Sex steroids and autoimmune rheumatic diseases: state of the art

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.