Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Sex steroids and autoimmune rheumatic diseases: state of the art

Abstract

In autoimmune rheumatic diseases, oestrogens can stimulate certain immune responses (including effects on B cells and innate immunity), but can also have dose-related anti-inflammatory effects on T cells, macrophages and other immune cells. By contrast, androgens and progesterone have predominantly immunosuppressive and anti-inflammatory effects. Hormone replacement therapies and oral contraception (and also pregnancy) enhance or decrease the severity of autoimmune rheumatic diseases at a genetic or epigenetic level. Serum androgen concentrations are often low in men and in women with autoimmune rheumatic diseases, suggesting that androgen-like compounds might be a promising therapeutic approach. However, androgen-to-oestrogen conversion (known as intracrinology) is enhanced in inflamed tissues, such as those present in patients with autoimmune rheumatic diseases. In addition, it is becoming evident that the gut microbiota differs between the sexes (known as the microgenderome) and leads to sex-dependent genetic and epigenetic changes in gastrointestinal inflammation, systemic immunity and, potentially, susceptibility to autoimmune or inflammatory rheumatic diseases. Future clinical research needs to focus on the therapeutic use of androgens and progestins or their downstream signalling cascades and on new oestrogenic compounds such as tissue-selective oestrogen complex to modulate altered immune responses.

Key points

  • Oestrogens have both pro-inflammatory and anti-inflammatory effects, acting as stimulators of B cell-mediated immune responses but inhibitors of pro-inflammatory macrophages and some T cells.

  • In contrast to oestrogens, androgens and progesterone have immunosuppressive and anti-inflammatory effects.

  • In men and postmenopausal women with rheumatic diseases, increased androgen-to-oestrogen conversion in inflamed tissues and local oestrogen metabolite synthesis support disease.

  • Pregnancy, sex hormone replacement therapies and oral contraceptives can negatively or positively affect the severity of autoimmune rheumatic diseases, depending on the respective predominance of oestrogens or androgens (and progesterone).

  • Sex-dependent differences in gut microbiota may lead to genetic or epigenetic changes in local gastrointestinal inflammation, systemic immunity and susceptibility to a range of rheumatic diseases.

  • Therapies with androgens and progestins, selective oestrogen receptor modulators and tissue-selective oestrogen complex need to be tested more rigorously in autoimmune rheumatic diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Effects of oestrogens and androgens on immune function.
Fig. 2: Effects of progesterone on immune function.

Similar content being viewed by others

References

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

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Benagiano, M., Bianchi, P., D’Elios, M. M., Brosens, I. & Benagiano, G. Autoimmune diseases: role of steroid hormones. Best Pract. Res. Clin. Obstet. Gynaecol. 60, 24–34 (2019).

    PubMed  Google Scholar 

  4. Lockshin, M. D. Nonhormonal explanations for sex discrepancy in human illness. Ann. N. Y. Acad. Sci. 1193, 22–24 (2010).

    PubMed  Google Scholar 

  5. Christou, E. A. A., Banos, A., Kosmara, D., Bertsias, G. K. & Boumpas, D. T. Sexual dimorphism in SLE: above and beyond sex hormones. Lupus 28, 3–10 (2019).

    CAS  PubMed  Google Scholar 

  6. Lambert, N. C. Nonendocrine mechanisms of sex bias in rheumatic diseases. Nat. Rev. Rheumatol. 15, 673–686 (2019).

    PubMed  Google Scholar 

  7. Cutolo, M. & Wilder, R. L. Different roles for androgens and estrogens in the susceptibility to autoimmune rheumatic diseases. Rheum. Dis. Clin. North Am. 26, 825–839 (2000).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  9. Cohen-Solal, J. F. et al. Hormonal regulation of B-cell function and systemic lupus erythematosus. Lupus 17, 528–532 (2008).

    CAS  PubMed  Google Scholar 

  10. Cutolo, M. Androgens in rheumatoid arthritis: when are they effectors? Arthritis Res. Ther. 11, 126 (2009).

    PubMed  PubMed Central  Google Scholar 

  11. 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. 335, 14–29 (2011).

    CAS  PubMed  Google Scholar 

  12. Cutolo, M., Sulli, A. & Straub, R. H. Estrogen metabolism and autoimmunity. Autoimmun. Rev. 11, A460–A464 (2012).

    CAS  PubMed  Google Scholar 

  13. Konttinen, Y. T. et al. Sex steroids in Sjögren’s syndrome. J. Autoimmun. 39, 49–56 (2012).

    CAS  PubMed  Google Scholar 

  14. Hughes, G. C. Progesterone and autoimmune disease. Autoimmun. Rev. 11, A502–A514 (2012).

    CAS  PubMed  Google Scholar 

  15. Hughes, G. C. & Choubey, D. Modulation of autoimmune rheumatic diseases by oestrogen and progesterone. Nat. Rev. Rheumatol. 10, 740–751 (2014).

    CAS  PubMed  Google Scholar 

  16. Trigunaite, A., Dimo, J. & Jorgensen, T. N. Suppressive effects of androgens on the immune system. Cell Immunol. 294, 87–94 (2015).

    CAS  PubMed  Google Scholar 

  17. Gubbels Bupp, M. R. Sex, the aging immune system, and chronic disease. Cell. Immunol. 294, 102–110 (2015).

    CAS  PubMed  Google Scholar 

  18. Lahita, R. G. The immunoendocrinology of systemic lupus erythematosus. Clin. Immunol. 172, 98–100 (2016).

    CAS  PubMed  Google Scholar 

  19. Traish, A., Bolanos, J., Nair, S., Saad, F. & Morgentaler, A. Do androgens modulate the pathophysiological pathways of inflammation? Appraising the contemporary evidence. J. Clin. Med. 7, 549 (2018).

    PubMed Central  Google Scholar 

  20. Gubbels Bupp, M. R. & Jorgensen, T. N. Androgen-induced immunosuppression. Front. Immunol. 9, 794 (2018).

    PubMed  PubMed Central  Google Scholar 

  21. Szekeres-Bartho, J. & Schindler, A. E. Progestogens and immunology. Best Pract. Res. Clin. Obstet. Gynaecol. 60, 17–23 (2019).

    CAS  PubMed  Google Scholar 

  22. Castagnetta, L. A. et al. Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis. J. Rheumatol. 30, 2597–2605 (2003).

    CAS  PubMed  Google Scholar 

  23. Olsen, N. J. & Kovacs, W. J. Gonadal steroids and immunity. Endocr. Rev. 17, 369–384 (1996).

    CAS  PubMed  Google Scholar 

  24. Sanchez-Maldonado, J. M. et al. Steroid hormone-related polymorphisms associate with the development of bone erosions in rheumatoid arthritis and help to predict disease progression: results from the REPAIR consortium. Sci. Rep. 9, 14812 (2019).

    PubMed  PubMed Central  Google Scholar 

  25. Xie, Q. M. et al. Association of oestrogen receptor alpha gene polymorphisms with systemic lupus erythematosus risk: an updated meta-analysis. Microb. Pathog. 127, 352–358 (2019).

    CAS  PubMed  Google Scholar 

  26. Lewis, M. J. et al. UBE2L3 polymorphism amplifies NF-κB activation and promotes plasma cell development, linking linear ubiquitination to multiple autoimmune diseases. Am. J. Hum. Genet. 96, 221–234 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Verma, S. et al. The ubiquitin-conjugating enzyme UBCH7 acts as a coactivator for steroid hormone receptors. Mol. Cell Biol. 24, 8716–8726 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Canet, L. M. et al. Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients. Pharmacogenomics J. 19, 83–96 (2019).

    CAS  PubMed  Google Scholar 

  29. Stark, K. et al. CYB5A polymorphism increases androgens and reduces risk of rheumatoid arthritis in women. Arthritis Res. Ther. 17, 56 (2015).

    PubMed  PubMed Central  Google Scholar 

  30. Plenge, R. M. et al. TRAF1-C5 as a risk locus for rheumatoid arthritis — a genomewide study. N. Engl. J. Med. 357, 1199–1209 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

    Google Scholar 

  32. Jaaskelainen, J. Molecular biology of androgen insensitivity. Mol. Cell. Endocrinol. 352, 4–12 (2012).

    CAS  PubMed  Google Scholar 

  33. Yu, S. F. et al. Association of tri-nucleotide (CAG and GGC) repeat polymorphism of androgen receptor gene in Taiwanese women with refractory or remission rheumatoid arthritis. Clin. Rheumatol. 26, 2051 (2007).

    CAS  PubMed  Google Scholar 

  34. 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).

    PubMed  PubMed Central  Google Scholar 

  35. Dziedziejko, V. et al. CAG repeat polymorphism in the androgen receptor gene in women with rheumatoid arthritis. J. Rheumatol. 39, 10–17 (2012).

    CAS  PubMed  Google Scholar 

  36. Lo, S. F. et al. Androgen receptor gene polymorphism and rheumatoid arthritis in Taiwan. Clin. Exp. Rheumatol. 24, 209–210 (2006).

    PubMed  Google Scholar 

  37. Kawasaki, T. et al. Polymorphic CAG repeats of the androgen receptor gene and rheumatoid arthritis. Ann. Rheum. Dis. 58, 500–502 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Tessnow, A. H., Olsen, N. J. & Kovacs, W. J. Expression of humoral autoimmunity is related to androgen receptor CAG repeat length in men with systemic lupus erythematosus. J. Clin. Immunol. 31, 567–573 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Olsen, N. J., Benko, A. L. & Kovacs, W. J. Variation in the androgen receptor gene exon 1 CAG repeat correlates with manifestations of autoimmunity in women with lupus. Endocr. Connect. 3, 99–109 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Robeva, R. et al. Androgen receptor (CAG)n polymorphism and androgen levels in women with systemic lupus erythematosus and healthy controls. Rheumatol. Int. 33, 2031–2038 (2013).

    CAS  PubMed  Google Scholar 

  41. Yu, S. F. et al. Androgen receptor genetic variants in male patients with ankylosing spondylitis in Taiwan. Int. J. Rheum. Dis. 16, 81–87 (2013).

    CAS  PubMed  Google Scholar 

  42. Mori, K., Ushiyama, T., Inoue, K. & Hukuda, S. Polymorphic CAG repeats of the androgen receptor gene in Japanese male patients with ankylosing spondylitis. Rheumatology 39, 530–532 (2000).

    CAS  PubMed  Google Scholar 

  43. Barlow, D. P. Genomic imprinting: a mammalian epigenetic discovery model. Annu. Rev. Genet. 45, 379–403 (2011).

    CAS  PubMed  Google Scholar 

  44. Liu, H. W. et al. Demethylation within the proximal promoter region of human estrogen receptor alpha gene correlates with its enhanced expression: implications for female bias in lupus. Mol. Immunol. 61, 28–37 (2014).

    CAS  PubMed  Google Scholar 

  45. Wu, Z. et al. 17β-oestradiol enhances global DNA hypomethylation in CD4-positive T cells from female patients with lupus, through overexpression of oestrogen receptor-α-mediated downregulation of DNMT1. Clin. Exp. Dermatol. 39, 525–532 (2014).

    CAS  PubMed  Google Scholar 

  46. Alivernini, S. et al. MicroRNA-155-at the critical interface of innate and adaptive immunity in arthritis. Front. Immunol. 8, 1932 (2017).

    PubMed  Google Scholar 

  47. Dai, R. et al. Suppression of LPS-induced Interferon-γ and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune modulation. Blood 112, 4591–4597 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Dupuis, M. L. et al. The natural agonist of estrogen receptor β silibinin plays an immunosuppressive role representing a potential therapeutic tool in rheumatoid arthritis. Front. Immunol. 9, 1903 (2018).

    PubMed  PubMed Central  Google Scholar 

  49. Tong, W. W. et al. Silibinin alleviates inflammation and induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes and has a therapeutic effect on arthritis in rats. Sci. Rep. 8, 3241 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Khan, D., Dai, R. & Ansar Ahmed, S. Sex differences and estrogen regulation of miRNAs in lupus, a prototypical autoimmune disease. Cell Immunol. 294, 70–79 (2015).

    CAS  PubMed  Google Scholar 

  51. Zan, H., Tat, C. & Casali, P. MicroRNAs in lupus. Autoimmunity 47, 272–285 (2014).

    PubMed  PubMed Central  Google Scholar 

  52. Perniola, R. Twenty years of AIRE. Front. Immunol. 9, 98 (2018).

    PubMed  PubMed Central  Google Scholar 

  53. Dragin, N. et al. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J. Clin. Invest. 126, 1525–1537 (2016).

    PubMed  PubMed Central  Google Scholar 

  54. Pauklin, S., Sernandez, I. V., Bachmann, G., Ramiro, A. R. & Petersen-Mahrt, S. K. Estrogen directly activates AID transcription and function. J. Exp. Med. 206, 99–111 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Jones, B. G. et al. Binding of estrogen receptors to switch sites and regulatory elements in the immunoglobulin heavy chain locus of activated B cells suggests a direct influence of estrogen on antibody expression. Mol. Immunol. 77, 97–102 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Baker, K. F. & Isaacs, J. D. Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Ann. Rheum. Dis. 77, 175–187 (2018).

    CAS  PubMed  Google Scholar 

  57. Joosten, L. A., Abdollahi-Roodsaz, S., Dinarello, C. A., O’Neill, L. & Netea, M. G. Toll-like receptors and chronic inflammation in rheumatic diseases: new developments. Nat. Rev. Rheumatol. 12, 344–357 (2016).

    CAS  PubMed  Google Scholar 

  58. Young, N. A. et al. Estrogen modulation of endosome-associated toll-like receptor 8: an IFNα-independent mechanism of sex-bias in systemic lupus erythematosus. Clin. Immunol. 151, 66–77 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Lee, J. et al. Oestrogen up-regulates interleukin-21 production by CD4+ T lymphocytes in patients with systemic lupus erythematosus. Immunology 142, 573–580 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Smith, S. et al. Estrogen receptor alpha regulates tripartite motif-containing protein 21 expression, contributing to dysregulated cytokine production in systemic lupus erythematosus. Arthritis Rheumatol. 66, 163–172 (2014).

    CAS  PubMed  Google Scholar 

  61. Lee, S. et al. Interleukin-23 drives expansion of Thelper 17 cells through epigenetic regulation by signal transducer and activators of transcription 3 in lupus patients. Rheumatology https://doi.org/10.1093/rheumatology/keaa176 (2020).

    Article  PubMed  Google Scholar 

  62. Scott, J. L. et al. Estrogen receptor alpha deficiency modulates TLR ligand-mediated PDC-TREM expression in plasmacytoid dendritic cells in lupus-prone mice. J. Immunol. 195, 5561–5571 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Xue, L. et al. Estrogen-induced expression of tumor necrosis factor-like weak inducer of apoptosis through ERα accelerates the progression of lupus nephritis. Rheumatology 55, 1880–1888 (2016).

    CAS  PubMed  Google Scholar 

  64. Lu, J. et al. Gene expression of TWEAK/Fn14 and IP-10/CXCR3 in glomerulus and tubulointerstitium of patients with lupus nephritis. Nephrology 16, 426–432 (2011).

    CAS  PubMed  Google Scholar 

  65. Schwartz, N. et al. Urinary TWEAK and the activity of lupus nephritis. J. Autoimmun. 27, 242–250 (2006).

    CAS  PubMed  Google Scholar 

  66. Lubberts, E. The IL-23-IL-17 axis in inflammatory arthritis. Nat. Rev. Rheumatol. 11, 415–429 (2015).

    CAS  PubMed  Google Scholar 

  67. Andersson, A. et al. Estrogen regulates T helper 17 phenotype and localization in experimental autoimmune arthritis. Arthritis Res. Ther. 17, 32 (2015).

    PubMed  PubMed Central  Google Scholar 

  68. Chen, R. Y. et al. Estradiol inhibits Th17 cell differentiation through inhibition of RORγT transcription by recruiting the ERα/REA complex to estrogen response elements of the RORγT promoter. J. Immunol. 194, 4019–4028 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Newcomb, D. C. et al. Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL-23 receptor signaling and IL-17A production in patients with severe asthma. J. Allergy Clin. Immunol. 136, 1025–1034 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Qin, J. et al. Estrogen receptor β activation stimulates the development of experimental autoimmune thyroiditis through up-regulation of Th17-type responses. Clin. Immunol. 190, 41–52 (2018).

    CAS  PubMed  Google Scholar 

  71. Engdahl, C. et al. Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women. Arthritis Res. Ther. 20, 84 (2018).

    PubMed  PubMed Central  Google Scholar 

  72. Zhu, M. L. et al. Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nat. Commun. 7, 11350 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Lu, L., Barbi, J. & Pan, F. The regulation of immune tolerance by FOXP3. Nat. Rev. Immunol. 17, 703–717 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Walecki, M. et al. Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+regulatory T-cells. Mol. Biol. Cell 26, 2845–2857 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Olsen, N. J., Gu, X. & Kovacs, W. J. Bone marrow stromal cells mediate androgenic suppression of B lymphocyte development. J. Clin. Invest. 108, 1697–1704 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Pongratz, G., Straub, R. H., Scholmerich, J., Fleck, M. & Harle, P. Serum BAFF strongly correlates with PsA activity in male patients only — is there a role for sex hormones? Clin. Exp. Rheumatol. 28, 813–819 (2010).

    CAS  PubMed  Google Scholar 

  77. Wilhelmson, A. S. et al. Testosterone is an endogenous regulator of BAFF and splenic B cell number. Nat. Commun. 9, 2067 (2018).

    PubMed  PubMed Central  Google Scholar 

  78. Hill, L., Jeganathan, V., Chinnasamy, P., Grimaldi, C. & Diamond, B. Differential roles of estrogen receptors alpha and beta in control of B-cell maturation and selection. Mol. Med. 17, 211–220 (2011).

    CAS  PubMed  Google Scholar 

  79. Drehmer, M. N., Suterio, D. G., Muniz, Y. C., de Souza, I. R. & Lofgren, S. E. BAFF expression is modulated by female hormones in human immune cells. Biochem. Genet. 54, 722–730 (2016).

    CAS  PubMed  Google Scholar 

  80. U.S. National Library of Medicine. Entrez Gene https://www.ncbi.nlm.nih.gov/gene/5770 (2019).

  81. Kissick, H. T. et al. Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation. Proc. Natl Acad. Sci. USA 111, 9887–9892 (2014).

    CAS  PubMed  Google Scholar 

  82. Wong, A. H., Agrawal, N. & Hughes, G. C. Altered IgG autoantibody levels and CD4+ T cell subsets in lupus-prone Nba2 mice lacking the nuclear progesterone receptor. Autoimmunity 48, 389–401 (2015).

    PubMed  PubMed Central  Google Scholar 

  83. Pauklin, S. & Petersen-Mahrt, S. K. Progesterone inhibits activation-induced deaminase by binding to the promoter. J. Immunol. 183, 1238–1244 (2009).

    CAS  PubMed  Google Scholar 

  84. Giaglis, S. et al. Multimodal regulation of NET formation in pregnancy: progesterone antagonizes the pro-NETotic effect of estrogen and G-CSF. Front. Immunol. 7, 565 (2016).

    PubMed  PubMed Central  Google Scholar 

  85. Taurog, J. D. et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J. Exp. Med. 180, 2359–2364 (1994).

    CAS  PubMed  Google Scholar 

  86. Manfredo Vieira, S. et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science 359, 1156–1161 (2018).

    CAS  PubMed  Google Scholar 

  87. Shamriz, O. et al. Microbiota at the crossroads of autoimmunity. Autoimmun. Rev. 15, 859–869 (2016).

    CAS  PubMed  Google Scholar 

  88. Tanoue, T., Atarashi, K. & Honda, K. Development and maintenance of intestinal regulatory T cells. Nat. Rev. Immunol. 16, 295–309 (2016).

    CAS  PubMed  Google Scholar 

  89. Rizzetto, L., Fava, F., Tuohy, K. M. & Selmi, C. Connecting the immune system, systemic chronic inflammation and the gut microbiome: the role of sex. J. Autoimmun. 92, 12–34 (2018).

    CAS  PubMed  Google Scholar 

  90. Vemuri, R. et al. The microgenderome revealed: sex differences in bidirectional interactions between the microbiota, hormones, immunity and disease susceptibility. Semin. Immunopathol. 41, 265–275 (2019).

    PubMed  Google Scholar 

  91. Ding, T. & Schloss, P. D. Dynamics and associations of microbial community types across the human body. Nature 509, 357–360 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Jaggar, M., Rea, K., Spicak, S., Dinan, T. G. & Cryan, J. F. You’ve got male: sex and the microbiota-gut brain axis across the lifespan. Front. Neuroendocrinol. 56, 100815 (2019).

    PubMed  Google Scholar 

  93. Menon, R. et al. Diet complexity and estrogen receptor beta status affect the composition of the murine intestinal microbiota. Appl. Env. Microbiol. 79, 5763–5773 (2013).

    CAS  Google Scholar 

  94. Andoh, A. Physiological role of gut microbiota for maintaining human health. Digestion 93, 176–181 (2016).

    CAS  PubMed  Google Scholar 

  95. Benedek, G. et al. Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells. J. Neuroimmunol. 310, 51–59 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Markle, J. G. et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084–1088 (2013).

    CAS  PubMed  Google Scholar 

  97. Yurkovetskiy, L. et al. Gender bias in autoimmunity is influenced by microbiota. Immunity 39, 400–412 (2013).

    CAS  PubMed  Google Scholar 

  98. Gomez, A. et al. Loss of sex and age driven differences in the gut microbiome characterize arthritis-susceptible 0401 mice but not arthritis-resistant 0402 mice. PLoS ONE 7, e36095 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Caprioli, M., Carrara, G., Sakellariou, G., Silvagni, E. & Scire, C. A. Influence of aromatase inhibitors therapy on the occurrence of rheumatoid arthritis in women with breast cancer: results from a large population-based study of the Italian Society for Rheumatology. RMD Open 3, e000523 (2017).

    PubMed  PubMed Central  Google Scholar 

  100. Tenti, S., Giordano, N., Cutolo, M., Giannini, F. & Fioravanti, A. Primary antiphospholipid syndrome during aromatase inhibitors therapy: a case report and review of the literature. Medicine 98, e15052 (2019).

    PubMed  PubMed Central  Google Scholar 

  101. Masi, A. T. et al. Lower serum androstenedione levels in pre-rheumatoid arthritis versus normal control women: correlations with lower serum cortisol levels. Autoimmune. Dis. 2013, 593493 (2013).

    PubMed  PubMed Central  Google Scholar 

  102. Heikkila, R. et al. Serum androgen-anabolic hormones and the risk of rheumatoid arthritis. Ann. Rheum. Dis. 57, 281–285 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Pikwer, M. et al. Association between testosterone levels and risk of future rheumatoid arthritis in men: a population-based case-control study. Ann. Rheum. Dis. 73, 573–579 (2014).

    CAS  PubMed  Google Scholar 

  104. Ciaffi, J., van Leeuwen, N. M., Schoones, J. W., Huizinga, T. W. J. & de Vries-Bouwstra, J. K. Sex hormones and sex hormone-targeting therapies in systemic sclerosis: a systematic literature review. Semin. Arthritis Rheum. 50, 140–148 (2020).

    CAS  PubMed  Google Scholar 

  105. Campochiaro, C., Host, L. V., Ong, V. H. & Denton, C. P. Development of systemic sclerosis in transgender females: a case series and review of the literature. Clin. Exp. Rheumatol. 36, 50–52 (2018).

    PubMed  Google Scholar 

  106. Baillargeon, J. et al. Hypogonadism and the risk of rheumatic autoimmune disease. Clin. Rheumatol. 35, 2983–2987 (2016).

    PubMed  PubMed Central  Google Scholar 

  107. Seminog, O. O., Seminog, A. B., Yeates, D. & Goldacre, M. J. Associations between Klinefelter’s syndrome and autoimmune diseases: English national record linkage studies. Autoimmunity 48, 125–128 (2015).

    CAS  PubMed  Google Scholar 

  108. Pakpoor, J., Goldacre, R. & Goldacre, M. J. Associations between clinically diagnosed testicular hypofunction and systemic lupus erythematosus: a record linkage study. Clin. Rheumatol. 37, 559–562 (2018).

    PubMed  Google Scholar 

  109. Chighizola, C. & Meroni, P. L. The role of environmental estrogens and autoimmunity. Autoimmun. Rev. 11, A493–A501 (2012).

    CAS  PubMed  Google Scholar 

  110. Warner, G. R., Mourikes, V. E., Neff, A. M., Brehm, E. & Flaws, J. A. Mechanisms of action of agrochemicals acting as endocrine disrupting chemicals. Mol. Cell Endocrinol. 502, 110680 (2019).

    PubMed  Google Scholar 

  111. Aljadeff, G., Longhi, E. & Shoenfeld, Y. Bisphenol A: a notorious player in the mosaic of autoimmunity. Autoimmunity 51, 370–377 (2018).

    CAS  PubMed  Google Scholar 

  112. Jayasuriya, N. A. et al. A lower maternal cortisol-to-cortisone ratio precedes clinical diagnosis of preterm and term preeclampsia by many weeks. J. Clin. Endocrinol. Metab. 104, 2355–2366 (2019).

    PubMed  PubMed Central  Google Scholar 

  113. Borba, V. V., Zandman-Goddard, G. & Shoenfeld, Y. Exacerbations of autoimmune diseases during pregnancy and postpartum. Best Pract. Res. Clin. Endocrinol. Metab. 33, 101321 (2019).

    CAS  PubMed  Google Scholar 

  114. Ursin, K., Lydersen, S., Skomsvoll, J. F. & Wallenius, M. Disease activity during and after pregnancy in women with axial spondyloarthritis: a prospective multicentre study. Rheumatology 57, 1064–1071 (2018).

    PubMed  Google Scholar 

  115. Ince-Askan, H., Hazes, J. M. W. & Dolhain, R. Identifying clinical factors associated with low disease activity and remission of rheumatoid arthritis during pregnancy. Arthritis Care Res. 69, 1297–1303 (2017).

    CAS  Google Scholar 

  116. Zbinden, A., van den Brandt, S., Ostensen, M., Villiger, P. M. & Forger, F. Risk for adverse pregnancy outcome in axial spondyloarthritis and rheumatoid arthritis: disease activity matters. Rheumatology 57, 1235–1242 (2018).

    PubMed  Google Scholar 

  117. Davis-Porada, J. et al. Low frequency of flares during pregnancy and post-partum in stable lupus patients. Arthritis Res. Ther. 22, 52 (2020).

    PubMed  PubMed Central  Google Scholar 

  118. Chen, D. et al. Fetal and maternal outcomes of planned pregnancy in patients with systemic lupus erythematosus: a retrospective multicenter study. J. Immunol. Res. 2018, 2413637 (2018).

    PubMed  PubMed Central  Google Scholar 

  119. Costenbader, K. H., Feskanich, D., Stampfer, M. J. & Karlson, E. W. Reproductive and menopausal factors and risk of systemic lupus erythematosus in women. Arthritis Rheum. 56, 1251–1262 (2007).

    PubMed  Google Scholar 

  120. Sammaritano, L. R. Menopause in patients with autoimmune diseases. Autoimmun. Rev. 11, A430–A436 (2012).

    PubMed  Google Scholar 

  121. Pfeifer, E. C., Crowson, C. S., Amin, S., Gabriel, S. E. & Matteson, E. L. The influence of early menopause on cardiovascular risk in women with rheumatoid arthritis. J. Rheumatol. 41, 1270–1275 (2014).

    PubMed  PubMed Central  Google Scholar 

  122. Wong, L. E. et al. Effect of age at menopause on disease presentation in early rheumatoid arthritis: results from the Canadian Early Arthritis Cohort. Arthritis Care Res. 67, 616–623 (2015).

    Google Scholar 

  123. Benagiano, G., Benagiano, M., Bianchi, P., D’Elios, M. M. & Brosens, I. Contraception in autoimmune diseases. Best Pract. Res. Clin. Obstet. Gynaecol. 60, 111–123 (2019).

    PubMed  Google Scholar 

  124. Buyon, J. P. et al. The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann. Intern. Med. 142, 953–962 (2005).

    CAS  PubMed  Google Scholar 

  125. Roman-Blas, J. A., Castaneda, S., Cutolo, M. & Herrero-Beaumont, G. Efficacy and safety of a selective estrogen receptor β agonist, ERB-041, in patients with rheumatoid arthritis: a 12-week, randomized, placebo-controlled, phase II study. Arthritis Care Res. 62, 1588–1593 (2010).

    CAS  Google Scholar 

  126. van Vollenhoven, R. F. et al. The selective estrogen receptor alpha agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: a phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine. Arthritis Rheum. 62, 351–358 (2010).

    PubMed  Google Scholar 

  127. Abdou, N. I., Rider, V., Greenwell, C., Li, X. & Kimler, B. F. Fulvestrant (Faslodex), an estrogen selective receptor downregulator, in therapy of women with systemic lupus erythematosus. clinical, serologic, bone density, and T cell activation marker studies: a double-blind placebo-controlled trial. J. Rheumatol. 35, 797 (2008).

    CAS  PubMed  Google Scholar 

  128. Adami, G. et al. Osteoporosis in rheumatic diseases. Int. J. Mol. Sci. 20, 5867 (2019).

    CAS  PubMed Central  Google Scholar 

  129. Schett, G., Saag, K. G. & Bijlsma, J. W. From bone biology to clinical outcome: state of the art and future perspectives. Ann. Rheum. Dis. 69, 1415–1419 (2010).

    CAS  PubMed  Google Scholar 

  130. Ellis, A. J., Hendrick, V. M., Williams, R. & Komm, B. S. Selective estrogen receptor modulators in clinical practice: a safety overview. Expert Opin. Drug Saf. 14, 921–934 (2015).

    CAS  PubMed  Google Scholar 

  131. Andersson, A. et al. Roles of activating functions 1 and 2 of estrogen receptor alpha in lymphopoiesis. J. Endocrinol. 236, 99–109 (2018).

    CAS  PubMed  Google Scholar 

  132. Borjesson, A. E. et al. SERMs have substance-specific effects on bone, and these effects are mediated via ERαAF-1 in female mice. Am. J. Physiol. Endocrinol. Metab. 310, E912–E918 (2016).

    PubMed  PubMed Central  Google Scholar 

  133. Börjesson, A. E. et al. Roles of transactivating functions 1 and 2 of estrogen receptor-α in bone. Proc. Natl Acad. Sci. USA 108, 6288–6293 (2011).

    PubMed  Google Scholar 

  134. Bernardi, A. I. et al. Effects of lasofoxifene and bazedoxifene on B cell development and function. Immun. Inflamm. Dis. 2, 214–225 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Mirkin, S. & Komm, B. S. Tissue-selective estrogen complexes for postmenopausal women. Maturitas 76, 213–220 (2013).

    CAS  PubMed  Google Scholar 

  136. Nordqvist, J., Bernardi, A., Islander, U. & Carlsten, H. Effects of a tissue-selective estrogen complex on B lymphopoiesis and B cell function. Immunobiology 222, 918–923 (2017).

    CAS  PubMed  Google Scholar 

  137. Andersson, A. et al. Suppression of experimental arthritis and associated bone loss by a tissue-selective estrogen complex. Endocrinology 157, 1013–1020 (2016).

    CAS  PubMed  Google Scholar 

  138. Straub, R. H., Bijlsma, J. W., Masi, A. & Cutolo, M. Role of neuroendocrine and neuroimmune mechanisms in chronic inflammatory rheumatic diseases — the 10-year update. Semin. Arthritis Rheum. 43, 392–404 (2013).

    CAS  PubMed  Google Scholar 

  139. Arver, S. & Lehtihet, M. Current guidelines for the diagnosis of testosterone deficiency. Front. Horm. Res. 37, 5–20 (2009).

    CAS  PubMed  Google Scholar 

  140. Cutolo, M., Balleari, E., Giusti, M., Intra, E. & Accardo, S. Androgen replacement therapy in male patients with rheumatoid arthritis. Arthritis Rheum. 34, 1–5 (1991).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Saad, F., Haider, A. & Gooren, L. Hypogonadal men with psoriasis benefit from long-term testosterone replacement therapy — a series of 15 case reports. Andrologia 48, 341–346 (2016).

    CAS  PubMed  Google Scholar 

  143. Porola, P., Straub, R. H., Virkki, L. M., Konttinen, Y. T. & Nordstrom, D. C. Failure of oral DHEA treatment to increase local salivary androgen outputs of female patients with Sjogren’s syndrome. Scand. J. Rheumatol. 40, 387–390 (2011).

    CAS  PubMed  Google Scholar 

  144. Hazelton, R. A., McCruden, A. B., Sturrock, R. D. & Stimson, W. H. Hormonal manipulation of the immune response in systemic lupus erythematosus: a drug trial of an anabolic steroid, 19-nortestosterone. Ann. Rheum. Dis. 42, 155–157 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Lahita, R. G., Cheng, C. Y., Monder, C. & Bardin, C. W. Experience with 19-nortestosterone in the therapy of systemic lupus erythematosus: worsened disease after treatment with 19-nortestosterone in men and lack of improvement in women. J. Rheumatol. 19, 547–555 (1992).

    CAS  PubMed  Google Scholar 

  146. Olsen, N. J. & Kovacs, W. J. Case report: testosterone treatment of systemic lupus erythematosus in a patient with Klinefelter’s syndrome. Am. J. Med. Sci. 310, 158–160 (1995).

    CAS  PubMed  Google Scholar 

  147. Crosbie, D., Black, C., McIntyre, L., Royle, P. L. & Thomas, S. Dehydroepiandrosterone for systemic lupus erythematosus. Cochrane Database Syst. Rev. 4, CD005114 (2007).

    Google Scholar 

  148. Letchumanan, P. & Thumboo, J. Danazol in the treatment of systemic lupus erythematosus: a qualitative systematic review. Semin. Arthritis Rheum. 40, 298–306 (2011).

    CAS  PubMed  Google Scholar 

  149. Jungers, P. et al. Influence of oral contraceptive therapy on the activity of systemic lupus erythematosus. Arthritis Rheum. 25, 618–623 (1982).

    CAS  PubMed  Google Scholar 

  150. Chabbert-Buffet, N. et al. Pregnane progestin contraception in systemic lupus erythematosus: a longitudinal study of 187 patients. Contraception 83, 229–237 (2011).

    CAS  PubMed  Google Scholar 

  151. Rivier, C. Neuroendocrine effects of cytokines in the rat. Rev. Neurosci. 4, 223–237 (1993).

    CAS  PubMed  Google Scholar 

  152. Rivier, C. & Vale, W. In the rat, interleukin-1 alpha acts at the level of the brain and the gonads to interfere with gonadotropin and sex steroid secretion. Endocrinology 124, 2105–2109 (1989).

    CAS  PubMed  Google Scholar 

  153. Masi, A. T., Josipovic, D. B. & Jefferson, W. E. Low adrenal androgenic-anabolic steroids in women with rheumatoid arthritis (RA): gas-liquid chromatographic studies of RA patients and matched normal control women indicating decreased 11-deoxy-17-ketosteroid excretion. Semin. Arthritis Rheum. 14, 1–23 (1984).

    CAS  PubMed  Google Scholar 

  154. Lahita, R. G., Bradlow, H. L., Ginzler, E., Pang, S. & New, M. Low plasma androgens in women with systemic lupus erythematosus. Arthritis Rheum. 30, 241–248 (1987).

    CAS  PubMed  Google Scholar 

  155. Cutolo, M., Balleari, E., Giusti, M., Monachesi, M. & Accardo, S. Sex hormone status of male patients with rheumatoid arthritis: evidence of low serum concentrations of testosterone at baseline and after human chorionic gonadotropin stimulation. Arthritis Rheum. 31, 1314–1317 (1988).

    CAS  PubMed  Google Scholar 

  156. Bijlsma, J. W., Cutolo, M., Masi, A. T. & Chikanza, I. C. The neuroendocrine immune basis of rheumatic diseases. Immunol. Today 20, 298–301 (1999).

    CAS  PubMed  Google Scholar 

  157. Straub, R. H. & Cutolo, M. Involvement of the hypothalamic–pituitary–adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role. Arthritis Rheum. 44, 493–507 (2001).

    CAS  PubMed  Google Scholar 

  158. Schmidt, M., Kreutz, M., Löffler, G., Schölmerich, J. & Straub, R. H. Conversion of dehydroepiandrosterone to downstream steroid hormones in macrophages. J. Endocrinol. 164, 161–169 (2000).

    CAS  PubMed  Google Scholar 

  159. Lahita, R. G., Bradlow, H. L., Kunkel, H. G. & Fishman, J. Alterations of estrogen metabolism in systemic lupus erythematosus. Arthritis Rheum. 22, 1195–1198 (1979).

    CAS  PubMed  Google Scholar 

  160. Weidler, C. et al. Patients with rheumatoid arthritis and systemic lupus erythematosus have increased renal excretion of mitogenic estrogens in relation to endogenous antiestrogens. J. Rheumatol. 31, 489–494 (2004).

    CAS  PubMed  Google Scholar 

  161. Herrmann, M., Schölmerich, J. & Straub, R. H. Influence of cytokines and growth factors on distinct steroidogenic enzymes in vitro: a short tabular data collection. Ann. N. Y. Acad. Sci. 966, 166–186 (2002).

    CAS  PubMed  Google Scholar 

  162. Straub, R. H. et al. Anti-interleukin-6 receptor antibody therapy favors adrenal androgen secretion in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled study. Arthritis Rheum. 54, 1778–1785 (2006).

    CAS  PubMed  Google Scholar 

  163. Straub, R. H., Cutolo, M., Buttgereit, F. & Pongratz, G. Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J. Intern. Med. 267, 543–560 (2010).

    CAS  PubMed  Google Scholar 

  164. Straub, R. H. The brain and immune system prompt energy shortage in chronic inflammation and ageing. Nat. Rev. Rheumatol. 13, 743–751 (2017).

    CAS  PubMed  Google Scholar 

  165. Browne, H. et al. Assessment of ovarian function with anti-Müllerian hormone in systemic lupus erythematosus patients undergoing hematopoietic stem cell transplant. Fertil. Steril. 91, 1529–1532 (2009).

    CAS  PubMed  Google Scholar 

  166. Brouwer, J., Laven, J. S., Hazes, J. M., Schipper, I. & Dolhain, R. J. Levels of serum anti-Müllerian hormone, a marker for ovarian reserve, in women with rheumatoid arthritis. Arthritis Care Res. 65, 1534–1538 (2013).

    CAS  Google Scholar 

  167. Clowse, M. E. et al. Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener’s). Arthritis Care Res. 63, 1777–1781 (2011).

    CAS  Google Scholar 

  168. Mont’Alverne, A. R. et al. Diminished ovarian reserve in Behçet’s disease patients. Clin. Rheumatol. 34, 179–183 (2015).

    PubMed  Google Scholar 

  169. de Souza, F. H. et al. Reduction of ovarian reserve in adult patients with dermatomyositis. Clin. Exp. Rheumatol. 33, 44–49 (2015).

    PubMed  Google Scholar 

  170. Henes, M. et al. Ovarian reserve alterations in premenopausal women with chronic inflammatory rheumatic diseases: impact of rheumatoid arthritis, Behçet’s disease and spondyloarthritis on anti-Müllerian hormone levels. Rheumatology 54, 1709–1712 (2015).

    CAS  PubMed  Google Scholar 

  171. de Souza, F. H. et al. Reduced ovarian reserve in patients with adult polymyositis. Clin. Rheumatol. 34, 1795–1799 (2015).

    PubMed  Google Scholar 

  172. Nelson, J. L. et al. Fecundity before disease onset in women with rheumatoid arthritis. Arthritis Rheum. 36, 7–14 (1993).

    CAS  PubMed  Google Scholar 

  173. Silva, C. A., Bonfa, E. & Ostensen, M. Maintenance of fertility in patients with rheumatic diseases needing antiinflammatory and immunosuppressive drugs. Arthritis Care Res. 62, 1682–1690 (2010).

    Google Scholar 

  174. Provost, M., Eaton, J. L. & Clowse, M. E. Fertility and infertility in rheumatoid arthritis. Curr. Opin. Rheumatol. 26, 308–314 (2014).

    PubMed  Google Scholar 

  175. Ostensen, M. Rheumatoid arthritis: the effect of RA and medication on female fertility. Nat. Rev. Rheumatol. 10, 518–519 (2014).

    PubMed  Google Scholar 

  176. Brouwer, J., Hazes, J. M., Laven, J. S. & Dolhain, R. J. Fertility in women with rheumatoid arthritis: influence of disease activity and medication. Ann. Rheum. Dis. 74, 1836–1841 (2015).

    CAS  PubMed  Google Scholar 

  177. Chatzimeletiou, K. et al. Fertility potential in a man with ankylosing spondylitis as revealed by semen analysis by light, electron and fluorescence microscopy. SAGE Open Med. Case Rep. https://doi.org/10.1177/2050313X18759898 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Fan, D. et al. Male sexual dysfunction and ankylosing spondylitis: a systematic review and metaanalysis. J. Rheumatol. 42, 252–257 (2015).

    PubMed  Google Scholar 

  179. Jaeger, V. K. & Walker, U. A. Erectile dysfunction in systemic sclerosis. Curr. Rheumatol. Rep. 18, 49 (2016).

    PubMed  Google Scholar 

  180. Luo, L. et al. Gout is associated with elevated risk of erectile dysfunction: a systematic review and meta-analysis. Rheumatol. Int. 39, 1527–1535 (2019).

    PubMed  Google Scholar 

  181. Moraes, A. J. et al. Minor sperm abnormalities in young male post-pubertal patients with juvenile dermatomyositis. Braz. J. Med. Biol. Res. 41, 1142–1147 (2008).

    CAS  PubMed  Google Scholar 

  182. Rabelo-Junior, C. N. et al. Penile alterations with severe sperm abnormalities in antiphospholipid syndrome associated with systemic lupus erythematosus. Clin. Rheumatol. 32, 109–113 (2013).

    PubMed  Google Scholar 

  183. Soares, P. M. et al. Gonad evaluation in male systemic lupus erythematosus. Arthritis Rheum. 56, 2352–2361 (2007).

    PubMed  Google Scholar 

  184. Taylan, A. & Birlik, M. Parenchymal neuro-Behçet disease with erectile dysfunction and micturition disturbances: case report and literature review. Rheumatol. Int. 38, 149–152 (2018).

    PubMed  Google Scholar 

  185. Villiger, P. M. et al. Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis. Ann. Rheum. Dis. 69, 1842–1844 (2010).

    CAS  PubMed  Google Scholar 

  186. Puchner, R., Danninger, K., Puchner, A. & Pieringer, H. Impact of TNF-blocking agents on male sperm characteristics and pregnancy outcomes in fathers exposed to TNF-blocking agents at time of conception. Clin. Exp. Rheumatol. 30, 765–767 (2012).

    PubMed  Google Scholar 

  187. Straub, R. H. & Schradin, C. Chronic inflammatory systemic diseases: an evolutionary trade-off between acutely beneficial but chronically harmful programs. Evol. Med. Public. Health 2016, 37–51 (2016).

    PubMed  PubMed Central  Google Scholar 

  188. Simard, J. F. et al. Perinatal factors and adult-onset lupus. Arthritis Rheum. 59, 1155–1161 (2008).

    PubMed  PubMed Central  Google Scholar 

  189. Ulff-Moller, C. J., Jorgensen, K. T., Pedersen, B. V., Nielsen, N. M. & Frisch, M. Reproductive factors and risk of systemic lupus erythematosus: nationwide cohort study in Denmark. J. Rheumatol. 36, 1903–1909 (2009).

    PubMed  Google Scholar 

  190. Rojas-Villarraga, A., Torres-Gonzalez, J. V. & Ruiz-Sternberg, A. M. Safety of hormonal replacement therapy and oral contraceptives in systemic lupus erythematosus: a systematic review and meta-analysis. PLoS ONE 9, e104303 (2014).

    PubMed  PubMed Central  Google Scholar 

  191. Washio, M. et al. Risk factors for development of systemic lupus erythematosus among Japanese females: medical history and reproductive factors. Int. J. Rheum. Dis. 20, 76–83 (2017).

    PubMed  Google Scholar 

  192. Tarvin, S. E. & O’Neil, K. M. Systemic lupus erythematosus, Sjogren syndrome, and mixed connective tissue disease in children and adolescents. Pediatr. Clin. North. Am. 65, 711–737 (2018).

    PubMed  Google Scholar 

  193. Lateef, A. & Petri, M. Hormone replacement and contraceptive therapy in autoimmune diseases. J. Autoimmun. 38, J170–J176 (2012).

    CAS  PubMed  Google Scholar 

  194. Petri, M. et al. Combined oral contraceptives in women with systemic lupus erythematosus. N. Engl. J. Med. 353, 2550–2558 (2005).

    CAS  PubMed  Google Scholar 

  195. Mostafavi, B. et al. Perinatal characteristics and risk of developing primary Sjogren’s syndrome: a case-control study. J. Rheumatol. 32, 665–668 (2005).

    PubMed  Google Scholar 

  196. Harris, V. M. et al. Klinefelter’s syndrome (47,XXY) is in excess among men with Sjogren’s syndrome. Clin. Immunol. 168, 25–29 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Ramirez Sepulveda, J. I., Kvarnstrom, M., Brauner, S., Baldini, C. & Wahren-Herlenius, M. Difference in clinical presentation between women and men in incident primary Sjogren’s syndrome. Biol. Sex Differ. 8, 16 (2017).

    PubMed  PubMed Central  Google Scholar 

  198. Ballester, C. et al. Pregnancy and primary Sjögren’s syndrome: management and outcomes in a multicentre retrospective study of 54 pregnancies. Scand. J. Rheumatol. 46, 56–63 (2017).

    CAS  PubMed  Google Scholar 

  199. Gupta, S. & Gupta, N. Sjögren syndrome and pregnancy: a literature review. Perm. J. 21, 16–047 (2017).

    PubMed  PubMed Central  Google Scholar 

  200. McCoy, S. S., Sampene, E. & Baer, A. N. Sjögren’s syndrome is associated with reduced lifetime sex hormone exposure: a case-control study. Arthritis Care Res. 72, 1315–1322 (2019).

    Google Scholar 

  201. d’Elia, H. F. & Carlsten, H. The impact of hormone replacement therapy on humoral and cell-mediated immune responses in vivo in post-menopausal women with rheumatoid arthritis. Scand. J. Immunol. 68, 661–667 (2008).

    PubMed  Google Scholar 

  202. 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).

    PubMed  PubMed Central  Google Scholar 

  203. Holroyd, C. R. & Edwards, C. J. The effects of hormone replacement therapy on autoimmune disease: rheumatoid arthritis and systemic lupus erythematosus. Climacteric 12, 378–386 (2009).

    CAS  PubMed  Google Scholar 

  204. Berglin, E., Kokkonen, H., Einarsdottir, E., Agren, A. & Rantapaa Dahlqvist, S. Influence of female hormonal factors, in relation to autoantibodies and genetic markers, on the development of rheumatoid arthritis in northern Sweden: a case-control study. Scand. J. Rheumatol. 39, 454–460 (2010).

    CAS  PubMed  Google Scholar 

  205. Salliot, C., Bombardier, C., Saraux, A., Combe, B. & Dougados, M. Hormonal replacement therapy may reduce the risk for RA in women with early arthritis who carry HLA-DRB1 *01 and/or *04 alleles by protecting against the production of anti-CCP: results from the ESPOIR cohort. Ann. Rheum. Dis. 69, 1683–1686 (2010).

    CAS  PubMed  Google Scholar 

  206. Orellana, C. et al. Postmenopausal hormone therapy and the risk of rheumatoid arthritis: results from the Swedish EIRA population-based case-control study. Eur. J. Epidemiol. 30, 449–457 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Desai, M. K. & Brinton, R. D. Autoimmune disease in women: endocrine transition and risk across the lifespan. Front. Endocrinol. 10, 265 (2019).

    Google Scholar 

  208. Chen, W. M. Y. et al. The association between gravidity, parity and the risk of developing rheumatoid arthritis: a systematic review and meta-analysis. Semin. Arthritis Rheum. 50, 252–260 (2020).

    PubMed  Google Scholar 

  209. Alpizar-Rodriguez, D., Forger, F., Courvoisier, D. S., Gabay, C. & Finckh, A. Role of reproductive and menopausal factors in functional and structural progression of rheumatoid arthritis: results from the SCQM cohort. Rheumatology 58, 432–440 (2019).

    PubMed  Google Scholar 

  210. Masi, A. T. & Medsger, T. A. Jr. A new look at the epidemiology of ankylosing spondylitis and related syndromes. Clin. Orthop. Relat. Res. 143, 15–29 (1979).

    Google Scholar 

  211. Ostensen, M. & Husby, G. Ankylosing spondylitis and pregnancy. Rheum. Dis. Clin. North Am. 15, 241–254 (1989).

    CAS  PubMed  Google Scholar 

  212. van der Linden, S. & van der Heijde, D. M. Clinical and epidemiologic aspects of ankylosing spondylitis and spondyloarthropathies. Curr. Opin. Rheumatol. 8, 269–274 (1996).

    PubMed  Google Scholar 

  213. Gran, J. T. & Husby, G. Clinical, epidemiologic, and therapeutic aspects of ankylosing spondylitis. Curr. Opin. Rheumatol. 10, 292–298 (1998).

    CAS  PubMed  Google Scholar 

  214. Ostensen, M. et al. Pregnancy in patients with rheumatic disease: anti-inflammatory cytokines increase in pregnancy and decrease post partum. Ann. Rheum. Dis. 64, 839–844 (2005).

    CAS  PubMed  Google Scholar 

  215. Lee, W., Reveille, J. D. & Weisman, M. H. Women with ankylosing spondylitis: a review. Arthritis Rheum. 59, 449–454 (2008).

    PubMed  Google Scholar 

  216. Rovensky, J., Imrich, R., Lazurova, I. & Payer, J. Rheumatic diseases and Klinefelter’s syndrome. Ann. N. Y. Acad. Sci. 1193, 1–9 (2010).

    CAS  PubMed  Google Scholar 

  217. Mahendira, D. et al. Analysis of the effect of the oral contraceptive pill on clinical outcomes in women with ankylosing spondylitis. J. Rheumatol. 41, 1344–1348 (2014).

    PubMed  Google Scholar 

  218. Ostensen, M. et al. State of the art: reproduction and pregnancy in rheumatic diseases. Autoimmun. Rev. 14, 376–386 (2015).

    PubMed  Google Scholar 

  219. Andreoli, L. et al. EULAR recommendations for women’s health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann. Rheum. Dis. 76, 476–485 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Carlsten, H. et al. Estrogen accelerates immune complex glomerulonephritis but ameliorates T cell-mediated vasculitis and sialadenitis in autoimmune MRL lpr/lpr mice. Cell Immunol. 144, 190–202 (1992).

    CAS  PubMed  Google Scholar 

  221. Bernardi, A. I. et al. Selective estrogen receptor modulators in T cell development and T cell dependent inflammation. Immunobiology 220, 1122–1128 (2015).

    CAS  PubMed  Google Scholar 

  222. Capellino, S., Straub, R. H. & Cutolo, M. Aromatase and regulation of the estrogen-to-androgen ratio in synovial tissue inflammation: common pathway in both sexes. Ann. N. Y. Acad. Sci. 1317, 24–31 (2014).

    CAS  PubMed  Google Scholar 

  223. Tengstrand, B., Carlstrom, K. & Hafstrom, I. Gonadal hormones in men with rheumatoid arthritis — from onset through 2 years. J. Rheumatol. 36, 887–892 (2009).

    CAS  PubMed  Google Scholar 

  224. Weidler, C. et al. Tumor necrosis factor inhibits conversion of dehydroepiandrosterone sulfate (DHEAS) to DHEA in rheumatoid arthritis synovial cells: a prerequisite for local androgen deficiency. Arthritis Rheum. 52, 1721–1729 (2005).

    CAS  PubMed  Google Scholar 

  225. Schmidt, M., Weidler, C., Naumann, H., Schölmerich, J. & Straub, R. H. Androgen conversion in osteoarthritis and rheumatoid arthritis synoviocytes — androstenedione and testosterone inhibit estrogen formation and favor production of more potent 5α-reduced androgens. Arthritis Res. Ther. 7, R938–R948 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Straub, R. H., Härle, P., Sarzi-Puttini, P. & Cutolo, M. Tumor necrosis factor-neutralizing therapies improve altered hormone axes: an alternative mode of antiinflammatory action. Arthritis Rheum. 54, 2039–2046 (2006).

    CAS  PubMed  Google Scholar 

  227. Ernestam, S., Hafstrom, I., Werner, S., Carlstrom, K. & Tengstrand, B. Increased DHEAS levels in patients with rheumatoid arthritis after treatment with tumor necrosis factor antagonists: evidence for improved adrenal function. J. Rheumatol. 34, 1451–1458 (2007).

    CAS  PubMed  Google Scholar 

  228. Genest, G., Spitzer, K. A. & Laskin, C. A. Maternal and fetal outcomes in a cohort of patients exposed to tumor necrosis factor inhibitors throughout pregnancy. J. Rheumatol. 45, 1109–1115 (2018).

    PubMed  Google Scholar 

  229. Jawaheer, D., Olsen, J. & Hetland, M. L. Sex differences in response to anti-tumor necrosis factor therapy in early and established rheumatoid arthritis — results from the DANBIO registry. J. Rheumatol. 39, 46–53 (2012).

    PubMed  Google Scholar 

  230. Cutolo, M. et al. Sex hormones modulate the effects of leflunomide on cytokine production by cultures of differentiated monocyte/macrophages and synovial macrophages from rheumatoid arthritis patients. J. Autoimmun. 32, 254–260 (2009).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

M.C. and R.H.S. are members of the EULAR Study Group on Neuroendocrine Immunology of Rheumatic Diseases (NEIRD).

Review criteria

A search for articles published between 2006 and 2020 was performed in PubMed, Embase and the Cochrane library using the following search terms alone and in combination: “oestrogens”, “androgens”, “progesterone”, “steroid hormone”, “immun*”, “inflam*”, “rheum*”, “SLE”, “vasculitis”, “autoimmun*” and “systemic sclerosis”.

Author information

Authors and Affiliations

Authors

Contributions

R.H.S. researched data for this article and wrote the draft. M.C. contributed substantially to discussions of content. Both authors wrote and reviewed or edited the manuscript before submission.

Corresponding author

Correspondence to Maurizio Cutolo.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cutolo, M., Straub, R.H. Sex steroids and autoimmune rheumatic diseases: state of the art. Nat Rev Rheumatol 16, 628–644 (2020). https://doi.org/10.1038/s41584-020-0503-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-020-0503-4

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing