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

Division of Medical Sciences (C.L.M., N.D., H.N., S.M.C., P.D., M.H., P.M.S.), Queen Elizabeth Hospital, and Division of Child and Reproductive Health (M.D.K.), Birmingham Women’s Hospital, University of Birmingham, Edgbaston, Birmingham, United Kingdom B15 2TH

Address all correspondence and requests for reprints to: Prof. Paul M. Stewart, M.D., F.R.C.P., FmedSci, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom B15 2TH. E-mail p.m.stewart{at}bham.ac.uk

Abstract

11ß-Hydroxysteroid dehydrogenase type 2 (11ß-HSD2) inactivates cortisol to cortisone. In the placenta 11ß-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 11ß-HSD2 gene invariably have reduced birth weight, and we have recently shown reduced placental 11ß-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 11ß-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 11ß-HSD2 mRNA expression in intrauterine growth restriction. 11ß-HSD2 mRNA expression increased more than 50-fold across gestation, peaking at term. Placental 11ß-HSD2 mRNA levels were significantly decreased in intrauterine growth restriction pregnancies when compared with gestationally matched, appropriately grown placentae [e.g. at term Ct (11ß-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 11ß-HSD2 gene in the intrauterine growth restriction cohort, and imprinting analysis revealed that the 11ß-HSD2 gene was not imprinted. Although the underlying cause is unknown, 11ß-HSD2 gene expression is reduced in intrauterine growth restriction pregnancies. These data highlight the important role of 11ß-HSD2 in regulating fetal growth, a known factor in determining fetal morbidity but also the subsequent development of cardiovascular disease in adulthood.

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