An interesting feature that multiple sclerosis (MS) shares with many other immune-mediated diseases is that susceptibility is higher in females than males. However, the female to male ratio (sex ratio) of MS appears to have been changing over time.
A recent meta-analysis of epidemiological studies has shown that the worldwide sex ratio of MS has been substantially changing over the past century.1 This change is particularly clear in large population-based studies from Denmark and Canada.1,2 In Canada, the sex ratio of MS patients born in the 1930s was lower than 2: the ratio then increased to more than 3 females for each male patient in the latest birth cohort analyzed (1976-1980).
This intriguing epidemiological phenomenon warrants particular attention because the sex ratio of MS parallels MS incidence, and the increasing frequency of MS among females is a key driver of the increasing prevalence of this devastating disorder worldwide. A change that occurs within a century is too short a time for a genetic cause. This suggests that environmental factor/s are at work in a sex-specific manner.
What are the environmental agent/s that may be influencing the sex ratio of MS? An interesting hypothesis comes from a recent Australian study, which found that a higher number of offspring was inversely associated with the risk of a first clinical demyelinating event among women—but not men.3 However, other studies that have investigated how pregnancy modifies the risk of MS have reported conflicting results, Reproductive history may well have an influence on female susceptibility to MS, but this single factor is unlikely to entirely explain temporal trends in the MS sex ratio.
Vitamin D deficiency, Epstein-Barr virus (EBV) infection, and smoking history are known to influence MS risk and therefore represent additional plausible candidates.4 Unfortunately, sex-specific reliable longitudinal data on both vitamin D deficiency and EBV infection are lacking.
Interestingly, a recent study has shown how trends in sex ratio of smoking behavior in both Canada and Denmark strongly correlate with sex ratio changes of MS. However, this was mainly driven by a decline of smoking among men and cannot therefore fully explain the increased incidence of MS among females.
The sex ratio of MS currently remains an intricate puzzle with no clear solution as yet. Future research is urgently needed to understand the environmental factor/s involved to aid disease prevention strategies.5
References
1. Koch-Henriksen N, Sorensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010;9:520-532.
2. Orton SM, Herrera BM, Yee IM, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 2006;5:932-936.
3. Ponsonby AL, Lucas RM, van der Mei IA, et al. Offspring number, pregnancy, and risk of a first clinical demyelinating event: the AusImmune Study. Neurology. 2012;78:867-874.
4. Ramagopalan S, Dobson R, Meier UC, Giovannoni G. Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurol. 2010;9:727-739.
5. Palacios N, Alonso A, Bronnum-Hansen H, Ascherio A. Smoking and increased risk of multiple sclerosis: parallel trends in the sex ratio reinforce the evidence. Ann Epidemiol. 2011;21:536-542.
