Effect of clomiphene citrate on preovulatory rat follicles in culture

The effect of clomiphene citrate was tested on rat preovulatory follicles in culture. Clomiphene inhibited both basal and luteinizing hormone (LH)-stimulated steroid accumulation. The dose-dependent effect of clomiphene was much more pronounced on follicles cultured with LH; while 0.01 mM had no effect, 2 mM clomiphene decreased progesterone accumulation by 97%, estradiol-17β by 90% and testosterone by 65% (P<0.001). The inhibitory action of the drug was not prevented by addition of 8-Br-cAMP (1 mM) or pregnenolone (1 μg/ml) to the culture medium. Clomiphene (0.01-0.5 mM) induced the resumption of meiotic maturation even in LH-free medium in approximately 60% of follicle-enclosed oocytes. At the higher concentrations tested (0.1-0.5 mM) degenerative changes were noted in a high proportion of oocytes (30-40%). Follicles incubated for 24 h with clomiphene exhibited dose-dependent atretic-like changes. These effects of clomiphene on preovulatory follicles may account for the discrepancy between ovulation and pregnancy rates observed in women treated with clomiphene.