Fetal programming of hypothalamic–pituitary–adrenal (HPA) axis function and behavior by synthetic glucocorticoids

Reduced fetal growth has been closely associated with an increased risk for the development of chronic disease in later life. Accumulating evidence indicates that fetal exposure to excess glucocorticoids represents a critical mechanism underlying this association. Approximately 7% of pregnant women are at risk of preterm delivery and these women are routinely treated with synthetic glucocorticoids (sGC) between 24 and 34 of weeks gestation to improve neonatal outcome. Animal studies have demonstrated that maternally administered sGC crosses the placenta, affecting fetal hypothalamic–pituitary–adrenal (HPA) development, resulting in changes in HPA axis function that persist throughout life. These changes appear to be modulated at the level of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in the brain and pituitary. As the HPA axis interacts with many other physiological pathways, the changes in endocrine function are also sex-specific and age-dependent. Alterations in behavior, particularly locomotion, in animals exposed to sGC in utero have also been demonstrated. Consistent with the finding in animal models, emerging human data are indicating attention deficit-hyperactivity disorder (ADHD)-like symptoms in children exposed to repeated courses of sGC in utero. This behavioral phenotype is likely linked to alterations in dopamine (DA) signaling, suggesting that sGC are able to permanently modify or ‘program’ this system. Finally, it is emerging that changes in HPA axis function and behavior following antenatal exposure to sGC are transgenerational and likely involve epigenetic mechanisms. A comprehensive understanding of the acute and long-term impact of sGC exposure in utero is necessary to begin to develop recommendations and treatment options for pregnant women at risk of preterm delivery.