Nerve bundle density around endometriosis lesions is associated with deep dyspareunia

Elevated peripheral nerve bundle density around endometriosis lesions of the posterior pelvis was significantly associated with deep dyspareunia—and with no other endometriosis-related pain type—supporting the proposal of "neuroproliferative dyspareunia" as a distinct biological subtype of endometriosis-associated pelvic pain, according to findings from a prospective registry study.¹

The study enrolled 180 patients undergoing initial endometriosis surgery at a tertiary referral center between December 2013 and December 2017, yielding 276 tissue samples from endometriosis lesions of the posterior pelvis, including the cul-de-sac, uterosacral ligaments, and rectosigmoid colon. Patients with postmenopausal status, malignancy, or bladder and pelvic floor tenderness were excluded to isolate neuroproliferative from central sensitization-mediated pain. Blinded immunohistochemical scoring assessed PGP9.5 nerve bundle density and nerve growth factor (NGF) expression in endometriosis epithelium and stroma, linked to preoperative pain data from the prospective registry.

"We found a direct correlation between PGP9.5 nerve bundle density and patient-reported deep dyspareunia, which we did not see in any other pain types such as superficial dyspareunia, dysmenorrhea, dyschezia, or chronic pelvic pain," said Mahfuza Sreya, BMLSc, a study investigator and PhD student at the University of British Columbia in Vancouver.

Patients with high deep dyspareunia—defined as preoperative severity of at least 5 out of 10 with reproduced vaginal apex tenderness on pelvic examination—had significantly higher mean PGP9.5 nerve bundle density (0.27, SD 0.51) compared with those with low deep dyspareunia (0.12, SD 0.09; P = .02). NGF expression in the endometriosis epithelium was correlated with PGP9.5 nerve bundle density in superficial lesions (rho: 0.24; P = .007), though neither epithelial nor stromal NGF expression differed significantly between deep dyspareunia groups (P = .88 and P = .89, respectively).

The findings build on a known clinical paradox in endometriosis: disease burden does not reliably predict pain severity.

"An issue we see in endometriosis is that the stage of disease or extent of disease doesn't often equate to the level of pain a patient is experiencing," Sreya said. The neuroproliferative dyspareunia framework proposes a mechanistic explanation—that excess peripheral nerve growth around posterior pelvic lesions produces amplified sensory signaling on contact, specifically with deep penetration.

"On contact, such as in deep dyspareunia, there is amplified pain signaling that leads to that experience," she said.

The concept draws on a parallel with neuroproliferative vestibulodynia, a recognized subtype of vulvodynia also characterized by elevated NGF expression and increased nerve fiber density. The investigators now propose an analogous entity—neuroproliferative dyspareunia—as a distinct subtype defined by its specific biological substrate and clinical presentation.

Sreya was measured about the readiness of these findings for clinical application.

"It's really too early to say that we can apply these findings to clinical practice," she acknowledged, noting that deep dyspareunia in endometriosis remains multifactorial. A patient with neuroproliferative dyspareunia may also have concurrent central sensitization or inflammatory contributors.

"This all goes into developing stronger diagnostic criteria as we continue to research this condition," she said. For now, the study offers a validated biological framework and a basis for future work on targeted diagnostic and therapeutic approaches.

Reference:

1. Sreya M, Williams C, Tucker DR, et al. Neuroproliferative dyspareunia in endometriosis: Validation of a novel subtype of endometriosis-associated sexual pain. Presented at: International Society for the Study of Women's Sexual Health Annual Meeting. February 12-15, 2026. Long Beach, California. Accessed April 21, 2026. Abstract 013