Possible effects of endometriosis-related immune events on reproductive function

Purpose To examine possible effects of endometriosis-related immune events on reproductive function.

The synthesis and review of the relevant current literature in English language.

The endometriosis-related immune events may have a negative impact on almost all components of the reproductive function including fallopian tube function, oocyte quality, sperm function, fertilization, embryo quality, endometrial receptivity, implantation and placentation.

An important portion of the cases of infertility or miscarriage seen in women with endometriosis may be due to some immunological alterations associated with endometriosis. Access this article We’re sorry, something doesn't seem to be working properly. Please try refreshing the page. If that doesn't work, please contact support so we can address the problem. Similar content being viewed by others

Kim KH, Lee EN, Park JK et al (2012) Curcumin attenuates TNF-α-induced expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and proinflammatory cytokines in human endometriotic stromal cells. Phytother Res 26:1037–1047 Nabeta M, Abe Y, Haraguchi R, Kito K, Kusanagi Y, Ito M (2010) Serum anti-PDIK1L autoantibody as a novel marker for endometriosis. Fertil Steril 94:2552–2557 Nabeta M, Abe Y, Kagawa L et al (2009) Identification of anti-α-enolase autoantibody as a novel serum marker for endometriosis. Proteomics Clin Appl 3:1201–1210 Bohler HC, Gercel-Taylor C, Lessey BA, Taylor DD (2007) Endometriosis markers: immunologic alterations as diagnostic indicators for endometriosis. Reprod Sci 14:595–604 Dias JA Jr, de Oliveira RM, Abrao MS (2006) Antinuclear antibodies and endometriosis. Int J Gynaecol Obstet 93:262–263 Carli C, Metz CN, Al-Abed Y, Naccache PH, Akoum A (2009) Up-regulation of cyclooxygenase-2 expression and prostaglandin E2 production in human endometriotic cells by macrophage migration inhibitory factor: involvement of novel kinase signaling pathways. Endocrinology 150:3128–3137 Veillat V, Carli C, Metz CN, Al-Abed Y, Naccache PH, Akoum A (2010) Macrophage migration inhibitory factor elicits an angiogenic phenotype in human ectopic endometrial cells and triggers the production of major angiogenic factors via CD44, CD74, and MAPK signaling pathways. J Clin Endocrinol Metab 95:403–412 Khoufache K, Michaud N, Harir N, Kibangou Bondza P, Akoum A (2012) Anomalies in the inflammatory response in endometriosis and possible consequences: a review. Minerva Endocrinol 37:75–92 Gupta S, Goldberg JM, Aziz N, Goldberg E, Krajcir N, Agarwal A (2008) Pathogenic mechanisms in endometriosis-associated infertility. Fertil Steril 90:247–257 Review Matalliotakis IM, Katsikis IK, Panidis DK (2005) Adenomyosis: what is the impact on fertility? Curr Opin Obstet Gynecol 17:261264 Review Tomassetti C, Meuleman C, Pexsters A et al (2006) Endometriosis, recurrent miscarriage and implantation failure: is there an immunological link? Reprod Biomed Online 13:5864 Review Iborra A, Palacio JR, UlcovaGallova Z, Martínez P (2000) Autoimmune response in women with endometriosis. Am J Reprod Immunol 44:236241 D’Hooghe TM, Hill JA III (2007) Endometriosis. In: Berek JS (ed) Berek and Novak’s gynecology, 14th edn. Lippincott Williams and Wilkins, Philadelphia, pp 1137–1184 Schenken RS (2008) Endometriosis. In: Gibbs RS, Karlan BY, Haney AF, Nygaard IE (eds) Danforth’s obstetrics and gynecology, 10th edn. Lippincott Williams and Wilkins, Philadelphia, pp 716–724 Kuohung W, Jones GL, Vitonis AF et al (2002) Characteristics of patients with endometriosis in the United States and the United Kingdom. Fertil Steril 78:767–772 Matsuzaki S, Darcha C, Maleysson E, Canis M, Mage G (2010) Impaired downregulation of E cadherin and betacatenin protein expression in endometrial epithelial cells in the midsecretory endometrium of infertile patients with endometriosis. J Clin Endocrinol Metab 95:3437–3445 Yi YC, Wang SC, Chao CC, Su CL, Lee YL, Chen LY (2010) Evaluation of serum autoantibody levels in the diagnosis of ovarian endometrioma. J Clin Lab Anal 24:357–362 Sampson JA (1927) Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol 3:93–110 Zanatta A, Rocha AM, Carvalho FM et al (2010) The role of the Hoxa10/HOXA10 gene in the etiology of endometriosis and its related infertility: a review. J Assist Reprod Genet 27:701–710 Bulun SE (2009) Endometriosis. N Engl J Med 360:268–279 Bischoff F, Simpson JL (2004) Genetic basis of endometriosis. Ann N Y Acad Sci 1034:284–299 Review Guo SW (2009) Epigenetics of endometriosis. Mol Hum Reprod 15:587–607 Review Bulun SE, Zeitoun KM, Kilic G (2000) Expression of dioxinrelated transactivating factors and target genes in human eutopic endometrial and endometriotic tissues. Am J Obstet Gynecol 182:767–775 Simpson JL, Bischoff FZ, Kamat A, Buster JE, Carson SA (2003) Genetics of endometriosis. Obstet Gynecol Clin North Am 30:21–40 Review Bianco B, André GM, Vilarino FL, Peluso C, Mafra FA, Christofolini CM, Barbosa CP et al (2012) The possible role of genetic variants in autoimmune-related genes in the development of endometriosis. Hum Immunol 73:306–315 Eisenberg VH, Zolti M, Soriano D (2012) Is there an association between autoimmunity and endometriosis? Autoimmun Rev 11:806–814 Zondervan KT, Cardon LR, Kennedy SH (2001) The genetic basis of endometriosis. Curr Opin Obstet Gynecol 13:309–314 Review Olovsson M (2011) Immunological aspects of endometriosis: an update. Am J Reprod Immunol 66(Suppl 1):101–104 Young SL, Lessey BA (2010) Progesterone function in human endometrium: clinical perspectives. Semin Reprod Med 28:5–16 Herington JL, Bruner-Tran KL, Lucas JA, Osteen KG (2011) Immune interactions in endometriosis. Expert Rev Clin Immunol 7:611–626 Riley CF, Moen MH, Videm V (2007) Inflammatory markers in endometriosis: reduced peritoneal neutrophil response in minimal endometriosis. Acta Obstet Gynecol Scand 86:877–881 Sel’kov SA, Pavlov RV (2007) Comparative efficiency of intraperitoneal interleukin-2 and interferon-A in rats with experimental endometriosis. Bull Exp Biol Med 143:363–367 Christodoulakos G, Augoulea A, Lambrinoudaki I, Sioulas V, Creatsas G (2007) Pathogenesis of endometriosis: the role of defective ‘immunosurveillance’. Eur J Contracept Reprod Health Care 12:194–202 Milewski Ł, Barcz E, Dziunycz P et al (2008) Association of leptin with inflammatory cytokines and lymphocyte subpopulations in peritoneal fluid of patients with endometriosis. J Reprod Immunol 79:111–117 Vinatier D, Dufour P, Oosterlynck D (1996) Immunological aspects of endometriosis. Hum Reprod Update 2:371–384 Hassa H, Tanir HM, Tekin B, Kirilmaz SD, Sahin Mutlu F (2009) Cytokine and immune cell levels in peritoneal fluid and peripheral blood of women with early- and late-staged endometriosis. Arch Gynecol Obstet 279:891–895 Nowak NM, Fischer OM, Gust TC, Fuhrmann U, Habenicht UF, Schmidt A (2008) Intraperitoneal inflammation decreases endometriosis in a mouse model. Hum Reprod 23:2466–2474 Seli E, Arici A (2003) Endometriosis: interaction of immune and endocrine systems. Semin Reprod Med 21:135–144 Sharma I, Dhaliwal LK, Saha SC, Sangwan S, Dhawan V (2010) Role of 8-iso-prostaglandin F2alpha and 25-hydroxycholesterol in the pathophysiology of endometriosis. Fertil Steril 94:63–70 Wu MH, Lu CW, Chuang PC, Tsai SJ (2010) Prostaglandin E2: the master of endometriosis? Exp Biol Med (Maywood) 235:668–677 Liu Y, Hu J, Shen W et al (2011) Peritoneal fluid of patients with endometriosis promotes proliferation of endometrial stromal cells and induces COX-2 expression. Fertil Steril 95:1836–1838 Chuang PC, Lin YJ, Wu MH, Wing LY, Shoji Y, Tsai SJ (2010) Inhibition of CD36-dependent phagocytosis by prostaglandin E2 contributes to the development of endometriosis. Am J Pathol 176:850–860 Lee J, Banu SK, Subbarao T, Starzinski-Powitz A, Arosh JA (2011) Selective inhibition of prostaglandin E2 receptors EP2 and EP4 inhibits invasion of human immortalized endometriotic epithelial and stromal cells through suppression of metalloproteinases. Mol Cell Endocrinol 332:306–313 Lee TC, Ho HC (2011) Effects of prostaglandin E2 and vascular endothelial growth factor on sperm might lead to endometriosis-associated infertility. Fertil Steril 95:360–362 Gazvani R, Templeton A (2002) Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis. Reproduction 123:217–226 Review Wu MH, Huang MF, Chang FM, Tsai SJ (2010) Leptin on peritoneal macrophages of patients with endometriosis. Am J Reprod Immunol 63:214–221 Tariverdian N, Theoharides TC, Siedentopf F et al (2007) Neuroendocrine-immune disequilibrium and endometriosis: an interdisciplinary approach. Semin Immunopathol 29:193–210 Berkkanoglu M, Arici A (2003) Immunology and endometriosis. Am J Reprod Immunol 50:48–59 Agic A, Xu H, Finas D, Banz C, Diedrich K, Hornung D (2006) Is endometriosis associated with systemic subclinical inflammation? Gynecol Obstet Invest 62:139–147 Review Olivares C, Ricci A, Bilotas M, Barañao RI, Meresman G (2011) The inhibitory effect of celecoxib and rosiglitazone on experimental endometriosis. Fertil Steril 96:428–433 Minici F, Tiberi F, Tropea A et al (2007) Paracrine regulation of endometriotic tissue. Gynecol Endocrinol 23:574–580 Bersinger NA, von Roten S, Wunder DM, Raio L, Dreher E, Mueller MD (2006) PAPP-A and osteoprotegerin, together with interleukin-8 and RANTES, are elevated in the peritoneal fluid of women with endometriosis. Am J Obstet Gynecol 195:103–108 Lee KS, Joo BS, Na YJ, Yoon MS, Choi OH, Kim WW (2000) Relationships between concentrations of tumor necrosis factor-alpha and nitric oxide in follicular fluid and oocyte quality. J Assist Reprod Genet 17:222–228 Kondera-Anasz Z, Sikora J, Mielczarek-Palacz A, Jonca M (2005) Concentrations of interleukin (IL)-1alpha, IL-1 soluble receptor type II (IL-1 sRII) and IL-1 receptor antagonist (IL-1 Ra) in the peritoneal fluid and serum of infertile women with endometriosis. Eur J Obstet Gynecol Reprod Biol 123:198–203 Garrido N, Navarro J, Remohi J, Simon C, Pellicer A (2000) Follicular hormonal environment and embryo quality in women with endometriosis. Hum Reprod Update 6:67–74 Punnonen J, Teisala K, Ranta H, Bennett B, Punnonen R (1996) Increased levels of interleukin-6 and interleukin-10 in the peritoneal fluid of patients with endometriosis. Am J Obstet Gynecol 174:1522–1526 Donnez J, Smoes P, Gillerot S, Casanas-Roux F, Nisolle M (1998) Vascular endothelial growth factor (VEGF) in endometriosis. Hum Reprod 13:1686–1690 Navarro J, Garrido N, Remohi J, Pellicer A (2003) How does endometriosis affect infertility? Obstet Gynecol Clin North Am 30:181–192 Martínez-Román S, Balasch J, Creus M et al (1997) Immunological factors in endo me trio sis-associated reproductive failure: studies in fertile and infertile women with and without endometriosis. Hum Reprod 12:1794–1799 Lebovic DI, Mueller MD, Taylor RN (2001) Immunobiology of endometriosis. Fertil Steril 75:1–10 Halis G, Arici A (2004) Endometriosis and inflammation in infertility. Ann N Y Acad Sci 1034:300–315 Pizzo A, Salmeri FM, Ardita FV, Sofo V, Tripepi M, Marsico S (2002) Behaviour of cytokine levels in serum and peritoneal fluid of women with endometriosis. Gynecol Obstet Invest 54:82–87 Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohi J, Simon C (1998) The follicular and endocrine environment in women with endometriosis: local and systemic cytokine production. Fertil Steril 70:425–431 Inagaki J, Kondo A, Lopez LR, Shoenfeld Y, Matsuura E (2005) Pregnancy loss and endometriosis: pathogenic role of anti-laminin-1 autoantibodies. Ann N Y Acad Sci 1051:174–184 Review Ohman H, Tiitinen A, Halttunen M et al (2009) Cytokine polymorphisms and severity of tubal damage in women with Chlamydia-associated infertility. J Infect Dis 199:1353–1359 Lyons RA, Djahanbakhch O, Saridogan E et al (2002) Peritoneal fluid, endometriosis, and ciliary beat frequency in the human fallopian tube. Lancet 360:1221–1222 Cahill DJ (2002) What is the optimal medical management of infertility and minor endometriosis? Analysis and future prospects. Hum Reprod 17:1135–1140 Review Barbieri RL, Missmer S (2002) Endometriosis and infertility: a cause-effect relationship? Ann N Y Acad Sci 955:23–33 Pellicer A, Albert C, Garrido N, Navarro J, Remohí J, Simón C (2000) The pathophysiology of endometriosis-associated infertility: follicular environment and embryo quality. J Reprod Fertil Suppl 55:109–119 Gajbhiye R, Suryawanshi A, Khan S et al (2008) Multiple endometrial antigens are targeted in autoimmune endometriosis. Reprod Biomed Online 16:817–824 Barrier BF (2010) Immunology of endometriosis. Clin Obstet Gynecol 53:397–402 Review Mathur SP (2000) Autoimmunity in endometriosis: relevance to infertility. Am J Reprod Immunol 44:89–95 Review Fernandéz-Shaw S, Kennedy SH, Hicks BR, Edmonds K, Starkey PM, Barlow DH (1996) Anti-endometrial antibodies in women measured by an enzyme-linked immunosorbent assay. Hum Reprod 11:1180–1184 Kennedy SH, Sargent IL, Starkey PM, Hicks BR, Barlow DH (1990) Localization of anti-endometrial antibody binding in women with endometriosis using a double-labelling immunohistochemical method. Br J Obstet Gynaecol 97:671–674 Sarapik A, Haller-Kikkatalo K, Utt M et al (2010) Serum anti-endometrial antibodies in infertile women—potential risk factor for implantation failure. Am J Reprod Immunol 63:349–357 Kondo A, Inagaki J, Kobayashi K et al (2005) Characterization of a murine anti-laminin-1 monoclonal antibody (AK8) produced by immunization with mouse-derived laminin-1. Clin Dev Immunol 12:67–73 Tunggal P, Smyth N, Paulsson M, Ott MC (2000) Laminins: structure and genetic regulation. Microsc Res Tech 51:214–227 Inagaki J, Sugiura-Ogasawara M, Nomizu M et al (2003) An association of IgG anti-laminin-1 autoantibodies with endometriosis in infertile patients. Hum Reprod 18:544–549 Inagaki J, Kondo A, Lopez LR, Shoenfeld Y, Matsuura E (2004) Anti-laminin-1 autoantibodies, pregnancy loss and endometriosis. Clin Dev Immunol 11:261–266 Review Inagaki J, Hao L, Nakatsuka M et al (2011) A possible mechanism of autoimmune-mediated infertility in women with endometriosis. Am J Reprod Immunol 66:90–99 Inagaki J, Matsuura E, Nomizu M et al (2001) IgG anti-laminin-1 autoantibody and recurrent miscarriages. Am J Reprod Immunol 45:232–238 Caccavo D, Pellegrino NM, Totaro I, Vacca MP, Selvaggi L, Depalo R (2011) Anti-laminin-1 antibodies in sera and follicular fluid of women with endometriosis undergoing in vitro fertilization. Int J Immunopathol Pharmacol 24:481–488 Dmowski WP, Rana N, Michalowska J, Friberg J, Papierniak C, el-Roeiy A (1995) The effect of endometriosis, its stage and activity, and of autoantibodies on in vitro fertilization and embryo transfer success rates. Fertil Steril 63:555–562 Horejsí J, Martínek J, Nováková D, Madar J, Brandejska M (2000) Autoimmune antiovarian antibodies and their impact on the success of an IVF/ET program. Ann N Y Acad Sci 900:351–356 Gleicher N, el-Roeiy A, Confino E et al (1987) Is endometriosis an autoimmune disease? Obstet Gynecol 70:115–122 Gleicher N, el-Roeiy A, Confino E et al (1989) Reproductive failure because of autoantibodies: unexplained infertility and pregnancy wastage. Am J Obstet Gynecol 160:1376–1380 Kaider AS, Kaider BD, Janowicz PB, Roussev RG (1999) Immunodiagnostic evaluation in women with reproductive failure. Am J Reprod Immunol 42:335–346 Cline AM, Kutteh WH (2009) Is there a role of autoimmunity in implantation failure after in vitro fertilization? Curr Opin Obstet Gynecol 21:291–295 Mathur SP, Lee JH, Jiang H et al (1999) Levels of transferrin and alpha 2-MS glycoprotein in women with and without endometriosis. Autoimmunity 29:121–127 Bondza PK, Maheux R, Akoum A (2009) Insights into endometriosis-associated endometrial dysfunctions: a review. Front Biosci (Elite Ed) 1:415–428 Review Giudice LC, Telles TL, Lobo S, Kao L (2002) The molecular basis for implantation failure in endometriosis. Ann N Y Acad Sci 955:25–64 Khorram O, Lessey BA (2002) Alterations in expression of endometrial endothelial nitric oxide synthase and alpha(v)beta(3) integrin in women with endometriosis. Fertil Steril 78:860–864 Koot YE, Teklenburg G, Salker MS, Brosens JJ, Macklon NS (2012) Molecular aspects of implantation failure. Biochim Biophys Acta 1822:1943–1950 Casals G, Ordi J, Creus M et al (2012) Expression pattern of osteopontin and αvβ3 integrin during the implantation window in infertile patients with early stages of endometriosis. Hum Reprod 27:805–813 Lessey BA (2002) Implantation defects in infertile women with endometriosis. Ann N Y Acad Sci 955:265–280 Lessey BA, Damjanovich L, Coutifaris C et al (1992) Integrin adhesion molecules in the human endometrium. Correlation with the normal and abnormal menstrual cycle. J Clin Invest 90:188–195 Donaghay M, Lessey BA (2007) Uterine receptivity: alterations associated with benign gynecological disease. Semin Reprod Med 25:461–475 Noble LS, Takayama K, Zeitoun KM et al (1997) Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells. J Clin Endocrinol Metab 82:600–606 Zeitoun KM, Bulun SE (1999) Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target. Fertil Steril 72:961–969 Banerjee P, Jana SK, Pasricha P, Ghosh S, Chakravarty B, Chaudhury K (2012) Proinflammatory cytokines induced altered expression of cyclooxygenase-2 gene results in unreceptive endometrium in women with idiopathic recurrent spontaneous miscarriage. Fertil Steril doi:10.1016/s0015-0282(12)02122-X Revel A (2012) Defective endometrial receptivity. Fertil Steril 97:1028–1032 Review Saito H, Seino T, Kaneko T, Nakahara K, Toya M, Kurachi H (2002) Endometriosis and oocyte quality. Gynecol Obstet Invest 53(Suppl 1):46–51 Van Langendonckt A, Casanas-Roux F, Donnez J (2002) Oxidative stress and peritoneal endometriosis. Fertil Steril 77:861–870 Szczepanska M, Kozlik J, Skrzypczak J, Mikolajczyk M (2003) Oxidative stress may be a piece in the endometriosis puzzle. Fertil Steril 79:1288–1293 Harlow CR, Cahill DJ, Maile LA et al (1996) Reduced preovulatory granulosa cell steroidogenesis in women with endometriosis. J Clin Endocrinol Metab 81:426–429 Cahill DJ, Hull MGR (2000) Pituitary ovarian dysfunction and endometriosis. Hum Reprod Update 6:56–66 Cahill DJ, Wardle PG, Maile LA, Harlow CR, Hull MG (1997) Ovarian dysfunction in endometriosis-associated and unexplained infertility. J Assist Reprod Genet 14:554–557 Bulun SE, Cheng YH, Pavone ME et al (2010) Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med 28:36–43 Fazleabas AT (2010) Progesterone resistance in a baboon model of endometriosis. Semin Reprod Med 28:75–80 Kawano Y, Nasu K, Li H et al (2011) Application of the histone deacetylase inhibitors for the treatment of endometriosis: histone modifications as pathogenesis and novel therapeutic target. Hum Reprod 26:2486–2498 Conflict of interest None. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Kokcu, A. Possible effects of endometriosis-related immune events on reproductive function. Arch Gynecol Obstet 287, 1225–1233 (2013). https://doi.org/10.1007/s00404-013-2767-2 Received: Accepted: Published: Issue date: DOI: https://doi.org/10.1007/s00404-013-2767-2