Sex-Related Differences in Lifestyle Factors Affecting Multiple Sclerosis Susceptibility and Disease Progression

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that affects women more frequently than men. This sex gap has widened over the past century, and appears to be shaped by lifestyle factors more than biological factors. This narrative review examines the evidence for sex-specific differences in lifestyle risk factors and their impact on both MS susceptibility and disease progression, with implications for diagnosis, monitoring, and treatment. Smoking, obesity, vitamin D deficiency, ultraviolet radiation exposure, and Epstein-Barr virus infection all interact with sex-related biological pathways to influence MS risk. Women appear to be more vulnerable to the pathogenic effects of smoking and obesity, both independently and in synergy with genetic risk alleles, while vitamin D and UV exposure confer stronger protective effects in females than in males. EBV infection also exhibits sex-dependent immune responses, shaped by hormonal regulation and host-virus genetic interactions. Sex-related lifestyle factors also modulate MS progression. Women experience more inflammatory activity and relapses, whereas men more often develop a progressive phenotype with greater neurodegeneration. Hormonal changes during female reproductive phases, such as pregnancy, breastfeeding, menopause, and hormone-based therapies, critically influence disease activity and progression in MS. Obesity, smoking, vitamin D status, diet, and gut microbiota further interact with sex hormones and genetic background, contributing to variable disease trajectories, also modulated by social determinants such as education level. These findings underscore the need to integrate into clinical practice the evaluation of lifestyle factors in a sex-specific way for diagnosis, monitoring, and treatment of MS.