Adrenal Agents

The adrenal cortex makes glucocorticoids, mineralocorticoids and androgens. In primary adrenal insufficiency (Addison disease) the gland itself fails, so both cortisol and aldosterone fall. In secondary or tertiary adrenal insufficiency, mineralocorticoid function is usually preserved, because aldosterone is regulated by the renin–angiotensin system, independent of the pituitary and hypothalamus.

Fludrocortisone is a synthetic adrenocortical steroid with very potent mineralocorticoid properties, used only for its mineralocorticoid effects. It acts on the distal tubules of the kidney to increase sodium reabsorption and to increase urinary excretion of potassium and hydrogen ions — so it causes marked sodium retention and a rise in blood pressure. It is labeled as partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison’s disease, given with a glucocorticoid such as hydrocortisone, and for salt-losing adrenogenital syndrome (congenital adrenal hyperplasia).

Because its whole action is salt and water retention, its harms are too much of the same: hypertension, edema, weight gain, heart enlargement or heart failure, and hypokalemia with alkalosis. Blood pressure and serum electrolytes are checked regularly. The glucocorticoid partner (hydrocortisone and the rest) is on the Corticosteroids page.

The enzyme 11β-hydroxylase (CYP11B1) makes the final step of cortisol synthesis in the adrenal gland. Osilodrostat (Isturisa) is a cortisol synthesis inhibitor that blocks it, and it is labeled for endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not an option or has not been curative. Metyrapone (Metopirone) blocks the same 11β-hydroxylation step; its label indication is diagnostic — the metyrapone test for adrenal insufficiency.

Blocking the last step has predictable effects. Cortisol falls, so it no longer suppresses ACTH, and ACTH rises. The precursors pile up behind the block: 11-deoxycortisol and 11-deoxycorticosterone. On osilodrostat, adrenal androgens rise too, 11-deoxycorticosterone can activate mineralocorticoid receptors, causing hypokalemia, edema and hypertension, and the androgens can cause hirsutism, hypertrichosis and acne in women. If cortisol falls too far, the result is hypocortisolism — sometimes life-threatening adrenal insufficiency.

Other adrenal steroidogenesis inhibitors used for Cushing disease include ketoconazole — an antifungal, and the most commonly prescribed medication for Cushing, limited by hepatotoxicity — as well as etomidate and mitotane.

Mifepristone is a selective antagonist of the progesterone receptor at low doses and blocks the glucocorticoid receptor at higher doses. As Korlym it is labeled to control hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing syndrome who have type 2 diabetes or glucose intolerance and have failed surgery or are not candidates for it — not for type 2 diabetes unrelated to Cushing syndrome.

Because it acts at the receptor, mifepristone does not lower cortisol: the HPA axis responds by raising circulating cortisol further while its effects are blocked. Two consequences follow. Serum cortisol cannot be used to judge adrenal insufficiency, which has to be recognized clinically (weakness, nausea, fatigue, hypotension, hypoglycemia). Hypokalemia is common — it was observed in 44% of patients in a Cushing study — and if it persists despite potassium the label suggests adding a mineralocorticoid antagonist (spironolactone and eplerenone are on the Cardiovascular › Potassium-Sparing Diuretics page). Elevated cortisol may also activate mineralocorticoid receptors in the heart, so Korlym is used with caution in heart failure and coronary disease.

Its progesterone-receptor blockade explains the rest. Korlym carries a boxed warning: it terminates pregnancy, so pregnancy is excluded before treatment and prevented with a non-hormonal method during treatment and for one month afterward. Unopposed endometrial proliferation can cause endometrial thickening and vaginal bleeding.