Sage Journals: Discover world-class research

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.

Keywords

NGF TrkA endometriosis deep dyspareunia prostaglandin E2

Get full access to this article

View all access options for this article.

References

Bulun

. Endometriosis. N Engl J Med. 2009;360(3):268–279.

Giudice

Kao

. Endometriosis. Lancet. 2004;364(9447):1789–1799.

Heim

. Evaluation and differential diagnosis of dyspareunia. American family physician. 2001;63(8):1535–1544.

Hummelshoj

De Graaff

Dunselman

Vercellini

. Let’s talk about sex and endometriosis. J Fam Plann Reprod Health Care. 2014;40(1):8–10.

Denny

Mann

. Endometriosis-associated dyspareunia: the impact on women’s lives. J Fam Plann Reprod Health Care. 2007;33(3):189–193.

Tripoli

Sato

Sartori

de Araujo

Girao

Schor

. Evaluation of quality of life and sexual satisfaction in women suffering from chronic pelvic pain with or without endometriosis. J Sex Med. 2011;8(2):497–503.

Fauconnier

Chapron

Dubuisson

Vieira

Dousset

Breart

. Relation between pain symptoms and the anatomic location of deep infiltrating endometriosis. Fertil Steril. 2002;78(4):719–726.

Vercellini

Somigliana

Buggio

Barbara

Frattaruolo

Fedele

. “I can’t get no satisfaction”: deep dyspareunia and sexual functioning in women with rectovaginal endometriosis. Fertil Steril. 2012;98(6):1503–1511 e1501.

Ferrero

Ragni

Remorgida

. Deep dyspareunia: causes, treatments, and results. Curr Opin Obstet Gynecol. 2008;20(4):394–399.

10.

Sacco

Portelli

Pollacco

Schembri-Wismayer

Calleja-Agius

. The role of prostaglandin E2 in endometriosis. Gynecol Endocrinol. 2012;28(2):134–138.

11.

Williams

Hoang

Yosef

. Nerve Bundles and Deep Dyspareunia in Endometriosis. Reprod Sci. 2016;23(7):892–901.

12.

Sofroniew

Howe

Mobley

. Nerve growth factor signaling, neuroprotection, and neural repair. Ann Rev Neurosci. 2001;24:1217–1281.

13.

Kelleher

Tewari

McMahon

. Neurotrophic factors and their inhibitors in chronic pain treatment. Neurobiol Dis. 2017;97(pt B):127–138.

14.

Wang

Tokushige

Markham

Fraser

. Rich innervation of deep infiltrating endometriosis. Hum Reprod. 2009;24(4):827–834.

15.

Kajitani

Maruyama

Asada

. Possible involvement of nerve growth factor in dysmenorrhea and dyspareunia associated with endometriosis. Endocr J. 2013;60(10):1155–1164.

16.

Yong

Williams

Allaire

. Laparoscopic inguinal exploration and mesh placement for chronic pelvic pain. JSLS. 2013;17(1):74–81.

17.

Nenutil

Smardova

Pavlova

. Discriminating functional and non-functional p53 in human tumours by p53 and MDM2 immunohistochemistry. J Pathol. 2005;207(3):251–259.

18.

Ehsanian

Brown

. YAP dysregulation by phosphorylation or DeltaNp63-mediated gene repression promotes proliferation, survival and migration in head and neck cancer subsets. Oncogene. 2010;29(46):6160–6171.

19.

Peng

Klausen

Campbell

Leung

Horne

Bedaiwy

. Gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor are expressed at tubal ectopic pregnancy implantation sites. Fertil Steril. 2016;105(6):1620–1627 e1623.

20.

Ryan

Schriock

Taylor

. Isolation, characterization, and comparison of human endometrial and endometriosis cells in vitro. J Clin Endocrinol Metab. 1994;78(3):642–649.

21.

Zhan

Ruan

. Elevated phosphatase of regenerating liver 3 (PRL-3) promotes cytoskeleton reorganization, cell migration and invasion in endometrial stromal cells from endometrioma. Hum Reprod. 2016;31(4):723–733.

22.

Barcena de Arellano

Arnold

Vercellino

Chiantera

Schneider

Mechsner

. Overexpression of nerve growth factor in peritoneal fluid from women with endometriosis may promote neurite outgrowth in endometriotic lesions. Fertil Steril. 2011;95(3):1123–1126.

23.

Barcena de Arellano

Arnold

Vercellino

. Influence of nerve growth factor in endometriosis-associated symptoms. Reprod Sci. 2011;18(12):1202–1210.

24.

Ettinger

Nevo

Marcinkiewicz

Lazarovici

. Nerve growth factor-induced myoprotection in C2C12 muscle cells is mediated by alpha9beta1 integrin via release of PGE2. J Basic Clin Physiol Pharmacol. 2015;26(4):411–415.

25.

Maranesi

Parillo

Leonardi

. Expression of nerve growth factor and its receptors in the uterus of rabbits: functional involvement in prostaglandin synthesis. Domest Anim Endocrinol. 2016;56:20–28.

26.

Toyomoto

Ohta

Okumura

. Prostaglandins are powerful inducers of NGF and BDNF production in mouse astrocyte cultures. FEBS Lett. 2004;562(1-3):211–215.

27.

Marshall

Gomi

Blennerhassett

Bienenstock

. Nerve growth factor modifies the expression of inflammatory cytokines by mast cells via a prostanoid-dependent mechanism. J immunol. 1999;162(7):4271–4276.

28.

Wuhanqimuge

Itakura A

Matsuki

Tanaka

Arioka

. Lysophosphatidylcholine enhances NGF-induced MAPK and Akt signals through the extracellular domain of TrkA in PC12 cells. FEBS Open Bio. 2013;3:243–251.

29.

Korner

Tarantino

Pleskoff

Lee

Debre

. Activation of nuclear factor kappa B in human neuroblastoma cell lines. J Neurochem. 1994;62(5):1716–1726.

30.

Tong

Werrbach-Perez

Perez-Polo

. Prolonged activation of transcription factor AP-1 during NGF-mediated rescue from apoptotic cell death in PC12 cells. Neurochem Res. 1999;24(11):1431–1441.

31.

Nie

Zhao

. IL-17 mediates inflammatory reactions via p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner in human nucleus pulposus cells. J Transl Med. 2016;14:77.

32.

Badawy

Choe

Cohn

Refaie

Stefanu

Cuenca

. Argon laser laparoscopy for treatment of pelvic endometriosis associated with infertility and pelvic pain. J Gynecol Surg. 1991;7(1):27–32.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.27 MB

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

Abstract

Keywords

Get full access to this article

References

Supplementary Material