Gender and Rheumatoid Arthritis

Summary of a presentation at the Living with RA Workshop at HSS

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.


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.


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.


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.


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.

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.


See the complete article on the Hospital for Special Surgery’s web site
Summary prepared by Diana Benzaia.

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