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Merits and pitfalls of mifepristone in Cushing's syndrome

Service d'Endocrinologie, diabète et maladies métaboliques, et Centre de reference des maladies rares d'origine hypophysaires DEFHY, Hôpital de la Timone, Marseille 13005, France¹ Endocrine and Diabetes Unit, Department of Medicine I, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97080 Wuerzburg, Germany² Dipartimento di Scienze Cliniche e Biologiche, Medicina Interna I, Orbassano 10043, Italy³ Service d'Endocrinologie, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, FR-75571 Paris Cedex 12, France⁴ Assistance Publique-Hôpitaux de Paris, Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre, and Université Paris Sud 11, and INSERM U693, F-94275 Le Kremlin-Bicêtre, France⁵ Clinique Endocrinologique Marc Linquette, CHU, 59037 Lille-Cedex, France⁶ Servicio de Endocrinología y Nutrición, Hospital General Universitario de Alicante, Alicante 03010, Spain

(Correspondence should be addressed to F Castinetti who is now at Laboratory of Dr Sally Camper, Department of Human Genetics, University of Michigan, 4109 Catherine Street, Ann Arbor, Michigan 48109, USA; Email: fredcast{at}umich.edu)

Objective: Mifepristone is the only available glucocorticoid receptor antagonist. Only few adult patients with hypercortisolism were treated to date by this drug. Our objective was to determine effectiveness and tolerability of mifepristone in Cushing's syndrome (CS).

Design: Retrospective study of patients treated in seven European centers.

Methods: Twenty patients with malignant (n=15, 12 with adrenocortical carcinoma, three with ectopic ACTH secretion) or benign (n=5, four with Cushing's disease, one with bilateral adrenal hyperplasia) CS were treated with mifepristone. Mifepristone was initiated with a median starting dose of 400 mg/day (200–1000). Median treatment duration was 2 months (0.25–21) for malignant CS, and 6 months (0.5–24) for benign CS. Clinical (signs of hypercortisolism, blood pressure, signs of adrenal insufficiency), and biochemical parameters (serum potassium and glucose) were evaluated.

Results: Treatment was stopped in one patient after 1 week due to severe uncontrolled hypokalemia. Improvement of clinical signs was observed in 11/15 patients with malignant CS (73%), and 4/5 patients with benign CS (80%). Psychiatric symptoms improved in 4/5 patients within the first week. Blood glucose levels improved in 4/7 patients. Signs of adrenal insufficiency were observed in 3/20 patients. Moderate to severe hypokalemia was observed in 11/20 patients and increased blood pressure levels in 3/20 patients.

Conclusion: Mifepristone is a rapidly effective treatment of hypercortisolism, but requires close monitoring of potentially severe hypokalemia, hypertension, and clinical signs of adrenal insufficiency. Mifepristone provides a valuable treatment option in patients with severe CS when surgery is unsuccessful or impossible.