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

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 X-linked 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.