Sex-specific associations between cortisol and birth weight in pregnancies complicated by asthma are not due to differential glucocorticoid receptor expression

Background: Fetal growth inhibition is a known sequelae of in utero glucocorticoid exposure and has long-term consequences for adult health. Sex-specific fetal growth patterns are observed in pregnancies with maternal asthma and may be due to differential sensitivity of the placenta to glucocorticoids. It is currently unknown whether expression of the placental glucocorticoid receptor (GR) becomes altered with asthma or the use of inhaled corticosteroids. Methods: Pregnant women with mild asthma (n = 52), moderate-severe asthma (n = 71) and without asthma (n = 51) were recruited at John Hunter Hospital, Newcastle, Australia. At delivery, placentae and cord blood were collected, and fetal sex and birth weight were recorded. Placental GR heterogeneous nuclear RNA (hnRNA), mRNA and protein were measured and cord blood cortisol concentrations were assessed. Results: Placental GR gene activity increased with cortisol exposure but decreased with inhaled corticosteroid treatment (p-0.05). With maternal asthma, female birth weight centiles were inversely associated with cortisol (r = -0.286, p=0.017) and, despite a decrease in placental GR mRNA (p=0.003), placental GR alpha protein levels were unchanged. In males, no change to cortisol, birth weight or placental GR were evident in pregnancies with asthma. Together, these results indicate that in pregnancies complicated by asthma, placental GR gene activity, but not mRNA expression or protein levels, is dependent on cortisol and inhaled corticosteroid treatment. Conclusions: The sex-specific associations between cortisol and birth weight observed in pregnancies with asthma are not due to altered GR expression; however, they may be due to differential glucocorticoid sensitivity via preferential transcription of GR isoforms or post-translational modifications