BY MARLEIGH SMITH
Why Endometriosis Pain Becomes Chronic
How endometriosis-related inflammation manifests into chronic pain
25% of women with endometriosis reported 3+ overlapping chronic pain conditions, compared to only 12% without endometriosis (1).
Endometriosis is a chronic pain condition, with sufferers experiencing dysmenorrhea (period pain), dyspareunia (pain associated with sex), dysuria (painful urination), dyschezia (painful defecation) and infertility (2).
So many questions surround endometriosis and chronic pain.
Why can endometriosis pain persist even after lesions are removed?
Why does it spread to areas without lesions?
Why does it feel different for everyone?
It's not in your head - it's in your nerves.
The answer lies in three key mechanisms:
1. Peripheral sensitization
2. Central sensitization
3. Cross sensitization.
And no - we aren’t talking about someone being “more sensitive” to pain. Actually, sensitization 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, as estrogen is required for the proliferation of lesions (3). It’s important to remember that 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).
Peripheral Sensitization: The Body’s Pain Response
The Role of Estrogen, Mast Cells and Histamine
Estrogen plays a primary role in endometriosis associated pain through the activation of nerve fibres and mast cells (3). Neurones contain estrogen receptors, so as endometriosis lesions produce their own estrogen, it can bind to the receptors on nearby neurones and increase their responsiveness and their likeliness to fire off signals to the brain (3).
Estrogen has also been shown to interact with mast cells around endometriosis lesions (3). Mast cells are immune cells that release inflammatory substances (e.g. histamine) when activated. It’s these little cells that are responsible for hay fever reactions!
In endometriosis, mast cells accumulate near lesions. Estrogen binds to receptors on the mast cells, activating them (3). After activation, mast cells then “explode”, or degranulate, and release these inflammatory substances, contributing to not only the inflammation associated with endometriosis, but also to the sensitization of the nerve fibres near the lesions (3).
In fact, these inflammatory substances create what is called a ‘neuroinflammatory soup’ around the neuron endings, and contribute to the responsiveness of the neurones, 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 neurons, contributing to central sensitization (4).
Central Sensitization: The Brain’s Pain Response
Central sensitization occurs when the central nervous system (your brain and spinal cord) become hyper-reactive to pain signals, and can even send them spontaneously, without any external triggers.
This is the mechanism by which endometriosis related pain becomes chronic, and means those suffering may end up with a lack of effective options in terms of pain management.
Brain imaging shows a decrease in resting functional connectivity between certain brain regions in those with endometriosis-related pain compared to controls (5)*:
This maladaptation in CNS pain processing is what contributes to the chronicity of the pain in endometriosis. The brain is receiving many pain signals from the lesions, and even when these stop, the pain continues.
Brain Structure Changes and Endometriosis Pain
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 areas receive repeated pain signals in endometriosis sufferers with chronic pain, contributing to central sensitization.
Interestingly, an increase in brain volume was seen in the cerebellum, which is associated with anticipation of pain, and could indicate the frequent anticipation of symptoms like menstrual pain and painful intercourse.
The Emergence of Chronic Sensitization
Together, the sensitization of peripheral nerve fibres creates a nerve that is more likely to fire off pain signals, and those signals are being sent to a brain that is more likely to have bigger reactions to them, creating a constantly worsening pain response that becomes chronic.
Pain Spreading: Nerves Can Also Recruit Their Neighbours
Moreover, cross sensitization can occur, where when one set of nerves becomes more sensitized, 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?
Your body develops three interconnected problems that together lead to chronic pain. Because this process involves multiple systems, treatments that target only one component (such as 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 [Internet]. 2025 Sep 21 [cited 2025 Oct 29];21(13):5891–904. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC12509920/#Section2
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 [Internet]. 2025 Jul 2 [cited 2025 Oct 29];39(13). Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC12218045/
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. doi: 10.1016/j.pain.2012.01.032. Epub 2012 Mar 2. PMID: 22387096; PMCID: PMC3613137.
7. Malykhina AP. Neural mechanisms of pelvic organ cross-sensitization. Neuroscience. 2007 Nov;149(3):660–72
