Expression of the 11β-Hydroxysteroid Dehydrogenase Types 1 and 2 Proteins in Human and Baboon Placental Syncytiotrophoblast

Prenatal glucocorticoid exposure has been associated with a reduction in birth weight and postnatal alterations in glucose homeostasis and hypothalamic-pituitary-adrenal (HPA) axis function. The mechanisms underlying these responses are unknown, although changes in fetal hepatic development may play an important role. The fetal liver produces key regulators of fuel metabolism and of the developing HPA axis that are altered by glucocorticoids. The local availability of glucocorticoids is regulated, in part, by corticosteroid-binding protein (CBG), glucocorticoid receptors (GR) and by the enzyme 11 -hydroxysteroid dehydrogenase (11 HSD), but the effects of maternal glucocorticoid administration on the expression of these genes in the fetal liver are unknown. 11 HSD1 is the predominant form of this enzyme present in the liver and is responsible for the conversion of cortisone to cortisol. To determine if prenatal glucocorticoid exposure alters fetal hepatic regulation of CBG, 11 HSD1 and GRs, we treated pregnant ewes with betamethasone (0·5 mg/kg) intramuscularly at 104, 111 and 118 days of gestation (term 150 days). Animals were killed at 125 or 146 days of gestation. Maternal betamethasone administration did not alter mean cord plasma glucose but significantly decreased cord plasma insulin levels (P<0·05) at 125 days of gestation. At 146 days of gestation, cord plasma glucose levels were significantly increased without alterations in insulin levels following maternal betamethasone treatment (P<0·05). Maternal betamethasone administration resulted in a significant increase in fetal hepatic 11 HSD1 mRNA and protein levels at 125 days of gestation (P<0·05). CBG mRNA levels were significantly elevated over control at 125 days although levels of CBG protein were not significantly different. GR protein levels were not statistically different at either 125 or 146 days of gestation following glucocorticoid administration. These data suggest that prenatal betamethasone exposure in the ovine fetus results in alterations in cord glucose and insulin levels as well as alterations in hepatic 11 HSD1 mRNA and protein expression. These changes in 11 HSD1 increase the potential to generate local cortisol from circulating cortisone. We speculate that this could affect expression of glucocorticoid-dependent hepatic enzymes involved with the regulation of glucose production and HPA responsiveness.

Section: Effects Of Maternal Betamethasone On Fetal Hepatic 11 Hsd1 mentioning

confidence: 98%

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Sloboda¹,

Newnham²,

Challis³

2002

“…The capacity for 11 -HSD2 to inactivate glucocorticoids in the placenta is very powerful, and this is supported by the placenta being the most abundant source of the enzyme, per mg of wet weight tissue (Shams et al 1998). 11 -HSD2 expression increases to term in the human, baboon and rat placenta (Burton & Waddell 1994, Shams et al 1998, Pepe et al 1999. In contrast, in the mouse placenta expression is reduced from gestation day 13 (term=19·5 days) (Brown et al 1996, Condon et al 1997.…”

Section: -Hsd2 Localisationmentioning

confidence: 99%

11β-Hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action

Draper¹,

Stewart²

2005

347

294

“…In contrast to the type 2 isozyme, 11b-HSD1 can catalyze both dehydrogenase (cortisol inactivation) and reductase (cortisol synthesis) activities, although in most tissues the latter predominates (Tomlinson et al 2004). Expression of 11b-HSD1 has been described in placental tissues from humans (Ricketts et al 1998, Pepe et al 1999, rats (Waddell et al 1998), and baboons (Pepe et al 1999), with activity data favoring reductase activity or cortisol generation (Sun et al 1999). The enzyme has been detected in extravillous trophoblasts, chorion, and amnion epithelial cells but is particularly abundant in decidual stromal cells (Sun et al 1997, Ricketts et al 1998.…”

Section: Introductionmentioning

confidence: 99%

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

Chan

Rabbitt

Innes

et al. 2007

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 11b-hydroxysteroid dehydrogenase 2 (11b-HSD2) located in the human placental trophoblast. By contrast, relatively little is known concerning the function of glucocorticoid-activating 11b-HSD1, which is strongly expressed within human maternal decidua. To address this we have assessed: i) changes in decidual 11b-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 (nZ32) and second (nZ10) trimesters, and elective caesarean sections in the third trimester (nZ9). Analysis of mRNA for 11b-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 11b-HSD1 with gestation were paralleled by increased expression of the apoptosis markers caspase-3 and annexin-V, particularly in cluster designation (CD)10 KVE 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 11b-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.