LCRS: Endocrinology
Usama Asif
ENDOCRINOLOGY 8:
The adrenals and their hormones
Professor John Laycock (j.laycock@imperial.ac.uk)
1. Describe the anatomy of the adrenal gland, identifying the medulla and the cortical zones
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The adrenal glands sit on top of the kidney (ad = above, renal = kidney, simple!)
They have two main zones: the adrenal cortex and the adrenal medulla. The cortex is on the edge
and the medulla is in the middle
The cortex has three zones, from the outmost in:
o The zona glomerulosa
o The zona fasciculata
o The zona reticularis
The whole gland is surrounded by a capsule
Arterial blood supply is to the outer part of the gland. The vessels go towards the medulla and join
at the central suprarenal vein at the medulla
2. List the main hormonal products from the adrenal medulla and the adrenal cortex
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The adrenal medulla has chromaffine cells. These produce catecholamines. The adrenal medulla
is part of the sympathetic nervous system – noradrenaline (20%) and adrenaline (80%) (and small
amounts of dopamine) are produced here. The innervated secretory cells here are stimulated by the
sympathetic nervous system and secrete the catecholamines when a stimulus is received
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The adrenal cortex produces corticosteroids – glucocorticoids (such as cortisol) and
mineralocorticoids (such as aldosterone)
It also produces small amounts of sex steroids (mainly androgens, but very little amounts)
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LCRS: Endocrinology
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Usama Asif
In terms of location, remember, the deeper you go, the sweeter it gets:
o Zona glomerulosal cells produce aldosterone (this has effects on the salt balance in the
body)
o Zona fasciculatal cells produce cortisol (this has effects on sugar)
o Zona reticularal cells produce sex steroids (these have effects on the reproductive system)
3. Draw simple pathways identifying the main intermediates in the synthesis of the adrenal steroids
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Remember that these are steroid hormones and are all derived from cholesterol
This means that the balance of enzymes in each discrete cortical zone is different, thus producing
different steroid hormones
For example, in the zona glomerulosa, the balance of enzymes is such that the cholesterol is
converted into aldosterone
The same is true for the other hormones and their respective zones in the adrenals
If we look at the above picture, we can see that:
o In all zones, there would be p450scc (cholesterol desmolase) and 3β-hydroxysteroid
dehydrogenase
o In both the zona fasiculata and the zona reticularis, there would be 17α-hydroxylase
o In both the glomerulosa and reticularis, there would be 21-hydroxylase and 11βhydroxylase
o In just the zona glomerulosa, there would be aldosterone synthase
o Etcetera.
o The presence and absence of certain enzymes in the pathway lead to the production of the
steroid hormones
LCRS: Endocrinology
Usama Asif
Corticosteroid transport in the blood
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Cortisol and aldosterone both bind to albumin and corticosteroid binding globulin or transcortin
o Cortisol – 75% is bound to CBG and 15% is bound to albumin. The remaining 10% is free
and bioactive
o Aldosterone – around 60% is bound to CBG and 40% is free and bioactive
Levels of the hormones under certain conditions
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Cortisol is subject to the circadian rhythm. Levels are higher in the morning than in the afternoon
and evening
o 8am = 140-690 nmol/L
4pm = 80-330 nmol/L
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Aldosterone is subject to activity – its levels increase whilst standing (due to its role regulating
blood pressure – see NEURO and CVS)
o Upright = 140-560 pmol/L
Note the 1000-fold difference in concentration of the hormones
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4. State that the adrenal steroids exert their main effects via intracellular receptors and genomic
mechanisms
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The above learning objective is true because of the fact that these are steroid hormones. For more
information on the general steroid mechanism of action, see the introduction lecture
LCRS: Endocrinology
Usama Asif
5. Identify the main mineralocorticoid in humans and describe its principal actions
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The main mineralocorticoid is aldosterone
Its principal actions are:
o To stimulate sodium ion reabsorption in the distal convoluted tubule and collecting duct
of the nephron in the kidney (and in sweat glands, gastric glands etc.)
o To stimulate potassium ion and proton secretion into the tubular lumen (i.e. excretion) in
the same areas (NB: this is the only way to regulate potassium levels in the body)
In this way, it indirectly retains water in the body, due to the osmotic flow of water
Mechanism of action
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Standard steroid mechanism of action – aldosterone binds to its receptor intracellularly and
becomes a transcription factor and promotes the production of new proteins, namely the sodium,
potassium and proton transporter in the kidney
6. Describe the control mechanisms for mineralocorticoid hormones
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Before we look at the control mechanisms, we need to understand some of the physiology of the
kidney:
The juxtaglomerular apparatus in the kidney
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This apparatus is in next to the glomerulus in the nephron of the kidney
Blood flows into the nephron via the afferent arteriole just before the glomerulus
Just before blood is ultrafiltered into the proximal convoluted tubule, it passes over a group of
cells, grouped together and called the juxtaglomerular apparatus
There are two functional cells in this region, cells of the macula densa and the juxtaglomerular
cells
Macula densa cells detect levels of sodium in the blood (via the nephron). Juxtaglomerular cells
detect blood pressure
If the levels of sodium in the blood are low, or the blood pressure is detected to be low, then a
paracrine/autocrine signal is sent to the juxtaglomerular cells to secrete RENIN
LCRS: Endocrinology
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Usama Asif
Renin (not to be confused with rennin) enters the bloodstream and acts as a hormone. It is
stimulated by:
o It causes decreased renal perfusion pressure (associated with decreased ABP?)
o Increased renal sympathetic activity
o Decreased sodium load to the macula densa cells
How does this relate to aldosterone?
The renin-angiotensin-aldosterone system
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Renin has other effects
The liver produces a pro-hormone called angiotensinogen. Renin breaks down angiotensinogen
to yield angiotensin I
Angiotensin I is converted to angiotensin II via the enzyme angiotensin converting enzyme
(useful name!) (ACE) (produced in the lungs)
Angiotensin II is a powerful vasoconstrictor so it increases blood pressure
Angiotensin II also controls the production of ALDOSTERONE
ACTH also has a small effect on stimulating the production of aldosterone
LCRS: Endocrinology
Usama Asif
7. Identify the main glucocorticoid in humans and describe its principal actions
8. State that cortisol plays an important role in the endocrine response to stress
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The main glucocorticoid is cortisol
Its principal actions are:
o The normal stress response:
 Metabolic effects:
 Peripheral protein catabolism
 Hepatic gluconeogenesis
 Increased blood glucose concentration
 Fat metabolism – lipolysis I adipose tissue
 Enhances effects of glucagon and catecholamines
 Some mineralocorticoid effects
 Renal and cardiovascular effects
 Excretion of water load
 Increased vascular permeability
 Other effects
 On bone
 CNS
 Growth
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The effects of large pharmacological amounts of cortisol include:
o Anti-inflammatory reaction
o Immunosuppressive action
o Anti-allergic action
All of the above are associated with decreased production of molecules such as leukotrienes,
histamine etc., as well as on the movement and function of leukocytes and the production of
interleukins
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LCRS: Endocrinology
Usama Asif
Cortisol mechanism of action
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Standard steroid mechanism of action – the proteins synthesise at the end of the mechanism
include annexin-1 and arachidonic acid that may carry out the effects
9. Describe the principal features of the hypothalamo-pituitary-adrenal axis
Recognise the necessity for adrenal steroids for survival
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The hypothalamo-pituitary-adrenal axis controls adrenal hormone release
STRESSORS stimulate the hypothalamus to secrete corticotrophin releasing hormone
The hypothalamus secretes CRH causing the adenohypophysis to secrete adrenocorticotrophic
hormone (ACTH/corticotrophin)
ACTH travels in the circulation and to the adrenals, where it stimulates the production of cortisol
in the zona fasciculata
Cortisol negatively feeds back both directly and indirectly on ACTH from the adenohypophysis
and CRH from the hypothalamus respectively
Other factors include:
o Vasopressin secretion from the hypothalamus to the adenohypophysis stimulates
corticotrophes to secrete ACTH
o ACTH also stimulates small amounts of androgens to be released from the zona reticularis
o The circadian rhythm affects the pulsatile secretions depending on the time of day
(increase pulses in the morning, decrease in the evening)
10. State that adrenal androgen production in women can be clinically important in conditions of
overproduction
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Dehydroepiandrosterone is a precursor for androgens and oestrogens. It is converted to active
hormones within target cells that have the appropriate enzymes for its conversion
It peaks in serum at 20-30 years of age and decreases with age
It is important in postmenopausal women as it is the precursor for oestrogen and needs to be
present for oestrogen synthesis to take place as the ovarian steroids have stopped
This can go wrong
LCRS: Endocrinology
Usama Asif
ENDOCRINOLOGY 9:
Adrenal disorders
Professor Karim Meeran (k.meeran@imperial.ac.uk)
Anatomy of the adrenals
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The adrenal glands are located on top of the kidneys
They have a rich blood supply with a lot of arterial blood but only one vein
The blood goes from the outside of the adrenal gland, to the middle
The left adrenal has venous drainage into the renal vein, whereas the right adrenal gland has
direct venous drainage into the inferior vena cava (makes sense anatomically)
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The spleen is at risk with left adrenectomy so, immunize with HIB (Haemophilus influenzae B)
and pneumovax before left adrenectomy
LCRS: Endocrinology
1. Describe the effects of deficiency of cortisol
Addison’s disease
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Addison’s disease is primary
adrenal failure – it is an
autoimmune disease where the
immune system wipes out the
adrenal cortex (in the developed
world = most common cause)
It can also be caused by tuberculosis
of the adrenal glands (commonest
cause worldwide)
The pituitary is not inhibited so
there is increased production of
ACTH
Because POMC (precursor of
ACTH) cleaves to form melanin
stimulating hormone as well, with
increased production of ACTH,
there is also increased secretion of
MSH
This results in a tanned look for
Addisonian patients
There may be autoimmune vitiligo
that coexists with the disease
Because Addison’s is primary
ADRENAL failure, that means that
there is no aldosterone (as the whole
adrenal gland isn’t working), thus,
these patients will also present with
a low blood pressure
Usama Asif
LCRS: Endocrinology
Usama Asif
Treating Addison’s (NEED TO KNOW)
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Rehydrate with normal saline
Give dextrose (glucose) to prevent hypoglycaemia, which is due to the glucocorticoid deficiency
Give a synthetic glucocorticoid – hydrocortisone or another one – dexamethasone
2. Describe the effects of excess of cortisol
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Excess cortisol can cause:
o Impaired glucose tolerance (diabetes)
o Weight gain (due to increased fat and loss of protein)
o Thin skin, easy bruising
o Striae (stretch marks)
o Proximal myopathy (muscle weakness)
o Mental changes (depression)
o Hypertension
o Fat redistribution – moon face and buffalo hump (interscapular fat pads)
Cushing’s syndrome
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All of the above are signs and symptoms of Cushing’s
It therefore occurs due to an excess of cortisol of other glucocorticoid
Cushing’s can be caused by:
o Taking steroids by mouth (dexamethasone medically, anabolic steroids?)
o Ectopic ACTH (from a lung adenoma)
o Adrenal adenoma or carcinoma producing cortisol
o Pituitary dependent Cushing’s DISEASE – this is a pituitary adenoma causing excess
release of ACTH
LCRS: Endocrinology
Clinical signs:
- Thin skin
- Proximal myopathy
- Centripetal obesity (lemon on sticks)
- Diabetes, hypertension and osteoporosis
- Immunosuppression
- Moon face
The syndrome is all the above symptoms – any cause
The disease is due to a pituitary adenoma
Side effects of taking steroids
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Same as above
Aldosterone producing adenoma
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This is Conn’s syndrome – causing hypertension that is very hard to treat
It also causes oedema and hypokalaemia
3. Understand the principles of treatment issues in the individual patient
See above
Usama Asif