TESTOSTERONE RECEPTOR BLOCKADE AFTER HEMORRHAGE IN MALES - RESTORATION OF THE DEPRESSED IMMUNE FUNCTIONS AND IMPROVED SURVIVAL FOLLOWING SUBSEQUENT SEPSIS

Background: Recent studies suggest that androgen depletion by castrati on before hemorrhage has protective effects on cell-mediated immunity in male mice after soft tissue trauma and hemorrhagic shock. Objective : To determine whether treatment with an androgen receptor blocker (eg , flutamide) after trauma-hemorrhage and sepsis has any salutary effec ts on cell-mediated immunity and on the survival of male animals under those conditions. Design: Male C3H/HeN mice were either sham operated or subjected to hemorrhagic shock (mean[+/-SEM] blood pressure, 35+/- 5 mm Hg for 90 minutes) followed by adequate fluid resuscitation (with shed blood and lactated Ringer solution). The animals then received e ither vehicle or 25-mg/kg body weight flutamide subcutaneously immedia tely after the resuscitation as well as 24 and 48 hours thereafter. At 48 hours after shock, sepsis was induced by cecal ligation and punctu re. Sham-operated animals underwent laparotomy only. At 24 hours after cecal ligation and puncture, the animals were killed, blood was colle cted, and splenocytes and splenic macrophages were harvested to produc e nonadherent and adherent cultures. Splenocytes were evaluated for sp lenocyte proliferation and interleukin 2 release, while interleukin 1 and interleukin 6 release were assayed in splenic macrophages. Plasma testosterone and corticosterone levels were also measured by radioimmu noassay. In a separate set of experiments, survival was measured over a period of 9 days after the induction of sepsis. Results: Hemorrhage followed by sepsis produced a significant (P<.05) depression of spleno cyte and macrophage functions in vehicle-treated animals. In contrast, animals treated with flutamide showed markedly improved immune functi ons, as evidenced by restoration of splenocyte proliferation, interleu kin 2 release, splenic macrophage interleukin 1 release, and improveme nt of splenic macrophage interleukin 6 release. Plasma corticosterone levels were notably elevated while testosterone levels were depressed after hemorrhage and the induction of sepsis. The survival rate of the animals in the flutamide-treated group was also notably higher than t he survival rate of animals in the vehicle-treated group subjected to hemorrhage and sepsis. Conclusion: The findings that flutamide not onl y markedly improves the depressed immune functions but also the surviv al of animals after hemorrhage and the induction of sepsis suggest tha t the short-term administration of androgen receptor blocker in males after trauma represents a safe and novel approach for preventing immun e deficiency and decreasing the mortality rate from subsequent sepsis.