Endocrinology 3b & 4a – Hyperadrenal Disorders
Anil Chopra
1. List and describe the clinical features of Cushing’s and Conn’s Syndromes.
2. Identify the four causes of Cushing’s Syndrome.
3. Describe the principal investigations required to determine the cause of
Cushing’s Syndrome in an individual.
4. List the drugs used to treat Cushing’s and Conn’s Syndromes.
5. List the surgical options for treatment of Cushing’s and Conn’s Syndromes.
6. List the clinical features of a patient with a phaeochromocytoma.
Summary of adrenals:
 Adrenal Medulla:
 Catecholamines – Adrenaline (epinephrine) 80%, Noradrenaline
(norepinephrin) 30%, Dopamine (associated with post-ganglionic
sympathetic neurones)
 Adrenal Cortex :
 Corticosteroids :
i. (Outer zona glomerulosa) = Mineralocorticoids – Aldosterone
ii. (Middle zona fasciculata) = Glucocorticoids – Cortisol
iii. (Inner zona reticularis) = Sex Steroids – Androgens, Oestrogens
 The main mineralocorticoid in humans is aldosterone
 Principal effects:
 Stimulates sodium reabsorption in distal convoluted tubules and cortical
collecting duct (and in sweat glands, gastric glands and colon)
 Stimulates potassium and hydrogen secretion, also in the distal convoluted
tubules and cortical collecting ducts
 Aldosterone release is stimulated by 3 main factors:
 Angiotensin II – in response to low blood volume as part of the renninangiotensin system
 High plasma potassium
 ACTH (Adenocorticotrophic Hormone) – secreted by the adenohypophysis,
less important as a regulator
Conn’s Syndrome = aldosterone producing tumour leading to hypertension, oedema
and low potassium
The main glucocortoid in humans is cortisol
Released from adrenal cortex in response to ACTH (corticotrophin) from the
adenohypohysis
 The principal actions are:
 The normal stress response
 General Adaptation Syndrome (GAS) divided into 3 phases:
 Alarm reaction = stressful stimulus causing sympathetic release of
noradrenaline, noradrenaline and adrenaline release from adrenal medulla and
cortisol release from adrenal cortex
 Resistance = cortisol has a slower and longer lasting effect that adrenaline and
noradrenaline, allows resistance to stress to be maintained
 Exhaustion = prolonged exposure to stress causes continuing cortisol release
 Metabolic effects


Peripheral protein catabolism
 Hepatic gluconeogenesis
 Increased blood glucose
 Fat metabolism (lipolysis in adipose tissue)
 Enhanced effect of glucagon and catecholamines
 Some mineralocorticoid effects
 Renal and cardiovascular effects
 Excretion of water load
 Increased vascular permeability
 Other effects e.g. on bone, CNS, growth etc
 Effects of large amounts of cortisol:
 Anti-inflammatory action
 Immunosuppressive action
 Anti-allergic action
 All are associated with decreased production of molecules such as prostaglandins,
leukotrienes, histamines etc as well as on the movement and function of leukocyte and
the production of interleukins
 Normal cortisol release follows a circadian rhythm with the main production
overnight

Cushing’s Syndrome – excessive cortisol production (or other glucocortoid) Possible
causes = taking steroids by mouth (most common), Cushing’s disease, Ectopic ACTH
production such as in lung carcinoma, adrenal adenoma or carcinoma
Cushing’s Disease – ACTH secreting tumour in the adenohypophysis
Addison’s Disease – deficiency
of cortisol and aldosterone
(primary adrenal failure). Can be
caused by autoimmune disease
where adrenal is wiped out (most
common in UK), or the
commonest cause worldwide
where tuberculosis destroys it

Cushing’s Syndrome
It is a condition caused by the
production of too much cortisol. It
causes protein to be converted to
fat.
Causes of Cushing’s Syndrome
- Taking too many steroids
- Pituitary dependent Cushing’s
disease
o Pituitary tumour that
secretes ACTH
- Ectopic ACTH e.g. from lung
cancer.
- Adrenal adenoma secreting
cortisol.
Symptoms of Cushing’s
- Muscle weakness (proximal
myopathy)
- Hypertension & Hypokalaemia
- Red straie, thin skin and easy
bruising due to lack of protein
synthesis
- Poor wound healing
- Moon face.
- Proximal myopathy
- Osteoporosis
-
Moon face
Centripetal obesity
Type II Diabetes
Hirsutism
Buffallo hump
Thin hair and balding
Increased pigmentation if
Cushing’s Disease
Oedema
Depression confusion, insomnia
Investigations
- 24h urine collection. Check cortisol
levels in urine.
- Blood diurnal cortisol levels (throughout
the day)
o Cortisols usually highest around
9 am and lowest around
midnight.
o In Cushings, it is high all the time
- Low dose dexamethasone (artificial
steroid) suppression test.
o 0.5mg every 6 hours for 48 hours
o Dexamethasone = artificial steroid that stops the production of ACTH
o Pituitary will switch off if normal.
o Any cause of Cushing’s will fail to suppress.
- High does dexamethasone
o Used to distinguish pituitary Cushing’s from other types
o Only pituitary Cushing’s will suppress to 50%
o Basal cortisol 500nM
o End of LDDST: 480nM
o End of HDDST: 325nM
o Ectopic and adrenal tumours will see no suppression
Treatment
- Removal of tumour by pituitary surgery (transsphenoidal hypophysectomy)
- Bi-lateral adrenalectomy
- Unilateral adrenalectomy
Pharmacology
The main drugs used in the
treatment of Cushing’s
syndrome are enzyme
inhibitors.
They inhibit different
enzymes in the biosynthesis
of cortisol:
Name – Metyrapone
Usage – Cushing’s Disease diagnosis. If given and ACTH and 11-deoxycortisol go
up, then diagnosis of Cushing’s disease is confirmed (pituitary adenoma). If ACTH
and 11-deoxycortisol don’t change then the tumour is ectopic (somewhere else) but
still secreting lots of ACTH. It is also used as long term treatment when surgery is not
possible.
Mode of action – blocks the action of 11β hydroxylase and hence decreases the
synthesis of cortisol very quickly.
Side Effects - Nausea, vomiting, dizziness, sedation, hypoadrenalism, impaired
performance in skilled tasks e.g. driving, operating machinery. Can also lead to
hypertension in long term use. Administered orally.
Name – Trilostane
Usage – Cushing’s syndrome, primary hyperaldosteronism and reduction in sex
steroid production (e.g. post-menopausal breast cancer).
Mode of action – blocks the action of 3β -hydroxysteroid dehydrogenase
and hence decreases the synthesis of all steroids.
Side Effects - Nausea, vomiting, diarrhea, flushing.
Name – Ketoconazole
Usage – mainly used as anti-fungal. Also used to inhibit steroidogeneisis.
Mode of action – blocks the action cytochrome P450 enzymes.
Side Effects - nausea, vomiting, abdominal pain, alopecia, (hair loss) gynaecomastia
(males developing breasts) oligospermia (low sperm count), ventricular tachycardias,
liver damage, reduced androgen production.
Name – Aminoglutethamide
Usage – malignant adrenocortical & prostate cancer
Mode of action – blocks conversion of cholesterol to pregnenolone.
Side Effects – corticosteroids need to be replaced. Administered orally.
Conn’s Syndrome
Cause by a benign adrenal tumour (zona glomerulosa). Aldosterone is secreted in
excess and results in hypertension and hypokalaemia.
Diagnosis
- Primary hyperaldosteronism
- Renin – angiotensin system should be suppressed (exclude secondary
hyperaldosteronism).
Treatment
- Removal of tumour
- Aldosterone receptor antagonist: spironolactone
- If both adrenal glands are responsible then patient should stay on spironolactone.
Pharmacology
The treatment of Conn’s syndrome involves the use of aldosterone receptor
antagonists.
Name – spironolactone
Usage – treating primary hyperaldosteronism,
oedema, congestive heart failure, nephrotic
syndrome and cirrhosis of the liver.
Mode of Action – it is a prodrug that is
converted to carenone. This
competitively antagonises the
mineralocorticoid receptor. It also
therefore decreases Na+ reabsorption
and K+ excretion.
Side effects - Menstrual irregularities,
gynaecomastia (androgen receptor
binding), GI tract irritation, blood
dyscrasias. Should not be used in renal
or hepatic disease.
Phaeochromocytomas
These are tumours of the adrenal
medulla that secrete catecholamines
(adrenaline and noradrenaline).
Symptoms of Phaeochromocytoma
• Hypertension in young people.
• Episodic severe hypertension (after
abdominal palpation).
• Can lead to myocardial infarction
and stroke.
• The high adrenaline can cause ventricular
fibrillation.
•
•
•
Treatment for Phaeochromocytoma
Surgery to remove tumour.
Anaesthetic should be cautioned as it could have hypertensive effects.
Should be immediately given α and β blockers.
Extra Facts
 10 % of tumours are extra-adrenal (sympathetic chain).
 10 % of tumours are malignant.
 10 % of tumours are bilateral. (both glands).
Pharmacology
In patients with phaeochromocytoma β blockers are given.
Name – Propanolol
Usage – anti-hypertensive, glaucoma, angina, anxiety, cardiac arrhythmias.
Mode of action – blocks β1 and β2 adrenoceptors and hence causes decrease in heart
rate, peripheral resistance, blood pressure, stoke volume, reduces renin release, and
central sympathetic outflow.
Side effects – bronchoconstriction (not used in asthmatics), cold extremities, heart
failure, heart block, also care when used in diabetics as it blocks glycolysis, increase
in GI tract motility. Can cause nightmares.
Name – Phentolamine
Usage – phaeochromocytoma, “cheese reaction” to tyramine.
Mode of Action – blocks α adrenoceptors causing fall in arterial blood pressure and
reduced peripheral resistance.
Side effects – reflex tachycardia, postural hypotension, flushing (increase flow
through cutaneous splanchnic vascular beds, nasal congestion, failure to ejaculate,
pupillary constriction (block of adrenergic tone to radial muscle of iris).
Name: Phenoxybenzamine
Usage: used in conjunction with β-adrenoceptor antagonists (propranolol, atenolol) to
treat hypertensive episodes in phaeochromocytoma and to prepare patients for
surgery.
Mode of Action: binds to α adrenoceptors, reduces blood pressure by blocking α1
receptors. It is a non-selective antagonist of acetylcholine, histamine and 5-HT.
Side effects: postural hypotension, reflex tachycardia and increased cardiac output.