The overall objective of this proposal is to determine the hormonal regulation of endometrial response during the primate menstrual cycle. The ability to produce artificial menstrual cycles in ovariectomized rhesus monkeys provides the experimental means necessary to analyze in detail the regulation of endometrial response to estradiol (E) and progesterone (P). Because the most common endocrinopathy in women with recurrent abortion and infertility is a luteal phase defect, our studies will focus on adequate versus inadequate secretory phases. Responsiveness of target cells to E and P appears to depend in large part on the availability of specific receptor protein for these hormones within target cells. Consequently, an understanding of the mechanisms that regulate target cell receptors for E and P is essential to our knowledge of endometrial response. The role of autocrine/paracrine factors that may act as secondary mediators of modulators of hormonal stimulation will be pursued. The above facots will be studied by semi-quantitatie RT-PCR, PCR, immunohistochemistry. and in situ hybridization. The presence and regulation of these factors by E and P within different endometrial cell types and zones in the primate is poorly understood. We will also use a subtracted P-dependent cDNA population and a subtracted cDNA population containing genes whose expression is highly induced or dependent on high P for pCR analysis of specific gene products. This later approach will allow us to determine which endometrial genes are not expressed or are underexpressed in inadequate luteal phases. In addition, we will continue to select P-dependent genes from our subtracted library for sequencing in order to find novel P-induced genes with the use of differential gene display techniques. Disorders of fertility, endometrial hyperplasia and endometriosis may be better understood by a thorough and systematic analysis of the factors which regulate endometrial proliferation, differentiation, regression and repair. An understanding of these mechanisms may provide an additional basis for the design and application of new therapies which can alter hormone action, as well as, provide an appreciation for their use and potential consequences during therapy.
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