Steroids Of The Adrenal Cortex Flashcards
Describe adrenal blood flow and functional zonation of steroid synthesis.
The blood flows from the outer cortex to the inner medulla.
There are layer-specific enzymes; this means that steroid synthesis in one layer can inhibit different enzymes in subsequent layers. This results in functional zonation of the cortex, with different hormones being made in each layer.
Describe mineralocorticoid function.
SODIUM RETENTION:
active reabsorption of sodium (with the associated passive reabsorption of water)
active secretion of potassium
VOLUME REGULATION (part of RAAS)
Describe the actions of aldosterone that aid in retaining water.
Aldosterone works by increasing the expression of specific membrane transporters for Na+, K+ and Cl-.
In particular, it stimulates Na+/K+ ATPase to make sure that there is a strong Na+ gradient for the Na+ to come in through an ENaC (epithelial Na channel), where water will also follow.
Cortisol and aldosterone have a similar affinity for the aldosterone receptor.
Circulating concentrations of cortisol are much higher than aldosterone, so why doesn’t cortisol stimulate salt and water retention?
cortisol is rapidly metabolised to inactive cortisone in the kidney
it requires an enzyme - 11 β-hydroxysteroid dehydrogenase type 2 - to be converted back to cortisol
liquorice contains a compound that blocks this enzyme
There is also a rare inactivating mutation of 11β-HSD2 that leads to a syndrome of apparent mineralocorticoid excess (AME).
Describe the glucocorticoid receptor.
It is a member of the nuclear receptor superfamily. It has a characteristic 3-domain structure:
ligand-binding
DNA-binding (binds to HRE on genomic DNA)
N-terminal transcription cofactor-binding
The receptors dimerise on ligand binding and translocate to the nucleus.
There is only one gene for the glucocorticoid receptor, but we get two different variants due to the alternate splicing of the 9th exon, giving rise to two major isoforms of the GR - α and β.
Glucocorticoid response elements can be positive or negative. The positive GREs result in transactivation, when the GR enhances transcription of the target gene. The negative GREs result in transrepression, when the GR represses transcription of the target gene.
Many anti-inflammatory effects of GCs are thought to be due to transrepression - this is a major therapeutic research target.
List the functions of glucocorticoids.
DECREASED GLUCOSE UTILISATION (GLUCOSE SPARING):
- proteolysis, gluconeogenesis, lipolysis
CARDIOVASCULAR EFFECTS:
required for vascular integrity and maintenance of blood pressure (it is thought that cortisol exerts its actions by modulating the NO system, downplaying the NO effect)
hypocortisolism: inapporpriate vasodilation, hypotension
hypercortisolism: hypertension
ANTI-INFLAMMATORY, IMMUNOSUPPRESSIVE:
we have had nearly 70 years of GC therapy; it is a highly profitable industry as they are extremely effective drugs
however, it is a double-edged sword (with the metabolic effect: if on the drugs long-term, more chance of developing hyperglycaemia, insulin resistance, etc.)
How are the anti-inflammatory effects of cortisol mediated?
Glucocorticoids inhibit the inflammatory response by inducing Annexin-1, which inhibits Phospholipase A2 (PLA2) and inhibits the induction of COX-2. Both of these are enzymes involved in the pathways to create inflammatory mediators.
EDIT: What are the different types of adrenal insufficiencies?
PRIMARY ADRENAL INSUFFICIENCY: Addison’s Disease
SECONDARY ADRENAL INSUFFICIENCY: hypothyroidism (isn’t it HYPOPITUITISM?), secondary to failure in RAAS
enzyme defects in the steroid synthesis pathways
What are the clinical features of Addison’s Disease?
low circulating adrenal steroids
high ACTH
plasma [Na+] normal to low
plasma [K+] normal to high
elevated plasma renin
It may be unmasked by significant stress or illness - shock, hypotensions, volume depletion (adrenal crisis).
Describe the ACTH receptor.
The ACTH receptor is a member of the melanocortin group of receptors.
Different forms of melanocyte-stimulating hormones bind to melanocortin receptors.
ACTH can also bind to other melanocortin receptors.
Excess circulating cortisol may cause skin pigmentation.
Describe hypercortisolism (plus its clinical features).
Cushing’s Syndrome is where there is excess glucocorticoid.
It can be ACTH-dependent:
Cushing’s Disease: due to an increased ACTH secretion (typically due to a pituitary oedema, secondary)
Ectopic ACTH-secreting tumour
It can also be ACTH-independent:
adrenal oedema or carcinoma (primary)
Iatrogenic: effect of GC therapy
CLINICAL FEATURES:
hypertension
hyperglycaemia
truncal obesity
fatigue, muscle weakness
virilisation (hirsutism in females)
depression, mood or psychiatric disturbances
How would you diagnose hypercortisolism?
First, we would confirm the hypersecretion of cortisol:
24-hour urinary cortisol
cortisol at nadir of secretion (around midnight)
Next, we determine the cause:
plasma ACTH
dexamethosome suppression test
Summarise what the different results of the dexamethasone suppression test mean.
low doses will normally suppress ACTH secretion via negative feedback
a low dose fails to suppress ACTH secretion with pituitary disease (Cushing’s)
a higher dose will suppress ACTH secretion in Cushing’s
no suppression with low or high doses suggests an ectopic source of ACTH (eg. a tumour elsewhere)
