Reversal by human chorionic gonadotropin of the inhibitory effect of clomiphene on progesterone production by granulosa-luteal cells in culture

The possibility of a direct ovarian effect of clomiphene citrate was assessed in vitro by measuring progesterone release from cultured human granulosa-lutheal cells in both the presence and absence of hCG. Granulosa-luteal cells obtained by laparoscopic follicle aspiration following ovarian stimulation with hMG and hCG in women undergoing in vitro fertilization/embryo transfer were incubated for 72 hours in medium containing increasing concentrations of clomiphene (10^-9-10^-5 M) both without and with hCG (1 IU/mL). Clomiphene stimulated progesterone production in both the presence and absence of additional hCG at concentrations ≤ 10⁷ M. In both the presence and absence of hCG a dose-dependent inhibition of progesterone production was observed with higher concentrations of clomiphene (> 10⁶ M). hCG (1 IU/mL) significantly increased progesterone production in control cells and at all concentrations of clomiphene (10^-9-10^-5 M) tested. Low clomiphene (10^-9-10^-7 M) and hCG concentrations appeared to have a synergistic effect on progesterone production. Thus it appears that clomiphene has a direct ovarian effect on progesterone production, which is stimulatory at low concentrations and inhibitory at higher concentrations.