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Epigenetics of Estrogen and Progesterone Receptors in Endometriosis

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Abstract

Endometriosis is an estrogen-dependent inflammatory gynecological disease. Increased estrogen activity and progesterone resistance are the main hormonal substrate of this disease and are associated with inflammatory response and debilitating symptoms, including pain and infertility. Estrogens and progesterone act via their specific nuclear receptors. The regulation of receptor expression by epigenetics maybe a critical factor for endometriosis. The present review aims to discuss the epigenetic mechanisms related to the expression of estrogen receptors (ERs) and progesterone receptors (PRs) in patients with endometriosis, including two classic epigenetic mechanisms: DNA methylation and histone modification, and, other non-classic mechanisms: miRNAs and lncRNA. Several in vitro and in vivo studies support the key role of epigenetics in the regulation of the expression of ERs and PRs, which may provide new molecules and targets for the diagnosis and treatment of endometriosis.

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References

  1. Yilmaz BD, Bulun SE. Endometriosis and nuclear receptors. Hum Reprod Update. 2019;25(4):473–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Giudice LC. Endometriosis. N Engl J Med. 2010;362(25):2389–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Reis FM, Petraglia F, Taylor RN. Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis. Hum Reprod Update. 2013;19(4):406–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Bulun SE, Cheng YH, Pavone ME, Xue Q, Attar E, Trukhacheva E, et al. Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med. 2010;28(1):36–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 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):2897–902.

    CAS  PubMed  Google Scholar 

  6. Huhtinen K, Stahle M, Perheentupa A, Poutanen M. Estrogen biosynthesis and signaling in endometriosis. Mol Cell Endocrinol. 2012;358(2):146–54.

    CAS  PubMed  Google Scholar 

  7. Mosselman S, Polman J, Dijkema R. ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett. 1996;392(1):49–53.

    CAS  PubMed  Google Scholar 

  8. Dyson MT, Kakinuma T, Pavone ME, Monsivais D, Navarro A, Malpani SS, et al. Aberrant expression and localization of deoxyribonucleic acid methyltransferase 3B in endometriotic stromal cells. Fertil Steril. 2015;104(4):953–63.e2.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Javobsen BM, Horwitz KB. Progesterone receptors, their isoforms and progesterone regulated transcription. Mol Cell Endocrinol. 212;357(1–2):18–29.

  10. Matsuzaki S, Murakami T, Uehara S, Canis M, Sasano H, Okamura K. Expression of estrogen receptor alpha and beta in peritoneal and ovarian endometriosis. Fertil Steril. 2001;75(6):1198–205.

    CAS  PubMed  Google Scholar 

  11. Xue Q, Lin Z, Cheng YH, Huang CC, Marsh E, Yin P, et al. Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis. Biol Reprod. 2007;77(4):681–7.

    CAS  PubMed  Google Scholar 

  12. Monsivais D, Dyson MT, Yin P, Coon JS, Navarro A, Feng G, et al. ERβ- and prostaglandin E2-regulated pathways integrate cell proliferation via Ras-like and estrogen-regulated growth inhibitor in endometriosis. Mol Endocrinol. 2014;28(8):1304–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Han SJ, Jung SY, Wu SP, Hawkins SM, Park MJ, Kyo S, et al. Estrogen receptor beta modulates apoptosis complexes and the inflammasome to drive the pathogenesis of endometriosis. Cell. 2015;163(4):960–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 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(3):764–6.

    CAS  PubMed  Google Scholar 

  15. Guo R, Zheng N, Ding S, Zheng Y, Feng L. Associations between estrogen receptor-beta polymorphisms and endometriosis risk: a meta-analysis. Diagn Pathol. 2014;9:184.

    PubMed  PubMed Central  Google Scholar 

  16. Rocha-Junior CV, Da Broi MG, Miranda-Furtado CL, Navarro PA, Ferriani RA, Meola J. Progesterone receptor B (PGR-B) is partially methylated in eutopic endometrium from infertile women with endometriosis. Reprod Sci. 2019;26(12):1568–74.

    CAS  PubMed  Google Scholar 

  17. Yang S, Thiel KW, Leslie KK. Progesterone: the ultimate endometrial tumor suppressor. Trends Endocrinol Metab. 2011;22(4):145–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kurita T, Lee KJ, Cooke PS, Lydon JP, Cunha GR. Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus. Biol Reprod. 2000;62(4):831–8.

    CAS  PubMed  Google Scholar 

  19. Wu Y, Strawn E, Basir Z, Halverson G, Guo SW. Promoter hypermethylation of progesterone receptor isoform B (PR-B) in endometriosis. Epigenetics. 2006;1(2):106–11.

    PubMed  Google Scholar 

  20. Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, et al. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology. 2003;144(7):2870–81.

    CAS  PubMed  Google Scholar 

  21. Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007;148(8):3814–26.

    CAS  PubMed  Google Scholar 

  22. Zhou M, Fu J, Xiao L, Yang S, Song Y, Zhang X, et al. miR-196a overexpression activates the MEK/ERK signal and represses the progesterone receptor and decidualization in eutopic endometrium from women with endometriosis. Hum Reprod. 2016;31(11):2598–608.

    CAS  PubMed  Google Scholar 

  23. Herington JL, Bruner-Tran KL, Lucas JA, Osteen KG. Immune interactions in endometriosis. Expert Rev Clin Immunol. 2011;7(5):611–26.

    PubMed  PubMed Central  Google Scholar 

  24. Pabalan N, Salvador A, Jarjanazi H, Christofolini DM, Barbosa CP, Bianco B. Association of the progesterone receptor gene polymorphism (PROGINS) with endometriosis: a meta-analysis. Arch Gynecol Obstet. 2014;290(5):1015–22.

    CAS  PubMed  Google Scholar 

  25. Dyson MT, Roqueiro D, Monsivais D, Ercan CM, Pavone ME, Brooks DC, et al. Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLoS Genet. 2014;10(3):e1004158.

    PubMed  PubMed Central  Google Scholar 

  26. Xue Q, Lin Z, Yin P, Milad MP, Cheng YH, Confino E, et al. Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5′ CpG island in endometriosis. J Clin Endocrinol Metab. 2007;92(8):3261–7.

    CAS  PubMed  Google Scholar 

  27. Utsunomiya H, Cheng YH, Lin Z, Reierstad S, Yin P, Attar E, et al. Upstream stimulatory factor-2 regulates steroidogenic factor-1 expression in endometriosis. Mol Endocrinol. 2008;22(4):904–14.

    CAS  PubMed  Google Scholar 

  28. Bernardi LA, Dyson MT, Tokunaga H, Sison C, Oral M, Robins JC, et al. The essential role of GATA6 in the activation of estrogen synthesis in endometriosis. Reprod Sci. 2019;26(1):60–9.

    CAS  PubMed  Google Scholar 

  29. Liu M, Liu X, Zhang Y, Guo SW. Valproic acid and progestin inhibit lesion growth and reduce hyperalgesia in experimentally induced endometriosis in rats. Reprod Sci. 2012;19(4):360–73.

    CAS  PubMed  Google Scholar 

  30. Wu Y, Starzinski-Powitz A, Guo SW. Prolonged stimulation with tumor necrosis factor-alpha induced partial methylation at PR-B promoter in immortalized epithelial-like endometriotic cells. Fertil Steril. 2008;90(1):234–7.

    PubMed  Google Scholar 

  31. Borghese B, Barbaux S, Mondon F, Santulli P, Pierre G, Vinci G, et al. Research resource: genome-wide profiling of methylated promoters in endometriosis reveals a subtelomeric location of hypermethylation. Mol Endocrinol. 2010;24(9):1872–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Borghese B, Zondervan KT, Abrao MS, Chapron C, Vaiman D. Recent insights on the genetics and epigenetics of endometriosis. Clin Genet. 2017;91(2):254–64.

    CAS  PubMed  Google Scholar 

  33. Monteiro JB, Colon-Diaz M, Garcia M, Gutierrez S, Colon M, Seto E, et al. Endometriosis is characterized by a distinct pattern of histone 3 and histone 4 lysine modifications. Reprod Sci. 2014;21(3):305–18.

    PubMed  PubMed Central  Google Scholar 

  34. Panir K, Shjenken JE, Robertson SA, Hull ML. Non-coding RNAs in endometriosis: a narrative review. Hum Reprod Update. 2018;24(4):497–515.

    CAS  PubMed  Google Scholar 

  35. Agrawal S, Tapmeier T, Rahmioglu N, Kirtley S, Zondervan K, Becker C. The miRNA mirage: how close are we to finding a non-invasive diagnostic biomarker in endometriosis? A Systematic Review. Int J Mol Sci. 2018;19(2).

  36. Moga MA, Balan A, Dimienescu OG. Circulating miRNAs as biomarkers for endometriosis and endometriosis-related ovarian cancer- an overview. J Clin Med 2019; 8(5).

  37. Pei T, Liu C, Liu T, Xiao L, Luo B, Tan J, et al. miR-194-3p represses the progesterone receptor and decidualization in eutopic endometrium from women with endometriosis. Endocrinology. 2018;159(7):2554–62.

    CAS  PubMed  Google Scholar 

  38. Joshi NR, Miyadahira EH, Afshar Y, Jeong JW, Young SL, Lessey BA, et al. Progesterone resistance in endometriosis is modulated by the altered expression of MicroRNA-29c and FKBP4. J Clin Endocrinol Metab. 2017;102(1):141–9.

    PubMed  Google Scholar 

  39. Cochrane DR, Spoelstra NS, Richer JK. The role of miRNA in progesterone action. Mol Cell Endocrinol. 2012;357(1–2):50–9.

    CAS  PubMed  Google Scholar 

  40. Guttilla IK, Adams BD, White BA. ERalpha, miRNAs and the epithelial-mesenchymal transition in breast cancer. Trends Endocrinol Metab. 2012;2382:73–82.

    Google Scholar 

  41. Sahin C, Manillapalli R. miRNA let-7b: a novel treatment for endometriosis. J Cell Mol Med. 2018;22(11):5346–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Klinge CM. miRNAs and estrogen action. Trends Endocrinol Metab. 2012;23(5):223–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Ghazal S, McKinnon B, Zhou J, Mueller M, Men Y, Yang L, et al. H19 lncRNA alters stromal cell growth via IGF signaling in the endometrium of women with endometriosis. EMBO Mol Med. 2015;7(8):996–1003.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Lin K, Zhan H, Ma J, Xu K, Wu R, Zhou C, et al. Silencing of SRA1 regulates ER expression and attenuates the growth of stromal cells in ovarian endometriosis. Reprod Sci. 2017;24(6):836–43.

    CAS  PubMed  Google Scholar 

  45. Lin K, Ma J, Wu R, Zhou C, Lin J. Influence of ovarian endometrioma on expression of steroid receptor RNA activator, estrogen receptors, vascular endothelial growth factor, and thrombospondin 1 in the surrounding ovarian tissues. Reprod Sci. 2014;21(2):183–9.

    PubMed  PubMed Central  Google Scholar 

  46. Lin K, Zhan H, Ma J, Xu K, Wu R, Zhou C, et al. Increased steroid receptor RNA activator protein (SRAP) accompanied by decreased estrogen receptor-beta (ER-beta) levels during the malignant transformation of endometriosis associated ovarian clear cell carcinoma. Acta Histochem. 2014;116(5):878–82.

    CAS  PubMed  Google Scholar 

  47. Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, 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):1603–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Bombail V, Gibson DA, Collins F, MacPherson S, Critchley HO, Saunders PT. A role for the orphan nuclear receptor estrogen-related receptor alpha in endometrial stromal cell decidualization and expression of genes implicated in energy metabolism. J Clin Endocrinol Metab. 2010;95(10):E224–8.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The study has been contributed with the support of “Fondazione Careggi-Academy for Women’s Health,” “Fondazione CR Firenze, project entitled The First 1000 Days of Life: Ambiental Disruptors and Women’s Health” endometriosis No.181010, the National Natural Science Foundation of China (81701401 to Luting Chen) and AHH and FP extend their appreciation to the International Scientific Partnership Program ISPP at King Saud University for funding this research work through ISPP# 152.

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Authors and Affiliations

  1. Obstetrics and Gynecology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy

    Huixi Chen, Francesca Malentacchi, Massimiliano Fambrini & Felice Petraglia

  2. International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Huixi Chen & Hefeng Huang

  3. Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China

    Huixi Chen & Hefeng Huang

  4. Department of Zoology, College of Science, King Said University, Riyadh, Saudi Arabia

    Abdel Halim Harrath

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  1. Huixi Chen
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  2. Francesca Malentacchi
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  5. Hefeng Huang
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Correspondence to Felice Petraglia.

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Chen, H., Malentacchi, F., Fambrini, M. et al. Epigenetics of Estrogen and Progesterone Receptors in Endometriosis. Reprod. Sci. 27, 1967–1974 (2020). https://doi.org/10.1007/s43032-020-00226-2

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  • DOI: https://doi.org/10.1007/s43032-020-00226-2

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