Combined anticortisolic therapy by metyrapone, ketoconazole and mitotane: an alternative to adrenalectomy in severe Cushings 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
Context: Mitotane due to its adrenolytic action is highly effective in long-term management of ACTH-dependent Cushings 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 1875 years, presenting with serious CS were included: 6 had ectopic ACTH CS, 3 Cushings 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 (34.5 g/24 h), ketoconazole (8001000 mg/24 h) and mitotane (36 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 13 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: 110 μg/dl. Metyrapone and ketoconazole could be discontinued after 24.5 months of treatment and CS control was maintained by mitotane alone (UFC: 560 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.