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

Human placenta and fetal membranes contain two types of 11(beta)- hydroxysteroid dehydrogenase (11(beta)-HSD). 11(Beta)-HSD1 interconverts cortisol and cortisone and is the predominant isoform found in the fetal membranes. 11(beta)-HSD2, which predominates in the placenta syncytiotrophoblast, converts cortisol to cortisone. It has been proposed that placental 11(beta)-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 11(beta)-HSD1 and 11(beta)-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. 11(beta)-HSD in the chorionic trophoblast was exclusively an 11(beta)-HSD1 reductase. Progesterone (0.001 -1 (mu)M) inhibited 11(beta)- HSD2 activity in a dose-dependent fashion. Inhibition of endogenous progesterone production with trilostane enhanced 11(beta)-HSD2 activity. The inhibitory effect of progesterone on 11(beta)-HSD2 activity was not reversed by the progesterone receptor antagonists RU-486 or onapristone. Progesterone (1 (mu)oM) also reduced levels of 11(beta)-HSD2 mRNA, an effect that was attenuated by both RU-486 and onapristone. Estradiol (1 (mu)M) inhibited type 2 oxidase activity as well. Activation of adenylate cyclase by forskolin (100 microM) up-regulated both 11(beta)-HSD2 activity and mRNA expression; there was no effect of PMA (1 (mu)M) on 11(beta)-HSD2. 11(beta)-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 11(beta)-HSD2 activity in term human placenta in vitro. Levels of 11(beta)-HSD2 activity and mRNA are increased by activation of the cAMP pathway. Progesterone also suppresses levels of 11(beta)-HSD2 mRNA.