Utama Endocrinology


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Tahun: 2015
Penerbit: JP Medical Publishers
Bahasa: english
ISBN 10: 1907816712
ISBN 13: 9781907816710
Series: Eureka
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Thomas Fox MBBS BSc MRCP

Bijay Vaidya MBBS PhD FRCP (Lon &

(Endo) PGCert Med Ed
Consultant Endocrinologist
The Royal Devon and Exeter NHS
Foundation Trust
Exeter, UK

Consultant Endocrinologist
The Royal Devon and Exeter NHS
Foundation Trust
Exeter, UK

Antonia Brooke MBBS MD MA
Consultant Endocrinologist
The Royal Devon and Exeter NHS
Foundation Trust
Exeter, UK

Series Editors
Janine Henderson MRCPsych

Stephen Parker BSc MS DipMedEd

MB BS Programme Director
Hull York Medical School
York, UK

Consultant Breast and General
Paediatric Surgeon
St Mary’s Hospital
Newport, UK

David Oliveira PhD FRCP
Professor of Renal Medicine
St George’s, University of London
London, UK

London • Philadelphia • New Delhi • Panama City

© 2015 JP Medical Ltd.
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The rights of Thomas Fox, Antonia Brooke and Bijay Vaidya to be identified as authors of this work have been
UK Copyright, Designs and Patents Act 1988, without the prior permission in writing of the publishers.
Permissions may be sought directly from JP Medical Ltd at the address printed above.
mentioned in this book.
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make the necessary arrangements at the first opportunity.

ISBN: 978-1-907816-71-0
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
Library of Congress Cataloging in Publication Data


Richard Furn

Development Editors: Thomas Fletcher, Paul Mayhew, Alison Whitehouse
Editorial Assistants:

Sophie Woolven, Katie Pattullo

Copy Editor:

Kim Howell

Graphic narratives:

James Pollitt

Cover design:

Forbes Design

Page design:

Designers Collective Ltd


Series Editors’ Foreword
Today’s medical students need to know a great deal to be effective as tomorrow’s doctors.
This knowledge includes core science and clinical skills, from understanding biochemical
pathways to communicating with patients. Modern medical school curricula integrate this
teaching, thereby emphasising how learning in one area can support and reinforce another.
At the same time students must acquire sound clinical reasoning skills, working with
complex information to understand each individual’s unique medical problems.
The Eureka series is designed to cover all aspects of today’s medical curricula and
reinforce this integrated approach. Each book can be used from first year through to
qualification. Core biomedical principles are introduced but given relevant clinical context:
the authors have always asked themselves, ‘why does the aspiring clinician need to know
Each clinical title in the series is grounded in the relevant core science, which is
introduced at the start of each book. Each core science title integrates and emphasises
clinical relevance throughout. Medical and surgical approaches are included to provide a
complete and integrated view of the patient management options available to the clinician.
Clinical insights highlight key facts and principles drawn from medical practice. Cases
featuring unique graphic narratives are presented with clear explanations that show how
experienced clinicians think, enabling students to develop their own clinical reasoning and
decision making. Clinical SBAs help with exam revision while starter questions are a unique
learning tool designed to stimulate interest in the subject.
Having biomedical principles and clinical applications together in one book will make
their connections more explicit and easier to remember. Alongside repeated exposure
to patients and practice of clinical and communication skills, we hope Eureka will equip
medical students for a lifetime of successful clinical practice.
Janine Henderson, David Oliveira, Stephen Parker

About the Series Editors
Janine Henderson is the MB BS undergraduate Programme Director at Hull York Medical School
(HYMS). After medical school at the University of Oxford and clinical training in psychiatry, she
combined her work as a consultant with postgraduate teaching roles, moving to the new Hull York
Medical School in 2004. She has a particular interest in modern educational methods, curriculum
design and clinical reasoning.
David Oliveira is Professor of Renal Medicine at St George’s, University of London (SGUL), where
he served as the MBBS Course Director between 2007 and 2013. Having trained at Cambridge
University and the Westminster Hospital he obtained a PhD in cellular immunology and worked as
a renal physician before being appointed as Foundation Chair of Renal Medicine at SGUL.
Stephen Parker is a Consultant Breast and General Paediatric Surgeon at St Mary’s Hospital, Isle
of Wight. He trained at St George’s, University of London, and after service in the Royal Navy was
appointed as Consultant Surgeon at University Hospital Coventry. He has a particular interest in
e-learning and the use of multimedia platforms in medical education.


Endocrine disorders are common and becoming more prevalent, not just in the United
Kingdom but worldwide. The complications of endocrine disease cause significant
of vital importance to all clinicians. Our goal in writing Eureka Endocrinology is to set out
this knowledge in the clearest manner possible.
The endocrine system is integral to the functioning of the human body. Chapter 1 of
Eureka Endocrinology therefore provides the reader with a detailed overview of normal
endocrine anatomy and physiology. Throughout the chapter, we have included correlating
clinical information to help students understand the relevance of the anatomy, physiology
and pathology to everyday practice.
In chapter 2 we explain how to take a history and examine the patient, exploring
and illustrating key symptoms and clinical signs, before discussing the most important
investigations and management options. In the subsequent chapters each endocrine
disease is described in depth, using illustrated cases to give the student a unique insight
into how patients present and how we manage their medical problems in real life.
The starter questions at the beginning of each chapter will help students consolidate
and apply their learning, and the clinical SBAs at the end of the book will provide them
with an invaluable revision aid.
We hope you enjoy reading and learning from Eureka Endocrinology.
Thomas Fox, Antonia Brooke, Bijay Vaidya
March 2015

About the Authors
Thomas Fox is lead for curriculum development in endocrinology at the University of
Exeter Medical School (UEMS). He has played an active role in teaching endocrinology and
clinical skills at UEMS both during specialist training and as a Consultant Endocrinologist.
He delivers a special study module in metabolic medicine.
Antonia Brooke is the clinical lead for endocrinology at the Royal Devon and Exeter
Hospital. She is Endocrinology Training Programme Director for the South West Peninsula,
supporting registrars as they work towards becoming consultants. In her role as tutor
for undergraduates and junior doctors she enjoys encouraging students into a career in
Bijay Vaidya is a Consultant Physician and Honorary Associate Professor of
Endocrinology. As well as playing an active role in teaching endocrinology at UEMS, he
has co-authored clinical reviews and learning modules on endocrine disorders for several
journals, including The BMJ and BMJ Learning.


Series Editors’ Foreword


About the Series Editors




About the Authors






Case 2 Recurrent thrush


Type 1 diabetes mellitus


Type 2 diabetes mellitus


Monogenic diabetes mellitus


Gestational diabetes




Lipid disorders


Chapter 1 First principles
Overview of the endocrine system


The thyroid gland


Chapter 4 Complications of

The parathyroid glands




The hypothalamus


Case 3 Red swollen foot


The pituitary gland


The adrenal glands


The pancreas


The gut


The male reproductive system


The female reproductive system


The pineal gland


Macrovascular complications


Microvascular disease


Diabetic foot disease


Chapter 5 Thyroid disease


Case 4 Tremor and irritability


Chapter 2 Clinical essentials





Thyroid eye disease


Common symptoms and how to take a








Common signs and how to examine a


Thyroid nodule




Thyroid cancer


Management options


Chapter 6 Pituitary disease

Chapter 3 Diabetes mellitus,
obesity and lipid


Case 1 Weight loss, thirst and excessive
amounts of urine




Case 5 Headaches and change in facial


Case 6 Weight gain and easy bruising







Disorders of sex development


Cushing’s syndrome


Hypogonadism in men




Klinefelter’s syndrome


Non-functioning pituitary tumours


Diabetes insipidus


Chapter 7 Adrenal disease

Chapter 10 Other endocrine




Case 12 Worsening vision and headache


Case 7 Headaches and profuse sweating


Multiple endocrine neoplasia syndromes


Addison’s disease


Autoimmune polyglandular syndromes


Conn’s syndrome


Ectopic hormone syndromes




Carcinoid tumours and carcinoid syndrome 300

Congenital adrenal hyperplasia



Cushing’s syndrome


Adrenal adenomas


Other neuroendocrine tumours:
gastrinoma, glucagonoma, vipoma and

Chapter 8 Calcium homeostasis
and metabolic bone

Chapter 11 Endocrine




Case 8 Sharp pain in the back and tiredness 256
Case 9 Leg pain while walking






Case 13 Diarrhoea, vomiting and lethargy
after a meal out
Diabetic ketoacidosis


Hyperosmolar hyperglycaemic state


Severe hypoglycaemia


Case 14 Collapse and agitation




Case 15 A
 bdominal pain, vomiting and


Addisonian crisis


Chapter 9 Reproductive system

Case 16 Weight loss and anxiety


Thyroid storm




Myxoedema coma


Case 10 Complete absence of menstrual
periods in a 16-year-old


Case 17 Worsening palpitations,
headaches and tremor


Case 11 Excessive hair growth


Hypertensive crisis


Polycystic ovary syndrome


Primary ovarian insufficiency


Case 18 S evere headache and double


Turner’s syndrome


Functional hypothalamic amenorrhoea


Pituitary apoplexy










Paget’s disease


Vitamin D deficiency





Chapter 12 Integrated care

Chapter 13 Self-assessment
SBA questions


Case 19 Poorly controlled diabetes mellitus 324


SBA answers


Community management of diabetes




Diabetes mellitus in adolescents


Monitoring thyroid function




ankle–brachial pressure index


low-density lipoprotein


angiotensin-converting enzyme


luteinising hormone


adrenocorticotrophic hormone


antineutrophil cytoplasmic antibody


multiple endocrine neoplasia






magnetic resonance imaging


melanocyte-stimulating hormone


polycystic ovary syndrome


positron emission tomography


body mass index


cyclic adenosine monophosphate


corticotrophin-releasing hormone


computerised tomography


dual-energy X-ray absorptiometry


protein kinase A








peroxisome proliferator-activated



recommended daily amount


syndrome of inappropriate antidiuretic






thyrotrophin-releasing hormone


transfer RNA


thyroid-stimulating hormone


UK Prospective Diabetes Study


vascular endothelial growth factor


vasoactive intestinal polypeptide


very-low-density lipoprotein


follicle-stimulating hormone


growth hormone


growth hormone-releasing hormone


gonadotrophin-releasing hormone


general practitioner


guanosine triphosphate


haemoglobin A1c


high-density lipoprotein


human leukocyte antigen

5-HIAA 5-hydroxyindole acetic acid

insulin-like growth factor


Thanks to the following medical students for their help reviewing chapters: Jessica Dunlop,
Aliza Imam, Roxanne McVittie, Daniel Roberts and Joseph Suich.
Thanks to Nidhi Choudhary for her help preparing chapters.
Figure 2.35a–b is reproduced from Pachl M, et al. Key Clinical Topics in Paediatric Surgery.
London: JP Medical, 2014.
The following figures are copyright of the Royal Devon & Exeter NHS Foundation Trust: 2.2,
2.7, 2.8a–b, 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.17, 2.18a, 2.19, 2.20, 2.22, 2.26, 2.29, 2.31a–
b, 2.32a–b, 3.1, 3.3, 3.5, 3.6, 3.7, 3.9, 4.1a–b, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, 4.10a–b, 4.11, 4.12,
4.13, 5.2a–c, 5.3a–d, 5.4a–b, 5.5a–b, 5.7, 5.8a–b, 5.9a–b, 5.10b, 5.11, 6.3, 6.5a–b, 6.8,
7.1a–b, 7.2a–b, 7.4a–b, 8.1, 8.3a–b, 9.2, 10.1, 10.3 and 11.3a–b.

We would like to thank our families for all their support and encouragement during the
process of writing Eureka Endocrinology.


Chapter 1
First principles
Overview of the
The thyroid gland .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 8
The parathyroid glands.  .  .  .  .  .  .  .  .  .  . 15
The hypothalamus.  .  .  .  .  .  .  .  .  .  .  .  .  .  . 20
The pituitary gland.  .  .  .  .  .  .  .  .  .  .  .  .  . 27

The adrenal glands .  .  .  .  .  .  .  .  .  .  .  .  .  .
The pancreas .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .
The male reproductive system.  .  .  .  .
The female reproductive system .  .  .
The pineal gland .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .


Starter questions
Answers to the following questions are on page 63.
1.	 Do hormone levels change as we age?
2.	 Why does menstruation stop during extreme stress?
3.	 Do we all have the same hormone levels?

Overview of the endocrine system
The endocrine system consists of several
anatomically and physiologically distinct
glands. Each of these glands is a group of
specialised cells that synthesise, store and
secrete hormones.
Hormones are chemical messengers that
travel in the bloodstream from an endocrine
gland to another organ or group of organs to
regulate a wide range of physiological processes. Hormones:

stimulate or inhibit growth
regulate metabolism by maintaining and
mobilising energy stores
promote sleep or wakefulness
activate or suppress the immune system
prepare the body for ‘fight or flight’ in
response to acute stress


produce the changes associated with
puberty and reproduction
affect mood and behaviour

Hormones also have a role in maintaining
homeostasis, a state of physiological equilibrium achieved by adjusting the body’s internal environment in response to changes in
the external environment.
In contrast to the rapid effects of the nervous system, endocrine effects are usually
slow to develop and produce a prolonged response lasting from minutes to weeks.
The human body produces many hormones for regulation of a myriad of physiological processes. New hormones continue to be
discovered, and research is ongoing to explain
their functions and how they interact to control the human body.


Chapter 1 First principles

Not all hormones are essential to life.
If untreated, cortisol deficiency arising
from destruction of the adrenal cortex
by an autoimmune disease quickly leads
to severe deterioration in health and
eventually death. However, deficiency of
female sex hormones from autoimmune
destruction of the ovaries increases
morbidity but not mortality.



Endocrine glands


Endocrine glands release their products,
hormones, into the blood. They have a rich
blood supply to ensure efficient transport of
hormones around the body.
The following are the major endocrine
glands (Figure 1.1).


Hypothalamus: as the main endocrine
control centre, this tiny gland in the brain
secretes many hormones that directly
affect hormone production by other
endocrine glands
Pituitary gland: this is connected to the
hypothalamus and produces a wide




range of hormones controlling growth,
metabolism and sexual development
Pineal gland: this gland in the brain
controls wakefulness
Thyroid gland: this gland produces thyroid
hormones, which set the body’s metabolic
rate, and calcitonin, which regulates
calcium metabolism
Parathyroid glands: these produce
parathyroid hormone, which controls the
absorption and excretion of calcium and
Thymus gland: secretes thymosin, a
hormone that stimulate the production of
immune T cells
Adrenal glands: these secrete many
hormones that mediate the body’s response
to physiological and psychological stress,
maintain fluid and electrolyte balance, and
modulate blood pressure
Pancreas: the endocrine cells of
the pancreas release insulin and
glucagon, which regulate blood glucose
Reproductive glands: these glands,
the testes in males and the ovaries in
females, produce sex hormones, which

The endocrine system
Pineal gland

Parathyroid glands

Pituitary gland
(anterior and posterior)

Thyroid gland

Thymus gland

Adrenal glands


Figure 1.1 The major glands
of the endocrine system are
the hypothalamus, the pituitary
glands, the pineal gland, the
thyroid and parathyroid glands,
the thymus gland, the adrenal
glands, the pancreas and the
reproductive glands (the testes
and ovaries). The intestine also
produces and secretes hormones
as part of its function.

Overview of the endocrine system
facilitate sexual maturation and enable
Although not major endocrine glands, the
following organs produce and secrete hormones as part of their primary function.


Intestine: several hormones are secreted
from the gut to help control blood glucose
concentration and growth
Adipose tissue: hormones produced by
body fat affect appetite and the feeling of
fullness (satiety)

Other organs, such as the liver, kidney, heart
and skin, have secondary endocrine functions unrelated to their primary function.
For example, the main function of the liver is
to metabolise carbohydrate, fat and protein.
However, it also has secondary endocrine
functions, such as producing the hormone
insulin-like growth factor-1, which promotes
the growth of body tissues.
An endocrine gland may produce more
than one hormone, for example the thyroid
gland produces thyroid hormones and calcitonin. This means that a single endocrine gland
can help control multiple body functions.

Chemical classification of
Hormones are grouped into three chemical
classes (Table 1.1):

lipids (mainly steroids)

Peptide hormones
The hormones in this class are chains of
amino acids (polypeptides). These chains
Types of hormones









Growth hormone





Table 1.1 Examples of different types of hormones

range in length. They may be short and comprise only a few amino acids (e.g. antidiuretic hormone), or they may be very long
molecules (e.g. follicle-stimulating hormone,
FSH). Peptide hormones have a large molecular weight.

Amine hormones
Amine hormones are derived from aromatic
amino acids such as tryptophan, phenylalanine and tyrosine. Aromatic amino acids
have an aromatic side chain, i.e. one containing a stable, planar unsaturated ring of atoms.

Lipid hormones
Hormones in this class are derived from cholesterol and are either alcohols or ketones.

Alcohol lipid hormones have names
ending in ‘-ol’ (e.g. oestradiol)
Ketone lipid hormones have names ending
in ‘-one’ (e.g. aldosterone)

Hormonal signalling
Hormonal signalling pathway involves hormone synthesis, storage (peptide and amine
hormones only), release from endocrine
cells, transport, receptor binding, release of
the hormone or its breakdown products from
the cells of the target organ, further transport
and excretion (Figure 1.2).
1. Synthesis: the hormone is produced by
cells in the endocrine gland
2. Storage: peptide and amine hormones
are stored in preparation for rapid release
when required (lipid hormones are not
stored before release)
3. Release from endocrine cells: the hormone
is released from the gland into the
4. Transport: the hormone travels in the
blood to the target organ either unbound,
i.e. in a free state (peptide hormones
and all amine hormones except thyroid
hormone) or bound to transport proteins
(lipid hormones and thyroid hormone)
5. Receptor binding: the hormone binds to
specific receptor molecules either on the



Chapter 1 First principles

Hormonal signalling

membrane of the cells of the target organ
or inside these cells
A hormone binding to receptor
molecules on the cell membrane
changes the cell’s metabolism through
a cascade of reactions involving various
2nd messenger chemicals
QQ Intracellular binding of a hormone
to nuclear or cytoplasmic receptors
directly affects the expression of genes
in the cell
6. Release from the cells of the target organ
QQ The cells secrete the hormone
QQ Alternatively, the cells metabolise the
hormone to an inactive form
7. Further transport: the hormone or
its breakdown products travel in the
bloodstream to the liver or kidneys

Figure 1.2 Hormonal signalling:
from production to metabolism.

8. Excretion: the hormone or its breakdown
are excreted by the liver (in bile) or the
kidneys (in urine)

Hormone synthesis and
Endocrine cells synthesise peptide and
amine hormones from amino acids, and lipid
hormones from cholesterol.

Peptide hormones
Hormones in this class are synthesised as
precursor molecules. These prohormones
undergo processing in the intracellular endoplasmic reticulum and Golgi apparatus. In the
Golgi apparatus, the processed peptide hormones are packaged into secretory granules.
They are stored in high concentration in these

Overview of the endocrine system
granules, ready for stimulated release from
the endocrine cells into the bloodstream.

the extracellular space (low) by random motion
of molecules (Brownian motion).

Amine hormones

Hormone transport

These hormones are synthesised from aromatic amino acids. These amino acids are
chemically altered by enzymes in the cells of
endocrine glands to synthesise specific hormones. For example, in cells of the adrenal
medulla, adrenaline (epinephrine) is synthesised from the amino acid tyrosine. Various enzymes catalyse the steps in adrenaline
production; the final step is the conversion of
noradrenaline (norepinephrine) to adrenaline by the enzyme phenylethanolamine-Nmethyltransferase. Like peptide hormones,
amine hormones are stored in secretory

Peptide hormones are able to travel unbound
(free) in the bloodstream, because they are
hydrophilic (‘water loving’). Amine hormones are also hydrophilic and also able to
travel unbound in the blood. The hydrophobic thyroid hormones are the exception.
Peptide and amine hormones, other than
thyroid hormones, are able to pass through
capillary membranes to reach their target
Lipid hormones are hydrophobic (‘water
hating’), so they must be bound to transport
proteins in plasma to enable them to travel
in the bloodstream. Lipid hormones undergo
continuous and spontaneous binding and
unbinding from their carrier molecules. Because lipid hormones are bound to transport
proteins, they have a longer half-life (the time
taken for half of the hormone molecules to
be excreted or metabolised) than amine hormones, which are transported unbound.
Only a small fraction of lipid hormones
present in the bloodstream are in an unbound
state. For example, 99% of cortisol in the blood
is bound to proteins; the unbound remainder,
the free cortisol, is biologically active. This is
true of all lipid hormones.

Lipid hormones
These are synthesised from cholesterol. The
cholesterol is metabolised by enzymes in the
cells of an endocrine gland to produce lipid
hormones that are either alcohols or ketones.
The onset of action of lipid hormones is
slower than that of amine hormones. Therefore, unlike amine and peptide hormones,
lipid hormones are not stored in secretory
granules for rapid release. Instead, they are
synthesised as required, with the rate of synthesis directly determining blood concentration.

Hormone release
When an endocrine cell is activated, secretory granules (containing peptide or amine
hormones) move to the cell surface. Here, the
vesicular membranes of the granules fuse
with the plasma membrane of the cell surface to release their contents to the exterior
of the cell. This process is called exocytosis,
which literally means ‘out of cell’.
Membrane transport of lipid hormones
(such as testosterone) occurs in a passive
manner across the cell membrane due to the
non-polarised nature of the lipid-rich cell
membrane. This form of hormone secretion
depends upon the difference in concentration
of the hormone in the intracellular space (high)
to equalise with the hormone concentration in

Hormone receptor binding
Hormones travel through the bloodstream
and thus come into contact with many cell
types. However, a cellular response is initiated only in cells with the specific receptors
for a hormone. These receptors may be on the
cell membrane or in the cytoplasm.
Multiple types of cell may have receptors
for a particular hormone. This allows a hormone, for example thyroxine (T4), to bind to
receptors in the cells of many different tissues
and thus have widespread effects on metabolism throughout the body.
The effects of a hormone binding to a receptor in one type of cell will differ from
those of the same hormone binding to a receptor on another type of cell due to differing downstream processes associated with



Chapter 1 First principles
each receptor. For example, when adrenaline
(epinephrine) binds to b adrenergic receptors
in cardiac myocytes, it causes the heart muscle
to contract more forcefully; however, the same
hormone causes muscle relaxation when it
binds to b receptors in the bronchioles.

Signal transduction system

Genetic mutations of hormone
receptors can lead to a failure of
hormonal signalling. For example,
Laron’s syndrome is caused by a
mutation in the gene for the growth
hormone receptor. This mutation
disables the receptor and thus renders
growth hormone inactive. Consequently,
people with this autosomal recessive
congenital disorder have a short stature.

Peptide hormone receptors
Peptide hormones are lipophobic (‘lipid hating’), so they are unable to diffuse freely
through the cell membrane, which consists of
two layers of lipid molecules. Therefore peptide
hormone receptors composed of transmembrane proteins are necessary to communicate
the hormonal message from outside the cell to
the target molecules inside the cell.
The peptide hormone receptor is part of
a signal transduction system (Figure 1.3). In
this system, the hormone acts as the 1st messenger by binding to its receptor on the extracellular surface of the cell. This hormone−receptor binding activates 2nd messengers such
as cyclic AMP (cAMP), which relay the signal
within the cell.
1. The peptide hormone binds to its specific
cell surface receptor
2. Hormone binding activates a coupled
G-protein (G-proteins are a class of protein
present in cell membranes and that
transmit signals from hormones binding
3. The G-protein converts guanosine
diphosphate to guanosine triphosphate
4. Guanosine triphosphate binds to and thus
activates the enzyme adenylate cyclase
5. Adenylate cyclase catalyses the conversion
of ATP to cAMP
6. The cAMP activates protein kinase A

Figure 1.3 The signal transduction system activated
by binding of a hormone to its receptor. cAMP,
cyclic AMP; GDP, guanosine diphosphate; GTP,
guanosine triphosphate; PKA, protein kinase A.

7. Now activated, protein kinase A is able to
phosphorylate (add a phosphate molecule
to) various cell proteins, altering their
structure and function and thus producing
a cellular response to hormone binding at
the cell surface
8. An enzyme called phosphodiesterase
breaks down cAMP, thereby inactivating it

Amine hormone receptors
Most amine hormones, for example adrenaline (epinephrine) and dopamine, are lipophobic. Therefore, like peptide hormones, they are
unable to diffuse through the cell membrane
and instead must bind to cell surface receptors
and activate 2nd messenger systems to induce
a cellular response.
Thyroxine is an exception. This amine hormone is lipophilic, so it can diffuse through
the cell membrane and directly modify gene
transcription in the nucleus by binding to intracellular nuclear receptors in the same way
as lipid hormones.

Overview of the endocrine system

Lipid hormone receptors
Lipid hormones are lipid-soluble, so they
can diffuse freely through the cell membrane. Once in the target cell, they bind with
their receptors, which are in the cytoplasm
(Figure 1.4). The combined hormone−receptor complex then diffuses across the nuclear
membrane through a nuclear pore (a channel that permits passage of the hormone−
receptor complex).
In the nucleus, the hormone−receptor
complex binds to specific DNA sequences
called hormone response elements. This binding either amplifies or suppresses the rate of
transcription of particular genes; thus, protein
synthesis is increased or decreased, respectively.

Hormone degradation and
The blood concentration of a hormone is
affected by the speed of its production and
the speed of its clearance. Circulating hormone in the blood can be cleared in several
1. The hormone binds to its receptor
temporarily removing it from the
2. The tissues metabolise the hormone to its
inactive form
Binding and action of a lipid hormone

Figure 1.4 Intracellular binding and action of a
lipid hormone. mRNA, messenger; RNA tRNA,
transfer RNA.

3. The hormone is excreted
QQ by the liver into the bile
QQ by the kidneys into the urine

Hormonal regulation
All endocrine glands have precise control
mechanisms to ensure appropriate hormonal secretion. Production of each hormone is
altered in response to the internal and external environment; external factors include
temperature, and internal factors include
blood glucose concentration.
Hormones maintain a state of optimum
chemical balance in which the body can function as efficiently as possible; they also enable
the body to respond appropriately to illness.
For example, cortisol production is increased
in times of illness, to induce physiological
changes that help the body to respond to the
effects of the stress from the illness. However,
at the same time, the production of sex hormones is decreased to reduce fertility (as reproduction is not the survival priority at that
point in time).

Feedback loops
All hormone production is controlled by
feedback loops. These can be negative or positive.

Negative feedback loops
Most hormonal regulation occurs through
negative feedback mechanisms, through
which the effects of a hormone inhibit its
secretion. Thus negative feedback helps maintain homeostasis by ensuring the controlled
release of hormones. Under- or overproduction of a hormone, or abnormalities in its control mechanisms, can disturb the homeostatic
An example of an endocrine negative feedback loop is the hypothalamic−pituitary−adrenal axis (Figure 1.5). The hypothalamus
secretes corticotrophin-releasing hormone
(CRH), which stimulates the anterior pituitary
gland to secrete adrenocorticotrophic hormone (ACTH; also known as corticotrophin).
In turn, ACTH stimulates the adrenal cortex to
secrete glucocorticoids, including cortisol.



Chapter 1 First principles

HPA axis negative feedback loop

production of CRH and ACTH, respectively.
These effects reduce the stimulus to the adrenal gland to produce cortisol and other

Positive feedback loops
In positive feedback, a hormone’s effects stimulate its secretion. An example occurs in the
female reproductive cycle. When luteinising
hormone causes a surge in the production of
oestrogen by the ovary, the released oestrogen
stimulates the anterior pituitary gland to produce more luteinising hormone. This positive
feedback mechanism results in the luteinising
hormone surge that stimulates ovulation.
Figure 1.5 The negative feedback loop of the
hypothalamic−pituitary−adrenal axis.

Glucocorticoids not only perform their
respective functions throughout the body
but also bind to receptors in the hypothalamus and the pituitary gland to inhibit the

Without negative feedback, hormone
production could become excessive and
lead to endocrine disorders. An example
would be Cushing’s disease, in which
pituitary ACTH secretion is not inhibited
by excessive cortisol.

The thyroid gland
Starter questions
The answer to the following question is on page 63.
4.	 Why is an adequate intake of iodine essential during pregnancy?

The thyroid gland is a bilobed (two-lobed)
endocrine gland in the neck.


The main role of the thyroid gland is
secretion of thyroid hormones, which have
effects on a wide variety of cells in the
body; thyroid hormones help control the
rate of metabolism
The gland’s secondary role is secretion
of calcitonin, which plays a part in the
regulation of calcium concentration in
the blood

The thyroid is the first endocrine gland to
develop in utero. It originates from endoderm.

Endoderm is the innermost of the three
embryological cell layers; the other two are
the mesoderm (the middle layer) and the
ectoderm (the outer layer).
On day 24 of gestation, the thyroid gland
arises from the floor of the embryological
pharynx. This site is known as the foramen
caecum, and is a depression at the junction of
the anterior two thirds and the posterior third
of the tongue. From this depression, the thyroglossal duct invaginates (folds back into itself
to form a pouch) and then descends within
the neck, anterior to the pharynx (Figure 1.6).
If the thyroid gland fails to descend, it can
remain in the base of the tongue. This results
in a lingual thyroid gland, which is present

The thyroid gland

Descent of the thyroid gland

Thyroid and parathyroid glands

Figure 1.7 Anatomy of the thyroid and parathyroid
glands (posterior view).

Figure 1.6 Embryological descent of the thyroid
gland from its origin the foramen caecum passing
down the thyroglossal duct.

in 1 in 100,000 to 1 in 300,000 people. Conversely, the thyroid may descend beyond its
normal anatomical position into the superior
mediastinum, resulting in a retrosternal goitre.
Thyroglossal cysts arise from remnants
of the thyroglossal duct that remain
at any point along its path of descent.
These cysts are found in the midline of
the neck, usually closely related and
often attached to the hyoid bone. The
results of one autopsy study showed
a prevalence of 15%. However, most
thyroglossal cysts are asymptomatic.

Figure 1.7 shows the structure of the thyroid
gland. The distal end of the thyroglossal duct
becomes bilobed to form the lateral lobes of
the thyroid gland. The distal remnant of the
duct may persist and become the pyramid al
lobe of the thyroid gland.
In the 1st trimester, the fetus does not
have a functioning thyroid. Therefore
it relies on T4 from its mother’s
blood, which crosses the placenta
into the fetal circulation. Untreated
maternal hypothyroidism causes fetal
hypothyroidism, which may result in
abnormalities in fetal development.

The ultimobranchial
Pharyngeal pouches are folds that appear
in the anterolateral part of the foregut during early embryological development. They
form cartilage, nerve, muscle and arterial
tissues. Ultimobranchial bodies arise from
the 4th pharyngeal pouch and become
affixed to the lateral border of each thyroid
The cells of the ultimobranchial bodies
originate from the neural crest, which consists of embryological cells from the ectoderm that differentiate into nerves, muscles
and some endocrine glands (e.g. the adrenal
medulla). Some of these cells attach to the
thyroid gland and eventually become the calcitonin-secreting parafollicular C cells of the
thyroid gland.

The thyroid is a highly vascular, butterflyshaped gland in the anterior lower neck, in
front of the trachea and larynx (Figure 1.8).
It extends from the level of the 5th cervical
vertebra down to the 1st thoracic vertebra.
The thyroid gland weighs 25−30 g and is
formed by two lateral lobes, each comprising a superior pole and an inferior pole.
The two lobes are connected by the median
isthmus, which is at the level of the 2nd to
4th tracheal ring. The gland is surrounded
by a thin, two-layer sheath of fibrous tissue
called the capsule.



Chapter 1 First principles

Relation of thyroid to trachea

Vascular supply
The thyroid gland is highly vascular, with a rich
arterial supply and venous drainage into the
inferior jugular vein. This permits rapid transport of thyroid hormones throughout the body.

The thyroid gland has a rich arterial supply,
with four or five arteries (Figure 1.9).



Figure 1.8 The thyroid gland in relation to the
trachea (anterior view).

Posterior but separate to the thyroid are the
four parathyroid glands (Figure 1.7) and the
carotid sheath. The carotid sheath is a fibrous
layer that envelops the carotid arteries, the
internal jugular veins and the recurrent
laryngeal nerves.
The location of masses in the neck can
provide clues to their nature. Masses in
the midline are probably embryological
abnormalities of thyroglossal duct, such
as thyroglossal cysts. Thyroglossal cysts
can be detected clinically; they elevate on
protrusion of the tongue.

Vasculature of the thyroid gland

Two superior thyroid arteries arising from
the external carotid arteries on each side
supply the upper pole of each lobe
Two inferior thyroid arteries arising from
the thyrocervical trunk of the subclavian
artery supply the lower pole of each lobe
The thyroid ima artery, which is present in
< 10% of people, arises inferiorly from the
arch of the aorta, the brachiocephalic or
inferior mammary arteries

Venous drainage is through:

the superior thyroid vein, which drains
into the internal jugular vein
the middle thyroid vein, which drains into
the internal jugular vein
the inferior thyroid vein, which drains into
the brachiocephalic vein

Lymphatic vessels in the thyroid gland drain
into the deep cervical nodes. These are the

Figure 1.9 Vasculature of the
thyroid gland.

The thyroid gland
periglandular, prelaryngeal, pretracheal and
paratracheal lymph nodes.

The follicular epithelial cells:

In cases of thyroidectomy for advanced
thyroid cancer, the local lymph nodes
are sometimes removed as well as the
thyroid gland (depending upon the
histological type and extent of the
thyroid cancer). Removal of the lymph
nodes reduces the risk of recurrence.


produce thyroglobulin
convert thyroglobulin into the thyroid
hormones (thyroxine, T4, and triiodothyronine, T3)
secrete thyroid hormones into the
surrounding capillary bed

The spaces between the thyroid follicles are
filled with:

fibroblasts (cells that produce fibrin)
lymphocytes (immune cells)
C cells (these produce the hormone
calcitonin, which maintains calcium



The thyroid is supplied by autonomic nerves.
Both sympathetic and parasympathetic
fibres have been postulated to affect blood
flow in the gland and thus have a secondary
role in thyroid hormone secretion.
The autonomic nerves enter the thyroid
gland alongside its blood vessels.




Sympathetic innervation is provided by
the superior, middle and inferior cervical
Parasympathetic innervation is provided
by branches of the vagus nerve

The functional unit of the thyroid gland is
the thyroid follicle (Figure 1.10). Each follicle measures about 0.1 mm in diameter
and comprises a layer of simple epithelium
enclosing a cavity filled with colloid (a protein-rich fluid). The colloid contains a glycoprotein called thyroglobulin, which is a
precursor of thyroid hormones. Thus the
colloid serves as a reservoir for the materials
needed for thyroid hormone production.
Microstrucrure of thyroid follicles

Figure 1.10 Microstructure of thyroid follicles.

The primary function of the thyroid gland is to
produce the hormones T3, T4 and calcitonin.


T3 and T4 act on most cells of the body to
promote carbohydrate, protein and lipid
metabolism; they increase basal metabolic
rate and oxygen consumption, and
regulate tissue growth and development
Calcitonin reduces serum calcium
concentration by opposing the action of
parathyroid hormone

Thyroglobulin is a large glycoprotein molecule,
i.e. a combination of carbohydrate and protein.
It is synthesised in the follicular cells of the thyroid gland, and stored in the colloid of thyroid
Numerous tyrosine amino acids are attached
to each thyroglobulin molecule. While attached,
these amino acids are iodinated in the production of T4 (Figure 1.11).

Thyroid hormones
The thyroid hormones (T3 and T4) have many
actions on most cells of the body (Table 1.2).
They affect metabolism, growth and development, and the cardiovascular, nervous and
reproductive systems, and thus determine
mental and physical alertness.
The two thyroid hormones differ in their effects (Table 1.3):



Chapter 1 First principles
Figure 1.11 The
synthesis of thyroid
hormones. 1a Iodide
ion moves into the
follicular cell via
the iodine-sodium
1b Synthesis of
thyroglobulin in the
follicular cells. 2
Iodide ion passes
into the colloid 3
Iodide is converted to
iodine by the enzyme
thyroid peroxidase
4 Iodination of 3’
and 5’ terminals of
the benzene ring of
the tyrosine residues
on the thyroglobulin
molecule. 5
Iodination produces
(MIT; T1) and diiodotyrosine (DIT; T2).
6 Combination of
MIT and DIT produces
tri-iodothyronine (T3)
and combination of
DIT and DIT produces thyroxine (T4), both stored in the colloid bound to thyroglobulin. 7 Stimulation by
TSH leads to cleavage of the T3 and T4 hormone from thyroglobulin and uptake into the follicular cells.
8 Release of T3 and T4 into systemic circulation.

Thyroid hormone synthesis

Actions of thyroid hormones



Increase basal metabolic rate and
heat production
Increase lipolysis
Increase cellular uptake of
triglycerides and cholesterol
Increase gluconeogenesis,
glycogenolysis and insulindependent glucose uptake


Essential to fetal and neonatal brain


Increase heart rate, cardiac
contractility and cardiac output
Increase peripheral vasodilation

Central nervous

Increase alertness


Essential for normal reproductive

Table 1.2 Actions of thyroid hormones


T3 is the active form
T4 is a prohormone and needs to be
converted to T3 before it can exert its

The synthesis of thyroid hormones relies on
iodination of the amino acid tyrosine. This
process, the addition of an iodide ion, is
made possible by the enzyme thyroid peroxidase.

Iodine trapping
This is the process by which iodine is accumulated in the thyroid gland for the production of thyroid hormones. Iodine is a rare
element, so the thyroid gland has evolved to
maintain a large store of it for use in times of
deficiency. Iodine, in the form of the iodide
ion (I–) present in blood, is pumped into the
follicular cells by the iodide and sodium
cotransporter. Thus the iodide passes into
the colloid, where the enzyme thyroid peroxidase oxidises it to its active form, iodine.

The thyroid gland
Comparison of T3 and T4





Inactive prohormone

Relative quantity produced 1
by the thyroid gland


Free in blood (%)



Relative potency



Half-life (days)



Speed of action

Rapid (hours)

Slow (days)

Table 1.3 Comparison of tri-iodothyronine (T3)
and thyroxine (T4)

The normal dietary intake of iodine is
150 µg/day, of which 125 µg is used by
the thyroid gland for hormone synthesis.
Seafood is a rich source of iodine, so areas
of iodine deficiency are often inland or
at high altitude, where the daily intake
may be as low as 25 µg. About 30% of
the world’s population is at risk of iodine

Iodination of thyroglobulin
As soon as it is produced by thyroid peroxidase, iodine binds to the 3' and 5' sites of the
benzene ring of tyrosine residues on thyroglobulin molecules (Figure 1.11). Iodination
with one or two iodine molecules produces
the hormone precursors monoiodotyrosine
and di-iodotyrosine, respectively.

Synthesis of T3 and T4
When monoiodotyrosine combines with
di-iodotyrosine, tri-iodothyronine (T3) is
produced. When two di-iodotyrosine molecules couple, the hormone T4 is produced.
The reactions creating these combinations of
iodinated tyrosine residues are catalysed by
the enzyme thyroid peroxidase. The thyroid
hormones are stored bound to thyroglobulin
in the colloid.

Insufficient dietary iodine can cause an
increase in the size of the thyroid gland
in a condition called endemic goitre.
Endemic goitre results from reduced
thyroid hormone synthesis and the
compensatory increased secretion of
thyroid-stimulating hormone (TSH), which
leads to hypertrophy of thyroid cells. This
enlargement of the thyroid is benign.
However, it is cosmetically unappealing
and may cause pain and compression of
the trachea and oesophagus.

Secretion of T3 and T4
When stimulated to release thyroid hormones by TSH from the anterior pituitary
gland, the follicular cells cleave the iodinated tyrosine residues, thus forming T3 and
T4. Thyroid hormones are lipophilic, so they
diffuse easily through the follicular cell
membrane and into the blood. About 90% of
hormone released from the thyroid gland is
T4; the remainder is T3. It is T3 that is the biologically active thyroid hormone; T4 is readily
converted to T3 in the peripheral tissues by
the deiodinase enzymes. The properties of T3
and T4 are compared in Table 1.3.

Most T4 produced by the thyroid gland is
converted to T3 by peripheral organs such
as the liver, kidney and spleen. Both thyroid
hormones are hydrophobic and therefore do
not dissolve; they are transported in the circulation bound to proteins, including albumin, T4-binding prealbumin and T4-binding
globulin. Only free hormone is physiologically active.
The lipophilic nature of thyroid hormones
allows them to diffuse easily into all cells of the

Tri-iodothyronine (T3) acts by binding to thyroid receptors in cell nuclei. These receptors,



Chapter 1 First principles
which are present in nearly every cell of the
body, are nuclear transcription factors that
regulate gene expression. The T3−thyroid
receptor complex is able to bind to DNA in
hormone response elements to stimulate gene
transcription and protein synthesis. Thus the
complex’s binding to DNA leads to the characteristic effects of thyroid hormones (Table 1.2).

Calcitonin is a polypeptide, a chain of 32
amino acids. This hormone is produced by
parafollicular cells (cells surrounding the
thyroid follicles) called C cells.
Generally, calcitonin opposes the action
of parathyroid hormone on blood calcium
levels; the main action of calcitonin is to decrease serum calcium concentration through
its effects on various organs (Table 1.4). It is
released in response to an increase in serum
The physiological effects of calcitonin seem
minor compared with the more dominant effects of parathyroid hormone. This is apparent
in patients who have undergone total thyroidectomy; the resulting calcitonin deficiency seems
to have no effect on calcium homeostasis.
The calcitonin receptor is a G-protein−
coupled receptor. Stimulation of the receptor
by calcitonin binding activates its G-protein,
which in turn activates adenylate cyclase and
thus increases cAMP production in target
cells. This increased cAMP production mediates the effects of calcitonin on various target
tissues (Table 1. 4).

thyroid axis
Thyroid hormone synthesis in the thyroid
gland is controlled by hormone secretions
Actions of calcitonin



Inhibits bone breakdown by osteoclasts
Simulates bone formation by osteoblasts


Inhibits calcium absorption


Inhibits calcium reabsorption by the renal tubules

Table 1.4 Actions of calcitonin

from the pituitary gland. The pituitary gland
is, in turn, regulated by the hypothalamus.
This system is called the hypothalamic−pituitary−thyroid axis. Negative feedback occurs
from the thyroid to the hypothalamus and
the pituitary, which adds further control (see
Figure 1.18).

Thyrotrophin-releasing hormone (TRH) is
synthesised and secreted by neurosecretory
cells (cells derived from the neural crest and
that secrete hormones) in the hypothalamus.
The hormone is cleaved from a larger precursor hormone called pro-TRH then released
from the hypothalamus for transport in the
blood to the anterior pituitary gland. TRH
stimulates the synthesis and release of TSH
from the pituitary gland. Through this action,
TRH indirectly increases secretion of T3
and T4.
The main inhibitor of TRH secretion is negative feedback by T3 and T4. TRH production is
also blunted by illness or starvation and by an
increased amount of glucocorticoids. In these
situations, a lower metabolic rate may be advantageous. In other situations, TRH secretion
is increased, for example when exposure to
cold activates central noradrenergic neurones;
the resulting increase in T3 and T4 speeds up
metabolism and thus generates heat.

The anterior pituitary gland synthesises and
releases TSH, a large glycoprotein hormone.
TSH increases the uptake of iodide by the
thyroid gland. This effect increases thyroid
peroxidase enzyme function and thus stimulates the synthesis and release of T3 and T4.
Thyrotrophin-releasing hormone is the
main stimulus for TSH production. Therefore destruction of TRH-secreting cells leads
to TSH deficiency and hypothyroidism. TSH
production is suppressed when T4 levels are
high to maintain a steady amount of thyroid
hormones in the circulation. The thyroid
and anterior pituitary glands form a negative
feedback loop.

The parathyroid glands

The parathyroid glands
Starter questions
Answers to the following questions are on page 63.
5.	 Can we survive without our parathyroid glands?
6.	 Why do South Asian individuals in the UK have a high incidence of vitamin D

The four parathyroid glands are in the neck,
behind the thyroid. They secrete parathyroid
hormone. Parathyroid hormone is the main
hormone responsible for maintaining calcium and phosphate homeostasis.
Accessory or supernumerary parathyroid
glands (extra glands) are common. They
are present in about 10% of people.
Accessory glands probably arise from
fragments of tissue that detach from the
parathyroid gland as it migrates during
embryonic development.

The four parathyroid glands arise from pharyngeal pouches (see page 9).

The parathyroid glands usually lie on the posterior aspect of the thyroid gland (Figure 1.7).
They are yellow or brown in colour about the
size of a small pea, and each weighs about
30-50 mg. The superior glands have a fairly
constant position, but the position of the inferior glands can be variable or aberrant. The
parathyroid glands are supplied by blood
from branches of the inferior thyroid arteries.
In about 5% of people, one or more parathyroid glands are absent. However, this has
no detectable clinical effect provided that at
least one parathyroid gland is present; the remaining gland or glands are able to secrete a
sufficient amount of parathyroid hormone.
Ectopic parathyroid glands (glands in
the wrong place) are present in 15−20%
of patients. Common ectopic locations
include the anterior mediastinum, the
posterior mediastinum, and the retrooesophageal and prevertebral regions.
The parathyroid gland may become
embedded in the thyroid gland, resulting
in an intrathyroidal parathyroid gland.

The superior parathyroid glands develop
from the 4th pharyngeal pouch
The inferior parathyroid glands develop
from the 3rd pharyngeal pouch

From their superior embryonic position, the
parathyroid glands migrate inferiorly into
the neck. The embryological origins explain
the variable anatomical positions of the
parathyroid glands.

Hyperparathyroidism occurs when one
or more parathyroid glands secrete
excessive parathyroid hormone. This
leads to hypercalcaemia and may result
in kidney stones, impaired renal function
and osteoporosis.

The parathyroid glands contain two types of
cell: chief cells and oxyphil cells.

Chief cells are the predominant cell
type in which parathyroid hormone is
synthesised, and the hormone is stored in
granules in their cytoplasm



Chapter 1 First principles

Oxyphil cells contain numerous
mitochondria (energy producing cell
organelles). These cells do not produce
parathyroid hormone; their role remains
Most cases of hyperparathyroidism
are caused by a parathyroid adenoma
(benign tumour), the common treatment
for which is surgical resection. Removal
of the affected gland or glands is
more complicated when they are in an
abnormal location, such as retrosternal.

Parathyroid hormone is the dominant hormone
controlling calcium and phosphate homeostasis (Figure 1.12). Vitamin D has complementary
roles (i.e. facilitating increased calcium levels
in the blood by increasing calcium absorption
from the gut) to those of parathyroid hormone,
and it depends on parathyroid hormone for

The calcium ion (Ca 2+) has a fundamental role in various physiological functions,

bone formation
muscle contraction
enzymatic reactions (as a cofactor)


stabilisation of membrane potentials in
muscle cells and neurones
blood coagulation

Mode of action of calcium
Many of the actions of calcium are brought
about by the binding of Ca 2+ to proteins,
which alters their structure and function.
These effects occur in calcium’s role as a 2nd
messenger in hormonal signalling.
1. Stimulation of G-protein−coupled
extracellular hormone receptors permits
opening of transmembrane Ca2+ channels
2. The open channels allow Ca2+ influx into
the cell, thus increasing intracellular Ca2+
3. The intracellular Ca2+ modifies the action
of extracellular signal−regulated kinases
4. The action of Ca2+ on these kinases
changes their biological activity in the
cell cytoplasm and nucleus, thus altering
the intracellular environment and gene
transcription, respectively

Distribution of calcium in the body
The adult human body contains about 1−2 kg
of calcium, 99% of which is in teeth and bone
as hydroxyapatite crystals. Of the remainder,
about 1% is intracellular, and a tiny fraction,
less than 0.1%, is extracellular. This small
extracellular fraction determines calcium
balance in the body and is regulated homeostatically by hormones.

Parathyroid hormone and calcium homeostasis

Figure 1.12 Parathyroid hormone
(PTH), calcium and phosphate
homeostasis. PTH acts on the
bone and kidney to increase
serum calcium. It causes release of
phosphate by bone reabsorption
and increases phosphate excretion
from the kidney. Vitamin D is
activated by the kidney and acts
on the gut to facilitate absorption
of calcium and phosphate.

The parathyroid glands

Calcium in the blood
The normal range of bound calcium in the
blood (serum) is narrow: 2.25−2.55 mmol/L.
Only about 1 mmol/L exists as free (unbound)
ionised calcium (Ca2+), and that in the blood
is the active calcium. About 45% of the bound
calcium is bound to serum proteins (mainly
albumin and, to a lesser extent, globulin),
and about 10% is bound to inorganic anions
such as citrate, phosphate and bicarbonate.
The bound forms of calcium are in equilibrium with the free ionised calcium.
The main factor determining the amount
of calcium in the blood is the concentration
of albumin. In low-albumin states such as
hepatic failure and nephrotic syndrome, the
amount of calcium in the extracellular space
is reduced.
Blood pH affects calcium protein binding:

Acidosis reduces protein binding, thus
increasing calcium concentration
Alkalosis increases protein binding, thus
reducing calcium concentration

Distribution of phosphate in the
Bone contains 85% of the phosphate in the
body. Just less than 5% is in the intracellular compartment, and less than 0.03% is in
the serum. The total phosphate concentration in serum is normally between 0.8 and
1.5 mmol/L. About half exists in free form,
and the other half is bound to serum proteins.
The extracellular concentrations of phosphates are inversely related to those of Ca 2+
and are regulated by the same hormones, i.e.
parathyroid hormone and 1,25-dihydroxyvitamin D (Figure 1.12).

Parathyroid hormone
Parathyroid hormone is a peptide hormone produced by the parathyroid gland in
response to low calcium, detected by calcium-sensing receptors on the surface of parathyroid cells. Parathyroid hormone acts on
bone and the kidneys to maintain serum calcium concentration within a narrow range.



Like calcium, phosphates are critical in
numerous physiological processes. Such
processes often require phosphorylation
(addition of a phosphate ion) and dephosphorylation (removal of a phosphate ion).
Examples of these processes are:

Calcium and phosphate levels depend on
bone metabolism, as well as their excretion
in the urine and their absorption in the gut
(Figure 1.12).
Parathyroid hormone increase serum calcium by:



energy transfer, in the form of conversion
of stored ATP to ADP
muscle contraction, when creatine
phosphate dissociates to form creatinine
and phosphate
2nd messenger systems, such as those
including cAMP and inositol phosphates

Phosphate is also a constituent of DNA, RNA
and phospholipids. These phosphate-containing compounds are termed organic phosphates, because the phosphate ion is bound to
a carbon-based compound. Inorganic phosphates (negatively charged) are also present
in the body and are associated with positively
charged ions such as K+ and Mg 2+.


stimulating osteoclast activity, which
releases calcium from bone
increasing renal reabsorption of calcium
promoting renal activation of vitamin D;
vitamin D facilitates calcium absorption
from the intestine

The release of parathyroid hormone leads to
a net decrease in serum phosphate. Parathyroid hormone−dependent bone breakdown
releases phosphate. However, to prevent
excessive phosphate accumulation in the
serum, parathyroid hormone also acts on
the kidney tubules to inhibit reabsorption of
phosphate from the urine, thereby increasing renal excretion of phosphate.



Chapter 1 First principles

Parathyroid hormone is produced in the cells
of the parathyroid glands. Preproparathyroid
hormone is cleaved to form proparathyroid
hormone, which is then cleaved to form parathyroid hormone. Production of parathyroid
hormone is stimulated when calcium-sensing receptors on parathyroid cells detect low
calcium concentration in the blood.

Secretion and clearance
Seconds after low calcium is detected, the
cells of the parathyroid gland release their
stored parathyroid hormone. This process
occurs by exocytosis.
An increase in Ca2+ binding to the calciumsensing receptor reduces the release of parathyroid hormone. Consequently, parathyroid
hormone secretion is inversely proportional
to serum calcium concentration and is thus
controlled by negative feedback.
Parathyroid hormone is transported unbound in the serum, has a short half-life of a few
minutes and is cleared by the kidney and liver.
The rapid release and breakdown of parathyroid hormone mean that this hormone system
is very quick to respond to changes in blood
calcium and thus maintain the serum calcium
concentration within its narrow range.




Vitamin D3 (cholecalciferol) is synthesised
from 7-dehydrocholesterol in the skin on
exposure to sunlight; vitamin D3 can also
be absorbed from the gut from foods such
as oily fish, milk and eggs, but because it is
very difficult to obtain enough vitamin D3
from the diet, synthesis on exposure to
sunlight is the main source (Table 1.5)
25-Hydroxyvitamin D (calcifediol) is
synthesised in the liver from hydroxylation
of vitamin D3 and vitamin D2
1,25-Dihydroxyvitamin D (calcitriol) is the
biologically active form of vitamin D; it is
produced when 25-hydroxyvitamin D is
hydroxylated in the kidneys
Vitamin D deficiency can result in
demineralisation of bones, causing
rickets in children and osteomalacia in
adults. Risk factors include malnutrition,
inadequate exposure to sunlight, dark
skin pigmentation and obesity.

In calcium and phosphate homeostasis,
active vitamin D facilitates calcium and
phosphate absorption from the gut.
Sources of vitamin D

Parathyroid hormone receptors are G-protein−coupled receptors. They are present
predominantly in bone and the kidneys, the
main sites of action of parathyroid hormone.

Vitamin D
Vitamin D is a lipid hormone derived from
cholesterol. In contrast to other vitamins, its
active form is not available in the diet. Instead,
vitamin D requires activation through a series
of metabolic steps. This means that activated
vitamin D deficiency can develop in people
on a normal diet, for example in cases of renal
Vitamin D exists in several forms:

Vitamin D2 (ergocalciferol) is absorbed
from the gut from plants and fungi; it is
also used in some vitamin supplements


Amount of vitamin D

Exposure to ultraviolet light in
sunlight (10−30 min)*

90% of RDA

Cod liver oil (one capsule)

25−100% of RDA

Fortified breakfast cereal (one

10−20% of RDA

Oily fish such as trout, salmon
and mackerel (100 g)

10% of RDA

Egg yolk

2.5% of RDA

Margarine and infant formula
milk containing vitamin D†

<5% RDA

RDA, recommended daily amount.
*The time required to synthesise vitamin D depends on
the time of year (e.g. summer or winter), the degree of
skin pigmentation and the amount of skin exposed.
†Vitamin D is supplemented to these foods in the UK and
other countries.
Table 1.5 Sources of vitamin D

The parathyroid glands
In the bone, active vitamin D stimulates activation of osteoclasts to enhance bone resorption. In the kidneys, it increases the effect of PTH
in the renal tubular reabsorption of calcium.
Vitamin D receptors are expressed in many
cell types throughout the body, including immune cells, neurones and skin cells. The wide
expression of these receptors suggests that
vitamin D has functions in addition to those in
calcium and phosphate physiology and bone
formation. For example, vitamin D appears to
have a role in immunity, because vitamin D
deficiency is linked to increased rates of infectious illness.

The vitamin D receptor is a nuclear receptor.
It is activated by the binding of 1,25-dihydroxyvitamin D. The activated receptor then
forms a transcription factor that facilitates
gene transcription.
The role of the vitamin D receptor is best
understood in the following:


Steps in the synthesis of active 1,25-dihydroxyvitamin D are shown in Figure 1.13.

Vitamin D synthesis

In the bone, binding of
1,25-dihydroxyvitamin D to the
receptor causes activation of osteoclasts
(specialised cells involved in reabsorption
of bone)
In the gut, activation of the vitamin D
receptor facilitates absorption of calcium
and phosphate

Figure 1.13 Vitamin D
synthesis pathway. Vitamin
D3 (cholecalciferol) is either
synthesised in the skin or
absorbed from the gut, along
with vitamin D2 (ergocalciferol).
Vitamin D2 and D3 undergo
hydroxylation in the liver to
produce 25-hydroxyvitamin D. The
final hydroxylation and activation
occurs in the kidney (catalysed by
PTH) resulting in the formation of
1,25-hydroxyvitamin D.



Chapter 1 First principles

The hypothalamus
Starter questions
Answers to the following questions are on page 63.
7.	 How does the body control its temperature if the hypothalamus is damaged?
8.	 Can hormones be replaced if the hypothalamus is damaged?

The hypothalamus is an almond-sized symmetrical structure in the brain. It is below
and anterior to the thalamus, superior to
the pituitary gland and either side of the 3rd
As an endocrine gland, the hypothalamus is
responsible for control of the pituitary gland. It
also has major effects on other, non-endocrine
physiological processes, such as regulation of
body temperature.

The hypothalamus develops from the neural tube at about 5 weeks’ gestation. The
neural tube is a group of cells that develops
into the brain, spinal cord and autonomic
ganglia. The neural origin of the hypothalamus underlies its role as a neuroendocrine
gland and allows neural connections with
many other parts of the central nervous system, such as the thalamus and the midbrain,
which determine the hypothalamus’s wideranging effects on the body.

and lateral), some of which share neuroendocrine functions (Figure 1.14).
The medial hypothalamus has projections
to the paraventricular hypothalamus as well as
the anterior and posterior pituitary glands; it
regulates higher functions such as body temperature, appetite, thirst, the sleep−wake cycle
and sexual behaviour.
The paraventricular hypothalamus, which
borders the 3rd ventricle, has neurones that
project to the anterior and posterior pituitary
The lateral hypothalamus is a ‘relay centre’ containing the medial forebrain bundles,
which have neuronal connections to the
amygdala, the hippocampus and olfactory
system, and the medial hippocampus.
Two different types of neuroendocrine cell
in the hypothalamus separately regulate the
anterior and posterior pituitary glands:

The neuroendocrine cells that make up the
tuberoinfundibular tract project into the
capillary bed, where they form synapses
(the end terminal of a nerve cell that

The hypothalamus is surrounded by the thalamus laterally and superiorly. The medial
border is the wall of the 3rd ventricle, and the
inferior border includes the pituitary stalk, a
structure connecting the hypothalamus and
posterior pituitary (also known as the neurohypophysis) and the continuation of the floor
of the 3rd ventricle.
There are three main anatomical areas of
the hypothalamus (medial, paraventricular

Hypothalamus: coronal view

Figure 1.14 The hypothalamus and its relations
(coronal view).

The hypothalamus


transmits the cells electrical or chemical
signal to another cell) and release
hormones that stimulate or inhibit the
anterior pituitary
The neuroendocrine cells that make up
the magnocellular−neurohypophysial
tract synapse directly in the posterior
pituitary gland and release the hormones
antidiuretic hormone and oxytocin.

Arterial supply
Arterial blood is supplied to the hypothalamus from terminal branches of the circle of
Willis. These branches are, in turn, fed by the
two major arteries supplying the brain: the
internal carotid and basilar arteries.

venous drainage from the hypothalamus occurs through the anterior cerebral and basilar

The hypothalamus consists of neurones
(nerve cells) and neuroendocrine cells (cells
that receive neuronal input and release hormones into the blood).
The neuroendocrine cells synthesise two
sets of hormone (Table 1.6):


Venous drainage
Hormones from the hypothalamus are transported in blood to the anterior pituitary
gland through the median eminence. This
midline structure comprises the hormonesecreting terminals of the hypothalamic
neuroendocrine cells, as well as a capillary
bed that transports hormones to the anterior
pituitary gland (termed the hypothalamicpituitary portal system).
The capillaries drain directly into the anterior pituitary gland, where the hypothalamic
hormones act on pituitary cells. The remaining

The first set are hormones (i.e. antidiuretic
hormone and oxytocin) are synthesised in
the hypothalamus and transported down
axons for storage and release from the
posterior pituitary gland
The second set are hormones (e.g. growth
hormone−releasing hormone, GHRH;
somatostatin; corticotrophin-releasing
hormone, CRH; thyrotropin releasing
hormone, TRH; gonadotrophin-releasing
hormone, GnRH; and dopamine) are
synthesised in the hypothalamus and
reach the anterior pituitary gland through
the hypothalamic−pituitary portal system
(a network of arteries and capillaries
carrying blood from the hypothalamus
to the anterior pituitary) to stimulate
or inhibit secretion of anterior pituitary

Hypothalamic hormones: sites of release and effects
Hypothalamic hormone

Site of release


Antidiuretic hormone

Posterior pituitary

Promotes renal reabsorption of water

Anterior pituitary

Induces secretion of growth hormone

Growth hormone−releasing hormone

Stimulates uterine contraction
Inhibits secretion of growth hormone

Corticotrophin-releasing hormone

Induces secretion of adrenocorticotrophic hormone

Thyrotrophin-releasing hormone

Induces secretion of thyroid-stimulating hormone

Gonadotrophin-releasing hormone

Stimulates secretion of luteinising hormone and folliclestimulating hormone


Inhibits secretion of prolactin

Table 1.6 Hypothalamic hormones: their sites of release and effects



Chapter 1 First principles

The hypothalamus is considered the body’s
‘master control centre’ for hormone secretion.
In this role, it controls and receives feedback signals from other endocrine glands.
End organs controlled by the hypothalamus
through hormones released by the anterior
pituitary include:

thyroid gland
adrenal glands

Body temperature is controlled by the hypothalamus, which also has effects on appetite
and thirst, the sleep−wake cycle and sexual
behaviour. Emotion is influenced through
connections to the limbic system. The hypothalamus affects the autonomic nervous
system (which regulates involuntary body
systems such as the heart and the smooth
muscle of the vascular system and gastrointestinal tract) through projections to spinal
and brain stem nuclei.
Hypothalamic hormones (Table 1.6) are
secreted either directly into the systemic circulation through the posterior pituitary or into
the hypothalamic−pituitary portal system to
reach the cells of the anterior pituitary. Here,
they stimulate or inhibit the release of anterior
pituitary gland hormones.

Antidiuretic hormone
Antidiuretic hormone (also known as vasopressin) is a polypeptide hormone. It is synthesised by hypothalamic neuroendocrine
cells that project into the posterior pituitary
gland, from which the hormone is secreted.
Antidiuretic hormone is stored in granules
at the terminal ends of magnocellular neuroendocrine cells in the posterior pituitary

The overall action of antidiuretic hormone
is to increase the water content of the body.
This is primarily achieved through its effect
on the collecting ducts of the kidney, where
antidiuretic hormone causes aquaporin 2
channel proteins to migrate to the luminal
membrane. Aquaporin 2 channels permit

water absorption from the urine into the kidney. Thus water transport across the impermeable membrane is increased, and more
water is reabsorbed from the collecting duct.
Insensitivity of antidiuretic hormone
receptors leads to their under-activation
by the hormone. For example, in
nephrogenic diabetes insipidus, the
target cells in the kidney are insensitive
to antidiuretic hormone resulting in
excessive free water excretion in the

Antidiuretic hormone also binds to receptors
on the vascular smooth muscle in blood vessel walls; it causes vasoconstriction and thus
increases blood pressure.

Antidiuretic hormone secretion is stimulated
by increased serum osmolarity (the concentration of solute in the blood), which reflects
water deficiency (Figure 1.15). Changes in
osmolarity are sensed by specialist cells
called osmoreceptors in the hypothalamus
and other areas of the brain (Figure 1.14).
The release of antidiuretic hormone is also
stimulated by low blood pressure, which is
sensed by baroreceptors (blood pressure detectors) in the large blood vessels and heart.
This mechanism is influenced by the autonomic nervous system being up-regulated by
sympathetic drive (which is synergistic in increasing blood pressure).
Antidiuretic hormone is transported unbound in the plasma.
Antidiuretic hormone receptors are
present in many types of body tissue.
They exert a wide range of effects,
including conserving water and
increasing blood pressure. Therefore
polyuria and the inability to conserve
water appropriately are features of
antidiuretic hormone deficiency (cranial
diabetes insipidus).

The three major antidiuretic hormone
receptors have various functions (Table 1.7).

The hypothalamus

Effects of osmolarity on antidiuretic hormone
secretion and thirst



Antidiuretic hormone receptors:
locations and effects
Type of



ADH 1a

Vascular smooth muscle

Increases blood

ADH 1b

Corticotrophs (cells in the Increases ACTH
anterior pituitary gland
that produce ACTH)


Collecting duct of kidney

Increases water

ACTH, adrenocorticotrophic hormone; ADH, antidiuretic
Table 1.7 The locations of different antidiuretic
hormone receptors and the physiological effects
when activated

The receptors are G-protein−coupled receptors (see page 6).

This peptide hormone is synthesised in magnocellular cells of the hypothalamus and
secreted from their terminal ends in the posterior pituitary.

The main roles of oxytocin are to stimulate:

Figure 1.15 (a) Secretion of
antidiuretic hormone (ADH)
increases with increasing serum
osmolarity, and there is no
secretion below osmolarity of
about 285 mOsm/kg. (b) Thirst
also increases as serum osmolarity

uterine contraction during labour
milk let-down to facilitate lactation

Oxytocin also has roles in the menstrual
cycle in women and in erectile function in
men but these are poorly understood.

Oxytocin is released from projections of the
magnocellular neurones of the hypothalamus into the posterior pituitary gland. Like
most peptide hormones, oxytocin is transported unbound in the serum.

The oxytocin receptor is a G-protein−coupled
receptor present in the uterus and breasts. It
is also in the central nervous system, which
suggests that oxytocin also has roles outside
childbirth, such as the establishment of complex bonding behaviours with the baby.
Labour can be induced by using
synthetic oxytocin to stimulate uterine
contraction. The procedure is used,
for example, for women with lifethreatening diabetes or pre-eclampsia,
or if the baby is overdue and labour has
not occurred spontaneously.

Growth hormone−
releasing hormone and
Growth hormone−releasing hormone and
somatostatin are peptide hormones produced in the tuberoinfundibular tract of the
hypothalamus that bind to G-protein−coupled receptors in somatotrophs (cells in the
anterior pituitary gland that produce growth



Chapter 1 First principles

Growth hormone−releasing hormone and
somatostatin have antagonistic actions on
the somatotrophs (Figure 1.16):

GHRH stimulates the production and
release of growth hormone
Somatostatin inhibits growth hormone

Growth hormone−releasing hormone also
promotes somatotroph replication.
As well as reducing the production of
growth hormone in the pituitary, somatostatin
inhibits the production of GHRH in the hypothalamus. Somatostatin also has other endocrine effects; for example, it is produced in the
pancreas and inhibits insulin secretion.

The control of GHRH and somatostatin
release is shown in Figure 1.16. The release of
GHRH is inhibited by negative feedback from
circulating growth hormone and insulin-like
growth factor-1. GHRH release is also inhibited by somatostatin-secreting neurones in
the hypothalamus.
Both GHRH and somatostatin are released
into the blood of the hypothalamic-pituitary
portal system and transported to the anterior
pituitary gland. These hormones are transported unbound in the blood.

Corticotrophin-releasing hormone is a peptide hormone produced in the hypothalamus.
Effects and control of GHRH

It binds to a G-protein−coupled receptor on
corticotrophs (ACTH-producing cells in the
anterior pituitary gland).

The actions of CRH, and their consequences,
are summarised in Figure 1.5. CRH stimulates corticotrophs to produce ACTH. ACTH,
in turn, increases the production of cortisol
in the adrenal glands (see page 31).

Figure 1.5 shows the feedback loops for
CRH. Release of CRH is stimulated by the
neurotransmitters noradrenaline (norepinephrine) and acetylcholine, histamine,
thus ‘stress’ neurotransmitters influence
the cortisol-secreting system. CRH therefore acts a final common pathway messenger of physiological stress that results in the
up-regulation of cortisol production. Conversely, CRH release is inhibited by negative
feedback to the hypothalamus from ACTH
and cortisol.
Corticotrophin-releasing hormone is released from hypothalamic neurones into the
blood of the hypothalamic-pituitary portal
system, where it is transported in an unbound
state to the anterior pituitary gland.

Thyrotrophin-releasing hormone is a peptide hormone produced in the paraventricular nucleus of the hypothalamus. It binds to
G-protein−coupled receptors on thyrotrophs
Figure 1.16 Secretion of growth
hormone−releasing hormone
(GHRH) from the hypothalamus,
and its effects on the anterior
pituitary gland. IGF1, insulin-like
growth factor 1; GH, growth

The hypothalamus
(cells in the anterior pituitary gland that produce TSH) to stimulate the production and
release of TSH (Figure 1.17).

The release of TSH is controlled by negative
feedback from the thyroid hormones, T3 and
T4 (Figure 1.17). In the physiological states of
fasting and illness, TRH production is downregulated by inhibitory neuronal input of
multiple cells of the peripheral and central
nervous system. This effect conserves energy
by producing a state of low thyroid hormone
levels and a reduced metabolic rate.

This hormone promotes sexual development, sex hormone production and reproduction by stimulating production of the gonadotrophins (hormones that stimulate gonadal
function, e.g. luteinising hormone and FSH).

Gonadotrophin-releasing hormone stimulates
gonadotrophin production by gonadotrophs
(cells in the anterior pituitary that produce
gonadotrophins) (Figure 1.18). GnRH activity is low in childhood but is activated around
puberty when genetic triggers are activated by
hypothalamic hormones called Kisspeptins.



Thyrotrophin-releasing hormone is transported unbound in the blood. Once secreted into
the median eminence from granules at the
distal end of the hypothalamic neurons it travels to the anterior pituitary gland in the blood
via the hypothalamic-pituitary portal system
the hypothalamic-pituitary portal system.

Gonadotrophin-releasing hormone is released
in pulses. The pulsatile nature of GnRH is
reflected in its effects on the gonadotrophs. For
example, changes in the frequency of GnRH
pulses determine the frequency of pulses of
gonadotrophins from the pituitary.


In women and girls, such changes enable
progression through the phases of the
menstrual cycle, as when a surge of
luteinising hormone precipitates ovulation
(see page 34)
In men, the pulsatility of GnRH and thus
gonadotrophins is less variable

Gonadotrophin-releasing hormone is a peptide hormone produced by cells widely distributed throughout the medial hypothalamus.
GnRH binds to a G-protein−coupled receptor
on cells of the anterior pituitary gland.

The pulsatile nature of GnRH release is vital
during puberty. There is an increase in the

Effects and control of TRH

Effects and control of GnRH

Figure 1.17 Secretion of thyrotrophin-releasing
hormone (TRH) from the hypothalamus, and
its effects on the anterior pituitary gland. T3,
tri-iodothyronine; T4, thyroxine; TSH, thyroidstimulating hormone.


Figure 1.18 Secretion of gonadotrophin-releasing
hormone (GnRH) from the hypothalamus, and its
effects on the anterior pituitary gland. FSH, folliclestimulating hormone; LH, luteinising hormone.



Chapter 1 First principles
frequency and amplitude of GnRH pulses
that ‘wakes up’ the entire reproductive system that has previously laid dormant.
Gonadotrophin-releasing hormone pulsatility is controlled by kisspeptin hormones,
which are produced in cells of the hypothalamus. These peptide hormones are vital triggers for sexual development and reproduction.
The frequency and amplitude of GnRH release provide chemical signals to the gonadotrophs to commence production of gonadotrophins. Production of luteinising hormone
and FSH is stimulated or inhibited accordingly.
Oestradiol and testosterone have a negative feedback effect on the hypothalamus that
down-regulates GnRH release (Figure 1.18).

From the median eminence, where it is
secreted, gonadotrophin-releasing hormone
is transported unbound in the blood through
the hypothalamic-pituitary portal system to
the anterior pituitary gland.
Women undergoing in vitro fertilisation
have daily injections of a GnRH analogue
to obliterate luteinising hormoneFSH pulsatility. Once the normal
menstrual cycle is switched off this way,
subcutaneous injections of a combination
of luteinising hormone and FSH are used
to artificially stimulate egg development
and ovulation. The resulting ova are then
harvested and fertilised.

Appetite regulation
The hypothalamus has a role in appetite regulation. Appetite is determined by two contradictory impulses: hunger and satiety. These
impulses, along with other factors, such as
the availability of food, social impulses, smell
and taste, determine energy intake.
The hypothalamus controls eating behaviour by:

responding to afferent nervous and
endocrine stimuli
acting through efferent nervous pathways
to control eating behaviour

Signals to the
Appetite is affected by nervous impulses and
hormonal signals (transported from endocrine cells through the blood) to the hypothalamus.

Satiety signals
Food entering the gut stretches the intestinal
wall and thus stimulates the vagus nerve. This
effect signals ‘fullness’ to the hypothalamus.
In addition, gut hormones such as glucagon-like peptide-1, cholecystokinin and peptide YY are released from the gut in response
to ingestion of food. These hormones provide
hormonal feedback to the hypothalamus to
increase the feeling of satiety.
Leptin is produced by adipose (fat) cells to
help regulate the amount of fat stored in adipose tissue. Leptin provides an endocrine signal to the hypothalamus to decrease appetite
and thus reduce food intake if fat stores are
In the rare cases of congenital leptin
deficiency, administration of leptin
suppresses appetite and promotes weight
loss. However, leptin therapy does not
reverse excessive body weight in the vast
majority of cases of obesity, in which the
causes are dietary and lifestyle factors.

Hunger signals
Ghrelin is a peptide hormone produced by
cells of the gastrointestinal tract. Ghrelin
receptors are present in the arcuate nucleus
of the hypothalamus. The arcuate nucleus
is responsible for the perception of hunger.
Ghrelin provides a hormonal ‘hunger signal’
from the gut to the brain. Once food is ingested, ghrelin production wanes.

Integration of signals
The hypothalamus integrates the endocrine
and neural impulses that it receives, and
communicates them through neural projections to the cerebral cortex. These hypothalamic signals are reincorporated with
other higher impulses, such as the hedonic

The pituitary gland
(pleasure) signals associated with food
intake. The cerebral cortex then acts on these
signals to determine food-seeking behaviour
and food intake.

The hypothalamus assesses temperature:

Temperature regulation
The preoptic region of the hypothalamus is
responsible for regulation of body temperature (thermoregulation). The temperature is
maintained at 36−37.5°C to maximise metabolic efficiency; enzymes function optimally
in this range.

peripherally through nerves in the skin
that sense external temperature
centrally through temperature-sensing
nerves that detect the temperature of
blood around the hypothalamus

These nervous signals feed back to the
hypothalamus, which then activates appropriate cooling or warming actions (Figure

Hypothalamic response to cold and heat

Figure 1.19 The response of the
hypothalamus to cold and heat.

The pituitary gland
Starter questions
Answers to the following questions are on page 63–64.
9.	 Does prolactin play a role in men?
10.	 Why does the anterior pituitary gland have little direct blood supply?
11.	 Why is the pulsatility of pituitary hormone secretion so important?
The pituitary gland lies in the pituitary fossa
at the base of the skull. Although small (about
0.5 cm in diameter), the gland controls many
of the body’s endocrine systems.

The gland is anatomically and functionally
separated into two parts:

the anterior pituitary gland (also known as
the adenohypophysis)



Chapter 1 First principles

the posterior pituitary gland (also known
as the neurohypophysis)

Pituitary gland: embryological

A wide variety of hormones are secreted from
multiple cell types in the anterior pituitary
gland (Table 1.8). Hormones of the posterior
pituitary gland (antidiuretic hormone and
oxytocin) are released in the posterior pituitary having been synthesised in the hypothalamus.




The anterior and posterior pituitary glands
have different embryological origins (Figure 1.20).


The anterior pituitary is an upgrowth
from the oral ectoderm of the stomodeum
(primitive oral cavity) called the Rathke’s
The posterior pituitary derives from
nervous tissue (the diencephalon) and
forms from an out-pouching of the neural
ectoderm or diencephalon that forms the
floor of the 3rd ventricle

Therefore the anterior pituitary has a rich
vascular supply but no neural tissue, whereas the posterior pituitary comprises mainly
neurones originating in the hypothalamus.
Development of the pituitary gland starts
at 4 weeks’ gestation. By 6 weeks of gestation,
the anterior pituitary gland has been formed

Figure 1.20 Embryological development of the
pituitary gland. (a) Development starts at 4 weeks
of gestation by upgrowth of the stomodeum to
form Rathke’s pouch and downgrowth of the
diencephalon to form the posterior pituitary; (b),
the two structures meet; (c) the anterior pituitary
gland has been formed by cleavage of Rathke’s
pouch and is attached to the posterior pituitary

by cleavage of Rathke’s pouch. The border between the anterior pituitary and the posterior
pituitary remains and is termed the pars intermedia.

Anterior pituitary gland hormones

Pituitary cell type


Hormone effect(s)

Growth hormone


Hepatocytes and
adipose cells

Promotes growth and regulates metabolism.
Stimulates IGF-1 production in the liver



Adrenal cortex

Increases secretion of corticosteroids



Thyroid gland

Stimulates secretion of thyroxine and triiodothyronine

Luteinising hormone


Testes (in males) or
ovaries (in females)

Increases sex hormone secretion




Stimulates spermatogenesis


Stimulates follicle production



Mammary glands

Promotes lactation

Table 1.8 Hormones secreted by the anterior pituitary gland, their cell type, hormone target and effects

The pituitary gland

A Rathke’s cleft cyst is thought to arise
as an overgrowth of the remnant from
the Rathke’s pouch. This fluid-filled,
benign structure is usually small and
discovered incidentally on radiographic
imaging. However, the cyst can enlarge,
even in adulthood, to compress the optic
chiasm causing a visual field defect.

The pituitary gland is in the pituitary fossa
and weighs about 0.5 g. The posterior pituitary is connected to the median eminence
of the hypothalamus through the pituitary
stalk, also known as the infundibulum. The
anterior pituitary makes up 80% of the pituitary gland and lies in contact with the posterior pituitary.
The pituitary gland is surrounded by a thick
covering (dura mater). The pituitary gland lies
in the pituitary fossa, in the sella turcica of the
sphenoid bone.
Magnocellular neurosecretory cells, which
originate in the hypothalamus and terminate
in the posterior pituitary, produce antidiuretic
hormone and oxytocin.
The tuberoinfundibular pathway is a collection of dopamine-transmitting neurones
that emanate from the hypothalamus and
feed into the pituitary stalk (infundibulum).
These terminate in a rich capillary bed of the
hypothalamic-pituitary portal system (in
which dopamine can circulate), passing down

Anatomy of the pituitary gland

the pituitary stalk and into the anterior pituitary gland (Figure 1.21).
If the pituitary fossa enlarges, for
example as a result of pituitary
adenoma, it compresses local structures,
including the infundibulum, the optic
chiasm and the pituitary gland itself
(Figure 1.22). The result may be pituitary
hormone dysfunction or loss of field of
vision (bitemporal heminaopia).

Structures lying close to the pituitary gland
in the pituitary fossa include:


optic chiasm superiorly (where the tracts
of the optic nerves carrying signals from
the temporal field of vision in each side
cavernous sinus laterally
internal carotid arteries laterally
sphenoid bone inferiorly
3rd ventricle posteriorly

Arterial supply
The two parts of the pituitary gland receive
blood from different sources.


The posterior pituitary receives most
of its blood supply from the inferior
hypophyseal artery
The anterior pituitary receives blood
directly from the superior hypophyseal
artery and indirectly from the same artery
through the hypothalamic-pituitary portal
system from the median eminence
Figure 1.21 Anatomy of the
pituitary gland.



Chapter 1 First principles
Figure 1.22 Coronal sections
through the pituitary gland. (a)
The normal pituitary gland. (b) A
large pituitary tumour occupies the
pituitary fossa, extending into the
cavernous sinus and compressing
the optic chiasm.

Effects of pituitary tumour



The blood in the portal system is rich in
hypothalamic stimulating and inhibitory
hormones, such as CRH, TRH, GHRH, somatostatin, GnRH and dopamine. These hormones are conveyed to the anterior pituitary
gland to control the synthesis and release of
anterior pituitary hormones.
The hypophyseal arteries are terminal
branches from the internal carotid artery.

Venous drainage
The pituitary gland is drained by the hypophyseal veins. This blood now contains hormones from the anterior and posterior
pituitary glands. These veins drain into the
petrosal sinuses and then the jugular vein,
from which the hormones are disseminated
systemically to their target tissues.

The posterior pituitary is directly innervated
by nerves from the magnocellular pathway
from the hypothalamus. At the termination
of these neurones, oxytocin and antidiuretic
hormone are released. Oxytocin is released
during labour and breastfeeding and causes
uterine contraction and help lactation.
Antidiuretic hormone is released in response
to increased blood osmolarity, decreased
blood volume and stress.

There is no direct innervation of the anterior pituitary gland. Information from the brain
is translated into hormones from the hypothalamic cells. These hormones are released into
the blood supply of the pituitary to stimulate
hormonal release. The connection between
the hypothalamus and the anterior pituitary
gland is therefore purely vascular.

The secretory area of the anterior pituitary
gland is the pars distalis (anterior lobe). The
pars distalis contains various types of epithelial cell. These are divided into two groups:

chromophils (cells that stain with dye)
chromophobes (cells that do not stain)

The chromophilic epithelial cells are further
subdivided into acidophilic and basophilic
cells (Table 1.9).
The posterior pituitary consists of a vascular bed and the terminal ends of myelinated
axons projecting from the hypothalamus.

Hormone release from the anterior pituitary
gland is controlled by hypothalamic hormones
(see page 20). Anterior pituitary hormone
production is also affected by negative feedback from the target endocrine gland, such

The pituitary gland

Histology of anterior pituitary cells
Type of epithelial

Secretory protein






No hormones


Hormone secreted


Growth hormone




Adrenocorticotrophic hormone


Luteinising hormone and follicle-stimulating hormone


Thyroid-stimulating hormone



Table 1.9 Histology of the anterior pituitary cells

as T4 acting directly on the pituitary to inhibit
TSH release but also to inhibit TRH release
from the hypothalamus.

This peptide hormone is derived from a large
precursor molecule called pro-opiomelanocortin. Cleavage of this polypeptide produces several peptides, including ACTH.
ACTH is synthesised by the corticotrophs of
the anterior pituitary gland. These cells make
up about a quarter of the anterior pituitary

The secretion of ACTH is stimulated by CRH
from the hypothalamus. The hormone is transported unbound in the systemic circulation.
There are many other physiological stimuli
for ACTH secretion. These include antidiuretic
hormone, catecholamines and growth hormone (i.e. other hormones that control the
stress response and affect metabolism). ACTH
secretion has physiological characteristics
that directly influence the reactive production
of cortisol:

Adrenocorticotrophic hormone binds to
ACTH receptors, which are transmembrane
receptors in the zona fasciculata and zona
reticularis of the adrenal cortex. Binding of
ACTH to its receptor stimulates the production of cortisol (see page 41).
In addition, ACTH binds to cells in the zona
glomerulosa and zona reticularis to stimulate
synthesis of aldosterone and adrenal androgens. However, these hormones have other,
more potent stimuli for secretion. For example,
aldosterone secretion is primarily stimulated
by angiotensin II.
Aside from its role in hormone production,
ACTH also stimulates proliferation of adrenal
cortex cells to maintain the adrenal cortex at
a size sufficient to produce adequate amounts
of cortisol.

ACTH secretion is pulsatile
ACTH secretion has a circadian rhythm
ACTH release is stimulated by stress

The circadian rhythm is a pattern of secretion that follows a 24-h cycle set by a hypothalamic pacemaker. ACTH is not unique in
having such a rhythm; other hormones, such
as testosterone and growth hormone, also
follow a circadian pattern.
The frequency of ACTH pulses remains
constant, but circadian rhythm occurs by
changes in the quantity of ACTH released with
each pulse. The highest peaks are early in the
morning, and the lowest troughs are in the
middle of the night.
Stress leads to cytokine, hormone and neurotransmitter release, which stimulates the release of CRH. CRH, in turn, increases overall
ACTH secretion and cortisol production. For
example, ACTH release can be caused by hypotension, pain, emotional strain and metabolic stressors such as hypoglycaemia.



Chapter 1 First principles
ACTH stimulates the release of cortisol,
which reduces the immune response and stimulates cytokine production; it also has other effects, such as increasing blood pressure.
Pituitary function is tested by using
intravenous insulin to deliberately
induce hypoglycaemia; this is the
insulin stress test. Hypoglycaemic stress
normally causes cortisol to peak. Failure
to do so confirms pituitary or adrenal

Adrenocorticotrophic hormone receptors are
G-protein−coupled transmembrane receptors. Once bound with ACTH, they transmit their signal by activating the adenylate
cyclase pathway (see page 6). ACTH receptors
are present in the zona reticularis and the
zona fasciculata of the adrenal cortex.

Physiological effects of growth hormone
and IGF-1
Cells (tissue)




Growth hormone
and IGF-1

Promote proliferation
and growth



Promotes proliferation



Stimulates adipose
metabolism to
release fatty acids






Impairs glucose

Increases amino acid

Increases amino acid
uptake and protein
Table 1.10 The physiological effects of growth
hormone and insulin-like growth hormone (IGF)-1

Growth hormone
Growth hormone is a polypeptide hormone
released from somatotrophs in the anterior
pituitary gland. It is the most abundant anterior pituitary hormone.
In childhood, growth hormone has a key
role in promoting growth. It also has a role in
adulthood in increasing muscle growth and
increasing blood glucose, even after the body
has reached its final height.

The biological effects of growth hormone are
varied and complex, but almost all its actions
are through its effector hormone, insulin-like
growth factor-1. Growth hormone stimulates
the production of insulin-like growth factor-1
(a peptide hormone with a similar chemical
structure to insulin) in the liver via activation
of growth hormone receptors.
Insulin-like growth factor-1 has effects
on multiple tissues, including promotion of
cellular proliferation and stimulation of metabolism (Table 1.10). However, the key target
organ of IGF-1 in childhood is the epiphyseal
growth plates in long bones; therefore ICF-1
stimulates long bone growth children.

Growth hormone also affects tissues directly to cause growth by cellular proliferation.
The precise mechanism for this is unclear.

The transcription and release of growth hormone are stimulated by GHRH. Growth hormone secretion is also stimulated by ghrelin
produced by the stomach, because ghrelin
augments GHRH and inhibits somatostatin
(an inhibitor of growth hormone release).
The release of growth hormone is pulsatile. Pulses occur less than a dozen times per
day. During the intervening times, growth
hormone levels are low. Growth hormone secretion has a circadian pattern; pulses occur
in greater frequency and amplitude during
sleep, when peak growth occurs in children
(Figure 1.23).
Growth hormone is present from birth.
However, the onset of puberty causes a
marked increase in the amplitude of