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

Main features:

Cholesterol–>pregnenolone–> progesterone

Progesterone–> 11-deoxycorticosterone (which–> corticosterone or Aldosterone)

OR 17alpha-hydroxyprogesterone (which –> 11-deoxycortisol–> cortisol)

NOTE: 17alpha-hydroxyprogesterone can be turned into androstenedione–> test but this happens mostly in Gonads

notable enzymes:

• 11beta- hydroxylase (cortisol and corticosterone production)
• CyP450 scc (cholesterol–>pregnenolone

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? (11-Beta-hydroxylase inhibitor)

Answer 13

It prevents the conversion of: 11-deoxycorticosterone –> corticosterone

11-deoxycortisol –> cortisol

This means that no corticosterone or cortisol is produced

Note: 11-deoxycortisol doesn’t have neg feedback so ACTH will be high

Question 14

State two uses of metyrapone.

(11-Beta-hydroxylase inhibitor)

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.

(11-Beta-hydroxylase inhibitor)

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 steroid synthesis pathway (inhibited Cholesterol–>pregnenolone).

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) (TOO MUCH ALDOSTERONE)

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-Mineralocorticoid-R antagonist)

Surgery to remove the tumour

Question 25

What is spironolactone and how does it work?

Answer 25

Spironolactone is an aldosterone (Mineralocorticoid) receptor antagonist

It reduces the effects of aldosterone so it decreases sodium reabsorption and decreases potassium excretion.
(K+ sparing diuretic)

Question 26

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

Answer 26

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 27

Describe the pharmacokinetics of spironolactone.

(Mineralocorticoid receptor antagonist / K+ sparing diuretic)

Answer 27

Orally active

Given daily in single or divided doses

Highly protein-bound and metabolised in the liver

Question 28

State some unwanted effects of spironolactone.

(Mineralocorticoid receptor antagonist / K+ sparing diuretic)

Answer 28

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 29

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

Answer 29

Eplerenone - less binding to progesterone and androgen receptors

Question 30

What is phaeochromocytoma?

Answer 30

Tumour of the adrenal medulla that is producing excessive amounts of catecholamines (Adrenaline or Noradrenaline)

Question 31

What are the features of phaeochromocytoma?

Answer 31

Episodic SEVERE hypertension

Hypertension in the young

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

Question 32

State some fatal consequences of phaeochromocytoma.

Answer 32

Myocardial infarction and stroke

It can also cause sudden cardiac death through ventricular fibrillation

It is a MEDICAL EMERGENCY

Question 33

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

Answer 33

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.