Sex-biased eicosanoid biology: Impact for sex differences in inflammation and consequences for pharmacotherapy

Abstract

The incidence, severity and progression of autoimmune diseases (e.g. scleroderma, multiple sclerosis, rheumatoid arthritis) and certain inflammatory diseases (e.g. asthma) are sex-biased where these pathologies dominate in women. However, other immune disorders such as sepsis, post-surgery infections and gout display higher incidence and severity in men. The molecular and cellular basis underlying this sex dimorphism remains incompletely elucidated but may provide important insights for sex-specific pharmacotherapy. Nevertheless, the sex as a variable in biochemical and preclinical research on inflammation is often neglected. Thus, respective animal studies are routinely performed with males, and experiments with isolated cells rarely report the sex of the donor. However, sex differences on the cellular level do exist, in particular related to inflammatory processes that prompt for sex-specific appreciation of inflammation research. For instance, the biosynthesis of pro-inflammatory eicosanoids is sex-biased where leukotriene (LT) formation is under control of testosterone that regulates the subcellular localization of the key enzyme 5-lipoxygenase, with possible implications for gender-tailored pharmacotherapy of LT-related disorders (i.e. asthma). Moreover, prostaglandin (PG) production is sex-biased, and sex-dependent efficacy of aspirin was evident in several clinical trials. Here, we highlight the sex bias in eicosanoid biology possibly underlying the obvious sex disparities in inflammation, stimulating scientists to take sex into account when studying the pathophysiology and pharmacotherapy of inflammatory diseases.

Keywords: Gender-tailored therapy; Inflammation; Leukotrienes; Prostaglandins; Sex differences; Sex hormones.