Repeated Endotoxin Treatment Decreases Immune and Hypothalamo-Pituitary-Adrenal Axis Responses: Effects of Orchidectomy and Testosterone Therapy

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Abstract
It is known that in vivo administration of bacterial endotoxin activates immune cells to release cytokines, these substances in turn enhancing hypothalamo-pituitary-adrenal (HPA) axis function; additional evidence supports the existence of an immune-neuroendocrine sexual dimorphism. 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 modulatory 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 oil alone (Odx and Sham) or containing 20 µg 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 µg per mouse) in a single (day 1 D1) or repeated (at 24-hour intervals for 5 consecutive days) form. Animals were decapitated (on Dl, D3 and D5 of the treatment) 2 h after the last injection of either vehicle alone or containing LPS (the two groups were run in parellel). Trunk blood was collected and the whole medial basal hypothalamus (wMBH), the anterior pituitary (AP) and adrenal glands were dissected. Plasma tumor necrosis factor-alpha (TNFα), ACTH and corticosterone (B) concentrations as well as wMBH CRH, AP ACTH and adrenal B contents were determined by specific assays. Our results indicate: (1) a significant decrease in mice body weight after repeated LPS injections, regardless of the group; (2) a sex steroid environment-independent increase in plasma ACTH, B and TNFα 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 the first, third and fifth LPS treatments and that such an effect was significantly enhanced by Odx and fully reversed by Odx followed by T therapy, and (5) that while hypothalamic CRH and AP ACTH were not modified by endogenous sex steroid environment or endotoxin administration, Odx significantly enhanced the LPS-induced ACTH release only 2 h after a single LPS treatment. Our findings suggest that endogenous TNFα plays a mediatory role in the acute activation of HPA axis function after LPS and that under persisting endotoxemia both immune and HPA functions are decreased. Finally, testosterone has an inhibitory role on adrenal glucocorticoidogenesis during endotoxic shock.

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