Steroids of the Adrenal Cortex Flashcards
Describe adrenal blood flow.
Flows from outer cortex to inner medulla.
Describe adrenal functional zonation of steroid synthesis.
- Layer-specific enzymes
- Steroid synthesis in one layer can inhibit different enzymes in subsequent layers.
- 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.
- Increase expression of specific membrane transporters for Na+, K+ and Cl-.
- Stimulates Na+/K+ ATPase
- Strong Na+ gradient for Na+ enter through an ENaC 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 rapidly metabolised to inactive cortisone in kidney
- Requires an enzyme - 11 β-hydroxysteroid dehydrogenase type 2 - to be converted back to cortisol
Describe the glucocorticoid receptor. PART 1
Member of the nuclear receptor superfamily. It has a characteristic 3-domain structure:
- ligand-binding area
- DNA-binding (binds to HRE on genomic DNA)
- N-terminal transcription cofactor-binding
Describe the glucocorticoid receptor. PART 2
- Receptors dimerise on ligand binding and translocate to the nucleus.
- Only one gene for the glucocorticoid receptor
- 2 different variants due to alternate splicing of the 9th exon, giving rise to two major isoforms of GR - α and β.
Describe the glucocorticoid receptor. PART 3
- Response elements can be positive or negative.
- Positive GREs result in transactivation, when GR enhances transcription of target gene.
- Negative GREs result in transrepression, when the GR represses transcription
List the functions of glucocorticoids on glucose utilisation.
DECREASED GLUCOSE UTILISATION:
- proteolysis, gluconeogenesis, lipolysis
List the functions of glucocorticoids on the CVS.
- Required for vascular integrity and maintenance of blood pressure
- Hypocortisolism: inappropriate vasodilation, hypotension
- Hypercortisolism: hypertension
List the pharmaceutical functions of glucocorticoids.
- Highly profitable industry
- SIDE EFFECTS: hyperglycaemia, insulin resistance
How are the anti-inflammatory effects of cortisol mediated?
- Inhibit inflammatory response
- Induces Annexin-1, which inhibits Phospholipase A2 (PLA2) and inhibits the induction of COX-2.
What are the different types of adrenal insufficiencies?
- PRIMARY ADRENAL INSUFFICIENCY: Addison’s Disease
- SECONDARY ADRENAL INSUFFICIENCY: Hypopituitarism and RAAS defect
What are the clinical features of Addison’s Disease?
- Low circulating adrenal steroids but high ACTH
- Hyponatremia
- Hyperkalaemia
- Hypotension, volume depletion (adrenal crisis).
- Skin pigmentation
Describe the ACTH receptor.
- Member of melanocortin group of receptors.
- Different forms of melanocyte-stimulating hormones bind to melanocortin receptors.
- ACTH can also bind to other melanocortin receptors.
Describe hypercortisolism
Cushing’s Syndrome - excess glucocorticoid.
Describe the ACTH-dependent causes of hypercortisolism
- Cushing’s Disease: due to an increased ACTH secretion (due to pituitary adenoma)
- Ectopic ACTH-secreting tumour
Describe the ACTH-independent causes of hypercortisolism.
- Adrenal oedema or carcinoma
- Iatrogenic causes - effect of GC therapy
Describe the clinical features of hypercortisolism.
- Hypertension
- Hyperglycaemia
- Muscle weakness
- Depression
How would you diagnose hypercortisolism?
Confirm the hypersecretion of cortisol:
- 24-hour urinary cortisol
- cortisol at nadir of secretion (around midnight)
Determine the cause:
- dexamethosome suppression test
Summarise what the different results of the dexamethasone suppression test mean.
- Low doses will suppress ACTH secretion via negative feedback
- Low dose fails to suppress ACTH secretion with pituitary disease (Cushing’s)
- 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)
Why does Addisons cause hyperpigmentation?
- Lack of negative feedback from cortisol leads to increased production of ACTH.
- ACTH is derived from pro-opiomelanocortin (POMC), which is cleaved into ACTH and α-MSH, which regulates production of melanin in the skin.
- Overproduction of α-MSH leads to hyperpigmentation
When there is very low cortisol what two hormones are high?
- ADH - plasma dilution so low Na+
- ACTH
What is the pathway for the production of cortisol?
→ Hypothalamus makes CRH
→ CRH stimulates anterior pituitary
→ Anterior pituitary makes ACTH
→ ACTH stimulates the adrenal cortex
→ Adrenal cortex makes cortisol
What are prostaglandins and leukotrienes derived from?
Lipid-derived compounds
What is the juxtaglomerular apparatus stimulated by?
→ Increased sympathetic activity
→ Decreased perfusion pressure
→ Decreased Na+ and Cl-
What is the function of mineralocorticoid?
→ Na+ retention
→ Active Na+ reabsorption
→ Active secretion of K+
What is the zona fasciculata pathway?
Progesterone
↓
17 OH progesterone
↓
Deoxycortisol
↓
Cortisol
What is the pathway in the zona glomerulosa?
Cholesterol
↓
Pregnenolone
↓
Progesterone
↓
Deoxycorticosterone
↓
Corticosterone
↓
Aldosterone
What do the adrenal cortex and medulla secrete?
→ Steroid hormones - CORTEX
→ Adrenaline - MEDULLA
What does steroid hormone synthesis always start with?
Cholesterol
What are the steroids of the adrenal cortex?
- Glucocorticoids - cortisol
- Mineralocorticoids - aldosterone
- Androgens
