There is a paradox in multiple sclerosis (MS): females appear to be more susceptible to the disease than males, but also have a better long-term prognosis. Could this be due to sex hormones? That was the subject of a presentation by Sandra Vukusic (Hôpital Pierre Wertheimer, Lyon, France) at this year’s virtual ACTRIMS/ECTRIMS joint meeting.
Dr Vukusic began by splitting the sex hormonal changes during a woman’s life between the “natural history” and the “treated history”. For each aspect, while there may be some intriguing results further research is certainly needed to define the role of sex hormones in MS.
Similar to migraines, in which an association between sex hormones and susceptibility has been discussed, there is also a gender imbalance between people with MS. Beginning with menarche, Dr Vukusic presented studies indicating that the sex ratio disparity between males and females begins at puberty,1 with one study pointing to changes occurring even 1 or 2 years before.2 Later age of menarche may be associated with a lower risk of developing MS,3 but as Dr Vukusic summarised “the results are still a little bit controversial.”
The situation with pregnancy is a little clearer: many studies have shown a decreased relapse rate during pregnancy, followed by an increased risk approximately 3 months post-partum.4 This pattern echoes the decrease and then increase of sex hormones during pregnancy and delivery, arguing for a connection between sex hormones and MS relapse.
While some correlation has been observed between childbirth and long-term disability associated with MS, Dr Vukusic explained this could be due to indication bias. Women who decide to have children may be at lower risk of disability than those who decide not to. To adjust for this confounding, a study by a group in Barcelona treated pregnancy as a time-dependent variable; however, they found no difference in prognosis between women having versus those not having children.5
Finally for the natural history category, Dr Vukusic shared that some studies have indicated an association between menopause and decreased disease activity, but again, the results require confirmation.
As well as the natural variations in sex hormones during a woman’s life stages, there are several points when hormone levels may change through use of medication. Use of oral contraceptives was reported to be associated with an enhanced anti-inflammatory treatment effect in a small Phase 2 trial,6 but findings from observational studies on the effect of oral contraception on MS risk and relapse are inconsistent.7 Findings from studies on assisted reproductive techniques (ART) and MS reported an increased risk of relapse – but interestingly, the increase was only significant if no pregnancy resulted from the ART.8
The final aspect Dr Vukusic discussed in treated history was hormone replacement therapy (HRT). There are very few studies investigating the effect of HRT on MS disease course, and as Dr Vukusic noted “this is a shame because we have a lot of women with MS that are currently over 50 years of age.”
Potential for new therapeutic targets
As Dr Vukusic concluded, given that sex hormones may have some impact on susceptibility to MS and on MS disease course, it is possible that they could be developed as a disease-modifying therapy. As well as determining the exact role of sex hormones in MS, further research is needed to discover the potential of hormones for treating MS.
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- Chitnis T. Clin Immunol. 2013;149:192–200.
- Boesen MS, et al. Mult Scler. 2018;24:1077–86.
- Azimi A, et al. BMC Neurol. 2019;19:286.
- Confravreux C, et al. N Engl J Med. 1998;339:285–91.
- Zuluaga MI, et al. Neurology.2019;92:e1507–16.
- Pozzilli C, et al. Neurol Neuroimmunol Neuroinflamm. 2015;2:e120.
- Bove R, Gilmore W. Mult Scler. 2018;24:17–21.
- Michel L, et al. J Neurol Neurosurg Psychiatry. 2012;83:796–802.