Age at Menarche and Risk of Multiple Sclerosis: Current Progress From Epidemiological Investigations

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disorder of the brain and spinal cord in which focal lymphocytic infiltration leads to the damage of myelin and axons. As a multi-factorial complex trait, both genetic background and environmental factors are involved in MS etiology. The disease is more prevalent among women, and an overall female-to-male sex ratio of around 3 is usually reported. The fact that the female preponderance is only apparent among patients with disease onset after age 12 points toward a role of puberty in MS. A key marker of female pubertal development is menarche, however, evidence from previous epidemiological investigations has been sparse and conflicting: although some studies have linked earlier age at menarche (AAM) to an increased risk of MS, others have found no association or an inverse association. Understanding the effect of AAM in MS could increase our knowledge to the disease etiology, as well as deliver meaningful implication to patients' care by aiding clinical diagnosis. Therefore, we reviewed all the currently available epidemiological studies conducted for AAM and risk of MS in adult human populations. We found evidence supporting a possible favorable role of late AAM on MS risk, but this should be further confirmed by well-designed large-scale epidemiological studies and meta-analysis. Future work may be focused on Mendelian randomization analysis incorporating genetic markers to provide additional evidence of a putative causal relationship between AAM and MS. More work should be conducted for non-European populations to increase generalizability, and among the males to complementary with results from females. Future work may also be conducted focusing on hormonal reproductive factors other than menarche, and their effects in MS prognosis, severity, and drug response.