How does MS differ in women and men?
Many diseases affect one sex more than the other (called a sex bias), which can provide insights on the processes underlying the disease. For example, women are generally more likely to develop autoimmune disorders, such as rheumatoid arthritis or lupus; whereas men are more likely to develop neurodegenerative conditions, such as Parkinson’s disease or ALS (amyotrophic lateral sclerosis, or “Lou Gehrig’s disease”).
The different risks for autoimmune and neurodegenerative disorders have a parallel in multiple sclerosis, as seen by three key differences.
- Risk of developing MS. It was once thought that women and men were equally likely to develop MS (Warren & Warren. Can J Neurol Sci 1992;19:72-75). But over the past 25 years, the number of cases of MS has increased disproportionately in women, so that women are now about three-fold more likely to be diagnosed with MS compared to men (Kingwell and colleagues. J Neurol 2015;262:2352-2363). This shift is the result of more cases in women rather than fewer cases in men, and has occurred too rapidly for it to be caused by genetic factors. Why MS is increasingly common in women is the subject of much speculation. Environmental factors – such as increasing obesity during adolescence, smoking, delayed pregnancy and diet – may play a role. Socioeconomic factors – more women in the workplace with improved drug coverage, greater awareness of MS – may also be contributing to the higher rate of diagnosis.
- Frequency of relapses. The hallmark sign of relapsing-remitting MS (RRMS) is relapses – episodes of neurological worsening (tingling, muscle weakness, pain, etc.) lasting days or weeks. Recent studies have found that women with RRMS have about 20% more relapses than men with RRMS – an effect that holds true throughout the course of MS (Kalincik and colleagues. Brain 2013;136(Pt 12):3609-3617).
- Progression of disability. Men are less likely to develop MS, but have a worse time of it if they do. A number of studies have shown that men develop disability earlier, reach key disability milestones sooner, and develop secondary-progressive MS (SPMS) at a younger age (Weinshenker and colleagues. Brain 1991;114(Pt 2):1045-1056; Confavreux and colleagues. Brain 2003;126(Pt 4):770-782; Koch and colleagues. J Neurol Neurosurg Psychiatry 2010;81:1039-1043). Differences are also seen in the onset and development of cognitive difficulties. The cognitive problems that can develop with MS are more evident and affect more areas of functioning in men than in women (Savettieri and colleagues. J Neurol 2004;251:1208-1214; Schoonheim and colleagues. Neurology 2012;79:1754-1761).
These findings suggest that as a general rule, women are more susceptible to the autoimmune or inflammatory component of MS, whereas men are more susceptible to the neurodegenerative aspects of MS. The reasons aren’t entirely clear but may involve differences in the reactivity of the immune response, which determine if a person does or does not develop MS; and/or differences in how susceptible the nervous system is to damage and how well it repairs itself, which would influence the extent and severity of nerve damage.
It’s known that women generally have a more active immune response (Pelfrey and colleagues. J Neuroimmunol 2002;130:211-223). So this may be part of the explanation. But a more fruitful line of inquiry has been to investigate hormonal effects – sex hormones (estrogen, testosterone) being one of the more obvious differences between the sexes. For example, the hormonal changes that occur during pregnancy – making the woman’s immune system more tolerant to the developing fetus – are associated with a lower risk of relapses. As hormone levels return to normal after childbirth, there is a corresponding increased risk of a relapse for about 3-6 months. Interestingly, this short-term flare-up in relapses during the postpartum period does not appear to have an impact on long-term disability (Jokubaitis and colleagues. Ann Neurol 2016;80:89-100). This may be because the period of flare-ups is quite short; the processes of inflammation and neurodegeneration are somewhat distinct; or that estrogens promote healing or other effects in the central nervous system.
Testosterone also appears to influence the course of MS in men. Men who produce low levels of testosterone have been shown to have a higher risk of developing MS, to have worse disability, and to have poor cognitive function compared to men with higher testosterone levels (Pakpoor and colleagues. Ann Neurol 2014;76:765–766; Bove and colleagues. Mult Scler 2014;20:1584-1592).
A number of preliminary studies have investigated whether hormonal therapies might provide some benefit in MS. There are three principal estrogens: estrone (E1), which predominates after menopause; estradiol (E2), which is the main estrogen during adulthood; and estriol (E3), which is produced during pregnancy. Increasing the levels of estradiol is associated with a higher risk of breast cancer risk. So attention has focused on estriol. A small study found that supplemental estriol reduced inflammatory activity in the brain in women with MS (Sicotte and colleagues. Ann Neurol 2002;52:421-428). A second study found that relapse rates were further reduced when estriol was combined with Copaxone (Voskuhl and colleagues. Lancet Neurol 2016;15:35-46).
Preliminary studies of testosterone supplementation have also indicated that there may be beneficial effects in men. Testosterone has been shown to reduce the rate of brain shrinkage in men with MS, with the further suggestion that hormonal therapy might improve cognitive function (Sicotte and colleagues. Arch Neurol 2007;64:683-688).
These findings suggest that hormonal therapies may reduce disease activity and preserve function in women and men. Additional studies are needed to determined if they would provide some benefit when added to conventional MS therapies.
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