The long-term objective of this research is to elucidate the mechanisms responsible for the regression of the corpus luteum at the termination of non-fertile menstrual cycles as well as to understand the mechanisms by which chorionic gonadotropin rescues the corpus luteum during early pregnancy. In previous years of support we investigated the role of pituitary LH secretion on the maintenance of luteal function and lifespan. While our results provided unequivocal evidence that LH secretion is absolutely required for progesterone production by the corpus luteum, our data also demonstrated that spontaneous luteal regression at the termination of non-fertile cycles in not due to changes in the pattern of LH secretion. Therefore, the overall goal of the current proposal is to investigate mechanisms intrinsic to the corpus luteum that may be responsible for luteal regression. The overall hypothesis we wil test is that the specialized functions of the corpus luteum (steroid and protein synthesis and release) are independently superimposed on a cellular timing mechanism that results in a highly reproducible 14-16 day lifespan of the tissue. The foundation for this hypothesis is a direct result of our previous studies in which we demonstrated that a three day interruption of LH support to the corpus luteum caused a total cessation of luteal progesterone secretion but did not interfere with the lifespan of the tissue. In pursuit of testing this hypothesis, we will determine if luteal regression is due to a type of programmed cell death in which the degradation of genomic DNA with the concomitant loss in the fidelity of transcriptional processes is an early event in the process of luteal regression. For this purpose, we wil examine the integrity of genomic DNA during the period of luteal regression as well as steady state levels of mRNAs for major luteal cell proteins. Our hypothesis would be supported by the observation that degradation of genomic DNA precedes reductions in steady state mRNA levels during luteal regression. In addition, we will determine if the rescue of the corpus luteum by hCG is due to a delay in the degradation of DNA and/or increases in either the concentration and/or the duration of expression of mRNAs for major luteal cell proteins. Lastly, we will use our GnRH-pulsed animal model to determine whether LH is involved in the moment to moment regulation of gene expression in the corpus luteum or whether LH serves solely to regulate pre-existing pathways for steroidogenesis. These studies, in addition to providing basic information on the regulation of the corpus luteum, may also shed new information on the cellular mechanisms involved in the pathological conditions of the inadequate luteal phase and the short luteal phase, both of which are associated with infertility in humans.
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