Testosterone and/or low estradiol: normally required but harmful immunologically for males after trauma-hemorrhage

Previous studies indicate that after severe hemorrhage, immune functions are markedly depressed in males, whereas females do not show any depression. Although androgen depletion by castration of mice before soft-tissue trauma and hemorrhagic shock prevents the depression of cell-mediated immunity, it remains unknown whether testosterone per se is responsible for producing immune depression.

Female C3H/HeN mice were pretreated with 5alpha-dihydrotestosterone (DHT) or vehicle for 20 days. The mice then underwent soft-tissue trauma (laparotomy) and hemorrhagic shock (blood pressure 35+/-5 mm Hg for 90 minutes) followed by adequate fluid resuscitation (shed blood and lactated Ringer's solution) or sham operation. Two groups of nontreated male C3H/HeN mice were included as controls: one group was subjected to hemorrhagic shock followed by resuscitation, and the second group underwent only sham operation. At 24 hours after trauma-hemorrhage and resuscitation, animals were killed, macrophages harvested from the peritoneum and spleen, and their ability to release interleukin (IL)-1 and IL-6 was evaluated. Plasma DHT, estradiol, and corticosterone levels were measured by radioimmunoassay.

Treatment of female mice with DHT produces a significant increase in DHT levels that was comparable with those seen in nontreated male mice. Alternatively, estradiol levels in female mice were significantly depressed by DHT treatment to levels comparable with those observed in control males. In the vehicle-treated female mice, no depression of the macrophage function was evident after trauma hemorrhage. In contrast, testosterone-treated female mice that had experienced hemorrhage showed significant depression in splenic and peritoneal macrophage IL-1 and IL-6 production, comparable with the values seen in macrophages from male mice that had experienced hemorrhage.

These findings indicate that pretreatment of female mice with DHT depresses macrophage function after trauma-hemorrhage, which mimics the changes seen in normal male mice subjected to trauma-hemorrhage. We propose, therefore, that high testosterone and/or low estradiol levels are responsible for producing the immune depression in male mice after trauma-hemorrhage. Testosterone receptor blocking agents, e.g., flutamide, and/or estradiol administration should thus be useful adjuncts for preventing immune depression in male trauma patients.