Follow the links below to the Hospital for Special Surgery web site and read Dr. Lockshin’s articles about Sex and Autoimmune Disease:
Current Theories
Michael D. Lockshin, MD
With some exceptions, autoimmune diseases affect far more women than men. For some time, physicians and researchers have been asking why this is so. The most popular theory to date has been that female hormones set the stage for diseases such as systemic lupus erythematosus, Sjogren’s syndrome, and rheumatoid arthritis. But more recent research calls this theory into question-and suggests that there may be other reasons for the greater incidence of autoimmune disease in women, an issue sometimes referred to as sex predominance. Possible explanations may be roughly divided up into four areas: (1) hormone theory, (2) environmental factors, (3) genetic influences, and (4) whole organism factors.
Discussion of these potential causes is sometimes complicated by disagreement about the definition of an autoimmune disease. For the most part, however, there is general agreement that the following are autoimmune diseases: system lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, scleroderma, primary biliary cirrhosis, chronic active hepatitis, Graves disease, Goodpasture’s disease, hemolytic anemia, idiopathic thrombocytic purpura and Hashimoto’s thyroiditis. Other diseases that many physicians would put in this category include: ankylosing spondylitis, Lyme disease, pemphigus, vitiligo, myasthenia gravis, multiple sclerosis, and juvenile onset diabetes. A number of other illnesses may have features that are similar to those of autoimmune diseases, but they are not labeled as autoimmune diseases.
Current Theories of Sex Predominance
1. Hormone Theory
Hormone theory refers to the traditional belief that estrogen production puts women at a greater risk for developing an autoimmune disease. In tests conducted in the laboratory, estrogen has been demonstrated to make women’s immune systems “over-react” when compared to men’s. This finding supports the standard definition for lupus and other auto-immune diseases, in which the immune system is said to over-react to the body’s own tissues. It also appears to explain the ratio of incidence in a disease like lupus, in which 9 women get the disease for every 1 man.
However, there are autoimmune diseases that occur more frequently in men than in women, including Goodpasture’s syndrome, in which the body creates antibodies that attack the lungs and kidneys. This disease occurs in 1 woman for every 3 men.
Another problem with the hormone theory is disease severity. If women are more likely to develop lupus because they produce estrogen, they could be expected to become more seriously ill. But, overall, men and women with lupus experience the disease with the same range of severity.
If estrogen were the deciding factor in who gets autoimmune diseases, it would also be reasonable to expect that similar diseases would have similar male-female ratios. However, there are a number of diseases that share characteristics with lupus (9:1) that have very different ratios, including Goodpasture’s disease (1:3), idiopathic thrombocytopenic purpura (2:1), and hemolytic anemia (2:1).
If hormones and immune response are linked, then one could also expect women to react differently than men to infections and immunizations. However, there appears to be no significant difference. Moreover, hormonal changes that occur when menstruation begins, during pregnancy, and with menopause, do not seem to affect the course of autoimmune disease. Neither does the use of birth control pills or hormone replacement therapy.
2. Environmental Factors
As these arguments against the role of hormones in explaining sex predominance and autoimmune disease have become more widely discussed, researchers are paying more attention to environmental factors. Some diseases that have been classified as autoimmune diseases are clearly caused by exposure to external toxins — medications or environmental pollutants. The differing roles of men and women at home and in the workplace help to explain who is exposed to these toxins.
Scleroderma, for example, is seen disproportionately in male gold and coal miners who are exposed to high levels of silica. Drug-induced lupus is a long-recognized disease that occurred in the 1960s and 1970s, mostly in men who were given certain drugs to treat heart disease, and still occurs today, but less often since better drugs are available.
Other examples of autoimmune disease caused by exposure include an epidemic of a disease that resembled scleroderma in Spain in the 1970s. In this case, 10,000 people, mostly women who were cooking at home with contaminated oil, developed the illness. While both men and women ate the cooked foods, women tasted the food as it was cooking, at a point when the heat had not yet destroyed the contaminant. By the time the food reached the table, the contaminant was destroyed, and no longer harmful.
In another instance, men who cleaned manufacturing vats used to make polyvinyl chloride (the plastic that is used in so many products that we use on a daily basis) developed scleroderma. It was later found that they were exposed to a monomer in the air, a toxic chemical compound that joins with other compounds during heating to become polyvinyl chloride.
The role of environmental factors may also be seen in children. In those under 12, for example, more boys develop Lyme disease than do girls. The reason for this difference can be found in the way children play. More boys play outside more of the time, and in doing so, increase their risk of exposure to disease-carrying ticks in wooded areas. (Looking at this example, one could come to the conclusion that a preference for a certain type of activity might be determined by hormones, which in turn could influence exposure to the environmental factor.)
In an area of Brazil, a disease that closely resembles pemphigus foliaceus, an autoimmune skin disorder characterized by blisters, has been associated with a certain kind of black fly that lives near the river. Men who fished in this river were more likely to develop the disease than women who had less exposure to the flies.
These examples support the idea that exposure to a toxin determines who will develop the disease, rather than the sex of the patient. Unfortunately, it does not yet help to explain female predominance in a disease like systemic lupus erythematosus. Researchers have looked at exposure to a number of products that women use with greater frequency, such as hair dye and lipstick, but have not identified any cause-and-effect link.
The role of behavior can also be considered to influence the development of disease. Examples include osteoporosis, which can be modified by doing weight-bearing exercise. Coronary disease, including strokes and atherosclerosis, can be affected by changes in diet and reduction of cholesterol levels. And, injury-related osteoarthritis risk can be reduced by avoiding extreme sports. The risk of developing Reiter’s disease-a kind of reactive arthritis sometimes caused by venereal disease-can also be reduced by modifying behavior.
It seems clear therefore, that behavior can cause illness, but we haven’t identified the specific behaviors involved with most autoimmune diseases.
3. Genetic Influences
Genetic differences between men and women have also been considered as an explanation for why one sex gets a disease more frequently than the other. Researchers have learned some interesting facts about these differences. Among them:
• Every cell in every man’s body is different from every cell in every woman’s body-even those found in identical tissues (e.g., a man’s liver and a woman’s liver).
• There are huge differences in the DNA between the sexes, the cell membranes, and the way cells associate in the body. For example, every woman gets X chromosomes from her mother and her father. Every man gets X chromosomes from his mother only (he gets the Y chromosome from his father.)
• Women who have been pregnant carry their baby’s cells in their bloodstream even after they have given birth to their children-sometimes for decades. In normal women the cells drop dramatically after birth. In women with autoimmune diseases, the cells are often present at much higher numbers for a much longer period of time. These diseases include: scleroderma, primary biliary cirrhosis, Sjogren’s syndrome, and autoimmune thyroid disease. In women with thyroid nodules, the cells within the nodules have been found to be male cells, while the rest of the thyroid is made up of female cells.
As fascinating as this information is, scientists have not yet figured out its significance. But we can expect much more study of these phenomena.
4. Whole organism Issues
Whole organism issues may also be a part of the picture-those that have nothing to do with sex or genes. For example, osteoporosis is, in large part dictated by body size. Very heavy people don’t get it, very thin people do. Moreover, tall, heavy people are less likely to have osteoporosis than are small, heavy people, since the disease relates to the size of the bones and how much calcium is lost from them. The likelihood of a woman developing breast cancer may be influenced by how many children she has, and Alzheimer’s disease appears to be linked with aging, although it is not understood whether it is part of the process itself, or something that takes 60 or 70 years to develop. Study of the aging process and autoimmune disease is underway as well. Can signs of the disease be detected in the bloodstream well before the patient has any symptoms? And, if so, are there ways to slow the progress of the disease or stop it?
Looking at all of these factors, Dr. Lockshin concludes that a variety of factors may explain why more women get autoimmune diseases than do men. Why is there a 9 to 1 ratio in a disease like lupus? Why does rheumatoid arthritis occur in 2 women for every one man? Why do more men than women develop Goodpasture’s syndrome? It could be environment, hormones, behavior, genetic differences, or a combination of some or all of these factors. The information available to us now is part of a continuing discussion that promises to yield new ways of thinking about and approaching autoimmune disease over the coming decade and beyond.
Additional Reading
If you are interested in reading more about the relationship between sex and disease, you may be interested in the following:
Exploring the Biological Contributions to Human Health: Does Sex Matter? This book compiles a vast range of writings on the role of sex in a range of diseases, not just autoimmune illnesses. It is available for purchase or for free on-line at www.nap.edu/catalog/10028.html
The X in Sex: How the X Chromosome Controls Our Lives by David Bainbridge. Available in bookstores and through on-line booksellers.
Y: The Descent of Men by Steve Jones. Available in bookstores and through on-line booksellers.
See the complete article on the Hospital for Special Surgery’s web site
Summary prepared by Nancy Novick.
Summary of a presentation at the Living with RA Workshop at HSS
Michael D. Lockshin, MD
The traditional answer to the question “Why are autoimmune diseases women’s diseases?” has been “It has to do with estrogen.” But that’s not a satisfactory answer because a lot of facts that don’t fit this theory. So the question has been researched with greater interest in recent years.
What is autoimmunity? Some define it by tests done in a laboratory that find antibodies (such as rheumatoid factor) to normal tissue (parts of the body). Others say it’s the kind of disease that cause arthritis and sometimes fevers, kidney disease and other problems. Others say any disease that causes arthritis is an autoimmune disease. Animal models are another way to define it because the autoimmune diseases that we recognize can be produced in animals by manipulating their immune systems. Because autoimmune diseases tend to run in families, we tend to use a positive family history as part of the definition. By and large, all the definitions require that an autoimmune disease not be an infectious disease, such as Lyme disease and some types of hepatitis, which would look like autoimmune disease if they were not clearly caused by an infection. (This suggests that diseases such as RA may also be infectious diseases but we just haven’t identified the cause of the infection.)
Which diseases are autoimmune? Again, the answer is not totally clear. Most physicians would agree to this list: Hashimoto’s thyroiditis, primary biliary disease, chronic active hepatitis, Grave’s disease, lupus, scleroderma, rheumatoid arthritis, Sjogren’s syndrome, and most rheumatic diseases, including ankylosing spondylitis. But there are many other diseases that some doctors consider autoimmune and others do not. The American Autoimmune Association would include such diseases as multiple sclerosis, hemolytic anemia, pemphigus, pernicious anemia, type 1 diabetes, myasthenia gravis, Goodpasture disease, and many others - but there is no clear consensus. And there is considerable controversy about some neurologic, skin, and intestinal diseases that are accepted as autoimmune by some doctors and not others.
Are all autoimmune diseases women’s diseases? Not necessarily. While many are much more common in women, others are more common in men. For RA, women are affected about two and a half times more common in women compared to men.
This again raises the question of why so many autoimmune diseases are much more common in women. Two important efforts to explore the question were: a conference at Hospital for Special Surgery in 1999 exploring Gender, Biology and Human Disease; and a commission of the Institute of Medicine of the National Academy of Sciences, which last year published a book Exploring the Biological Contributions to Human Health - Does Sex Matter? - available for purchase or for free online. The NIH study looked at male/female differences in the following factors.
Environmental differences - Women may develop autoimmune diseases because they are more susceptible - or more exposed - to something in the environment. For example, scleroderma occurs spontaneously, primarily in women, but also in men who are gold and coal miners and in workers that manufacture plastics. Scleroderma-like diseases also are seen in those exposed to some toxins. Further, some drugs can cause lupus, which primarily occurs in men taking those drugs. However, no environmental culprit has been identified.
Genes - Due to genetics, women and women have some chemical reactions that are different. No genes have yet been proven to explain female predominance, but the field is just beginning to be explored.
Behavior - Some diseases are different in men and women due to behavioral differences. For example, you can develop osteoporosis based solely on personal habits because the amount of exercise you do and your body fat levels affect bone strength. Women who are intense athletes, such as marathoners, lose huge amounts of body fat, stop menstruating, and get severely osteoporotic. Girls who are anorectic and don’t eat also lose their body fat and get very thin bones. Other examples are venereal diseases, which are more common in men because of their relative level of promiscuity. And Reiter’s syndrome is a form of arthritis that is often triggered by venereal disease. So the theory is that women can predominate in a disease if men and women differ in basic personalities, but we don’t know what personality factors could lead to diseases like RA.
Whole Organism - Issues related to being a living person at given time, for example, might include age, and most autoimmune diseases start between the ages of 15 and 45. So there is something interesting about that age range. Many issues related to age might explain female predominance, such as a long period between encountering what causes these diseases and their eventual appearance. So it might be theorized that little girls do different things from little boys but it doesn’t show up as disease until 10 or 20 years later. The Army keeps blood samples of its recruits for many years; researchers have now looked at samples of this blood and found that blood tests are positive more than 10 years before the appearance of lupus and RA. So the disease has existed for more than 10 years before someone gets joint pains.
Hormones - Estrogen increases the immune response in humans and many animals. However, in some animal models we don’t see more frequent disease but more severe disease in females. That’s the opposite of what we see in humans; for example, the severity of RA and lupus are the same in men and women but the frequency is different. And the influence of hormones is inconsistent: during pregnancy, RA gets better but lupus may get worse or be unchanged. So there may be big differences in the way different autoimmune diseases appear when you get pregnant or take birth control pills or estrogen replacement. However, in two recent studies, it looks as if birth control pills and estrogen replacement have no effect on women with lupus. It’s possible that reaching a certain threshold of hormones or the cycling of hormones in menstruation could influence disease. But we still don’t know whether hormones cause disease.
Other possible differences in men and women that might relate to autoimmune disease include anatomy, pregnancy, differing physiologic responses to drugs and toxic substances, differing genitourinary tracts, influences on the baby before birth, and other factors.
Dr. Lockshin’s guess is that hormones are not the explanation for female predominance of autoimmune disease. Rather, he thinks the predominance relates to different exposures to something in the environment or differences in the way men and women’s bodies handle something, or some mixture of the various causes discussed above.
The differences in the male to female ratio of autoimmune diseases is the single most bizarre clinical fact about these diseases. It has not received a great deal of research attention so far, but finding the answer will teach us a great deal about these diseases.
See the complete article on the Hospital for Special Surgery’s web site
Summary prepared by Diana Benzaia.
About the Living with RA Workshop at Hospital for Special Surgery