Evidence supporting the protective effects of estrogen has been accumulating for several decades. Most of these data are associated with dampening the hyperinflammatory state of sepsis by reducing expression levels of circulating proinflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α [21].

Experiments using proestrus female mice in a cecal ligation sepsis model demonstrated that immune functions of preserved splenocytes are associated with better survival [22]. Addition of 17β-estradiol to splenocytes from ovariectomized female mice normalized immune functional capacities in a trauma-hemorrhage model [23]. Another study performed with a mouse model of hemorrhage and subsequent sepsis showed a greater increase in plasma proinflammatory cytokines including IL-6, TNF-α, and prostaglandin E2 in male mice than proestrus female mice. They also showed a survival advantage of female sex hormones against subsequent septic challenge [24]. In addition, less pronounced cardiac dysfunction was seen in female mice than in male mice in a cecal ligation and puncture (CLP) sepsis model [25]. In that study, female mice showed decreased production of TNF-α, IL-6, and inducible nitric oxide synthase. Cardioprotective effects were shown in ovariectomized female mice after administration of landiolol in a CLP sepsis model. Such effects were assumed to be due to overexpression of genes involved in calcium influx. In contrast, inactivation of the β-adrenergic and a calcium efflux pathway was seen in control females [25]. The protective effect of estrogen against liver damage in sepsis has also been observed in a lipopolysaccharide (LPS)-induced sepsis model. Female septic mice showed liver damage with increased serum aspartate aminotransferase and alanine aminotransferase levels as well as extensive necrosis, and both were more severe in male septic mice. In addition, ovariectomy-aggravated sepsis-induced liver damage and activation of the pyroptosis signaling pathway could be alleviated by estrogen [26].

Sex-dependent differences in the incidence and severity of sepsis make males more susceptible to septic shock than females. Testosterone is a primary male sex hormone and has also been implicated in sex-dependent differences in sepsis. Testosterone has significant immunosuppressive effects on innate and adaptive immunity by reducing immunoglobulin, cytokine production, and lymphocyte proliferation [27,28]. LPS-induced TNF-α secretion in plasma was significantly enhanced in rats receiving neonatal androgen blockade with flutamide and in prepubertal orchiectomies rats, suggesting testosterone's immunosuppressive role in inflammation [29]. Another study showed that orchiectomized mice were significantly more susceptible to endotoxic shock, and that macrophages isolated from them had significantly higher toll-like receptor-4 cell surface expression than those derived from sham gonadectomized mice. However, these effects were dampened in orchiectomized mice receiving exogenous testosterone [30]. Although the details of the underlying molecular mechanisms remain unclear, effects of androgen receptor blockade are thought to be partly attributable to the upregulation of estrogen receptors or enhanced estrogen receptor-related pathways [31-33].

A higher prevalence of sepsis in men than in women has been reported in various nationwide or individual hospital-based epidemiologic studies [34]. A longitudinal, population-based epidemiological study of sepsis from 2005 to 2012 using the Korean National Health Insurance Service-National Sample Cohort—a population-based cohort representing 2.2% of the Korean population—reported that 53.5% to 58.0% of a total of 22,882 sepsis cases were males. It also found that female sex was an independent favorable risk factor for 6-month mortality in multivariate logistic regression analysis, showing an odds ratio (OR) of 0.7 (95% confidence interval [CI], 0.66–0.76; P<0.001) [35]. Potential mechanisms explaining the higher prevalence of sepsis in men are unclear. However, the combination of biological sex differences, such as the immune system, sex hormones, gene expression from a silent X-chromosome, anatomical differences, and pharmacokinetics and dynamics for drugs [10,11,36,37], and sociocultural gender differences in disease perception, risk behavior, accessibility to and use of healthcare resources, and service provision methods are thought to play a critical role in sex disparities in sepsis [38-40].

Sexual differences in bacterial infections have been reported in human and animal models. Diverse manifestations and outcomes of infections based on sex are intricately linked to genetic, biological, and behavioral differences, which are associated with gender preferences of specific bacterial infections, sex hormones, and immune responses by sex [41,42]. In general, men are more susceptible to gastrointestinal and respiratory bacterial diseases and sepsis, while women are more susceptible to genitourinary tract infections [43]. Recent studies have reported that tissue-specific expression of sex hormone receptors contributes to the sexual disparity in bacterial infections [43]. According to a prospective observational study on community-acquired severe sepsis and septic shock conducted in 12 university hospitals in South Korea, among a total of 1,192 patients, gastrointestinal (26.8% vs. 20.9%), respiratory (39.2% vs. 19.2%), and skin and soft tissue (11.0% vs. 4.7%) infections as a source of primary infection were higher in men (men vs. women), while urinary tract infection (11.4% vs. 44.8%) was more prevalent in women (P<0.05 for each) [44].

Numerous individual and nationwide studies have evaluated the relationship between sex and mortality from sepsis and septic shock. However, evidence showing an association of sepsis mortality with specific sex is conflicting. Although preclinical studies have suggested potential protective effects of estrogen on sepsis, some studies have shown higher mortality rates in women with sepsis [45-48]. In comparison, others have shown higher mortality rates in men with sepsis [49-51]. Furthermore, some studies have reported no difference in mortality rate from sepsis and septic shock between sexes [52-54]. According to a recently published meta-analysis including 13 studies with 80,520 participants, there were no sex-based differences in all-cause hospital mortality (OR, 1.02; 95% CI, 0.79–1.32; very low-certainty evidence) or all-cause ICU mortality (OR, 1.19; 95% CI, 0.79–1.78; very low-certainty evidence). Interestingly, however, females presented higher 28-day all-cause mortality (OR, 1.18; 95% CI, 1.05–1.32; very low-certainty evidence) and lower 1-year all-cause mortality (OR, 0.83; 95% CI, 0.68–0.98; low-certainty evidence) [55]. An epidemiologic study for severe community-acquired sepsis and septic shock conducted in South Korea reported that 28-day mortality (27.0% vs. 18.1%), in-hospital mortality (32.9% vs. 22.0%), and sepsis-related mortality (28.3% vs. 18.1%) were lower in females (P<0.001 for each) [44]. Several explanations have been suggested for these disparate findings in clinical studies of sex differences in sepsis and septic shock. The most critical issues were heterogeneous study designs (prospective vs. retrospective, single vs, multicenter or nationwide database), different definitions of sepsis, different baseline health statuses, comorbidities, severity of sepsis, age, and sociocultural differences affecting treatment attitudes for men and women [56]. Among these, age is a critical factor to consider when assessing the protective effects of estrogen against sepsis. Level of estradiol, the most potent estrogen, is highest in women between prepuberty and menopause. In contrast, the prevalence of sepsis and septic shock is significantly higher in patients over 60 years of age. Multiple comorbidities are also more common in these patients. Thus, when evaluating effects of sex factors on outcomes of sepsis, age stratification and control of confounding factors such as comorbidities should be considered [56]. In a study conducted on 143 polytraumatized patients with injury severity score >16 and between 16 and 65 years old, the prevalence of multiorgan dysfunction syndrome and sepsis was significantly lower in females younger than 50 years with an injury severity score >25 than in age-matched males [57]. However, when focusing on clinical studies specifically examining sex hormones in connection to sepsis patients, results are again conflicting. Higher circulating estradiol levels were associated with higher mortality rates in both male and female patients, and elevated serum estradiol levels were associated with the severity of renal dysfunction and the development of acute kidney injury [58-60]. In addition, while levels of proinflammatory cytokines such as TNF-α and IL-6 were increased in male patients, anti-inflammatory cytokine IL-10, which was defined as a predictor for the severity of sepsis, was higher in female patients [28,61,62]. Thus, differences in study conclusions might be attributed to differences in sex steroid levels among patients rather than a difference in the type of sex hormones alone.