Previous studies in the authors' laboratory suggest that the antiprogestin RU486 may directly affect human ovarian progesterone production. The possibility that this compound could affect other steps in human ovarian steroidogenesis was examined by studying its effects on estrogen production in cultured human granulosa cells and on human ovarian aromatase (AR) and 17-hydroxylase (17-OH) activities in vitro. RU486 had no effect on media estradiol (E2) levels as measured by radioimmunoassay (RIA) over a 24-hour incubation period. Furthermore, no effect on ovarian AR activity occurred at concentrations of RU486 100 times substrate. However, a dose-dependent decrease in the activity of 17-OH was observed with increasing amounts of drug. RU486 decreased 17-OH activity by 12 and 29% below that of basal activity at concentrations equal to and ten times substrate. At 50- and 100-fold excess, RU486 further decreased 17-OH activity by 42 (P less than 0.01) and 48% (P less than 0.005). In conclusion, RU486 directly inhibits human ovarian 17-OH activity, but does not affect AR activity or E2 production in vitro. Clinically observed decreases in serum E2 levels may be due to inhibition of enzymatic steps proximal to E2 synthesis. These findings support the authors' previous observations suggesting that RU486 has a direct affect on human ovarian steroidogenesis.
Read full abstract