The objectives of this research plan are to clarify the relationships among endocrine and vascular events during pregnancy which culminate in parturition. It is our expectation that data obtained in pregnant rhesus monkeys and baboons will provide insights into the mechanism of human labor (normal and premature) and placental hormone production. Major emphasis will be placed on physiological studies in unanesthetized chronic fetal preparations and on complementary in vitro studies of fetal and placental tissues to answer the following questions: (1) How do fetal and maternal adrenal steroids, prostaglandins (PGs), oxytocin, catecholamines and calcium antagonists interact with environmental cues (e.g., light:dark cycles) in regulating circadian patterns in uterine activity? (2) Are prostaglandins temporally or causally related to the initiation of parturition and by what mechanism? (3) Is there evidence for local """"""""progesterone withdrawal"""""""" in the primate uterus prior to the onset of labor? (4) What is the role of sex-steroid-binding protein (SBP) and corticosteroid binding globulin (CBG) in regulating free and bound steroid concentrations in maternal and fetal plasma and amniotic fluid? (5) How is fetoplacental steroidogenesis regulated by tropic factors, enzyme availability, precursor supply and/or placental blood flow? Estrone, estradiol, pregnenolone (P5), P5 sulfate, progesterone, DHEAS, DHEA, androstenedione, testosterone, ACTH, prolactin, oxytocin and prostaglandins (PGE, PGF, PGFM, PGEM-II, 6-keto-PGFl Alpha) will be measured by specific RIA's; cortisol by HPLC and RIA; catecholamines by radioenzymatic assays; SBP and CBG by filtered disk assay and immunoassay. Total and free (unbound) concentrations of steroid hormones will be compared in maternal, fetal and newborn blood and amniotic fluid. Metabolic clearance rates, and transfer rates of placental hormones and PGs will be determined in vivo by steady state infusions of isotopically-labeled hormones and in vitro by tissue superfusion techniques. Blood flow will be measured by electromagnetic flow-meter and radioactive microspheres and correlated with continuous measurements of fetal heart rate and uterine activity (by amniotic fluid pressure and electromyography). Computer methods will be used for on-line data acquisition, and for statistical analyses of wave forms, biorhythms, and hormonal time-trends.
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