The Pattern of Glucocorticoid and Estrogen Receptors May Explain Differences in Steroid Dependency of Intrauterine Prostaglandin Production at Parturition in Sheep

Background: We have recently described two distinct pathways of intrauterine prostaglandin (PG) synthesis: a cortisol-dependent/estradiol-independent mechanism within trophoblast tissue leading to elevations in fetal plasma PGE₂, and an estradiol-dependent mechanism within maternal endometrium that leads to increased maternal plasma PGF2_2α. We hypothesized that the differential effects of cortisol and estradiol on intrauterine PGH synthase-II (PGHS-II) expression and PG production may be because of the tissue specific expression of the glucocorticoid and estradiol receptors (GR and ER, respectively) within the intrauterine tissues. In addition, we suggest that these two pathways of PG production are linked through the expression of P450_{C17hydroxylase} (P450_C17) and subsequent increase in placental estradiol synthesis.

Methods: To test the hypotheses, we infused singleton, chronically catheterized fetal sheep beginning at day 125 of gestation (term 147 to 150 days) with (1) cortisol (0.45 mg/mL; n = 5); (2) cortisol and 4-hydroxyandrostenedione, a P450_aromatase inhibitor (4-OHA: 1.44 mg/h; n = 5); (3) saline (n = 5); or (4) saline and 4-OHA (n = 5). PGHS-II, ERα, ERβ, and GRα were localized using immuno-histochemistry. ERα, ERβ, P450_C17, and GRα protein expressions were determined by Western blot analysis. Data were analyzed by analysis of variance (ANOVA) (P ≤ .05).

Results: Fetal cortisol infusion in the presence or absence of a rise in placental estrogen synthesis increased placental expression of GRα; both PGHS-II and GRα localized to the uninucleate trophoblast cells of the placentome and were excluded from the maternal stroma and binucleate cells. Both forms of ER were excluded from the trophoblast tissue of the placentone. ERα, ERβ, and PGHS-II showed a similar pattern of distribution within the luminal epithelium of the endometrium; there were no alterations in the level of the ER in the presence of cortisol ± 4-OHA. Placental P450_C17 protein expression was increased in the presence of a rise in fetal cortisol independent of changes in placental estrogen synthesis.

Conclusions: We concluded that hte differential effects of cortisol and estradiol on intrauterine PGHS-II expression and PG production may be due to the tissue-specific expression of the GR and ER within the intrauterine tissues. Glucocorticoid effects on trophoblast PG production may be mediated in a positive feed-forward manner. We further suggest that either cortisol or a cortisol-stimulated intermediate, like PGE₂, increased P450_C17 expression, leading to a rise in placental estradiol synthesis and triggering maternal intrauterine tissue PG production.