Aromatase inhibitors III. Studies on the antifertility effect of 4-acetoxy-4-androstene-3,17-dione.
Aromatase inhibitors III. Studies on the antifertility effect of 4-acetoxy-4-androstene-3,17-dione.
复制标题
芳香酶抑制剂 III.
作者：
A. Brodie;J. Wu;D. Marsh;H. Brodie
乙酰氧基-4-雄甾烯-3，1，7-二酮（4-acetoxy-A）是一种有效的雌激素合成酶抑制剂。为了研究该化合物对雌激素依赖性过程的影响，用含有4-乙酰氧基-A（75 mg）的硅橡胶薄片处理大鼠。在间情期第1天将其插入皮下。当从预期的发情前期开始与雄性大鼠连续饲养时，7/8只大鼠在同居6-15天后没有交配。其他组的大鼠用含有4-乙酰氧基-A（100 mg）的硅橡胶薄片与s.c.每日两次注射（12.5 mg/kg）。卵巢静脉血中雌激素浓度测定表明，这种治疗可使动情前期雌激素激增幅度降低87%。随后的LH峰也被抑制超过90%，通过放射免疫测定法测量外周水平确定。只要给药持续（4天），所有大鼠均未交配。当雌二醇（100 μ g）加入到含有4-乙酰氧基-A的薄饼中时，对交配的影响可以逆转，9/10的大鼠在正常时间发生交配。多次注射4-乙酰氧基-A对交配大鼠进行治疗，可阻止或延迟着床。在较高剂量（100 mg/kg/天）下，该效应更为显著。与大鼠相反，仓鼠被认为不需要雌激素来植入。该过程在接受50 mg/kg/天4-乙酰氧基-A给药的所有仓鼠和接受100 mg/kg/天给药的73%的仓鼠中正常发生。我们的研究结果表明，芳香化酶抑制剂4-乙酰氧基-A通过阻止排卵和着床所需的雌激素产生而有效地抑制生育能力。
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.