Long-term effects of ketoconazole in the treatment of residual or recurrent Cushing's disease

Ketoconazole is an imidazole derivative used to treat systemic and superficial mycoses by inhibiting sterol synthesis in fungi. The drug impairs steroid hormone synthesis by blocking mitochondrial P450-dependent enzyme systems. Because of its potent inhibitory effects on adrenal steroidogenesis, ketoconazole is valuable in controlling hypercortisolism. We investigated the effects of long-term treatment of this drug on three patients who had residual or recurrent Cushing's disease after surgical treatment. Ketoconazole was administered orally and adjusted according to individual response and 24-hour urinary free cortisol excretion levels. All three patients had good clinical and biochemical responses to ketoconazole therapy without adverse effects. The 24-hour urinary free cortisol levels were kept around 114.8 +/- 52.4 mu g/24 h, 143.0+/-59.9 mu g/24 h, and 122.9+/-79.9 mu g/24 h, respectively (reference range, 35 to 120 mu g/24 h). All three patients had follow-up magnetic resonance imaging or computed tomography of the pituitary gland, which revealed no significant changes in the sellar region. Daily ketoconazole doses ranged from 200 to 1200 mg per day. Follow-up periods were 65, 86, and 83 months, respectively. In conclusion, ketoconazole is valuable in the long-term treatment of residual or recurrent Cushing's disease when surgical treatment is contraindicated or unsuccessful.