Sex steroid regulation of the inflammatory response: Sympathoadrenal dependence in the female rat

To investigate the role of sex steroids in sex differences in the response of rats to the potent inflammatory mediator bradykinin (BK), we evaluated t he effect of sex steroid manipulation on the magnitude of BK-induced synovi al plasma extravasation (PE). The magnitude of BK-induced PE is markedly le ss in females. Ovariectomy of female rats increased BK-induced PE, and admi nistration of 17 beta-estradiol to ovariectomized female rats reconstituted the female phenotype. Castration in male rats decreased BK-induced PE, and administration of testosterone or its nonmetabolizable analog dihydrotesto sterone reconstituted the male phenotype. The results of these experiments strongly support the role of both male and female sex steroids in sex diffe rences in the inflammatory response. Because the stress axes are sexually dimorphic and are important in the reg ulation of the inflammatory response, we evaluated the contribution of the hypothalamic-pituitary-adrenal and the sympathoadrenal axes to sex differen ces in BK-induced PE. Neither hypophysectomy nor inhibition of corticostero id synthesis affected BK-induced PE in female or male rats. Adrenal denerva tion in females produced the same magnitude increase in BK-induced PE as ad renalectomy or ovariectomy, suggesting that the adrenal medullary factor(s) in females may account for the female sex steroid effect on BK-induced PE. Furthermore, we have demonstrated that in female but not male rats, estrog en receptor a! immunoreactivity is present on medullary but not cortical ce lls in the adrenal gland. These data suggest that regulation of the inflamm atory response by female sex steroids is strongly dependent on the sympatho adrenal axis, possibly by its action on estrogen receptors on adrenal medul lary cells.