Although the hormonal mechanisms of the hypothalamic-pituitary-ovarian axis have been well studied in the primate, the growth, differentiation and response of the endometrium and uterus in menstruating primates remain largely undefined. To provide an experimental model applicable to the human uterus, an interdisciplinary study of the rhesus monkey uterus will continue to be used to determine cyclic endometrial patterns of cell growth, differentiation, and response. The model that is used is an ovariectomized rhesus monkey in which the hormonal milieu is provided by the timed insertion and withdrawal of silastic capsules containing estrogen or progesterone. In this fashion we simulate a standard artificial menstrual cycle (SAMC) or a manipulated artificial menstrual cycle (MAMC). On the appropriate days of either cycle, tissue specimens of endometrium will be obtained and, in some cases, tissues and blood samples will be obtained after an infusion of radiolabeled estrogens or androgens. The tissues so obtained will be studied with the following approaches: Zonal- dependent and cell-type specific changes in estradiol and progesterone receptors and potential autocrine/paracrine regulatory factors by immunohistochemistry, endometrial zonal proliferation patterns as assessed by immunohistochemistry of the Ki67 antigen, in situ hybridization and Northern analyses of ER and PR and potential autocrine/paracrine factors; estrogen uptake and metabolism, the role of SHBG and zonal cell-type immunohistochemical localization of aromatase enzymes; effects of E and P on endometrial prostaglandin production in vivo and in vitro and their mechanism of action; and zonal-dependent and cell-type specific changes in 3H-thymidine labeling indices and morphometric and structural analyses at the LM and EM level. Human disorders of fertility, endometrial hyperplasia, and endometriosis may be better understood by a thorough and systematic analysis of the factors that regulate primate endometrial proliferation and response.
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