(013) Neuroproliferative Dyspareunia in Endometriosis: Validation of a Novel Subtype of Endometriosis-associated Sexual Pain

Abstract Introduction Neuroproliferative vestibulodynia has been proposed as a subtype of vulvodynia characterized by an increase in nerve growth factor (NGF) expression and nerve fiber density in the vulvar vestibule, leading to superficial dyspareunia. Similarly, in endometriosis, retrospective studies have also shown an increase in NGF expression and nerve fiber density around endometriosis lesions that correlates with deep dyspareunia. Objective The primary objective of this study was to validate the association between nerve fiber (bundle) density, NGF expression, and deep dyspareunia in endometriosis by utilizing a prospective registry. Methods Subjects undergoing initial endometriosis surgery at a tertiary referral center between December 2013 and December 2017 were included based on the presence of endometriosis of the posterior pelvis (ie, cul-de-sac, uterosacral ligaments, rectosigmoid colon). Participants were excluded based on post-menopausal status, malignancy, or bladder and/or pelvic floor tenderness to control for non-neuroproliferative deep dyspareunia cases (eg, related to central sensitization). Blinded immunohistochemical (IHC) scoring for protein-gene-project 9.5 (PGP9.5) nerve bundle density around the endometriosis lesions and for NGF expression by the endometriosis epithelium/stroma were linked to baseline (pre-operative) data on pain symptoms from a prospective registry at the center. First, Spearman correlation was used to investigate sample-level associations between PGP9.5 nerve bundle density and NGF expression, as well as by endometriosis subtype. Second, the mean IHC scores between the high deep dyspareunia defined as: pre-operative deep dyspareunia severity ≥5/10 with reproduced vaginal apex tenderness on pelvic exam by a gynecologist, and low deep dyspareunia defined as: deep dyspareunia severity 5/10 with no vaginal apex tenderness groups were compared using Welch’s t-test. For comparison, the same analysis was done for other pain types without consideration of vaginal apex tenderness: superficial dyspareunia, dysmenorrhea, dyschezia, and chronic pelvic pain. Results This study involved 180 subjects with 276 endometriosis tissue samples, as subjects may have more than one sample of endometriosis. NGF expression in the endometriosis epithelium was associated with PGP9.5 nerve bundle density in superficial endometriosis lesions (rho: 0.24, P = 0.007). For pain, those with high deep dyspareunia (N = 64) had significantly higher mean PGP9.5 nerve bundle density (0.27, SD: 0.51) compared to those with low deep dyspareunia (N = 25) (0.12, SD: 0.09, P = 0.02). In contrast, neither NGF expression in the endometriosis epithelium (P = 0.88) nor the stroma (P = 0.89) significantly differed between the deep dyspareunia groups. No other endometriosis-associated pelvic pain symptoms (superficial dyspareunia, dysmenorrhea, dyschezia, chronic pelvic pain) were associated with nerve bundle density. Conclusions The association between deep dyspareunia and PGP9.5 nerve bundle density around endometriosis of the posterior pelvis was validated in this study utilizing a prospective registry. Therefore, we propose “neuroproliferative dyspareunia” as a distinct subtype of endometriosis-associated deep dyspareunia. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: AbbVie, Pfizer, Ferring, Baxter International, Helix Biopharma, GSK, AstraZeneca, Merck, Mosaica.