This proposal will test the hypothesis that: (1) the forward shift in the initiation of the nocturnal estradiol (E) surge induces biochemical alterations that initiate nocturnal uterine activity and generates molecular messages that are the genesis of labor and delivery in the baboon; (2) the ratio of E/P is important in determining the time of delivery in the baboon. A tethered baboon model will be used to test these hypotheses. Hypothesis one will be tested by: (1) performing a detailed analysis of the relationship among E, progesterone (P), oxytocin (OT) and uterine contraction by frequent (hourly) blood sampling during the critical 1500 to 2400 hours starting at day 140 of pregnancy through delivery; (2) mimic the shift in the estradiol surge by infusing E for 6 hours starting at 1400 hours on day 140 of pregnancy and monitoring plasma E, P and OT changes and uterine activity during the subsequent 3 days; (3) inhibit E synthesis with 40H androstenedione and CGS 16949 and follow the changes in uterine activity, E, P and OT levels; (4) test the tocolytic effects and monitor plasma OT levels in E treated animals administered an oxytocin antagonist; (5) determine the effects of E on uterine sensitivity to OT and to OT receptor number and affinity. The second hypothesis will be tested by: (1) infusing E intra-arterially daily from 1400 to 2000 hours starting on day 150 of pregnancy and monitoring the initiation of nocturnal uterine activity and-labor compared to control infusions; (2) infusing P, aromatase inhibitor (40HA) and P + 40HA daily from 1400 to 2000 hours starting at day 160 of pregnancy until delivery and compared the initiation of nocturnal uterine activity and delivery to control infusions. The conclusion of these studies will provide significant insights into the factors responsible for the initiation and progress of labor in primates. A better understanding of these factors will provide a basis for determining the causes and providing a treatment of preterm labor, the number one cause of fetal mortality and morbidity in humans.
