title: Fetal hypothalamic-pituitary adrenal (HPA) development and activation as a determinant of the timing of birth, and of postnatal disease.
abstract: Birth in most animal species is triggered by the fetus through activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis. Preterm birth, may be associated with precocious activation of fetal HPA function, reflecting the fetal response to an adverse intrauterine environment. There is a progressive and concurrent increase of ACTH1-39 and cortisol (F) in the circulation of fetal sheep during the last 15-20 days of pregnancy (term, day 145-150) associated with increased expression of hypothalamic CRH pituitary POMC and adrenal ACTH receptor and steroidogenic enzymes, particularly P450 C17. Similar changes occur with fetal hypoxemia. Negative feedback is ameliorated by decreased pituitary and hypothalamic glucocorticoid receptor, increased CBG, and altered fetal pituitary 11B-hydroxysteroid dehydrogenase type 1. Repeated fetal hypoxemia, diminishes the fetal-pituitary 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 reproduce 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.
authors.affiliation: Department of Physiology, University of Toronto, Ontario, Canada. j.challis@utoronto.ca
authors.forename: J
authors.initials: J
authors.lastname: Challis
authors.forename: D
authors.initials: D
authors.lastname: Sloboda
authors.forename: S
authors.initials: S
authors.lastname: Matthews
authors.forename: A
authors.initials: A
authors.lastname: Holloway
authors.forename: N
authors.initials: N
authors.lastname: Alfaidy
authors.forename: D
authors.initials: D
authors.lastname: Howe
authors.forename: M
authors.initials: M
authors.lastname: Fraser
authors.forename: J
authors.initials: J
authors.lastname: Newnham
mesh_terms: D000820:Animal Diseases / Q000209:etiology*; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D005314:Embryonic and Fetal Development; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000502:physiology*; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000196:embryology*; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000209:etiology*; D007743:Labor, Obstetric / Q000502:physiology*; D010913:Pituitary-Adrenal System / Q000196:embryology*; D011247:Pregnancy; D013997:Time Factors
chemical_list: D005938:Glucocorticoids