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MECHANISM OF ANTI-IMPLANTATION ACTION OF CLOMIPHENE

Summary.: Clomiphene causes failure in implantation of blastocysts when administered to rats before implantation. This may be due either to a direct blastotoxic effect of the chemical or to elimination of blastocysts from the uterus. Further studies were made to elucidate the anti-implantation effect of the chemical. Clomiphene (0·3 mg/kg/day) was administered orally to rats on Day 9, Days 9 and 10, or Days 9, 10 and 11 after mating during experimentally induced delayed implantation. Uterine horns were flushed 24 hr after the last treatment. While 100% of the rats showed an average of four blastocysts/rat in initial controls, there was a marked reduction in the percentage (37·5) of rats showing blastocysts and in the number of blastocysts recovered from uteri of treated rats, depending on the dose and the time interval allowed for action of the compound. Ligation of uterine horns at the cervical end before treatment resulted in recovery of normal numbers of blastocysts in 75% of rats. These results indicate that blastocysts are expelled from non-ligated uteri. Initiation of oestrogen treatment (1µg/day) 6, 24 and 48 hr after first administration of clomiphene failed to cause implantation of blastocysts in ligated uteri. However, normal numbers of implantation sites were seen in the ligated horns of controls. It is, therefore, conceivable that failure of implantation following clomiphene administration may be due : (a) to increased motility of the uterus resulting in expulsion of the blastocysts; (b) to its anti-oestrogenic and/or antihistaminic activity which prevents preimplantation changes in the uterus normally initiated by exogenously administered oestrogen. Our results show that clomiphene has no direct cytolytic effects on the blastocysts.