Mechanism of Cortisol/Progesterone Antagonism in the Regulation of 15-Hydroxyprostaglandin Dehydrogenase Activity and Messenger Ribonucleic Acid Levels in Human Chorion and Placental Trophoblast Cells at Term

Abstract

Prostaglandin dehydrogenase (PGDH) metabolizes prostaglandins (PGs) to render them inactive. We reported previously that cortisol (F) decreases and progesterone (P(4)) maintains PGDH activity/expression in human chorion and placenta. Furthermore, we have shown that F and P(4) compete for regulation of PGDH. We hypothesized that P(4) maintains PGDH activity through interaction with the glucocorticoid receptor (GR) and that elevations in F compete with P(4) at the GR, resulting in a decrease in PGDH at term. By immunohistochemistry and Western blotting analysis, we localized immunoreactive GR and progesterone receptor (PR) to chorion and placental trophoblast cells. We treated chorion and placental trophoblast cells in culture with F, dexamethasone (DEX), beta-methasone, P(4), trilostane (a 3 beta-hydroxysteroid dehydrogenase inhibitor), medroxyprogesterone acetate (MPA), and/or 21-hydroxy-6,19-oxidopregn-4-ene-3,20-dione (21OH-6OP; a GR antagonist). By RIA and Northern blotting analysis, all glucocorticoids (GCs) decreased PGDH activity/expression. Coincubation with 21OH-6OP reversed GC inhibition of PGDH; MPA, but not P(4), treatment stimulated PGDH activity. Trilostane inhibited PGDH activity, and coincubation with P(4) or MPA reversed trilostane inhibition of PGDH. Treatment with trilostane, P(4), 21OH-6OP, or MPA plus 21OH-6OP reversed P(4) and MPA up-regulation of PGDH activity. Our findings suggest that F inhibition and P(4) stimulation of PGDH may be mediated by PR, but also via the GR, in chorion and placenta.

Progesterone receptors A and B differentially modulate corticotropin-releasing hormone gene expression through a cAMP regulatory element

“…These results are consistent with the findings of Patel et al [39] where P4 stimulation of prostaglandin dehydrogenase is mediated not only by PR but also by GR. A number of other reports have also demonstrated physiological action of P4 via GR in both the absence and presence of PR [40 -44].…”

Relationships of circulating pregnanolone isomers and their polar conjugates to the status of sex, menstrual cycle, and pregnancy

“…In contrast to non-primate species, progesterone levels in human maternal serum do not change markedly around parturition, while estradiol levels escalate up to labor, as in other mammals (Mathur et al 1980). Despite the number of mechanism suggested (McLean & Smith 2001, Patel et al 2003, Condon et al 2004, Mesiano 2004, our knowledge regarding the primary impulse for the human parturition remains inadequate. The role of neuroactive reduced progesterone metabolites -and particularly the most abundant of them, PIs -in the timing of human parturition is still unclear, despite studies reporting their major effects in other mammals (Brussaard et al 1997(Brussaard et al , 2000.…”

Progesterone Attenuates Corticotropin-Releasing Factor-Enhanced But Not Fear-Potentiated Startle via the Activity of Its Neuroactive Metabolite, Allopregnanolone

“…However, the participation of the P receptor cannot be completely ruled out. Both P and MPA are agonists at the glucocorticoid receptor (GR), with MPA possessing a much higher affinity for GR than P (Kontula et al, 1983;Patel et al, 2003). Chronic (5 d) subcutaneous injections of corticosterone produced CRF-enhanced startle to a dose of CRF previously shown not to increase startle (Lee et al, 1994).…”