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-hydrox ysteroid dehydrogenase (11 beta-HSD). 11 beta-HSD2 interconverts corti sol and cortisone and is the predominant isoform found in the fetal me mbranes. 11 beta-HSD2, which predominates in the placenta syncytiotrop hoblast, converts cortisol to cortisone. It has been proposed that pla cental 11 beta-HSD protects the fetus from high levels of maternal glu cocorticoids. In this study, cultured term human placental and chorion ic trophoblasts were used to examine the regulation of 11 beta-HSD1 an d 11 beta-HSD2 activities and mRNA expression by progesterone, estroge n, and activators of adenylate cyclase (forskolin) and protein kinase C (phorbol 12-myristate 13-acetate, PMA). Placental trophoblast displa yed mainly type 2 oxidase activities. 11 beta-HSD in the chorionic tro phoblast was exclusively an 11 beta-HSD1 reductase. Progesterone (0.00 1-1 mu M) inhibited 11 beta-HSD2 activity in a dose-dependent fashion. Inhibition of endogenous progesterone production with trilostane enha nced 11 beta-HSD2 activity. The inhibitory effect of progesterone on 1 1 beta-HSD2 activity was not reversed by the progesterone receptor ant agonists RU-486 or onapristone. Progesterone (1 mu M) also reduced lev els 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 mu M) up-r egulated both 11 beta-HSD2 activity and mRNA expression; there was no effect of PMA (1 mu M) On 11 eta-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 proges terone and estrogen are inhibitors of 11 beta-HSD2 activity in term hu man placenta in vitro. Levels of 11 beta-HSD2. activity and mRNA are i ncreased by activation of the cAMP pathway. Progesterone also suppress es levels of 11 beta-HSD2 mRNA.