Response of pituitary-adrenal axis to corticotrophin releasing hormone in patients with Cushing's disease before and after ketoconazole treatment

Abstract

Ketoconazole is an antimycotic agent and a potent inhibitor of gonadal and adrenal steroidogenesis. It has been used successfully as a palliative treatment of Cushing's syndrome due to its ability to lower cortisol production. However, the effects of ketoconazole on ACTH and aldosterone secretion have not yet been clarified. We evaluated the effect of ovine corticotrophin releasing hormone (oCRH) (100 micrograms bolus) on plasma ACTH, cortisol and aldosterone levels in six patients with Cushing's disease before and after 4 to 6 weeks of treatment with ketoconazole 600 mg/d. Before treatment, plasma cortisol levels were high and significantly increased after oCRH stimulation in all cases, while various patterns of aldosterone secretion were observed. Patients with higher levels showed a greater response to oCRH, while two patients with very low aldosterone showed no response. ACTH showed a marked rise after oCRH administration in all patients with a maximum peak at 30-45 min. After ketoconazole treatment, both plasma cortisol and aldosterone were lowered and their response to oCRH was impaired. Basal ACTH levels were increased in four patients and ACTH response to oCRH was enhanced in all, compared to pretreatment. These findings confirm the inhibitory action of ketoconazole on basal and stimulated cortisol secretion. A similar inhibition affected aldosterone production, indicating that ketoconazole also interferes with the mineralocorticoid pathway. The enhanced response of ACTH to oCRH after the administration of ketoconazole argues against an inhibitory effect of this agent at the pituitary level and might best be explained by reduced negative cortisol feedback.