Regulation of 11β-hydroxysteroid dehydrogenase type 2 by progesterone, estrogen, and the cyclic adenosine 5'-monophosphate pathway in cultured human placental and chorionic trophoblasts

Abstract

Human placenta and fetal membranes contain two types of 11β- hydroxysteroid dehydrogenase (11β-HSD). 11β-HSD1 interconverts cortisol and cortisone and is the predominant isoform found in the fetal membranes. 11β- HSD2, which predominates in the placenta syncytiotrophoblast, converts cortisol to cortisone. It has been proposed that placental 11β-HSD protects the fetus from high levels of maternal glucocorticoids. In this study, cultured term human placental and chorionic trophoblasts were used to examine the regulation of 11β-HSD1 and 11β-HSD2 activities and mRNA expression by progesterone, estrogen, and activators of adenylate cyclase (forskolin) and protein kinase C (phorbol 12-myristate 13-acetate, PMA). Placental trophoblast displayed mainly type 2 oxidase activities. 11β-HSD in the chorionic trophoblast was exclusively an 11β-HSD1 reductase. Progesterone (0.001-1 μM) inhibited 11β-HSD2 activity in a dose-dependent fashion. Inhibition of endogenous progesterone production with trilostane enhanced 11β-HSD2 activity. The inhibitory effect of progesterone on 11β-HSD2 activity was not reversed by the progesterone receptor antagonists RU-486 or onapristone. Progesterone (1 μM) also reduced levels of 11β-HSD2 mRNA, an effect that was attenuated by both RU-486 and onapristone. Estradiol (1 μM) inhibited type 2 oxidase activity as well. Activation of adenylate cyclase by forskolin (100 μM) up-regulated both 11β-HSD2 activity and mRNA expression; there was no effect of PMA (1 μM) on 11β-HSD2. 11β-HSD1 reductase activity was unaffected by progesterone, estrogen, forskolin, or PMA in either the placental or chorionic trophoblasts. We conclude that both progesterone and estrogen are inhibitors of 11β-HSD2 activity in term human placenta in vitro. Levels of 11β-HSD2 activity and mRNA are increased by activation of the cAMP pathway. Progesterone also suppresses levels of 11β-HSD2 mRNA.