Multiple Sclerosis - Why are Women More at Risk?

by Women's Brain Health Initiative:Multiple sclerosis (MS) is an autoimmune disease in which the body’s immune system mistakenly attacks myelin, the “insulation” that surrounds and protects nerves in the brain and the spinal cord (i.e. the central nervous system or CNS). This process of demyelination can lead to neurodegeneration and the development of permanent disability.Resulting MS symptoms vary widely from person to person, and can fluctuate within one individual over time, depending on which part(s) of the CNS is/are affected. Potential MS symptoms include dizziness, bladder or bowel dysfunction, cognitive impairment, depression, fatigue, optic neuritis (inflammation damaging the optic nerve), pain, numbness/tingling, sexual dysfunction, tremor, weakness, and/or difficulty talking, swallowing, or walking.Relapsing-remitting MS (RRMS) is the most common form of the disease, characterized by episodes of symptom flare-up (i.e. relapses or exacerbations) followed by periods of partial or complete remission. Over time (typically decades), individuals with RRMS often stop experiencing relapses and remissions, and instead begin accumulating neurodegeneration slowly but consistently. When this occurs, these individuals are said to have secondary-progressive MS (SPMS).A small number of people with MS (approximately 10%) do not experience an initial relapsing-remitting phase and instead experience steady neurodegeneration from the beginning of the disease. This type of MS is referred to as primary-progressive MS (PPMS).MS is Becoming More Prevalent, Especially Among WomenThe worldwide prevalence of multiple sclerosis was estimated as part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016). The researchers reported - in the March 2019 issue of The Lancet Neurology - that there were over 2.2 million cases of MS globally (or 30.1 cases per 100,000 people) in 2016.The prevalence rates were found to vary substantially from region to region, with Canada having the highest MS prevalence (estimated to be between 150 and 180 cases per 100,000 people). Overall, the global prevalence of MS was found to have increased by 10.4% since 1990.In fact, the number of MS cases has been on the rise for at least six decades, and it is the prevalence of MS among women that is driving the overall increase.It has been recognized for a long time that MS affects women in greater numbers than men, and the gap between the sexes has grown even wider in recent years. The ratio of women to men reported to have MS in 1955 was 1.4 to 1. By the 1980s, that ratio had shifted to 2 to 1, and, by the mid-2000s, for every man with MS, there were three women with the disease.There is evidence that the increase in the female-to-male ratio of MS has occurred because of an increased incidence in women, not because of a decreased incidence in men. Although one driver of the rising prevalence of MS could be better detection and diagnosis, this does not explain why the incidence of MS has not risen as drastically in men.Why is MS on the Rise?It is not clear why some people develop MS and others do not, and why the prevalence rate is on the rise among women. MS is not a contagious disease, nor is it directly inherited.A combination of genetics, environmental Factors, and lifestyle factors are leading contributors to a diagnosis of MS. “Because the rapid increase in MS prevalence has occurred over a fairly short period of time, genetics alone cannot account for what is happening,” said Dr. Shannon Dunn, a scientist at the Keenan Research Centre for Biomedical Science in Canada who specializes in studying MS and, in particular, the role of sex in disease risk.“Genes could not have changed that quickly, so it is likely that changing environmental or lifestyle factors are interacting with female sex to increase MS risk.”While it remains unclear as to why women are at an increased risk of developing MS, researchers are exploring the various factors that may be involved.Autoimmune ResponseWomen have more robust immune responses than men. When women’s immune systems are faced with an infectious agent, they typically respond in a pro-inflammatory way (except during pregnancy). Men’s immune systems, on the other hand, tend to respond in an anti-inflammatory way. Inflammation is known to play a role in MS.Sex HormonesWhen a disease affects more women than men, researchers commonly consider the role of sex hormones. Immune cells have hormone receptors, so it is not surprising that sex hormones influence immune system function. There is a variety of evidence that suggests sex hormones do, in fact, play a role in MS. For example:

• MS rates are similar (and low) between girls and boys before puberty, and after puberty the females begin to experience higher rates of the disease. Furthermore, young women who get their first period at a younger age appear to have an increased risk of developing MS compared to those who get it at an older age.
• Pregnancy impacts remissions and relapses in MS. During pregnancy, women tend to experience a reduction in MS symptoms, which can be followed by flare-ups once the baby is born. (Pregnancy involves hormonal changes, and tends to suppress the mother’s immune system so that her body does not reject the fetus.)
• MS symptoms in women vary throughout the menstrual cycle.

There have been some shifts in women’s reproductive patterns over the past 50 years that may be affecting MS risk by impacting hormone levels. Women are having fewer children, on average, than they once did, and there is a shift towards women having children at an older age. Preclinical studies using animals suggest that during pregnancy the hormones progesterone and estriol induce anti-inflammatory and neuroprotective effects, explaining why delayed or fewer pregnancies could be a disease-promoting factor.An academic review conducted by Dr. Maunil K. Desai and Dr. Roberta Diaz Brinton – published in April 2019 in Frontiers in Endocrinology – looked at the risk of autoimmune disease (including MS) in women across the lifespan, and found clear evidence for the role of sex steroids in the immune disturbances that result in autoimmune diseases.The researchers emphasized that most women pass through the various endocrinological transition states (i.e. puberty, pregnancy, and menopause) without developing autoimmune diseases. However, a small percentage of women emerge from such transitions with an increased risk of the disease because of sustained hormonal changes combined with genetic susceptibility, exposure to environmental factors, and epigenetic influences.Exposure to Sunlight & Vitamin DEvidence to date suggests that sunlight exposure, and the associated higher levels of vitamin D, offers protection against developing MS. And, the protective effects appear to be stronger in females than males. Studies with mice have shown that vitamin D3 supplementation significantly inhibits experimental autoimmune encephalomyelitis (EAE) in the females, but not the males. Further, when female mice had their ovaries removed, it eliminated the protective effect, suggesting a link between female hormones and vitamin D3 metabolism.In addition, vitamin D has been shown to have a direct modulatory effect on the expression of the major MS risk gene. With the reconition that UV exposure puts individuals at an increased risk of skin cancer, sun exposure habits have changed at the population level over the last few decades. The resulting reduction in UV exposure could be yet another contributor to the rise in MS in women.Other Potential Factors

• Studies have uncovered a link between having a higher body mass index in childhood and MS risk. Women usually carry more body fat than men, and obesity rates are higher for women.
• Gut microbiota (i.e. the bacteria, viruses, and fungi that line the gastrointestinal tract) are known to affect immune responses. There may be sex-specific differences in gut microbiota that have consequences for the development of MS.
• Exposure to chemicals may be playing a role in the increased MS risk experienced by women. Environmental estrogens, in particular, may be impacting the immune system, and can be found in some cosmetics and personal care products, which are more commonly used by women.
• Smoking may be contributing to the increasing prevalence of MS among women. It is known to be a risk factor for MS, and the female-to-male ratio of smoking has been on the rise since the mid-1930s.

Complex Combinations of Factors are Likely InvolvedMany factors potentially affecting the prevalence of MS among women are being researched, but it is likely that no single factor will be solely responsible for the increased risk women face. “This research is complex because MS is a complex disease. It is likely a combination of these factors, and maybe others that have yet to be identified, are at play. And, perhaps the factors differ from person to person,” explained Dr. Dunn.“This is why research in animal models of the disease are powerful in that we can modulate just one of these factors and see what the impact is on MS-like disease in the males and females. Certainly, more research is required not only in animal models, but also in humans to fully understand what is driving the female-dominated increasing MS risk, and to discover interventions to prevent, delay, and treat this disabling disease.Given the many sex-specific differences in so many of the factors known to affect MS, it’s also likely that effective MS interventions will need to be catered differently for women and men.Source: MIND OVER MATTER V9