Introduction Different responses among the sexes

Introduction Different responses among the sexes are increasingly recognized as a major factor in the outcome of patients with trauma and sepsis. In the past years, several animal studies revealed that females had advantageous immunologic and cardiovascular responses during infectious challenges. In addition, some epidemiologic studies have reported that males had a higher incidence of sepsis than females. This would indicate that the advantageous female response to infection might also be present in humans. In several basic studies, sex steroids were found to influence the chemokine/adhesion molecule expression and neutrophil accumulation during trauma and sepsis. It is now universally accepted that heat shock proteins, heat shock factor 1, and peroxisome proliferators Y-activated receptor γ coactivator 1 are regulated by pannexin-1 inhibitor receptors and consequently contribute to organ protection after trauma–hemorrhage. In addition, sex steroids regulate inflammatory cytokines, leading to increased morbidity and mortality.
Animal studies The laboratory or animal studies, depending on the species and investigational model, have suggested that females seem to have an immunologic advantage in septic challenges after trauma or hemorrhage. Androgen may have immunosuppressive effects, and its administration may interfere with the development of fatal autoimmune disease.. Zellweger et al found that female mice sustained a significantly higher survival rate after similar infectious challenges than corresponding male mice. Faulkner et al also reported that sexual dimorphism in experimental super-antigen toxic shock resulted from increased systemic tumor necrosis factor alpha (TNF-α) in female mice, coupled with an increased susceptibility to TNF-α-induced hepatocyte apoptosis, both of which are dependent on estrogen receptor signaling.
Human studies Previous animal laboratory evidence indicated an estrogen-mediated female survival advantage during experimentally induced sepsis; therefore, the hospital mortality would be lower in female patients than in male patients with severe sepsis, septic shock, or both. In human studies, the data are difficult to interpret due to heterogeneous populations and varied end points. In a prospective human study, Schroder et al investigated sex-related differences in outcomes of patients with surgical sepsis and observed that women had better outcomes than men. Other investigators found that, in younger trauma patients, there was a significantly higher incidence of multiple organ failure, increased mortality, longer intensive care unit and hospital stays in male patients than in their female counterparts.
Bias in clinical studies Some current clinical sepsis studies of sex–mortality relationships are inconsistent with previous reports, which revealed no significant sex differences. The inconsistency may have resulted from some bias in the reported studies, such as lower estrogen production in postmenopausal female patients, while elevated estrogen concentrations were noticed in critically ill male patients with cirrhosis of the liver. Martin et al have identified more than 10 million sepsis cases from 1979 to 2001 and found that female patients with sepsis were older than male patients with sepsis, but there was no significant mortality difference. Angus et al have identified nearly 200,000 severe sepsis cases in 1995 and found that male patients had a higher mortality than female patients, but they found no differences among the sexes after adjusting for age, comorbidity, and infection site.
Different responses and immunomodulation among the sexes The available information indicates that sex steroids modulate cardiovascular responses after trauma. Modulation of the prevailing hormone milieu at the time of injury or infection seems to be a novel therapeutic option for improving outcome after trauma and sepsis. Immunonutrition has a confirmed role of enhancing the hormonal response in patients with septic complications that has been demonstrated in animal studies. We have reported that immunonutrition was more important for male rats than female rats during sepsis. Mortality in the nonorchiectomized male rats decreased from 88.9% to 16.7% after feeding on the immune-enhancing diet. The orchiectomized male rats displayed a reduction in cecal ligation and two-hole puncture (CLP) mortality from 88.9% to 50% after being fed an immune-enhancing diet. Moreover, the oophorectomized female rats displayed a reduced mortality from CLP after also being fed an immune-enhancing diet, i.e., from 55.6% to 44.4%. The nonoophorectomized female rats had a slightly lower mortality from CLP than the oophorectomized female rats following being fed with the control diet, and the difference was significantly lower after being fed the immune-enhancing diet.