NOVEL CONTRACEPTIVES: CONTROL OF GAMETE TRANSPORT AND FERTILIZATION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 其目的是研究一种新的女性避孕策略，该策略使用一类新的药物-选择性雌激素受体调节剂(SERM)。SERM是选择性地调节各种组织中雌激素作用的化合物。雌激素是生殖道正常功能所必需的，包括将精子运送到受精部位，以及在排卵后由输卵管捕获卵子。这项研究有三个目标。目的1是检查抗雌激素SERM(ZK-SERM；拜耳先灵制药公司)治疗是否会干扰/改变配子运输，从而影响恒河猴受精。目标2是通过U54非人灵长类避孕核心，确定SERM疗法是否会阻止猕猴在避孕试验中的生育。目的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：我们测试了一种新的SERM，SERM-710，剂量为0.1-0.6 mg/kg(S.C.)在猕猴和报道这些剂量的SERM-710阻断雌激素刺激子宫内膜生长。0.3 mg/kg以上剂量可抑制输卵管调节，0.6 mg/kg剂量可降低精子转运。超过0.3毫克/公斤的剂量也会阻止排卵，这应该是避孕药。我们评估了ZK-710的阴道给药情况，并报告了用含有50 mg SERM-710的猕猴大小的阴道环治疗动物可以阻止雌激素刺激的阴道角化和子宫内膜肿块，但不改变卵巢的周期性，表明局部应用SERM-710可能不会导致雌激素剥夺的全身影响。我们认为基于SERM-710的避孕药对女性是可行的。

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.