Journal List > J Korean Soc Menopause > v.19(2) > 1052104

Mun, Kim, Kim, Hwang, and Jang: Associations between Estrogen Receptor Gene Polymorphisms and Endometriosis


Endometriosis is common estrogen-related gynecological diseases related to interactions of dietary, genetic causes, social and environmental factors. The high prevalence approaches 5-15% in premenopausal women and 30% in infertile women, and it is unusual to occur after the onset of menopause. In this review, the gene polymorphisms of estrogen receptor (ER) α and βre-lated to the risks of endometriosis were investigated through statistical analysis by using the gene polymorphism for the risks of the disease examined trends. The polymorphism of ERα-PvuII in Europe tends to increase the risk of endometriosis and, ERα-XbaI polymorphisms in both Asia and Europe have a slightly increased risk of endometriosis. In the case of ERβ-RsaI, the risk of endometriosis increases in Brazil, while the polymorphism of ERβ-AluI reduces the disease risks in Asia. Polymorphism studies on ER associated with the risk of endometriosis in Asia and Europe showed that those polymorphisms may be used to predict the high or low risks of endometriosis, and potentially used for prevention, therapy or prognosis of endometriosis. Further studies on interacting with more related genes and environmental factors may provide a better understanding of associations between estrogen receptor gene polymorphisms and endometriosis.

Figures and Tables

Fig. 1
Four major mechanisms of estrogen and estrogen receptors (ER). (I) Classical ligand-dependent genomic target with direct binding actions; estrogen-ER complex directly binds to estrogen response element (ERE) in the target genes and then leads to regulations of transcription activity. (II) Non-classical ligand-dependent genomic target with indirect binding actions; estrogen-bound ER dimers interact with transcription factors, followed by regulations of target genes. (III) Ligand-dependent, non-genomic target actions; estrogen-ER complex phosphorylation (P) to target proteins lead to functions of proteins in cytoplasm or activations of transcription factor (TF) through phosphorylation in nucleus. (IV) Non-classical ligand-independent genomic target with direct binding actions; activation of growth factor receptor (GFR) phosphorylates ER to bind and regulate the target genes. The abbreviation are as follows; ER, ERE, TF, P, growth factor (GF), GFR, heat shock protein (HSP), RNA polymerase II (POL II) and coactivator (CoA). The dashed lines represent multiple pathways.
Fig. 2
Schematic representation of estrogen receptors (ER). ERα and ERβ variants show DNA-binding domains (DBD), hinge regions, ligand-binding domains (LBD) and two transcriptional activation functions, AF-1 and AF-2. Four major single nucleotide polymorphisms studied in this review are shown in the boxes: ERα-PvuII (rs2234693; c.435-397T > C), ERα-XbaI (rs9340799; c.453-351A > G), ERβ-RsaI (rs1256049; c.984G > A) and ERβ-AluI (rs4986938; c.4106+1872G > A).
Table 1
Summary of PvuII polymorphism of estrogen receptor α (ERα) gene on endometriosis risk

*χ2 value of each HWE. The red line indicates the OR number 1 and the x-axis is log-scaled.

OR: odds ratio, CI: confidence interval, HWE: Hardy-Weinberg equilibrium, NA: not applicable.

Table 2
Summary of XbaI polymorphism of estrogen receptor α (ERα) gene on endometriosis risk

OR: odds ratio, CI: confidence interval, HWE: Hardy-Weinberg equilibrium, NA: not applicable

Table 3
Summary of RsaI polymorphism of estrogen receptor β (ERβ) gene associated with endometriosis risk

CI: confidence interval, OR: odds ratio, HWE: Hardy-Weinberg equilibrium, NA: not applicable

Table 4
Summary of AluI polymorphism of estrogen receptor β (ERβ) gene associated with endometriosis risk

CI: confidence interval, HWE: Hardy-Weinberg equilibrium, OR: odds ratio, NA: not applicable


1. Sensky TE, Liu DT. Endometriosis: associations with menorrhagia, infertility and oral contraceptives. Int J Gynaecol Obstet. 1980; 17:573–576.
2. Houston DE. Evidence for the risk of pelvic endometriosis by age, race and socioeconomic status. Epidemiol Rev. 1984; 6:167–191.
3. Pellicano M, Magri G, Lacchi L. A case of ovarian endometriosis in late post-menopause. Clin Exp Obstet Gynecol. 1994; 21:57–58.
4. Fedele L, Bianchi S, Di Nola G, Candiani M, Busacca M, Vignali M. The recurrence of endometriosis. Ann N Y Acad Sci. 1994; 734:358–364.
5. Tandoi I, Somigliana E, Riparini J, Ronzoni S, Vigano P, Candiani M. High rate of endometriosis recurrence in young women. J Pediatr Adolesc Gynecol. 2011; 24:376–379.
6. Konishi I. Ovarian cancer in endometriosis. Int J Clin Oncol. 2009; 14:377.
7. Check JH, Check ML, Kiefer D, Aikins J Jr. Ovarian cancer in a woman previously diagnosed with endometriosis and an extremely high serum CA-125 level. Clin Exp Obstet Gynecol. 2001; 28:83–85.
8. Meng Q, Sun W, Jiang J, Fletcher NM, Diamond MP, Saed GM. Identification of common mechanisms between endometriosis and ovarian cancer. J Assist Reprod Genet. 2011; 28:917–923.
9. Georgiou I, Syrrou M, Bouba I, Dalkalitsis N, Paschopoulos M, Navrozoglou I, et al. Association of estrogen receptor gene polymorphisms with endometriosis. Fertil Steril. 1999; 72:164–166.
10. Kitawaki J, Obayashi H, Ishihara H, Koshiba H, Kusuki I, Kado N, et al. Oestrogen receptor-alpha gene polymorphism is associated with endometriosis, adenomyosis and leiomyomata. Hum Reprod. 2001; 16:51–55.
11. Choi YM, Ku SY, Hwang KR, Lim YT, Park SH, Jun JK, et al. Estrogen receptor gene PvuII and XbaI polymorphism in patients with endometriosis. Korean J Obstet Gynecol. 2003; 46:1531–1536.
12. Wang Z, Yoshida S, Negoro K, Kennedy S, Barlow D, Maruo T. Polymorphisms in the estrogen receptor beta gene but not estrogen receptor alpha gene affect the risk of developing endometriosis in a Japanese population. Fertil Steril. 2004; 81:1650–1656.
13. Hsieh YY, Chang CC, Tsai FJ, Lin CC, Tsai CH. Estrogen receptor alpha dinucleotide repeat and cytochrome P450c17alpha gene polymorphisms are associated with susceptibility to endometriosis. Fertil Steril. 2005; 83:567–572.
14. Kim SH, Choi YM, Jun JK, Kim SH, Kim JG, Moon SY. Estrogen receptor dinucleotide repeat polymorphism is associated with minimal or mild endometriosis. Fertil Steril. 2005; 84:774–777.
15. Ko HE, Whang DH, Noh JH, Kim YB. Association of progesterone receptor gene polymorphism (PROGINS) and estrogen receptor gene polymorphism with endometriosis in Korean population. Korean J Obstet Gynecol. 2006; 49:1471–1480.
16. Luisi S, Galleri L, Marini F, Ambrosini G, Brandi ML, Petraglia F. Estrogen receptor gene polymorphisms are associated with recurrence of endometriosis. Fertil Steril. 2006; 85:764–766.
17. Renner SP, Strick R, Oppelt P, Fasching PA, Engel S, Baumann R, et al. Evaluation of clinical parameters and estrogen receptor alpha gene polymorphisms for patients with endometriosis. Reproduction. 2006; 131:153–161.
18. Hsieh YY, Wang YK, Chang CC, Lin CS. Estrogen receptor alpha-351 XbaI*G and -397 PvuII*C-related genotypes and alleles are associated with higher susceptibilities of endometriosis and leiomyoma. Mol Hum Reprod. 2007; 13:117–122.
19. Lee GH, Kim SH, Choi YM, Suh CS, Kim JG, Moon SY. Estrogen receptor beta gene +1730 G/A polymorphism in women with endometriosis. Fertil Steril. 2007; 88:785–788.
20. Sato H, Nogueira-de-Souza NC, D'Amora P, Silva ID, Girão MJ, Schor E. Intron 1 and exon 1 alpha estrogen receptor gene polymorphisms in women with endometriosis. Fertil Steril. 2008; 90:2086–2090.
21. Bianco B, Christofolini DM, Mafra FA, Brandes A, Zulli K, Barbosa CP. +1730 G/A polymorphism of the estrogen receptor beta gene (ERbeta) may be an important genetic factor predisposing to endometriosis. Acta Obstet Gynecol Scand. 2009; 88:1397–1401.
22. Govindan S, Shaik NA, Vedicherla B, Kodati V, Rao KP, Hasan Q. Estrogen receptor-alpha gene (T/C) Pvu II polymorphism in endometriosis and uterine fibroids. Dis Markers. 2009; 26:149–154.
23. Xie J, Wang S, He B, Pan Y, Li Y, Zeng Q, et al. Association of estrogen receptor alpha and interleukin-10 gene polymorphisms with endometriosis in a Chinese population. Fertil Steril. 2009; 92:54–60.
24. Zulli K, Bianco B, Mafra FA, Teles JS, Christofolini DM, Barbosa CP. Polymorphism of the estrogen receptor beta gene is related to infertility and infertility-associated endometriosis. Arq Bras Endocrinol Metabol. 2010; 54:567–571.
25. Li Y, Liu F, Tan SQ, Wang Y, Li SW. Estrogen receptor-alpha gene PvuII (T/C) and XbaI (A/G) polymorphisms and endometriosis risk: a meta-analysis. Gene. 2012; 508:41–48.
26. Wang W, Li Y, Maitituoheti M, Yang R, Wu Z, Wang T, et al. Association of an oestrogen receptor gene polymorphism in Chinese Han women with endometriosis and endometriosis-related infertility. Reprod Biomed Online. 2013; 26:93–98.
27. Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol. 1927; 3:93–110.
28. van der Linden PJ. Endometriosis: a review on its pathogenesis. Front Biosci. 1997; 2:e48–e52.
29. Bulletti C, Coccia ME, Battistoni S, Borini A. Endometriosis and infertility. J Assist Reprod Genet. 2010; 27:441–447.
30. Moen MH. Endometriosis in monozygotic twins. Acta Obstet Gynecol Scand. 1994; 73:59–62.
31. Kashima K, Ishimaru T, Okamura H, Suginami H, Ikuma K, Murakami T, et al. Familial risk among Japanese patients with endometriosis. Int J Gynaecol Obstet. 2004; 84:61–64.
32. dos Reis RM, de Sá MF, de Moura MD, Nogueira AA, Ribeiro JU, Ramos ES, et al. Familial risk among patients with endometriosis. J Assist Reprod Genet. 1999; 16:500–503.
33. Küpker W, Felberbaum RE, Krapp M, Schill T, Malik E, Diedrich K. Use of GnRH antagonists in the treatment of endometriosis. Reprod Biomed Online. 2002; 5:12–16.
34. Abu Hashim H. Gonadotrophin-releasing hormone analogues and endometriosis: current strategies and new insights. Gynecol Endocrinol. 2012; 28:314–321.
35. Björnström L, Sjöberg M. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol. 2005; 19:833–842.
36. Bulun SE, Monsavais D, Pavone ME, Dyson M, Xue Q, Attar E, et al. Role of estrogen receptor-beta in endometriosis. Semin Reprod Med. 2012; 30:39–45.
37. Wedrén S, Lovmar L, Humphreys K, Magnusson C, Melhus H, Syvänen AC, et al. Estrogen receptor alpha gene polymorphism and endometrial cancer risk--a case-control study. BMC Cancer. 2008; 8:322.
38. Gennari L, Merlotti D, De Paola V, Calabrò A, Becherini L, Martini G, et al. Estrogen receptor gene polymorphisms and the genetics of osteoporosis: a HuGE review. Am J Epidemiol. 2005; 161:307–320.
39. Maguire P, Margolin S, Skoglund J, Sun XF, Gustafsson JA, Børresen-Dale AL, et al. Estrogen receptor beta (ESR2) polymorphisms in familial and sporadic breast cancer. Breast Cancer Res Treat. 2005; 94:145–152.
40. Silva RC, Costa IR, Bordin BM, Silva CT, Souza SR, Júnior CL, et al. RsaI polymorphism of the ERbeta gene in women with endometriosis. Genet Mol Res. 2011; 10:465–470.
Similar articles