Sex- and Gender-Dependent Differences in Clinical and Preclinical Sepsis

Abstract

In this mini-review we provide an overview of sex-and gender-dependent issues in both clinical and preclinical sepsis. The increasing recognition for the need to account for sex and gender in biomedical research brings a unique set of challenges and requires researchers to adopt best practices when conducting and communicating sex-and gender-based research. This may be of particular importance in sepsis, given the potential contribution of sex bias in the failures of translational sepsis research in adults and neonates. Clinical evidence of sex-dependent differences in sepsis is equivocal. Since clinical studies are limited to observational data and confounded by a multitude of factors, preclinical studies provide a unique opportunity to investigate sex differences in a controlled, experimental environment. Numerous preclinical studies have suggested that females may experience favorable outcomes in comparison with males. The underlying mechanistic evidence for sex-dependent differences in sepsis and other models of shock (e.g., trauma-hemorrhage) largely centers around the beneficial effects of estrogen. Other mechanisms such as the immunosuppressive role of testosterone and Xlinked mosaicism are also thought to contribute to observed sex-and gender-dependent differences in sepsis. Significant knowledge gaps still exist in this field. Future investigations can address these gaps through careful consideration of sex and gender in clinical studies, and the use of clinically accurate preclinical models that reflect sex differences. A better understanding of sex-and gender-dependent differences may serve to increase translational research success.

Aged IRF3-KO Mice are Protected from Sepsis

“…In addition to the effects of age, sepsis outcomes vary by gender. Most prior studies have reported worse sepsis outcomes in male vs female patients, [46][47][48][49][50] and similar data were obtained in animal studies. 40,[51][52][53] However, these results were not unequivocal as some studies identified worse outcomes in females, [54][55][56] or similar outcomes for both genders.…”

“…We speculate that the protection observed in females is likely due to direct and indirect effects of sex hormones on the immune response, as suggested by others. 47 , 51 , 52 For example, estrogens can suppress lymphocyte apoptosis, while androgens promote apoptosis. 63 Additionally, estrogens can enhance cellular and humoral adaptive immunity.…”

The Effects of Biological Sex on Sepsis Treatments in Animal Models: A Systematic Review and a Narrative Elaboration on Sex- and Gender-Dependent Differences in Sepsis

“…No studies reported sex-dependent effects of fluid resuscitation. One older study investigating antibiotics briefly stated that no differences were observed between males and females (i.e., line item result); however, no further details were provided ( 25 ).…”

Sex differences associate with late microbiome alterations after murine surgical sepsis

“…Regardless, our results may help to better explain sex differences in postsepsis ICU survival given that females may have better survival compared with males. [8][9][10][11] These unique sex-related changes may be imparted on the host microbiota by the impact of sepsis and chronic stress. Such changes may lead to a chronic inflammatory state seen in PICS.…”

“…In fact, one study demonstrated that, in patients younger than 90 years, women had significantly decreased 1-year mortality compared with males 10 . Regardless, it is clear that females and males respond differently to infection 8–10 . Future successful interventions for sepsis will need to use personalized/precision medical therapies, which will require a better understanding of the differences in host response due to severe infection.…”