Elevated Nerve Growth Factor and its Receptor Levels in Endometriotic Tissues are Associated with Deep Dyspareunia

CONTEXT; Deep dyspareunia (pelvic pain with sexual intercourse) affects half of women with endometriosis, but the underlying mechanisms are unclear. OBJECTIVE: To investigate whether nerve growth factor (NGF) and its receptor (TrkA/p75NTR) levels in endometriotic tissues are elevated in women with deep dyspareunia. DESIGN: In vitro study. SETTING: University hospital affiliated research laboratories. PATIENTS: 34 women with endometriosis in the posterior pelvic compartment (cul-de-sac/uterosacrals) were included, either with (n=18) or without (n=16) deep dyspareunia symptoms which was confirmed by endovaginal ultrasound-assisted palpation on examination. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Utilizing surgically excised cul-de-sac/uterosacral endometriosis, expression of NGF/TrkA/p75NTR was examined by immunohistochemistry and Histoscore. Cultured endometriotic stromal cells (ESCs, n=3) were incubated with/without NGF and/or Trk inhibitor K252a. Prostaglandin-endoperoxide synthase-2 (PGST-2/COX-2) mRNA and protein levels were examined by RT-qPCR and Western blot, respectively. Prostaglandin E2 (PGE2) secretion were examined by ELISA. RESULTS: NGF/TrkA/p75NTR were expressed in the epithelium and stroma of the cul-de- sac/uterosacral endometriosis, and were significantly elevated in women with deep dyspareunia compared to women without deep dyspareunia. NGF immunoreactivity in the stroma was also significantly associated with deep dyspareunia severity and with nerve bundle density. In cultured ESCs, NGF significantly increased PTGS-2/COX-2 mRNA and protein levels as well as PGE2 secretion, and these effects could be abolished by pretreatment of K252a. CONCLUSIONS: Elevated NGF/TrkA/p75NTR levels may be associated with sexual pain (deep dyspareunia) in women with cul-de-sac/uterosacral endometriosis. This association may be mediated by an increase in nerve bundle density and by COX-2 and PGE2 stimulation via Trk receptor.Medicine, Faculty ofOther UBCObstetrics and Gynaecology, Department ofUnreviewedFacult