{"paper_id":"0d602709-2110-471a-9305-9d89517376d2","body_text":"Abstract\nPurpose\nEndometriosis-associated pelvic pain appears due to persistent nociceptive stimulation, but the precise mechanisms remain poorly understood.\nMethods\nA search was conducted to screen and select articles from PubMed.\nMain results\nNeurotrophins (NTs), a family of neuronal growth factors, are overexpressed in endometriosis and encompass NGF, BDNF and NT-3 and NT-4/5. NT receptors, TrkA and p75NTR, and NT receptor-interacting proteins, MAGE and NDN, were also expressed. NTs and their receptors play a role in the development and maintenance of neural tissues in non-neuronal cell types such as endometriosis. Nerve fibers contain unmyelinated sensory C, myelinated sensory Adelta and adrenergic nerve fibers that innervate abnormal cell growths. An increased release of proinflammatory cytokines from endometriotic lesions is responsible for the excessive sensory innervation and development of chronic pelvic pain.\nConclusions\nThe preponderance of the inflammatory milieu and subsequent hyperinnervation might be involved in the pathophysiology of pain generation in women with endometriosis.\nSimilar content being viewed by others\nReferences\nOlive DL, Schwartz LB (1993) Endometriosis. N Engl J Med 328:1759–1769\nTrovó de Marqui AB (2012) Genetic polymorphisms and endometriosis: contribution of genes that regulate vascular function and tissue remodeling. Rev Assoc Med Braz 58:620–632\nAbu-Asab M, Zhang M, Amini D, Abu-Asab N, Amri H (2011) Endometriosis gene expression heterogeneity and biosignature: a phylogenetic analysis. Obstet Gynecol Int 2011:719059. doi:10.1155/2011/719059\nKao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, Osteen K, Lessey BA, Giudice LC (2003) Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology 144:2870–2881\nMatsuzaki S, Canis M, Vaurs-Barrière C, Pouly JL, Boespflug-Tanguy O, Penault-Llorca F, Dechelotte P, Dastugue B, Okamura K, Mage G (2004) DNA microarray analysis of gene expression profiles in deep endometriosis using laser capture microdissection. Mol Hum Reprod 10:719–728\nMettler L, Salmassi A, Schollmeyer T, Schmutzler AG, Püngel F, Jonat W (2007) Comparison of c-DNA microarray analysis of gene expression between eutopic endometrium and ectopic endometrium (endometriosis). J Assist Reprod Genet 24:249–258\nKhan MA, Sengupta J, Mittal S, Ghosh D (2012) Genome-wide expressions in autologous eutopic and ectopic endometrium of fertile women with endometriosis. Reprod Biol Endocrinol 10:84. doi:10.1186/1477-7827-10-84\nShigetomi H, Higashiura Y, Kajihara H, Kobayashi H (2012) A potential link of oxidative stress and cell cycle regulation for development of endometriosis. Gynecol Endocrinol 28:897–902. doi:10.3109/09513590.2012.683071\nWang G, Tokushige N, Markham R, Fraser IS (2009) Rich innervation of deep infiltrating endometriosis. Hum Reprod 24:827–834. doi:10.1093/humrep/den464\nBokor A, Kyama CM, Vercruysse L, Fassbender A, Gevaert O, Vodolazkaia A, De Moor B, Fülöp V, D’Hooghe T (2009) Density of small diameter sensory nerve fibres in endometrium: a semi-invasive diagnostic test for minimal to mild endometriosis. Hum Reprod 24:3025–3032. doi:10.1093/humrep/dep283\nAghaey Meibody F, Mehdizadeh Kashi A, Zare Mirzaie A, Ghajarie Bani Amam M, Shariati Behbahani A, Zolali B, Najafi L (2011) Diagnosis of endometrial nerve fibers in women with endometriosis. Arch Gynecol Obstet 284:1157–1162. doi:10.1007/s00404-010-1806-5\nTriolo O, Laganà AS, Sturlese E (2013) Chronic pelvic pain in endometriosis: an overview. J Clin Med Res. 5:153–163. doi:10.4021/jocmr1288w\nZhang X, Yao H, Huang X, Lu B, Xu H, Zhou C (2010) Nerve fibres in ovarian endometriotic lesions in women with ovarian endometriosis. Hum Reprod 25:392–397. doi:10.1093/humrep/dep427\nDai Y, Leng JH, Lang JH, Li XY, Zhang JJ (2012) Anatomical distribution of pelvic deep infiltrating endometriosis and its relationship with pain symptoms. Chin Med J (Engl) 125:209–213\nPark SG, Choi JW, Kim Hj, Roh GS, Bok J, Go MJ, Kwack K, Oh B, Kim Y (2008) Genome-wide profiling of antigen-induced time course expression using murine models for acute and chronic asthma. Int Arch Allergy Immunol 146:44–56\nEllis A, Bennett DL (2013) Neuroinflammation and the generation of neuropathic pain. Br J Anaesth 111:26–37. doi:10.1093/bja/aet128\nDefrère S, González-Ramos R, Lousse JC, Colette S, Donnez O, Donnez J, Van Langendonckt A (2011) Insights into iron and nuclear factor-kappa B (NF-kappaB) involvement in chronic inflammatory processes in peritoneal endometriosis. Histol Histopathol 26:1083–1092\nTokushige N, Russell P, Black K, Barrera H, Dubinovsky S, Markham R, Fraser IS (2010) Nerve fibers in ovarian endometriomas. Fertil Steril 94:1944–1947. doi:10.1016/j.fertnstert.2009.12.074\nJoseph EK, Green PG, Bogen O, Alvarez P, Levine JD (2013) Vascular endothelial cells mediate mechanical stimulation-induced enhancement of endothelin hyperalgesia via activation of P2X2/3 receptors on nociceptors. J Neurosci 33:2849–2859. doi:10.1523/JNEUROSCI.3229-12.2013\nBates D, Taylor GI, Minichiello J, Farlie P, Cichowitz A, Watson N, Klagsbrun M, Mamluk R, Newgreen DF (2003) Neurovascular congruence results from a shared patterning mechanism that utilizes Semaphorin3A and Neuropilin-1. Dev Biol 255:77–98\nTokushige N, Markham R, Russell P, Fraser IS (2006) High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis. Hum Reprod 21:782–787\nAl-Jefout M, Dezarnaulds G, Cooper M, Tokushige N, Luscombe GM, Markham R, Fraser IS (2009) Diagnosis of endometriosis by detection of nerve fibres in an endometrial biopsy: a double blind study. Hum Reprod 24:3019–3024. doi:10.1093/humrep/dep275\nBarcena de Arellano ML, Arnold J, Sacher F, Blöchle M, Staube M, Bartley J, Vercellino GF, Chiantera V, Schneider A, Mechsner S (2012) Eutopic endometrium from women with endometriosis does not exhibit neurotrophic properties. J Neuroimmunol 249:49–55. doi:10.1016/j.jneuroim.2012.04.020\nTokushige N, Markham R, Russell P, Fraser IS (2006) Nerve fibres in peritoneal endometriosis. Hum Reprod 21:3001–3007\nArnold J, Barcena de Arellano ML, Rüster C, Vercellino GF, Chiantera V, Schneider A, Mechsner S (2012) Imbalance between sympathetic and sensory innervation in peritoneal endometriosis. Brain Behav Immun 26:132–141. doi:10.1016/j.bbi.2011.08.004\nFerrero S, Haas S, Remorgida V, Camerini G, Fulcheri E, Ragni N, Straub RH, Capellino S (2010) Loss of sympathetic nerve fibers in intestinal endometriosis. Fertil Steril 94:2817–2819\nChapron C, Fauconnier A, Dubuisson JB, Barakat H, Vieira M, Bréart G (2003) Deep infiltrating endometriosis: relation between severity of dysmenorrhoea and extent of disease. Hum Reprod 18:760–766\nMay KE, Villar J, Kirtley S, Kennedy SH, Becker CM (2011) Endometrial alterations in endometriosis: a systematic review of putative biomarkers. Hum Reprod Update 17:637–653. doi:10.1093/humupd/dmr013\nCaterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313\nLiu J, Liu X, Duan K, Zhang Y, Guo SW (2012) The expression and functionality of transient receptor potential vanilloid 1 in ovarian endometriomas. Reprod Sci 19:1110–1124. doi:10.1177/1933719112443876\nSantanam N, Kavtaradze N, Murphy A, Dominguez C, Parthasarathy S (2013) Antioxidant supplementation reduces endometriosis-related pelvic pain in humans. Transl Res 161:189–195. doi:10.1016/j.trsl.2012.05.001\nAbu El-Asrar AM, Mohammad G, De Hertogh G, Nawaz MI, Van Den Eynde K, Siddiquei MM, Struyf S, Opdenakker G, Geboes K (2013) Neurotrophins and neurotrophin receptors in proliferative diabetic retinopathy. PLoS One 8:e65472. doi:10.1371/journal.pone.0065472\nBarcena de Arellano ML, Arnold J, Lang H, Vercellino GF, Chiantera V, Schneider A, Mechsner S (2013) Evidence of neurotrophic events due to peritoneal endometriotic lesions. Cytokine 62:253–261. doi:10.1016/j.cyto.2013.03.003\nYe Y, Dang D, Zhang J, Viet CT, Lam DK, Dolan JC, Gibbs JL, Schmidt BL (2011) Nerve growth factor links oral cancer progression, pain, and cachexia. Mol Cancer Ther 10:1667–1676. doi:10.1158/1535-7163.MCT-11-0123\nOrita S, Ishikawa T, Miyagi M, Ochiai N, Inoue G, Eguchi Y, Kamoda H, Arai G, Toyone T, Aoki Y, Kubo T, Takahashi K, Ohtori S (2011) Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain. BMC Musculoskelet Disord 12:134. doi:10.1186/1471-2474-12-134\nKanai-Azuma M, Kanai Y, Matsuda H, Kurohmaru M, Tachi C, Yazaki K, Hayashi Y (1997) Nerve growth factor promotes giant-cell transformation of mouse trophoblast cells in vitro. Biochem Biophys Res Commun 231:309–315\nSaruta J, Iida M, Kondo Y, To M, Hayashi T, Hori M, Sato S, Tsukinoki K (2012) Chronic stress induces neurotrophin-3 in rat submandibular gland. Yonsei Med J 53:1085–1092. doi:10.3349/ymj.2012.53.6.1085\nBeggs S, Alvares D, Moss A, Currie G, Middleton J, Salter MW, Fitzgerald M (2012) A role for NT-3 in the hyperinnervation of neonatally wounded skin. Pain 153:2133–2139. doi:10.1016/j.pain.2012.07.012\nBrowne AS, Yu J, Huang RP, Francisco AM, Sidell N, Taylor RN (2012) Proteomic identification of neurotrophins in the eutopic endometrium of women with endometriosis. Fertil Steril 98:713–719. doi:10.1016/j.fertnstert.2012.05.027\nZhang QY, Guan Q, Wang Y, Feng X, Sun W, Kong FY, Wen J, Cui W, Yu Y, Chen ZY (2012) BDNF Val66Met polymorphism is associated with Stage III-IV endometriosis and poor in vitro fertilization outcome. Hum Reprod 27:1668–1675. doi:10.1093/humrep/des094\nGeetha T, Rege SD, Mathews SE, Meakin SO, White MF, Babu JR (2013) Nerve growth factor receptor TrkA, a new receptor in insulin signaling pathway in PC12 cells. J Biol Chem 288:23807–23813 (Epub ahead of print)\nJung EJ, Lee SY, Kim CW (2013) Proteomic analysis of novel targets associated with TrkA-mediated tyrosine phosphorylation signaling pathways in SK-N-MC neuroblastoma cells. Proteomics 13:355–367. doi:10.1002/pmic.201200251\nHaley B, Paunesku T, Protić M, Woloschak GE (2009) Response of heterogeneous ribonuclear proteins (hnRNP) to ionising radiation and their involvement in DNA damage repair. Int J Radiat Biol 85:643–655. doi:10.1080/09553000903009548\nAnger DL, Zhang B, Boutross-Tadross O, Foster WG (2007) Tyrosine receptor kinase B (TrkB) protein expression in the human endometrium. Endocrine 31:167–173\nMatsuzaki S, Canis M, Pouly JL, Botchorishvili R, Déchelotte PJ, Mage G (2007) Both GnRH agonist and continuous oral progestin treatments reduce the expression of the tyrosine kinase receptor B and mu-opioid receptor in deep infiltrating endometriosis. Hum Reprod 22:124–128\nKawamura K, Kawamura N, Sato W, Fukuda J, Kumagai J, Tanaka T (2009) Brain-derived neurotrophic factor promotes implantation and subsequent placental development by stimulating trophoblast cell growth and survival. Endocrinology 150:3774–3782. doi:10.1210/en.2009-0213\nReichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 361:1545–1564\nTokushige N, Markham R, Russell P, Fraser IS (2009) Effect of progestogens and combined oral contraceptives on nerve fibers in peritoneal endometriosis. Fertil Steril 92:1234–1239. doi:10.1016/j.fertnstert.2008.07.1774\nXiao J, Chen HS (2004) Biological functions of melanoma-associated antigens. World J Gastroenterol 10:1849–1853\nSaburi S, Nadano D, Akama TO, Hirama K, Yamanouchi K, Naito K, Tojo H, Tachi C, Fukuda MN (2001) The trophinin gene encodes a novel group of MAGE proteins, magphinins, and regulates cell proliferation during gametogenesis in the mouse. J Biol Chem 276:49378–49389\nMouri A, Noda Y, Watanabe K, Nabeshima T (2013) The roles of MAGE-D1 in the neuronal functions and pathology of the central nervous system. Rev Neurosci 24:61–70. doi:10.1515/revneuro-2012-0069\nKuwako K, Hosokawa A, Nishimura I, Uetsuki T, Yamada M, Nada S, Okada M, Yoshikawa K (2005) Disruption of the paternal necdin gene diminishes TrkA signaling for sensory neuron survival. J Neurosci 25:7090–7099\nKuwajima T, Hasegawa K, Yoshikawa K (2010) Necdin promotes tangential migration of neocortical interneurons from basal forebrain. J Neurosci 30:3709–3714. doi:10.1523/JNEUROSCI.5797-09.2010\nMiller NL, Wevrick R, Mellon PL (2009) Necdin, a Prader-Willi syndrome candidate gene, regulates gonadotropin-releasing hormone neurons during development. Hum Mol Genet 18:248–260. doi:10.1093/hmg/ddn344\nKurita M, Kuwajima T, Nishimura I, Yoshikawa K (2006) Necdin downregulates CDC2 expression to attenuate neuronal apoptosis. J Neurosci 26:12003–12013\nSugihara K, Kabir-Salmani M, Byrne J, Wolf DP, Lessey B, Iwashita M, Aoki D, Nakayama J, Fukuda MN (2008) Induction of trophinin in human endometrial surface epithelia by CGbeta and IL-1beta. FEBS Lett 582:197–202\nWang HY, Xing FQ, Chen SL (2002) Expression of trophinin in the cycling endometrium and its association with infertility. Di Yi Jun Yi Da Xue Xue Bao 22:539–541\nPodgaec S, Abrao MS, Dias JA Jr, Rizzo LV, de Oliveira RM, Baracat EC (2007) Endometriosis: an inflammatory disease with a Th2 immune response component. Hum Reprod 22:1373–1379\nAntsiferova YS, Sotnikova NY, Posiseeva LV, Shor AL (2005) Changes in the T-helper cytokine profile and in lymphocyte activation at the systemic and local levels in women with endometriosis. Fertil Steril 84:1705–1711\nBesser M, Wank R (1999) Cutting edge: clonally restricted production of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2-polarized expression of their receptors. J Immunol 162:6303–6306\nBuchman VL, Sporn M, Davies AM (1994) Role of transforming growth factor-beta isoforms in regulating the expression of nerve growth factor and neurotrophin-3 mRNA levels in embryonic cutaneous cells at different stages of development. Development 120:1621–1629\nLi HY, Chen YJ, Chen SJ, Kao CL, Tseng LM, Lo WL, Chang CM, Yang DM, Ku HH, Twu NF, Liao CY, Chiou SH, Chang YL (2010) Induction of insulin-producing cells derived from endometrial mesenchymal stem-like cells. J Pharmacol Exp Ther 335:817–829. doi:10.1124/jpet.110.169284\nYi T, Song SU (2012) Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications. Arch Pharm Res 35:213–221. doi:10.1007/s12272-012-0202-z\nKunz G, Herbertz M, Beil D, Huppert P, Leyendecker G (2007) Adenomyosis as a disorder of the early and late human reproductive period. Reprod Biomed Online 15:681–685\nKissler S, Zangos S, Kohl J, Wiegratz I, Rody A, Gätje R, Vogl TJ, Kunz G, Leyendecker G, Kaufmann M (2008) Duration of dysmenorrhoea and extent of adenomyosis visualised by magnetic resonance imaging. Eur J Obstet Gynecol Reprod Biol 137:204–209\nLi Y, Zhang SF, Zou SE, Xia X, Bao L (2011) Accumulation of nerve growth factor and its receptors in the uterus and dorsal root ganglia in a mouse model of adenomyosis. Reprod Biol Endocrinol 9:30. doi:10.1186/1477-7827-9-30\nDonnez J, Nisolle M (1995) Advanced laparoscopic surgery for the removal of rectovaginal septum endometriotic or adenomyotic nodules. Baillieres Clin Obstet Gynaecol 9:769–774\nAcknowledgments\nThe present review was supported by grant-in-aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan to the Department of Obstetrics and Gynecology, Nara Medical University (to H.K.).\nConflict of interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nRights and permissions\nAbout this article\nCite this article\nKobayashi, H., Yamada, Y., Morioka, S. et al. Mechanism of pain generation for endometriosis-associated pelvic pain. Arch Gynecol Obstet 289, 13–21 (2014). https://doi.org/10.1007/s00404-013-3049-8\nReceived:\nAccepted:\nPublished:\nIssue date:\nDOI: https://doi.org/10.1007/s00404-013-3049-8","source_license":"public-domain-us","license_restricted":false}