Adrenal Cortex Flashcards
Describe the structure of the adrenal cortex and the hormones produced
Zona Glomerulosa - round cells - aldosterone - few lipid droplets
Zona Fasiculata - bundles of cells - glucocorticoids - lots of lipid
Zona Reticularis - nets of cells - adrenal androgens - few lipid droplets
What are the sources of free cholesterol in the body?
Acetate synthesis - little
Circulating lipoproteins - moderate
Synthesis from cholesterol esters from within the cell - main
Outline the enzyme pathways involved in cholesterol production.
Hydroxymethylglutaryl CoA reductase (HMG - CoA reductase) - sythesises cholesterol from acetate
Cholesterol ester hydrolase (CEH) (hormone sensitive lipase) - hydrolyses cholesterol esters from LDLs/HDLs and intracellular stores
acyl-CoA: cholesterol acyl transferase (ACAT) - responsible for synthesis of cholesterol esters from cholesterol
What is the role of StAR?
It shuttles cholesterol to the mitochondrial membrane.
Is it the only protein involved in this process?
No - StAR mutants still have some steroid synthesis which indicates a role for translocator protein or TSPO.
What might cells deficient in StAR look like?
They would have an accumulation of lipid droplets as there would be no negative feedback on the pituitary by steroid hormones. The pituitary would continue to produce trophic hormones that result in phosphorylation of CEH through protein kinases.
What does P450scc do?
This is a side chain cleavage enzyme that is present on the inner mitochondial membrane. The first stage in steroid synthesis of cholesterol to pregnenolone.
What chemicals increase/decrease aldosterone secretion?
INCREASE
ACTH
low K
ANG II - by blocking outward potassium channels
DECREASE
ANP
What is the mechanism of release?
Influx of calcium. Hence why low K leads to influx of Ca.
What are its actions?
Increase renal sodium retention and potassium secretion
Water conservation
Other than causing increase aldosterone secretion, how does intracellular calcium regulate aldosterone levels?
It increases mitochondrial activity, delivery of cholesterol to the outer mitochondrial membrane, increases cholesterol ester hydrolase activity and increases StAR transcription.
Is ACTH important for zona glomerulosa cells?
It is not thought to be. Hypophysectomy seems to have little effect on ZG size compared to its effects on the ZF.
What does ACTH do to the ZF and ZR?
Increase glandular blood flow, improving lipoprotein delivery.
Stimulation of steroid synthesis.
Depletion of ascorbic acid
What are the chronic effects of ACTH?
Increased adrenal weight, cell size and number
Increased steroid enzyme synthesis & therefore steroids
What is its pattern of secretion?
It has a diurnal pattern of secretion
What type of receptor does it act through?
G alpha stimulatory
On which gene is it encoded?
POMC gene
What receptor does ACTH act on and describe how it can be affected by other proteins in contrast to other receptors of the same type?
MCR2 receptor. Melanocortin receptor adapter proteins (MRAPs) seem to enhance shuttling of the receptor to the cell membrane from the ER. However, the effect of MRAPs is the opposite on other MCRs.
Other than ACTH, is there another hormone that may stimulate DHEA production?
Possibly prolactin
What is the cause and general features of Cushings?
Disease caused by chronic overexposure to glucocorticoids. This can be iatrogenic as well as due to excess endogenous GC production.
Varying signs and symptoms including fat deposition in certain areas, ammenhorrhea in women, decreased male fertility. (this is because GCs block the GnRH-R)
How does GC action vary between muscle and liver?
Anabolic in the liver and catabolic in muscle.
What are the reasons for increased GC production?
NOT causing cushings:
- stress
- pregnancy (late stage)
- athletes
- depression, alcoholism, malnutrition, anxiety
CAUSING cushings
- pituitary adenomas
- adrenal adenomas
- ectopic ACTH production
What do adrenal adenomas normally not produce?
Aldosterone
How could a pituitary adenoma/adrenal adenoma be distiguished grossly?
Pit - diffuse hyperplasia
Adrenal - nodular hyperplasia
What inherited disorders could cause increased GC production?
Multiple endocrine neoplasia type 1 (MEN-1)
Primary pigmented micronodular adrenal disease
Ectopic receptor expression coupled to GPCRs
Overexpression of eutopic receptors
What are the tests for cushings and the normal resposes to them?
24 free urinary cortisol
midnight plasma or late-night salivary cortisol
dexmethasone suppression test - normal response is <50nmol/l after 8hrs.
Why might aminoglutethimizide not be a good choice of treatment for cushings syndrome?
It blocks P450scc so will indescriminatly prevent steroid synthesis.
What is Conn’s syndrome?
Primary hyperaldosteronism.
What is the cause of secondary hyperaldosteronism?
High ANG II levels, diuretic therapy can cause this.
What effects does hyperaldosteronism have?
Hypertension and sodium retention
Low K levels leading to muscle weaknesses and arrhythmias.
Metabolic alkylosis
What are the reasons for adrenal insufficiency?
Damage to the adrenals leads to primary insufficiency (Addison’s)
Defective ACTH secretion can lead to secondary insufficiency which is more common than addison’s.
What signs are seen with addisons but not secondary adrenal insufficiency?
hyperpigmentation as there is no necative feedback to the pituitary which will continue to produce ACTH and therefore POMC.
Describe the outcome of an ACTH stimulation test for:
a) a normal individual
b) an individual with addison’s disease
c) an individual with secondary adrenal insufficieny
d) an individual with an adrenal neoplasia
a) a doubling in plasma and urinary cortisol
b) a lack of response to ACTH (hyporesponsive)
c) an exaggerated response
d) an exaggerated response
How should an ACTH stimulation test be combined with other clinical tests?
Clinical history probably useful as well as whether cortisol is abnormally high or reduced.
What genes are/can be mutated in congenital adrenal hyperplasia (CAH)?
CYP21 - 21 hydroxylase
CYP11B1 - 11B-hydroxylase
What is the difference between salt sparing and salt wasting CAH and why is this so?
Mutation to CYP21 is higher up in the steroid synthesis pathway so aldosterone cannot be produced so this is considered salt WASTING.
A salt SPARING form of the disease occurs when only CYP11B1 is affected or when CYP21 is only partially affected.
