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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.

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

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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”.

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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.

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Correspondence to Maurizio Cutolo.

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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

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