European Charcot Foundation Lecture: the natural history of multiple sclerosis and gender.

The role of gender in the natural history of multiple sclerosis (MS) is multi-faceted. Earliest debate on this topic was about the sex ratio (female:male) among affected individuals. It was only clearly shown within the last 4 decades that females are more often affected. The sex ratio continues to intrigue researchers. An observed increase in the sex ratio among more recently born MS patients has now been taken as a clear indication that the rate of MS is truly increasing in many geographical areas. This temporal increase in females has been relatively rapid, implicating environmental rather than genetic risk factors. Gender issues in MS expand beyond the scope of sex ratio. Gender has an impact on various aspects of MS, including age of onset, "parent-of-origin" effects (seen in half-siblings, twin sibships, avuncular pairs, transmission of HLA haplotype), recurrence risks for relatives of MS patients and the topic of reproduction when one parent has MS. Gender issues can also confound data collection and analyses with respect to studies on comorbidity, risk factors and family history. In fact, it has now been clearly validated and quantified that among persons with MS, there is a sex-specificity of recall and reporting bias as well a greater female awareness of medical history.