, through clinical train-
ing, to the knowledge required for the early postgraduate years and specialist training. The
text goes beyond core undergraduate medical education. Learning objectives, boxes, and
concluding ‘key points’ aim to emphasize the major topics. There is hopefully useful detail
for more advanced clinicians who, like the authors, enjoy trying to interpret clinical medi-
cine scientifically, but for whom memory occasionally fails. Although the structure of the
book is largely unchanged from the previous edition, readers of the old edition will recog-
nize welcome developments. For the first time, the book is in full colour, which has allowed
us to include colour photographs in the relevant chapter. We have introduced recap and
cross-reference guides at the beginning of each of the clinical chapters to help the reader
find important information in other parts of the book more easily. The case histories that
were introduced in the last edition proved to be a success and these have been expanded to
provide greater opportunity to put theory into practice.
We have brought our clinical and research experiences together to create this book.
While it has been a truly collaborative venture and the book is designed to read as a
whole, inevitably one of us has taken a lead with each chapter depending on our own
interests. As such, NAH was responsible for writing Part 1 and Part 2, while RIGH was
responsible for Part 3.
viii  /  Preface
Finally, we must thank a number of people without whom this book would not have
come to fruition. We are grateful for the skilled help of Wiley-Blackwell Publishing and
remain indebted to our predecessors up to and including the 4th edition, Charles Brook
and Nicholas Marshall, for their excellent starting point. We are also grateful to our
families without whose support this book would not have been possible and to whom
we dedicate this edition.
The authors
Richard Holt is Professor in Diabetes and Endocrinology at the
University of Southampton School of Medicine and Honorary
Consultant in Endocrinology at Southampton University
Hospitals NHS Trust. His research interests are broadly focused

around clinical diabetes with particular interests in diabetes in
pregnancy and young adults, and the relation between diabetes
and mental illness. He also has a long-standing interest in
growth hormone.
Neil Hanley is Professor of Medicine and Wellcome Trust
Senior Fellow in Clinical Science at the University of Manchester.
He is Honorary Consultant in Endocrinology at the Central
Manchester University Hospitals NHS Foundation Trust where
he provides tertiary referral endocrine care. His main research
interests are human developmental endocrinology and stem cell
biology.
Both authors play a keen role in the teaching of undergraduate medical students and
doctors. RIGH is a Fellow of the Higher Education Academy. NAH is Director of the
Academy for Training & Education at the Manchester Biomedical Research Centre.
R.I.G. Holt
University of Southampton
N.A. Hanley
University of Manchester
 Preface  /  ix
Further reading
The following major international textbooks make an excellent source of secondary
reading:
Melmed S, Polonsky KS, Reed Larsen P, Kronenberg HM, eds. Williams Textbook of
Endocrinology, 12th edn. Saunders, 2011.
Holt RIG, Cockram C, Flyvbjerg A, Goldstein BJ. Textbook of Diabetes, 4th edn. Wiley-
Blackwell, 2010.
In addition, the following textbooks cover topics, relevant to some chapters, in greater
detail:
Delves PJ, Martin SJ, Burton DR, Roitt IM. Roitt’s Essential Immunology, 12th edn.
Wiley-Blackwell, 2011.

Johnson M. Essential Reproduction, 6th edn. Wiley-Blackwell, 2007.
Nelson DL, Cox MM. Lehninger Principles of Biochemistry, 5th edn. W.H. Freeman,
2008.
List of abbreviations
5-HIAA 5-hydroxyindoleacetic acid
5-HT 5-hydroxytryptophan
αMSH α-melanocyte stimulating hormone
ACTH adrenocorticotrophic hormone
ADH vasopressin/antidiuretic hormone
AFP α-fetoprotein
AGE advanced glycation end-product
AGRP Agouti-related protein
AI angiotensin I
AII angiotensin II
ALS acid labile subunit
AMH anti-Müllerian hormone
AR androgen receptor
APS-1 type 1 autoimmune polyglandular
syndrome
APS-2 type 2 autoimmune polyglandular
syndrome
CAH congenital adrenal hyperplasia
cAMP cyclic adenosine monophosphate
CBG cortisol binding globulin
cGMP guanosine monophosphate
CRE cAMP response element
CREB cAMP response element-binding
protein
CNS central nervous system
CRH corticotrophin-releasing hormone

CSF cerebrospinal fluid
CT computed tomography
CVD cardiovascular disease
DAG diacylglycerol
DEXA dual energy X-ray absorptiometry
DHEA dehydroepiandrosterone
DHT 5α-dihydrotestosterone
DI diabetes insipidus
EGF epidermal growth factor
EPO erythropoietin
ER oestrogen receptor
FFA free fatty acid
FGF fibroblast growth factor
FIA fluoroimmunoassay
FISH fluorescence in situ hybridization
FSH follicle-stimulating hormone
fT
3
free tri-iodothyronine
fT
4
free thyroxine
GC gas chromatography
GDM gestational diabetes
GFR glomerular filtration rate
GH growth hormone (somatotrophin)
GHR GH receptor
GHRH growth hormone-releasing hormone
GI glycaemic index
GIP glucose-dependent insulinotrophic

peptide (gastric inhibitory peptide)
GLUT glucose transporter
GnRH gonadotrophin-releasing hormone
GPCR guanine-protein coupled receptor
GR glucocorticoid receptor
Grb2 type 2 growth factor receptor-bound
protein
hCG human chorionic gonadotrophin
hMG human menopausal gonadotrophin
HMGCoA hydroxymethylglutaryl coenzyme A
HNF hepatocyte nuclear factor
HPLC high performance liquid
chromatography
HRE hormone response element
HRT hormone replacement therapy
ICSI intracytoplasmic sperm injection
IDDM insulin-dependent diabetes mellitus
IFG impaired fasting glycaemia
IFMA immunofluorometric assay
IGF insulin-like growth factor
IGFBP IGF-binding protein
IGT impaired glucose tolerance
IP inositol phosphate
IPF insulin promoter factor
IR insulin receptor
IRMA intraretinal microvascular
abnormalities (Chapter 14)
IRMA immunoradiometric assay
(Chapter 4)
IRS insulin receptor substrate

IVF in vitro fertilization
JAK Janus-associated kinase
LDL low-density lipoprotein
LH luteinizing hormone
MAO monoamine oxidase
MAPK mitogen-activated protein kinase
List of abbreviations / xi
MEN multiple endocrine neoplasia
MIS Müllerian inhibiting substance
MODY maturity-onset diabetes of the young
MR mineralocorticoid receptor
MRI magnetic resonance imaging
MS mass spectrometry
MSH melanocyte-stimulating hormone
NEFA non-esterified fatty acid
NICTH non-islet cell tumour hypoglycaemia
NIDDM non–insulin-dependent diabetes
mellitus
NPY neuropeptide Y
NVD new vessels at the disc
NVE new vessels elsewhere
OGTT oral glucose tolerance test
PCOS polycystic ovarian syndrome
PCR polymerase chain reaction
PDE phosphodiesterase
PGE2 prostaglandin E
2
PI phosphatidylinositol
PIT1 pituitary-specific transcription
factor 1

PKA protein kinase A
PKC protein kinase C
PLC phospholipase C
PNMT phenylethanolamine N-methyl
transferase
POMC pro-opiomelanocortin
PPAR peroxisome proliferator-activated
receptor
PRL prolactin
PTH parathyroid hormone
PTHrP parathyroid hormone-related peptide
PTU propylthiouracil
RANK receptor activator of nuclear
factor-kappa B
RER rough endoplasmic reticulum
RIA radioimmunoassay
rT
3
reverse tri-iodothyronine
RXR retinoid X receptor
SERM selective ER modulator
SHBG sex hormone-binding globulin
SIADH syndrome of inappropriate
antidiuretic hormone
SoS son of sevenless protein
SRE serum response element
SS somatostatin
StAR steroid acute regulatory protein
STAT signal transduction and activation of
transcription protein

T1DM type 1 diabetes
T2DM type 2 diabetes
t
1/2
half-life
T
3
tri-iodothyronine
T
4
thyroxine
TGFβ transforming growth factor β
TK tyrosine kinase
TPO thyroid peroxidase
TR thyroid hormone receptor
TRE thyroid hormone response element
TRH thyrotrophin-releasing hormone
TSH thyroid-stimulating hormone
UFC urinary free cortisol
V vasopressin/antidiuretic hormone
(previously also known as arginine
vasopressin)
VEGF vascular endothelial growth factor
VIP vasoactive intestinal peptide
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R E V I S E D
311
Essential Endocrinology and Diabetes, Sixth Edition. Richard IG Holt, Neil A Hanley.
© 2012 Richard IG Holt and Neil A Hanley. Publlished 2012 by Blackwell Publishing Ltd.
CHAPTER 14
Complications of
diabetes
Key topics
■ Microvascular complications 312
■ Macrovascular disease 330
■ Cancer 334
■ Psychological complications 334
■ How diabetes care can reduce complications 335

■ Diabetes and pregnancy 336
■ Social aspects of diabetes 339
■ Key points 340
■ Answers to case histories 340
Learning objectives
■ To discuss the causes of microvascular and macrovascular
complications
■ To understand the importance of screening for complications
■ To understand the strategies to prevent and treat
complications
■ To discuss diabetes in pregnancy
■ To understand the psychosocial aspects of diabetes
This chapter discusses the microvascular and macrovascular
complications of diabetes, diabetes in pregnancy and
psychosocial aspects of diabetes
ons
on
s
s
s
s
R E V I S E D
3
Essential Endocrinology and Diabetes, Sixth Edition. Richard IG Holt, Neil A Hanley.
© 2012 Richard IG Holt and Neil A Hanley. Publlished 2012 by Blackwell Publishing Ltd.
CHAPTER 1
Overview of
endocrinology
Key topics
■ A brief history of endocrinology and diabetes 4

■ The role of hormones 5
■ Classification of hormones 8
■ Organization and control of endocrine organs 9
■ Endocrine disorders 13
■ Key points 13
Learning objectives
■ To be able to define endocrinology
■ To understand what endocrinology is as a basic science and
a clinical specialty
■ To appreciate the history of endocrinology
■ To understand the classification of hormones into peptides,
steroids and amino acid derivatives
■ To understand the principle of feedback mechanisms that
regulate hormone production
This chapter details some of the history to endocrinology and
diabetes, and introduces basic principles that underpin the
subsequent chapters
d
d
d
Cross-reference
The development of the parathyroid and parafollicular
C-cells is described alongside the thyroid in Chapter 8
Tumours of the parathyroid glands are an important
component of multiple endocrine neoplasia, covered in
Chapter 10
Other hormones such as cortisol (see Chapter 6) and sex
hormones (see Chapter 7) affect mineralization of the
bones
 Your textbook is full of useful photographs,

illustrations and tables. The Desktop Edition
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
102 / Chapter 6: The adrenal gland
Chapter 6: The adrenal gland / 103
Figure 6.2 Section through
the adrenal cortex. (a) The
blood vessels run from outer
capsule to medullary venule.
(b) A zona fasciculata cell with
large lipid droplets, extensive
smooth endoplasmic
reticulum and mitochondria.
Smooth endoplasmic reticulum
Lipid droplets
Mitochondria
Capsule
Zona
glomerulosa
Zona
fasciculata
Zona
reticularis
Medulla
(a) (b)
Capillary
Venule

Box 6.2 Zones of the adult adrenal
cortex and their steroid hormone
secretion
• Zona glomerulosa, nests of closely packed
small cells creating the thinnest, outermost
layer; secretes aldosterone
• Zona fasciculata, larger cells in columns
making up ∼three-quarters of the cortex;
secretes cortisol and some sex steroid
precursors
• Zona reticularis, ‘net-like’ arrangements of
innermost cells, formed at 6–8 years to
herald a poorly understood change called
‘adrenarche’; secretes sex steroid
precursors and some cortisol
cortisol measurement; an important clinical issue.
Like thyroid hormones, it is only the free compo-
nent that enters target cells. e free component
also passes into urine – ‘urinary free cortisol’ (UFC)
– where its collection and assay over 24 h has been
used as a test of glucocorticoid excess (UFC is ∼1%
of cortisol production by the adrenal glands).
Measuring salivary cortisol similarly avoids issues
with uctuating serum CBG.
Regulation of cortisol biosynthesis and
secretion – the hypothalamic–pituitary–
adrenal axis
e major regulation of the adrenal cortex
comes from the anterior pituitar y, via the produc-
tion and circulation of adrenocorticotrophic hor-

mone (ACTH), a cleavage product of the pro-
opiomelanocortin (POMC) gene (review Chapter 5).
In turn, ACTH is regulated by corticotrophin-
releasing hormone (CRH) from the hypothalamus
(Figure 6.4). By binding to cell-surface receptors
and activating cAMP second messenger pathways,
ACTH increases ux through the pathway from
cholesterol to cortisol, particularly at the rate-
limiting step catalyzed by CYP11A1. is happens
acutely such that a rise in ACTH increases cortisol
levels within 5 min. Cortisol provides feedback
to the anterior pituitary and hypothalamus to
17α-hydroxylase
(CYP17A1)
21-hydroxylase
(CYP21A2)
11β-hydroxylase
(CYP11B1)
21-hydroxylase
(CYP21A2)
11β-hydroxylase
(CYP11B2)
3β-hydroxysteroid
dehydrogenase
(HSD3B2)
18-hydroxylase
(CYP11B2)
Aldosterone synthase
(CYP11B2)
Cholesterol side chain

cleavage (CYP11A1)
17,20-lyase
(CYP17A1)
Sulphotransferase
(SULT2A1)
Cholesterol
Pregnenolone
Progesterone
Deoxy-
corticosterone
Corticosterone
18-hydroxy-
corticosterone
Cortisol
11-deoxycortisol
17a-hydroxy-
progesterone
17a-hydroxy-
pregnenolone
Dehydroepi-
androsterone
(DHEA)
(DHEAS)
DHEA
sulphate
Androstenedione
Aldosterone
Figure 6.3 Biosynthesis of adrenocortical steroid hormones. HSD3B activity in the adrenal cortex arises from
the type 2 isoform. The three steps from deoxycorticosterone to aldosterone are catalyzed by the same enzyme,
CYP11B2 (also see Figure 2.6).

Box 6.3 Adrenocortical steroidogenesis can be summarized into a few
key steps
• Transport of cholesterol into the
mitochondrion by the steroid acute
regulatory (StAR) protein
• The rate-limiting removal of the cholesterol
side chain by CYP11A1
• Shuttling intermediaries between
mitochondria and endoplasmic reticulum for
further enzymatic modification
• Action of two key enzymes at branch
points:
°
CYP17A1 prevents the biosynthesis of
aldosterone and commits a steroid to
cortisol or sex steroid precursor. Hence,
CYP17A1 is absent from the zona
glomerulosa
°
Early action of HSD3B2 steers steroid
precursors away from the sex steroid
precursors towards aldosterone or cortisol
• The presence and activity of CYP11B2 in the
zona glomerulosa permitting aldosterone
synthesis
• The presence and activity of CYP11B1 in the
fasciculata (and less so the reticularis) zone
allowing cortisol production
252 / Chapter 11: Overview of diabetes
Chapter 11: Overview of diabetes / 253

Table 11.6 Insulin actions on carbohydrate metabolism
Action Mechanism
Increases glucose uptake
into cells
Translocation of glucose transporter (GLUT)-4 to the cell surface
Increases glycogen synthesis Activates glycogen synthase by dephosphorylation
Inhibits glycogen breakdown Inactivates glycogen phosphorylase and its activating kinase by
dephosphorylation
Inhibits gluconeogenesis Dephosphorylation of pyruvate kinase and 2,6-biphosphate kinase
Increases glycolysis Dephosphorylation of pyruvate kinase and 2,6-biphosphate kinase
Converts pyruvate to acetyl
CoA
Activates the intramitochondrial enzyme complex pyruvate
dehydrogenase
phosphorylation and dephosphorylation of the
enzymes controlling glycogenolysis and glycogen
synthesis (Figure 11.12). e rate-limiting enzymes
are the catabolic enzyme glycogen phosphorylase
and the anabolic enzyme glycogen synthase. Insulin
increases glycogen synthesis by activating glycogen
synthase, while inhibiting glycogenolysis by
dephosphorylating glycogen phosphorylase kinase.
Glycolysis is stimulated and gluconeogenesis inhib-
ited by dephosphorylation of pyruvate kinase (PK)
and 2,6-biphosphate kinase. Insulin also enhances
the irreversible conversion of pyruvate to acetyl
CoA by activation of the intramitochondrial enzyme
complex pyruvate dehydrogenase. Acetyl CoA
may then be directly oxidized via the tricarboxylic
acid (Krebs’) cycle, or used for fatty acid synthesis

(Figure 11.13).
Lipid metabolism
Insulin increases the rate of lipogenesis in several
ways in adipose tissue and liver, and controls
the formation and storage of triglyceride. e
critical step in lipogenesis is the activation of the
insulin-sensitive lipoprotein lipase in the capillaries.
Fatty acids are then released from circulating
chylomicrons or very low-density lipoproteins
and taken up into the adipose tissue. Fatty acid
synthesis is increased by activation and increased
phosphorylation of acetyl CoA carboxylase, while
fat oxidation is suppressed by inhibition of carnitine
acyltransferase (Table 11.7). Lipogenesis is also
facilitated by glucose uptake, because its metabo-
lism by the pentose phosphate pathway provides
nicotinamide adenine dinucleotide phosphate
(NADPH), which is needed for fatty acid
synthesis.
Triglyceride synthesis is stimulated by ester-
ication of glycerol phosphate, while triglyceride
breakdown is suppressed by dephosphorylation of
hormone-sensitive lipase.
Cholesterol synthesis is increased by activation
and dephosphorylation of hydroxymethylglutaryl
co-enzyme A (HMGCoA) reductase, while choles-
terol ester breakdown appears to be inhibited
by dephosphorylation of cholesterol esterase.
Phospholipid metabolism is also inuenced by
insulin.

Protein metabolism
Insulin stimulates the uptake of amino acid into
cells and promotes protein synthesis in a range of
tissues. ere are eects on the transcription of
specic mRNA, as well as their translation into
proteins on the ribosomes (review Chapter 2 and
Figure 2.2). Examples of enhanced mRNA tran-
scription
include glucokinase and fatty acid syn-
thase. By contrast, insulin decreases mRNA
encoding liver enzymes such as carbamoyl phos-
phate synthetase, which is a key enzyme in the urea
cycle. However, the major action of insulin on
protein metabolism is to inhibit the breakdown of
proteins (Figure 11.14). In this way it acts synergis-
tically with GH and insulin-like growth factor I
(IGF-I) to increase protein anabolism.
Figure 11.12 Inter-relationships among alternative
routes of glucose metabolism. The central role of
glucose in carbohydrate, fat and protein metabolism
is summarized. The principal metabolic pathways
are shown enclosed in boxes in order to simplify
the diagram; some key intermediates and products
of metabolic interconversions are shown. The
reversibility of certain reaction sequences implied
by double-headed arrows is not necessarily
intended to suggest that the same enzymes are
involved in both the forward and reverse
reactions. The principal reversible pathways that
are activated during fasting are marked with heavy

arrows.
Glucose
Glycolytic-
gluconeogenic
pathways
Pentose
phosphate
pathway
Glucuronate-
xylulose
pathway
Tricarboxylic
acid cycle
Protein
degradation
Lipid
synthesis
Urea
cycle
Sorbitol route
Glucose-6- P
Glucose-1- P
UDP-Glucose
Ribose-5- P
α-Glycero- P
α-Glycero- P
NH
3
NADPH
NADP

+
Lactate
Pyruvate
Acetyl
CoA
ATP
Amino
acids
Fructose
Glycogen
Glycoprotein
Mucopoly-
saccharide
Nucleotides
RNA and DNA
Triglycerides
Urea
Table 11.7 Insulin actions on fatty acid metabolism
Action Mechanism
Releases fatty acids from circulating
chylomicrons or very low-density lipoproteins
Activates lipoprotein lipase
Increases fatty acid synthesis Activates acetyl CoA carboxylase
Suppresses fatty acid oxidation Inhibits carnitine acyltransferase
Increases triglyceride synthesis Stimulates esterification of glycerol phosphate
Inhibits triglyceride breakdown Dephosphorylates hormone-sensitive lipase
Increases cholesterol synthesis Activates and dephosphorylates HMGCoA reductase
Inhibits cholesterol ester breakdown Dephosphorylates cholesterol esterase
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Part 1
Foundations of
Endocrinology
3
Essential Endocrinology and Diabetes, Sixth Edition. Richard IG Holt, Neil A Hanley.
© 2012 Richard IG Holt and Neil A Hanley. Publlished 2012 by Blackwell Publishing Ltd.
CHAPTER 1
Overview of
endocrinology
Key topics
■ A brief history of endocrinology and diabetes 4
■ The role of hormones 5
■ Classification of hormones 8
■ Organization and control of endocrine organs 9
■ Endocrine disorders 13
■ Key points 13
Learning objectives
■ To be able to define endocrinology
■ To understand what endocrinology is as a basic science and
a clinical specialty
■ To appreciate the history of endocrinology
■ To understand the classification of hormones into peptides,
steroids and amino acid derivatives
■ To understand the principle of feedback mechanisms that
regulate hormone production

This chapter details some of the history to endocrinology and
diabetes, and introduces basic principles that underpin the
subsequent chapters
4 / Chapter 1: Overview of endocrinology
Figure 1.1 Cells that secrete regulatory substances to
communicate with their target cells and organs. (a)
Endocrine. Cells secrete hormone into the blood
vessel, where it is carried, potentially over large
distances, to its target cell. (b) Autocrine (A): hormones
such as insulin-like growth factors can act on the cell
that produces them, representing autocrine control.
Paracrine (P): cells secrete hormone that acts on
nearby cells (e.g. glucagon and somatostatin act on
adjacent β-cells within the pancreatic islet to influence
insulin secretion). (c) Stimulated neuroendocrine cells
secrete hormone (e.g. the hypothalamic hormones that
regulate the anterior pituitary) from axonic terminals
into the bloodstream. (d) Neurotransmitter cells secrete
substances from axonic terminals to activate adjacent
neurones.
Neurotransmitter
Neurone
Neurone
Target cell
Blood vessel
Axon
Axon
terminal
Nerve cell
Blood vessel

Hormone
Target cell
Local hormone
Target cell
A
P
(a) Endocrine (b) Autocrine (A) and
Paracrine (P)
(c) Neuroendocrine (d) Neurotransmitter
An organism comprised of a single or a few cells
analyzes and responds to its external environment
with relative ease. No cell is more than a short dif-
fusion distance from the outside world or its neigh-
bours, allowing a constancy of internal environment
(‘homeostasis’). This simplicity has been lost with
the evolution of more complex, larger, multicellular
organisms. Simple diffusion has become inadequate
in larger animal species where functions localize to
specific organs. In humans, there are ∼10
14
cells of
200 or more different types. With this compart-
mentalized division of purpose comes the need for
effective communication to disseminate informa-
tion throughout the whole organism – only a few
cells face the outside world, yet all respond to it.
Two communication systems facilitate this: the
endocrine and nervous systems (Box 1.1).
The specialized ductless glands and tissues of the
endocrine system release chemical messengers –

hormones – into the extracellular space, from where
they enter the bloodstream. It is this blood-borne
transit that defines endocrinology; however, the
principles are similar for hormone action on a
neighbouring cell (‘paracrinology’) or, indeed, itself
(‘auto- or intra-crinology’) (Figure 1.1).
The nervous and endocrine systems interact.
Endocrine glands are under both nervous and hor-
monal control, while the central nervous system is
affected by multiple hormonal stimuli – features
reflected by the composite science of neuroendo-
crinology (Figure 1.1).
A brief history of endocrinology
and diabetes
The term ‘hormone’, derived from the Greek word
‘hormaein’ meaning ‘to arouse’ or ‘to excite’, was
first used in 1905 by Sir Ernest Starling in his
Croonian Lecture to the Royal College of Physicians;
Box 1.1 Functions of the
endocrine and nervous systems,
the two main communication
systems
• To monitor internal and
external environments

maintain
homeostasis
• To allow appropriate
adaptive changes
• To communicate via

chemical messengers
}
Chapter 1: Overview of endocrinology / 5
however, the specialty is built on foundations that
are far older. Aristotle described the pituitary, while
the associated condition, gigantism, due to excess
growth hormone (GH), was referred to in the Old
Testament, two millennia or so before the 19th
century recognition of the gland’s anterior and pos-
terior components by Rathke, and Pierre Marie’s
connection of GH-secreting pituitary tumours to
acromegaly.
Diabetes was recognized by the ancient
Egyptians. Areteus later described the disorder in
the second century  as ‘a melting down of flesh
and limbs into urine’ – diabetes comes from the
Greek word meaning siphon. The pancreas was only
implicated relatively recently when Minkowski real-
ized in 1889 that the organ’s removal in dogs mim-
icked diabetes in humans.
The roots of reproductive endocrinology are
equally long. The Bible refers to eunuchs and
Hippocrates recognized that mumps could result in
sterility. Oophorectomy in sows and camels was
used to increase strength and growth in ancient
Egypt. The association with technology is also long-
standing. For instance, it took the microscope in the
17th century for Leeuwenhoek to visualize sperma-
tozoa and later, in the 19th century, for the mam-
malian ovum to be discovered in the Graafian

follicle.
During the last 500 years, other endocrine
organs and axes have been identified and character-
ized. In 1564, Bartolommeo Eustacio noted the
presence of the adrenal glands. Almost 300 years
later (1855), Thomas Addison, one of the forefa-
thers of clinical endocrinology, described the con-
sequences of their inadequacy. Catecholamines were
identified at the turn of the 19th century, in parallel
with Oliver and Schaffer’s discovery that these
adrenomedullary substances raise blood pressure.
This followed shortly after the clinical features of
myxoedema were linked to the thyroid gland, when,
in 1891, physicians in Newcastle treated hypothy-
roidism with sheep thyroid extract. This was an
important landmark, but long after the ancient
Chinese recognized that seaweed, as a source of
iodine, held valuable properties in treating ‘goitre’,
swelling of the thyroid gland.
Early clinical endocrinology and diabetes tended
to recognize and describe the features of the endo-
crine syndromes. Since then, our understanding has
advanced through:
• Successful quantification of circulating
hormones
• Pathophysiological identification of endocrine
dysfunction
• Molecular genetic diagnoses
• Molecular unravelling of complex hormone
action.

Some of the landmarks from the last 100 years
are shown in Box 1.2, and those researchers who
have been awarded the Nobel Prize for Medicine,
Physiology or Chemistry for discoveries that have
advanced endocrinology and diabetes are listed in
Table 1.1.
Traditionally, endocrinology has centred on spe-
cialized hormone-secreting organs (Figure 1.2),
largely built on the ‘endocrine postulates’ of Edward
Doisy (Box 1.3). While the focus of this textbook
remains with these organs, many tissues display
appreciable degrees of hormone biosynthesis, and,
equally relevant, modulate hormone action. All
aspects are important for a complete appreciation
of endocrinology and its significance.
The role of hormones
Hormones are synthesized by specialized cells
(Table 1.2), which may exist as distinct endocrine
glands or be located as single cells within other
organs, such as the gastrointestinal tract. The chap-
ters in Part 2 are largely organized on this anatomi-
cal basis.
Endocrinology is defined by the secretion of
hormones into the bloodstream; however, autocrine
or paracrine actions are also important, often mod-
ulating the hormone-secreting cell type. Hormones
act by binding to specific receptors, either on the
surface of or inside the target cell, to initiate a
cascade of intracellular reactions, which frequently
amplifies the original stimulus and generates a final

response. These responses are altered in hormone
deficiency and excess: for instance, GH deficiency
leads to short stature in children, while excess
causes over-growth (either gigantism or acromegaly;
Chapter 5).
6 / Chapter 1: Overview of endocrinology
Box 1.2 Some landmarks in endocrinology over the last 100 years or so
1905 First use of the term ‘hormone’ by Starling in the Croonian Lecture at the Royal
College of Physicians
1909 Cushing removed part of the pituitary and saw improvement in acromegaly
1914 Kendall isolated an iodine-containing substance from the thyroid
1921 Banting and Best extracted insulin from islet cells of dog pancreas and used it to
lower blood sugar
Early 1930s Pitt-Rivers and Harrington determined the structure of the thyroid hormone,
thyroxine
1935–40 Crystallization of testosterone
1935–40 Identification of oestrogen and progesterone
1940s Harris recognized the relationship between the hypothalamus and anterior pituitary
in the ‘portal-vessel chemotransmitter hypothesis’
1952 Gross and Pitt-Rivers identified tri-iodothyronine in human serum
1955 The Schally and Guillemin laboratories showed that extracts of hypothalamus
stimulated adrenocorticotrophic hormone (ACTH) release
1956 Doniach, Roitt and Campbell associated antithyroid antibodies with some forms of
hypothyroidism – the first description of an autoimmune phenomenon
1950s Adams and Purves identified thyroid stimulatory auto-antibodies
Gonadectomy and transplantation experiments by Jost led to the discovery of the
role for testosterone in rabbit sexual development
1955 Sanger reported the primary structure of insulin
1957 Growth hormone was used to treat short stature in patients
1966 First transplant of human pancreas to treat type 1 diabetes by Kelly, Lillehei, Goetz

and Merkel at the University of Minnesota
1969 Hodgkin reported the three-dimensional crystallographic structure of insulin
1969–71 Discovery of thyrotrophin-releasing hormone (TRH) and gonadotrophin-releasing
hormone (GnRH) by Schally’s and Guillemin’s groups
1973 Discovery of somatostatin by the group of Guillemin
1981–2 Discovery of corticotrophin-releasing hormone (CRH) and growth hormone-
releasing hormone (GHRH) by Vale
1994 Identification of leptin by Friedman and colleagues
1994 First transplantation of pancreatic islets to treat type 1 diabetes by Pipeleers and
colleagues in Belgium
1999 Discovery of ghrelin by Kangawa and colleagues
1999 Sequencing of the human genome – publication of the DNA code for
chromosome 22
2000 Advanced islet transplantation using modified immunosuppression by Shapiro and
colleagues to treat type 1 diabetes
Thyroid hormone acts on many, if not all, of the
200 plus cell types in the body. The basal metabolic
rate increases if it is present in excess and declines
if there is a deficiency (see Chapter 8). Similarly,
insulin acts on most tissues, implying its receptors are
widespread. Its importance is also underlined by
its role in the survival and growth of many cell types
in laboratory culture. In contrast, other hormones
may act only on one tissue. Thyroid-stimulating
hormone (TSH), adrenocorticotrophic hormone
(ACTH) and the gonadotrophins are secreted by
the anterior pituitary and have specific target tissues
Chapter 1: Overview of endocrinology / 7
Table 1.1 Nobel prize winners for discoveries relevant to endocrinology and diabetes
Year Prize winner(s) For work on . . .

1909 Emil Theodor Kocher Physiology, pathology and surgery of the thyroid
gland
1923 Frederick Grant Banting and John James
Richard Macleod
Discovery of insulin
1928 Adolf Otto Reinhold Windhaus Constitution of the sterols and their connection
with the vitamins
1939 Adolf Friedrich and Johann Butenandt Sex hormones
1943 George de Hevesy Use of isotopes as tracers in the study of chemical
processes
1946 James Batcheller Summer, John Howard
Northrop and Wendell Meredith Stanley
Discovery that enzymes can be crystallized and
prepared in a pure form
1947 Carl Ferdinand Cori, Getty Theresa Cori
(neé Radnitz) and Bernardo Alberto
Houssay
Discovery of the course of the catalytic conversion
of glycogen
1950 Edwin Calvin Kendall, Tadeus Reichstein
and Philip Showalter Hench
Discoveries relating to the hormones of the
adrenal cortex, their structure and biological
effects
1955 Vincent du Vigneaud Biochemically important sulphur compounds,
especially for the first synthesis of a polypeptide
hormone
1958 Frederick Sanger Structures of proteins, especially that of insulin
1964 Konrad Bloch and Feodor Lynen Discoveries concerning the mechanism and
regulation of cholesterol and fatty acid metabolism

1966 Charles Brenton Huggins Discoveries concerning hormonal treatment of
prostatic cancer
1969 Derek HR Barton and Odd Hassel Development of the concept of conformation and
its application in chemistry
1970 Bernard Katz, Ulf von Euler and Julius
Axelrod
Discoveries concerning the humoral transmitters in
the nerve terminals and the mechanism for their
storage, release and inactivation
1971 Earl W Sutherland Jr Discoveries concerning the mechanisms of the
action of hormones
1977 Roger Guillemin, Andrew V Schally and
Rosalyn Yalow
Discoveries concerning peptide hormones in the
production in the brain and the development of
radioimmunoassay from peptide hormones
1979 Allan M Cormack and Godfrey N
Hounsfield
Development of computer-assisted tomography
(Continued )
8 / Chapter 1: Overview of endocrinology
Year Prize winner(s) For work on . . .
1982 Sune K Bergström, Bengt I Samuelson
and John R Vane
Discoveries concerning prostaglandins and related
biologically active substances
1985 Michael S Brown and Joseph L Goldstein Discoveries concerning the regulation of
cholesterol metabolism
1986 Stanley Cohen and Rita Levi-Montalcini Discoveries of growth factors
1992 Edmond H Fischer and Edwin G Krebs Discoveries concerning reversible protein

phosphorylation as a biological regulatory
mechanism
1994 Alfred G Gilman and Martin Rodbell Discovery of G-proteins and the role of these
proteins in signal transduction in cells
2003 Peter Agre and Roderick MacKinnon Discovery of water channels, and the structural
and mechanistic studies of ion channels
2003 Paul Lauterbur and Sir Peter Mansfield Discoveries concerning magnetic resonance
imaging
2010 Robert G Edwards Development of in vitro fertilization
Table 1.1 (Continued )
– the thyroid gland, the adrenal cortex and the
gonads, respectively (Table 1.2).
Classification of hormones
There are three major groups of hormones accord-
ing to their biochemistry (Box 1.4). Peptide or
protein hormones are synthesized like any other
cellular protein. Amino acid-derived and steroid
hormones originate from a cascade of biochemical
reactions catalyzed by a series of intracellular
enzymes.
Peptide hormones
The majority of hormones are peptides and range
in size from very small, only three amino acids
[thyrotrophin-releasing hormone (TRH)], to small
proteins of over 200 amino acids, such as TSH or
luteinizing hormone (LH). Some peptide hormones
are secreted directly, but most are stored in granules,
the release from which is commonly controlled
by another hormone, as part of a cascade, or by
innervation.

Some peptide hormones have complex tertiary
structures or are comprised of more than one
peptide chain. Oxytocin and vasopressin, the two
posterior pituitary hormones, have ring structures
linked by disulphide bridges. Despite being remark-
ably similar in structure, they have very different
physiological roles (Figure 1.3). Insulin consists of
α- and β-chains linked by disulphide bonds. Like
several hormones, it is synthesized as an inactive
precursor that requires modification prior to release
and activity. To some extent this regulation protects
the synthesizing cell from being overwhelmed by its
own hormone action. The gonadotrophins, follicle-
stimulating hormone (FSH) and LH, TSH and
human chorionic gonadotrophin (hCG) also have
two chains. However, these α- and β-subunits are
synthesized quite separately, from separate genes.
The α-subunit is common; the distinctive β-subunit
of each confers biological specificity.
Amino acid derivatives
These hormones are small water-soluble com-
pounds. Melatonin is derived from tryptophan,
whereas tyrosine derivatives include thyroid hor-
Chapter 1: Overview of endocrinology / 9
Four parathyroid
glands
Stomach
Kidney
Pancreas:
Islets of

Langerhans
Two ovaries
(o)
Two testes
(o)
Duodenum
Two adrenal
glands: cortex
and medulla
Pituitary gland:
anterior and
posterior
Thyroid
gland
Hypothalamus
and median
eminence
Figure 1.2 The sites of the principal endocrine
glands. The stomach, kidneys and duodenum are
also shown. Not shown, scattered cells within the
gastrointestinal tract secrete hormones.
stituent of the cell membrane. Produced by the
adrenal cortex, gonad and placenta, steroid hor-
mones are insoluble in water and largely circulate
bound to plasma proteins.
Organization and control of
endocrine organs
The synthesis and release of hormones is regulated
by control systems, similar to those used in engineer-
ing. These mechanisms ensure that hormone signals

can be limited in amplitude and duration. Central
to the regulation of many endocrine organs is the
anterior pituitary gland, which, in turn, is controlled
by a number of hormones and factors released from
specialized hypothalamic neurones (see Chapter 5).
Thus, major endocrine axes comprise the hypotha-
lamus, anterior pituitary and end organ, such as the
adrenal cortex, thyroid, testis or ovary. An under-
standing of these control mechanisms is crucial for
appreciating both regulation of many endocrine
systems and their clinical investigation.
Simple control
An elementary control system is one in which the
signal itself is limited, either in magnitude or
Box 1.3 The ‘Endocrine
Postulates’: Edward Doisy,
St Louis University School of
Medicine, USA, 1936
• The gland must secrete something (an
‘internal secretion’)
• Methods of detecting the secretion must
be available
• Purified hormone must be obtained from
gland extracts
• The pure hormone must be isolated, its
structure determined and synthesized
To this could be added:
• The hormone must act on specific target
cells via a receptor such that excess or
deficiency results in a specific phenotype

mones, catecholamines, and dopamine, which
regulates prolactin secretion in the anterior pitui-
tary. The catecholamines from the adrenal medulla,
epinephrine (adrenaline) and norepinephrine
(noradrenaline), are also sympathetic neurotrans-
mitters, emphasizing the close relationship between
the nervous and endocrine systems (see Figure 1.2).
Like peptide hormones, they are stored in granules
prior to release.
Steroid hormones
Steroid hormones are lipid-soluble molecules
derived from cholesterol, which is itself a basic con-