Sex-specific and lasting effects of a single course of antenatal betamethasone treatment on human placental 11β-HSD2

Abstract Introduction We have previously shown that even a single course of antenatal betamethasone (BET) as an inductor for lung maturity reduces birth weight and head circumference. Moreover, animal studies link BET administration to alterations of the hypothalamic-pituitary-adrenal-gland-axis (HPA). The unhindered development of the fetal HPA axis is dependent on the function and activity of 11β-hydroxysteroiddehydrogenase type 2 (11β-HSD2), a transplacental cortisol barrier. Therefore, we investigated the effects of BET on this transplacental barrier and fetal growth. Methods Pregnant women treated with a single course of BET between 23 + 5 to 34 + 0 weeks of gestation were compared to gestational-age-matched controls. Placental size and neonatal anthropometrics were taken. Cortisol and ACTH levels were measured in maternal and umbilical cord blood samples. Placental 11β-hydroxysteroiddehydrogenase type 1 (11β-HSD1) protein levels and 11β-HSD2 protein and activity levels were determined. Parameters were analyzed independent of sex, and in subgroups divided by gender and gestational age. Results In term born females, BET administration was associated with reduced head circumference and decreased 11β-HSD2 protein levels and enzyme activity. Males treated with BET, especially those born prematurely, showed increased 11β-HSD2 protein levels. Conclusion A single course of BET alters placental glucocorticoid metabolism in a sex-specific manner. Decreased 11β-HSD2 levels in term born females may lead to an increased placental transfer of maternal cortisol and therefore result in a reduced head circumference and a higher risk for altered stress response in adulthood. Further research is needed to conclude the significance of increased 11β-HSD2 levels in males.