Skip to main content

Advertisement

Log in

Role of Brain-Derived Neurotrophic Factor in Endometriosis Pain

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Brain-derived neurotrophic factor (BDNF) is a regulator for the formation and maintenance of chronic pain in various chronic disorders and has been shown to increase in the serum of women with endometriosis. However, BDNF expression in the peritoneal fluid (PF) and ectopic lesions and its role in endometriosis pain remain unclear. Thus, this study aims to determine the BDNF concentrations in serum and PFs and BDNF expression levels in ectopic lesions and endometriotic stromal cells (ESCs) of women with endometriosis (n = 60). The obtained results were then compared with those of women without endometriosis (n = 38). Brai n-derived neurotrophic factor concentrations in serum and PF, as well as the BDNF expression levels in ectopic lesions and endometriotic cells, were evaluated through enzyme-linked immunosorbent assay, immunohistochemical staining, quantitative real-time polymerase chain reaction, and Western blot analysis. As a result, BDNF concentrations in serum and PF were significantly higher in women with endometriosis with pain (2284.3 ± 51.5pg/mL, n = 23;58.8 ± 6.4pg/mL, n = 16) than in women with endometriosis without pain (1999.8 ± 61.1 pg/mL, n = 37; 31.7 ± 2.9 pg/mL, n = 25; P <.01). Moreover, BDNF messenger RNA (mRNA) expression levels in ectopic lesions (8.97 ± 1.44, n = 29) were significantly higher than eutopic (0.97 ± 0.14, n = 16; P <.01) and control endometrium (1.23 ± 0.19, n = 18; P <.01) and were correlated with endometriosis pain (P <.05). Furthermore, increased BDNF mRNA and protein expression levels in ESCs induced by estradiol or interleukin 1α were removed using a phosphorylated extracellular-regulated protein kinase 1/2 inhibitor. These results suggest that BDNF may play an important role in the pathogenesis of endometriosis pain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Strathy JH, Molgaard CA, Coulam CB, Melton LJ III. Endometriosis and infertility: a laparoscopic study of endometriosis among fertile and infertile women. Fertil Steril. 1982;38(6):667–672.

    Article  CAS  PubMed  Google Scholar 

  2. Nnoaham KE, Hummelshoj L, Webster P, et al. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011;96(2):366–373.e8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Jacoby VL, Fujimoto VY, Giudice LC, Kuppermann M, Washington AE. Racial and ethnic disparities in benign gynecologic conditions and associated surgeries. Am J Obstet Gynecol. 2010;202(6):514–521.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sangi-Haghpeykar H, Poindexter AN III. Epidemiology of endometriosis among parous women. Obstet Gynecol. 1995;85(6): 983–992.

    Article  CAS  PubMed  Google Scholar 

  5. Houston DE. Evidence for the risk of pelvic endometriosis by age, race and socioeconomic status. Epidemiol Rev. 1984;6:167–191.

    Article  CAS  PubMed  Google Scholar 

  6. Sales KJ, Jabbour HN. Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium. Reproduction. 2003;126(5):559–567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sikora J, Mielczarek-Palacz A, Kondera-Anasz Z. Imbalance in cytokines from interleukin-1 family—role in pathogenesis of endometriosis. Am J Reprod Immunol. 2012;68(2):138–145.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang X, Yao H, Huang X, Lu B, Xu H, Zhou C. Nerve fibres in ovarian endometriotic lesions in women with ovarian endometriosis. Hum Reprod. 2010;25(2):392–397.

    Article  PubMed  CAS  Google Scholar 

  9. Barcena de Arellano ML, Munch S, Arnold J, Helbig S, Schneider A, Mechsner S. Calcium-binding protein expression in peritoneal endometriosis-associated nerve fibres. Eur J Pain. 2013;17(10):1425–1437.

    Google Scholar 

  10. Kobayashi H, Yamada Y, Morioka S, Niiro E, Shigemitsu A, Ito F. Mechanism of pain generation for endometriosis-associated pelvic pain. Arch Gynecol Obstet. 2014;289(1):13–21.

    Article  CAS  PubMed  Google Scholar 

  11. McKinnon BD, Bertschi D, Bersinger NA, Mueller MD. Inflammation and nerve fiber interaction in endometriotic pain. Trends Endocrinol Metab. 2015;26(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  12. Barcena de Arellano ML, Arnold J, Lang H, et al. Evidence of neurotrophic events due to peritoneal endometriotic lesions. Cytokine. 2013;62(2):253–261.

    Article  CAS  Google Scholar 

  13. Barcena de Arellano ML, Arnold J, Vercellino F, Chiantera V, Schneider A, Mechsner S. 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.

    Article  CAS  Google Scholar 

  14. Deitos A, Dussan-Sarria JA, Souza A, et al. Clinical value of serum neuroplasticity mediators in identifying the central sensitivity syndrome in patients with chronic pain with and without structural pathology. Clin J Pain. 2015;31(11): 959–967.

    Google Scholar 

  15. Schwertner A, Conceicao Dos Santos CC, Costa GD, et al. Efficacy of melatonin in the treatment of endometriosis: a phase II, randomized, double-blind, placebo-controlled trial. Pain. 2013;154(6):874–881.

    Article  CAS  PubMed  Google Scholar 

  16. Kras JV, Weisshaar CL, Quindlen J, Winkelstein BA. Brainderived neurotrophic factor is upregulated in the cervical dorsal root ganglia and spinal cord and contributes to the maintenance of pain from facet joint injury in the rat. J Neurosci Res. 2013;91(10):1312–1321.

    Article  CAS  PubMed  Google Scholar 

  17. Simao AP, Mendonca VA, de Oliveira Almeida TM, et al. Involvement of BDNF in knee osteoarthritis: the relationship with inflammation and clinical parameters. Rheumatol Int. 2014;34(8):1153–1157.

    Article  CAS  PubMed  Google Scholar 

  18. Grimsholm O, Rantapaa-Dahlqvist S, Dalen T, Forsgren S. BDNF in RA: downregulated in plasma following anti-TNF treatment but no correlation with inflammatory parameters. Clin Rheumatol. 2008;27(10):1289–1297.

    Article  PubMed  Google Scholar 

  19. Laske C, Stransky E, Eschweiler GW, et al. Increased BDNF serum concentration in fibromyalgia with or without depression or antidepressants. JPsychiatr Res. 2007;41(7):600–605.

    Article  Google Scholar 

  20. Slack SE, Pezet S, McMahon SB, Thompson SW, Malcangio M. Brain-derived neurotrophic factor induces NMDA receptor subunit one phosphorylation via ERK and PKC in the rat spinal cord. Eur J Neurosci. 2004;20(7):1769–1778.

    Article  PubMed  Google Scholar 

  21. Edelmayer RM, Brederson JD, Jarvis MF, Bitner RS. Biochemical and pharmacological assessment of MAP-kinase signaling along pain pathways in experimental rodent models: a potential tool for the discovery of novel antinociceptive therapeutics. Biochem Pharmacol. 2014;87(3):390–398.

    Article  CAS  PubMed  Google Scholar 

  22. Obata K, Yamanaka H, Dai Y, et al. Differential activation of MAPK in injured and uninjured DRG neurons following chronic constriction injury of the sciatic nerve in rats. Eur J Neurosci. 2004;20(11):2881–2895.

    Article  PubMed  Google Scholar 

  23. Wessels JM, Kay VR, Leyland NA, Agarwal SK, Foster WG. Assessing brain-derived neurotrophic factor as a novel clinical marker of endometriosis. Fertil Steril. 2016;105(1):119–128. e111–e115.

    Article  CAS  PubMed  Google Scholar 

  24. Giannini A, Bucci F, Luisi S, et al. Brain-derived neurotrophic factor in plasma of women with endometriosis. J Endometr. 2010;2(3):144–150.

    Article  Google Scholar 

  25. Rocha AL, Vieira EL, Ferreira MC, Maia LM, Teixeira AL, Reis FM. Plasma brain-derived neurotrophic factor in women with pelvic pain: a potential biomarker for endometriosis? Biomark Med. 2017;11(4):313–317.

    Article  CAS  PubMed  Google Scholar 

  26. Yu X, Ren H, Liu T, Yong M, Zhong H. Expression and significance of ERbeta and TrkB in endometriosis. Clin Exp Obstet Gynecol. 2016;43(1):75–81.

    Article  CAS  PubMed  Google Scholar 

  27. Borghese B, Vaiman D, Mondon F, et al. Neurotrophins and pain in endometriosis [in French]. Gynecol Obstet Fertil. 2010;38(7-8):442–446.

    Article  CAS  PubMed  Google Scholar 

  28. Dewanto A, Dudas J, Glueckert R, et al. Localization of TrkB and p75 receptors in peritoneal and deep infiltrating endometriosis: an immunohistochemical study. Reprod Biol Endocrinol. 2016; 14(1):43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Buyuk E, Seifer DB. Follicular-fluid neurotrophin levels in women undergoing assisted reproductive technology for different etiologies of infertility. Fertil Steril. 2008;90(5):1611–1615.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang QY, Guan Q, Wang Y, et al. BDNF Val66Met polymorphism is associated with stage III-IV endometriosis and poor in vitro fertilization outcome. Hum Reprod. 2012;27(6):1668–1675.

    Article  CAS  PubMed  Google Scholar 

  31. Dong F, Zhang Q, Kong W, et al. Regulation of endometrial cell proliferation by estrogen-induced BDNF signaling pathway. Gynecol Endocrinol. 2017;33(6):485–489.

    Article  CAS  PubMed  Google Scholar 

  32. Zhang X, Qi C, Lin J. Enhanced expressions of matrix metalloproteinase (MMP)-2 and -9 and vascular endothelial growth factors (VEGF) and increased microvascular density in theendometrial hyperplasia of women with anovulatory dysfunctional uterine bleeding. Fertil Steril. 2010;93(7):2362–2367.

    Article  CAS  PubMed  Google Scholar 

  33. Sun Y, Che X, Zhu L, et al. Pigment epithelium derived factor inhibits the growth of human endometrial implants in nude mice and of ovarian endometriotic stromal cells in vitro. PLoS One. 2012;7(9):e45223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Harel S, Jin S, Fisch B, et al. Tyrosine kinase B receptor and its activated neurotrophins in ovaries from human fetuses and adults. Mol Hum Reprod. 2006;12(6):357–365.

    Article  CAS  PubMed  Google Scholar 

  35. Seifer DB, Lambert-Messerlian G, Schneyer AL. Ovarian brainderived neurotrophic factor is present in follicular fluid from normally cycling women. Fertil Steril. 2003;79(2):451–452.

    Article  PubMed  Google Scholar 

  36. Nakahashi T, Fujimura H, Altar CA, et al. Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor. FEBSLett. 2000;470(2):113–117.

    Article  CAS  Google Scholar 

  37. Dissen GA, Garcia-Rudaz C, Ojeda SR. Role of neurotrophic factors in early ovarian development. Semin Reprod Med. 2009; 27(1):24–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Russo N, Russo M, Daino D, et al. Evaluation of brain-derived neurotrophic factor in menstrual blood and its identification in human endometrium. Gynecol Endocrinol. 2012;28(6):492–495.

    Article  CAS  PubMed  Google Scholar 

  39. Christian LM, Mitchell AM, Gillespie SL, Palettas M. Serum brain-derived neurotrophic factor (BDNF) across pregnancy and postpartum: associations with race, depressive symptoms, and low birth weight. Psychoneuroendocrinology. 2016;74:69–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Scott Bitner R. Cyclic AMP response element-binding protein (CREB) phosphorylation: a mechanistic marker in the development of memory enhancing Alzheimer’s disease therapeutics. Biochem Pharmacol. 2012;83(6):705–714.

    Article  CAS  PubMed  Google Scholar 

  41. Ferrero S, Remorgida V, Maganza C, et al. Aromatase and endometriosis: estrogens play a role. Ann N YAcad Sci. 2014;1317:17–23.

    Article  CAS  Google Scholar 

  42. Greaves E, Temp J, Esnal-Zufiurre A, Mechsner S, Horne AW, Saunders PT. Estradiol is a critical mediator ofmacrophage-nerve cross talk in peritoneal endometriosis. Am J Pathol. 2015;185(8):2286–2297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. McKinnon BD, Kocbek V, Nirgianakis K, Bersinger NA, Mueller MD. Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics. Hum Reprod Update. 2016;22(3).

    Google Scholar 

  44. Wu MH, Wang CA, Lin CC, Chen LC, Chang WC, Tsai SJ. Distinct regulation of cyclooxygenase-2 by interleukin-1beta in normal and endometriotic stromal cells. JClin Endocrinol Metab. 2005;90(1):286–295.

    Article  CAS  Google Scholar 

  45. Kight KE, McCarthy MM. Sex differences and estrogen regulation of BDNF gene expression, but not propeptide content, in the developing hippocampus. JNeurosci Res. 2017;95(1–2):345–354.

    Article  CAS  Google Scholar 

  46. Guo JQ, Deng HH, Bo X, Yang XS. Involvement of BDNF/TrkB and ERK/CREB axes in nitroglycerin-induced rat migraine and effects of estrogen on these signals in the migraine. Biol Open. 2017;6(1):8–16.

    CAS  PubMed  Google Scholar 

  47. Tokushige N, Markham R, Russell P, Fraser IS. Nerve fibres in peritoneal endometriosis. Hum Reprod. 2006;21(11): 3001–3007.

    Article  CAS  PubMed  Google Scholar 

  48. Tokushige N, Markham R, Russell P, Fraser IS. Different types of small nerve fibers in eutopic endometrium and myometrium in women with endometriosis. Fertil Steril. 2007;88(4):795–803.

    Article  PubMed  Google Scholar 

  49. Lentz SI, Knudson CM, Korsmeyer SJ, Snider WD. Neurotrophins support the development of diverse sensory axon morphologies. J Neurosci. 1999;19(3):1038–1048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mechsner S, Kaiser A, Kopf A, Gericke C, Ebert A, Bartley J. A pilot study to evaluate the clinical relevance of endometriosisassociated nerve fibers in peritoneal endometriotic lesions. Fertil Steril. 2009;92(6):1856–1861.

    Article  PubMed  Google Scholar 

  51. Howard FM. Endometriosis and mechanisms of pelvic pain. J Minim Invasive Gynecol. 2009;16(5):540–550.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xinmei Zhang MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ding, S., Zhu, T., Tian, Y. et al. Role of Brain-Derived Neurotrophic Factor in Endometriosis Pain. Reprod. Sci. 25, 1045–1057 (2018). https://doi.org/10.1177/1933719117732161

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719117732161

Keywords

Navigation