NOVEL CONTRACEPTIVES: CONTROL OF GAMETE TRANSPORT AND FERTILIZATION

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The 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. The study has 3 aims. Aim 1 is to examine whether therapy with an antiestrogenic SERM (ZK-SERM; Bayer-Schering Pharma AG) 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 U54 Nonhuman Primate Contraceptive Core. Aim 3 will further assess the reversibility and long-term safety of ZK-SERM therapy for contraception. Progress: We tested a new SERM, SERM-710, at doses 0.1- 0.6 mg/kg (s.c.) in macaques and report these doses of SERM-710 blocked estrogen stimulated endometrial growth. Doses above 0.3 mg/kg suppressed oviductal ciliation and 0.6 mg/kg reduced sperm transport. Doses above 0.3 mg/kg also blocked ovulation, which should be contraceptive. We assessed vaginal administration of ZK-710 and report that treating animals with macaque-sized vaginal rings filled with 50 mg SERM-710 blocked estrogen-stimulated vaginal cornification and endometrial mass, but did not alter ovarian cyclicity indicating that local administration of SERM-710 may not result in systemic effects of estrogen deprivation. We propose that a SERM-710 based contraceptive is feasible for women.