Reduced Placental 11β-Hydroxysteroid Dehydrogenase Type 2 mRNA Levels in Human Pregnancies Complicated by Intrauterine Growth Restriction: An Analysis of Possible Mechanisms

Abstract

11beta-Hydroxysteroid dehydrogenase type 2 (11beta-HSD2) inactivates cortisol to cortisone. In the placenta 11beta-HSD2 activity is thought to protect the fetus from the deleterious effects of maternal glucocorticoids. Patients with apparent mineralocorticoid excess owing to mutations in the 11beta-HSD2 gene invariably have reduced birth weight, and we have recently shown reduced placental 11beta-HSD2 activity in pregnancies complicated by intrauterine growth restriction. This is reflected in the literature by evidence of hypercortisolemia in the fetal circulation of small babies. In this study we have determined the levels of placental 11beta-HSD2 mRNA expression across normal gestation (n = 86 placentae) and in pregnancies complicated by intrauterine growth restriction (n = 19) and evaluated the underlying mechanism for any aberrant 11beta-HSD2 mRNA expression in intrauterine growth restriction. 11beta-HSD2 mRNA expression increased more than 50-fold across gestation, peaking at term. Placental 11beta-HSD2 mRNA levels were significantly decreased in intrauterine growth restriction pregnancies when compared with gestationally matched, appropriately grown placentae [e.g. at term DeltaCt (11beta-hydroxysteroid dehydrogenase type 2/18S) 12.8 +/- 0.8 (mean +/- SE) vs. 10.2 +/- 0.2, respectively, P < 0.001]. These differences were not attributable to changes in trophoblast mass in intrauterine growth restriction placentae, as assessed by parallel analyses of cytokeratin-8 mRNA expression. No mutations were found in the 11beta-HSD2 gene in the intrauterine growth restriction cohort, and imprinting analysis revealed that the 11beta-HSD2 gene was not imprinted. Although the underlying cause is unknown, 11beta-HSD2 gene expression is reduced in intrauterine growth restriction pregnancies. These data highlight the important role of 11beta-HSD2 in regulating fetal growth, a known factor in determining fetal morbidity but also the subsequent development of cardiovascular disease in adulthood.

Changes in the Maternal Hypothalamic-Pituitary-Adrenal Axis in Pregnancy and Postpartum: Influences on Maternal and Fetal Outcomes

“…In support of this concept, observational studies show that women who consume large amounts of liquorice which contains glycyrrhizin, an HSD11B2 inhibitor, during pregnancy have a shorter gestation [95] . Likewise, lower placental HSD11B2 activity is correlated with lower birth weight [96,97] and babies homozygous for deleterious mutations of the HSD11B2 gene are of lower birth weight, averaging 1.2 kg less than their heterozygote siblings [98] . Together these studies suggest increased exposure to cortisol is a critical factor regulating growth and gestation.…”

Moderate Prenatal Cadmium Exposure and Adverse Birth Outcomes: a Role for Sex‐Specific Differences?

“…There it can act as a barrier to the transfer of micronutrients, particularly zinc, by induction of metallothionein production,3 and this could restrict fetal growth directly. Cd may also have oestrogenic endocrine disrupting effects,4 which could restrict the expression of placental genes linked to growth and development (for example, 11β‐HSD2 and 3β‐HSD , which control the transfer of glucocorticoids to the fetus27). Finally, Cd can act as an epigenic modifier 28.…”

Biological effects of a maternal ED on pregnancy and foetal development: a review

“…This is turn increases foetal exposure to maternal cortisol, therefore suggesting a possible effect of maternal under-nutrition not only on nutritional programming, but also on foetal stress responses. In fact, foetal exposure to higher cortisol levels is also associated with lower birth-weight (McTernan et al, 2001).…”