NOVEL CONTRACEPTIVES: CONTROL OF GAMETE TRANSPORT AND FERTILIZATION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 而子项目的主要调查员可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 目的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）。 SERMs是选择性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和排卵后输卵管捕获卵母细胞。这项研究有三个目标。 目的1是检查是否与抗雌激素SERM（ZK-SERM;拜耳先灵制药公司）治疗将破坏/改变配子运输，因此在恒河猴受精。 目的2是确定SERM治疗是否会在避孕试验期间通过U 54非人灵长类避孕药核心阻断猕猴的生育能力。 目的3将进一步评估ZK-SERM避孕治疗的可逆性和长期安全性。 进度： 我们以0.1- 0.6mg/kg（s.c.）并报告了这些剂量的SERM-710阻断雌激素 刺激子宫内膜生长。 超过0.3毫克/千克的剂量会抑制输卵管纤毛形成，0.6毫克/千克的剂量会减少精子运输。超过0.3 mg/kg的剂量也会阻止排卵，这应该是避孕的。 我们评估了ZK-710的阴道给药，并报告用填充有50 mg SERM-710的猕猴大小的阴道环治疗动物阻断了雌激素刺激的阴道角化和子宫内膜质量，但没有改变卵巢周期性，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的避孕药对妇女是可行的。

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.