How Immune and Hormonal Dysfunction redefine the categorisation of Endometriosis

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Reframing Endometriosis part 2

Endometriosis is a chronic gynaecological condition characterised by symptoms such as dysmenorrhea (painful menstruation), non-menstrual pelvic pain, and infertility1,2,3. According to the World Health Organization, endometriosis affects approximately 1 in 10 women during their reproductive years, representing around 10% of women globally4. In the previous article, we explored the genetic link between endometriosis and autoimmune diseases, and discussed how defining endometriosis as a gynaecological disorder diminishes current scientific evidence, patient experience, and limits the scope for treatment. Here, we take a closer look at immune dysfunction and hormonal factors to continue exploring: is endometriosis truly just a gynaecological disorder? 

Endometriosis, Immune dysfunction,  Chronic inflammation, and Hormonal interactions

Endometriosis is increasingly recognised as a condition marked by immune system dysfunction. When endometrial-like cells migrate outside the uterus, the body’s usual defence mechanisms fail to eliminate them. Instead, the immune response becomes misdirected: in this new environment small proteins (cytokines) are produced by both immune cells and the endometrial cells themselves, driving persistent inflammation, while at the same time immune cells with killing capacity (eg. macrophages or NK cells) lose their ability to clear the tissue. Over time, this immune dysfunction creates an environment that supports the survival and growth of endometrial cells,  encourages the formation of new blood vessels, and promotes scarring. Hormonal influences further reinforce these changes, leading to a cycle in which the immune system is gradually exhausted and the ectopic tissue escapes recognition. In essence, endometriosis develops because the immune system is both overstimulated and undermined by the endometrial cells themselves, allowing misplaced cells to thrive.

Chronic inflammation is increasingly recognised as a key driver of endometriosis pathogenesis, underpinning its most debilitating clinical manifestations, including pelvic pain and infertility. While not formally classified as an autoimmune disorder, endometriosis exhibits immunological dysregulation and sustained inflammatory activity that parallels mechanisms observed in autoimmune diseases. Compton et al. 2025 systematic review and meta-analysis showed a significant bidirectional association between endometriosis and chronic fatigue syndrome, alerting to the need of elucidating causal pathways in immune dysregulation and chronic pain pathways between the two conditions to enable effective integrated care approaches5. Moreover, a similar inflammatory profile has been observed in other immune-mediated conditions, such as inflammatory bowel disease (IBD) which also concludes that the immune abnormalities seen in endometriosis are not confined to the reproductive system and instead reflect a broader pattern of systemic immune dysfunction6. Such findings highlight the need for diagnostic frameworks that account for extra-pelvic manifestations to fully capture the disease’s multisystem impact. Reframing endometriosis as a systemic immune-mediated condition would enable this by broadening the scope of research, clinical management, and policy interventions beyond the confines of gynaecology.  

Another key driver of pathogenesis in endometriosis is oestrogen, a hormone that supports the survival, proliferation, and inflammatory activity of ectopic endometrial tissue7. Oestrogen inhibits the natural cell death of these misplaced tissue cells, allowing them to persist outside the uterus and trigger chronic inflammation7. Beyond its role in tissue growth, oestrogen also influences immune system behaviour, potentially heightening immune activation and inflammatory responses in endometriosis7. This hormonal-immune interaction may help explain the higher prevalence of autoimmune diseases among women, including systemic rheumatoid arthritis,  lupus erythematosus, multiple sclerosis8, which we will analyse in future articles. Collectively, these findings reinforce the view that endometriosis is not merely a gynaecological disorder, but a complex condition shaped by the dynamic interplay between reproductive hormones and immune regulation.

The Benefits of Reframing Endometriosis

Growing evidence challenges the outdated view of endometriosis as a purely gynaecological condition. Reframing it as a systemic disorder, driven by immune dysfunction, chronic inflammation, and genetic links to autoimmune diseases, offers a powerful opportunity to improve care and understanding. This shift opens the door to integrated, multispecialty treatment, bringing together gynaecologists, immunologists, pain specialists, and researchers. It moves beyond narrow, symptom-focused models and towards a holistic approach that reflects the condition’s complexity.

Such reframing could transform the global landscape. Today, care is often limited to managing pelvic pain and reproductive symptoms, while systemic issues like fatigue, headaches, and immune-related comorbidities are overlooked. Furthermore, a lack of a multispecialty approach to treatment also contributes to inconsistent recognition of the disease and fragmented care globally. Portugal is the first country to adopt strategies such as paid menstrual leave for women with endometriosis and adenomyosis allowing up to three consecutive days of leave from work or academic obligations per month without forfeiting any rights, and a co-payment scheme for medications used to treat or manage the conditions9. This policy is a landmark recognition of the debilitating effects of the condition. However, many countries including the UK still lack robust policies or coordinated efforts to appropriately support women with endometriosis. Recognising endometriosis as a systemic disease would elevate its status in public health, unlocking needed research funding, insurance coverage, workplace accommodations, and policy opportunities similar to countries like Portugal. But above all, reframing endometriosis will validate the lived experience of those facing disabling symptoms and limited treatment options by ensuring endometriosis receives the urgency, visibility, and systemic response it demands. 

It is important to note that reframing isn’t about forcing endometriosis into a rigid autoimmune category. Instead, for us, reframing endometriosis calls for an immune-mediated model, one that reflects the interplay of inflammation, immune dysregulation, and hormonal influence shifting the focus from just fixing the symptoms of the condition to addressing it fully. This broader understanding empowers women to better navigate their condition, advocate for comprehensive care, and lead healthier, better supported lives.

References

  1. Farquhar, C. M. (2007). Endometriosis. BMJ, 334(7587), 249–253. https://doi.org/10.1136/bmj.39073.736829.be 
  2. Ballard, K. D., Seaman, H. E., de Vries, C. S., & Wright, J. T. (2008). Can symptomatology help in the diagnosis of endometriosis? Findings from a national case–control study—Part 1. BJOG: An International Journal of Obstetrics and Gynaecology, 115(11), 1382–1391. https://doi.org/10.1111/j.1471-0528.2008.01878.x 
  3. Shigesi, N., Kvaskoff, M., Kirtley, S., Feng, Q., Fang, H., Knight, J. C., Missmer, S. A., Rahmioglu, N., Zondervan, K. T., & Becker, C. M. (2019). The association between endometriosis and autoimmune diseases: A systematic review and meta-analysis. Human Reproduction Update, 25(4), 486–503. https://doi.org/10.1093/humupd/dmz014
  4. World Health Organization. (2023). Endometriosis. World Health Organization; World Health Organization. https://www.who.int/news-room/fact-sheets/detail/endometriosis 
  5. Compton, S., Rodolf Alkabalan, Cadet, J., Azin Mastali, & Prakash. (2025). Endometriosis and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review and Meta-Analysis. Diagnostics, 15(18), 2332–2332. https://doi.org/10.3390/diagnostics15182332 
  6. Zhang, H., Mo, Y., Wang, L., Zhang, H., Wu, S., Doblin Sandai, Shuid, A. N., & Chen, X. (2024). Potential shared pathogenic mechanisms between endometriosis and inflammatory bowel disease indicate a strong initial effect of immune factors. Frontiers in Immunology, 15. https://doi.org/10.3389/fimmu.2024.1339647 
  7. Piriyev, E., Schiermeier, S., & Römer, T. (2025). Hormonal Treatment of Endometriosis: A Narrative Review. Pharmaceuticals, 18(4), 588. https://doi.org/10.3390/ph18040588 
  8. Shigesi, N., Harris, H. R., Fang, H., Ndungu, A., Lincoln, M. R., International Endometriosis Genome Consortium, 23andMe Research Team, Cotsapas, C., Knight, J., Missmer, S. A., Morris, A. P., Becker, C. M., Rahmioglu, N., & Zondervan, K. T. (2025). The phenotypic and genetic association between endometriosis and immunological diseases. Human Reproduction (Oxford, England), 40(6), 1195–1209. https://doi.org/10.1093/humrep/deaf062 
  9. Fonseca, L., & Serrao, C. (2025). Portugal introduces paid menstrual leave for endometriosis and adenomyosis | Lockton. Lockton. https://global.lockton.com/us/en/news-insights/portugal-introduces-paid-menstrual-leave-for-endometriosis-and-adenomyosis

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