Sex differences in eicosanoid formation and metabolism: A possible mediator of sex discrepancies in cardiovascular diseases

Arachidonic acid is metabolized by cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes to produce prostaglandins, leukotrienes, epoxyeicosatrienoic acids (EETs), and hydroxyeicosatetraenoic acids (HETEs), along with other eicosanoids. Eicosanoids have important physiological and pathological roles in the body, including the cardiovascular system. Evidence from several experimental and clinical studies indicates differences in eicosanoid levels, as well as in the activity or expression levels of their synthesizing and metabolizing enzymes between males and females. In addition, there is a clear state of gender specificity in cardiovascular diseases (CVD), which tend to be more common in men compared to women, and their risk increases significantly in postmenopausal women compared to younger women. This could be largely attributed to sex hormones, as androgens exert detrimental effects on the heart and blood vessels, whereas estrogen exhibits cardioprotective effects. Many of androgen and estrogen effects on the cardiovascular system are mediated by eicosanoids. For example, androgens increase the levels of cardiotoxic eicosanoids like 20-HETE, while estrogens increase the levels of cardioprotective EETs. Thus, sex differences in eicosanoid levels in the cardiovascular system could be an important underlying mechanism for the different effects of sex hormones and the differences in CVD between males and females. Understanding the role of eicosanoids in these differences can help improve the management of CVD.