Endometriosis beyond hormones

Endometriosis affects around one in ten women of reproductive age in the UK, equating to more than 1.5 million people, yet symptoms and disease severity can vary enormously.

It is often described as a hormone-dependent condition, with oestrogen considered a major driver. As a result, many treatments focus on suppressing hormone production or interrupting the menstrual cycle. However, oestrogen alone does not explain the full disease process.

Endometriosis is characterised by endometrial-like tissue growing outside the uterus, where it can form lesions and trigger inflammation and pain. These lesions are biologically active. They can develop their own blood supply, while the growth and sensitisation of nerve fibres within and around them can alter pain signalling. Research has also identified changes in immune function and increased oxidative stress, both of which may contribute to the inflammatory environment that allows lesions to persist.

In this article, we will look at what allows these lesions to establish and persist, how hormone signalling is altered, why pain can become so complex, and how inflammatory, immune and neurological processes fit into the picture. I also explore nutritional and lifestyle factors that may be considered alongside appropriate medical care.

Why lesions develop and persist

One explanation for how endometrial-like cells reach the pelvic cavity is retrograde menstruation, where menstrual material flows backwards through the fallopian tubes. However, this also occurs in women who never develop endometriosis, suggesting that other factors determine whether displaced cells are cleared or are able to attach, survive and form lesions (Viganò et al., 2024).

Part of the explanation may lie in how the immune system responds to these cells. Changes in immune-cell activity can affect their recognition and clearance. Once lesions become established, their interaction with surrounding immune cells can maintain inflammation and, over time, contribute to tissue remodelling, fibrosis and adhesions.

Lesions are most commonly found within the pelvis, including on the pelvic lining, ovaries, bowel and bladder. They may remain superficial, grow more deeply into surrounding tissues or form ovarian endometriomas, often called ‘chocolate cysts’ because they contain old, altered blood. Although endometriotic tissue shares some characteristics with the uterine lining, it behaves differently in ways that help it survive outside the uterus.

As a lesion becomes established, low oxygen levels within the developing tissue can stimulate the growth of new blood vessels, providing the oxygen and nutrients it needs. Sensory nerve fibres can also develop within and around the lesion, linking its growth with changes in pain signalling.

The hormonal environment within the lesion can then help maintain this process. Endometriotic tissue can produce oestrogen locally through increased aromatase activity rather than depending entirely on oestrogen circulating in the bloodstream. Oestrogen and inflammatory prostaglandins can reinforce one another, creating a cycle that favours continued inflammation and lesion activity.

Changes in progesterone-receptor signalling can also make endometriotic tissue less responsive to progesterone. Known as progesterone resistance, this reduces some of progesterone’s normal regulation of oestrogen-driven growth and inflammation (Bulun et al., 2019).

Repeated bleeding from these vascularised, hormone-responsive lesions can lead to haemoglobin and iron accumulating within the lesions and surrounding tissue. Excess free iron can increase oxidative stress and tissue damage, provoking further inflammation and helping to create conditions in which lesions persist (Wyatt et al., 2023).

Pain and endometriosis

The severity of pain in endometriosis does not necessarily reflect the extent of the disease. Some women have extensive lesions with relatively little pain, while others experience severe pain with comparatively limited disease (Vercellini et al., 2007).

Part of the explanation may lie in the sensory nerve fibres that develop within and around endometriotic lesions. Prostaglandins, cytokines and other inflammatory substances can make these nerves more sensitive, causing them to respond more strongly to stimulation. With repeated exposure, the nerves can become increasingly reactive, a process known as peripheral sensitisation.

These pain signals travel through the spinal cord to the brain. If they continue over time, the pathways that process them can also become more responsive. This is known as central sensitisation and can amplify and prolong pain or cause sensations that would not normally hurt to become painful.

Once these changes are established, suppressing or removing the lesions may not completely reverse them. This may help explain why pelvic pain can sometimes persist following hormonal treatment or surgery, even when the original source of inflammatory signalling has been reduced (Maddern et al., 2020).

Emerging areas of research

Researchers are also investigating whether metabolic health, the gut microbiome, sleep and chronic stress may influence endometriosis symptoms.

Poor sleep and ongoing stress can affect inflammation and the way pain is processed, potentially increasing sensitivity to pain. Metabolic health is another area of interest because insulin resistance can create a more inflammatory environment and may interact with hormone signalling. However, its precise role in endometriosis is not yet clear (Naz et al., 2024).

The gut microbiome may provide another connection through its effects on inflammation and oestrogen metabolism. Certain gut bacteria produce enzymes that can allow oestrogen destined for elimination to be reabsorbed, while substances released by some bacteria may stimulate inflammatory signalling (Salliss et al., 2022).

Neither metabolic dysfunction nor changes in the gut microbiome are established causes of endometriosis. Both are being explored as possible ways of influencing inflammation, oestrogen signalling and symptoms without relying solely on hormonal treatment. For now, however, the research remains preliminary. There is not enough evidence to define an ‘endometriosis microbiome’ or recommend specific probiotics as a treatment.

Supporting endometriosis in practice

In the UK, treatment for endometriosis depends on symptoms, the location and extent of the disease, previous treatment and whether a woman is trying to conceive. Options may include pain relief, hormonal treatments and surgery to remove or destroy lesions. Hysterectomy, sometimes with removal of the ovaries, may be considered in selected cases, although it does not necessarily eliminate endometriosis elsewhere in the body.

Alongside medical treatment, nutritional support can address some of the wider factors discussed throughout this article, including nutritional status, inflammation, metabolic and gastrointestinal health, sleep and pain regulation.

Nutritional adequacy is a good place to start. Sufficient protein, essential fatty acids and micronutrients are needed for normal immune function and antioxidant defence. Heavy menstrual bleeding, fatigue or restrictive diets, including vegan diets, may warrant investigation of iron, vitamin B12, folate and vitamin D, with deficiencies corrected where identified.

Various nutrients and plant compounds are being studied for possible effects on inflammation, oxidative stress and pain. However, the evidence is still limited and does not currently support recommending any particular supplement as a treatment for endometriosis. Supplement use should be considered individually, taking account of diet, medication, health conditions and potential interactions.

Where there is central adiposity, impaired glucose regulation or other evidence of insulin resistance, improving carbohydrate quality, maintaining muscle mass and incorporating regular physical activity can support metabolic health.

Gastrointestinal symptoms may also need attention. Supporting regular bowel function and a varied diet can contribute to general gut health, although there is not yet enough evidence to recommend specific microbiome-based treatments for endometriosis. Persistent bloating, constipation or changes in bowel habits should also be discussed with a GP, particularly because endometriosis itself can affect the bowel.

Pain sensitisation brings in another aspect of support. Pain education, cognitive behavioural approaches, mindfulness, graded movement, breathing and relaxation techniques may help influence how pain is processed. Good sleep and regular movement are also important, while pelvic-health physiotherapy may be useful where pelvic-floor dysfunction or persistent pelvic pain is present.

Anyone experiencing symptoms of endometriosis should speak to their GP or gynaecologist about appropriate investigation, diagnosis and treatment. Nutritional and lifestyle support can then work alongside medical care, guided by the individual’s symptoms, nutritional status and wider health.

References

Bulun SE, Yilmaz BD, Sison C, et al. Endometriosis. Endocrine Reviews. 2019;40(4):1048–1079. doi:10.1210/er.2018-00242.

Coxon L, Horne AW, Vincent K. Pathophysiology of endometriosis-associated pain: a review of pelvic and central nervous system mechanisms. Best Practice & Research Clinical Obstetrics & Gynaecology. 2018;51:53–67. doi:10.1016/j.bpobgyn.2018.01.014.

Dai Y, Ye Z, Lin X, Zhang S. Immunopathological insights into endometriosis: from research advances to future treatments. Seminars in Immunopathology. 2025;47(1):31. doi:10.1007/s00281-025-01058-5.

Godin SK, Wagner J, Huang P, Bree D. The role of peripheral nerve signaling in endometriosis. FASEB BioAdvances. 2021;3(10):802–813. doi:10.1096/fba.2021-00063.

Gunther K, Fisher T, Liu D, Abbott J, Ford CE. Endometriosis is not the endometrium: reviewing the over-representation of eutopic endometrium in endometriosis research. eLife. 2025;14:e103825. doi:10.7554/eLife.103825.

Khan KN, Fujishita A, Hiraki K, Kitajima M, Nakashima M, Fushiki S, Kitawaki J. Bacterial contamination hypothesis: a new concept in endometriosis. Reproductive Medicine and Biology. 2018;17(2):125–133. doi:10.1002/rmb2.12083.

Lai ZZ, Yang HL, Ha SY, et al. Cyclooxygenase-2 in endometriosis. International Journal of Biological Sciences. 2019;15(13):2783–2797. doi:10.7150/ijbs.35128.

Liu P, Wang Y, Ji X, Kong W, Pan Z, Xu C, Geng Y, Miao J. Association between triglyceride-glucose index and risk of endometriosis in US population: results from NHANES (1999–2006). Frontiers in Endocrinology. 2024;15:1371393. doi:10.3389/fendo.2024.1371393.

Machairiotis N, Vasilakaki S, Thomakos N. Inflammatory mediators and pain in endometriosis: a systematic review. Biomedicines. 2021;9(1):54. doi:10.3390/biomedicines9010054.

Maddern J, Grundy L, Castro J, Brierley SM. Pain in endometriosis. Frontiers in Cellular Neuroscience. 2020;14:590823. doi:10.3389/fncel.2020.590823.

Mori T, Ito F, Koshiba A, et al. Local estrogen formation and its regulation in endometriosis. Reproductive Medicine and Biology. 2019;18(4):305–311. doi:10.1002/rmb2.12285.

Morotti M, Vincent K, Brawn J, Zondervan KT, Becker CM. Peripheral changes in endometriosis-associated pain. Human Reproduction Update. 2014;20(5):717–736. doi:10.1093/humupd/dmu021.

Reis FM, Coutinho LM, Vannuccini S, et al. Progesterone receptor ligands for the treatment of endometriosis: the mechanisms behind therapeutic success and failure. Human Reproduction Update. 2020;26(4):565–585. doi:10.1093/humupd/dmaa009.

Reis JL, Rosa NN, Ângelo-Dias M, Martins C, Borrego LM, Lima J. Natural killer cell receptors and endometriosis: a systematic review. International Journal of Molecular Sciences. 2023;24(1):331. doi:10.3390/ijms24010331.

Saei Ghare Naz M, Noroozzadeh M, Noori Ardebili S, Mousavi M, Azizi F, Ramezani Tehrani F. Cardio-metabolic risk profile of women with endometriosis: a population-based study. Endocrinology, Diabetes & Metabolism. 2024;7(6):e70008. doi:10.1002/edm2.70008.

Salliss ME, Farland LV, Mahnert ND, Herbst-Kralovetz MM. The role of gut and genital microbiota and the estrobolome in endometriosis, infertility and chronic pelvic pain. Human Reproduction Update. 2022;28(1):92–131. doi:10.1093/humupd/dmab035.

Sarsenova M, Lawarde A, Pathare ADS, et al. Endometriotic lesions exhibit distinct metabolic signature compared to paired eutopic endometrium at the single-cell level. Communications Biology. 2024;7:1026. doi:10.1038/s42003-024-06713-5.

Scutiero G, Iannone P, Bernardi G, et al. Oxidative stress and endometriosis: a systematic review of the literature. Oxidative Medicine and Cellular Longevity. 2017;2017:7265238. doi:10.1155/2017/7265238.

Vercellini P, Fedele L, Aimi G, Pietropaolo G, Consonni D, Crosignani PG. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Human Reproduction. 2007;22(1):266–271. doi:10.1093/humrep/del339.

Viganò P, Caprara F, Giola F, Di Stefano G, Somigliana E, Vercellini P. Is retrograde menstruation a universal, recurrent, physiological phenomenon? A systematic review of the evidence in humans and non-human primates. Human Reproduction Open. 2024;2024(3):hoae045. doi:10.1093/hropen/hoae045.

Wyatt J, Fernando SM, Powell SG, Ahmed S, Hapangama DK. The role of iron in the pathogenesis of endometriosis: a systematic review. Human Reproduction Open. 2023;2023(3):hoad033. doi:10.1093/hropen/hoad033.

Zhou Y, Zeng C, Li X, Wu PL, Yin L, Yu XL, Zhou YF, Xue Q. IGF-I stimulates ERβ and aromatase expression via IGF1R/PI3K/AKT-mediated transcriptional activation in endometriosis. Journal of Molecular Medicine. 2016;94(8):887–897. doi:10.1007/s00109-016-1396-1.