{"paper_id":"40599931-c79c-47a3-b448-d31e46bd66f3","body_text":"Abstract\nBackground\nReported associations of progesterone receptor gene polymorphism (PROGINS) with endometriosis have been inconsistent.\nAim of the study\nTo evaluate the association between the PROGINS polymorphism and the risk of endometriosis.\nMethodology\nA meta-analysis of 12 published case–control studies with a total sample size of 3,321 (1,323 cases/1,998 controls) was performed. We estimated the risk (odds ratio [OR] 95 % confidence intervals) of endometriosis association with the PROGINS polymorphism.\nResults\nAn association between the presence of the variant allele and risk of endometriosis was found, more in the homozygous and recessive models (OR 1.41–1.43, p = 0.15–0.17), and less in the dominant and co-dominant models (OR 1.22, p = 0.11–0.15). Reanalysis without the studies whose controls deviated from the Hardy–Weinberg Equilibrium did not materially alter the dominant and co-dominant effects (OR 1.19–1.22, p = 0.19–0.32), but exacerbated the homozygous and recessive effects (OR 1.59, p = 0.09). The subgroups based on geography showed increased risk associations, consistently significant in the European (OR 1.52–2.72, p = 0.0008–0.03) but not in the Brazilian studies, where ORs ranged from reduced (OR 0.70–0.74, p = 0.54–0.61) to increased (OR 1.11, p = 0.75) risks. Heterogeneity was confined in all comparisons to the dominant and co-dominant models (I 2 = 38–70 %), except in the European subgroup, which had zero heterogeneity (I 2 = 0 %) in all genetic models, as did all homozygous and recessive effects.\nConclusion\nThis meta-analysis provides a comprehensive profile of the role of the PROGINS polymorphism in endometriosis by exploring the magnitude of the summary effects with modifier analysis. This magnitude is expressed with modulation or exacerbation of the summary effects, as defined by the parameters of the analysis. Thus, the results showed trend towards an increased risk of the variant PROGINS allele and susceptibility for the endometriosis.\nSimilar content being viewed by others\nReferences\nGiudice LC, Kao LC (2004) Endometriosis. Lancet 364:1789–1799\nRanney B (1980) Endometriosis: pathogenesis, symptoms, and findings. Clin Obstet Gynecol l23:865–874\nMissmer SA, Cramer DW (2003) The epidemiology of endometriosis. Obstet Gynecol Clin North Am 30:1–19\nBischoff FZ, Simpson JL (2000) Heritability and molecular genetic studies of endometriosis. Hum Reprod Update 6:37–44\nTempfer CB, Simoni M, Destenaves B, Fauser BC (2009) Functional genetic polymorphisms and female reproductive disorders: part II—endometriosis. Hum Reprod Update 15:97–118\nBaranova H, Bothorishvilli R, Canis M, Albuisson E, Perriot S, Glowaczower E, Bruhat MA, Baranov V, Malet P (1997) Glutathione S-transferase M1 gene polymorphism and susceptibility to endometriosis in a French population. Mol Hum Reprod 3:775–780\nGeorgiou I, Syrrou M, Bouba I, Dalkalitsis N, Paschopoulos M, Navrozoglou I, Lolis D (1999) Association of estrogen receptor gene polymorphisms with endometriosis. Fertil Steril 72:164–166\nLattuada D, Somigliana E, Viganò P, Candiani M, Pardi G, Di Blasio AM (2004) Genetics of endometriosis: a role for the progesterone receptor gene polymorphism PROGINS? Clin Endocrinol (Oxf) 61:190–194\nDe Carvalho CV, Nogueira-De-Souza NC, Costa AM, Baracat EC, Girão MJ, D’Amora P, Schor E, da Silva ID (2007) Genetic polymorphisms of cytochrome P450cl7alpha (CYP17) and progesterone receptor genes (PROGINS) in the assessment of endometriosis risk. Gynecol Endocrinol 23:29–33\nBulun SE, Zeitoun KM, Takayama K, Sasano H (2000) Estrogen biosynthesis in endometriosis: molecular basis and clinical relevance. J Mol Endocrinol 25:35–42\nYoung SL, Lessey BA (2010) Progesterone function in human endometrium: clinical perspectives. Semin Reprod Med 28:5–16\nGimenes C, Bianco B, Mafra FA, Rosset V, Christofolini DM, Barbosa CP (2010) The progins progesterone receptor gene polymorphism is not related to endometriosis-associated infertility or to idiopathic infertility. Clinics (Sao Paulo) 65:1073–1076\nPunyadeera C, Verbost P, Groothuis P (2003) Oestrogen and progestin responses in human endometrium. J Steroid Biochem Mol Biol 84:393–410\nFabjani G, Tong D, Czerwenka K, Schuster E, Speiser P, Leodolter S, Zeillinger R (2002) Human progesterone receptor gene polymorphism PROGINS and risk for breast cancer in Austrian women. Breast Cancer Res Treat 72:131–137\nAttia GR, Zeitoun K, Edwards D, Johns A, Carr BR, Bulun SE (2000) Progesterone receptor isoform A but not B is expressed in endometriosis. J Clin Endocrinol Metab 85:2897–2902\nMisao R, Iwagaki S, Fujimoto J, Sun W, Tamaya T (1999) Dominant expression of progesterone receptor form B mRNA in ovarian endometriosis. Horm Res 52:30–34\nNisolle M, Casanas-Roux F, Donnez J (1997) Immunohistochemical analysis of proliferative activity and steroid receptor expression in peritoneal and ovarian endometriosis. Fertil Steril 68:912–919\nMcKenna NJ, Kieback DG, Carney DN, Fanning M, McLinden J, Headon DR (1995) A germline TaqI restriction fragment length polymorphism in the progesterone receptor gene in ovarian carcinoma. Br J Cancer 71:451–455\nRowe SM, Coughlan SJ, McKenna NJ, Garrett E, Kieback DG, Carney DN, Headon DR (1995) Ovarian carcinoma-associated TaqI restriction fragment length polymorphism in intron G of the progesterone receptor gene is due to an Alu sequence insertion. Cancer Res 55:2743–2745\nWieser F, Schneeberger C, Tong D, Tempfer C, Huber JC, Wenzl R (2002) PROGINS receptor gene polymorphism is associated with endometriosis. Fertil Steril 77:309–3012\nGovindan S, Ahmad SN, Vedicherla B, Kodati V, Jahan P, Rao KP, Ahuja YR, Hasan Q (2007) Association of progesterone receptor gene polymorphism (PROGINS) with endometriosis, uterine fibroids and breast cancer. Cancer Biomark 3:73–78\nNear AM, Wu AH, Templeman C (2011) Progesterone receptor gene polymorphisms and risk of endometriosis: results from an international collaborative effort. Fertil Steril 95:40–45\nvan Kaam KJ, Romano A, Schouten JP, Dunselman GA, Groothuis PG (2007) Progesterone receptor polymorphism +331G/A is associated with a decreased risk of deep infiltrating endometriosis. Hum Reprod 22:129–135\nDonaldson CJ, Crapanzano JP, Watson JC, Levine EA, Batzer MA (2002) PROGINS Alu insertion and human genomic diversity. Mutat Res 501:137–141\nGrechukhina O, Petracco R, Popkhadze S, Massasa E, Paranjape T, Chan E, Flores I, Weidhaas JB, Taylor HS (2012) A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis. EMBO Mol Med 4:206–217\nBianco B, André GM, Vilarino FL, Peluso C, Mafra FA, Christofolini DM, Barbosa CP (2012) The possible role of genetic variants in autoimmune-related genes in the development of endometriosis. Hum Immunol 73:306–315\nBorghese B, Vaiman D, de Ziegler D, Chapron C (2010) Endometriosis and genetics: what responsibility for the genes? J Gynecol Obstet Biol Reprod 39:196–207\nGuo SW (2006) Association of endometriosis risk and genetic polymorphisms involving sex steroid biosynthesis and their receptors: a meta-analysis. Gynecol Obstet Invest 61:90–105\nHu X, Zhou Y, Feng Q, Wang R, Su L, Long J, Wei B (2012) Association of endometriosis risk and genetic polymorphisms involving biosynthesis of sex steroids and their receptors: an updating meta-analysis. Eur J Obstet Gynecol Reprod Biol 164:1–9\nKitawaki J, Kado N, Ishihara H, Koshiba H, Kitaoka Y, Honjo H (2002) Endometriosis: the pathophysiology as an estrogen-dependent disease. J Steroid Biochem Mol Biol 83:149–155\nD’Amora P, Maciel TT, Tambellini R, Mori MA, Pesquero JB, Sato H, Girão MJ, Guerreiro da Silva ID, Schor E (2009) Disrupted cell cycle control in cultured endometrial cells from patients with endometriosis harboring the progesterone receptor polymorphism PROGINS. Am J Pathol 175:215–224\nBerchuck A, Schildkraut JM, Wenham RM, Calingaert B, Ali S, Henriott A, Halabi S, Rodriguez GC, Gertig D, Purdie DM, Kelemen L, Spurdle AB, Marks J, Chenevix-Trench G (2004) Progesterone receptor promoter +331A polymorphism is associated with a reduced risk of endometrioid and clear cell ovarian cancers. Cancer Epidemiol Biomarkers Prev 13:2141–2147\nGentilini D, Vigano P, Carmignani L, Spinelli M, Busacca M, Di Blasio AM (2008) Progesterone receptor +331G/A polymorphism in endometriosis and deep-infiltrating endometriosis. Fertil Steril 90:1243–1245\nLamp M, Peters M, Reinmaa E, Haller-Kikkatalo K, Kaart T, Kadastik U, Karro H, Metspalu A, Salumets A (2011) Polymorphisms in ESR1, ESR2 and HSD17B1 genes are associated with fertility status in endometriosis. Gynecol Endocrinol 27:425–433\nRenner SP, Strick R, Fasching PA, Oeser S, Oppelt P, Mueller A, Beckmann MW, Strissel PL (2008) Single nucleotide polymorphisms in the progesterone receptor gene and association with uterine leiomyoma tumor characteristics and disease risk. Am J Obstet Gynecol 199:648.e1–648.e9\nTreloar SA, Zhao ZZ, Armitage T, Duffy DL, Wicks J, O’Connor DT, Martin NG, Montgomery GW (2005) Association between polymorphisms in the progesterone receptor gene and endometriosis. Mol Hum Reprod 11:641–647\nChristofolini DM, Vilarino FL, Mafra FA, André GM, Bianco B, Barbosa CP (2011) Combination of polymorphisms in luteinizing hormone beta, estrogen receptor beta and progesterone receptor and susceptibility to infertility and endometriosis. Eur J Obstet Gynecol Reprod Biol 158:260–264\nCosta IR, Silva RC, Frare AB, Silva CT, Bordin BM, Souza SR, Ribeiro Júnior CL, Moura KK (2011) Polymorphism of the progesterone receptor gene associated with endometriosis in patients from Goias, Brazil. Genet Mol Res 10:1364–1370\nTrabert B, Schwartz SM, Peters U, De Roos AJ, Chen C, Scholes D, Holt VL (2011) Genetic variation in the sex hormone metabolic pathway and endometriosis risk: an evaluation of candidate genes. Fertil Steril 96(1401–1406):e3\nMantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748\nDerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188\nLau J, Ioannidis JP, Schmid CH (1997) Quantitative synthesis in systematic reviews. Ann Intern Med 127:820–826\nHiggins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560\nHiggins JP, Thompson SJ (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558\nEgger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634\nBegg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101\nGurates B, Bulun SE (2003) Endometriosis: the ultimate hormonal disease. Semin Reprod Med 21:125–134\nButtram VC (1985) Evolution of the revised American Fertility Society classification of endometriosis. Fertil Steril 43:347–350\nThakkinstian A, McElduff P, D’Este C, Duffy D, Attia J (2005) A method for meta-analysis of molecular association studies. Stat Med 24:1291–1306\nLancaster JM, Berchuck A, Carney ME, Wiseman R, Taylor JA (1998) Progesterone receptor gene polymorphism and risk for breast and ovarian cancer. Br J Cancer 78:277\nAcknowledgments\nNoel Pabalan is funded by Saint Louis University Multigrant. We thank Dr. Sevtap Savas from The Memorial University of Newfoundland, Canada, for reviewing the initial drafts.\nConflict of interest\nThe authors have no conflicts of interest to declare.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nRights and permissions\nAbout this article\nCite this article\nPabalan, N., Salvador, A., Jarjanazi, H. et al. Association of the progesterone receptor gene polymorphism (PROGINS) with endometriosis: a meta-analysis. Arch Gynecol Obstet 290, 1015–1022 (2014). https://doi.org/10.1007/s00404-014-3308-3\nReceived:\nAccepted:\nPublished:\nIssue date:\nDOI: https://doi.org/10.1007/s00404-014-3308-3","source_license":"public-domain-us","license_restricted":false}