Hypoadrenal Disorders Flashcards
How many carbon atoms does cholesterol have?
27
What determines which steroid hormones the different parts of the adrenal gland produce?
The combination of enzymes present in the different parts of the adrenal gland - hydroxylation in different positions of the cholesterol molecule gives different products
Which enzyme converts cholesterol to pregnenolone?
P450SCC = cholesterol side-chain cleavage enzyme
NOTE: Pregnenolone is the precursor for all the different steroid synthesis pathways (i.e. there is pregnenlone at the start of all of them)
The pituitary gland produces ACTH in response to what?
Stress → stimulates cortisol synthesis
Which enzyme converts corticosterone to aldosterone?
Aldosterone synthase (includes 18-hydroxylase)
State three causes of adrenocortical failure.
Adrenal glands destroyed
- Tuberculous Addison’s disease - TB (bacterial infection) commonest cause worldwide
- Autoimmune Addison’s disease - autoimmune disease commonest cause in UK
Congenital adrenal hyperplasia = disruption in the steroid synthesis pathway due to enzyme mutations → deficiency in functioning enzymes
State some consequences of adrenocortical failure.
In adrenocortical failure (Addison’s disease), you have a cortisol AND aldosterone deficiency
- Fall in blood pressure
- Loss of salt in the urine → hyponatraemia
- Increased plasma potassium → hyperkalaemia
- The above three consequences are all due to aldosterone deficiency
- Reduced Na+ reabsorption via Na+/K+ pump and hence reduced water reabsorption to increase blood volume
- Fall in glucose due to glucocorticoid deficiency
- Cortisol acts to increase blood glucose levels for use by the body in times of stress
- High ACTH resulting in increased pigmentation
- Vitiligo
- Eventual death due to severe hypotension
NOTE:
- Sex steroids (mainly testosterone and precursors) no longer produced in adrenal cortex too as a result of adrenocortical failure
- However, sex steroids can also be produced (from scratch) by gonads,
- Therefore, this lack of production by the adrenal cortex doesn’t cause much of a problem
Why does Addison’s cause skin pigmentation?
- The lack of cortisol stimulates the production of huge amounts of ACTH
- Lack of negative feedback on ACTH production by cortisol
- Due to the fact that cortisol levels are low, more and more ACTH is released to try and stimuate the adrenal cortex to produce cortisol
- POMC (pro-opiomelanocortin) is a pro-hormone - synthesisd in the anterior pituitary
- POMC is then broken down to form ACTH and MSH and endorphins and enkephalins and other peptides
-
High ACTH = high POMC = high MSH
- MSH (melanocyte-stimulating hormone) causes skin pigmentaion
NOTE:
- Endorphins = hormones naturally produced in response to pain
- Enkephalins = peptide released by CNS neurones and adrenal medulla which acts to reduce/control pain
Why do Addison’s patients get vitiligo?
Vitiligo is an autoimmune disease where you have antibodies attacking the melanocytes → white patches on skin (loss of pigment)
Autoimmune diseases tend to go hand-in-hand
- Probably due to the fact that there is already a fundamental problem in immune regulation, so when onea autoimmune disease develops, it is more likely another will develop too
State some tests for Addison’s disease.
You could measure:
- 9am cortisol = low in Addison’s (but should be high in normal person)
- Typical results in Addison’s = 100
- ACTH = high in Addison’s (but should be low in normal person)
- Normal range: 270-900
Then you could do a short synacthen test:
- Inject 250µg synthetic ACTH (synacthen) intramuscularly
- Measure cortisol response
- If they have functioning adrenals, they should start to produce cortisol
- However in Addison’s their cortiol levels would not increase regardless
- Typical results in Addison’s (cortisol at 9:30am) = 150
- Normal range: > 600
What is the most common cause of congenital adrenal hyperplasia (CAH)?
21-hydroxylase deficiency
What are the two degrees of CAH?
Complete enzyme deficiency
Partial enzyme deficiency
NOTE: Differences in the mutation of the gene determines whether the enzyme is completely non-functional (i.e. complete deficiency) OR the mutation allows lowe-level production of the functioning enzyme (i.e. partial deficiency)
- Mutation in the site determining active site structure could mean enzyme is non-functional
- Mutation is site recognised by TF could reduce rate of transcription and protein synthesis, resulting in lower amounts of functional enzyme
Which hormones are absent in complete 21-hydroxylase deficiency?
Cortisol
Aldosterone
Why are foetuses with CAH normally fine in utero?
In utero, the foetus will have maternal cortisol and aldosterone so don’t need to rely on their own endogenous production.
NOTE: These steroid hormones found in the mother’s blood circulation can cross the placenta to supply the foetus
What effect does 21-hydroxylase deficiency have on sex steroid synthesis?
It funnels the precursors towards the steroid synthesis pathway so you get an increase in adrenal sex steroids production
- Mainly testosterone (and androgens). will be in excess the adrenal cortex can’t produce oestradiol - doesn’t have the aromatase enzyme required
NOTE:
- Due to lack of cortisol, ACTH levels will be high to try and stimulate cortisol production in the adrenal cortex
- However, because the pathway for cortisol synthesis will be blocked due to 21-hydroxylase deficiency, the sex steroid synthesis pathway will be stimulated instead
-
NOTE:
- ACTH stimulates both cortisol and adrenal sex steroid production pathways, but cortisol is the main
- However, if one pathway is blocked, then the other pathway will be stimulated in excess
-
NOTE:
- Leads to excess sex steroid synthesis
- This could be the reason for the adrenal hyperplasia - increase in proliferation of the sex steroid producing cells (mainly in zona reticularis)
Describe and explain the presentation and explanation of complete 11-hydroxylase deficiency.
- With 11-beta hydroxylase deficiency there will be a build up of They will have high levels of 11-deoxycorticosterone
- 11-deoxycorticosterone has mineralocorticoid effects (behaves like alosterone)
- Therefore, they will have similar effects to having high aldosterone → HYPERTENSION and HYPOKALAEMIA
- There will still be some funnelling of precursors towards the sex steroid synthesis pathway so the child will also be
- NOTE: As virisation means masculanisation, boys may be missed because they tend to look normal
Describe and explain the presentation of 17-hydroxylase deficiency.
They will have high levels of mineralocorticoids: aldosterone (and 11-deoxycorticosterone - precursor for aldosterone synthesis)
- This is because the synthesis pathways for the other adrenocortical hormones are blocked
- High aldosterone → hypertension and hypokalaemia
Cortisol deficiency → borderline hypoglycaemia
- Because cortisol acts to increase blood glucose levels
- NOTE: They will also have a lot of infections because you need cortisol to cope with the stress of infections
Sex steroid deficiency → absence of secondary sexual characteristics, problems with puberty (i.e. becoming capable of reproduction)
