title: The pattern of glucocorticoid and estrogen receptors may explain differences in steroid dependency of intrauterine prostaglandin production at parturition in sheep.
abstract: 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(2alpha). 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, ER alpha, ER beta, and GR alpha were localized using immunohistochemistry. ER alpha, ER beta, P450(C17), and GR alpha protein expressions were determined by Western blot analysis. Data were analyzed by analysis of variance (ANOVA) (P < or =.05).
  
  
  RESULTS
  Fetal cortisol infusion in the presence or absence of a rise in placental estrogen synthesis increased placental expression of GR alpha; both PGHS-II and GR alpha 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 placentome. ER alpha, ER beta, 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 the 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.
authors.affiliation: Canadian Institutes of Health Research Group in Fetal and Neonatal Health and Development, Canada.
authors.forename: W L
authors.initials: WL
authors.lastname: Whittle
authors.forename: A C
authors.initials: AC
authors.lastname: Holloway
authors.forename: S
authors.initials: S
authors.lastname: Lye
authors.forename: J R G
authors.initials: JR
authors.lastname: Challis
authors.forename: W
authors.initials: W
authors.lastname: Gibb
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015237:Dinoprost / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D004717:Endometrium / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D005260:Female; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012756:Sheep; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D015237:Dinoprost; D051546:Cyclooxygenase 2; D015232:Dinoprostone