Hyperadrenal Disorders

Question 1

Describe the effects of excess cortisol on protein and fat synthesis.

Answer 1

Decrease protein synthesis

Increase fat synthesis

Question 2

Explain why people with Cushing’s disease get stretch marks.

Answer 2

They are putting on a lot of fat quickly, which stretches the skin.
Because protein synthesis is switched off, you can’t make the protein required for skin growth so the skin tears.

Question 3

Describe the clinical features of Cushing’s syndrome.

Answer 3

Moon face 
Interscapular fat pad (buffalo hump) 
Proximal myopathy 
Easy bruising  
Striae 
Thin skin 
Osteoporosis 
Diabetes  
Centripetal adiposity (lemon on sticks) 
Hypertension and hypokalaemia

Question 4

Why does Cushing’s syndrome cause hypertension and hypokalaemia?

Answer 4

At high concentrations, cortisol can have mineralocorticoid effects –> increased sodium absorption and potassium excretion

Question 5

State four causes of Cushing’s syndrome.

Answer 5

Pituitary adenoma
Ectopic ACTH
Oral glucocorticoid drugs
Adrenal adenoma

Question 6

What are the three main tests used to diagnose Cushing’s syndrome?

Answer 6

24-hour urine free cortisol
Blood diurnal cortisol levels (or midnight serum cortisol)
Low dose dexamethasone suppression test

Question 7

Describe the results you’d expect from a normal subject and a patient with Cushing’s syndrome in the 24-hour urine free cortisol and blood diurnal cortisol tests.

Answer 7

You would expect lower cortisol at night in a normal subject and high cortisol in the morning.
In someone with Cushing’s syndrome they would have high cortisol all the time.
NOTE: a problem with this test is that the cortisol levels are affected by stress.

Question 8

Explain the scientific basis of the low dose dexamethasone suppression test.

Answer 8

Dexamethasone is a glucocorticoid so by giving this extra glucocorticoid, it should suppress ACTH and reduce cortisol production.
So in a normal subject undertaking the dexamethasone suppression test, you would expect zero cortisol.
In a Cushing’s patient, cortisol will remain high despite the presence of dexamethasone.

Question 9

State some surgical treatments for Cushing’s syndrome.

Answer 9

Treatment is dependent on cause
Transsphenoidal Hypophysectomy (for Cushing’s disease)
Bilateral adrenalectomy
Unilateral adrenalectomy for adrenal mass

Question 10

State two drugs that are used to treat Cushing’s syndrome before surgery.

Answer 10

Metyrapone

Ketoconazole

Question 11

Draw the adrenal steroid synthesis pathway.

Answer 11

-

Question 12

Which enzyme is inhibited by metyrapone?

Answer 12

11-Beta-hydroxylase

Question 13

What effect does metyrapone have on the steroid synthesis pathway?

Answer 13

It prevents the conversion of: 11-deoxycorticosterone –> corticosterone
11-deoxycortisol –> cortisol
This means that no corticosterone or cortisol is produced

Question 14

State two uses of metyrapone.

Answer 14

Preparation of a Cushing’s patient for surgery (improves their healing abilities and makes them better surgical candidates)
Treatment of Cushing’s syndrome symptoms following radiotherapy (radiotherapy has a delayed effect)

Question 15

State two negative aspects of metyrapone.

Answer 15

Metyrapone causes the accumulation of 11-deoxycorticosterone (because it doesn’t have any negative feedback effects on the ACTH axis)
11-deoxycorticosterone has mineralocorticoid effects so causes SALT RETENTION and HYPERTENSION.
Metyrapone inhibits two limbs of the steroid synthesis pathway so it funnels the precursors towards the sex steroid synthesis pathway.
This leads to increased adrenal androgens, which has effects such as hirsuitism.

Question 16

State some unwanted effects of metyrapone.

Answer 16

Nausea, vomiting, dizziness
Hypertension
Hirsuitism
Sedation, hypoadrenalism

Question 17

What is ketoconazole and why is it no longer used?

Answer 17

Ketoconazole is an anti-fungal, which had an effect on the steroidsynthesis pathway.
It is no longer used because of its hepatotoxicity.

Question 18

What are the effects of ketoconazole on steroid production?

Answer 18

Ketoconazole inhibits cytochrome P450 short chain cleavage enzyme.
This enzyme converts cholesterol –> pregnenolone
This means that it inhibits the production of glucocorticoids, mineralocorticoids and sex steroids.

Question 19

State some unwanted actions of ketoconazole.

Answer 19

Nausea, vomiting, abdominal pain
Alopecia
Gynaecomasia, oligospermia, impotence, decreased libido Ventricular tachycardias
LIVER DAMAGE (could be fatal)
These unwanted effects are due to loss of sex steroids, glucocorticoids and mineralocorticoids

Question 20

What is Conn’s syndrome?

Answer 20

Aldosterone secreting adenoma of the adrenal gland (zona glomerulosa)

Question 21

What are the two main features of Conn’s syndrome?

Answer 21

Hypertension

Hypokalaemia

Question 22

What is primary hyperaldosteronism?

Answer 22

Hyperaldosteronism caused by an adrenal adenoma.

Question 23

What can you test to exclude secondary hyperaldosteronism?

Answer 23

Check for suppression of the renin-angiotensin system
Measure aldosterone and if that’s high, measure the renin and that should be low because if would be suppressed by the high blood pressure.

Question 24

What is the usual treatment plan for someone with Conn’s syndrome?

Answer 24

Medical management (spironolactone) 
Surgery to remove the tumour

Question 25

What is spironolactone and how does it work?

Answer 25

Spironolactone is an aldosterone receptor antagonist

It reduces the effects of aldosterone so it decreases sodium reabsorption and decreases potassium excretion.

Question 26

What is the active metabolite of spironolactone that acts as a mineralocorticoid receptor antagonist?

Answer 26

Canrenone

Question 27

What treatment would you give for someone with bilateral adrenal hyperplasia?

Answer 27

Long-term spironolactone
You don’t want to remove both adrenals because then they wouldn’t produce any cortisol or aldosterone so you give them long-term spironolactone to reduce the effects of excess aldosterone.

Question 28

Describe the pharmacokinetics of spironolactone.

Answer 28

Orally active
Given daily in single or divided doses
Highly protein-bound and metabolised in the liver

Question 29

State some unwanted effects of spironolactone.

Answer 29

Spironolactone is very non-specific so it has several side effects
Progesterone receptor agonist –> menstrual irregularities
Androgen receptor antagonist –> gynaecomastia
GI tract irritation
Contra-indications:
 Renal and hepatic disease

Question 30

Name another mineralocorticoid receptor antagonist that has fewer side effects than spironolactone.

Answer 30

Eplerenone

Question 31

What is phaeochromocytoma?

Answer 31

Tumour of the adrenal medulla that is producing excessive amounts of catecholamines

Question 32

What are the features of phaeochromocytoma?

Answer 32

Episodic severe hypertension (in the young)

They will get sudden bursts of panic attacks, anxiety, palpitations and a rapid rise in blood pressure.

Question 33

State some fatal consequences of phaeochromocytoma.

Answer 33

Myocardial infarction and stroke
It can also cause sudden cardiac death through ventricular fibrillation
It is a MEDICAL EMERGENCY

Question 34

Describe the steps that must be taken when preparing a phaeochromocytoma patient for surgery.

Answer 34

Anaesthetic could precipitate a hypertensive crisis.
You give the patient an alpha-blocker to prevent the vasoconstriction caused by adrenaline binding to alpha-receptors.
Alpha-blockers cause a drop in blood pressure so they are usually given with a bit of fluid.
Then you give beta-blockers to prevent tachycardia.
Once all the receptors are blocked, it means that a massive release in adrenaline will not be able to have its effects.

Question 35

What percentage of phaeochromocytoma is intra-adrenal?

Answer 35

90%

It is a very rare condition.