Dual Function of 11β-Hydroxysteroid Dehydrogenase in Placenta: Modulating Placental Glucocorticoid Passage and Local Steroid Action1

Abstract

Target cell metabolism of glucocorticoids is now recognized as an important modulator of ligand access to the glucocorticoid receptor (GR). This metabolism occurs via two distinct 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes (types 1 and 2) that catalyze interconversion of active glucocorticoids (cortisol and corticosterone) and their inactive 11-keto products (cortisone and 11-dehydrocorticosterone, respectively). The focus of this review is on the biology of the 11beta-HSD enzymes in the placenta, where they also regulate passage of maternal glucocorticoids to the fetus. The presence of this metabolic barrier at the maternal-fetal interface is potentially crucial to fetal growth and development, since maternal glucocorticoid levels are elevated in pregnancy and since excess glucocorticoid exposure in fetal life has detrimental effects on prenatal growth and increases susceptibility to disease in subsequent adult life. In primates, transplacental glucocorticoid passage also appears to play an important role in the induction of an autonomous fetal hypothalamic-pituitary-adrenal axis near term. Placental 11beta-HSD is also likely to modulate glucocorticoid actions within the placenta, per se, by regulating their access to placental GR. Moreover, because some progesterone effects are exerted via the GR, placental 11beta-HSD may regulate progesterone-glucocorticoid competition for access to this receptor and thereby affect the biological actions of both steroids in the placenta.

Myometrial expression of 11 beta-hydroxysteroid dehydrogenase type 2 in rat pregnancy

“…Moreover, 11 -HSD2 was immunolocalized to myometrial smooth muscle cells, the same localization as that for 11 -HSD-1 and the GR (Burton et al 1996). Colocalization of the two 11 -HSD enzymes within myometrial cells is similar to observations in the placenta of several species where both enzymes are expressed in trophoblast cells (for review see Burton & Waddell 1999). The physiological consequences of myometrial colocalization are uncertain, however, since each enzyme is thought to favour catalysis of opposite reactions in vivo.…”

Developmental programming of adult hyperinsulinemia, increased proinflammatory cytokine production, and altered skeletal muscle expression of SLC2A4 (GLUT4) and uncoupling protein 3

“…Indeed, maternal psychosocial stress was recently linked to subsequent disturbances in offspring insulin sensitivity (Entringer et al 2008). Therefore, further studies are required to determine the extent to which maternal stress and/or disturbances in the placental glucocorticoid barrier (Burton & Waddell 1999) can lead to increased fetal glucocorticoid exposure in humans.…”

Sex-Specific Effects of Prenatal Glucocorticoids on Placental Development

“…While glucocorticoids are essential for the development of many organs, during pregnancy, the placenta acts as a barrier to prevent excess entry of maternal glucocorticoids into the fetal compartment [12][13][14]. This placental barrier to glucocorticoids is achieved predominantly by the presence of 11 -hydroxysteriod dehydrogenase type 2 (11 HSD2), which converts the biologically active glucocorticoid (cortisol in humans, corticosterone in mice and rats) to its physiologically inert form [2].…”