Neuropeptides in endometriosis-associated pain: a review

G. Polenghi, A. Fiore, Maíra Casalechi, M Casalechi, P Viganò, Thomas T. Tapmeier
In: Journal of Endometriosis and Uterine Disorders · 2026 · vol. 16 , pp. 100186 · doi:10.1016/j.jeud.2026.100186 · W7212183330
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This narrative review synthesizes evidence that neuropeptides such as CGRP, substance P, and NPS are dysregulated in endometriosis, linking neuroimmune interactions to pain severity and lesion progression while highlighting their potential as non-hormonal therapeutic targets.

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Abstract

Background Endometriosis is a chronic estrogen-dependent inflammatory disease affecting approximately 10% of women of reproductive age and is a major cause of chronic pelvic pain. Increasing evidence indicates that neuroimmune interactions contribute substantially to pain generation and disease progression. Neuropeptides released by sensory and autonomic nerve fibers may play a key role in neurogenic inflammation, peripheral and central sensitization, angiogenesis, and lesion development. Objective To synthesize current experimental and clinical evidence on the role of neuropeptides in endometriosis-associated pain and to evaluate their contribution to neuroinflammation, neuroimmune crosstalk, lesion progression, and their potential as therapeutic targets. Methods A narrative review was conducted using PubMed, Embase, and Scopus. The literature search was performed on 9 September 2025 without publication year restrictions. English-language experimental and clinical studies investigating neuropeptide-mediated mechanisms in endometriosis-associated pain were included and reviewed qualitatively. Results The available evidence suggests that several neuropeptides, including calcitonin gene-related peptide (CGRP), substance P (SP), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), urocortin (UCN), neuropeptide S (NPS), phoenixin (PNX), and kisspeptin (KISS1), are dysregulated in endometriosis. Experimental studies indicate that CGRP, SP, and NPS/NPSR1 signaling promote lesion growth, invasion, and inflammatory responses, whereas alterations in KISS1 and PNX signaling may influence cellular migration and disease progression. Clinical studies further support associations between neuropeptide expression and pain severity, although findings remain heterogeneous. Conclusions Neuropeptides are important mediators that link inflammation, innervation and pain in endometriosis. In addition to their role in nociception, they may actively contribute to lesion progression and neuroimmune dysfunction. While the current evidence is limited and largely preclinical, neuropeptide signaling pathways are promising non-hormonal therapeutic targets that warrant further investigation in well-designed human studies.

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