Semin Reprod Med 2010; 28(1): 036-043
DOI: 10.1055/s-0029-1242991
© Thieme Medical Publishers

Estrogen Receptor-β, Estrogen Receptor-α, and Progesterone Resistance in Endometriosis

Serdar E. Bulun1 , You-Hong Cheng1 , Mary Ellen Pavone1 , Qing Xue2 , Erkut Attar3 , Elena Trukhacheva1 , Hideki Tokunaga4 , Hiroki Utsunomiya4 , Ping Yin1 , Xia Luo1 , Zhihong Lin1 , Gonca Imir5 , Stephen Thung6 , Emily J. Su1 , J. Julie Kim1
  • 1Division of Reproductive Biology Research, Department Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 2Department of Obstetrics and Gynecology, First Hospital of Peking University, Beijing, P.R. China
  • 3Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Istanbul University Capa School of Medicine, Istanbul, Turkey
  • 4Department of Obstetrics and Gynecology, Tohoku University School of Medicine, Sendai, Japan
  • 5Department of Obstetrics and Gynecology, Cumhuriyet University School of Medicine, Sivas, Turkey
  • 6Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut
Further Information

Publication History

Publication Date:
26 January 2010 (online)

ABSTRACT

Loss of progesterone signaling in the endometrium may be a causal factor in the development of endometriosis, and progesterone resistance is commonly observed in women with this disease. In endometriotic stromal cells, the levels of progesterone receptor (PR), particularly the PR-B isoform, are significantly decreased, leading to a loss of paracrine signaling. PR deficiency likely underlies the development of progesterone resistance in women with endometriosis who no longer respond to progestin therapy. Here we review the complex epigenetic and transcriptional mechanisms leading to PR deficiency. The initial event may involve deficient methylation of the estrogen receptor (ER)β promoter resulting in pathologic overexpression of ERβ in endometriotic stromal cells. We speculate that alterations in the relative levels of ERβ and ERα in endometrial tissue dictate E2-regulated PR expression, such that a decreased ERα-το-ERβ ratio may result in suppression of PR. In this review, we propose a molecular model that may be responsible for changes in ERβ and ERα leading to PR loss and progesterone resistance in endometriosis.

REFERENCES

  • 1 Giudice L C, Kao L C. Endometriosis.  Lancet. 2004;  364(9447) 1789-1799
  • 2 Eskenazi B, Warner M L. Epidemiology of endometriosis.  Obstet Gynecol Clin North Am. 1997;  24 235-258
  • 3 Olive D L, Schwartz L B. Endometriosis.  N Engl J Med. 1993;  328(24) 1759-1769
  • 4 Kennedy S MH, Mardon H, Barlow D. Familial endometriosis.  J Assist Reprod Genet. 1995;  12(1) 32-34
  • 5 Bulun S E, Cheng Y H, Yin P et al.. Progesterone resistance in endometriosis: link to failure to metabolize estradiol.  Mol Cell Endocrinol. 2006;  248(1-2) 94-103
  • 6 Vercellini P, Trespidi L, Colombo A, Vendola N, Marchini M, Crosignani P G. A gonadotropin-releasing hormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis.  Fertil Steril. 1993;  60(1) 75-79
  • 7 Vercellini P, Trespidi L, De Giorgi O, Cortesi I, Parazzini F, Crosignani P G. Endometriosis and pelvic pain: relation to disease stage and localization.  Fertil Steril. 1996;  65(2) 299-304
  • 8 Vercellini P, Cortesi I, Crosignani P G. Progestins for symptomatic endometriosis: a critical analysis of the evidence.  Fertil Steril. 1997;  68(3) 393-401
  • 9 Harris H A. Estrogen receptor-beta: recent lessons from in vivo studies.  Mol Endocrinol. 2007;  21(1) 1-13
  • 10 Halme J, Becker S, Hammond M G, Raj M H, Raj S. Increased activation of pelvic macrophages in infertile women with mild endometriosis.  Am J Obstet Gynecol. 1983;  145 333-337
  • 11 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
  • 12 Dmowski W P, Steele R W, Baker G F. Deficient cellular immunity in endometriosis.  Am J Obstet Gynecol. 1981;  141(4) 377-383
  • 13 Kao L C, 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
  • 14 Osteen K G, Bruner-Tran K L, Eisenberg E. Reduced progesterone action during endometrial maturation: a potential risk factor for the development of endometriosis.  Fertil Steril. 2005;  83(3) 529-537
  • 15 Kao L C, Tulac S, Lobo S et al.. Global gene profiling in human endometrium during the window of implantation.  Endocrinology. 2002;  143(6) 2119-2138
  • 16 Hornung D, Ryan I P, Chao V A, Vigne J L, Schriock E D, Taylor R N. Immunolocalization and regulation of the chemokine RANTES in human endometrial and endometriosis tissues and cells.  J Clin Endocrinol Metab. 1997;  82(5) 1621-1628
  • 17 Zeitoun K M, Bulun S E. Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target.  Fertil Steril. 1999;  72(6) 961-969
  • 18 Osteen K G, Bruner-Tran K L, Keller N R, 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
  • 19 Zeitoun K M, 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
  • 20 Kuiper G G, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson J A. Cloning of a novel receptor expressed in rat prostate and ovary.  Proc Natl Acad Sci U S A. 1996;  93(12) 5925-5930
  • 21 Mosselman S, Polman J, Dijkema R. ER beta: identification and characterization of a novel human estrogen receptor.  FEBS Lett. 1996;  392(1) 49-53
  • 22 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
  • 23 Hewitt S C, Harrell J C, Korach K S. Lessons in estrogen biology from knockout and transgenic animals.  Annu Rev Physiol. 2005;  67 285-308
  • 24 Brandenberger A W, Lebovic D I, Tee M K 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
  • 25 Fujimoto J, Hirose R, Sakaguchi H, Tamaya T. Expression of oestrogen receptor-alpha and -beta in ovarian endometriomata.  Mol Hum Reprod. 1999;  8 742-747
  • 26 Attia G R, Zeitoun K, Edwards D, Johns A, Carr B R, Bulun S E. Progesterone receptor isoform A but not B is expressed in endometriosis.  J Clin Endocrinol Metab. 2000;  85(8) 2897-2902
  • 27 Lin Z, Reierstad S, Huang C C, Bulun S E. 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
  • 28 Schultz J R, Petz L N, Nardulli A M. 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
  • 29 Xue Q, Lin Z, Cheng Y H et al.. Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis.  Biol Reprod. 2007;  77(4) 681-687
  • 30 Bergman M D, Schachter B S, Karelus K, Combatsiaris E P, Garcia T, Nelson J F. 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
  • 31 Bulun S E, 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
  • 32 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
  • 33 Donaghue C, Westley B R, May F E. Selective promoter usage of the human estrogen receptor-alpha gene and its regulation by estrogen.  Mol Endocrinol. 1999;  13(11) 1934-1950
  • 34 Grandien K, Bäckdahl M, Ljunggren O, Gustafsson J A, 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
  • 35 Grandien K F, Berkenstam A, Nilsson S, Gustafsson J A. 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
  • 36 Trukhacheva E, Lin Z, Reierstad S, Cheng Y H, Milad M, Bulun S E. Estrogen receptor (ER) beta regulates ERalpha expression in stromal cells derived from ovarian endometriosis.  J Clin Endocrinol Metab. 2009;  94(2) 615-622
  • 37 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
  • 38 Nardulli A M, Greene G L, O'Malley B W, Katzenellenbogen B S. 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
  • 39 Wei L L, Krett N L, Francis M D 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
  • 40 Read L D, Snider C E, Miller J S, Greene G L, Katzenellenbogen B S. Ligand-modulated regulation of progesterone receptor messenger ribonucleic acid and protein in human breast cancer cell lines.  Mol Endocrinol. 1988;  2(3) 263-271
  • 41 Petz L N, Ziegler Y S, Schultz J R, Nardulli A M. 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
  • 42 Matthews J, Wihlén B, Tujague M, Wan J, Ström A, Gustafsson J A. 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
  • 43 Petz L N, Ziegler Y S, Schultz J R, Kim H, Kemper J K, Nardulli A M. 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
  • 44 Petz L N, Nardulli A M. 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
  • 45 Petz L N, Ziegler Y S, Loven M A, Nardulli A M. 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
  • 46 Schultz J R, Petz L N, Nardulli A M. Estrogen receptor alpha and Sp1 regulate progesterone receptor gene expression.  Mol Cell Endocrinol. 2003;  201(1-2) 165-175
  • 47 Savouret J F, 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
  • 48 Montano M M, Kraus W L, Katzenellenbogen B S. 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
  • 49 Scott R E, Wu-Peng X S, Yen P M, Chin W W, Pfaff D W. 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

Serdar E BulunM.D. 

George H. Gardner Professor of Clinical Gynecology, Division of Reproductive Biology Research, Department Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine

303 E. Superior St., 4-123 Chicago, IL 60611

Email: s-bulun@northwestern.edu

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