Adrenal drugs compared — glucocorticoid vs mineralocorticoid activity, adrenal insufficiency vs Cushing syndrome

The adrenal cortex produces glucocorticoids, mineralocorticoids and androgens. Cortisol can activate both the glucocorticoid receptor and the mineralocorticoid (aldosterone) receptor; the enzyme 11β-hydroxysteroid dehydrogenase type II protects the mineralocorticoid receptor by converting cortisol to inert cortisone, but high cortisol levels — usually supraphysiologic doses of exogenous glucocorticoids — saturate it. Mineralocorticoid activity means retention of sodium and water with potassium excretion, which leads to edema and hypertension.

Aldosterone is regulated by the renin–angiotensin system, independent of the hypothalamus and pituitary. So in primary adrenal insufficiency (Addison disease) both cortisol and aldosterone fall, whereas secondary or tertiary insufficiency (loss of ACTH) typically preserves mineralocorticoid function. Exogenous glucocorticoids are the most common cause of secondary and tertiary adrenal insufficiency.

Hydrocortisone is the first choice for adrenocortical insufficiency, and it is the definitive treatment of an adrenal crisis, started on clinical suspicion. Primary insufficiency also lacks aldosterone — hyponatremia, hyperkalemia, volume loss, salt craving and orthostatic hypotension — so fludrocortisone is added: a very potent mineralocorticoid, used only for its mineralocorticoid effects, acting on the distal tubules and collecting ducts to retain sodium and water and excrete potassium. Its dose is judged by blood pressure, edema, potassium and plasma renin activity: high renin means too little, and hypertension with suppressed renin and hypokalemia means too much.

Which glucocorticoid is used changes the fludrocortisone need. Hydrocortisone provides some mineralocorticoid effect, and crisis-level hydrocortisone has enough that fludrocortisone is unnecessary in the acute phase; dexamethasone lacks a mineralocorticoid effect, so it requires full fludrocortisone replacement.

Iatrogenic hypercortisolism is the most common cause of Cushing syndrome, so patients receiving exogenous corticosteroids by any route are identified before a work-up. The low-dose dexamethasone suppression test screens: an intact axis suppresses cortisol after dexamethasone, while pathological hypercortisolism resists that feedback; an abnormal result is verified with a 24-hour urinary free cortisol or a late-night salivary cortisol. Plasma ACTH then separates ACTH-independent (low ACTH — adrenal) from ACTH-dependent disease (normal or high ACTH — pituitary or ectopic), and the high-dose test suppresses the ACTH of Cushing disease but not of ectopic tumors. Dexamethasone is the preferred steroid because it is long-acting, binds the glucocorticoid receptor strongly, has minimal mineralocorticoid activity and does not interfere with cortisol measurement.

The drugs act at two levels. Synthesis inhibitors block 11β-hydroxylation, the final step to cortisol: osilodrostat (CYP11B1) for Cushing syndrome when surgery is not an option or not curative, and metyrapone, labeled as a diagnostic test of adrenal insufficiency; StatPearls also lists metyrapone, ketoconazole and osilodrostat as steroidogenesis inhibitors for Cushing — for metyrapone an off-label use in the US, where its label indication is the diagnostic test — with ketoconazole limited by hepatotoxicity. Blocking the last step raises the precursors — 11-deoxycorticosterone activates the mineralocorticoid receptor (hypokalemia, edema, hypertension) — and raises ACTH. Mifepristone instead blocks the glucocorticoid receptor (and the progesterone receptor): cortisol rises while its effects are blocked, so serum cortisol cannot be used to detect adrenal insufficiency. Its boxed warning is termination of pregnancy, and its hypokalemia may need a mineralocorticoid antagonist.

Primary hyperaldosteronism — autonomous aldosterone from an adrenal adenoma (Conn syndrome) or bilateral hyperplasia — presents with suppressed renin, high aldosterone and often hypokalemia, and mineralocorticoid receptor antagonists are first-line medical therapy. Spironolactone competitively blocks aldosterone receptors but is nonselective, also binding androgen and progesterone receptors (gynecomastia, loss of libido, menstrual irregularity); eplerenone has 100- to 1000-fold lower affinity for glucocorticoid, progesterone and androgen receptors, is favored for primary aldosteronism, and is an alternative when spironolactone’s antiandrogen effects are a problem.