Exploring sex bias in cardiometabolic diseases

Cardiometabolic diseases (CMDs), such as cardiovascular diseases (CVDs), obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis (MASH), represent an alarming burden on healthcare systems. Differences in the prevalence, progression and outcomes of CMD are significantly sex specific, as are differences between premenopause and postmenopause. These differences lie in the distinct body fat distributions and lipid and lipoprotein profiles associated with estrogens, particularly 17β-estradiol (E2), which play a central protective role in female cardiometabolic health. Premenopausal women generally display a more favorable lipid profile, higher HDL-C levels and enhanced fatty acid oxidation, which collectively reduce CVD risk. On the other hand, a decrease in E2 during menopause promotes visceral adiposity, dyslipidemia, impaired hepatic handling, and a proinflammatory state that accentuates cardiovascular risk. This review explores the molecular mechanisms by which estrogens, particularly E2, regulate lipid and lipoprotein metabolism, mitochondrial fatty acid oxidation and inflammatory pathways. In this review, we also highlight the knowledge gaps that limit the development of sex-specific preventative and therapeutic strategies. Understanding sex differences in CMD is essential for improving the cardiometabolic health of women, particularly during the postmenopausal period.