Low dose ketoconazole attenuates serum androgen levels in patients with polycystic ovary syndrome and inhibits ovarian steroidogenesis in vitro

Objective: To investigate the effects of a low-dose ketoconazole on ovarian steroidogenesis and on serum androgen levels in polycystic ovary syndrome (PCOS). Design: In vitro, human granulosa-luteal cells were incubated with ketoconazole and radiolabeled steroid substrates, to follow their metabolic fate by thin-layer chromatography analysis. In vivo, normally cycling women (n = 7) in their luteal phase were administered one tablet of 200 mg ketoconazole at 8 A.M. Serum steroid levels, sampled basally and at 12 P.M., 4 P.M., and 8 A.M. the next morning, were compared with untreated control group (n = 7) values. Polycystic ovary syndrome women (n = 11) were similarly administered ketoconazole 6 to 10 days after occurrence of spontaneous menses. Adrenal origin of hyperandrogenemia was excluded by stimulation with ACTH and a normal basal DHEAS. The steroid diurnal variation was determined in the same patients a day before treatment. Results: In vitro, ketoconazole selectively inhibited the key steroidogenic cytochromes, namely P450(scc), P450(17α), and P450(arom) (IC₅₀ = 0.5 to 1.0 μg/mL). In vivo, in the luteal phase, ketoconazole transiently decreased serum values (mean ± SE) of E₂ (19.2% ± 2.1%) and P (38.3% ± 8.5%) within 4 to 8 hours. The same low-dose ketoconazole, administered to PCOS women, decreased serum values of androstenedione (17.6% ± 4.7%), T (24.6% ± 7.6%), and free T (30.7% ± 7.7%). In contrast, 17α-hydroxyprogesterone increased concomitantly (78.5% ± 10.8%), suggesting a greater suppressibility of the P450(17α) lyase activity. The E₂ levels in PCOS patients were slightly elevated (29.1% ± 5.6%), resulting in a 1.7- to 2.3-fold increase of the E₂:T ratio. Conclusions: These findings suggest that a low-dose ketoconazole may facilitate a decreased intraovarian T:E₂ ratio, which may prove favorable for follicular maturation in PCOS.