NOVEL CONTRACEPTIVES: CONTROL OF GAMETE TRANSPORT AND FERTILIZATION

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 目标是研究一种新的女性避孕策略，该策略利用一类新型药物——选择性雌激素受体调节剂（SERM）。 SERM 是选择性调节多种组织中雌激素作用的化合物。 生殖道的正常功能需要雌激素，包括将精子运输到受精部位以及排卵后输卵管捕获卵母细胞。该研究有 3 个目标。 目标 1 是检查抗雌激素 SERM（ZK-SERM；Bayer-Schering Pharma AG）治疗是否会破坏/改变恒河猴的配子运输并因此受精。 目标 2 是确定 SERM 疗法是否会在通过 U54 非人类灵长类动物避孕核心进行避孕试验期间阻止猕猴的生育能力。 目标 3 将进一步评估 ZK-SERM 避孕疗法的可逆性和长期安全性。 进展：我们在猕猴中测试了一种新的 SERM，SERM-710，剂量为 0.1-0.6 mg/kg（皮下），并报告这些剂量的 SERM-710 阻断了雌激素刺激的子宫内膜生长。 高于 0.3 mg/kg 的剂量会抑制输卵管纤毛，0.6 mg/kg 则会减少精子运输。高于 0.3 毫克/公斤的剂量也会阻止排卵，这应该起到避孕作用。 我们评估了 ZK-710 的阴道给药，并报告用装有 50 mg SERM-710 的猕猴大小的阴道环治疗动物，可阻断雌激素刺激的阴道角化和子宫内膜质量，但不会改变卵巢周期，表明 SERM-710 的局部给药可能不会导致雌激素剥夺的全身效应。 我们建议基于 SERM-710 的避孕药对女性来说是可行的。

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.