Fetal hypothalamic-pituitary adrenal (HPA) development and activation as adeterminant of the timing of birth, and of postnatal disease

Birth in most animal species is triggered by the fetus through activation o f the fetal hypothalamic-pituitary-adrenal (HPA) axis. Preterm birth, may b e associated with precocious activation of fetal HPA function, reflecting t he fetal response to an adverse intrauterine environment. There is a progressive and concurrent increase of ACTH(1-39) and cortisol ( F) in the circulation of fetal sheep during the last 15-20 days of pregnanc y (term, day 145-150) associated with increased expression of hypothalamic CRH pituitary POMC and adrenal ACTH receptor and steroidogenic enzymes, par ticularly P450 C17. Similar changes occur with fetal hypoxemia. Negative fe edback is ameliorated by decreased pituitary and hypothalamic glucocorticoi d receptor, increased CBG, and altered fetal pituitary 11 beta -hydroxyster oid dehydrogenase type 1. Repeated fetal hypoxemia, diminishes the fetal-pi tuitary ACTH response, but increases fetal adrenal responsiveness. Fetuses exposed to maternal glucocorticoid in late gestation are growth restricted with altered postnatal HPA responsiveness and glycemic responses that repro duce the insulin resistance of type 2 diabetes. We conclude that the level of fetal HPA activity is crucial not only for determining gestation length, but also predicts pathophysiologic adjustment in later life.