Steroid Regulation of Prostaglandin Dehydrogenase Activity and Expression in Human Term Placenta and Chorio-Decidua in Relation to Labor

Abstract

NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) is the key catabolic enzyme controlling levels of biologically active PGs. PGDH is localized to syncytiotrophoblast in placenta, and to trophoblast cells in chorion. To examine the regulation of PGDH by steroids and to determine any changes with labor, we obtained placenta and chorion from term elective cesarean section or spontaneous delivery and isolated trophoblast cells using a Percoll density gradient. Cells were treated with varying concentrations of cortisol, progesterone, the synthetic progestins R5020, and medroxyprogesterone acetate with or without RU486 or the specific progesterone receptor antagonist, onapristone, and the 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane. The activity of PGDH was assessed by measurement of 13,14-dihydro-15-keto-PGF2alpha. PGDH messenger ribonucleic acid was quantified by in situ hybridization and computerized image analysis. The basal output of 13,14-dihydro-15-keto-PGF2alpha was lower in placenta or chorion collected at spontaneous labor than in that obtained at elective cesarean section. Cortisol had a significant dose-dependent inhibitory effect on PGDH activity in both placental and chorion trophoblast cells and significantly decreased levels of PGDH messenger ribonucleic acid. Responses were similar between tissues from laboring and nonlaboring women. PGDH activity was increased by R5020 and medroxyprogesterone acetate and was inhibited by RU486, onapristone, and trilostane. We conclude that cortisol inhibits PGDH activity and expression and that progestagens increase PGDH activity in human chorion and placenta.

Course of placental 11beta-hydroxysteroid dehydrogenase type 2 and 15-hydroxyprostaglandin dehydrogenase mRNA expression during human gestation

“…PGDH mRNA expression is increased by progesterone (23). The inhibitory effect of cortisol on PGDH activity seems to be mediated by the mineralocorticoid receptor, as has been demonstrated recently (15,24).…”

“…This enables prostaglandins to reach the myometrium, increasing its contractility (18,23). With respect to the chorion, previous investigators have shown a reduction of PGDH gene expression and activity more often in patients with spontaneous labour than in patients who underwent caesarean section (16,18).…”

Prostaglandins and mechanisms of preterm birth

“…Glucocorticoids inhibit PGHS-2 transcription and reduce PGHS-2 mRNA stability (DeWitt and Meade, 1993;Evett et al, 1993), representing one pathway of anti-inflammatory action. However, several studies have shown that PG production in cultured amnion and chorion is stimulated by cortisol and the synthetic glucocorticoid dexamethasone (Novy and Walsh, 1983;Mitchell et al, 1988;Potestio et al, 1988;Zakar and Olson, 1989;Gibb and Lavoie, 1990;Smieja et al, 1993;Economopoulos et al, 1996;Patel et al, 1999;Blumenstein et al, 2000;Whittle et al, 2000b). The amnion consists of a single layer of epithelial cells and a subepithelial mesenchymal layer.…”

“…Studies directed towards understanding the mechanism by which steroid hormones might regulate PGDH (Patel et al, 1999) (Fig. 3) have also revealed a mechanism for local progesterone withdrawal within the human fetal membranes.…”

“…3) have also revealed a mechanism for local progesterone withdrawal within the human fetal membranes. Human chorionic PGDH gene expression and activity are inhibited by glucocorticoids (cortisol, betamethasone and dexamethasone) and maintained in a tonic fashion by progesterone (Patel et al, 1999). Chorion trophoblasts express 3β-hydroxysteroid dehydrogenase (3β-HSD) .…”