CGRP released by pain-sensing nerves drives fibrosis in adenomyosis, and blocking it with the FDA-approved migraine drug rimegepant reduced scarring and restored fertility in mice.
~80% of adenomyosis patientsexperience secondary dysmenorrhea, which may be driven by CGRP-releasing nerves that also promote fibrosis
What the researchers found
CGRP-positive nociceptive nerves were overexpressed within fibrotic lesions in both human adenomyosis patients and mouse models. The peptide CGRP activated the ERK signaling pathway in RAMP1-high CD140b+CD146+ fibroblasts, driving them toward an extracellular matrix deposition phenotype that worsens fibrosis.
Ablating nociceptive nerves reduced uterine fibrosis in mice with induced adenomyosis. Treatment with rimegepant, an FDA-approved CGRP/RAMP1 antagonist, alleviated fibrosis progression and promoted fertility restoration in the mouse model.
Why it matters
This study reveals a previously unknown connection between pain nerves and scarring in adenomyosis, suggesting the pain itself may be driving disease progression. More importantly, it identifies rimegepant — already FDA-approved for migraines — as a potential nonhormonal treatment option, which is especially significant for women of reproductive age who want to preserve fertility.
How the study worked
The researchers combined human tissue analysis from adenomyosis patients with mouse models of induced adenomyosis. They examined nociceptive nerve density and CGRP expression in fibrotic lesions, performed nerve ablation experiments, characterized fibroblast subtypes using surface markers (CD140b and CD146), and tested the ERK signaling pathway's role. They then treated mice with rimegepant to assess its effects on fibrosis and fertility.
What this study cannot tell us
The therapeutic results come from mouse models, and it remains to be seen whether rimegepant achieves similar anti-fibrotic effects in human adenomyosis patients. The study does not report specific quantitative measures of fibrosis reduction or fertility rates. Clinical trials would be needed to establish dosing, efficacy, and safety for this new indication.
How to read the evidence
This is a preclinical study combining human tissue analysis with mouse model experiments. While it provides strong mechanistic evidence and uses an FDA-approved drug, the therapeutic findings have not yet been validated in human clinical trials.
When this study was published
Published in 2025, this is a very recent study presenting novel findings about the nerve-fibroblast crosstalk mechanism in adenomyosis.
The bigger picture
This work sits at the intersection of neuroscience and reproductive medicine, demonstrating that nerve-derived peptides can directly drive tissue remodeling. It adds to growing evidence that neuropeptides like CGRP play roles far beyond pain signaling. The finding that a repurposed migraine drug could treat a gynecological condition opens a new nonhormonal therapeutic avenue for adenomyosis, a condition with limited treatment options.
Questions still open
- Would rimegepant be effective in human adenomyosis patients, and at what dose?
- Could CGRP-driven fibrosis play a similar role in other fibrotic conditions like endometriosis or uterine fibroids?
- Does blocking CGRP signaling also reduce the pain symptoms of adenomyosis, or only the fibrosis?
Common questions
What is CGRP and why does it matter in adenomyosis?
Could rimegepant become a treatment for adenomyosis?
Read the original research
Nociceptive Nerve-Derived CGRP Exacerbates Uterine Fibrogenesis in Adenomyosis by Promoting CD140b+ CD146+ Fibroblast Differentiation.
Advanced science (Weinheim, Baden-Wurttemberg, Germany), 12(45), e07128
Citation
Ye, Zi; Zhao, Anning; Li, Xia; Hao, Yanqing; Huang, Dong; Chen, Jianmin; Li, Tiantian; Dai, Yangyang; Sun, Wenchao; Ma, Lie; Zhang, Songying; Xin, Liaobing. (2025). Nociceptive Nerve-Derived CGRP Exacerbates Uterine Fibrogenesis in Adenomyosis by Promoting CD140b+ CD146+ Fibroblast Differentiation.. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 12(45), e07128. https://doi.org/10.1002/advs.202507128