on 11-Sep-2021 (Sat)

These are named after their effects on carbohydrate metabolism. Major actions are listed in Box 21.13. They act on intracellular corti- costeroid receptors and combine with coactivating proteins to bind the ‘glucocorticoid response element’ (GRE) in specific regions of DNA to cause gene transcription. Glucocorticoid action is modified locally by the action of 11β- hydroxysteroid dehydrogenase (11βHSD). 11βHSD type 1 converts inactive cortisone into active cortisol, hence amplifying the hormone signal, while 11βHSD type 2 does the opposite

The predominant effect of mineralocorticoids is on the extracellu- lar balance of sodium and potassium in the distal tubule of the kidney. Aldosterone, produced solely in the zona glomerulosa, is the predominant mineralocorticoid in humans (about 50%); corti- costerone makes a small contribution to overall mineralocorticoid activity. Mineralocorticoids act on type 1 corticosteroid receptors, while glucocorticoids act on type 2 receptors, both having a very similar structure. The mineralocorticoid activity of cortisol is weak but cortisol is present in considerable excess. The mineralocorti- coid receptor in the kidney is protected from this excess by the intrarenal conversion (‘shuttle’) of cortisol to cortisone by 11βHSD type 2

Although secreted in considerable quantities, most androgens have relatively weak intrinsic androgenic activity until metabolized periph- erally to testosterone or dihydrotestosterone. Dihydrotestosterone is metabolized from testosterone by 5α- reductase and is a potent androgen receptor agonist. The androgen receptor has been well characterized and mutations within this gene may cause androgen insensitivity syndromes

Cushing’s syndrome reflects a constellation of clinical features that result from chronic exposure to excess glucocor- ticoids of any etiology. The disorder can be ACTH-dependent (e.g., pituitary corticotrope adenoma, ectopic secretion of ACTH by nonpi- tuitary tumor) or ACTH-independent (e.g., adrenocortical adenoma, adrenocortical carcinoma [ACC], nodular adrenal hyperplasia), as well as iatrogenic (e.g., administration of exogenous glucocorticoids to treat various inflammatory conditions). The term Cushing’s disease refers specifically to Cushing’s syndrome caused by a pituitary corticotrope adenoma.

In the overwhelming majority of patients, Cushing’s syndrome is caused by an ACTH-producing corticotrope adenoma of the pitu- itary , as initially described by Harvey Cushing in 1912. Cushing’s disease more frequently affects women, with the exception of prepubertal cases, where it is more common in boys. By contrast, ectopic ACTH syndrome is more frequently identified in men. Only 10% of patients with Cushing’s syndrome have a primary, adrenal cause of their disease (e.g., autonomous cortisol excess independent of ACTH), and most of these patients are women. However, overall, the medical use of glucocorticoids for immunosuppression, or for the treatment of inflammatory disorders, is the most common cause of Cushing’s syndrome.