11Beta-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction

Abstract

The type 2 isoform of 11beta-hydroxysteroid dehydrogenase (11beta-HSD2), which inactivates cortisol (F) to cortisone (E), has been suggested to play a role in the ontogeny of the fetal pituitary-adrenal axis and also protect the developing fetus from the deleterious effects of circulating maternal glucocorticoids. The abundance of 11beta-HSD2 in the placenta and other fetal tissues was inferred from the F/E ratio in 17 term deliveries in both umbilical arterial (1.73 +/- 0.24, mean +/- SE) and umbilical venous blood (1.16 +/- 0.14) compared with adult peripheral venous blood (7.76 +/- 0.57, n = 70). Using sensitive assays for 11beta-HSD2 and an in-house human 11beta-HSD2 antibody, the expression and activity of this enzyme in fresh frozen human placenta increased progressively from first (8-12 weeks, n = 16) and second (13-20 weeks, n = 9) to third trimester (term) pregnancies (39-40 weeks, n = 50). Placental 11beta-HSD2 activity was significantly reduced in deliveries complicated by intrauterine growth restriction (IUGR) [25-36 weeks, n = 12, activity 380 pmol/mg/h median (225-671; 95% confidence interval)], compared with the term deliveries [888 (725-1362)] and with appropriately grown pre-term deliveries [27-36 weeks, n = 14, activity 810 (585-1269)], P < 0.05. In human pregnancy placental 11beta-HSD2 activity increases markedly in the third trimester of pregnancy at a time when maternal circulating levels of glucocorticoid are rising. The finding of attenuated placental 11beta-HSD2 activity in IUGR suggests that glucocorticoids may, in part, contribute to impaired fetal growth and that this is closely controlled in normal gestation through placental 11beta-HSD2 expression.

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

“…Studies have shown that 11 -HSD2 is expressed in the placental trophoblast (Brown et al 1993, Krozowski et al 1995, Sun et al 1997. 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.…”

“…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.…”

Site-specific methylation of placental HSD11B2 gene promoter is related to intrauterine growth restriction

“…Previous human studies have demonstrated that there was a significant reduction in 11b-HSD2 enzyme activity in placentas from deliveries complicated by IUGR, and further studies demonstrated that there were also reductions in placental HSD11B2 gene expression. [17][18][19][20][21] How to explain the reduced placental HSD11B2 gene expression in IUGR newborns? Although mutations in HSD11B2 gene were detected in all patients with the syndrome of apparent mineralocorticoid excess, which was due to 11b-HSD2 deficiency, 22 no mutation was found in HSD11B2 gene from DNA extracted from IUGR placentas.…”

Timing of fetal exposure to stress hormones: Effects on newborn physical and neuromuscular maturation

“…The enzyme 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2) has been isolated in the human placenta and likely accounts for the relatively low transfer of maternal cortisol to the fetus by converting cortisol to its inactive form cortisone (Benediktsson et al, 1997;Bernal, Flint, Anderson, & Turnbull, 1980). 11β-HSD-2 shows steady increases throughout gestation until the last few weeks of gestation when decreases in 11β-HSD-2 are observed (Lopez Bernal, Anderson, & Turnbull, 1982;Murphy & Clifton, 2003;Sandman et al, 2003;Schoof et al, 2001;Shams et al, 1998). Although, 11β-HSD-2 provides protection for the fetus from maternal cortisol, it does not provide complete protection; thus, some maternal cortisol continues to reach the fetus.…”