Ketoconazole revisited: a preoperative or postoperative treatment in Cushing's disease

Context: Although transsphenoidal surgery remains the first-line treatment in Cushing's disease (CD). recurrence is observed in about 20% of cases. Adjunctive treatments each have specific drawbacks. Despite its inhibitory effects on steroidogenesis, the antifungal drug ketoconazole was only evaluated in series with few patients and/or short-term follow-up. Objective: Analysis of long-term hormonal effects and tolerance of ketoconazole in CD. Design: A total of 38 patients were retrospectively studied with a mean follow-up of 23 months (6-72). Setting: All patients were treated at the same Department of Endocrinology in Marseille. France. Patients: The 38 patients with CD, of whom 17 had previous transsphenoidal surgery. Intervention: Ketoconazole was begun at 200-400 mg/day and titrated up to 1200 mg/day until biochemical remission. Main outcome measures: Patients were considered controlled if 24-h urinary free cortisol was normalized. Results: Five patients stopped ketoconazole during the first week because of clinical or biological intolerance. On an intention to treat basis, 45% of the patients were controlled as were 51%, of those treated long term. Initial hormonal levels were not statistically different between patients controlled or uncontrolled. Ketoconazole was similarly efficacious as a primary or postoperative treatment. Among 15 patients without visible adenoma at initial evaluation, subsequent follow-up allowed identification of the lesion in five cases. No adrenal insufficiency was observed. Adverse effects were rare in patients treated long term. Conclusions: Ketoconazole is a safe and efficacious treatment in CD. particularly in patients for whom surgery is contraindicated, or delayed because of the absence or image of adenoma on magnetic resonance imaging.