## Preoperative Management of Cushing Syndrome **Key Point:** Metyrapone is the preferred agent for rapid preoperative control of hypercortisolism in Cushing syndrome, particularly when surgery is planned within weeks. ### Mechanism of Action Metyrapone inhibits 11β-hydroxylase, the final enzyme in cortisol synthesis. This blocks the conversion of 11-deoxycortisol to cortisol, causing: - Rapid reduction in free cortisol (within 24–48 hours) - Shunting of precursors to ACTH-stimulated androgen production - Predictable dose–response relationship ### Why Metyrapone for Preoperative Use | Feature | Metyrapone | Ketoconazole | Mitotane | |---------|-----------|-------------|----------| | **Onset** | 24–48 hours | 3–5 days | 7–14 days | | **Reversibility** | Yes (stops within 24 h) | Yes | No (long half-life) | | **Preop suitability** | Excellent | Good | Poor | | **Monitoring** | 11-deoxycortisol, free cortisol | Free cortisol | 17-OH progesterone | **High-Yield:** Metyrapone allows rapid cortisol suppression before surgery and is completely reversible, making it ideal when a definitive procedure is imminent. ### Dosing Strategy - Start 750 mg/day in divided doses - Titrate based on 24-hour urinary free cortisol and plasma cortisol - Target: free cortisol in low-normal range (to avoid acute adrenal insufficiency) - Discontinue after surgery once pituitary function recovers **Clinical Pearl:** Metyrapone may cause hypokalemia and hypertension due to accumulation of 11-deoxycortisol (which has mineralocorticoid activity). Monitor electrolytes and BP closely. ### Adjunctive Measures - Potassium supplementation if needed - Antihypertensive therapy (e.g., calcium channel blocker) - Ensure adequate hydration [cite:Harrison 21e Ch 375]
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