Cortisol/progesterone antagonism in regulation of 15-Hydroxysteroid dehydrogenase activity and mRNA levels in human chorion and placental trophoblast cells at term

Abstract

PGs mediate parturition events. 15-Hydroxyprostaglandin dehydrogenase (PGDH) catalyzes the first step in the metabolism of PGs to render them inactive. We have reported previously that cortisol (F) decreases PGDH activity and progesterone (P4) maintains PGDH in human chorion and placenta at term. To study the interaction of P4 and F on the regulation of PGDH, we treated chorion and placental trophoblast cells in culture with combinations of F, dexamethasone, P4, trilostane, and medroxyprogesterone acetate (MPA). Following a 24-h steroid treatment period and 4-h PGF2α challenge, culture media and cells were collected for measurement of PGF2α levels and PGDH mRNA by RIA and Northern blotting analysis. F and dexamethasone decreased PGDH activity and mRNA levels. Exogenous P4 did not significantly alter PGDH activity or mRNA levels; however, MPA significantly stimulated PGDH activity. Trilostane decreased P4 production by more than 90% and also decreased PGDH activity and expression. Coincubation with P4 or MPA reversed trilostane inhibition of PGDH, consistent with a stimulatory role for endogenous P4 on PGDH. MPA significantly reversed F inhibition of PGDH activity and mRNA levels. In the presence of trilostane, P4 at equimolar concentration to F reversed F inhibition of PGDH mRNA levels. These findings suggest that F may be acting as an endogenous inhibitor of P4 action in the regulation of PGDH at term.