Hormonal programming and adrenal function. Studies in children and in a rat model

Abstract: Prenatal events during specific time windows have been found to be followed by permanent changes affecting neuroendocrine, so called programming. Undernutrition, placental dysfunction or maternal stress, are apparent examples of such stimuli. It has been hypothesized that a high level of glucocorticoids in the fetus is the major cause of programming of neuroendocrine axes. The aim of this study was to describe cortisol secretion and rhythm in healthy children and adolescents, as well as to study the correlation between birth size and adrenal function in short children. In an attempt to trace factors programming the hypothalamic-pituitary-adrenal (HPA) axis and to examine adult consequences, experimental studies were performed in rats. A cross sectional study in 235 healthy children showed large interindividual variability in mean cortisol levels but preserved individual cortisol levels and circadian rhythm throughout childhood and puberty. Prepubertal short children, born small for gestational age (SGA), were found to have similar cortisol levels to children born appropriate for gestational age (AGA), but higher levels of dehydroepiandrosterone-sulphate (DHEAS) during early childhood. Pregnant rats were exposed to the cytokines interleukin-6 (IL-6), tumour necrosis factor-" (TNF"), or to dexamethasone. Early prenatal exposure to cytokines or dexamethasone led to obesity in both male and female adult rats. Corticosterone response to stress was increased in the IL-6 group, showing hypersensitivity of the HPA axis. Adult dexamethasone exposed male rats showed blunted dexamethasone suppression. Female offspring exposed to cytokine showed a state of hyperandrogenicity. To conclude, the results in rats suggest that prenatal events lead to long-lasting programming of adrenal function. A remarkable narrow intra-individual variability, both in level and rhythm of cortisol secretion, was found from childhood to adult life. Children born SGA, were found to have normal cortisol levels and a normal cortisol secretory rhythm, but elevated DHEAS levels. The results in rats suggests that prenatal exposure to cytokines or dexamethasone can induce specific programming of neuroendocrine regulation with consequences in adult life. These results further emphasize the importance of prenatal programming to the risk of developing disease in adult life. This issue has marked implications for health in the general population