{"paper_id":"cd65f5b3-085f-4842-8ab4-95bf39a787f4","body_text":"Abstract\nPurpose\nTo investigate whether eutopic endometrial expression of leukaemia inhibitory factor (LIF), LIF receptor (LIFR) and glycoprotein 130 (gp130) in subfertile women with endometriosis and in healthy controls is related to the probability of spontaneous pregnancy. In addition, we aimed to study peritoneal fluid (PF) levels of interleukin (IL)-1α and IL-6 in the same subsets of women.\nMethods\nEutopic endometrial biopsy and PF samples were taken from patients with rASRM stage I–II endometriosis and healthy controls undergoing laparoscopy. Endometrial LIF, LIFR and gp130 immunostaining and PF levels of IL-1α and IL-6 were assessed. Endometrial biopsy samples were obtained again after postoperative goserelin acetate treatment and on-going pregnancies were registered during a 6-month follow-up period.\nResults\nReduced endometrial staining of LIF, LIFR and gp130, unaffected by surgery and goserelin, was seen in endometriosis patients without a recorded pregnancy during the study. Elevated PF levels of IL-6 and, in particular, IL-1α were detected in these patients.\nConclusions\nReduced eutopic endometrial LIF, LIFR and gp130 protein expression may be associated with subfertility in women with minimal–mild endometriosis. Combined surgical and goserelin acetate treatment does not seem to restore the expression of these members of the IL-6 cytokine superfamily. Elevated peritoneal fluid levels of IL-1α and IL-6 may further contribute to the difficulties of achieving pregnancy in these patients.\nSimilar content being viewed by others\nReferences\nMeuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D’Hooghe T (2009) High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril 92:68–74\nLessey BA, Lebovic DI, Taylor RN (2013) Eutopic endometrium in women with endometriosis: ground zero for the study of implantation defects. Semin Reprod Med 31:109–124\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\nBurney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, Lessey BA, Giudice LC (2007) Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 148:3814–3826\nStilley JA, Birt JA, Sharpe-Timms KL (2012) Cellular and molecular basis for endometriosis-associated infertility. Cell Tissue Res 349:849–862\nBrosens I, Brosens JJ, Benagiano G (2012) The eutopic endometrium in endometriosis: are the changes of clinical significance? Reprod Biomed Online 24:496–502\nDimitriadis E, Stoikos C, Stafford-Bell M, Clark I, Paiva P, Kovacs G, Salamonsen LA (2006) Interleukin-11, IL-11 receptor alpha and leukemia inhibitory factor are dysregulated in endometrium of infertile women with endometriosis during the implantation window. J Reprod Immunol 69:53–64\nKondera-Anasz Z, Sikora J, Mielczarek-Palacz A (2004) Leukemia inhibitory factor: an important regulator of endometrial function. Am J Reprod Immunol 52:97–105\nKimber SJ (2005) Leukaemia inhibitory factor in implantation and uterine biology. Reproduction 130:131–145\nDimitriadis E, White CA, Jones RL, Salamonsen LA (2005) Cytokines, chemokines and growth factors in endometrium related to implantation. Hum Reprod Update 11:613–630\nCharnock-Jones DS, Sharkey AM, Fenwick P, Smith SK (1994) Leukaemia inhibitory factor mRNA concentration peaks in human endometrium at the time of implantation and the blastocyst contains mRNA for the receptor at this time. J Reprod Fertil 101:421–426\nCullinan EB, Abbondanzo SJ, Anderson PS, Pollard JW, Lessey BA, Stewart CL (1996) Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation. Proc Natl Acad Sci USA 93:3115–3120\nFranasiak JM, Holoch KJ, Yuan L, Schammel DP, Young SL, Lessey BA (2014) Prospective assessment of midsecretory endometrial leukemia inhibitor factor expression versus alphanubeta3 testing in women with unexplained infertility. Fertil Steril 101:1724–1731\nAghajanova L, Stavreus-Evers A, Nikas Y, Hovatta O, Landgren BM (2003) Coexpression of pinopodes and leukemia inhibitory factor, as well as its receptor, in human endometrium. Fertil Steril 79(Suppl 1):808–814\nAghajanova L, Altmae S, Bjuresten K, Hovatta O, Landgren BM, Stavreus-Evers A (2009) Disturbances in the LIF pathway in the endometrium among women with unexplained infertility. Fertil Steril 91:2602–2610\nStarr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ (1997) A family of cytokine-inducible inhibitors of signalling. Nature 387:917–921\nDiao Y, Wang X, Wu Z (2009) SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by inhibiting the leukemia inhibitory factor-induced JAK1/STAT1/STAT3 pathway. Mol Cell Biol 29:5084–5093\nVenieratos PD, Drossopoulou GI, Kapodistria KD, Tsilibary EC, Kitsiou PV (2010) High glucose induces suppression of insulin signalling and apoptosis via upregulation of endogenous IL-1 beta and suppressor of cytokine signalling-1 in mouse pancreatic beta cells. Cell Signal 22:791–800\nKondera-Anasz Z, Sikora J, Mielczarek-Palacz A, Jonca M (2005) Concentrations of interleukin (IL)-1 alpha, 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\nMihalyi A, Gevaert O, Kyama CM, Simsa P, Pochet N, De Smet F, De Moor B, Meuleman C, Billen J, Blanckaert N, Vodolazkaia A, Fulop V, D’Hooghe TM (2010) Non-invasive diagnosis of endometriosis based on a combined analysis of six plasma biomarkers. Hum Reprod 25:654–664\nMay KE, Conduit-Hulbert SA, Villar J, Kirtley S, Kennedy SH, Becker CM (2010) Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update 16:651–674\nSikora J, Mielczarek-Palacz A, Kondera-Anasz Z (2012) Imbalance in cytokines from interleukin-1 family - role in pathogenesis of endometriosis. Am J Reprod Immunol 68:138–145\nMinici F, Tiberi F, Tropea A, Orlando M, Gangale MF, Romani F, Campo S, Bompiani A, Lanzone A, Apa R (2008) Endometriosis and human infertility: a new investigation into the role of eutopic endometrium. Hum Reprod 23:530–537\nOlovsson M (2011) Immunological aspects of endometriosis: an update. Am J Reprod Immunol 66(Suppl 1):101–104\nOral E, Olive DL, Arici A (1996) The peritoneal environment in endometriosis. Hum Reprod Update 2:385–398\nLebovic DI, Mueller MD, Taylor RN (2001) Immunobiology of endometriosis. Fertil Steril 75:1–10\nWu MY, Ho HN (2003) The role of cytokines in endometriosis. Am J Reprod Immunol 49:285–296\nGupta S, Goldberg JM, Aziz N, Goldberg E, Krajcir N, Agarwal A (2008) Pathogenic mechanisms in endometriosis-associated infertility. Fertil Steril 90:247–257\nVelasco I, Acien P, Campos A, Acien MI, Ruiz-Macia E (2010) Interleukin-6 and other soluble factors in peritoneal fluid and endometriomas and their relation to pain and aromatase expression. J Reprod Immunol 84:199–205\nPlante BJ, Lessey BA, Taylor RN, Wang W, Bagchi MK, Yuan L, Scotchie J, Fritz MA, Young SL (2012) G protein-coupled estrogen receptor (GPER) expression in normal and abnormal endometrium. Reprod Sci 19:684–693\nBudwit-Novotny DA, McCarty KS, Cox EB, Soper JT, Mutch DG, Creasman WT, Flowers JL, McCarty KS Jr (1986) Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res 46:5419–5425\nXiao Y, Sun X, Yang X, Zhang J, Xue Q, Cai B, Zhou Y (2010) Leukemia inhibitory factor is dysregulated in the endometrium and uterine flushing fluid of patients with adenomyosis during implantation window. Fertil Steril 94:85–89\nVercellini P, Somigliana E, Vigano P, Abbiati A, Barbara G, Crosignani PG (2009) Surgery for endometriosis-associated infertility: a pragmatic approach. Hum Reprod 24:254–269\nde Ziegler D, Borghese B, Chapron C (2010) Endometriosis and infertility: pathophysiology and management. Lancet 376:730–738\nOpoien HK, Fedorcsak P, Byholm T, Tanbo T (2011) Complete surgical removal of minimal and mild endometriosis improves outcome of subsequent IVF/ICSI treatment. Reprod Biomed Online 23:389–395\nSallam HN, Garcia-Velasco JA, Dias S, Arici A (2006) Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev CD004635\nMikolajczyk M, Wirstlein P, Skrzypczak J (2006) Leukaemia inhibitory factor and interleukin 11 levels in uterine flushings of infertile patients with endometriosis. Hum Reprod 21:3054–3058\nShuya LL, Menkhorst EM, Yap J, Li P, Lane N, Dimitriadis E (2011) Leukemia inhibitory factor enhances endometrial stromal cell decidualization in humans and mice. PLoS One 6:e25288\nSun X, Bartos A, Whitsett JA, Dey SK (2013) Uterine deletion of Gp130 or Stat3 shows implantation failure with increased estrogenic responses. Mol Endocrinol 27:1492–1501\nTawfeek MA, Eid MA, Hasan AM, Mostafa M, El-Serogy HA (2012) Assessment of leukemia inhibitory factor and glycoprotein 130 expression in endometrium and uterine flushing: a possible diagnostic tool for impaired fertility. BMC Womens Health 12:10\nFakih H, Baggett B, Holtz G, Tsang KY, Lee JC, Williamson HO (1987) Interleukin-1: a possible role in the infertility associated with endometriosis. Fertil Steril 47:213–217\nRier SE, Zarmakoupis PN, Hu X, Becker JL (1995) Dysregulation of interleukin-6 responses in ectopic endometrial stromal cells: correlation with decreased soluble receptor levels in peritoneal fluid of women with endometriosis. J Clin Endocrinol Metab 80:1431–1437\nHarada T, Yoshioka H, Yoshida S, Iwabe T, Onohara Y, Tanikawa M, Terakawa N (1997) Increased interleukin-6 levels in peritoneal fluid of infertile patients with active endometriosis. Am J Obstet Gynecol 176:593–597\nWickiewicz D, Chrobak A, Gmyrek GB, Halbersztadt A, Gabrys MS, Goluda M, Chelmonska-Soyta A (2013) Diagnostic accuracy of interleukin-6 levels in peritoneal fluid for detection of endometriosis. Arch Gynecol Obstet 288:805–814\nAcknowledgments\nThis work was supported by the Swedish Medical Research Council (Grant to M.O.; 8683) and The Family Planning Fund in Uppsala.\nConflict of interest\nWe declare that we have no conflicts of interest.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nAdditional information\nC. Moberg and V. Bourlev contributed equally to this work.\nRights and permissions\nAbout this article\nCite this article\nMoberg, C., Bourlev, V., Ilyasova, N. et al. Endometrial expression of LIF and its receptor and peritoneal fluid levels of IL-1α and IL-6 in women with endometriosis are associated with the probability of pregnancy. Arch Gynecol Obstet 292, 429–437 (2015). https://doi.org/10.1007/s00404-015-3626-0\nReceived:\nAccepted:\nPublished:\nIssue date:\nDOI: https://doi.org/10.1007/s00404-015-3626-0","source_license":"public-domain-us","license_restricted":false}