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Prostaglandin Production at the Onset of Ovine Parturition Is Regulated by Both Estrogen-Independent and Estrogen-Dependent Pathways¹

Medical Research Council Group in Fetal and Neonatal Health and Development; Departments of Physiology and Obstetrics and Gynecology, University of Toronto (W.L.W., A.C.H., S.J.L., J.R.G.C.), Toronto, Ontario, Canada M5A 1A8; and Department of Obstetrics and Gynecology, University of Ottawa W.G.), Ottawa, Canada

Address all correspondence and requests for reprints to: Dr. W. L. Whittle, Department of Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, Canada M5A 1A8. E-mail: wendy.whittle{at}utoronto.ca

A current hypothesis of ovine parturition proposes that fetal adrenal cortisol induces placental E₂ 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 E₂, progesterone (P₄), PGE₂, and 13,14-dihydro-15-keto-PGF₂ 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 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 E₂ concentrations and decreased the maternal plasma P₄ concentration significantly; concurrent 4-OHA infusion attenuated the increase in fetal and maternal plasma E₂, but not the decrease in maternal plasma P₄. The fetal plasma PGE₂ concentration increased after both cortisol and cortisol plus 4-OHA infusion. The maternal plasma 13,14-dihydro-15-keto-PGF₂ 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/E₂-independent mechanism within trophoblast tissue leading to elevations in fetal plasma PGE₂, and an E₂-dependent mechanism within maternal endometrium that leads to increased maternal plasma PGF₂ and appears necessary for uterine activity and parturition.

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