BY MARLEIGH SMITH
Why Endometriosis Pain Becomes Chronic
25% of women with endometriosis reported 3+ overlapping chronic pain conditions, compared to only 12% without endometriosis (1).
Endometriosis-related inflammation can manifest into chronic pain. with sufferers experiencing dysmenorrhea (period pain), dyspareunia (pain associated with sex), dysuria (painful urination), dyschezia (painful defecation) and infertility (2).
Lot of questions surround endometriosis and chronic pain.
- Why can endometriosis pain persist even after lesions are removed?
- Why does pain spread to areas without lesions?
- Why does the pain feel different for everyone?
It's not in your head - it's in your nerves. The answer lies in three key mechanisms: peripheral, central and cross sensitisation.
And no - we aren’t talking about someone being “more sensitive” to pain. Actually, sensitisation refers to the biological alteration of pain pathways in the central and peripheral nervous system, rather than emotions or perceptions of pain.
Before we dive in, much of this article will link back to estrogen. Endometriosis is an estrogen-dependent disease, because the estrogen is required for the proliferation of lesions (3). It’s important to remember: not only does estrogen that's already present in the body contribute to the progression of the disease, but the endometriosis tissue itself can produce its own estrogen supply.
This is why:
1. Hormonal treatments may not always be effective
2. Hysterectomy is not a cure
3. Endometriosis can persist past menopause (3).
The Body’s Pain Response (peripheral sensitisation)
The Role of Estrogen, Mast Cells and Histamine
Estrogen plays a big role in endometriosis associated pain, through the activation of nerve fibres and mast cells (3). Endometriosis lesions produce their own estrogen, which then binds to receptors on nearby neurones and increases their responsiveness and likeliness to fire off signals to the brain (3).
Estrogen has also been shown to interact with mast cells which accumulate around endometriosis lesions (3). Estrogen binds to receptors on the mast cells, activating them (3). Upon activation, mast cells “explode” (or degranulate) and release these inflammatory substances (e.g. histamine), contributing to not only the inflammation associated with endometriosis, but also to the sensitisation of the nerve fibres near the lesions (3).
In fact, these inflammatory substances create what is called a ‘neuroinflammatory soup’ around the neurone endings, which makes them more likely to fire pain signals to the brain. Histamine, specifically, can stimulate nerve endings on pain sensing neurones (3).
The role of histamine in endometriosis pain sensitivity is supported by the fact that endometriosis sufferers are seen to have elevated levels of histamine in the blood (3)
Also, mast cells seem to be essential in endometriosis related pain. Mouse studies that removed a key mast cell receptor showed an improvement in pain. In the same study, histamine administration increased calcium levels in the spinal cord, a key insight into increased sensitivity of pain sensing neurones (4).
In summary, neurones around the endometriosis lesions are more likely to fire due to both estrogen's direct and indirect (mast cell-related) activation of neurones.
The Brain’s Pain Response (central sensitisation)
Central sensitisation is when your central nervous system (brain and spinal cord) becomes hyper-sensitive to pain signals - like a faulty fire alarm that goes off even when there's no fire.
This is how endometriosis pain becomes chronic. Brain scans show that the pain-processing areas of the brain work differently in people with endometriosis compared to those without, detailed in the diagram below (5)*. Your brain gets bombarded with so many pain signals from the lesions that it essentially gets stuck in "pain mode" - even when the original signals stop.
It's a vicious cycle: the nerves around endometriosis lesions fire off more pain signals, while your brain is more likely to have bigger reactions to those signals. Together, they create worsening chronic pain that's incredibly difficult to manage.
Endometriosis Pain Changes Your Brain Structure
Decreased brain volume has been found in those with endometriosis and chronic pelvic pain - in brain regions essential for pain perception (6):
But, these changes were NOT seen in those who had endometriosis but with NO chronic pelvic pain.
Why? These brain areas receive repeated pain signals in endometriosis sufferers with chronic pain, contributing to central sensitisation.
Interestingly, an increase in brain volume was seen in the cerebellum, which is an area associated with the anticipation of pain. This could be from someone having frequent anticipation of upcoming symptoms they have to deal with all the time, like menstrual pain and painful intercourse.
Pain Spreading: Nerves Can Also Recruit Their Neighbours
Moreover, cross sensitisation can occur, where when one set of nerves becomes more sensitised, it can affect nearby nerves as they share a common pathway in the spinal cord (7). This is why endometriosis lesions near reproductive organs result in increased pain in surrounding organ systems, like the bladder, which is common in those with endometriosis.
What Does This Mean if You Have Endometriosis?
Because chronic pain involves multiple layers and systems, treatments that target only one component (e.g. hormonal suppression or anti-inflammatory medications) can provide limited relief. When pain becomes this complex, effective management usually requires a comprehensive, multimodal approach that addresses several mechanisms at once.
This can include often-overlooked therapies such as neuromodulating medications, pelvic health physiotherapy, nervous system regulation strategies, and techniques that retrain how the brain processes pain.
Endometriosis pain isn't one-size-fits-all. Your experience is likely shaped by multiple factors. This is why:
• Some people respond well to certain treatments while others don't
• Pain severity doesn't always match lesion severity
• What works for your friend with endometriosis might not work for you
Appendices
Brain regions seen to be associated with endometriosis related pain as described in Szabo et al (2022). The anterior insular cortex sends and receives signals from the cerebellum and the middle frontal gyrus. Please note that these regions are marked approximately, and the actual connections may vary. Additionally, this is the right hemisection of the brain, and the paper mentions the left middle frontal gyrus being involved. Created in https://BioRender.com.
References
1. Bartley EJ, Alappattu MJ, Manko K, Lewis H, Vasilopoulos T, Lamvu G. Presence of endometriosis and chronic overlapping pain conditions negatively impacts the pain experience in women with chronic pelvic–abdominal pain: A cross-sectional survey. Women’s health. 2024 Jan 1;20.
2. Tsamantioti ES, Mahdy H. Endometriosis [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK567777/
3. Wang J, Mao X, Zhu L, Zhang X. Unravelling the Intricate Link: Mast Cells and Estrogen-Induced Pain Sensitization in Endometriosis. International Journal of Biological Sciences. 2025;21(13):5891–904.
4. Mao X, Wang J, Ding S, Guo X, Xu X, Xu P, et al. MRGPRX2 Mediates Mast Cell‐Induced Endometriosis Pain Through the Sensitization of Sensory Neurons via Histamine/HRH1/TRPV1 Signaling Pathway. The FASEB Journal. 2025;39(13).
5. Szabo E, Timmers I, Borsook D, Simons LE, Sieberg CB. Altered anterior insula functional connectivity in adolescent and young women with endometriosis-associated pain: Pilot resting-state fMRI study. European Journal of Paediatric Neurology. 2022 Nov;41:80–90.
6. As-Sanie S, Harris RE, Napadow V, Kim J, Neshewat G, Kairys A, Williams D, Clauw DJ, Schmidt-Wilcke T. Changes in regional gray matter volume in women with chronic pelvic pain: a voxel-based morphometry study. Pain. 2012 May;153(5):1006-1014.
7. Malykhina AP. Neural mechanisms of pelvic organ cross-sensitization. Neuroscience. 2007 Nov;149(3):660–72
