Effects of Female Hormones

The impact that gender and sex hormones have on arthrofibrosis is rarely mentioned despite the fact that hormones significantly affect the immune system [1]. It is well known that women have a heightened inflammatory response to injury and infection compared to men that causes “collateral damage” to the body and results in an increased risk of osteoarthritis and autoimmune disease [2,3]. As a result, 80 % of autoimmune disease occurs in women [2]. However, the stronger immune system also provides better protection from infections [3].

Hormones have wide ranging effects in the body, and in addition to inflammation, research indicates that oestrogen can be pro-fibrotic, increasing myofibroblast activation and contraction [4]. This may be why women are at an increased risk of developing arthrofibrosis compared to men [5], however, it should be noted that men also have oestrogen. Myofibroblasts (the cells responsible for fibrosis) express oestrogen receptors, and oestrogen has been linked to capsular contraction [4].

80 % of autoimmune disease occurs in women

The effects of oestrogen and other female hormones on inflammation and fibrosis have implications for the timing of surgery. Unfortunately, the effects of oestrogen on fibrosis are not well studied, and its effects on inflammation are complicated and non-linear. In some contexts oestrogen is pro-inflammatory, and in others it is anti-inflammatory. However, we know that oestrogen levels fall just prior to menstruation, and low levels are known to be pro-inflammatory. Supporting this, menstruation is a highly inflammatory event that causes a systemic (whole body) increase in major inflammatory cytokines [6], so this may be a time to avoid surgery.

High levels of Inflammation and fibrosis are also associated with menstrual disorders [6]. A correct diagnosis and treatment of menstrual problems, including heavy bleeding and pain, should be a priority for women with arthrofibrosis, but are commonly difficult to obtain [7]. Endometriosis is a fibrotic condition [8] involving cells that line the uterus (womb) migrating into areas outside of the uterus and transforming into myofibroblasts, causing painful menstruation and sometimes infertility.

Menstruation is a highly inflammatory event that causes a systemic increase in major inflammatory cytokines

Polycystic ovary syndrome (PCOS) is a common condition that also involves chronic inflammation and fibrosis, this time of the ovarian capsule [9] (where eggs are made). Spironolactone and metformin are recognised treatments for PCOS [7] and are also used for treating other forms of fibrosis. Therefore, these medications may assist in treating arthrofibrosis.

References

1. Desai, M. K. & Brinton, R. D. Autoimmune Disease in Women: Endocrine Transition and Risk Across the Lifespan. Front Endocrinol (Lausanne) 10, 265, doi:10.3389/fendo.2019.00265 (2019).

2. Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat Rev Immunol 16, 626-638, doi:10.1038/nri.2016.90 (2016).

3. Straub, R. H. The complex role of estrogens in inflammation. Endocr Rev 28, 521-574, doi:10.1210/er.2007-0001 (2007).

4. Segreto, F. et al. The role of angiogenesis, inflammation and estrogen receptors in breast implant capsules development and remodeling. J Plast Reconstr Aesthet Surg 71, 637-643, doi:10.1016/j.bjps.2017.12.003 (2018).

5. Usher, K. M. et al. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. Bone Research 7, doi:10.1038/s41413-019-0047-x (2019).

6. Azlan, A., Salamonsen, L. A., Hutchison, J. & Evans, J. Endometrial inflammasome activation accompanies menstruation and may have implications for systemic inflammatory events of the menstrual cycle. Hum Reprod 35, 1363-1376, doi:10.1093/humrep/deaa065 (2020).

7. Neven, A. C. H., Laven, J., Teede, H. J. & Boyle, J. A. A Summary on Polycystic Ovary Syndrome: Diagnostic Criteria, Prevalence, Clinical Manifestations, and Management According to the Latest International Guidelines. Semin Reprod Med 36, 5-12, doi:10.1055/s-0038-1668085 (2018).

8. Garcia Garcia, J. M. et al. Endometriosis: Cellular and Molecular Mechanisms Leading to Fibrosis. Reprod Sci 30, 1453-1461, doi:10.1007/s43032-022-01083-x (2023).

9. Takahashi, N. et al. Activation of Endoplasmic Reticulum Stress in Granulosa Cells from Patients with Polycystic Ovary Syndrome Contributes to Ovarian Fibrosis. Sci Rep 7, 10824, doi:10.1038/s41598-017-11252-7 (2017).