Prostaglandin production at the onset of ovine parturition is regulated byboth estrogen-independent and estrogen-dependent pathways

A current hypothesis of ovine parturition proposes that fetal adrenal corti sol induces placental. E-2 production, which, in turn, triggers intrauterin e PG production. However, recent evidence suggests that cortisol may direct ly increase PG production in trophoblast-derived tissues. To separate corti sol-dependent and estrogen-dependent PG production in sheep intrauterine ti ssues, we infused singleton, chronically catheterized fetuses beginning on day 125 of gestation (term, 147-150 days) with 1) cortisol (1.35 mg/h; n = 5); 2) cortisol and 4-hydroxyandrostendione, a P450(aromatase) inhibitor (4 -OHA: 1.44 mg/h; n = 5); 3) saline (n = 5); or 4) saline and 4-OHA (n = 5). Fetal and maternal arterial blood samples were collected at 12-h intervals starting 24 h before infusion and continuing during treatment for 80 h or until active labor. Uterine contractility was measured by electromyogram re cording of myometrial activity. Plasma E-2, progesterone (P-4), PGE(2), and 13, 14-dihydro-15-keto-PGF(2 alpha) were quantified by RIA. PGHS-II messen ger RNA (mRNA) and protein expression were determined by in situ hybridizat ion and Western blot analysis, respectively. Data were analyzed by ANOVA (P less than or equal to 0.05). Labor-type uterine contractions were present after 68 h of cortisol infusion and had increased significantly by 80 h. La bor-type uterine contractions were induced after 68 h of cortisol plus 4-OH A infusion, but the contraction frequency remained less than that in the co rtisol-treated animals. Fetal cortisol infusion increased fetal and materna l plasma E-2 concentrations and decreased the maternal plasma P-4 concentra tion significantly; concurrent 4-OHA infusion attenuated the increase in fe tal and maternal plasma E-2, but not the decrease in maternal plasma P-4. T he fetal plasma PGE(2) concentration increased after both cortisol and cort isol plus 4-OHA. infusion. The maternal plasma 13,14dihydro-15-keto-PGF(2 a lpha) concentration rose after fetal cortisol infusion, but not after corti sol plus 4-OHA infusion. Placental trophoblast PGHS-II mRNA and protein exp ression were increased significantly after both cortisol and cortisol plus 4-OHA infusion. Endometrial PGHS-II mRNA and protein expression increased a fter cortisol infusion, but not after cortisol plus 4-OHA. infusion. Plasma steroid and PG concentrations, uterine activity pattern, and intrauterine PGHS-II expression were not altered in either control group. We conclude th at these data suggest distinct pathways of intrauterine PG synthesis: a cor tisol-dependent/E-2-independent mechanism within trophoblast tissue leading to elevations in fetal plasma PGE,, and an E-2-dependent mechanism within maternal endometrium that leads to increased maternal plasma PGF(2 alpha) a nd appears necessary for uterine activity and parturition.