NOVEL CONTRACEPTIVES: CONTROL OF GAMETE TRANSPORT AND FERTILIZATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our goal is to investigate a new strategy for female contraception that utilizes a novel class of drugs, the Selective Estrogen Receptor Modulators (SERMs). SERMs are compounds that selectively regulate estrogen action in various tissues. Estrogen is required for normal function of the reproductive tract, including transport of spermatozoa to the site of fertilization and capture of the oocyte by the fallopian tube after ovulation. Our study has 3 aims. Aim 1 is to examine whether therapy with an antiestrogenic SERM (ZK-SERM; Bayer-Schering Pharma) will disrupt/alter gamete transport and hence fertilization in rhesus macaques. Aim 2 is to determine if SERM therapy will block fertility in macaques during a contraceptive trial through the ONPRC Nonhuman Primate Contraceptive Core. Aim 3 will further assess the reversibility and long-term safety of ZK-SERM therapy for contraception. Progress: We tested 3, 5 and 10 mg ZK-SERM/kg on sperm passage to the site of fertilization in the oviduct. Only at 10 mg/kg was sperm transport reduced. This high dose would be unrealistic for a contraceptive trial. We have begun studies on a new SERM, SERM 710, at doses 0.1- 0.6 mg/kg in rhesus macaques. We found that all doses blocked estrogen stimulated endometrial growth, doses above 0.3 mg/kg suppressed oviductal ciliation and that at 0.6 mg/kg, sperm transport reduced. These studies provide supportive evidence for a SERM-based contraceptive in women that acts selectively at the level of the reproductive tract to prevent egg-sperm interaction and hence fertility.