Autoimmune diseases such as rheumatoid arthritis are more prevalent in women, and many studies have suggested that estrogen’s pro-inflammatory action may contribute to this phenomenon. An article by Cutolo et al. from 2003 discussed that while estrogen levels in synovial fluid of arthritis patients were not significantly elevated compared to healthy patients, they saw a significant decrease in androgen levels (testosterone/dihydrotestosterone, dehydroepiandrosterone). They speculated that it might be this imbalance of estrogen to androgens (high ratio of estrogens to androgens) that might play a role in arthritis incidence, since androgens have an anti-inflammatory role.
So why are androgen levels lower in RA patients? Inflammatory cytokines such as TNF-α, IL-1 and IL-6 stimulate aromatase activity, the enzyme that converts androgens to estrogens. Since arthritis causes an increase in the production of inflammatory cytokines, the conversion of androgens to estrogens are also increased. This causes an imbalance of the sex hormones, creating a low anti-inflammatory, high pro-inflammatory environment that may be ideal for arthritis development.
Furthermore, estrogens have been shown to play a part in activating the NF-κB pathway, an inflammatory pathway in arthritis. Estrogen also increases cell proliferation and growth, which could lead to synovial tissue hyperplasia. An imbalance of the sex hormones may be the cause of higher incidences of autoimmune diseases in women, and research looking at hormone replacement therapy to treat or prevent arthritis are underway.
(Clin Exp Rheum, 21:687-690, 2003)
I was surprised that estrogen is considered pro-inflammatory while testosterone and androgens are anti-inflammatory, so I looked up an article on sex differences and immune response. The article reinforced your article, and suggested the importance of females to have a heightened immune response for better protection for themselves and their offspring during pregnancy and nursing. This also makes females more susceptible to anxiety and mood disorders, and inflammatory and allergic problems. My question (since I haven't been keeping track) is considering the inflammatory diseases we've covered, are women more affected than men? I thought both genders were affected similarly, but if females have a heightened immune response, then shouldn't they be significantly more affected than men for most of these diseases and not just arthritis?
ReplyDeleteChrousos GP. Stress and Sex Versus Immunity and Inflammation. Sci. Signal., 12 October 2010
Vol. 3, Issue 143, p. pe36
I know for a fact that women are more susceptible to autoimmune diseases, and it's speculated that it's due to estrogen's pro-inflammatory effect. In regards to diabetes, I've read that in general those with a low socioeconomic status are more likely to become diabetic than individuals with higher socioeconomic status. The interesting part was that women were more prone to getting diabetes than men of the same socioeconomic status (AJPH 91(1):76-83, 2001). They didn't explain the mechanism behind this much, but this might also be due to estrogen. Estrogen also promotes adipose storage, and women tend to have a higher BMI than men (due to higher amounts of subcutaneous fat, but less visceral fat than men) so estrogen might also have an indirect pro-inflammatory role by promoting fat storage and increased production of inflammatory cytokines. Low testosterone levels have also been linked to metabolic syndrome, again emphasizing that it may be the imbalance of estrogens to androgens that might contribute to inflammatory diseases (Eur J Endocrinol, 149(6): 601-608, 2003).
ReplyDeleteOne of the articles I found looking at gender influences on inflammatory diseases speculated that sex hormones are probably influencing the results, but also gender of the mind (culture, traditions, behavior) can also play a major role in inflammatory disease incidence (Rejuvenation Res, 13(2-3):292-297, 2010). So I think that while higher levels of estrogen in women should make them more susceptible to all inflammatory diseases, we might not see a significant difference compared to men because of our lifestyles. To accurately determine the influence of estrogen on inflammatory diseases in humans we’d have to put the subjects through intensive screening and testing procedures, which as we all know is close to impossible.
I find this article interesting because we've seen in many of the readings (and as Aubrey pointed out) that women are more susceptible to autoimmune diseases. If estrogen does contribute to this, this may be the reason why we see women more affected. I'm curious to see if the hormone treatment will be an effective way to treat autoimmune diseases. Since autoimmune diseases can be caused by numerous pathways, I wonder if we'll see progress in some patients, but not in others.
ReplyDeleteIf estrogen is considered pro inflammatory, I wonder if there are any long term studies of women who have total hysterectomies, with the removal of ovaries at young ages due to something like severe ovarian cysts or endometriosis, that show a decreased percentage of inflammatory diseases like RA in that particular population.
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