SAT-039 - Metyrapone in the Management of Ectopic Cushing'S Syndrome: Clinical Insights from Three Cases

Background: Ectopic Cushing’s syndrome (ECS) is a rare, often rapidly progressive cause of ACTH-dependent hypercortisolism typically associated with metastatic neuroendocrine tumors (NET’s) and profound metabolic complications. While metyrapone is an established 11β-hydroxylase inhibitor, practical real-world guidance regarding initiation, dose titration, and monitoring in ECS is limited. We describe three patients with ECS treated with metyrapone, emphasizing biochemical response, clinical course, and implementation challenges.

Cases: Case 1 was a 56-year-old man with high-grade neuroendocrine carcinoma (Ki-67 90%) and severe hypercortisolism (urinary free cortisol [UFC] 22,528 µg/24h), refractory hypokalemia, and marked hyperglycemia. A 750 mg metyrapone test dose reduced serum cortisol within hours (>123 to 57 µg/dL), and metyrapone 250 mg QID with concurrent chemotherapy achieved biochemical control within days, enabling discontinuation of mineralocorticoid-directed therapies. Case 2 was a 67-year-old man with metastatic pulmonary neuroendocrine carcinoma and hypercortisolism (UFC 4,345 µg/24h) complicated by progressive hypertension, edema, metabolic alkalosis, and hypokalemia. After brief osilodrostat treatment, due to access limitations, metyrapone was initiated and titrated to 500 mg TID resulting in a more rapid cortisol decline with improvement in blood pressure, volume status, and electrolyte stability. Case 3 was a 64-year-old man with metastatic prostate cancer and marked hypercortisolism (UFC 4,453 µg/24h); metyrapone 250 mg QID reduced cortisol by the following day (60 to 15.5 µg/dL), allowing antihypertensive de-escalation and potassium stabilization. A block-and-replace strategy with physiologic glucocorticoid replacement was utilized to mitigate adrenal insufficiency risk. Across cases, metyrapone produced rapid biochemical control (hours to days) but required frequent monitoring (electrolytes, particularly potassium) and was complicated by medication access barriers and limited provider familiarity.

Conclusion: Metyrapone provides rapid and effective biochemical control of severe hypercortisolism in ECS associated with metastatic NET’s. In such circumstances we suggest initiating 1000 to 1500 mg of metyrapone daily, in divided doses, with physiologic hydrocortisone while simultaneously stopping mineralocorticoid antagonists and closely monitoring electrolytes. Morning cortisol and 24h urine cortisol can be used to assess control in conjunction with clinical parameters. While biochemical control can improve quality of life, mortality is high, and optimal management requires multidisciplinary coordination to expedite diagnosis and medication acquisition, its safe initiation, and alignment with patient-centered care goals.

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