Abstract


Glucocorticoids are essential for normal fetal growth and development yet in excess cause low birthweight. The placenta plays a key role in regulating fetal glucocorticoid exposure through the activity of 11beta-hydroxysteroid dehydrogenase (11β-HSD) 2 (deactivates cortisol) and 11β-HSD1 (resynthesizes cortisol), and glucocorticoid sensitivity via GR and MR (glucocorticoid and mineralocorticoid receptors respectively). Our recent finding of lower maternal cortisol levels through pregnancy in obese women (1) suggests a mechanism contributing to increased birthweight in obese pregnancy. view more

Glucocorticoids are essential for normal fetal growth and development yet in excess cause low birthweight. The placenta plays a key role in regulating fetal glucocorticoid exposure through the activity of 11beta-hydroxysteroid dehydrogenase (11β-HSD) 2 (deactivates cortisol) and 11β-HSD1 (resynthesizes cortisol), and glucocorticoid sensitivity via GR and MR (glucocorticoid and mineralocorticoid receptors respectively). Our recent finding of lower maternal cortisol levels through pregnancy in obese women (1) suggests a mechanism contributing to increased birthweight in obese pregnancy. Here we hypothesized that an increased placental glucocorticoid barrier may be a further mechanism explaining increased birthweight in obese pregnancy. We measured mRNA levels of placental 11β-HSD2, 11β-HSD1, GR and MR in placentas from 44 lean (BMI, mean [SD] = 23.12 [1.61] Kg/m2) and 51 very severely obese (SO, mean [SD] = 44.11 [4.13] Kg/m2) women participating in a longitudinal study of obesity in pregnancy. Maternal demographics were collected prospectively through pregnancy, infants’ birthweight recorded and adjusted for sex and gestational age (SDS birthweight). The mRNA levels were normalised to two housekeeping genes (YWHAZ and TBP) and log-transformed prior to analysis. The mRNA levels of 11β-HSD2 (p= 0.002) and GR (p=0.029) were higher in SO group compared with the lean, consistent with a greater placental barrier to glucocorticoids in obese pregnancy. Placental mRNA levels of 11β-HSD2 and MR were positively correlated (r=0.42, p<0.01) in SO group only. SDS birthweight tended to be higher in SO group than lean (mean [SD] SO = 0.54 [1.16] as compared to mean [SD] lean= 0.14 [0.94], p=0.072). In SO group increased SDS birthweight correlated with decreased MR (r=0.30, p<0.05). This finding remained significant in regression analyses (standardised coefficient β=0.58, p=0.028) adjusting for the significant 11β-HSD2*MR interaction product and other confounders and covariates linked to MR gene expression (circulating cortisol level at 3rd trimester and systolic blood pressure at 1st trimester). In a mediation analysis using the PROCESS algorithm (2) we showed significant association between increased 11β-HSD2 with increased SDS birthweight (R=0.3528, R2=0.1245, p= 0.0005) mediated by MR: for every 1 SD unit change of log MR there was a 1.94 unit [95% confidence interval -0.55- -0.01] reduction in SDS birthweight. Therefore despite higher placental 11β-HSD2 and thus potentially reduced glucocorticoid exposure in SO pregnancy, the interaction between 11β-HSD2 and MR is consistent with a placental adaptive mechanism to protect infants of SO pregnancy from excess birthweight. The consequence of this interaction on the future metabolic profile of infants of SO pregnancy remains to be investigated.

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