Effects of gonadectomy and sex hormone therapy on the endotoxin-stimulated hypothalamo-pituitary-adrenal axis: evidence for a neuroendocrine-immunological sexual dimorphism.

Abstract

Bacterial lipopolysaccharide (LPS) stimulates the hypothalamo-pituitary-adrenal axis by a mechanism involving the release of cytokines, which activate the CRH-ACTH system and, as a result, increase glucocorticoid secretion. In the present study we investigated the possibility that endogenous sex hormones modulate the in vivo endotoxin-stimulated adrenal and immune responses in adult BALB/c mice. In preliminary experiments we determined that the maximal glucocorticoid release in response to LPS (50 micrograms, ip) administration was reached 2 h after treatment. The endotoxin effect on the adrenal and immune responses was then tested in male, randomly cycling female, 20-day-gonadectomized and 20-day-gonadectomized mice treated with either testosterone or estradiol. In addition, in vitro experiments were performed to determine whether 1) LPS exerts any direct effect on basal and ACTH-stimulated corticosterone release, and 2) adrenal function is influenced by bilateral gonadectomy and sex steroid therapy. Our results indicate that 1) randomly cycling female mice have significantly more pronounced corticosterone secretion than males 2 h after endotoxin injection, although the tumor necrosis factor responses were similar; 2) the response of the hypothalamo-pituitary-adrenal axis to endotoxin stimulation in female mice was invariable throughout the different stages of the normal estrous cycle; 3) gonadectomy leads to enhanced (P < 0.05) adrenal and immune responses to LPS stimulation compared to the responses in shams; 4) the endotoxin-elicited adrenal and immune overresponses observed in gonadectomized mice are reversed by testosterone treatment, regardless of sex; 5) LPS does not directly modify spontaneous and ACTH-stimulated adrenal corticosterone secretion; and 6) gonadectomy alone or combined with sex steroid therapy does not increase the in vitro adrenal response to ACTH stimulation. Our findings further suggest an evident neuroendocrine-immunological sexual dimorphism during the acute phase of inflammatory processes.

Galanin GAL-R1 Receptor Null Mutant Mice Display Increased Anxiety-Like Behavior Specific to the Elevated Plus-Maze

“…The absence of differential corticosterone levels following test exposure may reflect the slower time course of the corticosterone response to stress. Thus, because corticosterone is released into the circulation from the adrenal cortex following stimulation by ACTH, the corticosterone response may not have reached peak levels in plasma 10 min after test exposure (Spinedi et al, 1992;Groenink et al, 1994). These data provide preliminary evidence to suggest that anxietylike behavior on the elevated plus-maze may not only be qualitatively distinct from anxiety-like behaviors on other tests in our battery, but may also reflect a response to a more stressful test situation.…”

Lipopolysaccharide facilitates partner preference behaviors in female prairie voles

“…It is unclear whether the cytokine-induced effects of ACTH on HPA axis function and subsequent release of corticosterone are dependent on the sex steroid environment. Previous studies in rats and mice have indicated that females may be more sensitive to the effects of endotoxin on the production of corticosterone [5,25]. It remains unknown whether this is also true in prairie voles, and should be investigated in future studies.…”

“…Exposure to either IL-1 ␤ or LPS significantly elevates adrenocorticotropic hormone (ACTH) and corticosterone concentrations in rats and mice [23,24]. While LPS has no direct effect on ACTH production or adrenal output in rats and mice, the release of cytokines stimulates the release of corticotropin releasing hormone (CRH) from the hypothalamus, and the subsequent release of ACTH from the pituitary [25].…”

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

“…In general, estrogen increases the immune response (Grossman, 1984) and androgens inhibit it (Spinedi et al, 1992) such that females have more pronounced responses than males to immune activation. Sex steroids also influence HPA axis activity, since estrogen positively (Vamvakopoulos and Chrousos, 1993) and androgen negatively (Bingaman et al, 1994) modulate corticotrophin releasing hormone (CRH) production such that females exhibit higher plasma corticosterone (CORT) levels compared to males.…”

“…There are also important developmental alterations in the innate immune response. For example, the HPA axis is markedly suppressed until near the end of the second postnatal week in rodents (Levine, 2001); at later time points, Spinedi et al (1992) found LPSstimulated CORT secretion to be higher in postnatal day (P) 30 than P45 males, and highest in P45 females, indicating that pubertal changes in gonadal activity results in sexual dimorphism of immune-neuroendocrine interactions. Thus exposure to an immunogen during the first postnatal week will result in a very different response than at later periods.…”