REPEATED ENDOTOXIN TREATMENT DECREASES IMMUNE AND HYPOTHALAMO-PITUITARY-ADRENAL AXIS RESPONSES - EFFECTS OF ORCHIECTOMY AND TESTOSTERONE THERAPY

It is known that in vivo administration of bacterial endotoxin activat es immune cells to release cytokines, these substances in turn enhanci ng hypothalamo-pituitary-adrenal (HPA) axis function; additional evide nce supports the existence of an immune-neuroendocrine sexual dimorphi sm. In the present study, we investigated: (1) the in vivo response of both the HPA and the immune systems to single and repeated endotoxin administrations in mice, and (2) whether testosterone possesses a modu latory effect on neuroendocrine-immune function under endotoxemia. For these purposes, adult male BALB/c mice were orchidectomized (Odx) or sham-operated and injected s.c., on alternate days, with either corn o il alone (Odx and Sham) or containing 20 mu g of testosterone (Odx+T) until animals were killed. One week after surgery, different groups of mice were treated i.p. with bacterial lipopolysaccharide (LPS; 25 mu g per mouse) in a single (day 1, D1) or repeated (at 24-hour intervals for 5 consecutive days) form. Animals were decapitated (on D1, D3 and D5 of the treatment) 2 h after the last injection of either vehicle a lone or containing LPS (the two groups were run in parellel). Trunk bl ood was collected and the whole medial basal hypothalamus (wMBH), the anterior pituitary (AP) and adrenal glands were dissected. Plasma tumo r necrosis factor-alpha (TNF alpha), ACTH and corticosterone (B) conce ntrations as well as wMBH CRH, AP ACTH and adrenal B contents were det ermined by specific assays. Our results indicate: (1) a significant de crease in mice body weight after repeated LPS injections, regardless o f the group; (2) a sex steroid environment-independent increase in pla sma ACTH, B and TNF alpha levels 2 h after a single LPS injection; (3) that all these responses decreased after repeated LPS administration; (4) that a significant rise in adrenal B content occurred 2 h after t he first, third and fifth LPS treatments and that such an effect was s ignificantly enhanced by Odx and fully reversed by Odx followed by T t herapy, and (5) that while hypothalamic CRH and AP ACTH were not modif ied by endogenous sex steroid environment or endotoxin administration, Odx significantly enhanced the LPS-induced ACTH release only 2 h afte r a single LPS treatment. Our findings suggest that endogenous TNF alp ha plays a mediatory role in the acute activation of HPA axis function after LPS and that under persisting endotoxemia both immune and HPA f unctions are decreased. Finally, testosterone has an inhibitory role o n adrenal glucocorticoidogenesis during endotoxic shock.