Fetal Glucocorticoid Exposure and Hypothalamo‐Pituitary‐Adrenal (HPA) Function After Birth

Abstract

The fetus may be exposed to increased endogenous glucocorticoid or synthetic glucocorticoid in late gestation. Indeed, 7-10% of pregnant women in Europe and North America are treated with synthetic glucocorticoid to promote lung maturation in fetuses at risk of preterm delivery. Such therapy is effective in reducing respiratory complications. However, very little is known about the mechanisms by which synthetic glucocorticoid or prenatal stress influence neurodevelopment in the human, or whether specific time windows of increased sensitivity exist. Glucocorticoids are essential for many aspects of normal brain development. However, there is growing evidence that exposure of the fetal brain to excess glucocorticoid can have lifelong effects on neuroendocrine function and behavior. We have shown that both endogenous glucocorticoid and synthetic glucocorticoid exposure has a number of rapid effects in the fetal brain in late gestation, including modification of neurotransmitter systems and transcriptional machinery. Such fetal exposure permanently alters hypothalamo-pituitary-adrenal (HPA) function in prepubertal, postpubertal, and aging offspring, in a sex-dependent manner. These effects are linked to changes in central glucocorticoid feedback machinery after birth. Prenatal glucocorticoid manipulation also leads to modification of HPA-associated behaviors, brain and organ morphology, as well as altered regulation of other endocrine systems. Permanent changes in endocrine function will have a long-term impact on health, since elevated cumulative exposure to endogenous glucocorticoid is linked to the premature onset of pathologies associated with aging.

Effect of periconceptional undernutrition and gender on hypothalamic–pituitary–adrenal axis function in young adult sheep

“…In addition, sex-specific regulation of the fetal and adult (Bloomfield et al 2003a) HPA axis per se has been noted previously (for review, see Matthews et al 2004). Furthermore, it is clear that responses to challenges that have been shown to incur developmental consequences exhibit a distinct sex-specific bias.…”

The Effects of Glucocorticoids on Fetal and Placental Development

“…High affinity low capacity GRs have been identified in the placenta of various species, including man, rat, and mouse [17,35,161,162]. This would have important clinical implications, because GC-induced downregulation of the placental glucose transport system(s) may contribute to the deleterious side-effects of GC treatment during pregnancy, such as the higher incidence of growthretarded fetuses [46,[163][164][165].…”

Sex-Specific Effects of Prenatal Glucocorticoids on Placental Development

“…However, when levels of cortisol are elevated, the barrier is overwhelmed and more cortisol is able to cross the placenta into the fetal circulation [4]. Deleterious effects of excess endogenous glucocorticoids on the fetus and newborn have been well documented [3,6,[22][23][24][25]. These effects are greater for male fetuses.…”

“…Women whose babies are at risk of congenital adrenal hyperplasia are administered antenatal glucocorticoid treatment to return fetal adrenal hormone level s t o n o r m a l a n d t h u s v i r i l i s a t i o n ( t h e abnormal development of male sexual characteristics in a female) and fertility problems are prevented [32]. Further, pregnant mothers threatening preterm birth (~7-10% of all pregnancies), receive antenatal glucocorticoids, to mature the lungs of the fetus prior to birth to reduce neonatal morbidity and mortality [25]. As for cortisol, synthetic glucocorticoids can be catalysed by 11 HSD2, however they are a poor substrate for the enzyme, and more freely cross the placenta than cortisol [33].…”

“…The National Institute of Health recommend treatment of all women at risk of preterm delivery, between 24 and 34 weeks of gestation, with synthetic glucocorticoids to prematurely mature fetal organs, primarily the lung, to improve neonatal survival [8]. Therefore a large proportion of this population of babies, are exposed to single, and sometimes multiple courses of synthetic glucocorticoids in the period leading up to birth [25]. While antenatal glucocorticoids are the most effective treatment for improving preterm birth survival rates, the scientific community continues to question whether the use of glucocorticoids to reduce the morbidity and mortality associated with preterm birth, is worth the risk of the potential negative outcomes on metabolism and neurodevelopment seen within these babies during childhood and into adulthood [9].…”