NOVEL CONTRACEPTIVES: CONTROL OF GAMETE TRANSPORT AND FERTILIZATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 我们的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）。 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。 我们的研究有三个目标。 目的1是检查是否与抗雌激素SERM（ZK-SERM;拜耳先灵葆雅）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疗法是否会在通过ONPRC非人灵长类避孕药核心的避孕试验期间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。 研究进展：我们测试了3、5和10 mg ZK-SERM/kg对精子通过输卵管受精部位的影响。 仅在10 mg/kg剂量下，精子运输减少。 这种高剂量对于避孕试验来说是不现实的。 我们已经开始研究一种新的SERM，SERM 710，剂量为0.1 - 0.6 mg/kg的恒河猴。 我们发现所有剂量都能阻断雌激素 在刺激子宫内膜生长的情况下，0.3 mg/kg以上的剂量抑制输卵管纤毛形成，0.6 mg/kg的剂量减少精子运输。这些研究为基于SERM的避孕药提供了支持性证据，该避孕药选择性地作用于生殖道水平，以防止卵子-精子相互作用，从而防止生育。

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.