Role of Estrogen Receptor-β in Endometriosis

Abstract

Endometriosis is an estrogen-dependent disease. The biologically active estrogen, estradiol, aggravates the pathological processes (e.g., inflammation and growth) and the symptoms (e.g., pain) associated with endometriosis. Abundant quantities of estradiol are available for endometriotic tissue via several mechanisms including local aromatase expression. The question remains, then, what mediates estradiol action. Because estrogen receptor (ER)β levels in endometriosis are >100 times higher than those in endometrial tissue, this review focuses on this nuclear receptor. Deficient methylation of the ERβ promoter results in pathological overexpression of ERβ in endometriotic stromal cells. High levels of ERβ suppress ERα expression. A severely high ERβ-to-ERα ratio in endometriotic stromal cells is associated with suppressed progesterone receptor and increased cyclo-oxygenase-2 levels contributing to progesterone resistance and inflammation. ERβ-selective estradiol antagonists may serve as novel therapeutics of endometriosis in the future.

Keywords

ER-β - nuclear receptor - estrogen - DNA methylation - epigenetic - promoter - ER-α - PR

• References

• 1 Giudice LC. Clinical practice. Endometriosis. N Engl J Med 2010; 362 (25) 2389-2398
• 2 Giudice LC, Kao LC. Endometriosis. Lancet 2004; 364 (9447) 1789-1799
• 3 Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am 1997; 24 (2) 235-258
• 4 Simpson JL, Elias S, Malinak LR, Buttram Jr VC. Heritable aspects of endometriosis. I. Genetic studies. Am J Obstet Gynecol 1980; 137 (3) 327-331
• 5 Kennedy SMH, Mardon H, Barlow D. Familial endometriosis. J Assist Reprod Genet 1995; 12 (1) 32-34
• 6 Bulun SE, Cheng YH, Yin P , et al. Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol 2006; 248 (1–2) 94-103
• 7 Bulun SE. Endometriosis. N Engl J Med 2009; 360 (3) 268-279
• 8 Schulke L, Berbic M, Manconi F, Tokushige N, Markham R, Fraser IS. Dendritic cell populations in the eutopic and ectopic endometrium of women with endometriosis. Hum Reprod 2009; 24 (7) 1695-1703
• 9 Vercellini P, Trespidi L, Colombo A, Vendola N, Marchini M, Crosignani PG. A gonadotropin-releasing hormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis. Fertil Steril 1993; 60 (1) 75-79
• 10 Vercellini P, Trespidi L, De Giorgi O, Cortesi I, Parazzini F, Crosignani PG. Endometriosis and pelvic pain: relation to disease stage and localization. Fertil Steril 1996; 65 (2) 299-304
• 11 Vercellini P, Cortesi I, Crosignani PG. Progestins for symptomatic endometriosis: a critical analysis of the evidence. Fertil Steril 1997; 68 (3) 393-401
• 12 Abushahin F, Goldman KN, Barbieri E, Milad M, Rademaker A, Bulun SE. Aromatase inhibition for refractory endometriosis-related chronic pelvic pain. Fertil Steril 2011; 96 (4) 939-942
• 13 Harris HA. Estrogen receptor-beta: recent lessons from in vivo studies. Mol Endocrinol 2007; 21 (1) 1-13
• 14 Halme J, Becker S, Hammond MG, Raj MHG, Raj S. Increased activation of pelvic macrophages in infertile women with mild endometriosis. Am J Obstet Gynecol 1983; 145 (3) 333-337
• 15 Halme J, White C, Kauma S, Estes J, Haskill S. Peritoneal macrophages from patients with endometriosis release growth factor activity in vitro. J Clin Endocrinol Metab 1988; 66 (5) 1044-1049
• 16 Dmowski WP, Steele RW, Baker GF. Deficient cellular immunity in endometriosis. Am J Obstet Gynecol 1981; 141 (4) 377-383
• 17 Kao LC, Germeyer A, Tulac S , et al. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology 2003; 144 (7) 2870-2881
• 18 Burney RO, Talbi S, Hamilton AE , et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 2007; 148 (8) 3814-3826
• 19 Osteen KG, Bruner-Tran KL, Eisenberg E. Reduced progesterone action during endometrial maturation: a potential risk factor for the development of endometriosis. Fertil Steril 2005; 83 (3) 529-537
• 20 Noble LS, Takayama K, Zeitoun KM , et al. Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells. J Clin Endocrinol Metab 1997; 82 (2) 600-606
• 21 Kao LC, Tulac S, Lobo S , et al. Global gene profiling in human endometrium during the window of implantation. Endocrinology 2002; 143 (6) 2119-2138
• 22 Hornung D, Ryan IP, Chao VA, Vigne JL, Schriock ED, Taylor RN. Immunolocalization and regulation of the chemokine RANTES in human endometrial and endometriosis tissues and cells. J Clin Endocrinol Metab 1997; 82 (5) 1621-1628
• 23 Zeitoun KM, Bulun SE. Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target. Fertil Steril 1999; 72 (6) 961-969
• 24 Osteen KG, Bruner-Tran KL, Keller NR, Eisenberg E. Progesterone-mediated endometrial maturation limits matrix metalloproteinase (MMP) expression in an inflammatory-like environment: a regulatory system altered in endometriosis. Ann N Y Acad Sci 2002; 955: 37-47; discussion 86–88, 396–406
• 25 Zeitoun K, Takayama K, Sasano H , et al. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol. J Clin Endocrinol Metab 1998; 83 (12) 4474-4480
• 26 Bulun SE, Lin Z, Imir G , et al. Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev 2005; 57 (3) 359-383
• 27 Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A 1996; 93 (12) 5925-5930
• 28 Mosselman S, Polman J, Dijkema R. ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett 1996; 392 (1) 49-53
• 29 Green S, Walter P, Kumar V , et al. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 1986; 320 (6058) 134-139
• 30 Hewitt SC, Harrell JC, Korach KS. Lessons in estrogen biology from knockout and transgenic animals. Annu Rev Physiol 2005; 67: 285-308
• 31 Brandenberger AW, Lebovic DI, Tee MK , et al. Oestrogen receptor (ER)-alpha and ER-beta isoforms in normal endometrial and endometriosis-derived stromal cells. Mol Hum Reprod 1999; 5 (7) 651-655
• 32 Fujimoto J, Hirose R, Sakaguchi H, Tamaya T. Expression of oestrogen receptor-alpha and -beta in ovarian endometriomata. Mol Hum Reprod 1999; 5 (8) 742-747
• 33 Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR, Bulun SE. Progesterone receptor isoform A but not B is expressed in endometriosis. J Clin Endocrinol Metab 2000; 85 (8) 2897-2902
• 34 Lin Z, Reierstad S, Huang CC, Bulun SE. Novel estrogen receptor-alpha binding sites and estradiol target genes identified by chromatin immunoprecipitation cloning in breast cancer. Cancer Res 2007; 67 (10) 5017-5024
• 35 Schultz JR, Petz LN, Nardulli AM. Cell- and ligand-specific regulation of promoters containing activator protein-1 and Sp1 sites by estrogen receptors alpha and beta. J Biol Chem 2005; 280 (1) 347-354
• 36 Attar E, Tokunaga H, Imir G , et al. Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis. J Clin Endocrinol Metab 2009; 94 (2) 623-631
• 37 Bulun SE, Utsunomiya H, Lin Z , et al. Steroidogenic factor-1 and endometriosis. Mol Cell Endocrinol 2009; 300 (1–2) 104-108
• 38 Xue Q, Lin Z, Cheng YH , et al. Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis. Biol Reprod 2007; 77 (4) 681-687
• 39 Bergman MD, Schachter BS, Karelus K, Combatsiaris EP, Garcia T, Nelson JF. Up-regulation of the uterine estrogen receptor and its messenger ribonucleic acid during the mouse estrous cycle: the role of estradiol. Endocrinology 1992; 130 (4) 1923-1930
• 40 Grandien K. Determination of transcription start sites in the human estrogen receptor gene and identification of a novel, tissue-specific, estrogen receptor-mRNA isoform. Mol Cell Endocrinol 1996; 116 (2) 207-212
• 41 Donaghue C, Westley BR, May FE. Selective promoter usage of the human estrogen receptor-alpha gene and its regulation by estrogen. Mol Endocrinol 1999; 13 (11) 1934-1950
• 42 Grandien K, Bäckdahl M, Ljunggren O, Gustafsson JA, Berkenstam A. Estrogen target tissue determines alternative promoter utilization of the human estrogen receptor gene in osteoblasts and tumor cell lines. Endocrinology 1995; 136 (5) 2223-2229
• 43 Grandien KF, Berkenstam A, Nilsson S, Gustafsson JA. Localization of DNase I hypersensitive sites in the human oestrogen receptor gene correlates with the transcriptional activity of two differentially used promoters. J Mol Endocrinol 1993; 10 (3) 269-277
• 44 Trukhacheva E, Lin Z, Reierstad S, Cheng YH, Milad M, Bulun SE. Estrogen receptor (ER) beta regulates ERalpha expression in stromal cells derived from ovarian endometriosis. J Clin Endocrinol Metab 2009; 94 (2) 615-622
• 45 Bonéy-Montoya J, Ziegler YS, Curtis CD, Montoya JA, Nardulli AM. Long-range transcriptional control of progesterone receptor gene expression. Mol Endocrinol 2010; 24 (2) 346-358
• 46 Kastner P, Krust A, Turcotte B , et al. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 1990; 9 (5) 1603-1614
• 47 Nardulli AM, Greene GL, O’Malley BW, Katzenellenbogen BS. Regulation of progesterone receptor messenger ribonucleic acid and protein levels in MCF-7 cells by estradiol: analysis of estrogen’s effect on progesterone receptor synthesis and degradation. Endocrinology 1988; 122 (3) 935-944
• 48 Wei LL, Krett NL, Francis MD , et al. Multiple human progesterone receptor messenger ribonucleic acids and their autoregulation by progestin agonists and antagonists in breast cancer cells. Mol Endocrinol 1988; 2 (1) 62-72
• 49 Read LD, Snider CE, Miller JS, Greene GL, Katzenellenbogen BS. Ligand-modulated regulation of progesterone receptor messenger ribonucleic acid and protein in human breast cancer cell lines. Mol Endocrinol 1988; 2 (3) 263-271
• 50 Petz LN, Ziegler YS, Schultz JR, Nardulli AM. Fos and Jun inhibit estrogen-induced transcription of the human progesterone receptor gene through an activator protein-1 site. Mol Endocrinol 2004; 18 (3) 521-532
• 51 Matthews J, Wihlén B, Tujague M, Wan J, Ström A, Gustafsson JA. Estrogen receptor (ER) beta modulates ERalpha-mediated transcriptional activation by altering the recruitment of c-Fos and c-Jun to estrogen-responsive promoters. Mol Endocrinol 2006; 20 (3) 534-543
• 52 Petz LN, Ziegler YS, Schultz JR, Kim H, Kemper JK, Nardulli AM. Differential regulation of the human progesterone receptor gene through an estrogen response element half site and Sp1 sites. J Steroid Biochem Mol Biol 2004; 88 (2) 113-122
• 53 Petz LN, Nardulli AM. Sp1 binding sites and an estrogen response element half-site are involved in regulation of the human progesterone receptor A promoter. Mol Endocrinol 2000; 14 (7) 972-985
• 54 Petz LN, Ziegler YS, Loven MA, Nardulli AM. Estrogen receptor alpha and activating protein-1 mediate estrogen responsiveness of the progesterone receptor gene in MCF-7 breast cancer cells. Endocrinology 2002; 143 (12) 4583-4591
• 55 Schultz JR, Petz LN, Nardulli AM. Estrogen receptor alpha and Sp1 regulate progesterone receptor gene expression. Mol Cell Endocrinol 2003; 201 (1-2) 165-175
• 56 Savouret JF, Bailly A, Misrahi M , et al. Characterization of the hormone responsive element involved in the regulation of the progesterone receptor gene. EMBO J 1991; 10 (7) 1875-1883
• 57 Montano MM, Kraus WL, Katzenellenbogen BS. Identification of a novel transferable cis element in the promoter of an estrogen-responsive gene that modulates sensitivity to hormone and antihormone. Mol Endocrinol 1997; 11 (3) 330-341
• 58 Scott RE, Wu-Peng XS, Yen PM, Chin WW, Pfaff DW. Interactions of estrogen- and thyroid hormone receptors on a progesterone receptor estrogen response element (ERE) sequence: a comparison with the vitellogenin A2 consensus ERE. Mol Endocrinol 1997; 11 (11) 1581-1592
• 59 Su EJ, Lin ZH, Zeine R , et al. Estrogen receptor-beta mediates cyclooxygenase-2 expression and vascular prostanoid levels in human placental villous endothelial cells. Am J Obstet Gynecol 2009; 200 (4) 427-, e1–e8
• 60 Su EJ, Ernst L, Abdallah N , et al. Estrogen receptor-β and fetoplacental endothelial prostanoid biosynthesis: a link to clinically demonstrated fetal growth restriction. J Clin Endocrinol Metab 2011; 96 (10) E1558-E1567