Steroids of the adrenal cortex Flashcards
What are the steroids of the adrenal cortex?
Glucocorticoids: principally cortisol in mammals: cortisol
Mineralocorticoids: aldosterone
Androgens
Cortisol:
“Stress hormone”, but essential to life
Metabolic, cardiovascular and immune functions
Aldosterone:
Maintains blood volume by regulating amount of body sodium
What is the adrenal gland divided into?
Medulla (in middle)
and
The cortex
What is the cortex divided into and what do each of these parts secrete?
Zona glomerulosa - Mineralocorticoids
Zona fasciculta - gluco-corticoids
Zona reticularis = adrenal androgens
What is found in the medulla?
Chromaffin cells
Medullary veins
Splanchnic nerves
What is the general function of mineralocorticoids?
Sodium retention (whole body sodium)
- Active reabsorption of sodium (with associated passive reabsorption of water)
- Active secretion of potassium
Volume regulation (part of RAAS) - Note: increased MC activity increases the amount of sodium retained in the body, not the concentration. This is because an osmotically-equivalent amount of water is retained with the sodium, so the concentration doesn’t change
What receptor does aldosterone bind to?
Can cortisol bind to this?
Mineralcorticoid receptor
yes
Circulating concentrations of cortisol much higher than aldosterone so why doesn’t cortisol stimulate salt and water retention?
Cortisol is rapidly metabolized to inactive cortisone in the kidney
Requires enzyme, 11beta-hydroxysteroid dehydrogenase type 2
Rare inactivating mutation of 11B-HSD2 leads to syndrome of apparent mineralocorticoid excess (AME)
Liquorice contains a compound that blocks this enzyme
What type of receptor do glucocorticoids bind to?
Describe the structure of these receptors
Member of the nuclear receptor super-family
Characteristic 3-domain structure:
Ligand-binding
DNA-binding (binds to HRE on genomic DNA)
N-terminal transcription cofactor-binding
Receptors dimerize on ligand binding and translocate to nucleus
What happens when a glucocorticoid binds to its receptor?
Transactivation
Transrepression
Transactivation: glucocorticoid receptor (GR) enhances transcription of target gene
Transrepression: GR represses transcription of target gene
Many anti-inflammatory effects of GCs thought to be due to transrepression – major therapeutic research target
What are the functions of glucocorticoids?
Decreased glucose utilization (glucose sparing)
- Proteolysis
- Gluconeogenesis (mainly from amino acids)
- Lipolysis
Overall: maintenance of blood glucose – essential for survival during fasting
How does glucocorticoids influence the CVS?
- Required for vascular integrity and maintenance of blood pressure
- hypocortisolism: inappropriate vasodilation, hypotension
- hypercortisolism: hypertension
How are glucocorticoids anti-inflammatory drugs and immunosuppressive?
60 years of GC therapy
Highly profitable industry
Extremely effective drugs
But it’s a double edged sword!
How can we get adrenal insufficiency?
Give an overview of Addison disease
Addison’s disease: primary adrenal insufficiency
Secondary (hypopituitarism; secondary to failure in RAAS)
Enzyme defect in steroid synthesis pathways
What does activation of ACTH receptors also cause?
What does this cause in Addison’s disease
Melanocyte receptors - epithelial cells - darkens the skin - protects from UV
Darkening of the skin
What is Cushing syndrome?
What causes Cushing’s syndrome?
Excess glucocorticoid
ACTH-dependent:
Cushing’s disease: due to increased ACTH secretion (typically due to pituitary adenoma: secondary)
Ectopic ACTH-secreting tumour
ACTH-independent:
Adrenal adenoma or carcinoma (primary)
Iatrogenic; effect of GC therapy
