First and second edition authors:

Madeleine Dubuse
Stephan Sanders

Third edition authors:

Alexander Finlayson
Stephan Sanders
4 th Edition

CRASH COURSE
SERIES EDITOR:
Dan Horton-Szar
BSc(Hons) MBBS(Hons) MRCGP
Northgate Medical Practice
Canterbury
Kent, UK

FACULTY ADVISORS:
Aftab Ahmad
Philip Weston
Consultant Diabetologist
Royal Liverpool University Hospital, Liverpool

Ronan O’Neill
Fourth Year Student Doctor

Richard Murphy
Fourth Year Student Doctor
Commissioning Editor : Jeremy Bowes
Development Editor: Catherine Jackson
Project Manager: Andrew Riley
Designer: Stewart Larking
Icon Illustrations: Geo Parkin
Illustration Manager: Jennifer Rose

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 Series editor foreword

The  Crash Course series first published in 1997 and now, 15 years on, we are still
going strong. Medicine never stands still, and the work of keeping this series
relevant for today’s students is an ongoing process. These fourth editions build on
the success of the previous titles and incorporate new and revised material, to keep
the series up to date with current guidelines for best practice, and recent
developments in medical research and pharmacology.

We always listen to feedback from our readers, through focus groups and student
reviews of the   Crash Course titles. For the fourth editions we have completely re-
written our self-assessment material to keep up with today’s ‘single-best answer’
and ‘extended matching question’ formats. The artwork and layout of the titles has
also been largely re-worked to make it easier on the eye during long sessions of
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Despite fully revising the books with each edition, we hold fast to the principles on
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checked by a team of faculty advisors from across the UK.

I wish you all the best for your future careers!

Dr Dan Horton-Szar 
 Overview of the endocrine system

Fig. 1.1 The routes by which

1. Endocrine 2. Paracrine
chemical signals are delivered to cells.

blood

3. Autocrine 4. Neurocrine

Fig. 1.2 The location of major 

hypothalamus pituitary gland
endocrine organs and the hormones
- several hormones - several hormones
secreted by them. to regulate to regulate
pituitary function endocrine tissue
  function

parathyroid glands thyroid gland

- parathyroid hormone - thyroid hormones

adrenal glands
- cortisol
- aldosterone
- catecholamines

pancreas
- insulin
- glycogen

ovaries
- oestrogen
- progesterone
testes
 Organization of the endocrine system 1

constant environment for appropriate biochemical pro-

signals indicating the
need for a hormone
+/−
cesses. If the equilibrium shifts, biochemical and neural
signals converge on hypothalamic cells to provide nega-
tive feedback to the hypothalamus so it can make the nec-
essary inhibitory or stimulatory adjustments to maintain
homeostasis.

hypothalamus Hypothalamus
e.g. TRH
 The hypothalamus is a structure located in the base
of the forebrain. It converts neural signals received from
+/−
the brain into chemical signals in the form of hor-
mones. These hormones cause the release of other hor-
anterior pituitary mones in the pituitary gland. For this reason, hormones
gland produced by the hypothalamus are known as ‘releasing 
e.g. TSH
hormones’, e.g. thyrotrophin-releasing hormone (from
the hypothalamus) which causes the release of thyrox-
+/−
ine in the pituitary gland. Releasing hormones therefore
act indirectly on peripheral target cells; their actions are
mediated through the release of pituitary hormones
endocrine tissue
e.g. thyroid hormones  which have a direct effect on target cells.
Hypothalamic activity is altered by homeostatic sig-
nals (e.g. osmolarity of the blood) and sensory informa-
tion arriving from the periphery (e.g. blood pressure,
actions on the body emotion). Hypothalamic hormones are released in a pul-
e.g. metabolism satile manner, with regular changes in activity over the
course of 24 hours (circadian rhythm). This change in
activity over 24 hours corresponds to daily cycles of 
Fig. 1.3 The organization of the endocrine system (TRH,
thyrotrophin-releasing hormone; TSH, thyroid-stimulating
daylight and darkness and alters physiological processes
hormone). such as body temperature, metabolic rate and blood
pressure.

Pituitary gland
turn, relay messages back to the hypothalamus about 
their effects and/or the levels of circulating hormones  The pituitary gland is found at the base of the brain, in-
in the blood, and this causes either stimulation or inhi- ferior to the hypothalamus. It releases hormones into
bition of hormone release by the hypothalamus the blood in response to signals from the hypothalamus
(Fig. 1.3). This is called negative feedback (Fig. 1.4). known as ‘stimulating hormones’. Hormones from the
 The key to understanding the endocrine system is un- pituitary gland regulate the function of peripheral endo-
derstanding that hormones produced by the hypothala- crine tissues throughout the body.
mus alter the actions of peripheral endocrine tissues
 which act to restore equilibrium in order to maintain a Peripheral endocrine tissues

 These tissues respond to signals from the pituitary by 

increasing or decreasing secretion of specific hormones
stimulus for  into the blood. It is the hormones secreted by these
hormone release peripheral tissues that affect the state of the body by 
e.g.TSH acting on target cells.
negative
+ −
feedback Target cells
 All cells in the body will be exposed to the circulating 
hormone
hormones in the blood. The cell will only respond to
e.g. thyroid hormone
the hormone, however, if it has the appropriate hormone
 Overview of the endocrine system

respond to different hormones. Target cells in different  What are the benefits of having
tissues may respond differently to the same hormone
depending on the presence of certain receptors.
an endocrine system?
 There are two main benefits to having an endocrine
system:
Control of hormone secretion
Overall control Amplification
Endocrine tissues are regulated by signals from a variety 
Subtle but important neural signals are detected by the
of neural and systemic sources. These signals are pro-
hypothalamus, which then releases a small amount of 
cessed by cells to determine the rate of hormone secre-
‘releasing hormone’. The pituitary gland is able to se-
tion. The strength and importance of the signals varies
crete a greater quantity of ‘stimulating hormone’, which
so that hormone secretion fits the needs of the body.
then stimulates the release of greater amounts of hor-
mone by peripheral endocrine tissue. In this manner,
A single hormone may have multiple actions; equally, the signal of a small number of neurons in the hypothal-
multiple hormones may have the same action. This is amus is amplified in three stages to affect the entire
demonstrated by insulin and the regulation of blood body.
glucose, respectively.

Control
Neural control  The endocrine system regulates all major body processes
that are essential for life. These processes must be con-
Higher neural centres can influence the activity of the trolled very tightly and kept within normal physiologi-
endocrine system by acting on the hypothalamus. They  cal ranges or else death may occur. The complexity of 
can increase or decrease the secretion of hypothalamic the endocrine system allows such tight control and en-
releasing hormones, which regulate the secretion of  sures the body can adapt and respond to any changes
pituitary gland hormones. For example, cold external rapidly.
temperature will stimulate TRH, ultimately increasing 
metabolism in cells, raising body temperature.

Negative and positive feedback HORMONE TYPES AND

 A hormone is released in response to a stimulus. The ac-
tions of the hormone directly or indirectly reduce the in-
tensity of the stimulus and restore equilibrium. Through
this mechanism, homeostasis is achieved. This is known
as negative feedback.
Hormones provide negative feedback:
Directly
 The level of circulating hormones in the blood is
detected by the hypothalamus or pituitary gland and
subsequently altered, e.g. thyroxine levels are detected
by the hypothalamus.
Indirectly
 The actions of the hormone produce physiological ef-
fects which are detected and subsequently altered by  Polypeptide hormones are synthesized in the same
the secretion of a hormone or hormones, e.g. low blood
glucose levels (hypoglycaemia).
Feedback can also be positive, where the effect pro-
SECRETION
Polypeptide hormones
Polypeptide hormones are proteins that act as hormones.
 They cannot pass through cell membranes due to their 
size and water-soluble nature. Protein hormones are
the most abundant type of hormone (a safe bet in an
exam). They are released by many structures including:
• Hypothalamus – TRH, GnRH, growth-hormone re-
leasing hormone (GHRH), etc.
• Pituitary – TSH, follicle-stimulating hormone (FSH),
luteinizing hormone (LH), oxytocin, etc.
• Pancreas and GI tract – insulin, glucagon, cholecys-
tokinin (CCK), etc.
Synthesis and secretion
manner as all proteins. Some polypeptide hormones
undergo modification in the Golgi apparatus or secre-
tory granules before secretion. Addition of carbohydrate
 Relationship of the nervous and endocrine systems 1

Hormonal control of neurons therapy. Endocrine disease can also occur in

 To complete this circuit, the hormones of the endocrine patients with infections, including HIV. Increasingly,
system also affect the nervous system. Negative feedback  associations are being demonstrated between
to the hypothalamus has already been described. How- endocrine disease and atherosclerotic cardiovascular 
ever, many hormones affect other areas of the brain, for  disease. Therefore, the endocrine system is important
example: to understand as it plays a key role in many other 
• Thyroid hormone deficiency causes depression. branches of medicine.
• Leptin and insulin regulate feelings of hunger.
• Adrenaline increases mental activity.
• Melatonin regulates the feeling of tiredness.
Nervous system
 The nervous system uses very localized chemical signals
Comparison between the nervous at synapses to transmit membrane depolarization be-
and endocrine systems tween neurons. The effects of the nervous system are
 very rapid but of short duration and expensive metabol-
 While the two systems function closely they have differ- ically (i.e. the neurotransmitters and depolarization re-
ent modes of action. The hypothalamus combines these quire a lot of energy). The specific target cell is
actions since it is an endocrine tissue composed of nerve determined mostly by the location of chemical release
cells called neurosecretory cells. rather than the receptors.

As endocrine hormones are very widespread in their 

distribution, the manifestations of endocrine disease
vary greatly. Endocrine disease can be seen in patients
of all ages, from congenital abnormalities in newborns
through a plethora of adult and old-age endocrine
problems. Patients with cancer can have endocrine
dysfunction as part of the primary cancer (i.e. the
cancer releases a hormone) or as a side effect of
Endocrine system
 The endocrine system uses very generalized chemical
signals, though a few endocrine tissues can depolarize.
 These signals require less energy than neural signals. The
signals travel throughout the body in the bloodstream,
and the target cell is determined mainly by the presence
and specificity of receptors. The signals of the endocrine
system tend to be slower but with a longer duration.
Intentionally left as blank
 The hypothalamus and
the pituitary gland 2
Objectives

By the end of this chapter you should be able to:

• Describe the function of the hypothalamic–pituitary axis
• Describe the embryological origin and anatomy of the hypothalamus and pituitary gland
• Name the pituitary hormones and the cells that secrete them
• Describe the aetiology of hypothalamic and pituitary gland disorders
• Recall the signs, symptoms, investigations and management of hypopituitarism and hyperpituitarism
• Differentiate between cranial and nephrogenic diabetes insipidus
• Describe the aetiology and clinical findings in SIADH.

 The hypothalamic–pituitary axis is the central regulatory   The base of the hypothalamus between the median em-
component of the endocrine system, consolidating signals inence and mamillary bodies is known as the tuberal
from the brain, environmental stimuli and various feed- area and contains nuclei which regulate pituitary gland
back loops, adjusting output to meet changing demands. function. This arrangement is shown in Fig. 2.2.
 The hypothalamus is sensitive to neural and hor-  The hypothalamus receives multiple inputs about 
monal stimuli. This information is then integrated by  the homeostatic state of the body (Fig. 2.3). These arrive
the hypothalamus to generate chemical signals that re- by two means:
lay the message on to the pituitary. The hypothalamus is • Circulatory, e.g. temperature, blood glucose, hor-
also sensitive to stimuli which affect hunger, thirst and mone levels
sexual behaviour; however, the output of these stimuli • Neuronal, e.g. autonomic function, emotional.
is not the pituitary gland.
 The ability of the hypothalamus to respond to circu-
Hypothalamic-releasing and -inhibitory hormones
latory stimuli is due to numerous connections to cir-
are carried in the hypophyseal portal vessels to the an-
cumventricular organs which surround the ventricles
terior pituitary, where they regulate the release of ante-
of the brain. The hypothalamus also has extensive con-
rior pituitary hormones.
nections to sensory nuclei of the brainstem and limbic
 The posterior pituitary gland functions in a slightly 
system which further modulate its activity (Fig. 2.4).
different way because it is a direct extension of the hy-
It responds to these inputs by secreting hormones that 
pothalamus. Neurosecretory cells in the hypothalamus
regulatethereleaseofhormonesfromtheanteriorpituitary 
synthesize hormones that are transported along axons
or releases hormones directly from the posterior pituitary.
that terminate in the posterior pituitary. These hor-
 The hypothalamus is composed of several compo-
mones are then released into capillaries within the pos-
nents:
terior pituitary gland to affect body parts directly.
• Mamillary bodies – regulate feeding reflexes (e.g.
swallowing) and memory 
• Autonomic centres – control nuclei which alter heart 
ANATOMY  rate and blood pressure
• Supraoptic nucleus – secretes ADH
Hypothalamus • Tuberal nuclei – control of anterior pituitary 
• Preoptic areas – control of thermoregulation
 The hypothalamus is situated at the base of the fore-
• Paraventricular nucleus – secretes oxytocin
brain, the diencephalon. Together with the thalamus,
• Suprachiasmatic nucleus – controls circadian rhythm.
 which is located superiorly, it forms the lateral walls
of the third ventricle. It is posterior and slightly superior 
to the optic chiasm and anterior to the mamillary 
Pituitary gland
 Microstructure 2

Fig. 2.6 Embryological development

Sagittal section through
of the anterior and posterior lobes of
the cephalic region of
the embryo at week the pituitary gland.
6 of gestation

infundibulum Rathke's pouch

notochord

primitive oral cavity

1. Formation of the infundibulum 2. Fusion of the two diverticula

and Rathke's pouch
infundibulum
growing down
from
hypothalamus
Rathke's pouch
growing up
from buccal
ectoderm

3. Regression of the stalk of 4. Maturation of pituitary lobes and

Rathke's pouch surrounding structures
neurohypophysis hypothalamus

adenohypophysis anterior lobe

regressing stalk
of Rathke's
pouch dura mater 
posterior lobe
sphenoid bone
roof of pharynx develops around
pituitary fossa

• Thyrotrophs – thyroid-stimulating hormone (TSH)

MICROSTRUCTURE
Hypothalamus
 There are a number of different secretory neurons in the
hypothalamus (see p. ••), each specialized to secrete
specific hormones. Neurons that secrete the same hor-
mones may be arranged in clusters called nuclei or they  secretes GH, LH, FSH, ACTH, TSH and prolactin.
may be scattered diffusely.
Anterior pituitary
 The anterior pituitary is composed of cords of secretory 
cells in a rich network of capillaries. Six types of secre-
tory cell can be distinguished in the anterior pituitary 
(Fig. 2.7). They are listed along with the hormone(s)
they secrete:
• Somatotrophs – growth hormone (GH)
• Gonadotrophs – luteinizing hormone (LH) and fol-
• Lactotrophs – prolactin
• Chromophobes – inactive secretory cells.
 The anterior pituitary can be further divided into three
parts, which have different secretory functions:
• Pars distalis: anterior portion of the adenohypo-
physis. This makes up the majority of the gland. It 
• Pars intermedia: a thin layer of corticotroph cells
between the pars distalis and the posterior pitui-
tary. It is poorly developed in humans. Secretes
melanocyte-stimulating hormone (MSH) in the
fetus and during pregancy.
• Pars tuberalis: surrounds the pituitary stalk. Contains
a small number of mostly gonadotroph cells.
Posterior pituitary
 The posterior pituitary can be divided into:
 The hypothalamus and the pituitary gland

Fig. 2.7 Hormones synthesized and secreted by the anterior pituitary and their effects

Hormone Synthesized by Stimulated by Inhibited by Target  Effect  Chapter 

organ

GH Somatotrophs GHRH GHIH and Liver  Stimulates IGF-1 9

IGF-1 production and
opposes insulin
TSH Thyrotrophs TRH T3 Thyroid Stimulates 3
gland thyroxine release
ACTH Corticotrophs CRH Glucocorti- Adrenal Stimulates 4
coids cortex glucocorticoid and
androgen release
LH+FSH Gonadotrophs GnRH, sex Prolactin, Reproductive Release of sex 11
steroids sex organs steroids
steroids
Prolactin Lactotrophs PRF and Dopamine Mammary Promotes growth 11
TRH glands and of these organs
reproductive and initiates
organs lactation
MSH Corticotrophs − − Melanocytes Stimulates melanin
in skin synthesis in fetus and −
during pregnancy

Beta- Corticotrophs − − Unknown May be involved −

endorphin in pain control
ACTH, adrenocorticotrophic hormone; CRH, corticotrophin-releasing hormone; FSH, follice-stimulating hormone;
GH, growth hormone; GHRH, growth-hormone releasing hormone; GnRH, gonadotrophin-releasing hormone;
GHIH, growth-hormone inhibiting hormone; LH, luteinizing hormone; MSH, melanocyte-stimulating hormone;
TRH, thyrotrophin-releasing hormone; TSH, thyroid-stimulating hormone.

 The posterior pituitary is composed of two cell types but  directly to the anterior pituitary, their concentration
it contains no secretory cells:
•   Non-myelinated axons, originating from the
hypothalamus
• Pituicytes, which are glial support cells similar to
astrocytes.
 Within the axons, there are microtubules and mito-
chondria that are involved in the transport of neu-
rosecretory granules. These granules travel from the
hypothalamus to the axon terminals in the posterior 
pituitary, where they are stored before release. The axon
terminals lie close to blood sinusoids, where the neuro-
secretory granules are released into the systemic circula-
tion (Fig. 2.8).
HORMONES
Hormones of the hypothalamus
is high enough to produce an effect. The hypothalamic
hormones are often released in a pulsatile manner. The
pulses vary in amplitude and rate, often with a
circadian rhythm (see Chapter 6). Hormones that in-
fluence the anterior pituitary are secreted by short par-
 vocellular neurons. Hypothalamic neurons that travel
directly to the posterior pituitary are magnocellular 
neurons.
Hormones that regulate anterior 
pituitary function
 The hormones secreted by the hypothalamus are small
peptides, except for dopamine, which is derived from
the amino acid tyrosine. These hormones are shown
in Fig. 2.9, along with their effects.
 They act on the secretory cells of the anterior 
pituitary in an excitatory or inhibitory manner. Some
 anterior pituitary posterior pituitary

In common with all protein-secreting cells,

the anterior pituitary cells contain abundant
rough endoplasmic reticulum and Golgi bodies,
and are packed with secretory vesicles

blood cells

neurosecretory
granules

mitochondria

secretory
 cells pituicytes
microtubules axon (glial support
terminals cells)

fenestrated fenestrated
sinusoid sinusoid

Fig. 2.8 Histology of the anterior and posterior pituitary gland.

Fig. 2.9 Hormones secreted by the hypothalamus and their effects on the secretion of the anterior pituitary hormones

Hormone Target cells in the Effect on the anterior 

anterior pituitary gland pituitary gland

Growth-hormone Somatotrophs ↑ GH release

releasing hormone
(GHRH)
Growth-hormone Somatotrophs and ↓ GH and TSH release
inhibiting hormone thyrotrophs
(GHIH also called
somatostatin)
Corticotrophin-releasing Corticotrophs ↑ ACTH release
hormone (CRH)
Gonadotrophin-releasing Gonadotrophs ↑ LH and FSH release
hormone (GnRH)
Thyrotrophin-releasing Thyrotrophs and ↑ TSH and prolactin release
hormone (TRH) lactotrophs
Prolactin-releasing Lactotrophs ↑ Prolactin release
factors (PRF)
Dopamine (prolactin- Lactotrophs ↑ Prolactin release
inhibiting hormone)
 The adrenal glands

By comp
compar aris
ison
on,, the veno
venousus drai
draina
nagege is mu
much
ch simp
simple ler 
r 
stress than the arterial supply. The right
The right adrenal vein is
vein  is short 
hypothalamus and immediately enters the inferior vena cava, whereas
+ the left adrenal gland trav
adrenal gland travel
elss infer
inferio
iorr to enter
enter the left
left re-
re-
nal vein.
 The outer cortex receives no significant innervations;
CRH −
instead it is regulated by ACTH from the pituitary gland
and other bloodborne factors.
+
 The medulla is innervated directly by the splanchnic
nerv
nerves
es,, whic
whichh aris
arisee from
from the thora
thoracicicc spin
spinal
al cord
cord and
and do
not synapse before reaching the adrenal medulla. The
nerves are therefore preganglionic sympathetic nerves
anterior 
pituitary ACTH − that release acetylcholine, while all other tissues receive
gland postganglionic sympathetic innervations. The cause of 
this relationship is apparent from their development 
(see below).
+
Lymphatic drainage of the adrenal glands is through
the para-aortic nodes.
adrenal
cortex

cortisol DEVELOPMENT

+ - Adrenal cortex
 The adrenal cortex develops from mesodermal cells that 
lie adjacent to the urogenital
urogenital ridge. The fetal zone of the
stimulates immune
breakdown of system cortex develops first. Later, more mesodermal cells sur-
glycogen, proteins round the fetal cortex to form the permanent cortex 
and fat found
fou nd in adu
adults
lts.. At birth,
birth, the perman
permanent
ent cortex
cortex has
two layers, while a third (the zona reticularis) develops
by the third year of life. At around this time the fetal
cortex regresses until only the developed medulla and
increased less immune permanent
permanent cortex are left.
metabolite activity, fewer 
availability cytokines, less
 The zona reticularis matures around the age of 
inflammation 8 years old and begins to secrete weak androgens. This
is called
called adrenarche
adrenarche and is discussed
discussed later.

Fig. 4.1 Hormonal regulation

regulation of cortisol. (ACTH,
adrenocorticotrophic hormone; CRH, corticotrophin-releasing
hormone.) Adrenal medulla
 The adrenal
adrena l medulla is derived
derive d from ectodermal
ectode rmal neu-
ral crest cells of the embryo. They form part of the
amine precursor uptake and decarboxylation (APUD)
Blood supply, nerves and system. These cells contribute to many diverse struc-
lymphatics tures, including all the noradrenaline-secreting post-
gangl
ganglio
ioni
nicc neuro
neurons
ns in the symp sympath
atheti
eticc nerv
nervou
ouss
 The blood supply to the adrenal glands is massive and system. The secretory cells in the adrenal medulla se-
comes from three main sources: crete
crete either
either adrenal
adrenaline
ine or noradr
noradrenal
enaline,
ine, and they 
• Superior suprarenal
suprarenal arteries   – multiple branches are essentially highly specialized neurons (Fig. ( Fig. 4.3).
4.3 ).
from the inferior phrenic arteries as they pass up-  The medullary
medulla ry precursor
precurs or cells also form paraganglia
paragan glia
 ward from the abdominal aorta in the organ of Zuckerkandl located around the origin
• Middle
Middle supraren
suprarenal artery    – branch
al artery  branches
es off direct
directly 
ly  of the inferior mesenteric artery and the aortic bifurca-
 Microstructure 4

Fig. 4.2 Location and blood supply

12th thoracic vertebra inferior phrenic artery
of the adrenal glands.
adrenal
right crus medulla left crus
of the diaphragm of the diaphragm

adrenal cortex

left adrenal gland

right (cut across)
adrenal
gland
adrenal arteries
branch from
inferior phrenic
and renal arteries

left kidney
right left adrenal vein drains
kidney into the left renal vein

right adrenal vein inferior aorta renal renal artery

drains into the vena cava vein (shorter on left side)
inferior vena cava
directly

Fig. 4.3 Comparison between the

CNS derived from derived from effector  adrenal medulla and the sympathetic
neuroepithelium neural crest cells nervous system (ACh, acetylcholine;
CNS, central nervous system; NA,
noradrenaline).
preganglionic postganglionic
ACh NA
sympathetic nerve sympathetic nerve

preganglionic via
ACh NA
sympathetic nerve blood

 The blood in these sinusoids passes directly into the

MICROSTRUCTURE adrenal medulla.

Adrenal cortex Adrenal medulla

 The adult adrenal
adren al cortex
corte x makes
make s up about 90% of the  The adrenal medulla comprises two types of neuroen-
adrenal gland by weight. It is functionally and ana- docrine cell:
tomical
tomically
ly divide
dividedd into three layers,
layers, which
which secrete
secrete • Noradrenaline-secreting cells (20%)
the following groups of steroid hormone ( Figs 4.4 • Adrenaline-secreting cells (80%).
and 4
and  4.5
.5):
):
Both types contain neuroendocrine granules that store
•   Outer
Outer zona
zona glom
glomer
erul
ulos
osaa secr
secret
etes
es mine
minera
ralo
loco
cor-
r- the hormone. In older textbooks, these cells are called
ticoids chromaffin cells because they turn a dark-brown colour 
• Middle zona fasciculata
fasciculata secretes glucocorticoids
glucocorticoids if expose
exposedd to oxygen
oxygen after fixati
fixation
on in chrome
chrome salts.
•   Inner
Inner zona
zona reti
reticu
cula
lari
riss secre
secretes
tes andr
androg
ogen
enss and
and  The cells are arranged around blood sinusoids.
glucocorticoids. Medullary cells require the steroid cortisol to convert 
 These hormone groups will be explained later in this noradr
noradrena
enalin
linee to adrena
adrenalin
line.
e. Cortis
Cortisol
ol is pro
produc
duced
ed in the
 The adrenal glands

Fig. 4.4 Microstructure of the adrenal gland and the major hormones secreted in each region

Region Name Cell structure Hormones synthesized

Outer cortex Zona glomerulosa Cells arranged in clumps Mineralocorticoids
(Latin, glomerulus: little ball) (mainly aldosterone
aldosterone))
Middle cortex Zona fasciculata Cells arranged in cords Glucocorticoids
alongside blood sinusoids; (mainly cortisol)
(Latin, fasciculus: bundle)
Inner cortex Zona reticularis Network of smaller cells Glucocorticoids and
(Latin, reticularis: network) androgens (DHEA)
Centre of gland Adrenal medulla Loose network of Catecholamines
neurosecretory
neurosecretory cells (adrenaline and
surrounded by blood sinusoids noradrenaline)
DHEA, dehydroepiandrosterone.

A capsule
zona glomerulosa
zona fasciculata adrenal cortex
adrenal medulla
zona reticularis

B
cells contain large adrenal medulla
nuclei and secretory vesicles neurosecretory cells
which store catecholamine
hormones prior to their  medullary artery
release
zona reticularis smaller cells arranged in network
around sinusoids

cells contain abundant zona fasciculata

rough and smooth cells arranged in cords
endoplasmic reticulum
and cholesterol stores;
  w
these are all involved   o
   l
   f
in the synthesis of    d
  o
blood sinusoid with
  o fenestrated endothelium
steroid hormones    l
   b
   f
  o
  n
  o
   i
   t
  c
  e
  r
   i
   d

zona glomerulosa cells arranged in clumps

capsule

adrenal artery
 Glucocorticoids and cortisol 4

HORMONES OF THE ADRENAL

low blood volume
CORTEX 
+
 The adrenal cortex secretes three groups of steroid
hormones:
• Mineralocorticoids, e.g. aldosterone, deoxycortisone angiotensin II
• Glucocorticoids, e.g. cortisol
• Androgens, e.g. dehydroepiandrosterone (DHEA). +
Steroid hormones are synthesized from cholesterol.
Steroid hormones are small lipid-soluble molecules that 
adrenal
cross membranes readily. Inside cells, they act on intra-
cortex
cellular receptors to regulate gene expression. The syn- high potassium
+
thesis and mechanism of action of steroid hormones levels
are discussed in more detail in  Chapter 1.
−
aldosterone

MINERALOCORTICOIDS AND + +
ALDOSTERONE
−
sodium potassium
Regulation of aldosterone reabsorption excretion
Mineralocorticoids help to regulate the electronic bal-
ance of plasma; their name is derived from this action + +
on the body’s minerals. Aldosterone is the main miner-
alcorticoid secreted by the zona glomerulosa. Aldoste- water  lowers
rone release is stimulated by: reabsorption potassium levels
• Angiotensin II
• High plasma potassium +
•   ACTH.
 Angiotensin II is released in response to low blood vol-
raises blood
ume as part of the renin–angiotensin system (see volume
Chapter 7 and Fig. 4.6). ACTH from the anterior pitui-
tary gland is less important as a regulator, so pituitary 
failure does not severely impair aldosterone secretion. Fig. 4.6 Control of aldosterone secretion.
 An excess of aldosterone due to an adrenal adenoma
is called Conn’s disease.  Aldosterone up-regulates the expression of four genes
in the cells of the DCT and collecting duct. The actions
Actions of aldosterone of the gene products (proteins) are described in Fig. 4.7.
 Aldosterone circulates in the plasma with 60%
 Aldosterone acts mainly on the distal convoluted tubule bound to albumin and 40% free, and therefore active.
(DCT) and the collecting duct of the kidney. It causes  The high proportion of free hormone causes aldoste-
reabsorption of sodium ions in exchange for potassium rone to be rapidly degraded by the liver, giving a short 
and hydrogen ions. Water is also reabsorbed and blood half-life of about 15 minutes.
 volume is increased. Other hormones are involved in
this mechanism and they are discussed in more detail
in Chapter 7 on fluid balance.
GLUCOCORTICOIDS AND
Intracellular actions of  CORTISOL
aldosterone Glucocorticoids regulate the metabolism of carbohy-
 The adrenal glands

blood vessel
A
H+ Na+ K+

aldosterone

+ Na+/K+ ATPase

H+ Na+ K+

Na+/H+ Na+ K+
ion channel channel
exchanger 

H+ Na+ Na+ K+
nephron lumen

Fig. 4.7B Effects of proteins induced by aldosterone in the nephron

Protein Location Action Physiological response

Na+/K+ Cell membrane on the
ATPase side of the blood supply
Na+ channel Cell membrane on the
side of the nephron
K+ channel Cell membrane on the
side of the nephron
Na+/H+ ion Cell membrane on the
exchanger  side of the nephron
Active pump that increases Creates an ion
cell potassium and lowers gradient that drives
cell sodium levels the other proteins
Reabsorbs sodium from Increases plasma
the nephron lumen sodium and water to
increase blood volume
Excretes potassium into Decreases plasma
the nephron lumen potassium
Reabsorbs sodium in Makes the plasma
exchange for hydrogen ions more alkaline

Fig. 4.7 Intracellular and physiological actions of aldosterone in the nephron. Aldosterone acts to increase the levels of the
four proteins shown (A) causing the physiological responses (B).

cortisol. Cortisol also plays an important part in meta- CRH to cause ACTH release. Cortisol has a negative
bolic adaptation in response to stressful stimuli. feedback effect on the hypothalamus (inhibits CRH
During fasting, glucocorticoids act to maintain transcription) and anterior pituitary gland (inhibits
plasma glucose levels. POMC transcription) to inhibit CRH and ACTH release.
Cortisol release displays a circadian rhythm, i.e. the
rate of secretion changes through a 24-hour period
Regulation of cortisol (Fig. 4.8). The highest levels of cortisol release are in
Corticotrophin-releasing hormone (CRH) is secreted by  the early morning, peaking at about 6 a.m., then falling 
the hypothalamus and stimulates the anterior pituitary  throughout the day. This circadian variation is initiated
to produce pro-opiomelanocortin (POMC), which is in the hypothalamus by changing sensitivity to cortisol
converted to ACTH and leads to increased ACTH re- levels. Cortisol exerts a weaker negative feedback effect 
 Androgens 4

 There is some overlap between the actions of mineralo-

400 corticoids and glucocorticoids. Cortisol can have miner-
   )
alocorticoid actions and aldosterone can act as a
   L
   /
   l
  o
300 glucocorticoid.
  m
  n
   (
   l
  o
  s
   i 200
   t
  r
  o
  c
  a
  m 100
Intracellular actions of cortisol
  s
  a
   l
  p Like all steroid hormones, cortisol acts via intracellular 
breakfast lunch supper  
0 receptors to regulate gene expression. The receptor and
10 p.m. 2 a.m. 6 a.m. 10 a.m. 2 p.m. 6 p.m. genes vary between cells, and this accounts for the wide
time of day range of actions. The anti-inflammatory actions are pro-
plasma cortisol levels 24-hour mean cortisol duced by inhibiting phospholipase A 2, an enzyme that 
in resting subjects concentration in is essential for the production of prostaglandins from
stressed subjects
plasma cortisol levels arachidonic acid.
in chronically stressed subjects 24-hour mean cortisol
concentration in Most cortisol (95%) is transported round the body 
resting subjects bound to plasma proteins:
Fig. 4.8 Circadian variation in plasma cortisol in resting and • 80% bound to cortisol-binding protein
chronically stressed subjects. • 15% bound to albumin
• 5% free and active.

Actions of cortisol Cortisol is inactivated in the liver by conjugation and

then excreted from the kidney. About 1% of cortisol is
Physical andpsychologicalstressors (e.g.trauma, haemor- excreted into the urine without metabolism. This can
rhage, fever) increase ACTH and cortisol secretion, which, be detected by 24-hour urine collection to estimate
in turn, regulate metabolic adaptations to these stimuli. blood cortisol levels.
 This effect is very important, and cortisol deficiency can
rapidly become life-threatening under stressful condi-
tions. The response to stress is called the general adapta- The immunosuppressive properties of synthetic
tion syndrome (GAS), and it is divided into three phases: corticosteroids (‘steroids’, e.g. prednisolone) are
commonly employed in the treatment of autoimmune
Alarm reaction conditions and inflammatory disorders.
 A stressful stimulus causes:
• Noradrenaline release from sympathetic nerves
• Adrenaline and noradrenaline release from adrenal ANDROGENS
medulla
• Cortisol release from adrenal cortex.
 Androgens are sex steroids, i.e. hormones involved
in the growth and function of the male and female gen-
Resistance ital tract. They also stimulate muscle growth (anabo-
 The effects of cortisol are slower to initiate, as they are lism), hence their use as an illicit drug in sport.
dependent on transcription. However they are longer-  Androgens are made in the adrenal gland in both males
lasting than those of adrenaline and noradrenaline; this and females. However, in males they account for only a
allows the resistance to stress to be maintained. It also small proportion of total androgen production.
counteracts the effects of other hormones (e.g. insulin)
to maintain substrates required to combat stress.

Exhaustion Actions of adrenal androgens

Prolonged stress causes continued cortisol secretion, and  Adrenal androgens are synthesized in the zona reticularis
it results in muscle wastage, immune system suppression of the adrenal gland; the main adrenal androgens are:
and hyperglycaemia. Cortisol affects almost every cell in • Dehydroepiandrosterone (DHEA)
the body. The physiological effects are described in •   Androstenedione.
Fig. 4.9. The main actions of cortisol are:  Androgens secreted by the adrenal glands have weak bi-
 The adrenal glands

Fig. 4.11 Symptoms and signs of

hair  eyes brain
Cushing’s syndrome.
- thin - cataracts - depression
- male-pattern baldness - confusion
- insomnia
adipose tissue - psychosis
- truncal obesity
- striae (stretchmarks) face
- ‘buffalo-hump’ - ‘moon face’ (due to
increased fat deposition)
heart  - acne
- predisposes to congestive - hirsutism (male-pattern
cardiac failure facial hair)

muscles
- skeletal muscle weakness
and wasting (causes thin
arms and legs)

stomach
- peptic ulceration
kidney
- renal calculi

uterus
blood pressure - menstrual disturbances
- hypertension e.g. amenorrhoea

skin
- thin skin
- easy bruising
bones - tendency to skin infections
- osteoporosis (increased skin
- tendency to fracture pigmentation in Cushing's
- vertebral collapse (kyphosis) disease only)

blood
- glucose intolerance,
some have diabetes
ankles
- oedema

Second-line investigations: reduce immune reactions. These conditions include

• Forty-eight-hour dexamethasone suppression test: asthma, inflammatory bowel disease, rheumatoid ar-
oral dexamethasone is given every 6 hours for  thritis and post-transplantation. Patients are treated
2 days with cortisol measured at 0 and 48 hours.  with the lowest dose that will control their condition be-
In Cushing’s syndrome, cortisol levels will remain cause prolonged use can cause the features of Cushing’s
elevated. syndrome. Inhaled steroids are used in asthma to reduce
•   Midnight cortisol: this is less commonly used as it re- the systemic dose, especially in children, in whom
quires admission and is often inaccurate. Cortisol growth retardation may occur.
levels are normally lowest at midnight, though it is  A review of the patient’s medication will locate any 
elevated in Cushing’s syndrome. iatrogenic cause and, if possible, the medication needs
to be gradually stopped.
 The next step is locating the source of the problem as
this will determine the course of treatment.
Cushing’s disease
Treatment with glucocorticoids Cushing’s disease refers to the specific condition of ex-
 Disorders of the adrenal cortex 4

negative feedback that normally prevents excess ACTH Deficiency of cortisol and
release is absent in the tumour.
 This type of tumour causes Cushing’s syndrome
aldosterone
 with the additional sign of pigmented skin. This is Congenital adrenal hyperplasia (CAH)
due to the melanocyte-stimulating action of ACTH
on the receptors for the structurally similar mela-  ACTH controls the production of all the hormones in
nocyte-stimulating hormone (a-MSH) – formed by  the zona fasciculata and the zona reticularis. Cortisol
the same gene (POMC) that makes ACTH. Cushing’s is solely responsible for negative feedback on ACTH
disease occurs most frequently in young adult  production. Therefore, any deficiency in cortisol relieves
 women. the suppression of ACTH release and glucocorticoid,
Cushing’s disease is treated by surgical removal of the mineralocorticoid and androgen production are per-
pituitary adenoma. This may result in panhypopituitar- turbed. The gland tends to get larger under the trophic
ism (see Chapter 2 for more details). influence of ACTH, and the condition is referred to as
congenital adrenal hyperplasia (CAH).
One cause of CAH is an autosomal recessive defi-
Ectopic adrenocorticotrophic hormone ciency of 21-hydroxylase. This enzyme is required for 
the synthesis of aldosterone and cortisol, and both hor-
production mones are deficient. Low cortisol triggers ACTH release,
Ectopic ACTH can be secreted by the rare, but highly  resulting in hyperplasia of the adrenal cortex. Low aldo-
malignant, small-cell anaplastic carcinoma of the lung  sterone results in salt loss and neonatal shock in some
(also called oat-cell carcinoma). This carcinoma dis- babies. The enlarged adrenal cortex secretes excess an-
plays the characteristics of a neuroendocrine cell despite drogens, causing adrenogenital syndrome. This presents
developing from bronchial epithelium. Even more differently in each sex. It can cause ambiguous genitalia
rarely, tumours of the thymus, ovary, pancreas and car- in both males and females. In males, it causes early (pre-
cinoid tumors can secrete ACTH or CRH. The excess cocious) pseudopuberty; signs of secondary sexual de-
production is so dramatic that patients rarely exhibit   velopment can be found by 6 months of age, but the
features of Cushing’s syndrome before death. Ectopic child is not fertile. Early bone epiphyseal fusion causes
hormones are discussed in Chapter 10. short adult height.
In females, androgen excess causes masculinization
(also called virilization). The symptoms are similar to
Neoplasia of the adrenal cortex those found in polycystic ovarian syndrome. They in-
Benign adenoma of the adrenal cortex is relatively com- clude masculine body shape, balding of temporal skull,
mon, but only a small proportion secrete hormones. If  increased muscle bulk, deepening of the voice and
cortisol is secreted, then Cushing’s syndrome develops; al- enlargement of the clitoris. (For greater detail, see  Crash
dosterone-secreting adenomas cause Conn’s syndrome. Course Obstetrics and Gynaecology .)
 Adrenal adenomas are the most common cause of 
Cushing’s syndrome in children, but they account 
for only 10% of adult disease. In Conn’s syndrome, ad- Precocious puberty, salt-losing crisis or ambiguous
enomas of the adrenal cortex are the most common genitalia all indicate a possible diagnosis of CAH.
cause of primary hyperaldosteronism in all age groups. Plasma levels of 17-hydroxyprogesterone, which are
 Adenomas associated with either syndrome are re- raised in CAH, are used as a screen. Treatment
moved surgically, but cortisol replacement is necessary  focuses on determining the baby’s gender by
due to long-term ACTH inhibition. karotyping and replacing glucocorticoids and
Carcinoma of the adrenal cortex is a very rare condi- mineralocorticoids.
tion. Such carcinomas secrete vast excesses of glucocor-
ticoids and androgens. The patient usually dies before
the physical features of Cushing’s syndrome develop.
 The main way to localize the cause of elevated corti- Adrenal cortex insufficiency
sol is with a plasma ACTH measurement following a 48-  Adrenal cortex insufficiency tends to affect the whole
hour dexamethasone suppression test. adrenal cortex rather than specific layers. Accordingly, de-
Undetectable ACTH levels indicate an adrenal tu- ficiencies of glucocorticoids, mineralocorticoids and an-
mour, which requires imaging and further investiga- drogens occur together, although clinical effects are due
tions to locate and diagnose. If ACTH is detectable, to cortisol and aldosterone deficiency. These effects are
 The adrenal glands

Fig. 4.12 Symptoms and signs of

Addison’s disease. (ACTH, brain
- lethargy
adrenocorticotrophic hormone.)
- nausea
ECG - depression
- U waves seen after  - dizziness
T waves (V 1–V6) due
to hypokalaemia

muscles
- skeletal muscle
weakness, fatigue

intestines
- abdominal pain
- constipation
- nausea
- anorexia

adipose tissue
- weight loss
blood pressure
- postural hypotension
(shock in Addisonian
crisis due to circulatory skin
  collapse) - general increase in
pigmentation (due to
increased ACTH)

blood
- hyponatraemia
- hyperkalaemia
- hypoglycaemia
- tendency for hypercalcaemia

Suspected adrenal cortex insufficiency is investigated  An acute exacerbation of Addison’s disease is called
using the ACTH stimulation test. A synthetic ACTH an- an adrenal crisis. It is a life-threatening emergency 
alogue is injected and plasma cortisol levels are mea- caused by stressful events such as infection. Its presenta-
sured every 30 minutes. If the cortisol levels do not  tion is the same as acute adrenocortical failure.
rise sufficiently, then the disease is of the adrenal cortex 
(i.e. Addison’s disease). Acute adrenocortical failure
 This is a life-threatening condition characterized by:
Addison’s disease • Hypotensive shock 
Primary insufficiency of the adrenal cortex is called • Hypovolaemic shock 
 Addison’s disease; it is characterized by deficient  •   Hypoglycaemia.
secretion of glucocorticoids and mineralocorticoids.
It is a rare chronic condition caused by progressive de-
The inhibitory action of cortisol on ACTH release is
struction of the adrenal cortex. This destruction can re-
sult from autoimmune adrenalitis, infection (e.g. important clinically. Patients treated with long-term
tuberculosis, fungi) or tumour. Addison’s disease ‘steroids’cannotsimplystopbecauseACTHrelease,and
Intentionally left as blank
 The pancreas 5
Objectives

After reading this chapter you should:

• Know the relevant anatomy and developmental physiology of the pancreas and its ducts
• Understand the role of pancreatic hormones in the regulation of blood glucose
• Be able to explain the aetiology, symptoms, complications and treatment of diabetes mellitus
• Briefly discuss neoplasia of the endocrine pancreas.

 The pancreas is an organ with both exocrine and endo- resistance (type 2, formerly non-insulin-dependent dia-
crine functions. As an exocrine organ it is responsible for  betes mellitus). In both cases, blood glucose rises,
producing and secreting digestive enzymes; however, resulting in hyperglycaemia and dehydration caused
this chapter will focus on the endocrine functions of  by excessive urination as water follows the movement 
the gland. Specifically, the pancreatic control of blood of glucose (glycosuria) out of the body through the
glucose levels will be studied as the pancreas responds kidneys. Poorly controlled diabetes can lead to serious
to different control mechanisms than other endocrine organ damage and life-threatening complications.
organs. The pancreas secretes two very important hor-
mones that directly affect blood glucose,   insulin and
Important words:
glucagon. However, their secretion is regulated by the
Anabolism: processes that build large molecules
levels of glucose detected by the pancreas directly and
not secreted in response to hormones from the hypo- Catabolism: processes that break down large
thalamus and pituitary gland (Fig. 5.1). molecules
 The pancreas is a flattened retroperitoneal gland lo- Glycosuria: glucose in the urine
cated posterior and inferior to the stomach and between Polyuria: large volume of urine
the stomach and duodenum. The endocrine cells of the
pancreas are arranged in small clusters around the larger 
exocrine cell clusters, called acini. The endocrine clusters
are called islets of Langerhans and within them are four 
types of cells, the most abundant being the b-cells which ANATOMY 
secrete insulin. Insulin is responsible for lowering blood
glucose by various means including increasing cellular   The pancreas is a long, flat organ that lies posterior to the
uptake of glucose and converting glucose to glycogen. stomach and extends between the duodenum and
So as food enters our gastrointestinal tract, glucose is the spleen. The pancreas consists of four main parts,
absorbed into the body and the bloodstream. Insulin the head, uncinate process, body and tail (Fig. 5.2).
acts to prevent the glucose in the blood from rising  • The head lies in the C-shaped curve of the duode-
too high and thus keeps it within tightly controlled num, anterior to the inferior vena cava.
ranges. • The uncinate process is a projection from the poste-
 To prevent blood glucose from dropping too far, we rior surface of the head, forming the ‘hook’ of the
have a hormone to also raise the blood glucose, gluca- pancreas. The superior mesenteric vessels run ante-
gon. This is normally inhibited by insulin; however, rior to the uncinate process, separating it from the
falling blood glucose causes inhibition of insulin secre- head.
tion and glucagon secretion. The glucagon acts in the re- • The body and tail run anteriorly over the aorta and
 verse of many of insulin’s actions, e.g. causing glucose to left kidney and posterior to the stomach. The tail ter-
leave cells and enter the blood. minates at the hilum of the spleen. A branch of the
 The most common endocrine disorder is diabetes aorta (the coeliac trunk) lies superior and gives rise
 The pancreas

Fig. 5.1 Hormonal regulation of

blood glucose and metabolism by blood glucose
insulin and glucagon.
low high

–
glucagon insulin

catabolism fat metabolism glucose metabolism anabolism

- glycogenolysis - inhibits glucose uptake - glucose uptake - glycogenesis
- gluconeogenesis - ketone body production - glycolysis - protein synthesis
- lipolysis - inhibits anabolism - inhibits catabolism - lipogenesis

raises blood glucose lowers blood glucose

splenic stomach Blood, nerves and lymphatics

artery
 The body and tail of the pancreas are supplied by small
coeliac trunk branches of the splenic artery (largest branch of the coe-
liac trunk). The head and uncinate process are supplied
spleen
 duodenum
by the inferior and superior, posterior and anterior pan-
creaticoduodenal artery, branches of the common he-
patic artery. Blood drains from the pancreas through
3 4 the pancreatic veins. These flow into the splenic veins
2 and the portal vein, which leads to the liver. Lymph
1 drains through small nodes and vessels and into the pre-
left kidney aortic lymph nodes.
right kidney  The endocrine pancreas is controlled by hormones
mainly; however, some autonomic nerves do reach
pancreatic duct enters the pancreas. These are derived from the coeliac and su-
the duodenum perior mesenteric plexuses.
with the bile duct 1 uncinate process
2  head
3 body
4  tail
inferior vena cava aorta MICROSTRUCTURE
Fig. 5.2 Location of the pancreas in the retroperitoneal  The pancreas contains two major tissue types, exocrine
abdomen. (enzyme-secreting) and endocrine (hormone-secreting).
 The endocrine cells are arranged in spherical clusters
called islets of Langerhans within the exocrine tissue
(Fig. 5.3). Each islet has a rich network of fenestrated
Pancreatic duct capillaries; however, only 10% of endocrine cells are in-
 The digestive secretions of the pancreas are carried to the nervated by the autonomic nervous system.
duodenum along the pancreatic duct. It begins at the tail  The islets are made up of endocrine cells containing 
and travels along the length of the pancreas to the head dense secretory granules. These cells are APUD (amine
 where it intersects the bile duct to become the ampulla precursor uptake and decarboxylation) cells (see
 Examination of the diabetic patient 5

2 DM is a chronic, progressive disorder, pharmacologi- • GLP-1/Incretin mimetic – administered via injection.

cal treatment will become part of a patient’s manage- It acts to promote insulin secretion, reduces gluca-
ment at some point. Recent studies advocate intensive gon activity and slows glucose absorption in the
therapy to aggressively manage blood glucose in type gut. Given as a third-level therapy in people with
2 diabetes. a BMI  35.0 kg/m2 or where insulin administra-
tion would have occupational implications. Side
effects
effects include
include nausea,
nausea, vomiting
vomiting,, diarrhoea
diarrhoea and
Oral hypoglycaemic agents
stomach pain.
 These are the
t he front-line treatment in those patients who
still have functioning insulin secretion. A number of 
medications are available: Patients with type 2 diabetes are often treated
• Biguanides – increase peripheral glucose uptake uptake and with insulin in a similar manner to those with type
reduce glucose output from the liver. Their mecha- 1. This does not mean that they have developed
nism of action is not fully understood. Side effects type 1. Insulin treatment helps to control blood
include nausea, diarrhoea and lactic acidosis. They  glucose, which has been proven to reduce
are the first line of most treatments; the only avail- complications.
able biguanide is metformin.
• Sulphonyl
Sulphonylureasureas – stimulate
stimulate b-cells-cells by inhibi
inhibitin
ting 
g 
þ
the membra
membrane-b ne-boun
ound d K  channe
channel; l; the result
resulting 
ing 
depola
depolarizrizati
ation
on causes
causes insuli
insulinn releas
releasee side
side effect
effectss
including weight gain and hypoglycaemia. This is EXAMINATION OF THE
usually the second line of treatment. Examples of  DIABETIC PATIENT
this class of drugs are gliclazide and glimepiride.
• Acarbose inhibits intestinal enzymes, preventing the  The presentation of the patient determines the examina-
dige
digesti
stion
on of star
starch
ch,, resu
resultltin
ingg in a slow
slower er rise
rise in bloo
blood d tions that will be preformed. All newly diagnosed dia-
glucose after a meal. Side effects include flatulence betics
betics will
will underg
undergo o a series
series of genera
generall examin
examinati
ations
ons
and diarrhoea. (Fig. 5.14)
5.14) and investigations that will be checked on
• Thiazolidi
Thiazolidinedio
nediones
nes – drugs
drugs that promote insulin a regular basis as part of good clinical practice and on-
sensiti
sensitivit
vity,
y, and they are usuall
usuallyy used
used in combin
combinati ation
on going management.
 with other drugs. They are contraindicated in people Undiagno
Undiagnosedsed patients
patients with type 1 diabetes
diabetes will
 with heart failure (they cause fluid retention) or at  have a fairly typical presentation and will undergo
higher risk of fractures. They are recommended as a series of routine tests to determine the cause of 
a substitute second-line treatment instead of either  their symptoms. They are not likely to require an
metform
metformin in or sulpho
sulphonylnylure
ureas.
as. The only
only availa
available
ble gli-
gli- examination in the clinical setting unless they pre-
tazone is pioglitazone sent with an associat
associated
ed prob
problem.
lem. Possible
Possible presen-
presen-
• Gliptins,
Gliptins, also called dipeptidyl
dipeptidyl peptidase
peptidase 4 inhibi- ting
ting comp
complalain
ints
ts that
that woul
wouldd requ
requir
iree addi
additi
tion
onal
al
tors
tors (DPP-4
(DPP-4)) – relati
relativel
velyy new drudrug.
g. Their
Their mechan
mechanism ism examination:
of acti
action
on is not
not full
fullyy unde
unders rsto
tood
od and
and is thou
thoughghtt to be
as a result of increased incretin (GLP-1 and GIP) • Thrush – GU examination
levels
levels,, which
which result
resultss in inhib
inhibite
ited
d glucag
glucagon,
on, in- • Altered sensation – sensory examination
creased insulin secretion and therefore lower blood • Abdominal pain
pain – abdominal
abdominal examination
glucose. Side effects include headaches, nausea and • Palpitations – cardiovascular examination.
nasopharyngitis. Its use as an additional treatment  Undiag
Undiagnos
nosed
ed type
type 2 diabet
diabetics
ics will
will presen
presentt with
with a specif
specific
ic
afte
afterr metfo
metformrminin or sulp sulpho hony
nylu
lure
reas
as is recorecom-
m- problem and associated symptoms that will point to
mended. Currently sitagliptin and vildagliptin are the diagnosis. Possible presenting complaints and the
available for use. associated examinations:

Fig. 5.14 Examination of a newly diagnosed diabetic

General Height, weight, BMI

Cardiovascular Blood pressure, heart rate, peripheral pulses

 The pancreas

• Visual
Visual prob
problems
lems – ophthalmos
ophthalmoscopy
copy,, visual
visual fields
fields an established protocol but the current supply of tissue
and acuity  is outstripped
outstripped by demand. Our understanding
understanding of certain
• ‘Pins and needles/altered sensation – CNS examina- factors (e.g. Notch, sonic hedgehog  and
 and TGF-beta) is aimed
tion noting extent of change at devi
devisi
sing
ng a mean
meanss to crea
create
te new
new beta
beta isle
islett cell
cellss or rege
regen-
n-
• Ulcers – foot examination and peripheral
peripheral pulses erate
erate existi
existing
ng cell
cellss in vivo
vivo.. This
This coul
could
d over
overcocomeme the tissu
tissuee
• Thrush
Thrush – GU examinat
examination.
ion. shortage
shortage as well
well as immunol
immunologi ogical
cal compli
complicati
cations
ons of 
transplantation. Alternatively, the use of stem cells to
re-grow specific cells or entire organs is developing and
Hypoglycaemia in non-diabetic this could be another treatment in the future (Fig. (Fig. 5.15).
5.15).
patients
Most peop
Most people
le shou
should
ld be able
able to tole
tolera
rate
te fasti
fasting
ng for
for seve
severa
rall
days without developing hypoglycaemia. If a patient is
unable to do so then the mnemonic ‘EXPLAIN’ can be OTHER DISORDERS OF THE
useful: PANCREAS
• EX ogenous
ogenous drugs (e.g. alcohol and insulin)
• Pituitary insufficiency, growth hormone deficiency  Endocrine pancreatic neoplasia
• Liver failure or defective
defective liver enzymes
enzymes
• A ddison’s
ddison’s disease – deficiency of cortisol that raises  Tumours of the endocrine cells in the pancreas are
blood glucose levels ( A 
( A utoimmune
utoimmune causes) call
called
ed isle
islett cell
cell tumo
tumour
urs;
s; they
they are
are usua
usuall
llyy beni
benign
gn and
and sol-
sol-
• Insul
nsulin
inom
omas
as – a type
type of isle
islett cell
cell tumo
tumour
ur (see
(see belo
below)
w) itary, but they often secrete a specific hormone. Tu-
• Non-pancreatic tumour – by ectopic insulin secre- mour
mo urss are
are name
named d acco
accordrdin
ingg to the
the horm
hormon
onee they 
they 
tion or excess glucose consumption. secrete:
• Insulin
Insulinoma
omass are the most
most common
common type of islet  islet 
cell
cell tumou
tumour.
r. The excess
excess insuli
insulin
n that
that they
they secret
secretee
Diabetes, pancreatic transplants causes severe hypoglycaemic attacks, which can lead
and stem cells to coma.
 Type 1 diabetes results from autoimmune destruction of  • Glucag
Glucagono
onomas
mas are very rare
rare tumour
tumourss that
that secret
secretee
beta islet cells and type 2 can be as a result of those cells glucag
glucagon.
on. They
They are often
often asympt
asymptoma
omatic
tic,, but they 
failing to produce enough insulin to match rising resis- may cause diabetes mellitus.
tance, possibly leading to them dying out. Extremely infrequently, islet cell tumours can secrete
Understanding the molecular biology of pancreatic other hormones, such as gastrin in Zollinger–Ellison
development and the pathology of diabetes is the main syndrome. Other rare tumours can produce vasoactive
 way of advancing
advancing the management
management and possibly
possibly even intestinal
intestinal polypepti
polypeptide
de (VIP) or adrenocorti
adrenocorticotro
cotrophic
phic
treatmen
treatmentt of diabetes
diabetes.. Transpl
Transplanta
antatio
tionn of islet
islet cells
cells is hormone (ACTH).

Fig. 5.15 The action

action of leptin
leptin on
in vivo in vitro
fertility. (FSH, follicle-stimulating
hormone; GnRH, gonadotrophin-
factors which promote
releasing hormone; LH, luteinizing clonal expansion stem cell
hormone.) and maturation factors which
stimulate beta islet
differentiation

beta islet
progenitor 

factors which
promote clonal
expansion
mature beta and maturation
beta islet islet cells
progenitor 
mature beta
islet cells
injection of
 Other disorders of the pancreas 5

Metabolic syndrome/Syndrome X  and very-low

very-low-den
-density
sity lipopr
lipoprotei
oteins
ns (VLDL),
(VLDL), which
which in turn
turn
 Type 2 diabetes
diabetes is often associated
associated with hyperglycaem
hyperglycaemia, ia, lead to obesity and coronary vascular disease. Alterna-
hyperi
hyperinsul
nsulinae
inaemi
mia,
a, dyslip
dyslipida
idaemi
emia,
a, hyperte
hypertensio
nsionn and tively, as adipose tissue produces several hormones that 
central obesity (adipose tissue in an abdominal distribu- mediate insulin
insulin sensitivity, it may be obesity itself which
tion). This collection
collection of problems
problems is collectively
collectively referred creates
creates the metabo
metaboliclic syndrom
syndrome.e. Growing
Growing adipoc
adipocyteytess
to as the metabolic syndrome and is associated with an produc
pro ducee tumour
tumour necrosis
necrosis factor
factor (TNF-
(TNF-a), which
which increas
increaseses
incr
increa
eased
sed risk
risk of stro
stroke
ke and coro
corona
nary
ry heart
heart disea
disease
se,, whic
whichh insulin resistance. Adiponectin is produced by adipose
may be the result of hypertriglycer
hypertriglyceridaemi
idaemiaa or hyperinsu- tissue and decreases insulin resistance but its levels de-
linaemi
linaemia.a. There
There are several
several theories
theories about why these these crease with obesity. Whilst the identification of a single
factors cluster. Suggestions include simple genetic link- underl
underlying
ying cause
cause remains
remains elusive
elusive,, the metabol
metabolicic syn-
age, whilst others think that insulin
insulin resistan
resistance
ce is the drome
dro me serves
serves to highligh
highlightt the importa
importance
nce of treating 
treating 
initiating event, as it drives the synthesis of triglycerides other cardiac risk factors in diabetes patients.
Intentionally left as blank
 Up and coming hormones 6
Objectives

By the end of this chapter you should be able to:

• Recall the constituents of the gut–brain axis
• Describe the role of APUD cells
• Describe the action of GI tract peptides and the stimuli for their release
• Describe the structure and function of the pineal gland and the role it plays in jet lag.

 This chapter describes several tissues whose endocrine • Adiposity signals – leptin and adiponectin
functions are still being realized: • Growth – somatostatin.
• Gastrointestinal tract – secretes many hormones that   Together, these hormones and the vagus nerve consti-
regulate digestive function. Some act locally as medi- tute the ‘gut–brain axis’. This intricate system relays in-
ators, some travel through the blood to act on dis- formation to the hypothalamus and brainstem about 
tant organs energy homeostasis in the GI tract. The ‘gut–brain axis’
• Pineal gland – secretes melatonin, which regulates serves a number of functions:
circadian rhythms. • Regulates food intake and appetite
• Regulates glucose and fat metabolism
• Regulates the secretion and sensitivity of GI tract 
ENDOCRINE CELLS IN THE hormones.
GASTROINTESTINAL TRACT
Enteroendocrine cells are the product of one of the four 
THE APUD CONCEPT
stem-cell lineages that exist within intestinal epithelium
and are considered to be part of the ‘diffuse endocrine
 APUD cells are a group of endocrine cells that secrete
system’. They secrete a variety of peptides, in different 
small peptide hormones in many tissues throughout 
combinations, in response to stimuli reflecting nutrient 
the body. The name ‘APUD’ (amine precursor uptake
consumption and utilization (e.g. intestinal distension
and decarboxylation) reflects the conversion of actively 
or chemical stimuli) both locally in the intestine and
absorbed amine precursors into amino acids, which are
systemically. They potentiate or inhibit the release
used to make peptide hormones. These cells are linked
and action of each other. The main peptides will be con-
by three features:
sidered individually below but the role of these peptides
in concert is just beginning to emerge and this complex  • Appearance under an electron microscope (e.g. neu-
system may have a significant role to play in the treat- rosecretory granules)
ment of obesity and diabetes in the future. •   Biochemical pathway for amine or peptide hormone
Some GI tract peptides, e.g. vasoactive intestinal synthesis
polypeptide (VIP), cholecystokinin (CCK), gastrin, • Embryological origin is from neural crest cells,
ghrelin and pancreatic polypeptides (PP), also act as  which migrate to foregut and other locations.
neurotransmitters in the CNS and the neurons that in-  They are also called neuroendocrine cells, due to
nervate the GI tract (called the enteric nervous system). their secretion of both neurotransmitters and ‘hor-
 The following functions are regulated in the CNS by  mones’. The following cells are examples of APUD
these peptide neurotransmitters: cells:
• Biological rhythms – VIP • Islets of Langerhans cells which secrete insulin and
• Orexigenic (stimulate appetite) – ghrelin glucagon
 Up and coming hormones

• Juxtaglomerular complex that secretes renin; found Gastrin

in kidneys
• Neuroendocrine cells of the respiratory tract which Gastrin is predominantly secreted by G cells in the an-
secrete serotonin and calcitonin. trum of the stomach after a meal. It is secreted in re-
sponse to:
• Peptides or amino acids in the stomach
GASTROINTESTINAL TRACT • Vagal stimulation (i.e. parasympathetic)
• Stomach distension
PEPTIDES • Gastrin releasing peptide.

 The major peptides secreted by the GI tract are described
below. Figs 6.1 and 6.2 show the location of GI tract pep-
tide release and the major actions of four GI tract hor-
mones.Theactionsofotherpeptidesareshownin Fig.6.3.
Delivery
GI tract peptides reach their target cells via two means:
• Endocrine – via blood
• Paracrine – act locally to affect nearby cells.
Some peptides have both endocrine and paracrine func-
tions, e.g. somatostatin.
It acts to increase protein breakdown, specifically by:
• Stimulating enterochromaffin-like cells to secrete his-
tamine. This acts on histamine-2 receptors (H2)ofpa-
rietal cells in the stomach to promote the release of 
hydrochloric acid and intrinsic factor 
• Stimulating the release of hydrochloric acid directly 
through its action on the CCK receptors of parietal
cells
• Stimulating parietal cell maturation and growth of 
the mucosa
• Stimulating chief cells to secrete pepsinogen
• Stimulating pancreatic hormone secretion

liver  Hormones secreted

by the stomach
gastrin
somatostatin
stomach bombesin
enteroglucagon
gall bladder 

Hormones secreted
by the duodenum bile
Hormones secreted
secretin pancreas by the pancreas
cholecystokinin
glucose-dependent somatostatin
insulinotrophic peptide pancreatic
motilin polypeptide
bombesin

Hormones secreted
by the small intestine
coils of small intestine Hormones secreted
secretin by the colon
(jejunum and ileum)
neurotensin
substance P vasoactive intestinal
enkephalin colon peptide
VIP enteroglucagon
peptide YY
 Gastrointestinal tract peptides 6

Fig. 6.2 Major actions of four 

gastrointestinal tract hormones. (CCK,
cholecystokinin; GIP, glucose-
dependent insulinotrophic peptide.)

liver 

−
stomach
HCO3

gastrin +
secretin
gastric acid
bile
+ secretin
+
CCK pancreas
−
HCO3 insulin
+
duodenum
GIP

Fig. 6.3 The sites of secretion, stimuli for secretion and actions of the minor gut peptides

Gut peptide Site of secretion Stimulus for secretion Action of peptide

Enteroglucagon A cells in the stomach Presence of glucose and Reduces gastric acid
and L cells in the colon fat in the stomach secretion and gut motility
Bombesin P cells in the stomach Fasting Stimulates gastrin release
and duodenum
Motilin EC cells in Absence of food Speeds gastric emptying and
the duodenum in the duodenum stimulates colonic motility
Vasoactive intestinal D1 cells and neurons Gut distension Stimulates local gut secretion,
polypeptide (VIP) in the small intestine motility and blood flow
and colon
Peptide YY (related to PYY cells of Presence of Inhibits gastric motility and
pancreatic polypeptide) the colon intestinal fat acid secretion (peptide YY
is elevated in coeliac disease
and cystic fibrosis)
Substance P Enteric neurons in Cholecystokinin (CCK), Stimulates gut motility,
the small intestine 5-hydroxytryptamine (5-HT) secretion and immune
response; may have a role
in inflammatory bowel disease
Enkephalin Enteric neurons in Unknown Inhibits gut motility
the small intestine and secretion
Neurotensin N cells of the Presence of Stimulates local gut motility,
small intestine intestinal fat secretion and
immune response
 Hormones involved in fluid balance 7

afferent arteriole
Effects of angiotensin II
detects renal blood pressure  Angiotensin II has four important actions which serve to
increa
increase
se blood
blood volume
volume and pressu
pressure
re to app
approp
ropria
riate
te
 juxtaglomerular granular cells
 juxtaglomerular levels:
that release renin • Stimulating
Stimulating aldosterone
aldosterone release from the adrenal
adrenal
cort
cortex
ex,, whic
which
h acti
activa
vates
tes the
the pump
pumpss in the
the prox
proxim
imal
al tu-
tu-
extraglomerular cells
bule to increase sodium reabsorption, thereby in-
(lacis cells) that also
release renin creasing water reabsorption
• Peripheral vasoconstriction
vasoconstriction to raise blood pressure
• Stimulating sensation of thirst in
in the hypothalamus
hypothalamus
section • Inhibiting renin
renin release (negative feedback).
through  Thus angiotensin II conserves sodium and water and
DCT
raises blood pressure.
 ACE inhibitors reduce blood volume and peripheral
PCT
resistance by blocking the synthesis of angiotensin II
glomerulus by ACE. Both actions reduce blood pressure,
pressure, so these
macula drugs are useful in the treatment of hypertension and
densa
cells of PCT heart failure. ACE inhibitors also act on other sub-
Bowman's capsule
efferent strates including kinins (e.g. bradykinin), which are
arteriole thought to contribute to the hypotensive effect. Angio-
tensin II receptor blockers (ARBs) do not affect kinin
Fig. 7.5 Structure of the juxtaglomerular
juxtaglomerular complex. levels and are also used to treat hypertension. They 
(DCT, distal convoluted tubule, lying very close to the are often used when side effects from ACE inhibitors
afferent and efferent arterioles; PCT, proximal convoluted
are intolerable.
tubule.)

A persistent dry cough is a common side effect of

Effects of renin ACE inhibitors that is caused by the decreased
Renin is a proteolytic enzyme that acts on the plasma degradation of bradykinin in the lungs. Bradykinin
protein angiotensinogen which is synthesized by the is usually broken down by ACE.
liver
liver.. It cleave
cleavess this
this pro
protei
tein
n to form
form angiot
angiotens
ensinin I,
 which is then rapidly converted into angiotensin
angioten sin II
by the
the acti
action
on of angiangiot
oten
ensi
sin-c
n-con
onve
vert
rtin
ingg enzy
enzymeme Aldosterone
(ACE) which is found in vascular beds, especially in
 Aldosterone is a mineralocorticoid synthesized by the
the lungs. ACE inhibitors are a class of drug which
zona glomerulosa cells of the adrenal cortex. The main
are
are used
used to trea
treatt hype
hypert
rten
ensi
sion
on.. Thei
Theirr effe
effect
ctss are
are
stimulus for secretion is angiotensin II. Other factors
mediated by blocking the conversion of angiotensin
that inhibit the synthesis of aldosterone include hepa-
I to angiotensi
angiotensin n II by ACE.
rin, atrial natriuretic factor (ANF) and dopamine. Aldo-
sterone causes the conservation of sodium and water. It 
regulates extracellular volume and potassium levels in
Haemorrhage, dehydration, salt loss and renal
the blood. See   Chapter 4   for a complete description
artery stenosis all generate a stimulus for the of aldosterone and the associated disorders. The regula-
 juxtaglomerular
 juxtaglomer ular cells to secrete renin. In most tion and actions of aldosterone are shown in  Figs 7.2
cases, this is a useful response to conserve water. and 7.4
and  7.4..
However, in renal artery stenosis, the response is  Aldost erone receptors
rece ptors are also found in the
maladaptive and results in inappropriate sodium and colon, illustrating its importance in regulating fluid
water retention. Prostaglandins are involved in levels.
regulating the tone of the renal arterioles. Non-
steroidal anti-inflammatory (NSAID) drugs, such as Intracellular actions
ibuprofen, inhibit prostaglandins, which can lead to  Aldosterone acts on intracellular receptors in the distal
 Endocrine control of fluid balance

Effects Natriuretic peptides also cause dilation of veins, which

 Aldosterone
 Aldosterone is secreted in response potassium reduce
response to high potassium reducess preloa
preload
d on the heart
heart and therefo
therefore
re reduce
reducess
levels or low blood volume through the actions of renin cardiac
cardiac outpu
output.
t. They also cause arterial
arterial vasodilati
vasodilation,
on,
and angiotensin
angiotensin II.
II. It acts to conserve water,  which decreases vascular resistance and therefore
conserve sodium and water,
therebypreven
therebypreventin
tingg itsfurtherrelease
itsfurtherrelease bynega
by negativefeedba ck. afterload
tivefeedback. afterload on the heart; this reduces blood pressure.
pressure.

Kinins
OTHER
OTHE R HO
HORM
RMON
ONES
ES IN
INVO
VOLV
LVED
ED IN Kinins
Kinins are pot
potent
ent vasoac
vasoactiv
tivee polyp
polypept
eptide
idess formed
formed in the
THE REGULATION OF FLUID bloo
blood
d vess
vessel
elss by the
the acti
action
on of kall
kallik
ikre
rein
in on the prec
precur
urso
sor 
r 
BALANCE kininogen. They act in the kidney to:
• Inhibit
Inhibit the action
action of ADH
ADH
Natriuretic factors • Stimulate vasodilation
vasodilation in most vessels, but
but vasocon-
striction of the pulmonary vasculature
Natriuresis is the excretion of large amounts of sodium • Stimulate prostaglandin synthesis
in the urin
urine.e. Diur
Diuresi
esiss is the prod
produc
ucti
tion
on of larg
largee amou
amount ntss • Decrease sodium
sodium reabsorption.
of urin
urine.
e. Natr
Natriu
iure
reti
ticc fact
factororss have
have a diur
diureti
eticc effec
effect,
t, the
the op-
op-
posite effect of ADH, angiotensin II and aldosterone. Renal prostaglandins
 They increase sodium excretion, resulting in concomi-
tant water excretion. This causes blood volume to de- Renal prostaglandins are locally acting lipid molecules
crease and blood pressure to drop. Natriuretic factors synthesized by kidney cells. They act in the kidney to:
act as an ‘escape mechanism’ to prevent excessive water  • Inhibit
Inhibit the action of ADH and aldosteron
aldosteronee
retent
retention
ion.. Inappr
Inappropr
opriatiatee natriur
natriuresi
esiss leads
leads to a salt-l
salt-losi
osing 
ng  • Stimulate vasodilatation
vasodilatation in the kidney.
syndro
syndromeme entail
entailing
ing dehydr
dehydrati ation,
on, hypote
hypotensi nsion
on and eveneven
sudden death. Dopamine
Dopamine is an amine synthesized in the proximal tu-
Atrial natriuretic peptide (ANP) bules. It acts in the kidney to:
and br
brai
ain
n nat
natri
riur
uret
etic
ic pe
pept
ptid
ide
e (BN
(BNP)
P) • Inhibit tubular Naþ /K þ-ATPas
Inhibit tubular -ATPasee and decrea
decrease
se so-
 ANP is a polypeptide hormone synthesized and stored dium reabsorption
in atrial myocytes and released in response to cardiac • Induce
Induce renal
renal vasodi
vasodilat
latati
ation,
on, thereby
thereby increa
increasin
singg renal
renal
muscle distension due to high blood volume and fluid bloodf
bloodflow
low,, glomer
glomerula
ularr filtra
filtratio
tion
n rate,
rate, natriu
natriures
resis
is and
overlo
overload.
ad. ANP levels
levels are a goo
good d indica
indicatortor of hyperv
hypervolaolae-
e- diuresis.
mic states,
states, which
which occur
occur in condit
conditionionss such
such as conges
congestiv
tivee
heart failure. A more sensitive diagnostic indicator of 
heart failure is BNP and NT-pro-BNP (which is a bypro- DISORDERS
DISOR DERS OF FLUID BALANCE
duct of BNP synthesis). These are synthesized by the
 ventricles (and also the brain, where they were discov-  A deficiency of water is called dehydration, which may 
ered). Serum natriuretic peptides (especially BNP and or may not be accompanied by sodium deficiency. The
NT-pro-BNP) should be measured in any patient with causes and effects of dehydration are shown in Fig. in  Fig. 7.6.
7.6.
clinical signs and symptoms of heart failure. The serum  An excess of water is called fluid retention,
retention, which may 
level helps to guide management and dictates the sever- or may may not
not be acco
accompa
mpaninied
ed by an excess
excess of sodi
sodiumum.. The
ity
ity of hear
heartt fail
failur
ure.e. Seru
Serumm leve
levels
ls of BNP
BNP in part
partic
icul
ular cor- caus
ar cor- causes
es and
and effec
effects
ts of flui
fluid
d retent
retentio
ion
n are
are shown
shown in FiFig.
g. 7.
7.7
7.
relate closely with prognosis in patients with congestive
heart failure. Intravenous fluid replacement in patients otherwise
 The main actions of natriuretic peptides are to stim-
unable
unable to acquire
acquire fluids is essential.
essential. Normal daily fluid
ulat
ulatee natr
natriu
iure
resi
siss and
and diur
diuresi
esiss by thethe kidn
kidney ey whic
which h
requirements (2400 mL) must be maintained and, in
lowers blood pressure. They do this by:
addition, extraordinary losses from haemorrhage,
• Incr
Increa
easi
sing
ng the
the glom
glomererul
ular
ar filt
filtra
rati
tion
on rate
rate.. This
This is
vomit or other causes must be restored. The principal
brought about by vasodilation
vasodilation of the afferent
afferent arteriole
arteriole
fluid categories are crystalloids, colloids and blood
and vasoc
vasocononstr
strict
ictio
ionn of the effere
efferent
nt arteri
arteriol
olee of the glo-
glo-
merul
merulus,
us, increa
increasinsingg hydros
hydrostat
tatic
ic press
pressur
uree in the capsul
capsulee products. Crystalloids include normal saline (0.9%),
• Decreasing
Decreasing sodium
sodium and water reabsorption
reabsorption by the which is used to replace water and sodium but long-
 Disorders
Disorders of fluid balance 7

Fig. 7.6 Causes and effects of dehydration

Deficient sodium Deficient water 

and water 

Cause Deficient input Decreased ingestion, Unable to find water,

e.g. unconscious hypothalamic
hypothala mic thirst
disorder 
Excess output Diarrhoea, vomiting, Diabetes insipidus
burns, haemorrhage, and mellitus
aldosterone deficiency
Effect  Plasma osmolarity No change Raised
Symptoms Thirst, postural dizziness, weakness, collapse,
headache, apathy, confusion, coma
Signs Hypotension, tachycardia, slow capillary refill,
Hypotension,
reduced skin turgor, cool peripheries, sunken eyes,
dry membranes, weight loss

Fig. 7.7 Causes and effects of fluid retention

Excess sodium and water  Excess water 

Cause Excess input Excess fluid transfusion Excess drinking,

e.g. psychological or iatrogenic
Deficient output Cardiac, re
renal or
or he
hepatic failure Renal hy
hypoperfusion – cardiac,
hepatic, renal causes or SIADH
Effect  Plasma osmolarity No change, oedema Decreased, no oedema
Symptoms Swelling of extremities or  Drowsiness, confusion, nausea,
abdomen, dyspnoea, weight gain vomiting, anorexia, muscle
weakness, headache, apathy,
fits, coma
Signs Hypertension, raised JVP,
Hypertension, As above
displaced apex beat, ascites,
peripheral pitting oedema
 JVP, jugular venous pressure.
Intentionally left as blank
 Endocrine control of 
calcium homeostasis 8
Objectives

By the end of this chapter you should be able to:

• Describe what happens when blood calcium levels rise and fall
• Describe the actions of the hormones responsible for maintaining calcium homeostasis
• Recall the aetiology, signs, symptoms, investigations and management of disorders of calcium
homeostasis
• Define osteoporosis and osteopenia and recall the risk factors for developing osteoporosis
• Describe the principles of management of osteoporosis.

Hormones play an important role in the regulation of 

several mineral ions, notably calcium, phosphate and
magnesium. Calcium is a cofactor for enzymatic reac-
tions, a common intracellular signalling molecule and
is essential for nerve conduction and skeletal, cardiac
and smooth muscle contraction. It is also required for  calcium
the release of neurotransmitters and both endocrine
and exocrine hormones. Serum calcium levels must  Reabsorption: when substances are reclaimed from the
be tightly regulated to maintain these processes and pre-
 vent complications such as cardiac arrest. Hormones
serve to maintain calcium homeostasis through their ac-
tions on the uptake of calcium in the intestines, release
of calcium from the bone and excretion of calcium
through the kidneys.
Blood calcium levels are regulated by three hor-
mones (Fig. 8.1):
• Parathyroid hormone (PTH) – raises blood calcium
levels
• Calcitonin – reduces blood calcium by increasing ex-
cretion of calcium
• Vitamin D3  and its metabolite calcitriol – raise cal-
cium intake from the gastrointestinal tract.
Blood calcium levels in the extracellular fluid (ECF)
are kept within a very narrow range to maintain nor-
mal physiological processes. The two main hormones
responsible for this are PTH and calcitonin which have
opposing actions. They act on the free, ionized calcium
in the blood. Calcium-sensing receptors on the para-
thyroid cells monitor serum calcium and release PTH
in response to falling serum calcium levels. PTH has
three target organs: the intestine, bone and kidneys.
 These effector organs act to increase serum calcium
in response to PTH. An excess or deficiency of this
ho hy d hy lc
Important words:
Hyperparathyroidism: an excess of parathyroid
hormone
Osteoclast : a cell that breaks down bone, releasing
Osteoblast : a cell that lays down bone using calcium
kidney tubule after being filtered out of the blood.
THE ROLE OF CALCIUM
Calcium is a mineral obtained from the diet and ex-
creted by the kidneys. Ninety-nine per cent of the total
body calcium is in bone. The remaining 1% can be ex-
changed freely between plasma and the extracellular 
and intracellular compartments.
Calcium is essential for:
• Bone mineralization, acting in concert with phos-
phate ions (PO4–)
• Skeletal, cardiac and smooth muscle contraction
• All processes that involve exocytosis, including syn-
aptic transmission and hormone release
• Enzymatic reactions
• Intracellular signalling.
 The processes requiring calcium are described in
Fig. 8.2.
Forty per cent of serum calcium is bound to albumin,
a further 10% is bound to other proteins and the rest is
in an unbound ionized form. Unbound ionized cal-
cium (Ca2 þ) is physiologically active and is the only 
onent of blood calci under direct influ
 Endocrine control of calcium homeostasis

balance, only 20% of the dietary calcium is absorbed.

↑ blood  Absorption is influenced by:
calcium • Diet – lactose in milk increases absorption; phytic
+ + acid in brown bread, tannins and caffeine in tea de-
−
+ crease absorption
• Age – absorption is increased in the young and de-
PTH vitamin D creased in the elderly 
calcitonin +
secretion activation • Hormones – vitamin D increases absorption
• Pregnancy and lactation – both increase absorption.
−
+
+
Calcium balance
↓ blood
calcium Calcium balance is calculated as absorbed calcium mi-
nus excreted calcium. This balance is affected by age and
some diseases:
Fig. 8.1 Hormonal regulation of blood calcium by parathyroid
hormone (PTH), vitamin D and calcitonin.
• Children usually have a positive calcium balance;
this allows bones to grow.
calcium which is most important. Normal levels are • In adults, input and output should be the same.
1.0–1.25 mmol/L. • Postmenopausal women tend to have a negative cal-
 The amount of ionized calcium is affected by: cium balance (i.e. calcium is lost).
• Blood pH – calcium binding is reduced by low pH (ac-
idosis) and increased by high pH (alkalosis). This in-
creases and decreases free ionizedcalcium, respectively.
Calcium in the blood
Calcium levels must be maintained within tight limits
and the normal range of total serum calcium is 2.12–
MECHANISMS INVOLVED IN 2.65 mmol/L. Dietary intake is variable, so the body 
CALCIUM HOMEOSTASIS must be able to adapt to increased or reduced plasma
calcium. Calcium regulation involves the loss or gain
of calcium via three tissues: kidneys, intestines and
Calcium intake bones.
 The recommended daily allowance (RDA) of calcium is  The movements and distribution of calcium in the
1 g for normal adults, 1.2 g for pregnant women. If an body are shown in  Fig. 8.3. The movements are regu-
individual is effectively maintaining the calcium lated by the three hormones discussed below.

Fig. 8.2 Processes that require calcium

System Role of calcium

Bone formation Calcium is a vital mineral component of bone; it
makes the bone strong and rigid
Blood clotting Many clotting factors are activated by calcium
Muscle contraction Calcium binds to troponin, which allows myosin to bind
to actin
Intracellular  Calcium regulates the activity of a number of intracellular 
signalling proteins in response to the second messenger IP 3
Nervous system Calcium is essential for membrane potential and
depolarization; synapses use calcium to release
neurotransmitters
Endocrine system All processes that involve exocytosis (e.g. hormone
secretion) require calcium
 Endocrine control of growth

stress sleep hypoglycaemia

epiphysis

− + epiphyseal
growth plate

growth-hormone
releasing hormone growth-hormone
inhibiting hormone
diaphysis

hypothalamus −
+

Fig. 9.2 The regions of a growing bone.

growth
anterior 
hormone
pituitary Growth actions
gland
 The increase in protein synthesis caused by the meta-
bolic effects of IGF hormones causes cells to grow. This
stimulates cell division and maturation, causing organs
liver  and soft tissues to enlarge.
 The growth of the long bones depends on the
insulin-like
growth factors
state of the epiphyseal growth plate. This is a layer of 
chondrocytes (cartilage cells) located between the
end (epiphysis) and shaft (diaphysis) of the bone
(Fig. 9.2). Before puberty, IGFs stimulate these chon-
drocytes to grow, divide and mature into osteocytes
stimulates growth and
fusion of the growth
(bone cells), allowing the bone to lengthen whilst 
stimulates anabolism maintaining a population of chondrocytes in the plate
plate of long bones
causing cell growth
for further growth. During puberty, IGFs and sex ste-
and division
roids stimulate the chondrocytes within the plate to
Fig. 9.1 Hormonal regulation of growth hormone.
mature into osteocytes so that the epiphysis and diaph-
 ysis become fused together. The bone is no longer able
to lengthen with further IGF stimulation so final adult 
GH exerts most of its effects via IGFs. GH promotes height is reached.
their synthesis, mainly in the liver but also in other 
tissues.
GH is transported in the blood bound to GH- Other growth factors
binding protein. It acts via G-protein and Janus kinase
Growth in specific tissues is also stimulated by a number 
(JAK) receptors on the cell surface of the target cells.
of growth factors, many of which are small peptides that 
act in a paracrine (local) manner. Their relationship to
Insulin-like growth factors GH is not known. The actions and secretion of several
such peptides are described in Fig. 9.3.
Insulin-like growth factors (IGFs or somatomedins) are
polypeptide hormones that exist in two forms: IGF-1
and IGF-2. They resemble insulin in structure and they 
act via similar receptors. IGF-1 is more important as a
stimulator of growth. It is transported in the blood by 
INDIRECT CONTROL OF
a number of IGF-binding proteins. HORMONES
Many factors apart from GH control growth,
Metabolic actions including:
Both IGF hormones have some insulin-like actions, e.g. • Genetics – tall parents often have tall children
increasing amino acid uptake and protein synthesis. • Adequate nutrition – however, excess nutrition does
 Determination of height 9

Fig. 9.3 The secretion of growth factors and their effects

Growth factor  Mode of Action on growth and development Method and control of secretion
delivery
Nerve growth Paracrine Induces neuron growth and helps to Secreted by cells in path of growing axon;
factor (NGF) guide growing sympathetic nerves to regulation of secretion not yet understood
organs they will innervate (may also act
on the brain and aid memory retention)
Epidermal Paracrine and Promotes cell proliferation in the Secreted by many cell types, i.e. not only
growth factor  endocrine epidermis, maturation of lung epidermal cells (EGF is also found in
(EGF) epithelium and skin keratinization breast milk); regulation of secretion
not yet understood
Transforming Paracrine Stimulate growth of fibroblast cells; Secreted by most cell types but especially
growth factors TGF-α acts similarly to EGF; TGF-β platelets and cells in placenta and bone;
(TGF-α, TGF-β) especially affects chondrocytes, regulation of secretion not yet understood
osteoblasts and osteoclasts
Fibroblast Paracrine Mitogenic effect in several cell types; Secreted by most cell types; regulation of
growth factor  may induce angiogenesis (formation of secretion not yet understood
(FGF) new blood vessels), which is essential
for growth and wound healing
Platelet-derived Paracrine Potent cell-growth promoter; Secreted by activated blood platelets during
growth factor  chemotactic factor (involved blood vessel injury
(PDGF) in inflammatory response)
Erythropoietin Endocrine Stimulates the production of Secreted by the kidney in response to falling
erythrocyte precursor cells tissue oxygen concentration

Interleukins Autocrine IL-1 stimulates B-cell proliferation and IL-1 is secreted by activated macrophages;
(IL) (33 known) and helper T cells to produce IL-2; IL-2 IL-2 is secreted by activated helper T cells
paracrine autoactivates helper T cells and
activates cytotoxic T cells

Other hormones Fetal growth

Growth problems can be caused by the abnormal secre- In the fetus, a hormone called placental lactogen is se-
tion of a number of hormones, including: creted from the placenta. It stimulates fetal cartilage de-
 velopment and acts in a similar manner to prolactin on
•   Insulin
the maternal mammary glands.
• Antidiuretic hormone (ADH)
 Thyroid hormones are essential for the development 
• Parathyroid hormone and vitamin D
of the skeleton and CNS. A deficiency in the fetus or ne-
•   Cortisol
onate results in cretinism.
• Sex steroids.

Thyroid hormones Puberty

 Thyroid hormones, described in  Chapter 3, stimulate Sexual maturation and the pubertal growth spurt are de-
cell metabolism, promoting cell growth and division, scribed later in this chapter.
especially in the skeleton and developing central ner-
 vous system (CNS). Thyroid hormones also stimulate
GH secretion from the pituitary. DETERMINATION OF HEIGHT
Cortisol is described in Chapter 4; it inhibits pituitary 
GH secretion, so chronic ill health or stress can suppress  A person’s final height is determined simply by the rate
growth. and duration of growth.
 Endocrine control of growth
Complete fusion occurs between 18 and 20 years of age
in males, and earlier in females.
Fusion of the epiphyseal plates is stimulated primar-
ily by GH and sex steroids; however, thyroid hormone
also promotes this effect. A simple increase in GH dur-
ing puberty is not sufficient to increase final height since
bones simply mature faster and stop growing.
Only the bones that grow in this manner are pre-
 vented from responding to further GH. The jaw and
skull can continue to grow past puberty; this effect is
seen in GH excess. Ultimately, height is determined
by multiple genetic factors.
Short stature, defined as a height less than the third
centile, is associated with poor academic achievement
and anxiety. Growth rates less than the 25th centile
will result in a child dropping down centiles on a
growth chart. Short stature can be primary, secondary
or idiopathic. Primary disorders reflect an intrinsic
bone defect and include achondroplasia and some
causes of intrauterine growth retardation. Secondary
disorders occur in the presence of other factors that
limit bone growth. Malnutrition, chronic disease and
endocrine disorders, such as Cushing’s, can also be
secondary causes. Idiopathic short stature is the most
common cause of short stature and is a variant of
normal.
DISORDERS OF GROWTH
Excess of growth hormone
Excess GH prior to epiphyseal fusion causes gigantism,
proportional abnormal growth. Since the epiphyses
also fuse at an earlier age, the child may have an unre-
markable height in adulthood. Diabetes is very com-
mon in this group because of the opposing actions of 
insulin and GH on blood glucose.
 An excess of GH is slightly more common in adults,
 where it manifests as acromegaly (prevalence approxi-
mately 60 per million). The signs and symptoms are
shown in   Fig. 9.4. The long bones can no longer  ciency is subcutaneous injections of recombinant hu-
lengthen, so there is no increase in height. However,
the soft tissues and other bones can still grow, causing 
the distinctive features of this condition (Fig. 9.5). Acro-
megaly is a serious condition, associated with an increase
in mortality from cardiovascular disease, respiratory dis-
ease and malignancy. A therapeutic reduction in plasma
GH is effective in reducing this excess mortality.
GH-secretion pituitary adenomas are the most com-
of acromegaly should therefore include demonstration
of excess GH, localization of the tumour, global assess-
ment of anterior pituitary function and assessment of 
metabolic and structural complications.
Diagnosis
Excess GH can be diagnosed by high IGF-1 levels, but 
the best test is to measure GH levels following an oral
glucose tolerance test. GH levels should fall with the
rise in glucose. Computed tomography (CT) or mag-
netic resonance imaging (MRI) scans can be used
to confirm the presence of a functional pituitary 
adenoma.
Treatment 
 The mainstay of treatment is surgical removal of the
tumour. At 3 months post-op, a day curve of GH levels
is measured (4–5 samples, aiming for a mean GH
>5 mU/L) or a repeat oral glucose tolerance test 
(OGTT), measure IGF-1, and do pituitary function tests
to rule out hypopituitarism.
 Additional treatments may be needed if surgery 
is unsuccessful. These include somatostatin/GHIH
analogues, recombinant GH analogue (acts as a GH
receptor antagonist) and radiotherapy.
Deficiency of growth hormone
 The deficiency of GH in children is called dwarfism. It is
detected by short stature along with either:
• Dropping between growth chart centiles (i.e. not fol-
lowing the expected course)
• Being significantly shorter than mean parental
height (MPH).
 The most common cause of dwarfism is a deficiency 
of GHRH from the hypothalamus; craniopharyngiomas
can also be responsible. See Chapter 2 for more details.
Diagnosis and treatment 
GH deficiency is diagnosed using a stimulation test.
Impaired GH rise is seen after sleep, hypoglycaemia in-
duced by IV insulin (used less often because of risks) or 
an arginine stimulation test. The treatment for GH defi-
man growth hormone (rhGH) before sleep each night.
Genetic short stature
Children can be short as a consequence of genetics
without pathological correlates. These children have
short parents and they start growing below the 5th
centile but at a normal rate with a normal age

 The increase in growth is caused by increased GH and
sex steroid secretion. Sex steroids also cause bone mat-
uration. As the bones mature, the growing plates
(epiphyses) fuse, preventing further growth. This fusion
occurs 2 years earlier in females, giving males an extra
2 years of growth. This largely accounts for the increased
height of adult males.
Puberty in the male
Puberty usually occurs between 9 and 14 years of age
in boys; however, it is considered normal if it occurs
between 9 and 16 years of age. Once the testes have
developed, male pubertal changes are brought about  larynx, cricothyroid cartilage and laryngeal muscles en-
by the secretion of androgens such as DHT and
testosterone.
Testes development and early puberty
Growth of the testes from <2 mL to >4 mL is often the
first sign of puberty noticed in boys around 12 years.
 The increase is mainly due to proliferation of the semi-
niferous tubules under the influence of FSH. LH stimu-
lates the interstitial Leydig cells to secrete testosterone.
 The scrotum becomes larger, thicker and pigmented;
pubic hair growth follows.
Spermatogenesis begins once the testes have en-
larged and matured and is associated with a rise in se-
rum inhibin B. Nocturnal emissions and daytime
ejaculations are often around 13–14 years of age at stage
3 of Tanner’s male genital staging, with fertile ejacula-
tions around 15 years.
HINTS AND TIPS
Clinically, male puberty has begun when the
testes reach 4 mL. This is measured with an
orchidometer.
Penile development and late puberty
 The penis begins to enlarge after the testes about the
same time the growth spurt is noticed. The penis dou-
bles in size during puberty to reach an average size of 
9.5 cm flaccid or 13.2 cm erect.
Klinefelter’s syndrome (XXY) is associated with small
testicles, abnormal spermatogenesis and infertility. The
syndrome is also associated with delayed motor 
learning. Treatment is with testosterone. Women with
Turner’s syndrome lack part of the X chromosome (or a
Puberty 9
development and acquisition of normal secondary
sexual characteristics. These women are often
amenorrhoeic, infertile and have abnormal breast and
pubic hair development. Treatment is with oestrogen
to promote sexual development and growth hormone
to encourage growth.
Facial and axillary hair growth usually starts at about 
15 years of age. The sebaceous glands in the skin are also
activated, often causing acne.
 The breaking of the voice is also a late feature. The
large to give an Adam’s apple.
HINTS AND TIPS
Tanner’s staging is used to assess puberty milestones
and compare individuals. The stages are based on testis,
scrotum and penile growth and pubic hair in males:
Stage 1: height increases 5 cm per year, no pigmented
pubic hair, testes volume < 4 mL, no penis growth.
Stage 2: height increases 5 cm per year, small amount
of pigmented pubic hair, testes volume 4–6 mL,
increased penis dimensions. Stage 3: height increases
7.5 cm per year, darker pubic hair, testes volume
8–10 mL, increased penis dimensions. Stage 4: height
increases 10 cm per year, testes volume 14–16 mL,
increased penis dimensions, adult pubic hair quality.
Stage 5: adult pubic hair distribution, testes volume
18–25 mL, maximum height reached, mature penis
size reached.
Additional changes: axillary hair, increased muscle
mass, voice breaks.
Puberty in the female
Puberty in females usually occurs between 8 and
13 years of age in girls; however, it is considered normal
between 8 and 15 years of age. The changes caused by 
oestrogens and progesterone are shown in Fig. 9.6.
Breast development and early puberty
 The development of breast buds is often the first sign of 
puberty noticed in girls. The breast then continues to
grow under the influence of oestrogen while the ductal
system develops; the number of lobules remains the
 Endocrine control of growth
Fig. 9.6 The changes caused by oestrogen and progesterone during female puberty
Oestrogen-mediated changes
Fat deposition and proliferation of the
ductal system in the breasts, causing
growth
Growth of the vagina and maturation
of the epithelium
Growth of the clitoris
Menarche and late puberty
 The uterus begins to enlarge after the development of 
pubic hair. The onset of menstruation (periods) is called
menarche. The mean age of menarche is 13 years, mak-
ing it a late feature of puberty. In the ovary, follicular  elevated. Stage 3: juvenile smooth stage with further
development begins and the first ovulation occurs
10 months after the first menarche, on average, i.e.
the early menstrual cycle are often anovulatory and
infertile.
Tanner’s stages and the female
In the female, the stages are based on breast and pubic
hair development.
Progesterone-mediated changes
Proliferation of the secretory lobules and
acini in the breast
Contribution to vaginal and uterine
growth
Initiation of cyclical changes in
endometrium and ovary
Breast development 
Stage 1: preadolescent, only papillae are elevated. Stage
2: breast bud develops with papillae and breasts
 
growth of breasts and areolae. Stage 4: areolae and
papillae project above the breasts. Stage 5: adult pattern
with areolae on the same level as the rest of the breasts.
Pubic hair development 
Stage 1: preadolescent, no pubic hair. Stage 2: sparse
hair on labia majora. Stage 3: darker, coarser and curlier 
hair, spreads over pubis. Stage 4: adult-type pattern
but covers smaller area. Stage 5: adult pattern.
 Endocrine disorders of 
neoplastic origin 10
Objectives

By the end of this chapter you should be able to:

• Describe the theories of MEN tumour formation
• List the common tumours associated with each of the MEN syndromes
• Describe the theories behind ectopic hormone secretion
• List tumours that secrete hormones ectopically, along with the relevant tumour 
• Understand carcinoid tumours and carcinoid syndrome.

Endocrine organs can undergo neoplastic change and MEN-I (Werner’s syndrome)
non-endocrine organs can acquire an endocrine pheno-
type as a result of neoplastic change. When several dif-  The most common tumours are:
ferent endocrine tumour types affect a single individual • Parathyroid hyperplasia – most common
they are usually part of a multiple endocrine neoplasia • Pancreatic islet cell tumours/duodenal tumours
(MEN) syndrome. These syndromes result when several • Pituitary adenoma (secrete growth hormone, prolac-
endocrine disorders, share a common genetic basis. tin or ACTH).
 There are three patterns, referred to as MEN-I, MEN-IIa  The pancreatic islet cell tumours may secrete ectopic
and MEN-IIb. These syndromes are rare, but they can hormones (e.g. glucagonoma or insulinoma) and
cause tumours in young adults. They are usually inher- the duodenal tumours may secrete gastrin causing 
ited and genetic testing can be used to determine the risk  Zollinger–Ellison syndrome. Thirty per cent of the very 
in family members. rare Zollinger–Ellison tumours are caused by MEN-I.
Other endocrine syndromes are caused when tissues
outside the endocrine system give rise to ‘ectopic’ hor-
MEN-1 is caused by loss-of-function of a tumour 
mone-secreting tumours. These tumours can present 
 with symptoms pertinent to the hormone that is being  suppressor gene, the  MEN-I  gene, which produces a
secreted. protein that regulates cell proliferation. Patients
typically have a germline mutation in one allele and
acquire somatic mutations in the other allele. MEN-II
syndromes are caused by gain-of-function mutations in
MULTIPLE ENDOCRINE the RET   proto-oncogene. The precise genetic location
NEOPLASIA SYNDROMES of this mutation determines the exact phenotype. If
family members test positive for these mutations, they
MEN syndromes are clusters of endocrine tumours that  can be treated with prophylactic surgery.
often occur in the same patient. The tumours are rare,
usually aggressive and arise in multiple tissues; they oc-
cur earlier than single sporadic tumours. The underlying  Less commonly, MEN-I is associated with:
cause is probably genetic, since these syndromes are • Parathyroid adenoma
usually inherited in an autosomal dominant fashion al- • Hyperplasia of thyroid parafollicular cells
though some cases are sporadic. • Adrenal cortical hyperplasia.

MEN syndromes are rare, but they may be life-

MEN-IIa (Sipple’s syndrome)
threatening.  The main tumours of the MEN-II syndrome are:
• Phaeochromocytoma (often bilateral)
 The menstrual cycle 11

Fig.
Fig. 11.6
11.6   Synthesi
Synthesiss of oestro
oestrogen
genss by
thecal
the developing follicle. (FSH, follicle-
cell
cholesterol LH FSH stimulating hormone; LH, luteinizing
hormone.)
+

pregnenolone

nucleus

androgens

diffusion through the

basement membrane

granulosa
cell
androgens

+
(aromatase)

nucleus
oestrogens

circulation

During menstruation, LH and FSH levels rise as oes- shown in Fig. 11.5.
11.5. It is compos
composed
ed of seven
seven laye
layers.
rs. From
From
trogen
trogen and pro proges
gester
terone
one pro
produc
ductio
tion n subsid
subside.e. As its the inside out these are as follows:
name
name implie
implies,s, FSH stimul
stimulates
ates severa
severall antral
antral (secon
(secondar
dary)y) • Primary oocyte
oocyte – the female gamete, arrested in first 
follicles to mature. Cell cooperation between the gran- meiotic prophase
ulosa cells and the thecal cells allows oestrogen produc- • Zona
Zona pelluc
pellucida
ida – a glycop
glycoprot
rotein
ein layer
layer that
that surrou
surrounds
nds
tion to begin and for the next 12 days oestrogen levels the oocyte like an egg shell
rise exponentially. Most of the oestrogen output is from • Granulosa cells – cuboidal cells surrounding
surrounding the oo-
the dominant follicle. cyte; they secrete oestrogens
 The oestrogens stimulate synthesis of LH receptors in • Antru
Antrum m – fluid
fluid-fi
-fill
lled
ed cavi
cavity
ty withi
within
n the
the gran
granul
ulosa
osa cell
cellss
the granulosa cells and growth accelerates. With the LH • Basement membrane/lamina
surge, usually only one follicle will be released (the • Theca interna
interna – a layer of stromal cells
cells that secrete
dominant follicle). The other follicles regress (a process androgens
called atresia). • Theca externa
externa – a non-secretory
non-secretory stromal
stromal cell layer.
layer.
Oral contracept
contraceptives:
ives: administr
administration
ation of synthetic
synthetic
oest
oestro
roge
gen
n and/
and/oror prog
proges
esto
toge
gen
n thro
througughh the
the firs
first 
t 
half
half of the menstr
menstrualual cycle
cycle preven
prevents
ts FSH
FSH secret
secretio
ion.
n. This
This Endometrial changes
prevents
prevents follicul
follicular
ar growth
growth so that ovulation
ovulation cannot 
 Hormones of the reproductive system

Fig. 11.7 Actions of oestrogens

oestrogens and
oestrogens progesterone
progesterone.

brain brain
- hypothalamic and - hypothalamic and
pituitary feedback pituitary feedback
- raises basal
body temperature

breasts breasts
- growth and development - development of the
- fat deposition   milk-producing
  lobules
fat 
- deposited on hips

uterus
- growth uterus
- regrowth of - secretion by
functional endometrium uterine glands
- maintains functional
uterine tubes
  endometrium
- increase
i ncrease secretion and cilia
- inhibits contractions
  action
- increase motility
uterine tubes
cervix - increases secretion
- make cervical mucus
receptive to sperm
cervix
- makes cervical
vagina
mucus hostile
- growth
to sperm
- maturation of epithelium
- production of glycogen

bones
- growth
- fusion of epiphyses

During the menstrual phase (days 1–4) the ischaemic turn turnss from
from nega
negatitive
ve to posi
positi
tive
ve and
and the very
very high
high oestr
oestro-
o-
and necrotic functional layer of the endometrium is gen gen leve
levels
ls caus
causee a dram
dramatatic
ic surg
surgee in the
the rele
releas
asee of LH and,
and,
lost
lost.. This
This slou
slough
ghed
ed tiss
tissue
ue pass
passes
es out
out of the
the vagi
vagina
na,, alon
along 
g  to a less
lesser
er exte
extent,
nt, FSH.
FSH. LH caus
causes
es the foll
follic
icle
le to comp
complelete
te
 with blood from the degenerating spiral arteries. the first meiotic division and rupture through the ger-
 The proliferative phase (days 4–13) is caused by the minal epithelium – a process called ovulation. The sec-
rising oestrogen levels. These stimulate cells in the basal ondary oocyte and its first polar body are released into
layer of the endometrium to proliferate and form a new  the peritoneal cavity; they are surrounded by the zona
functional layer. Glands are formed in this layer but  pellucida and a few granulosa cells. The released oocyte
they are not yet active. is swept into the uterine tubes by the wafting action of 
 The rising oestrogen
oestrogen also stimulates
stimulates secretion
secretion of a the cilia of the fimbriae.
 watery cervical
cervical mucus that facilitates
facilitates sperm transport 
transport 
acro
acrossss the
the cervi
cervix.
x. At other
other times
times,, the mu
mucu
cuss is scan t  The second half of the cycle
scant 
and thick.  The second half of the cycle is the time between ovula-
tion and menstruation; the average length is 14 days
Ovulation and this
this remain
remainss consta
constant
nt despit
despitee change
changess in cycle
cycle
 The menstrual cycle 11

Phases of female reproductive cycle

Menstrual Preovulatory phase Ovulation Postovulatory phase

Days 0 phase 5 10 14 28
22

LH

Progesterone
  n
  o
   i
   t
  a
  r
   t
  n
  e Oestrogens
  c
  n
  o
  c FSH
  e
  n
  o
  m
  r
  o
   H

preantral antral preovulatory ovulation corpus luteum corpus albicans

follicle follicle (Graafian) follicle

primary follicles ovarian

cycle
Follicular phase (1–13) Luteal phase (15–28)

progesterone
and oestrogens
oestrogens

 s e
  h a
 p
 r 
 y
y
 e t o
 r e
 o
 s e c

 s e
  h a
 p endometrial
 v e
 v
m  
 
 e
e a  i
   t
 r a
menstrual
e  n    
 f
f
s  t  r  
u  a  
 o  l  i
 p r o
cycle
functional t  i   
o  n  
endometrium
basal
endometrium

Days 0 4 13 22 28
Menstrual Proliferative Secretory Late secretory
phase phase phase phase

necrotic functional endometrium endometrial glands endometrial glands

endometrium and glands regrow start to secrete become tortuous
from previous and full of glycogen-
cycle is shed rich secretion
shedding begins to
appear in the absence
of progesterone

Fig. 11.8 The hormonal, ovarian and endometrial changes during

during the menstrual cycle. (FSH, follicle-stimulating hormone; LH,
 Hormones of the reproductive system

Ovarian changes Other ovarian hormones

 The LH surge continues to act on the granulosa and
Inhibin and activin
theca cells in the empty follicle once ovulation has oc-
curred. The cells change and become yellow. They are Inhibin and activin are polypeptide hormones secreted
now called lutein cells (lutein means yellow, hence by the granulosa cells of the ovarian follicles. Inhibin in-
the name ‘luteinizing’ hormone) and the rump of the hibits pituitary FSH secretion, while activin stimulates
ruptured follicle is called the corpus luteum. FSH secretion and inhibits androgen production but 
Over the next 10 days, these cells secrete high levels of  stimulates conversion to oestrogens. Together, they reg-
progesterone andoestrogens, buttheythen spontaneously  ulate FSH secretion and local sex steroid levels and the
involute (shrink) and lose their secretory ability unless balance between oestrogens and androgens.
they are rescued by the signal of human chorionic gonad-
otrophin (hCG) produced by the implanting conceptus. Relaxin
 The progesterone and oestrogen secreted by the cor-  This is a polypeptide hormone secreted by the corpus
pus luteum inhibit LH and FSH release from the pitui- luteum and placenta. It prepares the body for childbirth
tary gland. The falling LH levels fail to maintain the by causing cervical softening and relaxation of pelvic
corpus luteum, so it undergoes involution. As a result, ligaments.
progesterone and oestrogen levels fall dramatically so
their negative feedback to the pituitary gland is lost.
FSH and LH secretion rise, causing ovarian follicles to
Polycystic ovary syndrome (PCOS/ 
grow, thus starting the next cycle. Stein–Leventhal syndrome)
Oral contraceptives: the use of oestrogen and/or pro-  This is a syndrome composed of hyperandrogenism,
gestogen in oral contraceptives aims to mimic the early  oligo-ovulation and polycystic ovaries. The polycystic
stages of the second half of the menstrual cycle. ovaries must be in the absence of other conditions,
e.g. congenital adrenal hyperplasia (late onset) or Cush-
Endometrial changes ing’s syndrome, that can cause them. The exact cause of 
 After ovulation, the progesterone secretion by the cor- PCOS is not known and while it is often familial, there
pus luteum activates the endometrium by stimulating  have been no genes yet linked to it.
differentiation. A number of changes occur: Patients with this condition often have associated in-
• Nutrients are stored in the cells sulin resistance and hyperinsulinaemia, and diabetes/
• Glands become tortuous (irregularly shaped) in metabolic syndrome may appear as a complication later 
preparation for secretion. in those patients who are obese.
Patients with this condition typically present with
 About 5 days after ovulation, the glands begin to secrete
irregular or infrequent periods or possibly with infertil-
a glycogen-rich ‘milk’ in preparation for a potential em-
ity. The patients may also have a number of other signs:
bryo; as a result the changes to the endometrium during 
the second half of the menstrual cycle are called the • Hirsutism (excessive growth of thick dark hair in
secretory phase. an androgen-dependent pattern) usually over the
 As progesterone and oestrogen levels fall, the spiral upper lip
arteries supplying the functional endometrium begin • Male-pattern baldness
to coil and constrict, causing ischaemia and necrosis. • Acanthosis nigricans (darkened, thick velvety skin in
Blood leaks from the damaged vessels into the endome- the body folds, usually the neck)
trium before the whole functional endometrium is •   Obesity 
shed. Menstruation occurs, and this marks the first  • Deep voice
day of the next cycle. •   Acne.
If pregnancy occurs then the implanting conceptus
produces hCG, which binds to LH receptors on the lu- Diagnosis
teal cells exerting a luteotrophic signal for the corpus Raised LH:FSH ratio (approximately 3:1) with raised
luteum to maintain itself. testosterone and prolactin. Ultrasound scan will show 
at least five small follicles, < 5 mm in diameter, along 
The role of peptides in the menstrual cycle the periphery of the ovaries.
FSH controls the production of inhibin and activin in
the granulosa cells. Inhibin A suppresses FSH release Management 
 The male reproductive system 11

confirmed. Pharmacologically, metformin is recom- • Prostate and seminal vesicles – secrete seminal fluid
mended in women of BMI > 25 trying to conceive be- to support ejaculated sperm
cause of the improvement in insulin sensitivity, • Penis – deposits sperm in the vagina.
ovulatory function and menstrual disturbance. Also  The blood supply, lymphatics and innervation of the
available is clomifene, which can stimulate ovulation male reproductive organs are shown in Fig. 11.10.
but increases risks of ovarian cancer. Additionally, the
use of ovarian drilling (diathermy creates holes in the
ovaries to reduce steroid production) is useful both as Hormones
a primary treatment of infertility or when clomifene
Testicular sex steroids
does not work. The combined oral contraceptive pill is
found to provide relief of irregular bleeding and can help The testes secrete 95% of the male sex steroids called an-
to reverse the increase in risk of endometrial cancer. drogens; the adrenal cortex is responsible for the
remaining 5%. The main androgen is testosterone.
Complications  Testicular androgens are secreted by the interstitial
Patients with PCOS are seen to have increased risk of  Leydig cells found between the seminiferous tubules.
both endometrial and ovarian cancer. Infertility and hy-  They convert cholesterol into the steroid testosterone
pertension are also known associated problems. by a series of reactions. The Leydig cells also secrete
small quantities of oestrogens and progestogens as by-
products of testosterone synthesis.
THE MALE REPRODUCTIVE  Testosterone is a strong androgen. However, some
SYSTEM target tissues can convert it to the more potent form
called dihydrotestosterone (DHT). The conversion re-
 The male reproductive system consists of five main com- quires the 5-alpha reductase enzyme and occurs in the:
ponents (Fig. 11.9): • Sertoli cells
• Testes – produce the sperm • Prostate gland
• Epididymis – stores and matures the sperm •   Skin.
• Vas (ductus) deferens – transports sperm from the  Testosterone is transported in the plasma by sex-
epididymis to the penis hormone-binding globulin (SHBG) or albumin. It acts

Fig. 11.9 Arrangement of the male

reproductive system. This diagram is
not to scale.
bladder 

prostate seminal
prostatic urethra vesicle
membranous urethra
ampulla
penile urethra
corpora cavernosa ejaculatory duct
corpus bulbo-urethral vas
spongiosum gland deferens

efferent
ductules
in head of
epididymis

straight tubules epididymis

epididymal
glans penis
duct
skin
dartos muscle rete testis
terminal
tunica vaginalis seminiferous sections of vas deferens
 Hormones of the reproductive system

Fig. 11.10 Blood supply, lymphatics and innervation of the male reproductive organs

Organ Arterial supply Venous drainage Innervation Lymphatic 

drainage

Testis Testicular arteries Pampiniform plexus, which forms Sympathetic innervation Para-aortic
from the aorta via the testicular veins. Left drains into via the splanchnic nerves lymph nodes
the spermatic cord the left renal vein, right into the
inferior vena cava
Scrotum Pudendal arteries Scrotal veins Branches of the Superficial
genitofemoral, ilioinguinal inguinal
and pudendal nerves lymph nodes
Prostate Vesicular and rectal Prostatic venous plexus drains Parasympathetic via Internal iliac
branches of the into the internal iliac veins splanchnic nerves; and sacral
internal iliac artery sympathetic from inferior  lymph nodes
hypogastric plexus
Penis Internal pudendal Venous plexus, which joins Branches of the Superficial
arteries the prostatic venous plexus pudendal nerve inguinal
lymph nodes

 via intracellular receptors to regulate protein synthesis, • Development of male secondary sexual characteris-
producing the actions shown in  Fig. 11.11. The main tics (e.g. male hair pattern, muscle growth)
actions are: • Stimulation of spermatogenesis
• Growth and development of the male reproductive • Stimulation of growth and the fusion of the growth
tract  plates of the long bones.

Fig. 11.11 Actions of testosterone

brain
- hypothalamic and pituitary
  feedback

larynx face
- voice deepens - hair growth

axillary
- hair growth
muscle
- growth

pubis
- hair growth

penis
bones - growth
- growth
- fusion of
the epiphyses
testes
- growth
- spermatogenesis
 Sources of reproductive hormones 11

Control of testicular steroid production •   TFTs

 Testosterone synthesis and release is controlled by the • CXR, to look for tumours.
same hormones in the male as oestrogen synthesis in  The next line of investigation would be to check LH,
the female. Gonadotrophin-releasing hormone (GnRH) FSH, oestrogen and testosterone levels. If these tests in-
from the hypothalamus is transported to the anterior pi- dicate any abnormalities, further investigations are re-
tuitary gland by the portal veins. It stimulates the gona- quired. Some specific investigations include:
dotroph cells to secrete gonadotrophins (LH and FSH).
•   Mammography 
 This process is described in more detail in Chapter 2.
• Chromosome analysis – Klinefelter’s syndrome
LH acts on the Leydig cells to stimulate the first step
• b  human chorionic gonadotrophin (hCG), alpha-
in testosterone production. Testosterone feeds back to
fetoprotein (AFP) – testicular tumour 
the hypothalamus and pituitary gland to inhibit LH re-
• Basal serum prolactin – prolactinoma
lease, but it has little effect on FSH.
• CT head – pituitary tumour.
FSH acts on the Sertoli cells; it increases the number 
of testosterone receptors to stimulate spermatogenesis.
It also causes inhibin B release from the Sertoli cells,
 which feeds back to the hypothalamus and pituitary  SOURCES OF REPRODUCTIVE
gland to inhibit further FSH release. Inhibin has little ef- HORMONES
fect on LH and therefore regulates sperm production
 without inhibiting testosterone levels.
Endocrine signals are essential for implantation and the
maintenance of pregnancy. As the pregnancy progresses,
Other testicular hormones the hormone levels change, as shown in Fig. 11.12. There
 The fetal Sertoli cells produce the Müllerian inhibiting  are two phases of hormonal secretion during pregnancy:
substance. This hormone prevents development of the • Corpus luteum phase – the corpus luteum secretes
female internal genitalia by causing the Müllerian ducts hormones to maintain the endometrium and the de-
to regress.  veloping placenta
• Placental phase – the placenta takes over hormonal
Gynaecomastia secretion to allow maternal adaptation to preg-
nancy, birth and lactation.
 The male breast contains the same tissue components as
the female breast in the undeveloped, prepubescent 
state. If the male breast enlarges, the condition is known Corpus luteum phase
as gynaecomastia. It can be defined as the presence of 
In the normal menstrual cycle, the corpus luteum secretes
> 2 cm of palpable, firm, subareolar gland and ductal
progesterone and oestrogen for about 10 days following 
breast tissue.
ovulation, after which it regresses. The dramatic fall
It is caused by any condition or process that raises
oestrogen or lowers testosterone levels. It can often oc-
cur in puberty, but will usually resolve with time. The
underlying cause should be treated if it fails to resolve.
progesterone
Common causes include:
•   Oestrogen-containing products or oestrogen-like
compounds, e.g. opiates or anabolic steroids
• Hypogonadism or complete gonadal failure; this re- hPL
sults in an increase in the oestrogen:testosterone ratio oestrogens
• Hyperthyroidism and liver cirrhosis can lead to in-
creased synthesis of oestrogens fromandrostenedione
• Adrenal and testicular tumours.

Investigations
hCG
 A clear history will help point to the appropriate inves-
5 10 15 20 25 30 35 40
tigation but in the absence of a clear cause, general in-
weeks of pregnancy
 vestigations can be undertaken. These include:
 SAQ answers

SINGLE BEST ANSWERS

Chapter 7
1. D
Chapter 2
2. C
1. E
3. D
2. C
3. A

Chapter 8
1. D
Chapter 3
2. E
1. B, C
3. C
2. A, B

Chapter 9
Chapter 4
1. A, D
1. D, A
2. B, D

Chapter 10
1. B, A, C
Chapter 5
1. D, D
2. C, B
Chapter 11
1.   A , A, B

Chapter 6
1. E
2. D
3. D
Intentionally left as blank
 EMQ answers

1. The pancreas and diabetes 6. Symptoms of pregnancy

1. A 1. F
2. F 2. A
3. E 3. C
4. D 4. D
5. B 5. B

2. The hypothalamus and the pituitary 7. Disorders of pregnancy

gland 1. C

1. I 2. D

2. B 3. A

3. G 4. B

4. C 5. E

5. F

8. Signs of endocrine disease

3. The adrenal glands 1. G

1. F 2. E

2. B 3. F

3. A 4. H

4. D 5. D

5. E

9. Signs of endocrine disease

4. Endocrine disease 1. F

1. B 2. D

2. F 3. A

3. C 4. C

4. A 5. B

5. E

10. Imaging and endocrine disease

5. Thyroid disease 1. A

1. F 2. C

2. E 3. E

3. B 4. F

4. A 5. D

5. C
Intentionally left as blank
 Index
multiple endocrine neoplasia
syndromes (Continued)
MEN-II (Sipple’s syndrome) 103, 104 f  pancreas 53–68, 54 f  disorders 20–24, 22 f , 24 f
MEN-IIb 104, 104 f  anatomy   53–54, 54 f  hormones 16, 17 f , 18–19, 18 f , 19 f
myxoedema coma 35
N diabetes mellitus 60–63
natriuretic factors 80
negative feedback  3 f , 4,
18–19
neoplasia 103–106
adrenal cortex  47
carcinoid syndrome 105
carcinoid tumours 104–105
MEN syndromes see multiple
endocrine neoplasia syndromes
pancreatic endocrine 66
thyroid gland 34, 34 f 
familial medullary thyroid
carcinoma 104
 see also individual tumour types
nerve growth factor (NGF)  97 f 
nervous system
chemical signalling  9
relationship with endocrine system
8–9
neurocrine 1, 2 f 
neuroendocrine 1
neurotensin 71 f 
noradrenaline 49–50, 49 f 
physiological effects 50 f 
 see also  catecholamines
norepinephrine see noradrenaline
 Notch 55, 66
O
octreotide 21
oestrogens 102 f , 107, 109
actions 112 f  development  101
pregnancy  118
synthesis 111 f  phaeochromocytoma 50
oral contraceptives 111, 114
oral hypoglycaemic agents  65
osteoblasts 83b
osteoclasts 83b
osteomalacia 90 f  structure 73–74, 73 f  puberty   97, 99–102
osteoporosis 92–93
ovarian sex steroids 107–108
regulation 108 f , 110
ovaries 109 f  pituitary apoplexy  22
follicular development  110 f  pituitary gland 3
ovulation 112
oxyphil cells 27, 86
P compression 23
development   12–14, 15 f 
 
 
blood supply, nerves and  see also individual hormones
lymphatics 54 infarction 21–23
development   55, 55 f  location 12 f 
disorders posterior   15–16, 16 f 
placenta 118
endocrine pancreatic neoplasia 66 platelet-derived growth factor (PDGF)
metabolic syndrome/syndrome X  97 f 
67 polycystic ovary syndrome (PCOS)
hormones 55–58 114–115
glucagon 54 f , 55, 58 polycythaemia 105 f 
insulin 54 f , 55–57 polypeptide hormones 4
islets of Langerhans 53, 55 f  polyuria 53b
microstructure 54–55, 55 f  positive feedback   4, 18–19
pancreatic duct  54 pregnancy   117–119, 117 f 
pancreatic polypeptides (PP) 69, 73 corpus luteum phase 117–118
pancreatic transplant  66 hormones 119–120, 120 f 
panhypopituitarism 21 hCG 118
paracrine 1, 2 f  human placental lactogen
parathyroid glands 85–86 118–119
anatomy  26 inhibin 119
blood supply, nerves and oestrogens 118
lymphatics 85–86 progesterone 118
development   27, 86 prolactin 119
disorders relaxin 119
hyperparathyroidism metabolic changes 119
 see hyperparathyroidism amino acids 120
hypoparathyroidism 91–92 carbohydrates 119–120
microstructure 27, 86 fat  120
parathyroid hormone (PTH) 83, 84 f , 85, placental phase 118
86 progesterone 102 f , 107
actions 85 f , 86, 86 f  actions 112 f 
ectopic secretion 105 f  pregnancy  118
synthesis and receptors 86 progestogens 107, 109
parturition 120–121 prolactin 17 f , 119
oxytocin 120 disorders 22 f 
prostaglandins 120–121 ectopic secretion 105 f 
relaxin 121 excess see hyperprolactinaemia
PCOS see polycystic ovary syndrome lactation 121
penis 116 f  prolactin-releasing factors (PRF)  17 f 
prolactinoma 20–21
peptide YY  71 f  investigations 20–21
treatment  21
phosphate 89 prostaglandins
pineal gland 73–74 parturition 120–121
function 74 renal 80
regulation 74, 74 f  prostate 116 f 
pioglitazone 65 body weight  100
pituitary adenoma 21, 22 f  female 101–102
growth hormone-secreting  98 breast development  101
menarche 102
gonadarche 99–100
anatomy   11–12 growth spurt  100–101
anterior   15, 16 f  male 101
 Index

R syndrome of inappropriate antidiuretic  see also thyroxine; tri-iodothyronine

hormone see SIADH thyroid ima artery  25
Rathke’s pouch 12 syndrome X  67 thyroid-stimulating hormone (TSH) 17 f 
relaxin 114 disorders 22 f 
parturition 121 pregnancy  119
pregnancy  119 thyroiditis 34
renin 75, 76 f  T
De Quervain’s 33
effects 79  Tanner’s staging  101b, 102b Hashimoto’s 33
synthesis and secretion 78, 79 f  target cells 3–4 thyrotoxic crisis/thyroid storm 35
renin-angiotensin-aldosterone system testes 116 f  thyrotoxicosis 31 f 
78–80 development  101 thyrotrophin-releasing hormone (TRH)
 see also individual hormones sex steroids 115–117 17 f , 36
reproductive hormones 107–122 testosterone 116 f  thyroxine 28 f , 30 f 
 see also menstrual cycle; pregnancy; thiazolidinedones 65 transforming growth factors (TGF)  55,
reproductive system thyroglobulin 66, 97 f 
reproductive system iodination 28 tri-iodothyronine 28 f , 30 f 
female 107–110 synthesis 28  Trousseau’s sign  92 f 
anatomy   107, 108 f , 109 f  thyroid autoantibody assay  36  Turner’s syndrome 101b
hormones 107–110, 108 f  thyroid diverticulum 27 tyrosine kinase receptors 7 f 
male 115–117, 115 f  thyroid gland 25–36
anatomy  116 f  anatomy   25–26, 26 f , 27 f 
hormones 107, 115–117 blood supply, nerves and U
 see also individual organs lymphatics 25–26 ultrasound
rickets 90 f  development  27 adrenal gland 51
disorders 30–36 liver metastases 105
dyshormonogenesis 33
S parathyroid glands 89
goitres 33–34 PCOS 114
scrotum 116 f  Graves’ disease 32 uterine tubes 109 f 
secretin 71 f , 72 hyperthyroidism 25, 31–32, 31 f  uterus 109 f 
short stature 98b, 99 f  hypothyroidism 22 f , 25, 32–33, 33 f 
SIADH 20, 24 thyroid hormone resistance
Sipple’s syndrome 103 syndrome 32 V
sitagliptin 65 examination 35–36, 35 f 
sodium 75 investigations 36  vagina 109 f 
hyponatraemia 105 f  hormone assays 36  vasoactive intestinal polypeptide (VIP)
somatostatin 17 f , 73, 95 medical emergencies 35 69, 71 f 
 sonic hedgehog   55, 66 microstructure 26, 27 f   vildagliptin 65
spermatogenesis 101 neoplasia 34, 34 f   vitamin D  83, 84 f , 87
sphincter of Oddi 54 familial medullary thyroid actions 85 f , 87, 88 f 
starvation 62 carcinoma 104 activation 87, 87 f 
Stein-Leventhal syndrome  see polycystic molecular biology  34–35 deficiency  90 f 
ovary syndrome thyroid hormone resistance syndrome
stem cell therapy in diabetes mellitus 66 32
steroid hormones 5, 5 f  thyroid hormones 26 f , 27–30, 97 W
synthesis 6 f  actions 30, 30 f 
 water  75
 see also individual hormones assay  36
 Werner’s syndrome  103
substance P 71 f  feedback  30
sulfonylureas 65 regulation 29
superior suprarenal arteries 38 secretion 28, 29 f 
Z
superior thyroid artery  25 synthesis 28, 28 f , 29 f 
superior thyroid vein 25 transport   29–30 Zollinger-Ellison syndrome 103
Intentionally left as blank