Peng Bo, Zhan Hong, Alotaibi Fahad, Alkusayer Ghadeer M, Bedaiwy Mohamed A, Yong Paul J
1 Department of Obstetrics & Gynaecology, The University of British Columbia, Vancouver, British Columbia, Canada.
2 Child & Family Research Institute, Vancouver, British Columbia, Canada.
Reprod Sci. 2018 Apr;25(4):540-549. doi: 10.1177/1933719117716778. Epub 2017 Jul 4.
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.
子宫内膜异位症在每10名育龄女性中就有1例存在，其中半数经历深部性交困难（性交时盆腔疼痛）。我们的目的是研究神经生长因子（NGF）及其受体（TrkA/p75NTR）在子宫内膜异位症相关深部性交困难中的作用。共纳入32例盆腔后间隙（直肠子宫陷凹/子宫骶骨韧带）子宫内膜异位症女性患者，其中有深部性交困难症状（经阴道超声辅助触诊检查确诊，n = 17）和无深部性交困难症状（n = 15）的患者各占一半。通过免疫组织化学和对疼痛表型不知情的组织评分，检测手术切除的直肠子宫陷凹/子宫骶骨韧带子宫内膜异位症组织中NGF、TrkA和p75NTR的表达。此外，培养来自异位子宫内膜异位症病灶的子宫内膜间质细胞（ESC；n = 3），并分别在有或无NGF和/或Trk抑制剂K252a的情况下进行孵育，随后进行前列腺素内过氧化物合酶2（PTGS-2）/环氧化酶2（COX-2；逆转录定量实时聚合酶链反应和蛋白质印迹法）的表达分析以及前列腺素E2（PGE2）分泌（酶联免疫吸附测定）。我们发现，与无深部性交困难的女性相比，有深部性交困难的女性子宫内膜异位症间质和上皮中NGF和TrkA的免疫强度显著升高，但p75NTR没有升高。间质中的神经生长因子免疫反应性也与深部性交困难强度和局部神经束密度显著相关。在培养的ESC中，NGF显著增加PTGS-2/COX-2 mRNA和蛋白质水平以及PGE2分泌，而Trk抑制剂K252a预处理可消除这些作用。总之，NGF水平升高与直肠子宫陷凹/子宫骶骨韧带子宫内膜异位症女性的深部性交困难有关。这种关联可能是由神经束密度增加以及通过Trk受体的COX-2/PGE2刺激介导的。神经生长因子信号传导可能在子宫内膜异位症相关性疼痛中起重要作用。
