Aromatase inhibitors III. Studies on the antifertility effect of 4-acetoxy-4-androstene-3,17-dione.

Abstract

Acetoxy-4-androstene-3,1 7-dione (4-acetoxy-A) was demonstrated to be an effective aroma- tase (estrogen synthetase) inhibitor in vitro. To study the effect of the compound on estrogen-dependent processes, rats were treated with silastic wafers containing 4-acetoxy-A (75 mg). These were inserted under the skin on Day 1 of diestrus. When housed continuously with male rats from the expected day of proestrus, 7/8 rats did not mate after 6-15 days of cohabita- tion. Other groups of rats were treated with silastic wafers containing 4-acetoxy-A (100 mg) together with s.c. injections twice daily (12.5 mg/kg). This treatment decreased the magnitude of the proestrus estrogen surge 87% as indicated by estrogen concentrations measured in ovarian vein blood. The subsequent LH surge was also inhibited over 90% as determined by measuring peripheral levels by radioimmunoassay. None of the rats mated as long as treatment lasted (4 days). When estradiol (100 �zg) was added to the wafers containing 4-acetoxy-A, the effect on mating could be reversed and mating occurred at the normal time in 9/10 rats. Treatment of mated rats with multiple injections of 4-acetoxy-A either prevented or delayed implantation. The effect was more marked at the higher dose (100 mg/kg/day). In contrast to the rat, the hamster is believed not to require estrogen for implantation. This process occurred normally in all hamsters treated with 50 mg/kg/day 4-acetoxy-A and in 73% of animals treated with 100mg/kg/day. Our results indicate that 4-acetoxy-A, an arOmatase inhibitor, effectively inhibits fertility by preventing estrogen production required for ovulation and implantation.