Adrenal Pathway Dysfunction

Question 1

What hormones does the adrenal cortex produce?

Answer 1

Corticosteroids - aldosterone and cortisol (and sex steroids)

Question 2

What is a steroid?

Answer 2

A molecule that comes from cholesterol

Question 3

What are the effects of angiotensin II on the adrenal glands?

What are the effects of aldosterone?

Answer 3

Activation of 3 hydroxysteroid dehydrogenases: 21, 11 and 18 hydroxylases to form aldosterone

Aldosterone controls BP, retains sodium and lowers potassium

Question 4

What are the effects of ACTH on the adrenal glands?

Answer 4

Activation of 3 hydroxysteroid dehydrogenases: 17, 21, 11 hydroxylases

Question 5

What are the steroid synthetic pathways?

Cholesterol —> aldosterone

Cholesterol —> cortisol

Answer 5

Hydroxylase = H

Cholesterol –> progesterone –(21H)–> 11-deoxycorticosterone –(11H)–> corticosterone –(18H)–> aldosterone

Cholesterol –> progesterone –(17H)–> 17-OHprogesterone –(21H)–> 11-deoxycortisol –(18H)–> cortisol

Cholesterol –> progesterone –(17H)–> 17-OHprogesterone –> sex steroids –> androgens –? oestrogen

Question 6

How does cortisol change over a day?

Answer 6

Has a dirunal rhythm, v. low at midnight, peaks at 8:30 before waking up, then declines throughout the day

Cortisol controls day and night - when we wake and sleep

Question 7

What is Addison’s disease?

What are the possible causes?

Answer 7

Primary adrenal failure due to:
Autoimmune system destroys adrenal cortex (most common in the UK)
TB of the adrenal glands (most common worldwide cause esp. in Africa)
Congenital adrenal hyperplasia - adrenal glands are big when born but not working
Tumour of the adrenal glands

Question 8

What are the clinical presentations of Addison’s disease and why?

Answer 8

Vitiligo may coexist

Increased pigmentation due to lack of cortisol = increased ACTH production = increased melanocyte stimulating hormone (MSH) production as they both come from the same precursor - POMC (which is cleaved to form ACTH and MSH)

No cortisol or aldosterone = low BP

Question 9

What are the consequences of adrenocortical failure?

Answer 9

Fall in BP
Loss of Na+ in the urine (lack of aldosterone - main function is to retain Na+ as it stimulates Na+ reabsorption in the DCT and CD)
Increased plasma potassium
Fall in glucose due to glucosteroid deficiency

Question 10

What is POMC?

Answer 10

Synthesised in pituitary, precursor to ACTH and MSH

Question 11

What are clinical suspicions for Addison’s?

Answer 11

Low Na+

Hyperpigmentation

Question 12

What are the tests for Addison’s disease?

Answer 12

Low 9am cortisol = 100 (270-900 normally) nM
High ACTH

Give them synthetic ACTH (synACTHen) 250ug via injection - then measure cortisol levels (in normal people it rises to more than 600nM, but cortisol levels in Addison’s barely change)

Question 13

What is the treatment for Addison’s / adrenal failure?

Answer 13

Aldosterone and cortisol replacement:

Aldosterone = short half life, degrades too quickly to give daily
Put fluorine into the aldosterone to make fludrocortisone = more stable as fluorine does not exist in natural steroids

Cortisol = given hydrocortisone which has too short of a half life for once daily, so the doses are given 3 times a day - 10mg in the morning, 5mg in the afternoon, 2.5mg in the evening

Question 14

How can cortisol be slowed down in degradation?

Answer 14

By adding a double bond in the stucture making 1-2 dehydro-hydrocortisone - has the right half life now

This is called Prednisolone - once daily, more potent (3-4mg)

Fludrocortisone 50 to 100 mcg daily

Question 15

What is the most common cause of congenital adrenal hyperplasia? Which hormones are affected?

How is this treated?

Answer 15

Commonest cause = 21 hydroxylase (21H) deficiency
Missing 21H - no aldosterone and no cortisol production (as 21H is required for both pathways)

Same treatment as Addison’s - aldosterone and cortisol replacement

Question 16

What are some side effects of congenital adrenal hyperplasia?

Answer 16

Due to the pathways of aldosterone and/or cortisol being blocked off - sex steroid pathway = more active

Girls = present more ambigious (harder to distinguish whether boy or girl due to increased testosterone)

Boys = more likely to miss increased testosterone levels

Question 17

At what age do they present (congenital adrenal hyperplasia)?

Answer 17

After birth - babies may have Addisonian crisis at home. If not treated, survive less than 24 hours

Question 18

What happens if the congenital adrenal hyperplasia is caused by partial 21H deficiency?

What age are they likely to present?

Answer 18

Some aldosterone and cortisol to get by

Issue is with excess sex steroids and testosterone

They can present at any age - early apparent puberty (e.g. when they are 4 or 5 years old, precocious puberty)

Question 19

How may girls present clinically with partial 21H deficiency?

Answer 19

Some pigmentation - high ACTH 
Lots of facial hair 
Lack of breast
Clitoralmegaly (i.e. developing into a penis) 
Heavy muscular appearance

Question 20

What occurs if there is an 11H deficiency?

How does it present clinically?

Answer 20

Cortisol and aldosterone are deficient

11-deoxy corticosterone (11DCS) behaves like aldosterone

Presents as hypertension, low K, virilisation (development of physical male characteristics) as the 11DCS and sex steroid pathways are elevated

Also have too much testosterone as the sex steroid pathway is elevated

Question 21

What occurs if there is a 17H deficiency?

How does it present clinically?

Answer 21

No sex steroid released, and no cortisol

Aldosterone pathway elevated = hypertension, low K

Males = produce no testosterone = feminised
Never go through puberty = no sex steroids
Always tired = no cortisol

Question 22

What is the treatment for 21H deficiency?

How much more potent is prednisolone that hydroxycortisone?

Answer 22

Replacement of cortisol and adosterone (like in Addison’s)

Prednisolone = 6-8x more potent than the hydroxycortisone

Question 23

What would be the treatment for 17H deficiency?

Answer 23

Only cortisol replacement

When they reach adolescence, they’re given sex steroid replacement

Question 24

What would be the treatment for 11H deficiency?

Answer 24

Only cortisol replacement