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Pain Mechanisms in Peritoneal Diseases Might Be Partially Regulated by Estrogen

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Abstract

To identify factors influencing the differential pain pathogenesis in peritoneal endometriosis (pEM) and peritoneal carcinomatosis in ovarian cancer (pOC), we undertook an experimental study. Tissue samples of 18 patients with pEM, 15 patients with pOC, and 15 unaffected peritoneums as controls were collected during laparoscopy or laparotomy. Immunohistochemical stainings were conducted to identify nerve fibers and neurotrophins in the tissue samples. Additionally, 23 pEM fluids, 25 pOC ascites fluids, and 20 peritoneal fluids of patients with myoma uteri as controls were collected. In these fluids, the expression of neurotrophins was evaluated. The effects of peritoneal fluids and ascites on the neurite outgrowth of chicken sensory ganglia were estimated by using a neuronal growth assay. An electrochemiluminescence immunoassay was carried out to determine the expression of estrogen in the peritoneal fluids and ascites. The total and sensory nerve fiber density was significantly higher in pEM than in pOC (P <.001 and P <.01). All neurotrophins tested were present in tissue and fluid samples of pEM and pOC. Furthermore, the neurotrophic properties of pEM and pOC fluids were demonstrated, leading to sensory nerve fiber outgrowth. Estrogen concentration in the peritoneal fluids of pEM was significantly higher compared to ascites of pOC (P <.001). The total and sensory nerve fiber density in the tissue samples as well as the estrogen expression in the peritoneal fluid of pEM was considerably higher than that in pOC, representing the most notable difference found in both diseases. This might explain the differential pain perception in pEM and pOC. Therefore, estrogen might be a key factor in influencing the genesis of pain in endometriosis.

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References

  1. Sikandar S, Dickenson AH. Visceral pain: the ins and outs, the ups and downs. Curr Opin Support Palliat Care. 2012;6(1):17–26.

    Article  PubMed  PubMed Central  Google Scholar 

  2. van Furth R, Raeburn JA, van Zwet TL. Characteristics of human mononuclear phagocytes. Blood. 1979;54(2):485–500.

    Article  PubMed  Google Scholar 

  3. Vigano P, Parazzini F, Somigliana E, Vercellini P. Endometriosis: epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):177–200.

    Article  PubMed  Google Scholar 

  4. Gruppo Italiano per lo Studio dell’Endometriosi. Relationship between stage, site and morphological characteristics of pelvic endometriosis and pain. Hum Reprod. 2001;16(12):2668–2671.

    Article  Google Scholar 

  5. Vercellini P, Fedele L, Aimi G, Pietropaolo G, Consonni D, Crosignani PG. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: amultivariate analysis of over 1000 patients. Hum Reprod. 2007;22(1):266–271.

    Article  CAS  PubMed  Google Scholar 

  6. Goff BA, Mandel LS, Melancon CH, Muntz HG. Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. JAMA. 2004;291(22):2705–2712.

    Article  CAS  PubMed  Google Scholar 

  7. Goff BA, Mandel LS, Drescher CW, et al. Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer. 2007;109(2):221–227.

    Article  PubMed  Google Scholar 

  8. Matsuo K, Ahn EH, Prather CP, Eno ML, Im DD, Rosenshein NB. Patient-reported symptoms and survival in ovarian cancer. IntJ Gynecol Cancer. 2011;21(9):1555–1565.

    Article  Google Scholar 

  9. Heintz AP, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obs. 2006;95(suppl 1): S161–S192.

    Article  Google Scholar 

  10. 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 

  11. Mechsner S, Schwarz J, Thode J, Loddenkemper C, Salomon DS, Ebert AD. Growth-associated protein 43-positive sensory nerve fibers accompanied by immature vessels are located in or near peritoneal endometriotic lesions. Fertil Steril. 2007;88(3): 581–587.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  13. Arnold J, Vercellino GF, Chiantera V, Schneider A, Mechsner S, Barcena de Arellano ML. Neuroimmunomodulatory alterations in non-lesional peritoneum close to peritoneal endometriosis. Neuroimmunomodulation. 2013;20(1):9–18.

    Article  CAS  PubMed  Google Scholar 

  14. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139(2):267–284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pearce FL, Thompson HL. Some characteristics of histamine secretion from rat peritoneal mast cells stimulated with nerve growth factor. J Physiol. 1986;372:379–393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Woolf CJ, Safieh-Garabedian B, Ma QP, Crilly P, Winter J. Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience. 1994;62(2):327–331.

    Article  CAS  PubMed  Google Scholar 

  17. Bennett DL. Neurotrophic factors: important regulators of nociceptive function. Neuroscientist. 2001;7(1):13–17.

    Article  CAS  PubMed  Google Scholar 

  18. Eskander MA, Ruparel S, Green DP, et al. Persistent nociception triggered by nerve growth factor (NGF) is mediated by TRPV1 and oxidative mechanisms. JNeurosci. 2015;35(22):8593-603.

    Article  CAS  Google Scholar 

  19. Haney AF, Muscato JJ, Weinberg JB. Peritoneal fluid cell populations in infertility patients. Fertil Steril. 1981;35(6):696–698.

    Article  CAS  PubMed  Google Scholar 

  20. Olive DL, Weinberg JB, Haney AF. Peritoneal macrophages and infertility: the association between cell number and pelvic pathology. Fertil Steril. 1985;44(6):772–777.

    Article  CAS  PubMed  Google Scholar 

  21. Dunselman GA, Hendrix MG, Bouckaert PX, Evers JL. Functional aspects of peritoneal macrophages in endometriosis of women. J Reprod Fertil. 1988;82(2):707–710.

    Article  CAS  PubMed  Google Scholar 

  22. Khan KN, Masuzaki H, Fujishita A, Kitajima M, Sekine I, Ishimaru T. Differential macrophage infiltration in early and advanced endometriosis and adjacent peritoneum. Fertil Steril. 2004;81(3):652–661.

    Article  PubMed  Google Scholar 

  23. Tran LV, Tokushige N, Berbic M, Markham R, Fraser IS. Macro-phages and nerve fibres in peritoneal endometriosis. Hum Reprod. 2009;24(4):835–841.

    Article  CAS  PubMed  Google Scholar 

  24. Bolin LM, Murray R, Lukacs NW, et al. Primary sensory neurons migrate in response to the chemokine RANTES. JNeuroimmunol. 1998;81(1-2):49–57.

    Article  CAS  Google Scholar 

  25. George A, Schmidt C, Weishaupt A, Toyka KV, Sommer C. Serial determination of tumor necrosis factor-alpha content in rat sciatic nerve after chronic constriction injury. Exp Neurol. 1999;160(1):124–132.

    Article  CAS  PubMed  Google Scholar 

  26. Murphy PG, Ramer MS, Borthwick L, Gauldie J, Richardson PM, Bisby MA. Endogenous interleukin-6 contributes to hypersensitivity to cutaneous stimuli and changes in neuropeptides associated with chronic nerve constriction in mice. Eur J Neurosci. 1999;11(7):2243–2253.

    Article  CAS  PubMed  Google Scholar 

  27. Beste MT, Pfaffle-Doyle N, Prentice EA, et al. Molecular network analysis of endometriosis reveals a role for c-Jun-regulated macrophage activation. Sci Transl Med. 2014;6(222):222ra16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Ting AY, Blacklock AD, Smith PG. Estrogen regulates vaginal sensory and autonomic nerve density in the rat. Biol Reprod. 2004;71(4):1397–1404.

    Article  CAS  PubMed  Google Scholar 

  29. Blacklock AD, Cauveren JA, Smith PG. Estrogen selectively increases sensory nociceptor innervation of arterioles in the female rat. Brain Res. 2004;1018(1):55–65.

    Article  CAS  PubMed  Google Scholar 

  30. Chaban V. Estrogen and visceral nociception at the level of primary sensory neurons. Pain Res Treat. 2012;2012(2012). pii:960780.

    PubMed  Google Scholar 

  31. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med. 1991;324(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  32. Berkley KJ, Dmitrieva N, Curtis KS, Papka RE. Innervation of ectopic endometrium in a rat model of endometriosis. Proc Natl AcadSci USA. 2004;101(30):11094–11098.

    Article  CAS  Google Scholar 

  33. Eisermann J, Gast MJ, Pineda J, Odem RR, Collins JL. Tumor necrosis factor in peritoneal fluid of women undergoing laparoscopic surgery. Fertil Steril. 1988;50(4):573–579.

    Article  CAS  PubMed  Google Scholar 

  34. Tseng JF, Ryan IP, Milam TD, et al. Interleukin-6 secretion in vitro is up-regulated in ectopic and eutopic endometrial stromal cells from women with endometriosis. J Clin Endocrinol Metab. 1996;81(3):1118–1122.

    CAS  PubMed  Google Scholar 

  35. Punnonen J, Teisala K, Ranta H, Bennett B, Punnonen R. Increased levels of interleukin-6 and interleukin-10 in the peritoneal fluid of patients with endometriosis. Am J Obs Gynecol. 1996;174(5):1522–1526.

    Article  CAS  Google Scholar 

  36. Arici A, Tazuke SI, Attar E, Kliman HJ, Olive DL. Interleukin-8 concentration in peritoneal fluid of patients with endometriosis and modulation of interleukin-8 expression in human mesothelial cells. Mol Hum Reprod. 1996;2(1):40–45.

    Article  CAS  PubMed  Google Scholar 

  37. Gazvani MR, Christmas S, Quenby S, Kirwan J, Johnson PM, Kingsland CR. Peritoneal fluid concentrations of interleukin-8 in women with endometriosis: relationship to stage of disease. Hum Reprod. 1998;13(7):1957–1961.

    Article  CAS  PubMed  Google Scholar 

  38. Wang XQ, Yu J, Luo XZ, et al. The high level of RANTES in the ectopic milieu recruits macrophages and induces their tolerance in progression of endometriosis. J Mol Endocrinol. 2010;45(5): 291–299.

    Article  CAS  PubMed  Google Scholar 

  39. Charbonneau B, Goode EL, Kalli KR, Knutson KL, Derycke MS. The immune system in the pathogenesis of ovarian cancer. Crit Rev Immunol. 2013;33(2):137–164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Aloe L, Levi-Montalcini R. Mast cells increase in tissues of neonatal rats injected with the nerve growth factor. Brain Res. 1977;133(2):358–366.

    Article  CAS  PubMed  Google Scholar 

  41. Susaki Y, Shimizu S, Katakura K, et al. Functional properties of murine macrophages promoted by nerve growth factor. Blood. 1996;88(12):4630–4637.

    Article  CAS  PubMed  Google Scholar 

  42. Safieh-Garabedian B, Poole S, Allchorne A, Winter J, Woolf CJ. Contribution of interleukin-1 beta to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia. Br J Pharmacol. 1995;115(7):1265–1275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhou XF, Deng YS, Xian CJ, Zhong JH. Neurotrophins from dorsal root ganglia trigger allodynia after spinal nerve injury in rats. Eur JNeurosci. 2000;12(1):100–105.

    Article  CAS  Google Scholar 

  44. Apfel SC, Wright DE, Wiideman AM, Dormia C, Snider WD, Kessler JA. Nerve growth factor regulates the expression of brainderived neurotrophic factor mRNA in the peripheral nervous system. Mol Cell Neurosci. 1996;7(2):134–142.

    Article  CAS  PubMed  Google Scholar 

  45. Cho HJ, Kim SY, Park MJ, Kim DS, Kim JK, Chu MY. Expression of mRNA for brain-derived neurotrophic factor in the dorsal root ganglion following peripheral inflammation. Brain Res. 1997;749(2):358–362.

    Article  CAS  PubMed  Google Scholar 

  46. Cho HJ, Kim JK, Zhou XF, Rush RA. Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation. Brain Res. 1997;764(1-2):269–272.

    Article  CAS  PubMed  Google Scholar 

  47. Malcangio M, Garrett NE, Cruwys S, Tomlinson DR. Nerve growth factor- and neurotrophin-3-induced changes in nociceptive threshold and the release of substance P from the rat isolated spinal cord. J Neurosci. 1997;17(21):8459–8467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Helgren ME, Cliffer KD, Torrento K, et al. Neurotrophin-3 administration attenuates deficits of pyridoxine-induced largefiber sensory neuropathy. J Neurosci. 1997;17(1):372–382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Barcena de Arellano ML, Arnold J, Vercellino GF, et al. Influence of nerve growth factor in endometriosis-associated symptoms. Reprod Sci. 2011;18(12):1202–1210.

    Article  CAS  Google Scholar 

  50. 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 

  51. Kajitani T, Maruyama T, Asada H, et al. Possible involvement of nerve growth factor in dysmenorrhea and dyspareunia associated with endometriosis. Endocr J. 2013;60(10):1155–1164.

    Article  CAS  PubMed  Google Scholar 

  52. Davidson B, Reich R, Lazarovici P, et al. Expression and activation of the nerve growth factor receptor TrkA in serous ovarian carcinoma. Clin Cancer Res. 2003;9(6):2248–2259.

    CAS  PubMed  Google Scholar 

  53. Campos X, Munoz Y, Selman A, et al. Nerve growth factor and its high-affinity receptor trkA participate in the control of vascular endothelial growth factor expression in epithelial ovarian cancer. Gynecol Oncol. 2007;104(1):168–175.

    Article  CAS  PubMed  Google Scholar 

  54. Arnold J, Barcena de Arellano ML, Ruster C, et al. Imbalance between sympathetic and sensory innervation in peritoneal endometriosis. Brain Behav Immun. 2012;26(1):132–141.

    Article  CAS  PubMed  Google Scholar 

  55. Blacklock AD, Johnson MS, Krizsan-Agbas D, Smith PG. Estrogen increases sensory nociceptor neuritogenesis in vitro by a direct, nerve growth factor-independent mechanism. Eur J Neurosci. 2005;21(9):2320–2328.

    Article  CAS  PubMed  Google Scholar 

  56. Cho T, Chaban VV. Expression of P2X3 and TRPV1 receptors in primary sensory neurons from estrogen receptors-a and estrogen receptor-b knockout mice. Neuroreport. 2012;23(9):530–534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rowan MP, Berg KA, Roberts JL, Hargreaves KM, Clarke WP. Activation of estrogen receptor a enhances bradykinin signaling in peripheral sensory neurons of female rats. J Pharmacol Exp Ther. 2014;349(3):526–532.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Ferreira A, Caceres A. Estrogen-enhanced neurite growth: evidence for a selective induction of Tau and stable microtubules. J Neurosci. 1991;11(2):392–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Brinton RD, Tran J, Proffitt P, Montoya M. 17 beta-Estradiol enhances the outgrowth and survival of neocortical neurons in culture. Neurochem Res. 1997;22(11):1339–1351.

    Article  CAS  PubMed  Google Scholar 

  60. Chakrabarty A, Blacklock A, Svojanovsky S, Smith PG. Estrogen elicits dorsal root ganglion axon sprouting via a renin-angiotensin system. Endocrinology. 2008;149(7):3452–3460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Sylvia Mechsner PhD.

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Börner, C., Scheerer, C., Buschow, R. et al. Pain Mechanisms in Peritoneal Diseases Might Be Partially Regulated by Estrogen. Reprod. Sci. 25, 424–434 (2018). https://doi.org/10.1177/1933719117715126

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