Actions of adrenal steroids and treatment of adrenal disorders

Question 1

What is the Structural Anatomy of the Adrenal Gland ?

Answer 1

Adrenal Medulla;
- Neural crest origin
- Secretes Catecholamines (Important in immobilisation of glucose and fatty acids in fight or flight)

Adrenal Cortex;
- Mesodermal origin
- Zona Glomerulosa - Produces Mineralcoticoids (Aldosterone)
- Zona Fasciculata - Produces mainly Glucocorticoids (Cortisol and Corticosterone)
- Zona Reticularis - Produces mainly Androgens (DHEA and Testosterone precursors)

Question 2

What is the Physiology behind Adrenal Steroids?

Answer 2

Adrenal Steroids Physiology;
- Mineralocorticoids regulate salt/electrolyte and water balance - important for Na+ retention in the kidney to maintain blood pressure
- The main mineralocorticoid is Aldosterone

• The Glucocorticoids have widespread actions affecting carbohydrate and protein metabolism but also have potent effects on host defence mechanisms - largely immunosuppressive and anti-inflammatory
• The main Glucocorticoid in humans is hydrocortisone (also called Cortisol)
• Hydrocortisone actions are not completely separate from mineralcorticoid actions because it has equal potency for the GR and MR, so have substantial effects on water and electrolyte balance
• To limit the overlapping effects, synthetic drugs have been designed that are more selective
• With the exception of replacement therapy, glucocorticoids are used mostly for their anti-inflammatory and immunosuppressive properties

Important as treating with hydrocortisone can have substantial water and electrolyte affects

Question 3

How do we Regulate Adrenal Corticosteroids ?

Answer 3

Regulation of Adrenal Corticosteroids;

• Adrenals are part of the (H-P-A) axis.
• CRF and ADH (vasopressin) act on corticotrophs
  in anterior pituitary inducing ACTH release.
• ACTH stimulates the synthesis and secretion of
  both glucocorticoids and mineralocorticoids
  from the adrenal cortex.
• Renin-Angiotensin system aids ACTH to
  promote mineralocorticoid secretion.
• Recombinant ACTH is seldom used, instead a synthetic analogue is used - Tetracosactide (then check hydrocortisone levels).
• To mimic mineralocorticoid effect Fludrocortisone is principally used.
• To mimic glucocorticoids effect Prednisolone is principally used.

Question 4

What defects might inhibit how we make Corticosteroids, Mineralocorticoids and Sex Hormones?

Answer 4

• Diseases of Adrenocortical dysfunction are life threatening
• Conversion to Pregnenolone is rate-limiting step (RLS) regulated by ACTH which is stimulated by ACTH and Angiotensin 2
• Aminoglutethimide inhibits the rate limiting step
• Trilostane blocks 3-B-dehyd which can be used in treating Cushing’s and primary hyperaldosteronism
• Metyrapone prevents the B-hydroxylation of C11 (precursors of Aldosterone and Cortisone)
• Carbenoxolone inhibits conversion of hydrocortisone to cortisone in kidney

Question 5

What is the mechanism of action of Glucocorticoids ?

Answer 5

• Glucocorticoids bind to intracellular receptors and migrate to the nucleus, dimerise and regulate gene transcription
• Also rapid non-genomic effects mediated through signalling systems in cytosol, mediated by enzymes like cAMP-dependent protein kinase (PKA) but not all target genes are known (varies between tissues)
• Common glucocorticoids: Hydrocortisone, Prednisolone and Dexamethasone