The glucocorticoid-sparing effect of mifepristone in Cushing's syndrome is paradoxical because mifepristone is a glucocorticoid receptor (GR) antagonist, not a steroid synthesis inhibitor. ACTH and cortisol levels typically rise on mifepristone because:

• A Mifepristone stimulates adrenal CYP11B1 expression, increasing cortisol synthesis
• B Mifepristone acts as an ACTH secretagogue via CRH receptor agonism in the hypothalamus
• C Mifepristone inhibits cortisol binding to CBG (corticosteroid-binding globulin), increasing free cortisol
• D GR blockade removes cortisol's negative feedback on the HPA axis, increasing ACTH and cortisol output ✓

Explanation

Mifepristone (RU-486) blocks glucocorticoid receptors in target tissues and in the pituitary/hypothalamus, preventing cortisol from exerting negative feedback on ACTH secretion. As a result, the HPA axis perceives glucocorticoid deficiency and increases CRH and ACTH release. Cortisol levels rise compensatorily, but since GR is blocked, the clinical features of hypercortisolism (Cushing's) improve despite elevated cortisol. Monitoring ACTH and cortisol levels during mifepristone therapy is therefore not useful for assessing efficacy; clinical response and glucose levels are used instead. This is a clinically important pharmacological paradox.

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

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Written and medically reviewed by the StethoPrep medical team.