Glucocorticoid-induced apoptosis in human decidua: a novel role for 11beta-hydroxysteroid dehydrogenase in late gestation.

Glucocorticoids play a fundamental role in the endocrinology of pregnancy but excess glucocorticoids in utero may lead to abnormalities of fetal growth. Protection against fetal exposure to cortisol is provided by the enzyme 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) located in the human placental trophoblast. By contrast, relatively little is known concerning the function of glucocorticoid-activating 11beta-HSD1, which is strongly expressed within human maternal decidua. To address this we have assessed: i) changes in decidual 11beta-HSD1 expression across gestation and ii) the functional role of glucocorticoids in decidua. Human decidua was collected from women undergoing surgical termination of pregnancy in first (n = 32) and second (n = 10) trimesters, and elective caesarean sections in the third trimester (n = 9). Analysis of mRNA for 11beta-HSD1 by real-time RT-PCR showed increased expression in second (9.3-fold, P < 0.01) and third (210-fold, P < 0.001) trimesters. Studies using primary cultures of decidual cells also revealed higher levels of cortisol generation in the third trimester. Changes in decidual 11beta-HSD1 with gestation were paralleled by increased expression of the apoptosis markers caspase-3 and annexin-V, particularly in cluster designation (CD)10(-VE) non-stromal cells (20-fold in third trimester relative to first trimester). Apoptosis was also readily induced in primary cultures of third trimester decidual cells when treated with cortisol, cortisone, or dexamethasone (all 100 nM for 24 h). The effect of cortisone but not cortisol or dexamethasone was blocked by an 11beta-HSD inhibitor confirming the functional significance of endogenous cortisol generation. These data show that autocrine metabolism of glucocorticoids is an important facet of the feto-placental unit in late gestation and we propose that a possible effect of this is to stimulate programmed cell death in human decidua.