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Sexual dimorphism of RA manifestations: genes, hormones and behavior

Nature Reviews Rheumatology volume 7, pages 307–310 (2011)Cite this article

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Abstract

Women are more likely than men to develop rheumatoid arthritis (RA), and recent data suggest that they also suffer greater disability than men with this disease. The reasons for these sexually dimorphic patterns of disease incidence and progression are unknown, but investigations into the underlying mechanisms could provide useful insights into RA pathogenesis and may also suggest new treatment approaches. The processes of sexual differentiation involve genetic input, gonadal hormone signaling and responses from target cells and tissues. Layered upon these processes are behavioral characteristics of males and females acquired as a result of their social context. Differences in disease presentation between the sexes could be the result of complex combinations of all these factors. Recent research suggests that the developmental processes of sexual differentiation might render women more susceptible than men to similar levels of immune or inflammatory burden by virtue of sex-specific differences in body composition and structure.

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Figure 1: Cellular targets and processes in the immune system that have been shown to be modulated by gonadal steroids.

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References

  1. Myasoedova, E., Crowson, C. S., Kremers, H. M., Therneau, T. M. & Gabriel, S. E. Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955–2007. Arthritis Rheum. 62, 1576–1582 (2010).

    Article  Google Scholar 

  2. Iikuni, N. et al. The influence of sex on patients with rheumatoid arthritis in a large observational cohort. J. Rheumatol. 36, 508–511 (2009).

    Article  Google Scholar 

  3. Sokka, T. et al. Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study. Arthritis Res. Ther. 11, R7 (2009).

    PubMed  PubMed Central  Google Scholar 

  4. Ahlmen, M., Svensson, B., Albertsson, K., Forslind, K. & Hafstrom, I. Influence of gender on assessments of disease activity and function in early rheumatoid arthritis in relation to radiographic joint damage. Ann. Rheum. Dis. 69, 230–233 (2010).

    Article  CAS  Google Scholar 

  5. Gossec, L. et al. Influence of sex on disease severity in patients with rheumatoid arthritis. J. Rheumatol. 32, 1448–1451 (2005).

    PubMed  Google Scholar 

  6. Tengstrand, B., Ahlmen, M. & Hafstrom, I. The influence of sex on rheumatoid arthritis: a prospective study of onset and outcome after 2 years. J. Rheumatol. 31, 214–222 (2004).

    PubMed  Google Scholar 

  7. Wolfe, F. & Sharp, J. T. Radiographic outcome of recent-onset rheumatoid arthritis: a 19-year study of radiographic progression. Arthritis Rheum. 41, 1571–1582 (1998).

    Article  CAS  Google Scholar 

  8. Sawalha, A. H., Harley, J. B. & Scofield, R. H. Autoimmunity and Klinefelter's syndrome: when men have two X chromosomes. J. Autoimmun. 33, 31–34 (2009).

    Article  CAS  Google Scholar 

  9. Hench, P. S. The ameliorating effect of pregnancy on chronic atrophic (infectious rheumatoid) arthritis, fibrositis and intermittent hydrarthrosis. Mayo Clin. Proc. 13, 161–167 (1938).

    Google Scholar 

  10. Fisk, G. H., Howard, R. P. & Fay, K. Rheumatoid arthritis. I. Clinical effects of testosterone and pregnenolone therapy. Can. Med. Assoc. J. 63, 342–344 (1950).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hellbaum, A. A., Ishmael, W. K., Duffy, M. L. & Payne, R. W. The effect of estrogen, androgen, and thyroid in degenerative joint disease. J. Gerontol. 13, 163–166 (1958).

    Article  CAS  Google Scholar 

  12. Cohen, A., Dubbs, A. W. & Myers, A. The treatment of atrophic arthritis with estrogenic substance. N. Engl. J. Med. 222, 140–142 (1940).

    Article  Google Scholar 

  13. Walitt, B. et al. Effects of postmenopausal hormone therapy on rheumatoid arthritis: the women's health initiative randomized controlled trials. Arthritis Rheum. 59, 302–310 (2008).

    Article  Google Scholar 

  14. Costenbader, K. H. & Manson, J. E. Do female hormones affect the onset or severity of rheumatoid arthritis? Arthritis Rheum. 59, 299–301 (2008).

    Article  Google Scholar 

  15. Bijlsma, J. W., Huber-Bruning, O. & Thijssen, J. H. Effect of oestrogen treatment on clinical and laboratory manifestations of rheumatoid arthritis. Ann. Rheum. Dis. 46, 777–779 (1987).

    Article  CAS  Google Scholar 

  16. D'Elia, H. F. et al. Influence of hormone replacement therapy on disease progression and bone mineral density in rheumatoid arthritis. J. Rheumatol. 30, 1456–1463 (2003).

    CAS  PubMed  Google Scholar 

  17. Hall, G. M., Daniels, M., Huskisson, E. C. & Spector, T. D. A randomised controlled trial of the effect of hormone replacement therapy on disease activity in postmenopausal rheumatoid arthritis. Ann. Rheum. Dis. 53, 112–116 (1994).

    Article  CAS  Google Scholar 

  18. MacDonald, A. G., Murphy, E. A., Capell, H. A., Bankowska, U. Z. & Ralston, S. H. Effects of hormone replacement therapy in rheumatoid arthritis: a double blind placebo-controlled study. Ann. Rheum. Dis. 53, 54–57 (1994).

    Article  CAS  Google Scholar 

  19. van den Brink, H. R., van Everdingen, A. A., van Wijk, M. J., Jacobs, J. W. & Bijlsma, J. W. Adjuvant oestrogen therapy does not improve disease activity in postmenopausal patients with rheumatoid arthritis. Ann. Rheum. Dis. 52, 862–865 (1993).

    Article  CAS  Google Scholar 

  20. Margolis, H. M. & Caplan, P. S. The effect of some steroids (testosterone propionate, desoxycorticosterone acetate and ascorbic acid, and 21-acetoxy delta-5-pregnenolone, artisone acetate, Wyeth) in rheumatoid arthritis. Ann. Intern. Med. 34, 61–71 (1951).

    Article  CAS  Google Scholar 

  21. Booji, A. et al. Androgens as adjuvant treatment in postmenopausal female patients with rheumatoid arthritis. Ann. Rheum. Dis. 55, 811–815 (1996).

    Article  CAS  Google Scholar 

  22. Cutolo, M. et al. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus 13, 635–638 (2004).

    Article  CAS  Google Scholar 

  23. Islander, U., Jochems, C., Lagerquist, M. K., Forsblad-d'Elia, H. & Carlsten, H. Estrogens in rheumatoid arthritis; the immune system and bone. Mol. Cell Endocrinol. doi:10.1016/j.mce.2010.05.018.

  24. Martin, J. T. Sexual dimorphism in immune function: the role of prenatal exposure to androgens and estrogens. Eur. J. Pharmacol. 405, 251–261 (2000).

    Article  CAS  Google Scholar 

  25. Straub, R. H. The complex role of estrogens in inflammation. Endocr. Rev. 28, 521–574 (2007).

    Article  CAS  Google Scholar 

  26. Whitacre, C. C. Sex differences in autoimmune disease. Nat. Immunol. 2, 777–780 (2001).

    Article  CAS  Google Scholar 

  27. Karlson, E. W. et al. A prospective study of androgen levels, hormone-related genes and risk of rheumatoid arthritis. Arthritis Res. Ther. 11, R97 (2009).

    Article  Google Scholar 

  28. Camacho, E. M. et al. The relationship between post-onset pregnancy and functional outcome in women with recent onset inflammatory polyarthritis: results from the Norfolk Arthritis Register. Ann. Rheum. Dis. 69, 1834–1837 (2010).

    Article  CAS  Google Scholar 

  29. Nelson, J. L. Naturally acquired microchimerism: for better or for worse. Arthritis Rheum. 60, 5–7 (2009).

    Article  Google Scholar 

  30. Rak, J. M. et al. Transfer of the shared epitope through microchimerism in women with rheumatoid arthritis. Arthritis Rheum. 60, 73–80 (2009).

    Article  CAS  Google Scholar 

  31. Angst, F. et al. Prediction of grip and key pinch strength in 978 healthy subjects. BMC Musculoskelet. Disord. 11, 94 (2010).

    Article  Google Scholar 

  32. Stoll, T., Huber, E., Seifert, B., Michel, B. A. & Stucki, G. Maximal isometric muscle strength: normative values and gender-specific relation to age. Clin. Rheumatol. 19, 105–113 (2000).

    Article  CAS  Google Scholar 

  33. Hanna, F. S. et al. Women have increased rates of cartilage loss and progression of cartilage defects at the knee than men: a gender study of adults without clinical knee osteoarthritis. Menopause 16, 666–670 (2009).

    Article  Google Scholar 

  34. Mansfield, A. K., Addis, M. E. & Mahalik, J. R. “Why won't he go to the doctor?”: the psychology of men's help seeking. Int. J. Mens Health 2, 93–109 (2003).

    Article  Google Scholar 

  35. Englund, M. et al. Prevalence and incidence of rheumatoid arthritis in southern Sweden 2008 and their relation to prescribed biologics. Rheumatology (Oxford) 49, 1563–1569 (2010).

    Article  Google Scholar 

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Authors and Affiliations

  1. Division of Endocrinology, Department of Medicine, The Pennsylvania State University Milton S. Hershey Medical Center, 500 University Drive, Hershey, 17033, PA, USA

    William J. Kovacs

  2. Division of Rheumatology, Department of Medicine, The Pennsylvania State University Milton S. Hershey Medical Center, 500 University Drive, Hershey, 17033, PA, USA

    Nancy J. Olsen

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Both authors contributed equally to researching data for the article, discussing its content, writing and review/editing of the manuscript before publication.

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Correspondence to Nancy J. Olsen.

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Competing interests

N. J. Olsen has received grant/research support from Genentech. W. J. Kovacs declares no competing interests.

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Kovacs, W., Olsen, N. Sexual dimorphism of RA manifestations: genes, hormones and behavior. Nat Rev Rheumatol 7, 307–310 (2011). https://doi.org/10.1038/nrrheum.2010.231

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