Nerve Growth Factor Is Associated With Sexual Pain in Women With Endometriosis

Abstract

Endometriosis is present in 1 in 10 reproductive-age women, and half experience deep dyspareunia (pelvic pain with sexual intercourse). Our objective was to investigate nerve growth factor (NGF) and its receptors (TrkA/p75NTR) in endometriosis-associated deep dyspareunia. A total of 32 women with endometriosis in the posterior pelvic compartment (cul-de-sac/uterosacrals) were included, either with (n = 17) or without (n = 15) deep dyspareunia symptoms confirmed by endovaginal ultrasound-assisted palpation on examination. Expression of NGF, TrkA, and p75NTR in the surgically excised cul-de-sac/uterosacral endometriosis was examined by immunohistochemistry and Histoscore blinded to pain phenotypes. Additionally, endometriotic stromal cells (ESCs; n = 3) from ectopic endometriosis lesions were cultured and incubated with/without NGF and/or Trk inhibitor K252a, followed by expression analysis of prostaglandin-endoperoxide synthase 2 (PTGS-2)/cyclooxygenase 2 (COX-2; reverse transcription quantitative real-time polymerase chain reaction and Western blot) and prostaglandin E2 (PGE2) secretion (enzyme-linked immunosorbent assay). We found that the immunointensity of NGF and TrkA, but not p75NTR, was significantly elevated in endometriotic stroma and epithelium from women with deep dyspareunia compared to women without deep dyspareunia. Nerve growth factor immunoreactivity in the stroma was also significantly associated with deep dyspareunia intensity and local 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 Trk inhibitor K252a. In conclusion, elevated NGF levels were associated with deep dyspareunia in women with cul-de-sac/uterosacral endometriosis. This association may be mediated by increased nerve bundle density and by COX-2/PGE2 stimulation via Trk receptor. Nerve growth factor signaling may play an important role in endometriosis-associated sexual pain.

Plasminogen activator inhibitor-1 (PAI-1) expression in endometriosis

“…Some of these cases overlap with our previous studies: 23 SUP cases were previously used for work on nerve density and nerve growth factor in endometriosis;[10, 11] and 7 DIE cases, 7 OMA cases, and 6 UE cases have been previously used for studies on HOXB4 in endometriosis [12].…”

Neurotrophins and glial cell line-derived neurotrophic factor in the ovary: physiological and pathophysiological implications

“…Emerging evidence has suggested a critical role for NTs in uterine physiology and endometrial pathology (Barcena de Arellano et al , 2013; Wessels et al , 2014). The immunointensity of NGF and TrkA was higher in both the endometriotic stroma and epithelium obtained from women with endometriosis and deep dyspareunia than that in those obtained from women with endometriosis without deep dyspareunia, indicating that NGF signaling may play an important role in endometriosis-associated sexual pain (Peng et al , 2018). A clinical study demonstrated that women with endometriosis had higher levels of NGF in their FF than did patients with male factor infertility (Buyuk and Seifer, 2008).…”

Deep Dyspareunia: Review of Pathophysiology and Proposed Future Research Priorities

“…Pelvic adhesions are common in endometriosis, especially with deep infiltrating endometriosis, and may also contribute to deep dyspareunia [10,11]. With respect to superficial peritoneal endometriosis, one study showed that superficial endometriotic lesions of the pouch of Douglas in women with deep dyspareunia had increased density of nerve bundles, as well as elevated immune-intensity of nerve growth factor and its TrkA receptor, compared to patients with endometriotic lesions of the same anatomic location but without deep dyspareunia [12,13]. These findings suggest that local neurogenesis around endometriosis may also contribute to pain with intercourse [12,13].…”

“…With respect to superficial peritoneal endometriosis, one study showed that superficial endometriotic lesions of the pouch of Douglas in women with deep dyspareunia had increased density of nerve bundles, as well as elevated immune-intensity of nerve growth factor and its TrkA receptor, compared to patients with endometriotic lesions of the same anatomic location but without deep dyspareunia [12,13]. These findings suggest that local neurogenesis around endometriosis may also contribute to pain with intercourse [12,13]. Local inflammation via cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2)-estrogen and other inflammatory positive feedback loops may also contribute to deep dyspareunia in endometriosis [14].…”