Steroid synthesis inhibition by ketoconazole: sites of action

Ketoconazole is an antifungal agent that, in high doses, inhibits testicular and adrenal steroid synthesis. The ability of ketoconazole to block steroid synthesis has prompted us to use it in the treatment of advanced prostatic carcinoma. This study was designed to determine the site of steroid synthetic blockade that was induced by ketoconazole. Twelve patients with metastatic prostate carcinoma on long term high dose ketoconazole therapy were compared with 12 control volunteers. Values of serum progesterone, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone sulphate, testosterone, and cortisol were measured in a baseline state and after Cosyntropin and human chorionic gonadotropin stimulation. Baseline data showed that serum levels of testosterone, androstenedione, and dehydroepiandrosterone sulphate were lower and that plasma progesterone, luteinizing hormone, and adrenocorticotropin were higher in the ketoconazole group. With Cosyntropin, plasma cortisol, androstenedione, and dehydroepiandrosterone sulphate increased only in the control group. With human chorionic gonadotropin, testosterone increased only in the control group. Basal 17-hydroxyprogesterone and progesterone rose after Cosyntropin only in the ketoconazole group. Following human chorionic gonadotropin, progesterone rose in the ketoconazole group but not in the control group. These results suggest that ketoconazole is a potent inhibitor of steroid synthesis. The major site of action appears to be in the inhibition of 17-20 desmolase. A moderate blockade of 17-hydroxylase may be present. There is a marked inhibition of 21- and/or 11-hydroxylase. The ability of ketoconazole to inhibit steroid synthesis should have therapeutic potential in the treatment of steroid dependent disease. Frequent high dose ketoconazole therapy can inhibit adrenal steroid synthesis, which can be important for patients undergoing stressful situations.