Association of the progesterone receptor gene polymorphism (PROGINS) with endometriosis: a meta-analysis

Background Reported associations of progesterone receptor gene polymorphism (PROGINS) with endometriosis have been inconsistent. Aim of the study To evaluate the association between the PROGINS polymorphism and the risk of endometriosis. Methodology A 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.

An 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.

This 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. Similar content being viewed by others

Giudice LC, Kao LC (2004) Endometriosis. Lancet 364:1789–1799 Ranney B (1980) Endometriosis: pathogenesis, symptoms, and findings. Clin Obstet Gynecol l23:865–874 Missmer SA, Cramer DW (2003) The epidemiology of endometriosis. Obstet Gynecol Clin North Am 30:1–19 Bischoff FZ, Simpson JL (2000) Heritability and molecular genetic studies of endometriosis. Hum Reprod Update 6:37–44 Tempfer CB, Simoni M, Destenaves B, Fauser BC (2009) Functional genetic polymorphisms and female reproductive disorders: part II—endometriosis. Hum Reprod Update 15:97–118 Baranova 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 Georgiou 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 Lattuada 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 De 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 Bulun SE, Zeitoun KM, Takayama K, Sasano H (2000) Estrogen biosynthesis in endometriosis: molecular basis and clinical relevance. J Mol Endocrinol 25:35–42 Young SL, Lessey BA (2010) Progesterone function in human endometrium: clinical perspectives. Semin Reprod Med 28:5–16 Gimenes 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 Punyadeera C, Verbost P, Groothuis P (2003) Oestrogen and progestin responses in human endometrium. J Steroid Biochem Mol Biol 84:393–410 Fabjani 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 Attia 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 Misao 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 Nisolle 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 McKenna 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 Rowe 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 Wieser 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 Govindan 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 Near 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 van 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 Donaldson CJ, Crapanzano JP, Watson JC, Levine EA, Batzer MA (2002) PROGINS Alu insertion and human genomic diversity. Mutat Res 501:137–141 Grechukhina 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 Bianco 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 Borghese 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 Guo 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 Hu 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 Kitawaki 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 D’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 Berchuck 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 Gentilini 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 Lamp 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 Renner 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 Treloar 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 Christofolini 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 Costa 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 Trabert 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 Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748 DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188 Lau J, Ioannidis JP, Schmid CH (1997) Quantitative synthesis in systematic reviews. Ann Intern Med 127:820–826 Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560 Higgins JP, Thompson SJ (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558 Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634 Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101 Gurates B, Bulun SE (2003) Endometriosis: the ultimate hormonal disease. Semin Reprod Med 21:125–134 Buttram VC (1985) Evolution of the revised American Fertility Society classification of endometriosis. Fertil Steril 43:347–350 Thakkinstian 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 Lancaster 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 Acknowledgments Noel 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. Conflict of interest The authors have no conflicts of interest to declare. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Pabalan, 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 Received: Accepted: Published: Issue date: DOI: https://doi.org/10.1007/s00404-014-3308-3