We know why people develop some diseases. Cystic fibrosis, for example, is caused by a single defective gene. If you have that gene, you will have the disease. Diseases such as tuberculosis are caused by environmental pathogens and whether you develop the illness will depend on both your exposure to that pathogen and the ability of your immune system to manage it. But what causes many diseases—for example, multiple sclerosis—is not so black and white.
Scientists have been studying MS since the mid 1800s to figure out what causes it. There is not a simple answer. It is a complex chronic disease that involves the two most complicated systems in the human body—the central nervous system and the immune system. What we do know is that there are multiple interactive factors that influence whether or not someone develops MS. We know that genetics play a role because you are more likely to develop it if you belong to certain ethnic groups and if a parent or sibling has it. There is also an environmental piece because it is more common in certain places than in others. And there is a sex component too, because MS occurs about twice as often in women than in men, and that ratio is increasing.
This issue of InforMS provides an overview of some of the different factors that participate in the development of MS, with special emphasis on the role played by sex and hormones. We will also look at issues that are specific to women—pregnancy, breastfeeding, and menopause and related hormonal concerns.
More than 100 genes have been identified that are more common in people who have multiple sclerosis, but there isn’t a specific MS gene. What people inherit is a genetic predisposition that tips the scale towards the development of the disease but doesn’t directly cause it. Roughly 1 in 750 people in the general population develop MS. If, however, you have close relative who has MS, your risk increases to about 1 in 40. If you have an identical twin with MS your risk is 1 in 4. That said, the majority of people who are diagnosed with MS do not have a family member with the disease. In fact, genetics probably contribute less than 20 percent to your risk, so clearly there are other factors that also drive development of the disease.
Each of us has in the neighborhood of 25,000 genes, but we only turn on—or express—a fraction of these at any given time.
Genes contain the instructions for building and running our unique bodies. Each of us has in the neighborhood of 25,000 genes, but we only turn on—or express—a fraction of these at any given time. We turn off the rest by the process known as gene regulation. Switching genes on and off is a part of normal development and can also occur in response to changes in the environment by a complex process that is not yet fully understood.
Imagine that in your DNA you have the necessary genes to become a world-class ski racer. Although you have this genetic potential, whether it actually develops will depend on lots of other factors. Where you live is one. If you grow up in the Swiss Alps, it is much more likely that these genes will be expressed than if you are born and spend your life in sub-Sahara Africa. What’s going on in the rest of your life is another factor. If you are diagnosed with leukemia when you are eight and spend the next five years in chemotherapy you probably won’t have the time or resources to ski. You inherit genes that incline you in a direction, but there are many other factors that influence the direction you actually go. Where and how we live—our physical and emotional environments, lifestyle, diet—all interact with and sculpt our potential.
What are factors in the environment that seem to “flip the switch” and favor the development of MS?
GEOGRAPHY, GERMS, AND HABITS
MS is not equally distributed around the globe. The prevalence increases the further you travel from the equator in either direction. Latitude and geography are associated with many variables, among them such things as sunlight exposure and differences in climate, diet, and diseases. Researchers have looked at all of these and more to figure out why and how location might influence the risk of MS. Increased availability of sunlight is consistently associated with lower rates of MS. Sunshine is the primary source of vitamin D for most of us. People who live in the higher latitudes have less exposure to sunlight, especially during winter month, and therefore have less opportunity to synthesize vitamin D. High blood levels of vitamin D, dietary vitamin D supplementation and exposure to ultra violet radiation are all associated with a decreased risk of developing MS.
Epstein Barr virus (EBV) is a common cause of childhood infection, and probably 95 percent of the world has been infected with it. It can establish a life-long dormant infection in our immune systems. MS researchers are particularly interested in EBV because it is everywhere and because, although 90-95 percent of the general population has EBV antibodies, 99 percent of people with MS do. The presence of these antibodies indicates that if there’s been exposure to the virus; the more of them someone has, the more likely they are to develop MS. When EBV develops in late adolescence or early adulthood it can be a more serious problem and 35 to 50 percent of the time can cause infectious mononucleosis. People who have been ill with infectious mononucleosis are two to three times more likely to acquire MS.
For decades researchers have tried, but failed, to establish EBV as the cause of MS. The current speculation is that EBV is an important contributor—or risk factor—for the development of MS, but by itself does not cause the disease. Our immune system is effective at protecting us because it learns and changes in response to environmental events. One theory is that exposure to EBV might change the immune system in subtle ways that later predisposes us to develop MS.
Cigarette smoking is also a risk factor for MS. People who smoke cigarettes have an increased risk of developing MS. Studies have also found that smoking intensifies disease progression. Researchers speculate that cigarette smoking may disrupt immune system regulation generally because it increases the risk of other autoimmune conditions as well.
Another factor that tips the scales in favor of MS is being born female.
Men and women are different from each other. The popular press has over simplified these dissimilarities and overemphasized their behavioral manifestations, but men and women really are different from each other. These differences are known as sexual dimorphisms and aren’t just limited to body parts, facial hair, and communication styles. They occur throughout the body. For example, the brains of men and women have both physiological and functional differences. Men’s brains are proportionally larger. Women’s brains have a larger ratio of gray matter to white matter. There are also variations in the circuits linked to memory, emotion, and stress.
There are sex-related differences in the immune system, too. Women have a more robust immune response and tend to live longer than men. Women respond to lower doses of flu vaccine than men and experience more adverse reactions to flu shots. A downside of the strong female immune response, however, is that women are much more likely than men to develop autoimmune diseases.
A downside of the strong female immune response is that women are much more likely than men to develop autoimmune diseases.
Men and women also have differences in their sex hormones. Both sexes have both types of hormones but in much different amounts. Estrogens are the most abundant in females, and testosterone in males.
Because of these and scores of other differences, it makes sense that men and women might experience diseases differently, and in fact, they do. Women are more likely to develop Alzheimer’s disease than men but men are more likely to develop Parkinson’s disease. Although heart disease is a leading cause of death for both, women are more likely than men to die following a heart attack. Women are more likely than men to become addicted to nicotine and the available strategies to help people stop smoking appear to be less effective in women. And the list goes on.
Pregnancy appears to have beneficial effects on MS and women generally have significantly fewer MS-related problems during those nine months.
Men and women also experience MS differently. Women are two to three times more likely to develop it, although before puberty the female to male ratio is about equal. The incidence of relapsing-remitting MS appears to be increasing among females, but not among males. There are gender differences in the disease course as well. Men tend to develop MS a little later than women do and are likely to have a more progressive disease course. In late onset MS—when someone is diagnosed after age 50—men and women progress at a similar rate. A few studies have suggested that there are MRI differences, that different brain regions are differentially affected, and that men have more brain atrophy and cognitive impairment.
We have known for a long time that women are more susceptible than men to inflammatory autoimmune disorders like rheumatoid arthritis and multiple sclerosis and lupus. Because these conditions occur more frequently in women and because pregnancy and other hormonal fluctuations often effect the disease manifestations, sex hormones are thought to be important players in the autoimmune disease process. But what exactly are these hormones and how might they be important in MS?
WHAT ARE HORMONES?
Hormones are chemical messengers that regulate different body functions. Insulin is a hormone that regulates blood sugar, cortisol regulates the stress response, and there are many others. Sex hormones—estrogens, progesterone, and testosterone—are probably the most famous hormones, known especially for the role they play in our sexual development and functioning, but they impact other aspects of our metabolism, too.
Sex hormones appear to play a role in the inflammation, damage and repair mechanisms in MS. Estrogen is a sex hormone that has a biphasic effect: it is proinflammatory at lower doses but at higher doses may be immunosuppressive. Women often report that their MS symptoms are much more noticeable in the week before their period and this is, coincidentally, the time during the menstrual cycles when estrogen levels are normally slightly elevated.
Pregnancy appears to have beneficial effects on MS and women generally have significantly fewer MS-related problems during those nine months. Pregnancy requires immune suppression; otherwise the immune system would attack the fetus. Estriol is a type of estrogen that is present at high levels during pregnancy and seems to promote immune cells that reign in inflammation. These protective effects appear to reverse during the first three months postpartum when hormone levels drop.
Sex hormones also play a role in the way MS affects men. Men get MS less often than women and later in life, which might be related to testosterone. Testosterone has anti-inflammatory properties—it reduces the production of proinflammatory cytokines—and may have neuroprotective properties as well. Men generally have a less aggressive immune response than women. About a quarter of male MS patients have significantly less testosterone than healthy controls. Testosterone levels also decline with age.
Clearly, the sex hormones have a role to play in MS. They have been the subjects of lots of recent research to see if manipulating hormones levels might help improve function or disease progression in MS. Although it is a topic of great interest, the studies have been limited in number and mostly small in size, and the results have been uneven and underwhelming. One study used Estriol in combination with Copaxone to see if the combination might boost the effectiveness of the drug. It did a little, but not a lot, and the effect diminished over time. Another tiny study administered testosterone patches to men and found this had positive effects on cognitive functioning and brain atrophy. The results of these and other studies are interesting and thought provoking, but the only uniform recommendation coming from any of them is that the results are inconclusive and that we need more research.
So, what does sex have to do with it? A lot, apparently, but beyond that, it’s not really clear. We will have to get back to you on that.