Control of Gamete Transport and Fertilization

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Our goal in this proposal is to investigate a novel strategy for female contraception that utilizes a new class of drugs, the Selective Estrogen Receptor Modulators (SERMs). SERMs are compounds that selectively regulate estrogen action in various tissues. Estrogen action is required for normal function of reproductive tract tissues. These functions include: the transport of spermatozoa to the site of fertilization in the fallopian tube; the capture of the oocyte by the fallopian tube after ovulation; the transport of the developing embryo to the uterus; and implantation of the embryo into the endometrium. Our hypothesis is that anti-estrogenic SERM therapy, targeting the reproductive tract, will result in a selective blockade of spermatozoa/oocyte transport and hence fertilization. Evidence for this possibility emanates from our observation that daily administration of a novel nonsteroidal SERM, ZK-SERM (Schering AG) blocked estrogen action in the rhesus macaque reproductive tract, resulting in atrophy of the cervical and endometrial mucosa, and suppression of oviductal ciliation and secretion. To test this hypothesis, we propose in Specific Aim 1 to examine whether therapy with ZK-SERM, our prototype SERM, will disrupt gamete transport and or fertilization in rhesus macaques. In additional experiments, we will examine morphological, biochemical and molecular endpoints within the reproductive tract that may participate in altered gamete transport and fertilization. We further hypothesize that SERMs, like ZK-SERM, that selectively block estrogen action in the reproductive tract, can provide a promising group of compounds for contraception. In Specific Aim 2 we propose to demonstrate that SERM therapy will block fertility in cynomologus macaques during a contraceptive trial through the ONPRC Nonhuman Primate Contraceptive Core. We will then assess the reversibility of the SERM-based contraceptive effect. In Specific Aim 3 we will assess the long-term effects of SERM treatment on ovarian function, menstrual cyclicity, bone mass and pelvic floor connective tissues. This research, "at the end of the day" will provide a definitive assessment of the contraceptive potential of selective antiestrogenic SERM therapy targeting the reproductive tract. We will have a strong understanding of the effects of antiestrogenic SERM therapy on gamete transport and reproductive tract functions. In addition we will have data on the safety of SERM therapy. These data will provide a basis for new studies on the mechanisms of SERM action "down stream" of estrogen receptor-ligand interactions in future studies.