Correct Answer: A. Metyrapone
Metyrapone is a selective 11β-hydroxylase inhibitor that blocks the final step of glucocorticoid synthesis in the adrenal cortex. This enzyme catalyzes the conversion of 11-deoxycortisol to cortisol in the zona fasciculata. By inhibiting this critical enzymatic step, metyrapone directly prevents glucocorticoid (cortisol) synthesis. Clinically, metyrapone is used diagnostically in the metyrapone stimulation test to assess hypothalamic-pituitary-adrenal (HPA) axis function and therapeutically in severe Cushing's syndrome when surgery is delayed or contraindicated. The drug causes a compensatory rise in ACTH (due to loss of negative feedback from cortisol), which drives accumulation of 11-deoxycortisol—a finding used diagnostically. Unlike other endocrine inhibitors, metyrapone's mechanism is specific to glucocorticoid synthesis and does not affect mineralocorticoid or androgen production significantly. This makes it the only option that directly inhibits glucocorticoid synthesis as its primary mechanism KD Tripathi Ch. 58.
Why the other options are wrong
B. Finasteride — Finasteride is a 5α-reductase inhibitor that blocks conversion of testosterone to dihydrotestosterone (DHT). It affects androgen metabolism, not glucocorticoid synthesis. While used in benign prostatic hyperplasia and androgenetic alopecia, it has no role in inhibiting cortisol production. NBE traps students who confuse endocrine inhibitors across different hormone pathways. C. Flutamide — Flutamide is a non-steroidal androgen receptor antagonist used in prostate cancer and severe acne. It blocks androgen action at the receptor level, not glucocorticoid synthesis. It does not interfere with any step of the adrenal steroidogenic pathway. This is a common distractor for students who recognize it as an endocrine drug but confuse its target hormone. D. Mifepristone — Mifepristone is a progesterone and glucocorticoid receptor antagonist (competitive antagonist at GR). It blocks glucocorticoid action at the receptor level after synthesis, not glucocorticoid synthesis itself. While it causes clinical signs of glucocorticoid deficiency, cortisol levels actually rise because negative feedback is lost. This is the key discriminator—antagonism ≠ synthesis inhibition.
High-Yield Facts
- Metyrapone blocks 11β-hydroxylase, the final enzyme in cortisol synthesis (11-deoxycortisol → cortisol).
- Metyrapone stimulation test: Normal response is ↑ ACTH and ↑ 11-deoxycortisol; absent response suggests pituitary or hypothalamic disease.
- Mifepristone is a GR antagonist (blocks action), not a synthesis inhibitor—cortisol levels rise due to loss of negative feedback.
- Finasteride and flutamide affect androgen pathways, not glucocorticoid synthesis.
- Metyrapone is used therapeutically in severe Cushing's syndrome when surgery is delayed, causing rapid cortisol reduction.
Mnemonics
SYNTHESIS vs ACTION inhibitors Metyrapone = Synthesis (blocks enzyme 11β-hydroxylase). Mifepristone = Action (blocks receptor). Remember: Metyrapone = Metabolic block; Mifepristone = Membrane receptor block. Metyrapone's 3 C's Cortisol ↓, CACTH ↑, C11-deoxycortisol ↑ (diagnostic triad in metyrapone test).
NBE Trap
NBE pairs metyrapone with mifepristone to trap students who confuse synthesis inhibition with receptor antagonism. Both affect glucocorticoid physiology, but metyrapone prevents cortisol production while mifepristone prevents cortisol action—a critical mechanistic distinction.
Clinical Pearl
In Indian tertiary centers, metyrapone is increasingly used as a bridge therapy in severe Cushing's syndrome (from pituitary adenomas) while awaiting transsphenoidal surgery—it provides rapid symptom relief by lowering cortisol within 24–48 hours, unlike other agents. The metyrapone stimulation test remains a gold-standard diagnostic tool in Indian endocrinology practice for differentiating central from primary adrenal insufficiency.
_Reference: KD Tripathi Pharmacology Ch. 58 (Adrenocorticosteroids); Harrison Ch. 375 (Adrenal Insufficiency)_