Use of Sex Steroid Metabolites as Therapeutic Regimens After Trauma Hemorrhage

In addition to the use of inhibitors of sex hormone synthesis pathways, studies have also utilized approaches in which animals were treated with sex steroid metabolites such as dehydroepiandrosterone (DHEA) and androstenediol (adiol). Both DHEA and adiol are intermediate metabolites of sex hormone synthesis (Fig. 6.2). DHEA, synthesized in the adrenal glands, is present both as a biologically active free form and as an inactive sulfated form (Nestler et al., 1991; Brown et al., 1999; Baulieu et al., 2000; Jarrar et al., 2000a, 2001). DHEA is the most abundant sex steroid in the circulation and is an intermediate in the pathway for the synthesis of testosterone and estrogen. However, depending on the hormonal milieu, andro-genic and estrogenic effects of DHEA have been reported (Nestler et al., 1991; Jarrar et al., 2001). DHEA has been shown to have immunoenhanc-ing effects on splenocytes harvested from normal animals (Brown et al., 1999; Jarrar et al., 2001). Studies have shown that administration of DHEA in male animals prevented the depression in immune, cardiac, and hepato-cellular function after trauma-hemorrhage (Angele et al., 1998b; Jarrar et al., 2001). Moreover, the survival rate also markedly improved in trauma-hemorrhaged animals after polymicrobial sepsis. To determine whether the salutary effects of DHEA on immune, cardiovascular, and hepatocellular function after trauma-hemorrhage were owing to a direct effect of DHEA or its conversion into 170-estradiol or testosterone, DHEA and the specific estrogen receptor antagonist ICI 182,780 or androgen receptor antagonist flutamide were administered simultaneously in separate experiments. The results indicated that the salutary effects of DHEA on the depressed organ functions after trauma-hemorrhage were abolished in the presence of the estrogen receptor antagonist ICI 182,780. However, the beneficial effects of DHEA were not affected in animals treated with androgen receptor blocker, flutamide (Angele et al., 1998b; Catania et al., 1999; Jarrar et al., 2001). These findings suggest that the salutary effects of DHEA on the depressed organ and immune functions after trauma-hemorrhage are mediated via the estrogen receptor.

Similar to DHEA, recent studies have evaluated the role of another metabolite, adiol, in altered cardiac and hepatocellular function after trauma-hemorrhage (Shimizu et al., 2004,2005). Adiol, one of the metabolites of DHEA, has been reported to have greater protective effects than DHEA against lethal bacterial infections and endotoxin shock. Furthermore, adiol has also been reported to produce protective effects after ionizing radiation in mice (Whitnall et al., 2002). Recently, studies from our laboratory have shown that adiol administration after trauma-hemorrhage improves cardiac and hepatic function in male animals. Additional recent findings from our laboratory suggested that adiol ameliorates hepatic functions via activation of PPAR-y (unpublished observations). However, whether adiol affects the cardiac/hepatic function either directly or via modulation of sex hormones remains to be established.

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