The peritoneum—an important factor for pathogenesis and pain generation in endometriosis

Endometriosis (EM) is an oestrogen-dependent disease affecting 10–15 % of women during reproductive age. It is characterised by the presence of endometrial glands, stromal- and smooth muscle-like cells outside of the uterine cavity. Fifty to sixty per cent of women and teenage girls with pelvic pain suffer from EM. EM causes disability and compromises the quality of life in women and young girls significantly. Pain generation in EM is an intricate interplay of several factors such as the endometriotic lesions themselves and the pain-mediating substances, nerve fibres and cytokine-releasing immune cells such as macrophages. These interactions seem to induce a neurogenic inflammatory process. Recently published data demonstrated an increased peptidergic and decreased noradrenergic nerve fibre density in peritoneal lesions. These data could be substantiated by in vitro analyses demonstrating that the peritoneal fluids of patients suffering from EM induced an enhanced sprouting of sensory neurites from chicken dorsal root ganglia and decreased neurite outgrowth from sympathetic ganglia. These findings might be directly involved in the perpetuation of inflammation and pain. Furthermore, the evidence of EM-associated smooth muscle-like cells seems another important factor in pain generation. The peritoneal endometriotic lesion leads to reactions in the surrounding tissue and, therefore, is larger than generally believed. The identification of EM-associated nerve fibres and smooth muscle-like cells fuel discussions on the mechanisms of pain generation in EM, and may present new targets for innovative treatments. Similar content being viewed by others

Cramer DW, Missmer SA (2002) The epidemiology of endometriosis. Ann N Y Acad Sci 955:11–22, discussion 34–16, 396–406 Milingos S, Protopapas A, Drakakis P, Liapi A, Loutradis D, Kallipolitis G, Milingos D, Michalas S (2003) Laparoscopic management of patients with endometriosis and chronic pelvic pain. Ann N Y Acad Sci 997:269–273 Sepulcri Rde P, do Amaral VF (2009) Depressive symptoms, anxiety, and quality of life in women with pelvic endometriosis. Eur J Obstet Gynecol Reprod Biol 142:53–56 Fedele L, Bianchi S, Bocciolone L, Di Nola G, Parazzini F (1992) Pain symptoms associated with endometriosis. Obstet Gynecol 79:767–769 Gruppo Italiano per lo Studio dE (2001) Relationship between stage, site and morphological characteristics of pelvic endometriosis and pain. Hum Reprod 16:2668–2671 Vercellini P, Trespidi L, De Giorgi O, Cortesi I, Parazzini F, Crosignani PG (1996) Endometriosis and pelvic pain: relation to disease stage and localization. Fertil Steril 65:299–304 Fauconnier A, Chapron C (2005) Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update 11:595–606 Fauconnier A, Chapron C, Dubuisson JB, Vieira M, Dousset B, Breart G (2002) Relation between pain symptoms and the anatomic location of deep infiltrating endometriosis. Fertil Steril 78:719–726 Koninckx PR, Meuleman C, Demeyere S, Lesaffre E, Cornillie FJ (1991) Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil Steril 55:759–765 Parker JD, Leondires M, Sinaii N, Premkumar A, Nieman LK, Stratton P (2006) Persistence of dysmenorrhea and nonmenstrual pain after optimal endometriosis surgery may indicate adenomyosis. Fertil Steril 86:711–715 Vercellini P (1997) Endometriosis: what a pain it is. Semin Reprod Endocrinol 15:251–261 Chapron C, Fauconnier A, Dubuisson JB, Barakat H, Vieira M, Breart G (2003) Deep infiltrating endometriosis: relation between severity of dysmenorrhoea and extent of disease. Hum Reprod 18:760–766 Perper MM, Nezhat F, Goldstein H, Nezhat CH, Nezhat C (1995) Dysmenorrhea is related to the number of implants in endometriosis patients. Fertil Steril 63:500–503 Vernon MW, Beard JS, Graves K, Wilson EA (1986) Classification of endometriotic implants by morphologic appearance and capacity to synthesize prostaglandin F. Fertil Steril 46:801–806 Drake TS, O'Brien WF, Ramwell PW, Metz SA (1981) Peritoneal fluid thromboxane B2 and 6-keto-prostaglandin F1 alpha in endometriosis. Am J Obstet Gynecol 140:401–404 Moon YS, Leung PC, Yuen BH, Gomel V (1981) Prostaglandin F in human endometriotic tissue. Am J Obstet Gynecol 141:344–345 Wu MH, Sun HS, Lin CC, Hsiao KY, Chuang PC, Pan HA, Tsai SJ (2002) Distinct mechanisms regulate cyclooxygenase-1 and -2 in peritoneal macrophages of women with and without endometriosis. Mol Hum Reprod 8:1103–1110 Wu MY, Ho HN (2003) The role of cytokines in endometriosis. Am J Reprod Immunol 49:285–296 Ota H, Igarashi S, Sasaki M, Tanaka T (2001) Distribution of cyclooxygenase-2 in eutopic and ectopic endometrium in endometriosis and adenomyosis. Hum Reprod 16:561–566 Bulun SE (2009) Endometriosis. N Engl J Med 360:268–279 Garry R (2004) The effectiveness of laparoscopic excision of endometriosis. Curr Opin Obstet Gynecol 16:299–303 Teodoro MC, Genovese F, Rubbino G, Palumbo M, Zarbo G (2012) Chronic pelvic pain in patients with endometriosis: results of laparoscopic treatment. Minerva Ginecol 64:9–14 Vercellini P, Somigliana E, Vigano P, Abbiati A, Barbara G, Fedele L (2009) Chronic pelvic pain in women: etiology, pathogenesis and diagnostic approach. Gynecol Endocrinol 25:149–158 Lamvu G, Steege JF (2006) The anatomy and neurophysiology of pelvic pain. J Minim Invasive Gynecol 13:516–522 Anaf V, Simon P, El Nakadi I, Fayt I, Buxant F, Simonart T, Peny MO, Noel JC (2000) Relationship between endometriotic foci and nerves in rectovaginal endometriotic nodules. Hum Reprod 15:1744–1750 Anaf V, Simon P, El Nakadi I, Fayt I, Simonart T, Buxant F, Noel JC (2002) Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosis. Hum Reprod 17:1895–1900 Berkley KJ, Dmitrieva N, Curtis KS, Papka RE (2004) Innervation of ectopic endometrium in a rat model of endometriosis. Proc Natl Acad Sci U S A 101:11094–11098 Zhang 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 Arnold J, Barcena de Arellano ML, Ruster 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 Mechsner S, Schwarz J, Thode J, Loddenkemper C, Salomon DS, Ebert AD (2007) Growth-associated protein 43-positive sensory nerve fibers accompanied by immature vessels are located in or near peritoneal endometriotic lesions. Fertil Steril 88:581–587 Tokushige N, Markham R, Russell P, Fraser IS (2006) Nerve fibres in peritoneal endometriosis. Hum Reprod 21:3001–3007 Arnold J, Vercellino GF, Chiantera V, Schneider A, Mechsner S, Barcena de Arellano ML (2013) Neuroimmunomodulatory alterations in non-lesional peritoneum close to peritoneal endometriosis. Neuroimmunomodulation 20:9–18 Tran LV, Tokushige N, Berbic M, Markham R, Fraser IS (2009) Macrophages and nerve fibres in peritoneal endometriosis. Hum Reprod 24:835–841 Barcena de Arellano ML, Arnold J, Lang H, Vercellino GF, Chiantera V, Schneider A, Mechsner S (2014) Evidence of neurotrophic events due to peritoneal endometriotic lesions. Cytokine (in press) Barcena de Arellano ML, Arnold J, Vercellino F, Chiantera V, Schneider A, Mechsner S (2011) Overexpression of nerve growth factor in peritoneal fluid from women with endometriosis may promote neurite outgrowth in endometriotic lesions. Fertil Steril 95:1123–1126 Barcena de Arellano ML, Arnold J, Vercellino GF, Chiantera V, Ebert AD, Schneider A, Mechsner S (2011) Influence of nerve growth factor in endometriosis-associated symptoms. Reprod Sci 18:1202–1210 Nothnick WB (2001) Treating endometriosis as an autoimmune disease. Fertil Steril 76:223–231 Badaway SZ, Cuenca V, Freliech H, Stefanu C (1990) Endometrial antibodies in serum and peritoneal fluid of infertile patients with and without endometriosis. Fertil Steril 53:930–932 Matarese G, De Placido G, Nikas Y, Alviggi C (2003) Pathogenesis of endometriosis: natural immunity dysfunction or autoimmune disease? Trends Mol Med 9:223–228 Mathur S, Peress MR, Williamson HO, Youmans CD, Maney SA, Garvin AJ, Rust PF, Fudenberg HH (1982) Autoimmunity to endometrium and ovary in endometriosis. Clin Exp Immunol 50:259–266 Chan OT, Madaio MP, Shlomchik MJ (1999) The central and multiple roles of B cells in lupus pathogenesis. Immunol Rev 169:107–121 Levine JD, Collier DH, Basbaum AI, Moskowitz MA, Helms CA (1985) Hypothesis: the nervous system may contribute to the pathophysiology of rheumatoid arthritis. J Rheumatol 12:406–411 Nance DM, Sanders VM (2007) Autonomic innervation and regulation of the immune system (1987–2007). Brain Behav Immun 21:736–745 Sanders VM, Kasprowicz DJ, Kohm AP, Swanson MA (2001) Neurotransmitter receptors on lymphocytes and other lymphoid cells2. Academic Press, San Diego, CA Baerwald C, Graefe C, von Wichert P, Krause A (1992) Decreased density of beta-adrenergic receptors on peripheral blood mononuclear cells in patients with rheumatoid arthritis. J Rheumatol 19:204–210 Heijnen CJ, Rouppe van der Voort C, Wulffraat N, van der Net J, Kuis W, Kavelaars A (1996) Functional alpha 1-adrenergic receptors on leukocytes of patients with polyarticular juvenile rheumatoid arthritis. J Neuroimmunol 71:223–226 Kohm AP, Sanders VM (2000) Norepinephrine: a messenger from the brain to the immune system. Immunol Today 21:539–542 Straub RH (2007) Autoimmune disease and innervation. Brain Behav Immun 21:528–534 Ader R (2007), 4th edn. Alicea C, Belkowski S, Eisenstein TK, Adler MW, Rogers TJ (1996) Inhibition of primary murine macrophage cytokine production in vitro following treatment with the kappa-opioid agonist U50,488H. J Neuroimmunol 64:83–90 Bouma MG, Stad RK, van den Wildenberg FA, Buurman WA (1994) Differential regulatory effects of adenosine on cytokine release by activated human monocytes. J Immunol 153:4159–4168 Spengler RN, Chensue SW, Giacherio DA, Blenk N, Kunkel SL (1994) Endogenous norepinephrine regulates tumor necrosis factor-alpha production from macrophages in vitro. J Immunol 152:3024–3031 Kavelaars A, Broeke D, Jeurissen F, Kardux J, Meijer A, Franklin R, Gelfand EW, Heijnen CJ (1994) Activation of human monocytes via a non-neurokinin substance P receptor that is coupled to Gi protein, calcium, phospholipase D, MAP kinase, and IL-6 production. J Immunol 153:3691–3699 Lotz M, Vaughan JH, Carson DA (1988) Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science 241:1218–1221 Serra MC, Calzetti F, Ceska M, Cassatella MA (1994) Effect of substance P on superoxide anion and IL-8 production by human PMNL. Immunology 82:63–69 Jancsó N, Jancsó-Gabor A, Szolcsányi J (1967) Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharmacol Chemother 31:138–151 Levine JD, Clark R, Devor M, Helms C, Moskowitz MA, Basbaum AI (1984) Intraneuronal substance P contributes to the severity of experimental arthritis. Science 226:547–549 Harle P, Mobius D, Carr DJ, Scholmerich J, Straub RH (2005) An opposing time-dependent immune-modulating effect of the sympathetic nervous system conferred by altering the cytokine profile in the local lymph nodes and spleen of mice with type II collagen-induced arthritis. Arthritis Rheum 52:1305–1313 Mapp PI, Walsh DA, Garrett NE, Kidd BL, Cruwys SC, Polak JM, Blake DR (1994) Effect of three animal models of inflammation on nerve fibres in the synovium. Ann Rheum Dis 53:240–246 Ahmed M, Bjurholm A, Schultzberg M, Theodorsson E, Kreicbergs A (1995) Increased levels of substance P and calcitonin gene-related peptide in rat adjuvant arthritis. A combined immunohistochemical and radioimmunoassay analysis. Arthritis Rheum 38:699–709 Goode T, O'Connell J, Anton P, Wong H, Reeve J, O'Sullivan GC, Collins JK, Shanahan F (2000) Neurokinin-1 receptor expression in inflammatory bowel disease: molecular quantitation and localisation. Gut 47:387–396 Miller LE, Weidler C, Falk W, Angele P, Schaumburger J, Scholmerich J, Straub RH (2004) Increased prevalence of semaphorin 3C, a repellent of sympathetic nerve fibers, in the synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum 50:1156–1163 Chen H, He Z, Tessier-Lavigne M (1998) Axon guidance mechanisms: semaphorins as simultaneous repellents and anti-repellents. Nat Neurosci 1:436–439 Ferrero 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 Mechsner S, Bartley J, Loddenkemper C, Salomon DS, Starzinski-Powitz A, Ebert AD (2005) Oxytocin receptor expression in smooth muscle cells of peritoneal endometriotic lesions and ovarian endometriotic cysts. Fertil Steril 83(Suppl 1):1220–1231 Fukunaga M (2000) Smooth muscle metaplasia in ovarian endometriosis. Histopathology 36:348–352 van Kaam KJ, Schouten JP, Nap AW, Dunselman GA, Groothuis PG (2008) Fibromuscular differentiation in deeply infiltrating endometriosis is a reaction of resident fibroblasts to the presence of ectopic endometrium. Hum Reprod 23:2692–2700 Barcena de Arellano ML, Gericke J, Reichelt U, Okuducu AF, Ebert AD, Chiantera V, Schneider A, Mechsner S (2011) Immunohistochemical characterization of endometriosis-associated smooth muscle cells in human peritoneal endometriotic lesions. Hum Reprod 26:2721–2730 Abbott JA, Hawe J, Clayton RD, Garry R (2003) The effects and effectiveness of laparoscopic excision of endometriosis: a prospective study with 2–5 year follow-up. Hum Reprod 18:1922–1927 Vercellini P, Chapron C, De Giorgi O, Consonni D, Frontino G, Crosignani PG (2003) Coagulation or excision of ovarian endometriomas? Am J Obstet Gynecol 188:606–610 Jones KD, Haines P, Sutton CJ (2001) Long-term follow-up of a controlled trial of laser laparoscopy for pelvic pain. JSLS 5:111–115 Sutton CJ, Ewen SP, Whitelaw N, Haines P (1994) Prospective, randomized, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertil Steril 62:696–700 Jarrell J, Mohindra R, Ross S, Taenzer P, Brant R (2005) Laparoscopy and reported pain among patients with endometriosis. J Obstet Gynaecol Can 27:477–485 Yeung P Jr, Sinervo K, Winer W, Albee RB Jr (2011) Complete laparoscopic excision of endometriosis in teenagers: is postoperative hormonal suppression necessary? Fertil Steril 95:1909–1912, 1912 e1901 Murphy AA, Green WR, Bobbie D, dela Cruz ZC, Rock JA (1986) Unsuspected endometriosis documented by scanning electron microscopy in visually normal peritoneum. Fertil Steril 46:522–524 Lessey BA, Bushnell GA, Miller SE, Price TA (2011) Focal peritoneal dysfunction and endometriosis: a new theory for pelvic pain. World congress on endometriosis, Montpellier, France, pp. 30 Zoubina EV, Fan Q, Smith PG (1998) Variations in uterine innervation during the estrous cycle in rat. J Comp Neurol 397:561–571 Zoubina EV, Mize AL, Alper RH, Smith PG (2001) Acute and chronic estrogen supplementation decreases uterine sympathetic innervation in ovariectomized adult virgin rats. Histol Histopathol 16:989–996 Attar E, Bulun SE (2006) Aromatase and other steroidogenic genes in endometriosis: translational aspects. Hum Reprod Update 12:49–56 Bulun SE, Imir G, Utsunomiya H, Thung S, Gurates B, Tamura M, Lin Z (2005) Aromatase in endometriosis and uterine leiomyomata. J Steroid Biochem Mol Biol 95:57–62 Kitawaki J, Noguchi T, Amatsu T, Maeda K, Tsukamoto K, Yamamoto T, Fushiki S, Osawa Y, Honjo H (1997) Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in human endometriotic and adenomyotic tissues but not in normal endometrium. Biol Reprod 57:514–519 Noble LS, Takayama K, Zeitoun KM, Putman JM, Johns DA, Hinshelwood MM, Agarwal VR, Zhao Y, Carr BR, Bulun SE (1997) Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells. J Clin Endocrinol Metab 82:600–606 Zoubina EV, Smith PG (2001) Sympathetic hyperinnervation of the uterus in the estrogen receptor alpha knock-out mouse. Neuroscience 103:237–244 Chalar C, Richeri A, Viettro L, Chavez-Genaro R, Bianchimano P, Marmol NM, Crutcher K, Burnstock G, Cowen T, Brauer MM (2003) Plasticity in developing rat uterine sensory nerves: the role of NGF and TrkA. Cell Tissue Res 314:191–205 Krizsan-Agbas D, Pedchenko T, Hasan W, Smith PG (2003) Oestrogen regulates sympathetic neurite outgrowth by modulating brain derived neurotrophic factor synthesis and release by the rodent uterus. Eur J Neurosci 18:2760–2768 Kohn J, Aloyz RS, Toma JG, Haak-Frendscho M, Miller FD (1999) Functionally antagonistic interactions between the TrkA and p75 neurotrophin receptors regulate sympathetic neuron growth and target innervation. J Neurosci 19:5393–5408 Bamji SX, Majdan M, Pozniak CD, Belliveau DJ, Aloyz R, Kohn J, Causing CG, Miller FD (1998) The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death. J Cell Biol 140:911–923 Hasan W, Smith HJ, Ting AY, Smith PG (2005) Estrogen alters trkA and p75 neurotrophin receptor expression within sympathetic neurons. J Neurobiol 65:192–204 Richeri A, Chalar C, Martinez G, Greif G, Bianchimano P, Brauer MM (2012) Estrogen up-regulation of semaphorin 3F correlates with sympathetic denervation of the rat uterus. Auton Neurosci 164:43–50 Straub RH, Lowin T, Klatt S, Wolff C, Rauch L (2011) Increased density of sympathetic nerve fibers in metabolically activated fat tissue surrounding human synovium and mouse lymph nodes in arthritis. Arthritis Rheum 63:3234–3242 Fassold A, Falk W, Anders S, Hirsch T, Mirsky VM, Straub RH (2009) Soluble neuropilin-2, a nerve repellent receptor, is increased in rheumatoid arthritis synovium and aggravates sympathetic fiber repulsion and arthritis. Arthritis Rheum 60:2892–2901 Lepelletier Y, Moura IC, Hadj-Slimane R, Renand A, Fiorentino S, Baude C, Shirvan A, Barzilai A, Hermine O (2006) Immunosuppressive role of semaphorin-3A on T cell proliferation is mediated by inhibition of actin cytoskeleton reorganization. Eur J Immunol 36:1782–1793 Chavez-Genaro R, Crutcher K, Viettro L, Richeri A, Coirolo N, Burnstock G, Cowen T, Brauer MM (2002) Differential effects of oestrogen on developing and mature uterine sympathetic nerves. Cell Tissue Res 308:61–73 Sporrong B, Alm P, Owman C, Sjoberg NO, Thorbert G (1981) Pregnancy is associated with extensive adrenergic nerve degeneration in the uterus. An electronmicroscopic study in the guinea-pig. Neuroscience 6:1119–1126

The authors thank PD Dr. Andreas Kaufmann for the critical reading and constructive discussion. Conflict of interest The authors declare that they have no conflict of interests. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article de Arellano, ML.B., Mechsner, S. The peritoneum—an important factor for pathogenesis and pain generation in endometriosis. J Mol Med 92, 595–602 (2014). https://doi.org/10.1007/s00109-014-1135-4 Received: Revised: Accepted: Published: Issue date: DOI: https://doi.org/10.1007/s00109-014-1135-4