Adrenal Agents

The adrenal cortex makes glucocorticoids, mineralocorticoids and androgens. Cortisol is driven by ACTH from the pituitary, but aldosterone is regulated by the renin–angiotensin system, independent of hypothalamic or pituitary signals. So in secondary or tertiary adrenal insufficiency mineralocorticoid function is typically preserved, while primary adrenal insufficiency (Addison disease) loses both cortisol and aldosterone.

The laboratory picture follows. Chronic primary adrenal insufficiency most commonly shows anemia, hyponatremia and hyperkalemia, with salt craving and orthostatic hypotension from volume depletion. Secondary adrenal insufficiency is more likely to cause hypoglycemia but not dehydration, hyperkalemia or skin hyperpigmentation. Mineralocorticoid deficiency is therefore the mark of primary disease, which is where fludrocortisone matters most (its label covers partial replacement in both primary and secondary insufficiency).

Fludrocortisone acetate is an inactive prodrug, hydrolyzed by esterases in the liver and body fluids. It binds a cytoplasmic receptor that moves to the nucleus and switches on responsive genes; its main sites of action are the distal convoluted tubules and collecting ducts, where it increases sodium and water retention and potassium and hydrogen-ion excretion. Its glucocorticoid activity is high, but at replacement doses the glucocorticoid side effects are not usually a problem, so it is used only for its mineralocorticoid effects — given together with a glucocorticoid such as hydrocortisone.

Replacement is judged by its effects. Supine and standing blood pressure, pulse, edema, serum potassium and plasma renin activity are followed, with liberal salt intake; the dose is set to keep renin in the reference range, and an elevated renin calls for more. In salt-wasting congenital adrenal hyperplasia the same reading applies: hypotension, hyperkalemia and high renin mean too little, while hypertension, tachycardia, suppressed renin and hypokalemia mean too much. The glucocorticoid partner matters too: hydrocortisone has some mineralocorticoid effect, but dexamethasone lacks it, so a patient on dexamethasone needs full mineralocorticoid replacement. In an adrenal crisis, the large hydrocortisone doses carry enough mineralocorticoid activity that fludrocortisone is unnecessary during the acute phase.

Congenital adrenal hyperplasia is the other labeled use (the salt-losing adrenogenital syndrome): about 75% of infants with classic 21-hydroxylase deficiency have the salt-wasting form, in which both cortisol and aldosterone are deficient.

11β-hydroxylase (CYP11B1) catalyzes the final step of cortisol synthesis, 11-deoxycortisol to cortisol. Osilodrostat inhibits it and is labeled for endogenous hypercortisolemia in Cushing syndrome when surgery is not an option or has not been curative; metyrapone inhibits the same 11β-hydroxylation step. Cortisol falls, its feedback on the pituitary is removed, and ACTH rises, pushing more steroid into the pathway behind the block.

The congenital form of the same defect predicts the side effects. In 11β-hydroxylase-deficient congenital adrenal hyperplasia, cortisol deficiency redirects synthesis toward mineralocorticoid and androgen excess: 11-deoxycorticosterone accumulates, causing hypertension, hypokalemia and alkalosis with suppressed renin, along with virilization. Osilodrostat reproduces this — 11-deoxycorticosterone can activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension, and accumulating androgens can cause hirsutism, hypertrichosis and acne in women. Push cortisol too low and the result is hypocortisolism, sometimes life-threatening, which can persist after the drug is stopped.

Metyrapone’s US label uses this physiology diagnostically. In the metyrapone test, an intact HPA axis responds to the block with a rise in 11-deoxycortisol — ACTH alone cannot separate normal from abnormal responses — while a gland without reserve can be tipped into acute adrenal insufficiency, so the test is done in hospital when insufficiency is suspected. Metyrapone may also suppress aldosterone synthesis, causing a mild natriuresis. StatPearls lists it with ketoconazole (an antifungal, limited by hepatotoxicity), etomidate, mitotane and osilodrostat among the adrenal steroidogenesis inhibitors used for Cushing disease — for metyrapone an off-label use in the US, where its label indication is the diagnostic test — and in the rare pregnancy with hypercortisolism it calls metyrapone the best medical adjunctive option.

Mifepristone antagonizes the progesterone receptor at low doses and the glucocorticoid receptor at higher doses, with little affinity for the mineralocorticoid receptor. Mifepristone and its active metabolites bind the glucocorticoid receptor more avidly than dexamethasone or cortisol. As Korlym it is labeled to control hyperglycemia from hypercortisolism in adults with endogenous Cushing syndrome and type 2 diabetes or glucose intolerance who have failed surgery or are not candidates for it.

Because it acts at the receptor, the HPA axis answers the blockade by raising circulating cortisol further while its effects stay blocked. Serum cortisol therefore cannot diagnose adrenal insufficiency on mifepristone; it has to be recognized clinically — weakness, nausea, fatigue, hypotension, hypoglycemia. Treatment is to stop Korlym and give glucocorticoids without delay, and high doses may be needed to overcome the receptor blockade; the long half-life (85 hours) shapes how long glucocorticoids are continued. Hypokalemia was observed in 44% of patients in a Cushing study, and the label suggests a mineralocorticoid antagonist (spironolactone or eplerenone — Cardiovascular › Potassium-Sparing Diuretics) if it persists despite potassium.

The progesterone-receptor blockade gives the box: Korlym terminates pregnancy, so pregnancy is excluded before treatment and after any interruption of more than 14 days, with non-hormonal contraception during treatment and for one month after. Unopposed endometrial proliferation can thicken the endometrium and cause vaginal bleeding. Mifepristone also inhibits CYP3A, which is why simvastatin, lovastatin and narrow-range CYP3A substrates are contraindicated with it, and at least 2 weeks should pass after stopping it before an interacting drug is started or increased.