Previous work from the applicant's laboratory has demonstrated that the administration of a gonadotropin-releasing hormone (GnRH) agonist brought about the suppression of luteal steroidogenesis that results in the termination of pregnancy. The applicant demonstrated that the administration of a GnRH agonist induces impairments in the steroidogenic pathway as well as in the apoptotic pathway in the corpus luteum (CL). Further, preliminary data indicate that GnRH mRNA levels increase as measured by RT-PCR and GnRH-immunoreactive peptide is higher in day 22 CL as compared to day 8 CL of pregnancy. Based on these findings, the applicant proposes that as pregnancy progresses in the rat, there is an increase in the expression of GnRH in the CL that ultimately leads to apoptosis and suppression of steroidogenesis in the CL and the termination of pregnancy. The applicant proposes to extend his observations in the rodent to the monkey in the current proposal. Studies proposed under the Specific Aim 1 will confirm in the monkey the earlier observations made in the rodents and other species that GnRH induces luteolysis. However, the real contribution of the proposed study would be establishing that GnRH acts directly at the level of the ovary/CL in inducing luteolysis in the monkey. This will be addressed under Specific Aim 2. The applicant proposes, under Specific Aim 3, to use various molecular approaches on the harvested CL, to determine how the administered GnRH suppresses the luteal production of progesterone by studying various steps in the steroidogenic pathway and also studying the apoptotic pathway.
Specific Aim 4 will determine the presence of GnRH, bradykinin and their receptors in the ovary/CL during the luteal phase of the menstrual cycle to determine if these transmitters play any role in the regulation of ovarian function in sub-human primates. The findings of this proposed study in the monkey model, will complement the preliminary data already obtained in other species, such as rat, bat and human and the data anticipated to be generated in these species should establish a role for the ovarian GnRH in the regulation of luteal function. Thus, the results of this study can help to facilitate fertility in infertile women where high levels of ovarian GnRH could be the cause for infertility or, GnRH could be used as an attractive agent in preventing pregnancy when desired.
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