Endocrine Abstracts (2010) 22 OC4.4

Combined anticortisolic therapy by metyrapone, ketoconazole and mitotane: an alternative to adrenalectomy in severe Cushing's syndrome

Peter Kamenicky1,2, Céline Droumaguet1,2, Eric Baudin1,3, Sylvie Salenave1,2, Séverine Trabado1,4, Laure Cazabat1,2, Philippe Chanson1,2 & Jacques Young1,2

1Université Paris Sud-11, 94275 Le Kremlin-Bicêtre, France; 2Service d’Endocrinologie et des Maladies de la Reproduction, CHU de Bicêtre, 94275 Le Kremlin-Bicêtre, France; 3Service de Médecine Nucléaire et de Cancérologie Endocrinienne, Institut Gustave-Roussy, 94805 Villejuif, France; 4Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, CHU de Bicêtre, 94275 Le Kremlin-Bicêtre, France.

Context: Mitotane due to its adrenolytic action is highly effective in long-term management of ACTH-dependent Cushing’s syndrome (CS). However, the slow onset of its anticortisolic effect makes its use problematic in severe CS, when very rapid therapeutic response is required. Association with metyrapone and ketoconazole, rapidly acting steroidogenesis inhibitors, could warrant CS control while waiting for the full efficiency of mitotane and thus avoid urgently performed bilateral adrenalectomy.

Patients and methods: Ten patients, aged 18–75 years, presenting with serious CS were included: 6 had ectopic ACTH CS, 3 Cushing’s disease and 1 macronodular adrenal hyperplasia. All patients had clinical features of serious CS, 3 subjects had pulmonary embolism, 2 had serious specific cardiomyopathy, 1 developed pelvic abscesses and bedsore and 6 had severe hypokalemia. Their 24 h urine free cortisol excretion (UFC) ranged from 330 to 7080 μg/24 h (normal <50 μg/24 h). High dose combined medical therapy associating metyrapone (3–4.5 g/24 h), ketoconazole (800–1000 mg/24 h) and mitotane (3–6 g/24 h) was started concomitantly. UFC, morning plasma cortisol (F8h) and liver enzymes were monitored daily during the first week, once a week during the first month and then once monthly.

Results: In all cases, a rapid and dramatic improvement of clinical symptoms of hypercortisolism was observed. UFC levels normalized in 1–3 days ranging from 5 to 65 μg/24 h and remained low to normal at first and second month after the treatment onset. F8h was low: 1–10 μg/dl. Metyrapone and ketoconazole could be discontinued after 2–4.5 months of treatment and CS control was maintained by mitotane alone (UFC: 5–60 μg/24 h). Clinical tolerance was acceptable and no significant liver toxicity was observed.

Conclusion: In severe hypercortisolism, when no etiological treatment is possible, combined anticortisolic therapy allows to avoid bilateral adrenalectomy which is associated with increased morbidity and results in permanent hypoadrenalism requiring lifelong steroid replacement.

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