Trauma remains the single leading cause of deaths in the United States and elsewhere in the world (1-10). Numerous advances in the last decade in intensive care units and patient management have helped short-term survival (1-3). However, despite these advances, sepsis and subsequent multiple organ failure continue to be the major cause of morbidity and mortality in injured patients who survive initial injury (1, 4-10). Intensive investigation in this area has identified that postinjury pathogenesis is complex and is influenced by more than one factor (7-14). These factors include age, preclinical conditions, and lifestyle (alcoholism/drug abuse, socio-economic background, etc.). However, gender has turned out to be the major risk factor in postinjury pathogenesis (11-26). Studies have shown that men and women respond differently to injuries (15-24). As has been indicated in a recent article that gender-specific pharmacological responses have been recognized as early as in 1932, when it was reported that compared with male rats, female rats required one-half the dose of barbiturate to induce sleep (27). Despite that information, the importance of naturally occurring sexual dimorphism in response to injury was not appreciated until recently. In one retrospective analysis of a septic patient population, Bone (5) observed increased morbidity and mortality in males compared with females. In a prospective study, Schroder et al. (17) enrolled 52 patients (19 women and 33 men) to determine the role of gender plays in surgical sepsis. Although the findings from this study suggested no difference in the multiple organ dysfunction score from day 1 to 28, the prognosis of sepsis was significantly different in women compared with men. Moreover, there were more deaths in men (70%) compared with women (26%). In conclusion, this study suggests that gender differences exist in human sepsis, with a significantly better prognosis for women. In accordance with these findings, Wichmann et al. (25) concluded that although there was no difference in overall mortality between men and women after sepsis, significantly smaller numbers of female patients require intensive care. Furthermore, the incidence of severe sepsis/septic shock in women was lower in intensive care patients. In another study, findings reported by Offner et al. (18) support the suggestion that the male gender is associated with dramatically increased risk of major infection after trauma. In a recent retrospective analysis of over 150,000 patients involved in blunt or penetrating trauma, George et al. (19, 24) concluded that after blunt trauma, male patients had a significantly higher risk of death compared with female patients. For penetrating trauma patients, however, there was no significant difference associated with gender. Findings from this study further indicated (24) that premenopausal women had a survival advantage in blunt trauma patients; however, the converse pattern prevails for the penetrating trauma patients. Interestingly, in another hospital-based study, McGwin et al. (20) suggested that up to age 60, the mortality rate among females was twice that of males. However, this association was lost among patients who were 60 and older. Women less than 60 years of age who sustain burn injuries have an increased risk of death compared with males (20). Although the underlying mechanism of gender-specific responses after acute injury remains to be established, findings from previous studies suggest that women in their reproductive years have more vigorous immune responses than males (28-37). Women have more developed thymus, higher immunoglobulin concentrations, and a greater ability to reject tumor and homografts. Furthermore, studies have suggested that physiological levels of estrogen stimulate humoral and cell-mediated immune responses, whereas the male hormone, 5αdihydrotestosterone, negatively influences these responses (11-13, 26, 28, 29, 35, 37). These clinical studies support the suggestion that gender plays a significant role in the outcome of trauma patients. In contrast, several other studies did not agree with this suggestion simply because they failed to establish the relationship of gender with the outcome of trauma patients (15, 16, 22, 23). In an analysis of patients admitted to intensive care units with symptoms of systemic inflammatory response syndrome, Eachempati et al. (23) did not find significant differences in mortality between males in females. Similarly, in another retrospective evaluation of trauma population, Bowles et al. (22) failed to establish a difference in outcome between male and female trauma patients. In their study, age, mechanism and severity of injury, but not gender, were identified as factors influencing survival. A definitive cause for these differences remains to be established. Many factors including the sample size, patient triage, and patient care protocols may account for the observed variations in these studies. Moreover, the differences in the outcome could also result from differences in the hormonal levels at the time of injury. Because there is no information on hormonal levels in these studies, it is difficult to ascertain the underlying differences between these findings. Furthermore, to understand the role of sex hormones in response to trauma, it is necessary to perform these studies in a more controlled setting. This is not possible in a patient population because it is difficult to control all the factors that are known to influence outcome in trauma patients. However, these studies are possible in an experimental setting. In view of these clinical findings, experimental studies were initiated to determine the role of gender in postinjury complications. Some of the approaches that are used to determine the role of sex hormones in postinjury pathogenesis in experimental setting are described below.
APPROACHES TO MODULATE MALE HORMONES
There are multiple approaches in the literature that have been and can be used to modulate male sex hormones. A common approach that has been used to determine the effect of male sex hormone in experimental conditions is the surgical removal of both testes, a process referred to as castration (38). Normally, animals are castrated at least 2 weeks before performing trauma procedure. The 2-week time period markedly lowers circulating androgen levels. These animals are then used to study the immunologic and other physiologic responses. However, castration is not a viable option in the real scenario, particularly in dealing with a patient population. Pharmacological agents provide alternative options to study the role of male hormones. Flutamide, a known androgen receptor antagonist, is a nonsteroidal agent (39, 40). It inhibits androgen uptake or nuclear binding of the activated androgen receptor to nuclear response elements in the nucleus. It is used clinically for the treatment of androgen-sensitive prostatic carcinoma. Animal studies have shown that flutamide prevents suppression in immune, cardiovascular, and hepatocellular function. Another common antiandrogenic compound is bucalutamide. Bucalutamide, like flutamide, is a nonsteroidal and shares the same mechanism of action as does flutamide (41-44). It also inhibits the binding of androgen to its cytosolic receptor in targets tissues and is used clinically in the treatment of prostate cancer. Bucalutamide has an advantage over flutamide in that it has little effect on serum testosterone levels.
APPROACHES TO MODULATE FEMALE HORMONES
To determine the role of female sex hormones, experimental studies have used approaches such as the surgical removal of ovaries, a process commonly referred to as ovariectomy. Females are ovariectomized at least 2 weeks before the trauma procedure. The 2-week time period allows for the marked decrease in female sex hormones. Estrogen (a female sex hormone) is shown to prevent suppression in immune and cardiovascular functions after trauma. The estrus cycle of the mouse and rat can be divided into four stages: diestrus, proestrus, estrus, and post- or met-estrus. Because estrogen levels are high in the proestrus cycle, the use of females in proestrus stage helps in delineating the role of endogenous estrogen in postinjury pathogenesis. Alternatively, endogenous estrogen levels or estrogen interaction with its receptor can be modulated via pharmacological agents. Among them, ICI 182,780 and EM-800 were used in many studies dealing with the role of estrogen in trauma (11-13, 45-49). EM-800 is an estrogen receptor antagonist that blocks the transcriptional functions of estrogen receptor α and β (42, 45, 46). ICI 182, 780, on the other hand, inhibits estrogen binding to the receptor complex. ICI is 10 times more potent than EM-800 and can be administered orally or subcutaneously. Studies have shown that physiological actions of estrogens are mediated by two receptors, estradiol receptor (ER)-α and ER-β. There are compounds that work as agonist and are recognized for their specificity toward ER-α and ER-β. Propyl pyrazole triol (PPT) is a potent ER-α agonist that does not activate ER-β (47-49). In contrast, the compound diarylpropionitrile (DPN) is a potency-selective agonist for ER-β with a more than 70-fold higher binding affinity for ER-β than ER-α. Tamoxifen is one of the oldest commonly prescribed medications for breast-cancer patients with estrogen receptor-positive tumors. A newly developed drug raloxifene (Evista), was initially approved to prevent osteoporosis. Raloxifene's anticancer effect is currently being investigated in a trial comparing it with tamoxifen. Raloxifene has an advantage over tamoxifen, notably in terms of less risk of developing uterine cancer. In addition, another class of antiestrogen-referred aromatase inhibitors is also used to suppress estrogen level in the blood by inhibiting one of the enzymes needed to produce the hormone. These drugs, which include letrozole, anastrozole, and exemestane, work best in postmenopausal women. Another aromatase inhibitor, anastrozole, was approved by the FDA to treat the early stage of invasive breast cancer in postmenopausal women. These drugs allow for evaluating their role beyond cancer area and thus can easily be used to determine the role of estrogen in postinjury pathogenesis. Nonetheless, it could be argued that administration of estrogen could cause adverse effects, including thromboembolism. However, it should be noted that these deleterious effects are likely from excessive and chronic use of estrogen such as in hormone replacement therapy. In our studies, we have used only a single dose of estrogen and we have not observed any adverse effects after trauma-hemorrhage (11, 13).
GENDER DIFFERENCES AND EXPERIMENTAL MODELS OF ACUTE INJURIES
There are large numbers of experimental models that have been used in the past to mimic clinical trauma. These can be grouped into three major categories: models of trauma, i.e., excessive blood loss, models of thermal injury, and models of sepsis. However, except for the model of excessive blood loss, only a few studies have characterized other two models (i.e., thermal injury or sepsis) in terms of gender dimorphism (11-13, 50-57). Because the focus of this article is on gender dimorphism in acute response to trauma-hemorrhage, we will review studies that were conducted using the model of excessive blood loss.
As described by Deitch (58) recently, there are three kinds of experimental models that mimic the excessive loss of blood in clinical setting. These are fixed-pressure or Wiggers preparations where an animal is bled to a fixed pressure and maintained at that pressure for predetermined time, the fixed-volume model where removal of fixed volume of blood occurs over a defined time period, and continuing hemorrhage model where bleeding is not controlled by tourniquet or surgically. Among these, the experimental model described in category one has been characterized extensively in the context of sexual dimorphism (11-13, 59-82). In this model, animals are fasted overnight before the experiment. Under anesthesia with isoflurane inhalation, the right and left femoral arteries and right veins are cannulated with PE-50 tubing. The right femoral artery is connected to a blood pressure analyzer for the measurement and monitoring of mean arterial pressure (MAP) and heart rate (HR). The right femoral vein is used for fluid resuscitation and the left femoral artery is used for withdrawing blood. The total circulating blood volume is calculated using the equation: circulating blood volume = body weight × 6%). MAP is monitored continuously before the onset of hemorrhage, during, and until the end of resuscitation. The animals are bled rapidly to an MAP of 35 to 40 mmHg within 10 min and they are then maintained at that pressure by further withdrawing small volumes of blood until maximum bleed out (MBO) occurs. The amount of blood withdrawn to reach MBO is ∼60% of the total circulating blood volume. The animals are then maintained at the pressure by returning small volumes of Ringer's lactate until 40% of the MBO is returned in the form of Ringer's lactate. The animals are resuscitated with Ringer's lactate (4× the MBO) at 90 min after the onset of bleeding via right femoral venous catheter over 1 h.
Using this model, findings from a series of studies have shown that trauma-hemorrhage causes alterations in immune and cardiac functions in mature males, and ovariectomized and aged females (Fig. 1) (11-13). Alterations in immune responses were characterized by a decrease in Th-1 cytokines, i.e., IL-2 and IFN-γ, and an increase in Th-2 cytokine IL-10 (59-65). In contrast, female mice in their proestrus stage of estrus cycle exhibit enhanced release of splenocyte production of Th-1 cytokines and a decrease in Th-2 cytokine (59-61, 66-70). In addition to immune perturbations, cardiac functions are significantly depressed in male mice and rats after trauma hemorrhage, whereas they are maintained in proestrus females (11-13, 74, 75). Moreover, the survival rate of proestrus females subjected to sepsis after trauma-hemorrhage is significantly higher than age-matched males or ovariectomized females (Fig. 1) (67). Castration of males 2 weeks before trauma-hemorrhage prevented the post-traumatic suppression of immune and cardiac functions (11-13, 62, 74, 75). Moreover, castration of male mice prevented the increase in Kupffer cell production proinflammatory cytokines (73). Administration of 5α-dihydrotestosterone (DHT) to castrated males results in suppression of splenic and peritoneal macrophage cytokine production (65). Conversely, pretreatment of female mice with physiological amount of DHT for 2 weeks before trauma-hemorrhage also caused suppression of splenic and peritoneal macrophage cytokine production (63). DHT-treated female mice exhibit suppression in Th1 cytokines after trauma-hemorrhage (65). However, DHT did not affect the release of IL-10 by splenocyte after trauma-hemorrhage. On the other hand, female sex steroids have been shown to maintain immune and cardiac function after trauma-hemorrhage (11-13). Treatment of male mice with 17β-estradiol prevented the depression in splenic and peritoneal macrophage production of cytokines (66). The depression of Th1 cytokine after trauma-hemorrhage was also prevented in estrogen-treated male mice. Importantly, the treatment of male mice with estradiol was associated with increased survival after the induction of subsequent sepsis. Conversely, surgical removal of ovaries in female mice before trauma-hemorrhage increased the lethality from subsequent sepsis (Fig. 1). Therefore, these results suggest that the changes in immune and cardiac functions after trauma-hemorrhage are gender specific. In particular, 5α-dihydrotestosterone is a major contributor to the immunosuppression in male mice, whereas estrogen protects mice after trauma-hemorrhage.
Studies have also suggested that sex hormones (i.e., testosterone, 5α-DHT, and 17βestradiol) are synthesized in peripheral tissues (76-82). The presence of steroidogenic enzymes, 5α-reductase, aromatase, 3β-hydroxysteroid dehydrogenase (3β-HSD), and 17β-hydroxysteroid dehydrogenase (17β-HSD) in peripheral tissues especially in spleen and T lymphocytes has recently been documented (Fig. 2) (76-82). In addition, immune cells also possess receptors for estrogen and androgen (78-81). Although no significant differences between the androgen and estrogen receptor distribution were observed after trauma-hemorrhage, upregulation of 5α-reductase and a decrease in the expression of 17β-HSD-oxidative (17β-HSD-O) activity in T cells after trauma-hemorrhage in males results in increased 5α-DHT synthesis (80, 82). Increased 5α-DHT synthesis can lead to T cell suppression (80, 82). In contrast, 5α-reductase activity is not influenced in females after trauma-hemorrhage. Additional findings suggest that 5α-DHT levels are low in the T lymphocytes of proestrus females because of lower 5α-reductase activity. In contrast, aromatase as well as 17β-HSD-reductive (17β-HSD-R) activities increase significantly in proestrus females after trauma-hemorrhage, leading to increased synthesis of 17β-estradiol. The increase in 17β-estradiol level likely plays a role in maintaining T cell responses after trauma-hemorrhage. Thus, gender difference in T cell response after trauma-hemorrhage also involves a dimorphic response in steroidogenic enzyme activity in males and females, respectively, after trauma.
The role of gender in postinjury complications remains controversial. Although a number of previous studies suggest that gender plays a significant role in the outcome of trauma patients, others have failed to establish such differences between men and women. The results obtained from rodent models of trauma-hemorrhage support the suggestion that gender does play a decisive role in shaping the immune response after injury. However, the question remains whether gender-specific responses are global across injuries or are only observed in a specific injury situation. Moreover, it is not clear whether the existence of a gender-specific response is more prominent in mild, moderate injuries or remains evident even after severe injuries. Therefore, additional studies are needed to dissect the role of gender as well as underlying mechanisms responsible for the gender dimorphic differences in males and females after adverse circulatory conditions. These aspects must also be examined in other experimental models of injuries, including the experimental models of burn injury and sepsis. The information obtained from these experimental studies will help in developing novel therapies for the treatment of patients with acute injuries.
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