M. Gal et al., LOW-DOSE KETOCONAZOLE ATTENUATES SERUM ANDROGEN LEVELS IN PATIENTS WITH POLYCYSTIC-OVARY-SYNDROME AND INHIBITS OVARIAN STEROIDOGENESIS IN-VITRO, Fertility and sterility, 61(5), 1994, pp. 823-832
Objective: To investigate the effects of a low-dose ketoconazole on ov
arian 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 fo
llow their metabolic fate by thin-layer chromatography analysis. In vi
vo, normally cycling women (n = 7) in their luteal phase were administ
ered 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 selec
tively 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, i
n the luteal phase, ketoconazole transiently decreased serum values (m
ean +/- SE) of E(2) (19.2% +/- 2.1%) and P (38.3% +/- 8.5%) within 4 t
o 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-hydroxyp
rogesterone increased concomitantly (78.5% +/- 10.8%), suggesting a gr
eater suppressibility of the P450(17 alpha) lyase activity. The E(2) l
evels in PCOS patients were slightly elevated (29.1% +/- 5.6%), result
ing in a 1.7- to 2.3-fold increase of the E(2):T ratio. Conclusions: T
hese findings suggest that a low-dose ketoconazole may facilitate a de
creased intraovarian T:E(2) ratio, which may prove favorable for folli
cular maturation in PCOS.