Hypoadrenal Disorders

Question 1

How many carbon atoms does cholesterol have?

Answer 1

27

Question 2

What determines which steroids the different parts of the adrenal gland produce?

Answer 2

The combination of enzymes present in the different parts of the adrenal gland – hydroxylation in different positions of the cholesterol molecule gives different products.

Question 3

Which enzyme converts cholesterol to pregnenolone?

Answer 3

Cytochrome P450 (short chain cleavage)

Question 4

Which sets of enzymes are switched on by ACTH?

Answer 4

Cortisol synthesis enzymes

Sex steroid synthesis enzymes

Question 5

The pituitary gland produces ACTH in response to what?

Answer 5

Stress

Question 6

Which enzyme converts corticosterone to aldosterone?

Answer 6

18-hydroxylase (part of aldosterone synthase)

Question 7

State three causes of adrenocortical failure.

Answer 7

Tuberculous Addison’s Disesae – most common cause worldwide
Autoimmune Addison’s Disease – most common cause in the UK
Congenital Adrenal Hyperplasia

Question 8

State some consequences of adrenocortical failure.

Answer 8

those due to lack of aldosterone:
1. Hypotension 
2. Hyperkalaemia 
3. Loss of salt (sodium) in urine  
(Aldosterone causes the kidneys to retain sodium and fluid while excreting potassium in the urine)

4. Hypoglycaemia (due to lack of cortisol)
5. High ACTH –> pigmentation (high ACTH)
   - due to loss of negative feedback by cortisol on pituitary
   - POMC breaks down into ACTH + MSH (leading to hyperpigemntation) and endorphins +enkephalinis

Eventual death due to severe hypotension

Question 9

Why do Addison’s patients get vitiligo?

Answer 9

Vitiligo is an autoimmune disease where you have antibodies against melanin
Autoimmune diseases tend to go hand-in-hand

Question 10

Why does Addison’s cause skin pigmentation?

Answer 10

The lack of cortisol stimulates the production of huge amounts of ACTH.
ACTH is formed from the cleavage of POMC (pro-opiomelanocortin) to ACTH and alpha-MSH High ACTH also means high alpha-MSH –> skin pigmentation

Question 11

State some tests for Addison’s disease.

Answer 11

9 am cortisol (this should be high in a normal person) is LOW
ACTH is HIGH in Addison’s
Short synacten test
Inject synthetic ACTH (synacthen) 250micrograms which is a large dose so should get a large increase in cortisol, if response barely changes then they have Addisons

Question 12

What is the most common cause of congenital adrenal hyperplasia (CAH)?

Answer 12

21-hydroxylase deficiency

Question 13

What are the two degrees of CAH?

Answer 13

Partial or Complete (absence of the enzyme)

Question 14

Why are foetuses with CAH normally fine in utero?

Answer 14

In utero, the foetus’ will have maternal cortisol and aldosterone so don’t need to rely on their own endogenous production.

Question 15

Which hormones are absent in complete 21-hydroxylase deficiency?

Answer 15

Cortisol and Aldosterone

Question 16

What effect does 21-hydroxylase deficiency have on sex steroid synthesis?

Answer 16

It funnels the precursors towards the steroid synthesis pathway so you get an increase in adrenal sex steroids.

Question 17

What will happen to a baby with complete 21-hydroxylase deficiency after they are born?

Answer 17

They will have a salt losing Addisonian crisis due to the lack of aldosterone.

Question 18

What are the two main features of 21-hydroxylase deficiency?

Answer 18

Hypotension

Virilisation (more obvious in female babies as will be born with ambiguous genitalia and may have clitoromegaly)

Question 19

Describe the presentation of partial 21-hydroxylase deficiency.

Answer 19

Present at any age as they’ll survive
Main issue is later in life- effects of the excess adrenal sex steroids are hirsutism and virilisation in girls and and precocious puberty in boys.

Question 20

Describe and explain the presentation and explanation of complete 11-hydroxylase deficiency.

Answer 20

With 11-beta hydroxylase deficiency there will be a build up of 11-deoxycorticosterone
-deficient in Cortisol and Aldosterone
11-deoxycorticosterone behaves like aldosterone and has mineralocorticoid effects so they don’t have a salt losing Addisonian crisis – they will behave as if they have HIGH aldosterone

They will be HYPERTENSIVE and HYPOKALAEMIC and Virilisation -the development of male physical characteristics (such as muscle bulk, body hair, and deep voice) in a female or precociously in a boy, typically as a result of excess androgen (male characteristic giving steroid hormone) production.

Question 21

Describe and explain the presentation of 17-hydroxylase deficiency.

Answer 21

Excess aldosterone, 1–deoxy corticosterone (the mineralocorticoids) meaning that they are hypertensive and hypokalaemic
Deficient in cortisol and sex steroids - hypoglycaemia

Question 22

What is the overall structure of the adrenal glands and what hormones are produced where?

Answer 22

Capsule is outermost, then cortex, then medulla innermost.
Adrenal cortex has three layers;
1. Zona glomerulosa (outer)- Mineralcorticoids including (Aldosterone)

2. Zona fasciculata- Glucocorticoids including Cortisol and 11-deoxycorticisterone, a aldosterone precursor,
3. Zona reticularis (inner)- Androgens including DHEA and androstenedione (the precursor to testosterone)

Question 23

What are the four types of Congenital Adrenal Hyperplasia?

Answer 23

1. Complete 21 hydroxylase deficiency
2. Partial 21 hydroxylase deficiency
3. 11 hydroxylase deficiency
4. 17 hydroxylase deficiency

Question 24

Describe the steroid hormone synthesIs pathway including the relevant hormones

Answer 24

Cholesterol 3 main pathways; cortisol, aldosterone, sex steroids
Sex steroids
Progestrone to 17OH progesterone via 17a hydroxylase which goes onto sex steroids

Cortisol
Progestrone to 17OH progesterone via 17a hydroxylase
17 OH progesterone to deoxycortisol via 21 hydroxylase
Deoxycortisol to cortisol via 11beta hydroxylase

Aldosterone
Progestrone to 11 deoxycorticosterone via 21 hydroxylase
11 deoxycorticosterone to corticosterone via 11beta hydroxylase
Corticosterone to aldosterone via aldosterone synthase

Question 25

What is the steroid precursor to these hormone?

Answer 25

Cholesterol