Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids

Abstract

Prenatal stress (PS) and maternal exposure to exogenous glucocorticoids can lead to permanent modification of hypothalamo-pituitary-adrenal (HPA) function and stress-related behaviour. Both of these manipulations lead to increased fetal exposure to glucocorticoids. Glucocorticoids are essential for many aspects of normal brain development, but exposure of the fetal brain to an excess of glucocorticoids can have life-long effects on neuroendocrine function. Both endogenous glucocorticoid and synthetic glucocorticoid exposure have a number of rapid effects in the fetal brain, including modification of neurotransmitter systems and transcriptional machinery. Such fetal exposure permanently alters HPA function in prepubertal, postpubertal and ageing offspring, in a sex-dependent manner. Prenatal stress and exogenous glucocorticoid manipulation also lead to the modification of behaviour, brain and organ morphology, as well as altered regulation of other endocrine systems. It is also becoming increasingly apparent that the timing of exposure to PS or synthetic glucocorticoids has tremendous effects on the nature of the phenotypic outcome. Permanent changes in endocrine function will ultimately impact on health in both human and animal populations.

Figure 1. The hypothalamo-pituitary-adrenal (HPA) axis

Parvocellular neurons in the PVN produce corticotrophin-releasing hormone (CRH) and vasopressin (AVP), which in turn stimulate adrenocorticotrophin (ACTH) synthesis and release from the anterior pituitary corticotroph cells. ACTH then initiates the production and release of cortisol from the adrenal cortex. Glucocorticoids act at multiple loci within the body to maintain homeostasis, but also act in the brain to modify behaviour and learning. Due to the damaging effects of extended glucocorticoid exposure the HPA axis is tightly regulated. Glucocorticoids feedback, via glucocorticoid and mineralocorticoid receptors in the limbic system and glucocorticoid receptors in the PVN and anterior pituitary, to decrease HPA activity. POMC, pro-opimelanocortin.

Figure 2

A, representative expression of inducible nerve growth factor A (NGFI-A) mRNA in coronal sections of fetal guinea pig hippocampus at gestational days (d) 40, 50 and 60. NGFI-A mRNA expression is shown in hippocampal subfields (CA1, CA2 and CA3), and cingulate cortex (CCx). Scale bar: 1.5 mm. B, relative levels of NGFI-A mRNA expression in the hippocampus (CA1) in female (open bars) and male (filled bars) fetuses in the second half of gestation. *Significant (P < 0.05) differences compared to previous gestational age. C, plasma cortisol concentrations in female (open bars) and male (filled bars) fetuses in late gestation. *Significant (P < 0.05) differences compared to previous gestational age. Adapted from Andrews et al. (2004) with permission from Blackwell Publishing Ltd.

Figure 3

Twenty-four hour plasma ACTH (A) and cortisol (B) concentrations (area under the curve, AUC; mean ± s.e.m.) in male offspring born to mothers that were undisturbed throughout pregnancy (Control), exposed to a strobe light on gestational days 50–52 (PS50) or gestational days 60–62 (PS60) *P < 0.05 PS50 versus control. C, plasma testosterone concentrations (mean ± s.e.m.) in the same male offspring *P < 0.05 PS50 versus control. Adapted from Kapoor & Matthews (2005) with permission from Blackwell Publishing Ltd.