Infertility is a medical problem of major importance int he United States. A major portion of infertility in humans is due to embryonic and fetal wastage which occurs in at least 70-80% of all conceptions. The incidence of early embryonic mortality in swine is approximately 30-40% and is similar to that reported for women. Understanding the factors associated with conceptus survival during the period of early pregnancy will lead to development of techniques which improve these critical reproductive processes resulting ina greater rate of embryo survival. In swine, uterine secretion of prostaglandins (i.e. PGF 2alpha) is necessary for establishment of pregnancy and is also responsible for corpus luteum regression. Elucidating the physiological and biochemical mechanisms which control uterine PGF2alpha release during early pregnancy may lead to development of techniques which can alter uterine PG secretion and enhance embryonic survival. This also requires an understanding of the regulation of PGF2alpha release during luteolysis. However, these mechanisms are relatively unknown. A series of ten experiments will be conducted, during the next five years, to determine the biochemical mechanisms controlling uterine PGF2alpha release during days 12-16 of pregnancy and estrogen-induced pseudopregnancy compared to an equivalent period of the estrous cycle (i.e. before and during luteolysis). This project focuses on oxytocin (OT) as the physiological stimulus for endometrial pGF2alpha secretion and the biochemical mechanism by which OT promotes PGF2alpha secretion during the estrous cycle and early pregnancy in swine. The first two studies will determine if changes in OT-stimulated PGF2alpha secretion, which occur during the estrous cycle, early pregnancy or estrogen-induced pseudopregnancy, result from altered sensitivity of stromal and endometrial epithelial cells to OT, or if these changes are primarily due to a shift in direction of PGF2alpha secreted from the epithelial cells. The second phase of this project (Exp 3-8) will be to determine the role of OT in stimulating endometrial phosphoinositide (PI) hydrolysis and pGF2alpha secretion by stromal and epithelial endometrial cells from cyclic, pregnant and estrogen-induced pseudopregnant gilts. Cultures of stromal and epithelial endometrial cells will be probed with pharmacological stimulators or inhibitors of the PI second-messenger pathways, and PGF2alpha secretion in response to these agents will be quantified. The final phase of this project (exp 9-10) will determine the role of PI hydrolysis in orienting endometrial secretion of pGF2alpha toward an endocrine (toward the uterine vasculature) or exocrine (toward the uterine lumen) direction. PI hydrolysis in endometrium from cyclic, pregnant and estrogen-induced pseudopregnant gilts will be pharmacologically stimulated or inhibited in vitro and the effects on orientation of PGF2alpha secretion from perifused endometrium will be studied. The regulation of uterine pGF2alpha secretion is poorly understood. Results from these studies will greatly enhance our knowledge of the physiological and biochemical mechanisms controlling uterine PGF2alpha release during early pregnancy and leuteolysis in mammals. This will provide a foundation for future studies which will define the role(s) of uterine PGF2alpha secretion in establishment of pregnancy and facilitate our ability to modify endometrial prostaglandin secretion to enhance embyro and fetal survival in humans and other species in which this is desirable.
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