Studies that characterize race-based differences after trauma are limited. A study of functional outcome differences among pediatric traumatic brain injury patients in a national US database suggested that black children had worse clinical and functional outcomes at discharge when compared with equivalently injured white children (24). A study to identify the effect of race and insurance status on trauma mortality demonstrated that race and insurance status each independently predict outcome disparities after trauma (22). This study concluded that, even without considering insurance status, race is still an independent factor influencing prognosis in trauma patients. We recently reported (23) the strength of sex-based outcome differences across different racial groups, which suggested that an exaggerated survival advantage was afforded to Asian females relative to Asian males when compared with whites, Hispanics, and blacks in a US population study. The results reported here confirm these preliminary results and show an even more exaggerated sexual dimorphism after severe trauma than that found in our initial study when studying a Chinese cohort of Asian patients. Chinese females exhibited a 62% reduction in mortality compared with equivalent males. Although NI rates did not vary between the sexes, our results further show a possible racial specificity in sex-based outcome differences in trauma patients. One explanation is that the different immune responses to infections associated with sex-related polymorphisms and the different sex hormone levels and effects in men and women might potentially alter the outcomes of infections (28).
The present study showed that only females younger than 50 years had a statistically significant survival advantage compared with males younger than 50 years and that there was no significant difference in patients older than 50 years. This is consistent with previous clinical studies (10, 11). At approximately 50 years old, most women will have experienced changes consistent with menopause. Therefore, these results suggest a contribution of sex hormones for the observed differences in mortality. After menopause, a marked reduction of serum estrogen levels occurs in women (29). Administration of 17β-estradiol, the primary circulating estrogen, has been shown to improve the hepatocellular and cardiovascular organ depression in males after trauma-hemorrhage (30–33). Laboratory studies also show that only proestrus (when estrogen levels are at the peak) animals experience a protective effect against mortality after trauma-hemorrhage (34, 35). Age also influences the levels of testosterone (36–38). This is important because laboratory studies indicated that testosterone or its derivatives exert an adverse effect after injury and lead to worse outcomes for males (39). Males have a significantly higher mortality after injury and are more susceptible to develop subsequent sepsis than females under such conditions (34). Castration or administration of a testosterone receptor antagonist also prevents suppression in immune, hepatocellular, and cardiovascular functions (40, 41). Interestingly, clinical studies (42) revealed that estradiol was significantly elevated in nonsurvivors compared with survivors. Similar research by May et al. (43) also showed that an estradiol level of 100 pg/mL was associated with a 4.6 times greater mortality after severe trauma compared with a reference estradiol level of 45 pg/mL. However, these two studies tested sex hormones only at one time point (48 h after injury) and did not address dynamic changes in hormone levels. We also did not measure hormone levels and therefore can only speculate that hormonal status is one of the factors.
Although ours was a single-center study, the patients studied had high homogeneity and comparability. This analysis is limited by its relative small sample size; therefore, our ability to conduct further comparisons between sexes based on other subgroups is limited. In addition, patients with isolated head injury were not excluded in this analysis, and this may have influenced the final outcomes. However, isolated head injury accounted for only a small proportion of all trauma patients.
The present study also demonstrates that sexual dimorphism was only found in patients with an ISS of 25 or higher and not in patients with an ISS less than 25. Sperry et al. (23) also showed that protection of female trauma patients against mortality was strongest in those with severe injury. We speculate that minor trauma does not typically lead to exaggerated or sustained immune alterations and sex-based outcome differences may be more obvious in severe blunt trauma patients.
In conclusion, the current study showed an exaggerated sexual dimorphism in severely injured Chinese patients. Moreover, this difference only exists in those patients younger than 50 years and with ISS of 25 or higher. These results show a possible strong racial influence on the injury response in humans. One potential contributor to the higher survival rates in females could be the role of sex hormones; however, other genetic factors cannot be excluded. Gene association studies and future investigation of circulating biomarkers comparing Asian with non-Asian populations could lead to insights on factors that determine sex-based differences on trauma outcomes.
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