Skip to main content
SpringerLink
Log in

Progesterone Receptor B (PGR-B) Is Partially Methylated in Eutopic Endometrium From Infertile Women With Endometriosis

  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Endometriosis is frequently related to infertility and little is known about the mechanisms underlying this association. Some studies point to an endometrial factor involved in this condition, which could compromise embryo implantation. Progesterone plays crucial role in endometrial receptivity by acting through progesterone receptor (PGR) isoforms PR-A and PR-B whose expression is epigenetically regulated by DNA methylation, in a specific promoter region for each isoform. Epigenetic changes in PGR-A and PGR-B may be related to progesterone resistance of endometriosis-related infertility. In order to better understand the mechanisms involved in endometrial receptivity, this case–control study aimed to compare the methylation pattern of PGR-A and PGR-B in eutopic endometrium from infertile women with and without endometriosis during the secretory phase. Endometrial biopsies from 19 patients (10 infertile women with endometriosis and 9 infertile controls) with regular cycles were performed during the secretory phase and were dated according to Noyes’ criteria. The percentage of DNA methylation at PGR-A and PGR-B was carried out by high-resolution melting assay. The PGR-A gene showed 0% of DNA methylation (unmethylated) in both control and endometriosis groups. However, PGR-B gene showed a partially methylated pattern in majority of the patients (n = 7), with methylation percentage corresponding to 50%, while in the control group the percentage of methylation was 20% (hypo-methylated; P =.04). The increased percentage of methylation at PGR-B may be related to reduced gene expression, which could compromise the endometrial receptivity in patients with endometriosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–519.

    Article  CAS  PubMed  Google Scholar 

  2. Gupta S, Agarwal A, Krajcir N, Alvarez JG. Role of oxidative stress in endometriosis. Reprod Biomed Online. 2006;13(1):126–134.

    Article  CAS  PubMed  Google Scholar 

  3. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 1997;24(2):235–258.

    Article  CAS  PubMed  Google Scholar 

  4. Medicine PCotASfR. Endometriosis and infertility: a committee opinion. Fertil Steril. 2012;98(3):591–598.

    Article  Google Scholar 

  5. Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med. 1997;337(4):217–222.

    Article  CAS  PubMed  Google Scholar 

  6. Akande VA, Hunt LP, Cahill DJ, Jenkins JM. Differences in time to natural conception between women with unexplained infertility and infertile women with minor endometriosis. Hum Reprod. 2004;19(1):96–103.

    Article  PubMed  Google Scholar 

  7. Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Marshall LM, Hunter DJ. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol. 2004;160(8):784–796.

    Article  PubMed  Google Scholar 

  8. Holoch KJ, Lessey BA. Endometriosis and infertility. Clin Obstet Gynecol. 2010;53(2):429–438.

    Article  PubMed  Google Scholar 

  9. Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril. 2006;86(5 suppl 1): S156–S160.

    Article  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. Igarashi TM, Bruner-Tran KL, Yeaman GR, et al. Reduced expression of progesterone receptor-B in the endometrium of women with endometriosis and in cocultures ofendometrial cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fertil Steril. 2005;84(1):67–74.

    Article  CAS  PubMed  Google Scholar 

  12. Lessey BA, Castelbaum AJ, Sawin SW, et al. Aberrant integrin expression in the endometrium of women with endometriosis. J Clin Endocrinol Metab. 1994;79(2):643–649.

    CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. Taylor HS, Bagot C, Kardana A, Olive D, Arici A. HOX gene expression is altered in the endometrium of women with endometriosis. Hum Reprod. 1999;14(5):1328–1331.

    Article  CAS  PubMed  Google Scholar 

  15. Riesewijk A, Martin J, van Os R, et al. Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7by microarray technology. Mol Hum Reprod. 2003;9(5):253–264.

    Article  CAS  PubMed  Google Scholar 

  16. Aghajanova L, Hamilton AE, Giudice LC. Uterine receptivity to human embryonic implantation: histology, biomarkers, and transcriptomics. Semin Cell Dev. 2008;19(2):204–211.

    Article  CAS  Google Scholar 

  17. Graham JD, Clarke CL. Physiological action of progesterone in target tissues. Endocr Rev. 1997;18(4):502–519.

    CAS  PubMed  Google Scholar 

  18. Tung L, Mohamed MK, Hoeffler JP, Takimoto GS, Horwitz KB. Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors. Mol Endocrinol. 1993;7(10):1256–1265.

    CAS  PubMed  Google Scholar 

  19. Vegeto E, Shahbaz MM, Wen DX, Goldman ME, O'Malley BW, McDonnell DP. Human progesterone receptor A form is a cell-and promoter-specific repressor of human progesterone receptor B function. Mol Endocrinol. 1993;7(10):1244–1255.

    CAS  PubMed  Google Scholar 

  20. Lee B, Du H, Taylor HS. Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium. Biol Reprod. 2009;80(1):79–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Young SL. Oestrogen and progesterone action on endometrium: a translational approach to understanding endometrial receptivity. Reprod Biomed Online. 2013;27(5):497–505.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. Bulun SE. Progesterone resistance and endometrial disease. Preface. Semin Reprod Med. 2010;28(1):3.

    Article  PubMed  Google Scholar 

  24. Bedaiwy MA, Dahoud W, Skomorovska-Prokvolit Y, et al. Abundance and localization of progesterone receptor isoforms in endometrium in women with and without endometriosis and in peritoneal and ovarian endometriotic implants. Reprod Sci. 2015;22(9):1153–1161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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.

    CAS  PubMed  Google Scholar 

  26. Shen F, Yan C, Liu M, Feng Y, Chen Y. Decreased expression of mucin-1 in endometriosis endometrium correlated with progesterone receptor B involved in infertility. Arch Gynecol Obstet. 2015;291(2):439–445.

    Article  CAS  PubMed  Google Scholar 

  27. Lessey BA, Damjanovich L, Coutifaris C, Castelbaum A, Albelda SM, Buck CA. Integrin adhesion molecules in the human endometrium. Correlation with the normal and abnormal menstrual cycle. J Clin Invest. 1992;90(1):188–195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Surrey ES, Minjarez DA, School Craft WB. The incidence of aberrant endometrial alphavbeta(3) vitronectin expression in a high risk infertility population: could prolonged GnRH agonist therapy play a role? J Assist Reprod Genet. 2007;24(11):553–556.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Aghajanova L, Hamilton A, Kwintkiewicz J, Vo KC, Giudice LC. Steroidogenic enzyme and key decidualization marker dysregulation in endometrial stromal cells from women with versus without endometriosis. Biol Reprod. 2009;80(1):105–114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Matsuzaki S, Canis M, Pouly JL, Dechelotte PJ, Mage G. Analysis of aromatase and 17beta-hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid expression in deep endometriosis and eutopic endometrium using laser capture microdissection. Fertil Steril. 2006;85(2):308–313.

    Article  CAS  PubMed  Google Scholar 

  31. Moberg C, Bourlev V, Ilyasova N, Olovsson M. Endometrial expression of LIF and its receptor and peritoneal fluid levels of IL-1a and IL-6 in women with endometriosis are associated with the probability of pregnancy. Arch Gynecol Obstet. 2015;292(2):429–437.

    Article  CAS  PubMed  Google Scholar 

  32. Alizadeh Z, Shokrzadeh N, Saidijam M, Sanoee MF. Semiquantitative analysis of HOXA11, leukemia inhibitory factor and basic transcriptional element binding protein 1 mRNA expression in the mid-secretory endometrium of patients with endometriosis. Iran Biomed J. 2011;15(3):66–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Wei Q, St Clair JB, Fu T, Stratton P, Nieman LK. Reduced expression of biomarkers associated with the implantation window in women with endometriosis. Fertil Steril. 2009;91(5):1686–1691.

    Article  PubMed  Google Scholar 

  34. Cho S, Ahn YS, Choi YS, et al. Endometrial osteopontin mRNA expression and plasma osteopontin levels are increased in patients with endometriosis. Am J Reprod Immunol. 2009;61(4):286–293.

    Article  CAS  PubMed  Google Scholar 

  35. 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):106–111.

    Article  PubMed  Google Scholar 

  36. Fraser IS, Critchley HO, Munro MG, Broder M; Writing Group for this Menstrual Agreement P. A process designed to lead to international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding. Fertil Steril. 2007;87(3):466–476.

    Article  PubMed  Google Scholar 

  37. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817–821.

    Google Scholar 

  38. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122(2):262–263.

    Article  CAS  PubMed  Google Scholar 

  39. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. New York, NY: Lawrence Erlbaum Associates; 1988.

    Google Scholar 

  40. Koukoura O, Sifakis S, Spandidos DA. DNAmethylation in endometriosis (Review). Mol Med Rep. 2016;13(4):2939–2948.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013;38(1):23–38.

    Article  CAS  PubMed  Google Scholar 

  42. Wolfler MM, Küppers M, Rath W, Buck VU, Meinhold-Heerlein I, Classen-Linke I. Altered expression of progesterone receptor isoforms A and B in human eutopic endometrium in endometriosis patients. Ann Anat. 2016;206:1–6.

    Article  PubMed  Google Scholar 

  43. Jackson KS, Brudney A, Hastings JM, Mavrogianis PA, Kim JJ, Fazleabas AT. The altered distribution of the steroid hormone receptors and the chaperone immunophilin FKBP52 in a baboon model of endometriosis is associated with progesterone resistance during the window of uterine receptivity. Reprod Sci. 2007;14(2):137–150.

    Article  CAS  PubMed  Google Scholar 

  44. Yu X, Ren H, Liu T, Yong M, Zhong H. Expression and significance of ERβ and TrkB in endometriosis. Clin Exp Obstet Gynecol. 2016;43(1):75–81.

    CAS  PubMed  Google Scholar 

  45. Moberg C, Bourlev V, Ilyasova N, Olovsson M. Levels of oestrogen receptor, progesterone receptor and aB-crystallin in eutopic endometrium in relation to pregnancy in women with endometriosis. Hum Fertil (Camb). 2015;18(1):30–37.

    Article  CAS  PubMed  Google Scholar 

  46. Lessey BA, Palomino WA, Apparao KB, Young SL, Lininger RA. Estrogen receptor-alpha (ER-alpha) and defects in uterine receptivity in women. Reprod Biol Endocrinol. 2006;4(suppl 1):S9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank the staff of the Human Reproduction Division. University Hospital, Department of Gynecology and Obstetrics. Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP) specially Dr Filomena Marino Carvalho, Dr Júlio César Rosa e Silva, Dr Stael Porto Leite, Dr Anderson Melo, Dr Valeria Leitão, Dr Ludimila Seko, Dr Lilian A. Nunes, Dr Danielle M. Teixeira, Dr Clarissa V. Dias, Dr Marcela Alencar, Dr Maria Lucia Lima, Dr José Vitor Zanardi, Cristiana Padovan, Maria Auxiliadora Rosa, Ocelia Vasconcelos, Lourdes Adriana Andrade and Marisa Blanco and the staff of SERPAT—Pathology Service of the Department of Pathology, FMRP-USP, specially Dr Alfredo Ribeiro and Dr Francesca Maia Faria for their valuable assistance.

Author information

Author notes

  1. Cristiana Libardi Miranda-Furtado (PhD)

    Present address: Drug Research and Development Center, Federal University of Ceara, Fortaleza, Ceara, Brazil

Authors and Affiliations

  1. Human Reproduction Division, Department of Obstetrics and Gynecology, Ribeirao Preto School of Medicine, University of Sao Paulo, Avenida Bandeirantes, 3900, CEP: 14049-900, Ribeirao Preto, SP, Brazil

    Carlos Valério Rocha Junior (MSc), Michele Gomes Da Broi (PhD), Cristiana Libardi Miranda-Furtado (PhD), Paula Andrea Navarro (PhD), Rui Alberto Ferriani (PhD) & Juliana Meola (PhD)

  2. National Institute of Hormones and Woman's Health, CNPq, Porto Alegre, RS, Brazil

    Paula Andrea Navarro (PhD), Rui Alberto Ferriani (PhD) & Juliana Meola (PhD)

Authors
  1. Carlos Valério Rocha Junior
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michele Gomes Da Broi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cristiana Libardi Miranda-Furtado
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paula Andrea Navarro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rui Alberto Ferriani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Juliana Meola
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlos Valério Rocha Junior.

Supplemental Material

Supplemental Material

Supplemental material for this article is available online.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rocha, C.V., Da Broi, M.G., Miranda-Furtado, C.L. et al. Progesterone Receptor B (PGR-B) Is Partially Methylated in Eutopic Endometrium From Infertile Women With Endometriosis. Reprod. Sci. 26, 1568–1574 (2019). https://doi.org/10.1177/1933719119828078

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719119828078

Keywords

Search

Navigation