Mifepristone (RU-486) blocks progesterone receptors but is also used to treat Cushing's syndrome. Which additional receptor interaction explains its use in hypercortisolism?

• A It inhibits adrenal 11-beta-hydroxylase reducing cortisol synthesis
• B It blocks CRH receptors in the hypothalamus suppressing the HPA axis
• C It competitively inhibits cortisol binding to corticosteroid-binding globulin
• D It is an antagonist at glucocorticoid receptors (type II glucocorticoid receptor / GR-II) ✓

Explanation

Mifepristone is a potent antagonist at both progesterone receptors (causing its abortifacient/contragestive effect) and glucocorticoid receptors (GR-II/NR3C1). By blocking glucocorticoid receptors peripherally without lowering cortisol levels, mifepristone is FDA-approved for controlling hyperglycaemia in patients with Cushing's syndrome who cannot have surgery. Metyrapone and ketoconazole inhibit adrenal steroidogenic enzymes (including 11-beta-hydroxylase). Pasireotide acts on somatostatin receptors to reduce ACTH secretion.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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