Therapeutic Use of Adrenal Steroids

Question 1

What affects adrenal steroid production?

Answer 1

HPA axis - circadian stimuli/stress -> CRH -> ACTH -> adrenal gland (ZF) -> cortisol (negative feedback)
* ACTH also controls some sex hormone release from ZR but mainly from gonads

RAS - angiotensin -> A1 -> A2 -> ZG -> aldosterone

Question 2

What are the actions of adrenal hormones?

Answer 2

cortisol - essential for life

aldosterone - promotes Na+ retention and K+ excretion - > water retention

androgens/oestrogens - main source is gonads

Question 3

Compare the two types of corticosteroid receptors.

Why is this clinically relevant?

Answer 3

glucocorticoid receptors

• widely distributed
• selective for glucocorticoids
• low affinity for cortisol

mineralocorticoid receptor

• discrete distribution (kidneys)
• non- selsctive between alsosterone and cortisol
• high affinity for cortisol

in Cushing’s, you are producing too much cortisol and so 11b hydroxysteroid dehydrogenase 2 (11b HSD2) is overwhelmed (doesnt deaxtivate cortisol) and cortisol binds too much to the MR causing hypertensive episodes.

Question 4

What drugs are used to mimic human hormones?

Answer 4

Hydrocortisone - glucocorticoid with mineralocorticoid activity at HIGH DOSES

Prednisolone -glucocorticoid with WEAK mineralocorticoid activity.

Dexamethasone - glucocorticoid (synthetic) with NO mineralocorticoid activity.

Fludrocortisone - Aldosterone analogue.
- Used as an aldosterone substitute

Question 5

What are the different routes of administration of corticosteroids?
How are the distributed?
What is their duration of action?

Answer 5

Oral

• hydrocortisone
• prednisolone
• dexamethasone
• fludrocortisone

Parenteral (IV or IM)
- hydrocortisone
- dexamethasone.
I.E. in an Addisonian crisis

Distribution
Often bind to plasma binding proteins (e.g. CBG and albumin) as cortisol does in the blood.

Duration of Action

• Hydrocortisone - ~8 hours- Hence why hydrocortisone is re-administered several times a day in Addison’s patients.
• Prednisolone – ~12 hours.
• Dexamethasone - ~40 hours

Question 6

What happens in corticosteroid replacement therapy for primary adrenocorticoid failure?

Answer 6

i.e. Addison’s Disease/Syndrome

Patients lack cortisol and aldosterone.

Treated with hydrocortisone (for cortisol) and fludrocortisone (for aldosterone) orally.

Question 7

What happens in corticosteroid replacement therapy for secondary adrenocortical failure?

Answer 7

i.e. ACTH Deficiency

Patients lack cortisol but aldosterone is normal.

Treat with hydrocortisone.

Question 8

What happens in corticosteroid replacement therapy for acute adrenocortical failure?

Answer 8

i. e. Addisonian Crisis
1. IV saline (0.9% NaCl) - rehydrate.
2. High dose hydrocortisone - IV or IM every 6h. The high dose ensures there is a mineralocorticoid effect as the 11bHSD2 is overwhelmed.
3. 5% dextrose - if hypoglycaemic.

Question 9

What happens in corticosteroid replacement therapy for congenital adrenal hyperplasia?

Answer 9

i.e. 21-Hydroxylase Deficiency

Approx. 95% of cases are due to a lack of enzyme 21-hydroxylase - In 21-hydroxylase deficiency, 17a-hydroxyprogesterone accumulates as this is immediately before the enzyme block.

There is no cortisol production so ACTH rises and high ACTH drives further androgen production.

Therapy includes:
- Replace cortisol – dexamethasone/hydrocortisone.

• Supress ACTH (and thus adrenal androgen production).
• Replace aldosterone – fludrocortisone.

Monitor/optimise therapy by measuring:
- 17-hydroxyprogesterone levels.

Clinical assessments:

• GC dose too high – cushingoids.
• GC dose too low – hirsutism (as androgens still in excess).