Corticosterone, Adrenal, and the Pituitary-Gonadal Axis in Neonatal Rats: Effect of Maternal Separation and Hypoxia

Hypoxia, a common stressor in prematurity, leads to sexually dimorphic, short- and long-term effects on the adult hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. We hypothesized that these effects are due to stress-induced increases in testosterone during early postnatal life. We evaluated this phenomenon by systematically assessing the short-term effects of normoxic or hypoxic separation on male and female pups at birth, postnatal hours (H) 2, 4, and 8, and postnatal days (PD) 2 to 7. Our findings were (a) hypoxic separation led to a large increase in plasma corticosterone from 4H-PD4, (b) neither normoxic nor hypoxic separation affected critical adrenal steroidogenic pathway genes; however, a significant decrease in baseline Cyp11a1, Mc2r, Mrap, and Star adrenal expression during the first week of neonatal life confirmed the start of the adrenal stress hyporesponsive period, (c) a luteinizing hormone/follicle-stimulating hormone–independent increase in plasma testosterone occurred in normoxic and hypoxic separated male pups at birth, (d) testicular Cyp11a1, Lhcgr, and Star expression was high at birth and decreased thereafter suggesting a hyporesponsive period in the testes, and (e) elevated estrogen in the early neonatal period occurred independently of gonadotropin stimulation. We conclude that a large corticosterone response to hypoxia during the first 5 days of life occurs as an adaptation to neonatal stress, that the testosterone surge during the first hours after birth occurs independently of gonadotropins but is associated with upregulation of the steroidogenic pathway genes in the testes, and that high postnatal estrogen production also occurs independently of gonadotropins.