Neuropeptides substance P and CGRP promote endometriosis progression and fibrosis by triggering tissue remodeling through their specific receptors, with blocking these receptors halting the process.
Fibrosis halted by receptor blockadeNeutralizing substance P and CGRP receptors stopped the cellular transformation cascade that drives scarring in endometriosis, pointing to a potential therapeutic strategy.
What the researchers found
Substance P (SP) and calcitonin gene-related peptide (CGRP), acting through their receptors NK1R and CRLR/RAMP-1, induced a cascade of cellular transformations in endometriotic tissue: epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), and conversion of stromal cells into smooth muscle cells.
This cascade resulted in increased cell migration, invasiveness, contractility, collagen production, and ultimately fibrosis. Neutralizing NK1R and/or CGRP/CRLR/RAMP-1 signaling abrogated these processes. Deep endometriosis lesions showed significantly higher nerve fiber density, receptor expression, and fibrotic content than ovarian endometriomas, with fibrosis extent correlating positively with receptor staining levels and nerve fiber density.
Why it matters
Endometriosis affects roughly 10% of women of reproductive age and current treatments are limited. This study reveals that sensory nerves don't just transmit pain — they actively drive disease progression through neuropeptide signaling. This opens the door to targeting substance P and CGRP receptors as a therapeutic strategy, potentially treating both the pain and the underlying tissue damage of endometriosis.
How the study worked
Researchers used cultured endometriotic stromal cells treated with substance P, CGRP, or rat dorsal root ganglia supernatant to study cellular transformations in vitro. They also performed immunohistochemistry on human endometriosis lesion samples comparing deep endometriosis to ovarian endometriomas, measuring nerve fiber density, receptor expression, and fibrotic markers including α-SMA, desmin, and smooth muscle myosin heavy-chain.
What this study cannot tell us
The in vitro cell culture experiments may not fully replicate the complex microenvironment of endometriosis in vivo. The human tissue analysis was observational and correlational — it shows association between nerve density and fibrosis but doesn't prove causation in living patients. No clinical intervention was tested, so it remains unknown whether blocking these receptors would reduce fibrosis in patients with endometriosis.
How to read the evidence
This is a preclinical study combining in vitro cell experiments with correlational analysis of human tissue samples. While mechanistically detailed and compelling, no clinical intervention was tested and the human data is observational.
When this study was published
Published in 2019, this study predates the widespread clinical use of anti-CGRP antibodies for migraine and remains highly relevant as researchers explore whether these same drugs could be repurposed for endometriosis.
The bigger picture
This research bridges two fields — neuropeptide biology and endometriosis — by showing that sensory nerves actively participate in disease progression, not just pain perception. With CGRP-targeting drugs already approved for migraine and substance P antagonists available, there may be existing medications that could be repurposed for endometriosis. This also supports the emerging view that endometriosis lesions behave like chronic wounds undergoing repeated injury and repair.
Questions still open
- Could existing CGRP-targeting migraine drugs (anti-CGRP antibodies) reduce fibrosis progression in endometriosis patients?
- Would NK1R antagonists (substance P blockers) be effective as endometriosis treatments targeting both pain and disease progression?
- Does the nerve-neuropeptide-fibrosis axis explain why some women develop deep infiltrating endometriosis while others have superficial disease?
Common questions
What are substance P and CGRP, and what do they normally do?
Could migraine drugs that target CGRP also help with endometriosis?
Read the original research
Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis.
Scientific reports, 9(1), 2698
Citation
Yan, Dingmin; Liu, Xishi; Guo, Sun-Wei. (2019). Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis.. Scientific reports, 9(1), 2698. https://doi.org/10.1038/s41598-019-39170-w