The Brain-Body Connection in Endometriosis Pain

Do you know what’s really driving your endometriosis pain?

It’s not just inflammation, it’s also neuroinflammation.

Neuroinflammation happens when your immune system and nervous system amplify each other. Here’s how it works:

•       The signal (inflammation): Endometriosis lesions release inflammatory mediators like IL-6 and TNF-alpha. This establishes that the lesion is active, a living factor of chemicals. 

•       The Building (Neuroangiogenesis & Neurogenesis): These inflammatory signals trigger the growth of new blood vessels (angiogenesis) that act as a supply line for the lesion. Simultaneously, new nerve fibres (neurogenesis) follow these vessels, infiltrating the lesion and hard wiring it directly into your central nervous system. (1) This shows how the lesion roots itself into the body.

•       The immune response (mast cells): These activate mast cells, immune cells that live in your tissues. Lesions have more mast cells than normal, so when activated, they release histamine, prostaglandins, tryptase, and other growth factors.

•       The Feedback loop (seld-perpetuating cycle): These chemicals directly sensitise your sensory nerves, making them more sensitive to pain signals.The nerves then release neuropeptides like Substance P, which activate even more mast cells, creating a self-perpetuating cycle. (2)

This constant bidirectional loop of inflammation and nerve activation is partly driven by the JAK/STAT pathway, a cellular signalling system that regulates both immune activation and nerve fibre growth. (1) When this pathway is overactive, the cycle perpetuates, which is why endometriosis pain can feel relentless.

This is also why, even after endometrial lesions are surgically removed, pain can persist. Through neurogenesis, the body has created a high density network of nerves in the pelvic area that didn't exist before. Even if the lesion is gone, these redundant nerve pathways can remain sensitised, creating a kind of pain memory so even small or normal signals can trigger intense pain.I see this in clinic all the time, patients dismissed or told it’s ‘normal.’ But this is real. It’s not just in your head. It reflects an intricate interplay between neurobiology, endocrinology, and immunology, which is why we can’t focus on hormones alone. Understanding this connection is the first step to supporting you as an individual, acknowledging your experience, and helping you navigate what this looks like for your body.

(1)  Golinska M, Wołyniak M, Kulesza P and Fendler W (2025) Neuroinflammation is responsible for pain in endometriosis - targeting the JAK-STAT pathway and mast cell activation. Front. Immunol. 16:1621178. doi: 10.3389/fimmu.2025.1621178

(2)  Velho, R. V., Taube, E., Sehouli, J., & Mechsner, S. (2021). Neurogenic Inflammation in the Context of Endometriosis-What Do We Know?. International journal of molecular sciences, 22(23), 13102. https://doi.org/10.3390/ijms222313102