Ketoconazole inhibits multiple steroidogenic enzymes involved in androgen biosynthesis in the human ovary

Ketoconazole (KZ) has been shown to inhibit testicular and adrenal steroidogenesis and is useful in the medical management of gonadotropin-independent precocious puberty, prostatic cancer, and Cushing's syndrome. To determine whether KZ similarly affects ovarian steroidogenesis, the authors examined its effect on the activity of the human ovarian 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD), 17-hydroxylase (17-OH), and aromatase (AR) in vitro. A dose-dependent decrease in the activities of 3β-HSD and 17-OH was observed with increasing amounts of KZ. With 10, 50, and 100-fold excess KZ, the activity of 3β-HSD decreased by 59% (P < 0.001), 73% (P < 0.005), and 85% (P < 0.005), respectively. At equimolar concentrations with substrate (50 μM), KZ inhibited 17-OH by 70% (P < 0.01). No significant effect on ovarian AR activity was observed, except at the highest concentration of KZ tested. The authors conclude that low concentrations of KZ profoundly inhibit the activity of human ovarian 3β-HSD and 17-OH in vitro. These observations suggest that KZ might be useful in the medical management of women with hyperandrogenism, but further experimentation and clinical trials will be necessary.