Background: Glucocorticoids are essential for fetal development and organ maturation, and therefore normal transition to extra-uterine life. This process is facilitated by a natural increase in maternal cortisol as pregnancy progresses. Cortisol bioavailability and local tissue delivery is regulated by corticosteroid binding globulin (CBG). Progesterone also binds to CBG, however with over a 3 fold lower affinity than cortisol. In order to understand the regulation of cortisol bioavailability in-utero, we assessed gestational changes in free and total cortisol, CBG (both high and low affinity forms; haCBG and laCBG) and progesterone in cord blood from preterm and term deliveries.
Methods: Cord blood was collected from preterm (n=141) and term (n=176) neonates at the Women’s and Children’s Hospital Adelaide. Ha/la CBG levels were assessed by an in-house ELISA. Total cortisol and progesterone were measured by electro-chemiluminescence immunoassay and ELISA, respectively. Free cortisol fraction was determined using a temperature-controlled ultrafiltration/ligand-binding method. Clinical data were extracted from medical records.
Results: Cord blood total and free cortisol, and the proportion of haCBG, increased significantly across pregnancy (p<0.05). Cord blood progesterone levels were over 100-fold those in women in the luteal phase (mean 7476nM/L, IQR 4184-9697nM/L), and did not significantly rise over pregnancy. Free cortisol fractions were elevated approximately 3-fold in gestation. While the progesterone to CBG ratio did not change over gestation, it was correlated with free cortisol concentrations at each gestational time point (r=0.155, p=0.03).
Conclusion: A high free cortisol fraction in utero may allow a fetal-specific, cortisol tissue distribution necessary for development. This is not driven through altered CBG ha/la levels. High progesterone levels found in cord blood suggest a ‘progesterone switch’ in CBG function in utero, resulting in displacement of cortisol from CBG. This results in predominant free cortisol in the neonatal circulation, with potential important physiological implications for neonatal transition.