Sex differences in hypothalamic-pituitary-adrenal responding to endotoxin challenge in the neonate: reversal by gonadectomy

Abstract

Exposure to endotoxin is known to activate hypothalamic-pituitary-adrenal (HPA) responses in both adult and neonatal animals. We have previously reported that female rat pups exhibit greater HPA responses to endotoxin challenge than males. It is unclear, however, whether observed gender differences at this early age are mediated by gonadal factors. In the present investigation we assessed the effects of neonatal gonadectomy on HPA responses to endotoxin challenge in the developing rat. On the first day of life Long-Evans rat pups were gonadectomized or subjected to sham surgery. On the third day of life the pups were injected i.p. with 0.05 mg/kg Salmonella enteritidis endotoxin. Four hours following injection, trunk blood and tissues were collected for determination of plasma hormones and median eminence corticotropin-releasing hormone (CRH) content. Intact female rat pups were found to exhibit greater plasma adrenocorticotrophic hormone (ACTH) and corticostcronc responses to endotoxin challenge compared with male animals. Plasma corticosteronc levels, both total and free steroid, were markedly altered by removal of gonads such that responding to endotoxin was elevated in males, while it was reduced in females. In contrast, ACTH responding in male pups was not altered following gonadectomy, whereas female ACTH responses were significantly reduced compared with endotoxin-treated intact controls. CRH levels in the median eminence were reduced following endotoxin challenge to an equivalent extent in both male and female pups and this effect was partially attenuated by the removal of gonadal hormones. These data suggest that sex differences in HPA responses to immune challenge may be mediated at different levels of the HPA axis. Changes in HPA responses following gonadectomy may compensate for removal of gonadal steroid immunoregulatory influences in the neonate.