Reduced placental 11 beta-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies complicated by intrauterine growth restriction: An analysis of possible mechanisms

11 beta -Hydroxysteroid dehydrogenase type 2 (11 beta -HSD2) inactivates co rtisol to cortisone. In the placenta 11 beta -HSD2 activity is thought to p rotect the fetus from the deleterious effects of maternal glucocorticoids. Patients with apparent mineralocorticoid excess owing to mutations in the 1 1 beta -HSD2 gene invariably have reduced birth weight, and we have recentl y shown reduced placental 11 beta -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 11 beta -HSD2 mRNA e xpression across normal gestation (n = 86 placentae) and in pregnancies com plicated by intrauterine growth restriction (n = 19) and evaluated the unde rlying mechanism for any aberrant 11 beta -HSD2 mRNA expression in intraute rine growth restriction. 11 beta -HSD2 mRNA expression increased more than 50-fold across gestation, peaking at term. Placental 11 beta -HSD2 mRNA lev els were significantly decreased in intrauterine growth restriction pregnan cies when compared with gestationally matched, appropriately grown placenta e [e.g. at term Delta Ct (11 beta -hydroxysteroid dehydrogenase type 2/18S) 12.8 +/- 0.8 (mean +/- SE) vs. 10.2 +/- 0.2, respectively, P < 0.001]. The se differences were not attributable to changes in trophoblast mass in intr auterine growth restriction placentae, as assessed by parallel analyses of cytokeratin-8 mRNA expression. No mutations were found in the 11<beta>-HSD2 gene in the intrauterine growth restriction cohort, and imprinting analysi s revealed that the 11 beta -HSD2 gene was not imprinted. Although the unde rlying cause is unknown, 11 beta -HSD2 gene expression is reduced in intrau terine growth restriction pregnancies. These data highlight the important r ole of 11 beta -HSD2 in regulating fetal growth, a known factor in determin ing fetal morbidity but also the subsequent development of cardiovascular d isease in adulthood.