Approximately 10% of women in North America are treated with synthetic glucocorticoid (sGC) between 24 and 32 weeks of pregnancy (term approximately 40 weeks), to promote lung maturation in fetuses at risk of preterm delivery. Such therapy is highly effective in reducing the frequency of respiratory complications, and as a result, repeated course treatment has become widespread. Nothing is known about the impact of repeated sGC treatment on neuroendocrine development in the human, or if specific time windows of increased sensitivity exist. Glucocorticoids are essential for many aspects of normal brain development. However, there is growing evidence from a number of species, that exposure of the fetal brain to excess glucocorticoid can have life-long effects on behaviour and neuroendocrine function. We have shown that exposure of fetuses to sGC in late gestation permanently alters HPA function in pre-pubertal, post-pubertal, and aging offspring, in a sex-dependent manner. These effects are linked to changes in central glucocorticoid feedback. Prenatal glucocorticoid exposure also leads to modification of HPA-associated behaviours and organ morphology, as well as altered regulation of other neuroendocrine systems. Permanent changes in HPA function will have a long-term impact on health, since elevated cumulative exposure to endogenous glucocorticoid has been linked to the premature onset of pathologies associated with aging.

Pregnant guinea pigs were treated with dexamethasone (1 mg kg −1 ) or vehicle on days 40-41, 50-51 and 60-61 of gestation, after which animals delivered normally. Adult male offspring were catheterized at 145 days of age and subjected to tests of hypothalamic-pituitary-adrenal (HPA) axis function in basal and activated states. Animals exposed to dexamethasone in utero (mat-dex) exhibited increased hippocampus-to-brain weight ratio, increased adrenal-to-body weight ratio and increased mean arterial pressure. There were no effects on gestation length, birth weight and postnatal growth. There were no overall differences in diurnal plasma adrenocorticotropic hormone (ACTH) and cortisol profiles, though there were subtle differences during the subjective afternoon between control and mat-dex offspring. A significant decrease in initial ACTH suppression was observed following dexamethasone injection in mat-dex offspring compared to control offspring. Molecular analysis revealed significantly increased MR mRNA expression in the limbic system and particularly in the dentate gyrus in mat-dex offspring. In the anterior pituitary, both pro-opiomelanocortin (POMC) and glucocorticoid receptor (GR) mRNA levels were significantly elevated in mat-dex offspring. In conclusion, (1) repeated prenatal treatment with synthetic glucocorticoid (sGC) permanently programmes organ growth, blood pressure and HPA regulation in mature male offspring and these changes involve modification of corticosteroid receptor expression in the brain and pituitary; (2) the effects of prenatal sGC exposure on HPA function appear to change as a function of age, indicating the importance of investigating HPA and cardiovascular outcome at multiple time points throughout life.

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.