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 occurence 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(17 alpha), and P450(arom) (IC50 = 0.5 to 1.0 mu g/mL). In vivo, in the luteal phase, ketoconazole transiently decreased serum values (mean +/- SE) of E(2) (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, 17 alpha-hydroxyprogesterone increased concomitantly (78.5% +/- 10.8%), suggesting a greater suppressibility of the P450(17 alpha) lyase activity. The E(2) levels in PCOS patients were slightly elevated (29.1% +/- 5.6%), resulting in a 1.7- to 2.3-fold increase of the E(2):T ratio. Conclusions: These findings suggest that a low-dose ketoconazole may facilitate a decreased intraovarian T:E(2) ratio, which may prove favorable for follicular maturation in PCOS.