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Sex Steroids/Receptor Antagonist: Their Use as Adjuncts After Trauma-Hemorrhage for Improving Immune/Cardiovascular Responses and for Decreasing Mortality from Subsequent Sepsis

Section Editor(s): Takala, JukkaRaju, Raghavan PhD; Chaudry, Irshad H. PhD

doi: 10.1213/ane.0b013e318163213d
Critical Care and Trauma: Review Article

Studies in human as well as animal models demonstrate that females in the proestrus cycle (i.e., with high estrogen) tolerate trauma-hemorrhage and sepsis far better than males. The female sex steroid, estrogen, is the significant factor contributing to this observed gender difference in outcome. One reason for the lack of significant gender association in some clinical studies is the possibility of heterogeneity of the population in terms of their hormonal status at the time of injury. Several experimental investigations have revealed that androgens produce immune and cardiovascular depression after trauma-hemorrhage. However, the use of an androgen receptor antagonist after trauma-hemorrhage has salutary effects of immune and cardiovascular function. Likewise, estrogen produces beneficial effects on immune and cardiovascular function after trauma-hemorrhage and significantly decreases mortality rates from subsequent sepsis. The salutary effects of estrogen after trauma-hemorrhage have been shown to be due to both genomic and nongenomic effects. Thus, the use of an estrogen or androgen receptor antagonist as an adjunct after trauma-hemorrhage is a safe and novel approach for restoring immune and cardiovascular function after trauma-hemorrhage and for decreasing the mortality from subsequent sepsis.

From the Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama.

Accepted for publication November 15, 2007.

Supported by USPHS grants R37 GM39519 and RO1 GM37127.

Address correspondence and reprint requests to Irshad H. Chaudry, PhD, Center for Surgical Research, The University of Alabama at Birmingham, Volker Hall G094, 1670 University Blvd., Birmingham, AL 35294-0019. Address e-mail to

Historically, women live longer than men in almost every country in the world.1 However, women are more susceptible to several autoimmune diseases than men.2 The most striking sex differences are observed in Sjogren’s syndrome, systemic lupus erythematosus, autoimmune thyroid disease (Hashimoto’s thyroiditis as well as Graves’ disease), and scleroderma, which are a spectrum of inflammatory diseases in which the patient population is >80% women.3 In contrast to autoimmune diseases, female gender is better protected from complications and mortality associated with injury, trauma, and sepsis.4–7

Inflammation, as a defense process, is manifested by the infiltration of activated immune cells to the site of injury and/or secretion of cytokines and chemokines in an attempt to rid the body of foreign substances or deal with an insult. Although women have an increased propensity to inflammatory diseases such as rheumatoid arthritis, men are believed to have less active immune systems leading to more infections after trauma. The better prognosis reported for women when compared with men in systemic inflammatory response syndrome as well as sepsis is probably due to a better immune response in females than in males, leading to clearing of infections.2 However, the precise reason for the increased susceptibility of women to autoimmune inflammatory diseases or protection after injury, more predominantly in women of child bearing age,4,8,9 is not well understood.

Basic immune responses differ between females and males, with most of the evidence gathered from work done in rodents.10 In response to immunization, female mice produce more antibody and stronger T cell response than males.11,12 Women are more resistant to infection, mount stronger humoral immune responses to vaccines, and reject allograft more rapidly than males.13,14 Also, the absolute number of CD4+ T cells in females is significantly higher than that in males.15 Sex steroid hormones, such as estrogens influence the development and function of immune cells, though their mechanisms of action on the immune system are not completely understood. In this review, we will focus on the role of sex hormones, more specifically estrogen, after trauma-hemorrhage and whether higher levels at the time of injury maintain cell and organ function and decrease mortality from subsequent sepsis.

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Gender Difference in Trauma-Hemorrhage-Sepsis

Although studies indicate that postinjury pathogenesis is complex and is influenced by multiple factors, gender is clearly recognized as a significant factor.16–20 As early as in 1898, Calzolari demonstrated a relationship between sexual environment and immunity when he observed an enlargement of the thymus when rabbits were castrated before sexual maturity.21 Several studies demonstrate a naturally occurring gender difference in immune responses which persists after traumatic injury6,22 and male gender and age are reported to be risk factors for development of sepsis and multiple organ failure after trauma.17,23–27 Oberholzer et al. observed that the incidence of posttraumatic sepsis and multiple organ dysfunction syndrome was significantly increased in severely injured males in comparison to the equivalent group of females.5 They concluded that sex influences posttraumatic morbidity in severely injured patients and support the concept that females are immunologically better positioned toward a septic challenge.5 Hospital-based clinical studies have shown that females have a higher mortality rate after myocardial infarction compared with males.24,28 In a prospective study of 20 men and 20 women with colorectal diseases requiring surgical intervention, better posttraumatic immune competence was seen in women than in men.29 A significant postoperative gender difference regarding B-lymphocyte, T-lymphocyte, T-helper cell counts, and natural killer cell counts was clearly evident.29

In a study of more than 17,000 trauma patients, Croce et al. observed a survival advantage for women ≤40-yr-of-age in the Injury Severity Score (ISS) of 16–24, but these patients had statistically less severe injury. Overall, men tended to have more infectious complications, women had lower survival from infection.30 However, there was no overall difference in mortality. In a study that queried the National Trauma Data Bank, yielding data for more than 150,000 patients involved in blunt or penetrating trauma, an association between gender and mortality among blunt trauma patients, particularly those aged ≥50 years was observed.31,32 Another study concluded that female gender was not associated with decreased mortality when patients are appropriately stratified for other variables, including ISS and age, that significantly affect outcomes.33 In a prospective study of more than 30,000 trauma patients, a significantly increased incidence of postinjury pneumonia was found in the moderate injury group (ISS >15) male trauma patients.19 They did not observe any gender difference in postinjury pneumonia mortality rate, demonstrating that when women are at an advantage in getting less frequent infections, those with infections do not fare better than men. However, a 1996 retrospective population-based study of trauma-related injuries and deaths in the county of Los Angeles by Demetriades et al. found that males were at significantly higher risk of dying in traffic accidents than females.34 Offner et al. studied 545 trauma patients older than 15 yr with ISS more than 15 and prospectively identified those with survival more than 48 h. They found male gender to be associated with a dramatically increased risk of major infections after trauma and this effect was most significant after injuries of moderate severity.16

There are conflicting reports on gender-specific differences in clinical outcome after traumatic brain injury (TBI) in humans. A recent study of more than 20,000 individuals with TBI from a Colorado population-based surveillance system for 1994–1998 demonstrated differences in TBI mortality comparing males and females.35 They found estimated odds of mortality for males compared with females to be 1.21 for pre-hospital fatalities, and 1.19 for hospital fatalities.35 However, in an earlier study using fewer subjects, a significantly different outcome based on gender difference was observed; females age 30 yr or older had significantly poorer outcome than either males or younger females.36 Similarly, another recent study also demonstrated poorer outcome for females young than 60 yr after TBI.37 A recent study using the National Institute on Disability Rehabilitation and Research-funded Traumatic Brain Injury Model Systems database, examined the effect of gender on presentation of executive dysfunction after TBI.38 They found that female subjects performed significantly better on the Wisconsin Card Sort Test than male subjects as shown by analyses of variance on scores of 1331 patients for Categories Achieved (means for females = 4.09, males = 3.67, P = 0.003) and Perseverative Responses (means for females = 32.17, males = 36.42, P = 0.003).38

Sepsis is an acute infection wherein the host is toxic (febrile, anorexic, weak, lethargic, etc.) because of invasive infection, and “septic shock” occurs when the events of sepsis lead to circulatory failure.39 Thus, the sepsis syndrome is a manifestation of an acute bacterial infection and is characterized by a generalized inflammatory response. In an ex vivo endotoxin model of septic shock, when peripheral blood mononuclear cell samples from healthy male and female volunteers were incubated with lipopolysaccharide (LPS), the tumor necrosis factor (TNF) α level of male peripheral blood mononuclear cells was significantly higher after 6 h, compared with that in females.40 When cytokine secretion in the male and female patients sustaining blunt injuries with an ISS >16 was examined, increased cytokine-producing capacities in the males corresponded to enhanced inflammatory responses, which increased susceptibility to sepsis.41 Coyle et al. prospectively evaluated 72 adult subjects (48 men, aged 29 ± 1.0 yr; 24 women, aged 26 ± 1.0 yr) before and after IV administration of LPS and found increased core temperature and decreased mean arterial blood pressure in men compared with women. It should be noted, however, that they did not find detectable differences between the male and female cohort responses of circulating white blood cell count and cortisol or cytokine levels.20 In a more recent study of 15 males and 15 females, women showed increased proinflammatory response to LPS than men, illustrated by a larger increase in C-reactive protein and more leukocyte sequestration.42 The females were studied in the follicular phase and nine used oral contraceptives. This contradicting finding may be because, as Dr. Suffredini suggested, the levels of estrogen resulting from oral contraceptive use were not sufficient to suppress acute inflammatory response.43

Although several clinical studies demonstrated the influence of gender in the outcome after trauma, a more pronounced gender-associated difference was observed in better controlled animal studies. One of the reasons for contradictory or less convincing evidence for the influence of gender in postinjury and sepsis in some studies of humans is the heterogeneity of the population studied in relation to their hormonal status. Use of experimental models allows the use of well controlled laboratory animals and administration of drugs to modulate the physiology before or after trauma injury.

After acute hemorrhage and resuscitation, proestrus female rats showed improved endothelial function and tissue perfusion patterns. This gender-specific response might be a potential mechanism contributing to the beneficial effects of the proestrus stage under such conditions.44 Diodato et al. clearly demonstrated a gender difference in the inflammatory response and survival after hemorrhage and subsequent sepsis in a mouse model.45 They concluded that the female sex hormones appear to play an important role not only in maintaining immune function after hemorrhage, but also provide a survival advantage against subsequent septic challenge. Studies have also shown enhanced immune responses in females as opposed to decreased responses in males after trauma-hemorrhagic shock and resuscitation.46 Several studies in various animal models have now established a significant influence of gender and hormonal status in postinjury pathogenesis and recovery.6,17,43,47,48

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Role of Estrogen After Trauma-Hemorrhage and Sepsis

Several studies have shown that cardiovascular, hepatic, and immune functions are depressed in males as well as ovariectomized and aged females after trauma-hemorrhagic shock and remain depressed despite fluid resuscitation.9,17,49–52 However, both cardiovascular and immune function are maintained in proestrus females after trauma-hemorrhage.17

In rodents, estrogen levels are lowest during estrus and metestrus stages, gradually increasing during diestrus and reaching a peak at proestrus stage.53 It has been demonstrated that female hormones modulate immune responsiveness in adult mice and that the proestrus stage of the estrus cycle is characterized by a more vigorous immune response compared with the diestrus stage.54–56 Zellweger et al. found that proliferative capacity and splenocyte interleukin (IL)-2 and IL-3 release were markedly decreased in male, but not in female, septic mice and that females were more resistant to experimental sepsis when compared with males.57 Splenocyte proliferation and splenocyte IL-2 and IL-3 release were significantly depressed in sham-castrated animals after trauma-hemorrhage but not in precastrated males when male C3H/HeN mice were castrated 2 wk before the induction of soft-tissue trauma.58 Furthermore, only sham-castrated animals showed significantly increased levels of IL-6 release from Kupffer cells, which is believed to contribute to the systemic inflammatory response to trauma-hemorrhage.59 These experiments showed that male sex steroids are involved in the immunodepression observed after trauma-hemorrhage. Angele et al. showed that male and female sex steroids differentially affect the release of T helper (Th)1 and Th2 cytokines after trauma-hemorrhage.60 A significant depression of splenocyte Th1 cytokines, i.e., IL-2, interferon (IFN)-γ, was observed in 5α-dihydrotestosterone (DHT)-treated castrated animals after trauma-hemorrhage, as opposed to maintained Th1 cytokine release in 17β-estradiol (E2)-treated and E2/DHT-treated castrated animals and females. An increased thymocyte apoptosis was also evident in males, but not in proestrus females, after trauma-hemorrhage.61

All of the above evidence points to the role of estrogens in ameliorating the pathology associated with trauma-hemorrhage. The significance of estrogen in modulating the pathophysiology can be assessed by using females in the proestrus cycle or supplementing estrogen to the males and postmenopausal patients. Also, specific estrogen agonists or antagonists can be used to pinpoint the role of estrogen receptors (ER). The physiological action of estrogen is mediated through its receptor, the ER. The major ER isoforms, ER-α and ER-β, are located intracellularly and act as transcription factors in modifying gene transcription after ligand binding. Further, the use of ER-α-specific (PPT, 4,4′,4′-(4-propyl-(1H)-pyrazole-1,3,5-triyl) trisphenol) or ER-β-specific (DPN, 2,3-bis (4-hydroxy-phenyl)-propionitrile) agonists can pinpoint the individual role of these nuclear isoforms in estrogen-mediated physiological effects.62 A cell surface receptor, GPR (G-protein coupled receptor) 30, is also described to have affinity to estrogen63–65 (Fig. 1).

Figure 1

Figure 1

Mizushima et al. showed that administration of estrogen restores cardiovascular and hepatocellular function after trauma-hemorrhage in male rats.66 Left ventricular performance, cardiac output, and hepatocellular function were significantly decreased after trauma-hemorrhage and resuscitation. Plasma IL-6 levels were also elevated. Administration of estradiol after trauma-hemorrhage significantly improved cardiac contractility, cardiac output, and hepatocellular function, and attenuated the increase in plasma IL-6 levels, thus clearly demonstrating the salutary effect of estrogen after trauma-hemorrhage. Interestingly, administration of flutamide, an androgen receptor antagonist, also improved the depressed immune responses and cardiac and hepatic function in male animals after trauma-hemorrhage.67,68 Studies have shown that in addition to blockade of androgen receptors, flutamide upregulates aromatase activity.69 Aromatase converts testosterone to 17β-estradiol and upregulates ER, and thus flutamide produces its salutary effects after trauma-hemorrhage via that mechanism.70

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Effect of Estrogen on Cardiac Function

Cardiac output, stroke volume, and cardiac contractility (±dP/dt) decrease significantly after trauma-hemorrhage.66,71,72 These variables were normalized after estrogen treatment.66,71 However, simultaneous administration of the ER-specific receptor antagonist, ICI 182,780, abolished the salutary effects of estrogen treatment despite high circulating levels of estrogen.73 Estrogen exerts complex biological effects through the two isoforms of estrogen receptors ER-α and ER-β. Ischemia/reperfusion injury is strongly linked to cardiomyocyte loss via apoptosis, probably due to a combination of a significant ischemic burden and oxidative stress from reperfusion, and estrogen has been found to reduce cardiomyocyte apoptosis.74,75 Studies have also shown that trauma-hemorrhage decreased cardiomyocyte PI3K protein expression and Akt phosphorylation (p-Akt); estradiol or estradiol-bovine serum albumin (BSA) treatment after trauma-hemorrhage prevented such decreases in cardiomyocyte PI3K protein expression and p-Akt.76 Estradiol treatment also increased phosphorylation of cardiac p38 MAPK, heat shock protein 27, and α(B)-crystallin.76 These latter findings demonstrate the ability of estrogen to elicit physiological effects through mechanisms other than using nuclear ER receptors.

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Effect of Estrogen on Liver Function

Several studies have shown a beneficial effect of estradiol in trauma-hemorrhage shock models. As assessed by indocyanine green clearance, depressed hepatocellular function was significantly increased after estradiol administration in rats after trauma-hemorrhage.66 The inflammatory cytokines and chemokines such as IL-6, MCP-1, and keratinocyte-derived chemokine (KC) released by Kupffer cells are also efficiently attenuated by estradiol administration.77,78 ER-α has been demonstrated to be predominantly present in rat liver and is shown to be important in the attenuation of estrogen-mediated hepatic injury after trauma-hemorrhage.79,80 However, the decreased protein kinase A activity in hepatocytes after trauma-hemorrhage was normalized if the animals were treated with estrogen conjugated to BSA, which effectively acts at the plasma membrane level.81,82 Further, the effect of estrogen-BSA treatment was abolished when hepatocytes were treated with GPR30 siRNA, demonstrating the role of this cell membrane receptor in estrogen signaling. The GPR30-mediated effect is distinct from the ER-mediated salutary effect of estrogen and the former is also referred to as a nongenomic effect (Fig. 1). Nongenomic effects are usually measured as an increase in phosphorylation of proteins, or increase in intracellular calcium.83 Compared with that in the conventional genomic effect, which constitutes intracellular binding of estrogen to ER, dimerization, nuclear translocation, and gene activation, there is a more rapid (milliseconds to minutes) effect due to the nongenomic pathway, which is initiated at the plasma membrane by estrogen binding to GPR30.65,84

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Effect of Estrogen on Pulmonary Function

Untreated hemorrhagic shock can lead to severe lung injury, sepsis, acute respiratory distress syndrome, multiple organ failure, and death.85 Caruso et al. showed that protection against trauma-hemorrhage-induced lung injury was greatest during the estrus and proestrus stages of the menstrual cycle and decreased with progression to diestrus.7 During the diestrus stage of the menstrual cycle when gonadal hormone levels are lowest, rats were more sensitive to the induced lung injury, indicating that gonadal hormones modulate trauma-hemorrhage-induced lung injury.7 Trauma-hemorrhage increased lung myeloperoxidase activity and ICAM-1, CINC-1, and CINC-3 levels in ovariectomized females.86 Estrogen administration after trauma-hemorrhage prevented lung neutrophil infiltration and edema formation.87 This was concomitant with a decrease in KC, TNF-α and IL-6 production by Kupffer cells. A similar decrease was also found in their plasma levels after estrogen administration. These studies show a beneficial role for estrogen in the restoration of lung function after trauma-hemorrhage.

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Immune Modulation by Estrogen

Trauma-hemorrhage, shock, and injury induce marked dysregulation of the systemic immune response, end organ damage, and death.85,88–92 T cell activation and proliferation are subdued; macrophage and dendritic cell function are also altered after trauma-hemorrhage and burn.93–98 Proestrus females are not immunodepressed compared with male and ovariectomized mice, and estrogen is demonstrated to protect immune function after trauma-hemorrhage.99 Splenic T lymphocytes express receptors for ER and contain enzymes involved in estrogen metabolism.100 Also, steroid synthesizing enzymes are present in the spleen, specifically in T lymphocytes.100,101 5α-Reductase expression and activity was found increased in male T lymphocytes, whereas aromatase activity, but not expression, increased in female T lymphocytes.101 Increased 5α-reductase activity in male T lymphocytes is immunosuppressive because of increased 5α-DHT synthesis, whereas in females, increased aromatase activity triggering 17β-estradiol synthesis is immunoprotective. Hemorrhaged mice exhibited a marked decrease in antigen-presenting capacity beginning as little as 30 min and lasting up to 3–5 days posthemorrhage.102 Recently, Kawasaki et al. showed that CD11c-positive splenic dendritic cells isolated from mice after trauma-hemorrhage showed a lower capacity to stimulate T cell proliferation than those from sham controls.95 They also demonstrated a decreased percentage of these cells in the mice after trauma-hemorrhage. The splenic dendritic cells produced decreased IFN-γ and IL-12 further demonstrating a functional suppression after trauma-hemorrhage. A hormonal influence on immune function after trauma-hemorrhage was demonstrated by studies, which showed that precastration prevented the suppression of major histocompatibility complex class II expression after trauma-hemorrhage.

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Gender influences the outcome after trauma-hemorrhage and sepsis, and the female gender has a clear advantage. High circulating estrogen levels, endogenous or due to exogenous administration, have a protective effect after injury and sepsis. Extensive studies have shown that the salutary effect of estrogen in restoring cardiac, hepatic, pulmonary, and immune function is through a genomic effect mediated through intracellular receptors, ER-α and ER-β, or a nongenomic effect mediated through cell surface estrogen binding receptors such as GPR30. The reason for conflicting reports on female sex advantage in trauma, injury, and sepsis is likely due to the lack of correlation between the critical variable, estrogen level at the time of injury, and clinical outcome. Nevertheless, experimental studies emphasize the importance of estrogen as a therapeutic agent in improving immune cell function after injury and preventing postinjury organ dysfunction and septic complications.

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