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Originally published online as doi:10.1189/jlb.0607360 on September 25, 2007

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(Journal of Leukocyte Biology. 2008;83:499-506.)
© 2008 by Society for Leukocyte Biology

Gender dimorphism following injury: making the connection from bench to bedside

Jason L. Sperry1 and Joseph P. Minei

University of Texas Southwestern Medical Center, Department of Surgery and the Division of Burn/Trauma/Critical Care, Dallas, Texas, USA

1 Correspondence at current address: Division of General Surgery and Trauma, Department of Surgery, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA. E-mail: sperryjl{at}upmc.edu

ABSTRACT

Despite ongoing prevention efforts, injury remains the leading cause of mortality over the first three decades of life in the United States. Those who survive their initial injury continue to be plagued with the development of sepsis and multiple organ failure and their attributable morbidity and mortality. An important and persistent finding has been that males and females respond differently following traumatic injury and hemorrhagic shock. A significant advancement in the experimental understanding of the gender dimorphism in response to trauma-hemorrhage and sepsis has occurred. Experimental evidence for the differential effects of sex hormones on cell-mediated immunity and organ system tolerance of shock continues to expand. Clinical studies, however, have been unable to reproduce these laboratory bench findings consistently. There continues to be a divide between the "bench and bedside" in regard to our understanding of gender-based differences following injury. Relative to controlled animal experiments, predisposing comorbidities, injury characteristics, and a lack of information about the hormone milieu of the trauma patient disallow reproducible results from clinical analyses. Continued clinical research into potential sex hormone-based differences, genetic differences, and the cellular and molecular mechanisms responsible for these gender-based differential responses is required to close this gap. This may ultimately promote therapeutic interventions, which will allow for improved outcomes for males and females in the near future.

Key Words: clinical research • laboratory research • gender-based outcome differences

INTRODUCTION

Traumatic injury represents a major public health problem and results in a substantial economic and societal burden [1 ]. Despite ongoing prevention efforts, injury remains the leading cause of mortality over the first three decades of life in the United States. It is responsible for over 100,000 deaths per year and ranks as the fourth leading cause of overall U.S. mortality [2 ]. Although significant advances in trauma-care delivery and post-injury management practices have occurred over the last decade, those who survive their initial injury continue to be plagued with the development of sepsis and multiple organ failure and their attributable morbidity and mortality [3 4 5 6 7 8 ]. Despite a significant increase in our understanding of the pathophysiological processes responsible for these detrimental outcomes, there remains a paucity of effective interventions [9 , 10 ]. One important and persistent finding has been that males and females respond differently following traumatic injury and hemorrhagic shock [11 ]. The underlying mechanisms for this gender dimorphism have been investigated extensively in experimental animal studies, and they have revealed consistently that sex hormones are responsible for these differential outcomes [12 ]. Validation of these experimental research findings clinically, however, has been less consistent [13 14 15 16 ]. The primary aim of this analysis is to review the most up-to-date experimental findings and clinical evidence concerning this gender-based, dimorphic response following injury in an attempt to bridge any divide, which exists between the "bench and bedside". Further insight and understanding into the mechanisms responsible for this gender dimorphism may aid in the clinical validation of these experimental research findings and thereby, increase the potential for future therapeutic interventions, which can improve outcomes for males and females following traumatic injury.

EXPERIMENTAL EVIDENCE

An increasing body of evidence from animal models has revealed that sex hormones and/or their derivatives play an intricate role in the pathological response to trauma-hemorrhage. They have been shown to influence the hemodynamic, immunologic organ system and cellular responses to traumatic insult [11 12 13 ]. The hormonal milieu of the proestrus female rodent has been found to be protective [17 , 18 ]. 17β-Estradiol is the primary circulating estrogen in female animals, and studies have demonstrated that cardiovascular and immunologic function is preserved in female rodents when they are in the proestrus phase (when 17β-estradiol levels are highest), following trauma and hemorrhagic insult [18 , 19 ]. Tolerance of severe hypoxia without associated hemorrhage or shock has also been shown to be improved in the proestrus female rodent [20 ]. In a hemorrhagic shock model, Wichmann and colleagues [21 ] showed that the female rodent had preservation of splenocyte-proliferative capacity and IL-3 secretion along with maintenance of macrophage IL-1 secretion. Male rodents had reduced expression of all inflammatory cytokines as well as a reduced splenocyte-proliferative capacity. These protective effects of estrogen were also shown to result in a significant improvement in survival in septic animals, following cecal ligation and puncture (CLP) [22 ]. Subsequently, ovariectomized females were shown to have no preservation of immune function following trauma-hemorrhage, reacting similarly to their male counterparts, and administration of 17β-estradiol to males or ovariectomized females again preserved their immunologic function [18 , 23 ]. The proestrus female has also been shown to have improved cardiac and hepatocellular function following trauma-hemorrhage, relative to the estrus female or male rodent. Administration of 17β-estradiol to male rodents improved myocardial contractility, cardiac output, and hepatocellular function, as demonstrated by indocyanine green clearance, and also reduced IL-6 secretion following trauma-hemorrhage [17 , 19 ]. Along with estrogen’s enhancing effect on cell-mediated immunity, it has been shown to reduce neutrophil chemotaxis and neutrophil activation [24 ]. Secondary to these proposed effects, the proestrus female rodent was shown to be protected from trauma-hemorrhage-induced pulmonary injury, demonstrating reduced leukosequestration and attenuated pulmonary permeability, as compared with other stages of the female rodent reproductive cycle [25 ]. It can be concluded from these analyses that the female rodent is able to better tolerate the detrimental effects of hemorrhagic shock, and this beneficial effect is derived primarily from 17β-estradiol, which can provide protection in male and female animals.

A similar, large body of evidence has accumulated concerning the detrimental effects of testosterone and its derivatives following trauma-hemorrhage. Castration of male rodents prior to trauma-hemorrhage was shown to prevent the immunosuppression, which developed in sham-castrated male animals, implicating testosterone, specifically 5{alpha}-dihydrotestosterone (DHT), responsible for a significant reduction in splenocyte proliferation and splenocyte IL-2 and IL-3 release [26 ]. Treatment with DHT, the most active male sex steroid, in previously castrated males also suppressed splenic and peritoneal macrophage cytokine production following trauma-hemorrhage, and a similar response was found in females treated with DHT [12 , 27 28 29 ]. The depressant effects of testosterone or its derivatives have also been demonstrated by a testosterone receptor blockade. Male animals treated with flutamide, a nonsteroidal testosterone receptor antagonist, showed significant improvement in cardiac contractility and output along with hepatocellular function following trauma-hemorrhage, as compared with animals, which received placebo treatment only [30 ]. Similar findings for flutamide and the prevention of cell-mediated immunosuppression and improved survival in a sepsis rodent model have been found [31 32 33 ]. Mayr et al. [34 ] showed further that this immune suppression secondary to testosterone was attributible to a reduction in MHC class II receptor expression on peritoneal and splenic macrophages. This reduction in MHC class II expression was prevented if castration occurred prior to hemorrhagic insult.

In addition to estrogen and testosterone, other mediators with sex hormone effects have been analyzed experimentally. Dihydroepiandrosterone (DHEA) is the most abundant steroid hormone in plasma and is a precursor or intermediate to estrogen and testosterone moieties with androgen- and estrogen-like properties, depending on the local environment of its action [35 ]. In males, it has been shown to restore splenocyte and macrophage and T cell function following trauma-hemorrhage and improved survival in a CLP model of sepsis [36 , 37 ]. This was hypothesized to occur as a result of the conversion of DHEA to estrogen, as similar findings are found with 17-β estriadiol treatment in males prior to insult. In females, DHEA is thought to be converted to testosterone and have primary androgen effects. It is interesting that in proestrus female animals, DHEA enhanced splenocyte and macrophage immune function further and in addition, caused a reduction in anti-inflammatory IL-10 release [38 ]. Similar beneficial effects of a metabolite of DHEA, adrostenediol, have been found in a two-hit model of trauma-hemorrhage and sepsis [39 , 40 ].

These results demonstrate definitively the dichotomous nature of male and female sex hormones in response to trauma-hemorrhage in animals. Estrogen is protective and immune-enhancing, and testosterone is deleterious and immunosuppressant. Further validation of these conclusions results from the fact that estrogen and testosterone modulate splenic macrophage release of cytokines differentially in rodents. DHT has been shown to inhibit Th1 cytokine expression (those cytokines, which promote cell-mediated immunity), and 17β-estradiol promotes Th1 cytokine expression by reducing IL-10 secretion (a potent anti-inflammatory cytokine with anti-Th1 effects) [27 , 41 ]. Differential cytokine expression may also be involved with the hemodynamic differences between male and female animals following injury. The depressed cardiac response to trauma-hemorrhage has been shown to correlate with cardiomyocyte IL-6 production [42 , 43 ]. 17β-Estradiol treatment in male animals has been shown to diminish cardiomyocyte IL-6 production and result in improved cardiac function following trauma-hemorrhage, and castration of male animals offered similar improvement in the cardiac tolerance of hemorrhagic insult [44 ]. A reduced myocardial inflammatory response and improved cardiac function for proestrus females have also been shown following experimentally induced burn injury [45 ].

More recent experimental evidence has also accumulated concerning the mechanism by which sex hormones have their effects. Several studies have demonstrated the presence of estrogen receptors (ERs) on various immune cells, including thymocytes, macrophages, and leukocytes [46 , 47 ]. It has also been shown that the two known subtypes of ERs (ER-{alpha} and ER-β) are expressed in a tissue and cell type-specific manner in the rodent [48 ]. Adding further complexity, the protective effects of estrogen are also tissue- and cell type-specific [49 , 50 ]. The beneficial effects of 17β-estradiol on proinflammatory cytokine expression has been shown to be mediated primarily by ER-{alpha} in Kupffer cells (the primary liver macrophage), splenic macrophages, and T cells (CD3+), and these effects are mediated via ER-β in alveolar macrophages and PBMCs [51 ]. Further work on splenic T cell cytokine production has revealed that the favorable effects of 17β-estradiol, via the ER-{alpha}, are in part mediated by restoration of MAPK, NF-{kappa}B, and AP-1 signaling pathways [52 , 53 ]. In contrast to the immune-enhancing effects on lymphocytes and macrophages, hepatic injury following trauma-hemorrhage has been shown to be ameliorated by an ER-{alpha}-mediated reduction in NF-{kappa}B, AP-1 activity, and inducible NO synthase (iNOS) expression [54 ], and a similar protection from lung injury was found as a result of an ER-β-induced down-regulation of iNOS [55 ]. Further studies have revealed that the estrogen-mediated protection from trauma-hemorrhage-induced lung and hepatic injury results from down-regulation of LR4 signaling and a concordant reduction in lung and Kupffer cell inflammatory cytokine production [56 57 58 ]. In addition, the protective effects of 17β-estradiol on lung inflammation following trauma-hemorrhage have been shown to be mediated via down-regulation of lung macrophage inhibitory factor, which has been shown to up-regulate gene expression of TLR4 and is thought to play a central role in the promotion and exacerbation of the inflammatory response following sepsis [59 ]. Finally, it has been demonstrated recently that the mechanism by which flutamide results in protective effects in the liver following hemorrhagic insult is mediated by a down-regulation of NF-{kappa}B DNA binding activity by an ER signaling pathway [60 ].

A tremendous advancement in the experimental understanding of the gender dimorphism in response to trauma-hemorrhage and sepsis has occurred. Evidence for the differential effects of sex hormones on cell-mediated immunity and organ system tolerance of shock continues to expand. The signaling pathways and mechanisms associated with these dimorphic effects have begun to be uncovered. The reproducibility and strength of these experimental findings have even led some to consider estrogen-based or testosterone receptor antagonist therapy as a possible therapeutic intervention following traumatic injury in human patients [23 , 61 ].

CLINICAL EVIDENCE

Despite these advancements as reviewed above, clinical studies have been unable to reproduce these laboratory bench findings consistently (Table 1 ). Large, single center and multicenter studies have looked at the gender dimorphism following injury and have resulted in conflicting and varied conclusions. In one of the largest population-based studies by Gannon et al. [68 ], which looked at 22,332 patients, gender was not a significant independent predictor of mortality. This lack of a gender-based survival advantage has been a consistent finding in multiple other studies, including those looking at outcomes following traumatic brain injury [14 , 64 , 70 71 72 ]. Offner and colleagues [63 ], in a prospective cohort analysis, which included over 500 patients, similarly found no difference in mortality across gender, however did show that male gender was a significant independent risk factor for nosocomial infection. The independent risk specifically for post-injury pneumonia has also been shown to be significantly greater in males [77 ]. These associations were strongest in those with significant injury. Other studies have found that females suffer less commonly from multiple system organ failure and sepsis and are thought to be immunologically better able to tolerate a septic challenge following injury [64 ]. Studies in noninjured patient cohorts have reproduced these findings and have shown that females require intensive care less commonly, have a lower incidence of severe sepsis, and suffer less morbidity and mortality following hip fracture [74 , 78 , 79 ]. It is interesting that Rappold et al. [70 ] found that the female gender offered no protection from the development of adult respiratory distress syndrome, pneumonia, or sepsis post-injury, and others [67 , 80 , 81 ] have demonstrated that female gender is a risk factor for mortality in patients with documented infection. Despite some studies revealing protection from infectious and organ failure complications for females, long-term functional outcomes for women following major trauma were found to be significantly worse, even out 18 months from the time of injury [66 ].


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  		Table 1. Published Clinical Literature Investigating the Effects of Gender on Outcome Following Nonthermal Traumatic Injury

Possible reasons for these conflicting results may be secondary to the nonhomogeneous nature of the patient sets analyzed or possibly the significant variation in post-injury care, which can occur in a multicenter studies. Relative to controlled animal experiments, predisposing comorbidities, injury characteristics, and the hormonal milieu of the female patient at the time of injury may be variable or unknown in these types of analyses. Age at the time of injury also plays a significant role when analyzing gender-based differential outcomes in humans, as the overall levels of estrogen and testosterone are determined by the female reproductive status [82 ]. The average age of menopause in the United States has remained relatively stable and occurs at 50 years of age in women [83 , 84 ]. Physiologic changes, which occur in women following menopause, result in a significant reduction in serum estrogen levels with a relative maintenance of serum testosterone levels [82 ]. Large cohort studies, which do not account for or stratify by age and the reproductive status of the female, may result in these inconsistent conclusions.

Studies have looked at the effect of age and its association with the gender dimorphism following injury; however, they also have produced conflicting results. In the largest multicenter analysis by Wohltmann et al. [16 ], which looked at 20,261 patients, female gender was associated with a significant survival advantage in patients less than 50 years of age. Subsequent studies have reproduced these findings [14 ], and others have found, in addition, that the female gender, in women less than 45 years of age, was protective for the development of multiple organ failure and mortality and was associated with reduced Intensive Care Unit and hospital length of stay [69 ]. A recent study by Frink et al. [76 ] found that the female gender was associated with a significant reduction in multiple organ failure and sepsis, as compared with similarly aged males. These outcome differences were associated with lower serum inflammatory cytokine levels in females, yet were found only in those with an injury severity score >25 and in women younger than 50 years of age. These studies’ findings are consistent with the known physiological hormone changes, which occur at menopause, where a significant reduction in estrogen plasma levels occurs [82 ]. In contrast, George et al. [15 ] found that the female gender was also protective for mortality; however, this occurred only in women greater than 50 years of age. Similar results by the same authors, demonstrating protection for women under 50 years of age following blunt injury, were found; however, males over 50 were found to be protected following penetrating injury [73 ]. Finally, women with moderate-to-severe traumatic brain injury were found to have a significant improvement in survival, but this was found only in postmenopausal (≥50 years of age) women when compared with similarly aged men [75 ].

Studies about thermal injury have revealed more consistent findings, however, in direct contrast to nonthermal injury. Clinical evidence following significant burn injury has shown a persistent detrimental effect of the female gender on survival, which was age-dependent. McGwin et al. [85 ] found that females less than 60 years of age had over a twofold higher independent risk of mortality, after adjusting for important confounders. O’Keefe et al. [86 ] analyzed prospectively maintained data about 4927 burn patients and also found that the female gender was an independent risk factor for mortality, specifically in those 30–59 years of age. It is interesting that in the largest pediatric burn patient study (age <16 years), no gender-based mortality differences were found [87 ]. It may be that outcomes following injury are age- and gender-specific, but it is even more important that they may also be injury type-specific as a result of differences in the inflammatory response and immune system mediators brought on by injury type.

Adding even further to the controversy, in a recent presentation at the 7th World Congress on Trauma, Shock, Inflammation and Sepsis (2007), Sperry and colleagues [88 ] found that the female gender was significantly associated with a reduced risk of multiple system organ failure and nosocomial infection following injury, and this protective effect remained significant in premenopausal females (young: age <48) and postmenopausal females (old: age >52) when compared with similarly aged men. Females had a lower independent risk of mortality overall and in the age-stratified groups; however, these findings did not reach statistical significance (Fig. 1 .) To derive the final independent results, important confounders, including injury characteristics, resuscitation requirements, early interventions, and importantly, the prehospital use of oral contraceptives and estrogen replacement therapy, were controlled for via multivariate analysis. Data for this analysis were derived from ref. [89 ], which is an ongoing, prospective, multicenter cohort study looking at the genomic and proteomic responses in patients at high risk for the development of multiple organ failure, secondary to significant blunt injury and hemorrhagic shock. The conflicting nature of prior studies and these results call into question the sex hormone-based mechanism for the gender dimorphism following injury, which has been found consistently in experimental animal studies.


Figure 1
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  		Figure 1. Hazard ratio (HR) associated with gender [female (F) vs. male (M)] for mortality, multiple organ failure, and nosocomial infection outcomes. All, Entire cohort (n=1036); YOUNG, <48 years of age (n=668); OLD, >52 years of age (n=281). Confidence interval (CI) criteria, Blunt mechanism of injury, presence of systolic hypotension (<90 mmHg) or elevated base deficit (>6 meq/L), blood transfusion requirement in first 12 h, abbreviated injury score ≥2, exclusive of brain. Cohort exclusion criteria, Isolated traumatic brain injury, patients <16 or >90 years of age, cervical spinal cord injury.

Alternative explanations for gender-based differential outcomes following injury have been postulated. Males and females are also different genetically, primarily as a result of genes, which reside on the X chromosome. Females do have two X chromosomes by definition; however, only one is functional, as the other is inactivated early in development. This process occurs randomly in each cell; thus, a female is a mosaic having different proportions of cells in each tissue with X-linked genes derived from either of her parents. It has been shown in other disease processes that this mosaic expression can be protective [90 ]. Recent evidence by Arcaroli et al. [91 ] has demonstrated that the IL-1R-associated kinase 1 (IRAK-1) gene in humans can exist as a variant haplotype, which contains a single nucleotide polymorphism. IRAK-1 plays a central role in the regulation and expression of sepsis-associated, proinflammatory mediators [92 93 94 ]. This gene resides on the X chromosome, and this variant haplotype was found to be significantly associated with more severe organ dysfunction and higher mortality in patients with sepsis [91 ]. It may be that genetic differences as a result of this female mosaic expression provide a clinical benefit following injury, which is not hormonally based.

A relative, persistent finding from the reviewed clinical literature is that these gender-based differences are most apparent in more severely injured patients and result in a protective effect for females from organ failure and infectious complications. It has been postulated that these differences may be secondary to differential cytokine expression across gender [95 ]. Schroder et al. [96 ] found enhanced expression of IL-10, an important anti-inflammatory cytokine, in females with sepsis, and others [76 , 95 ] have shown a more proinflammatory cytokine expression pattern in females, with elevated IL-6 levels following significant injury and postoperatively. Administration of endotoxin to young volunteers has been shown to promote a more proinflammatory response in females with a higher rise in C-reactive protein levels, TNF-{alpha} expression, greater leukocyte sequestration (leukopenia), and attenuation of norepinephrine sensitivity [97 ]. It is interesting that Coyle et al. [98 ] found no difference in inflammatory cytokine expression across gender following endotoxin administration, and in postmenopausal females, estrogen replacement therapy was shown to decrease IL-6 and TNF-{alpha} expression [99 ]. Irrespective of these conflicting results, if the gender dimorphism following injury were a result of differential expression of inflammatory cytokines, then outcome differences would be most apparent in patients with more severe injuries, where a significant inflammatory response is expected.

Conclusions based on the clinical evidence for a gender dimorphism following injury remain contradictory and inconsistent. Lacking from all the above clinical analyses is evidence of the hormonal milieu of males and females at the time of injury. It may be that the hormonal environment just prior to a trauma event is a direct determinate of the immune response, which ensues, whether it be proinflammatory or immunosuppressant. Attributing a sex hormonal-based mechanism for gender-related outcome differences will require documentation of estrogen and DHT levels at the time of injury. If not more important, the time course of sex hormone expression in the post-injury and recovery phase will be required to decipher appropriately the mechanisms responsible for potential outcome differences. Evidence exists that serum testosterone levels are reduced significantly in males following critical illness or surgical stress, which can last up to 7 days out from insult [100 , 101 ]. Serum estrogen levels were shown to remain relatively stable in males following acute illness [102 ]. In postmenopausal women, DHEA and testosterone were also shown to be decreased significantly, and 17β-estradiol levels were increased following acute illness [103 ]. For males and females, the magnitude of these serum changes in sex hormone levels was proportional to the patients’ Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, a derived score for disease severity and survival prediction [104 , 105 ]. Similar findings in patients with sepsis, by Fourrier et al. [106 ], demonstrated that an increase in estrogen levels occurs in women and men, and males had significantly reduced testosterone levels. Finally, recent evidence suggests that elevated estrogen levels in males and females following major illness are a result of increased rates of peripheral conversion of androgens to estrogens, resulting from increased aromatase gene expression found in peripheral adipose tissue [107 ].

DISCUSSION

The importance of clinical validation of experimental research findings cannot be underestimated. Despite an impressive expansion of our knowledge based on the gender dimorphism following trauma-hemorrhage in animal models, results from clinical studies remain less than adequate and call into question our current understanding of the underlying processes involved in these gender-based outcome differences. Translating impressive experimental animal evidence to the bedside has also been proven difficult for other interventions, particularly in the management of sepsis. Anti-TNF-{alpha} and IL-1 antagonist therapy were shown to improve survival significantly in animal models of sepsis [108 109 110 111 112 ]. However, clinical trials were unable to reproduce these experimental animal findings [113 114 115 116 117 118 ]. Following injury, the nature of the inflammatory response and the resultant effects on a specific individual are rather complex [119 ]. An excessive, early inflammatory response is thought to promote distal end organ effects, which can culminate into multiple system organ failure [120 ]. In contrast, a less-than-adequate response or subsequent anergy of the cell-mediated immune response may result in infectious complications and secondary poor outcome [121 , 122 ]. It may be that the intricate nature of this response in humans following injury cannot be reproduced fully in experimental animal studies. Genetic predisposition to an excessive or inadequate response following traumatic injury may add further complexity to understanding these gender-based outcome differences [123 , 124 ]. Alternatively, clinical studies may just lack important information to demonstrate these gender dimorphic differences appropriately. With additional knowledge of male and female sex hormone levels at the time of injury and the time course with which they change over time post-injury, clinical analyses may be able to provide evidence and insight consistently into these gender-based differences.

In conclusion, there continues to be a divide between the bench and bedside in regard to our understanding of gender-based differences following injury. Continued clinical research into potential sex hormone-based differences, genetic differences, and the cellular and molecular mechanisms for these responses is required to continue to close this gap. This review in no way aims to diminish the use of ongoing experimental research findings about this gender dimorphism; rather, it should only reinforce the necessity of increasing our experimental and clinical understanding, so successful therapeutic interventions are ultimately found, which will allow for improved outcomes for males and females in the near future.

Received June 8, 2007; revised August 21, 2007; accepted August 30, 2007.

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