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

A current hypothesis of ovine parturition proposes that fetal adrenal cortisol induces placental. E-2 production, which, in turn, triggers intrauterine PG production. However, recent evidence suggests that cortisol may directly increase PG production in trophoblast-derived tissues. To separate cortisol-dependent and estrogen-dependent PG production in sheep intrauterine tissues, 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 recording 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 messenger RNA (mRNA) and protein expression were determined by in situ hybridization 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. Labor-type uterine contractions were induced after 68 h of cortisol plus 4-OHA infusion, but the contraction frequency remained less than that in the cortisol-treated animals. Fetal cortisol infusion increased fetal and maternal plasma E-2 concentrations and decreased the maternal plasma P-4 concentration significantly; concurrent 4-OHA infusion attenuated the increase in fetal and maternal plasma E-2, but not the decrease in maternal plasma P-4. The fetal plasma PGE(2) concentration increased after both cortisol and cortisol plus 4-OHA. infusion. The maternal plasma 13,14dihydro-15-keto-PGF(2 alpha) concentration rose after fetal cortisol infusion, but not after cortisol plus 4-OHA infusion. Placental trophoblast PGHS-II mRNA and protein expression were increased significantly after both cortisol and cortisol plus 4-OHA infusion. Endometrial PGHS-II mRNA and protein expression increased after 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 that these data suggest distinct pathways of intrauterine PG synthesis: a cortisol-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) and appears necessary for uterine activity and parturition.