Sex Hormones and Rheumatoid Arthritis: A Review of Their Role in Disease Development

Abstract

Rheumatoid arthritis (RA) is a kind of persistent inflammation of the joints that affects 0.5 to 1.0% of people worldwide. It can cause increasing disability, which results in a considerable socioeconomic burden. RA can be caused by genetic and environmental factors. Both genetic and environmental factors can increase the likelihood of developing RA. Hormonal factors have also been identified as risk factors for RA. Sex hormones have an impact on both males and females throughout their entire brain via receptors, both genomic and nongenomic. Sex hormones have the power to modify behavior, change the way that neuronal systems are organized and operate, and even offer neuroprotection. Progesterone, androgens, and estrogens all influence the immunological response. While progesterone and androgens are naturally occurring immune suppressors, estrogens can strengthen humoral immunity. Research point to a possible involvement of sex hormones in the pathogenesis of RA. The highest incidence of RA at menopause, decreased disease activity during pregnancy, and postpartum flare are indicative of this. The findings that demonstrate a link between sex hormones and the pathogenesis of rheumatoid arthritis are the main topic of this review.

Keywords:

autoimmune diseases, rheumatoid arthritis, sex hormones, estrogen, androgens, testosterone

References

Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet, 2010, 376: 1094-108.‏

AL-GHAZALY, Zakaria M.; JASSIM, Nizar Abdul Latif. Polypharmacy and potential drug–drug interactions in patients with rheumatoid arthritis. Medical Journal of Babylon, 2022, 19.3: 396-403.‏

AMJADIPOOR, Nasrin Mostafa; SHNAWA, Bushra Hussain. Investigating the potential correlation between vitamin D with rheumatoid factor, anticyclic citrullinated peptides antibody, and interleukin-12 levels in rheumatoid arthritis women in Erbil, Iraq. Medical Journal of Babylon, 2023, 20.3: 517-524.‏

Aletaha, D., & Smolen, J. S. Diagnosis and management of rheumatoid arthritis: a review. Jama, 2018, 320.13: 1360-1372.‏

Cutolo, M., Villaggio, B., Craviotto, C., Pizzorni, C., Seriolo, B., & Sulli, A. Sex hormones and rheumatoid arthritis. Autoimmunity reviews, 2002, 1.5: 284-289.‏

Favalli, E.G., Biggioggero, M., Crotti, C., Becciolini, A., Raimondo, M.G. and Meroni, P.L., 2019. Sex and management of rheumatoid arthritis. Clinical reviews in allergy & immunology, 56, pp.333-345.

FÖRGER, Frauke; VILLIGER, Peter M. Immunological adaptations in pregnancy that modulate rheumatoid arthritis disease activity. Nature Reviews Rheumatology, 2020, 16.2: 113-122.‏

ROMO-GARCÍA, Maria Fernanda, et al. The role of estrogens in rheumatoid arthritis physiopathology. Rheum. Arthritis—Other Perspect. Towards a Better Practice, 2020, 27.

Ackerman, L. S. Sex hormones and the genesis of autoimmunity. Archives of Dermatology, 2006, 142.3: 371-376

Nicholson LB. Essays in biochemistry,(3). The immune system. Essays Biochem, 2016, 60: 275-301.‏

Cutolo M, Sulli A, Capellino S, et al. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus, 2004, 13.9: 635-638.‏

Kim, J. R., & Kim, H. A. Molecular mechanisms of sex-related differences in arthritis and associated pain. International journal of molecular sciences, 2020, 21.21: 7938.‏

Cutolo M, Capellino S, Sulli A et al. Estrogens and autoimmune diseases. Annals of the New York Academy of Sciences, 2006, 1089.1: 538-547.‏

Deane KD, Holers VM. Rheumatoid arthritis pathogenesis, prediction, and prevention: an emerging paradigm shift. Arthritis & Rheumatology, 2021, 73.2: 181-193

Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology, 2012, 51.suppl_5: v3-v11.‏

Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. The lancet, 2007, 370.9602: 1861-1874

Weyand CM, Hicok KC, Conn DL, Goronzy JJ. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Annals of internal medicine, 1992, 117.10: 801-806.‏

Klareskog L, Padyukov L, Alfredsson L. Smoking as a trigger for inflammatory rheumatic diseases. Current opinion in rheumatology, 2007, 19.1: 49-54

Goemaere S, Ackerman C, Goethals K, De Keyser F, Van der Straeten C,Verbruggen G, et al. Onset of symptoms of rheumatoid arthritis in relation to age, sex and menopausal transition. The Journal of rheumatology, 1990, 17.12: 1620-1622.‏

Jethwa H, Lam S, Smith C, Giles I. Does rheumatoid arthritis really improve during pregnancy? A systematic review and metaanalysis. The Journal of rheumatology, 2019, 46.3: 245-250.‏

Pikwer, M. Hormonal factors in rheumatoid arthritis–Their impact on disease risk and severity. 2012

Pikwer, M., Giwercman, A., Bergström, U., Nilsson, J. Å., Jacobsson, L. T., & Turesson, C. Association between testosterone levels and risk of future rheumatoid arthritis in men: a population-based case–control study. Annals of the rheumatic diseases, 2014, 73.3: 573-579.‏

Hughes GC, Choubey D. Modulation of autoimmune rheumatic diseases by oestrogen and progesterone. Nature Reviews Rheumatology, 2014, 10.12: 740-751.‏

Cutolo M. Androgens in rheumatoid arthritis: when are they effectors?. Arthritis research & therapy, 2009, 11: 1-3.‏

Castagnetta LA, Carruba G, Granata OM, Stefano R, Miele M, Schmidt M, Cutolo M, Straub RH. Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis. The Journal of rheumatology, 2003, 30.12: 2597-2605.‏

Stark K, Straub RH, Rovensky J, Blazickova S, Eiselt G, Schmidt M. CYB5A polymorphism increases androgens and reduces risk of rheumatoid arthritis in women. Arthritis research & therapy, 2015, 17: 1-11.‏

Van Riel P, van de Putte L, Bardin T, Prum B, Buchegger-Podbielski U, Emmrich F, Melchers I, Corne-lis F, Ahnert P. Association of the X-chromosomal genes TIMP1 and IL9R with rheumatoid arthritis. The Journal of rheumatology, 2009, 36.10: 2149-2157.

Jawaheer D, Olsen J, Hetland ML.Sex differences in response to anti-tumor necrosis factor therapy in early and established rheumatoid arthritis—results from the DANBIO registry. The Journal of rheumatology, 2012, 39.1: 46-53.‏

Ostensen M, Villiger PM. The remission of rheumatoid arthritis during pregnancy. In: Seminars in immunopathology. Springer-Verlag, 2007. p. 185-191.

S. Oertelt-Prigione. The influence of sex and gender on the immune response. Autoimmunity reviews, 2012, 11.6-7: A479-A485.‏

I.A. Buskiewicz, S.A. Huber, D. Fairweather. Sex hormone receptor expression in the immune system. In: Sex differences in physiology. Academic Press, 2016. p. 45-60.‏

W.P. Benten, M. Lieberherr, O. Stamm, C. Wrehlke, Z. Guo, F. Wunderlich. Testosterone signaling through internalizable surface receptors in androgen receptor-free macrophages. Molecular biology of the cell, 1999, 10.10: 3113-3123.‏

CutoloM, Straub RH. Sex steroids and autoimmune rheumatic diseases: state of the art. Nature Reviews Rheumatology, 2020, 16.11: 628-644.‏

Pauklin S, Sernandez IV, Bachmann G, Ramiro AR, Petersen-Mahrt SK. Estrogen directly activates AID transcription and function. Journal of Experimental Medicine, 2009, 206.1: 99-111.‏

Dragin N, Bismuth J, Cizeron-Clairac G, Biferi MG, Berthault C, Serraf A, et al. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. The Journal of clinical investigation, 2016, 126.4: 1525-1537.

Dupuis ML, Conti F, Maselli A, Pagano MT, Ruggieri A, Anticoli S, et al. The natural agonist of estrogen receptor β silibinin plays an immunosuppressive role representing a potential therapeutic tool in rheumatoid arthritis. Frontiers in immunology, 2018, 9: 1903.‏

TongWW, Zhang C, Hong T, Liu DH,Wang C, Li J, et al. Silibinin alleviates inflammation and induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes and has a therapeutic effect on arthritis in rats. Scientific reports, 2018, 8.1: 3241.‏

Mattsson R, Mattsson A, Holmdahl R, Whyte A, Rook GA. Maintained pregnancy levels of oestrogen afford complete protection from post‐partum exacerbation of collagen‐induced arthritis. Clinical & Experimental Immunology, 1991, 85.1: 41-47.‏

Subramanian S, Tovey M, Afentoulis M, Krogstad A, Vandenbark AA,Offner H. Ethinyl estradiol treats collagen-induced arthritis in DBA/1LacJ mice by inhibiting the production of TNF-α and IL-1β. Clinical Immunology, 2005, 115.2: 162-172.‏

Inoue K, Inoue E, Imai Y. Female sex hormones ameliorate arthritis in SKG mice. Biochemical and Biophysical Research Communications, 2013, 434.4: 740-745.‏

CutoloM, Straub RH. Sex steroids and autoimmune rheumatic diseases: state of the art. Nature Reviews Rheumatology, 2020, 16.11: 628-644.‏

Correale J, Arias M, Gilmore W. Steroid hormone regulation of cytokine secretion by proteolipid protein-specific CD4+ T cell clones isolated from multiple sclerosis patients and normal control subjects. The Journal of Immunology, 1998, 161.7: 3365-3374.‏

Szereday L, Varga P, Szekeres-Bartho J. Cytokine production by lymphocytes in pregnancy. American Journal of Reproductive Immunology, 1997, 38.6: 418-422.‏

Lee JH, Lydon JP, Kim CH. Progesterone suppresses the m TOR pathway and promotes generation of induced regulatory T cells with increased stability. European journal of immunology, 2012, 42.10: 2683-2696.‏

Lee JH, Ulrich B, Cho J, Park J, Kim CH. Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. The Journal of Immunology, 2011, 187.4: 1778-1787.‏

Aristimuno C, Teijeiro R, Valor L, Alonso B, Tejera-Alhambra M, de Andres C, et al. Sex-hormone receptors pattern on regulatory T-cells: clinical implications for multiple sclerosis. Clinical and experimental medicine, 2012, 12: 247-255.‏

Hellberg S, Raffetseder J, Rundquist O, Magnusson R, PapapavlouG, Jenmalm MC, et al. Progesterone dampens immune responses in in vitro activated CD4+ T cells and affects genes associated with autoimmune diseases that improve during pregnancy. Frontiers in Immunology, 2021, 12: 672168.‏

Gubbels Bupp MR, Jorgensen TN. Androgen-induced immunosuppression. Frontiers in immunology, 2018, 9: 370132.‏

Cutolo M, Wilder RL. Different roles for androgens and estrogens in the susceptibility to autoimmune rheumatic diseases. Rheumatic Disease Clinics of North America, 2000, 26.4: 825-839.‏

Zhu ML, Bakhru P, Conley B, Nelson JS, Free M, Martin A, et al. Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nature communications, 2016, 7.1: 11350.‏

CHENG, Lulu; WANG, Siyu. Lower serum testosterone is associated with increased likelihood of arthritis. Scientific Reports, 2023, 13.1: 19241.

RAINE, Charles and GILES, Ian. What is the impact of sex hormones on the pathogenesis of rheumatoid arthritis?. Frontiers in Medicine, 2022, 9: 909879.‏

ROMO-GARCÍA, Maria Fernanda, et al. The role of estrogens in rheumatoid arthritis physiopathology. Rheum. Arthritis—Other Perspect. Towards a Better Practice, 2020, 27.‏

CUTOLO, Maurizio and GOTELLI, Emanuele. Complex role of oestrogens in the risk and severity of rheumatoid arthritis in menopause. RMD open, 2023, 9.2.‏

PARK, Eun Hye, et al. Impact of early age at menopause on disease outcomes in postmenopausal women with rheumatoid arthritis: a large observational cohort study of Korean patients with rheumatoid arthritis. RMD open, 2023, 9.1: e002722.‏

DARAGHMEH, Dala N., et al. Female reproductive status and exogenous sex hormone use in rheumatoid arthritis patients treated with tocilizumab and csDMARDs. Rheumatology, 2023, 62.2: 583-595.‏

JIANG, Ling-Qiong, et al. Hormonal and reproductive factors in relation to the risk of rheumatoid arthritis in women: a prospective cohort study with 223 526 participants. RMD open, 2024, 10.1: e003338.‏

GUPTA, Pulin Kumar, et al. Association of Sex Hormones and Androgens with Disease Activity in Premenopausal Females with Rheumatoid Arthritis. Mediterranean Journal of Rheumatology, 2023, 34.2: 152.‏