Skip to main content

Advertisement

SpringerLink
Log in

Endometriosis Located Proximal to or Remote From the Uterus Differentially Affects Uterine Gene Expression

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

The mechanisms that lead to the altered uterine gene expression in women with endometriosis are poorly understood. Are these changes in gene expression mediated by proximity to endometriotic lesions or is endometriosis a systemic disease where the effect is independent of proximity to the uterus? To answer this question, we created endometriosis in a murine model either in the peritoneal cavity (proximal) or at a subcutaneous remote site (distal). The expression of several genes that are involved in endometrial receptivity (homeobox A10 [Hoxa10], homeobox A11 [Hoxa11], insulin-like growth factor binding protein 1 [Igfbp1], Kruppel-like factor 9 [Klf9], and progesterone receptor [Pgr]) was measured in the eutopic endometrium of mice transplanted with either proximal or distal endometriosis lesions. Decreased expression of Hoxa10, Igfbp1, Klf9, and total Pgr genes was observed in the eutopic endometrium of mice with peritoneal endometriosis. In the mice with distal lesions, overall expression of these genes was not as severely affected, however, Igfbp1 expression was similarly decreased and the effect on Pgr was more pronounced. Endometriosis does have a systemic effect that varies with distance to the end organ. However, even remote disease selectively and profoundly alters the expression of genes such as Pgr. This is the first controlled experiment demonstrating that endometriosis is not simply a local peritoneal disease. Selective alteration of genes critical for endometrial receptivity and endometriosis propagation may be systemic. Similarly, systemic effects of endometriosis on other organs may also be responsible for the widespread manifestations of the disease.

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. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447): 1789–1799.

    PubMed  Google Scholar 

  2. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279.

    CAS  PubMed  Google Scholar 

  3. Macer ML, Taylor HS. Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin North Am. 2012;39(4):535–549.

    PubMed  PubMed Central  Google Scholar 

  4. Sampson J. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Ostet Gynecol. 1927;14(1):422–469.

    Google Scholar 

  5. Gruenwald P. Origin of endometriosis form the mesenchyme of the celomic walls. Am J Obs Gynecol. 1942;44(3):470–474.

    Google Scholar 

  6. Bruner-Tran KL, Herington JL, Duleba AJ, Taylor HS, Osteen KG. Medical management of endometriosis: emerging evidence linking inflammation to disease pathophysiology. Minerva Ginecol. 2013;65(2):199–213.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Taylor HS, Osteen KG, Bruner-Tran KL, et al. Novel therapies targeting endometriosis. Reprod Sci. 2011;18(9):814–823.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA. 2004;292(1):81–85.

    CAS  PubMed  Google Scholar 

  9. Du H, Taylor HS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007;25(8): 2082–2086.

    CAS  PubMed  Google Scholar 

  10. Sasson IE, Taylor HS. Stem cells and the pathogenesis of endometriosis. Ann N Y Acad Sci. 2008;1127:106–115.

    PubMed  PubMed Central  Google Scholar 

  11. Figueira PG, Abrão MS, Krikun G, Taylor HS. Stem cells in endometrium and their role in the pathogenesis of endometriosis. Ann N Y Acad Sci. 2011;1221:10–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang X, Mamillapalli R, Mutlu L, Du H, Taylor HS. Chemoat-traction of bone marrow-derived stem cells towards human endometrial stromal cells is mediated by estradiol regulated CXCL12 and CXCR4 expression. Stem Cell Res. 2015;15(1):14–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kinugasa S, Shinohara K, Wakatsuki A. Increased asymmetric dimethylarginine and enhanced inflammation are associated with impaired vascular reactivity in women with endometriosis. Atherosclerosis. 2011;219(2):784–7888.

    CAS  PubMed  Google Scholar 

  14. Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5): 261–275.

    CAS  PubMed  Google Scholar 

  15. Riley CF, Moen MH, Videm V. Inflammatory markers in endometriosis: reduced peritoneal neutrophil response in minimal endometriosis. Acta Obstet Gynecol Scand. 2007;86(7):877–881.

    PubMed  Google Scholar 

  16. Agic A, Xu H, Finas D, Banz C, Diedrich K, Hornung D. Is endometriosis associated with systemic subclinical inflammation? Gynecol Obstet Invest. 2006;62(3):139–147.

    PubMed  Google Scholar 

  17. Ness RB, Modugno F. Endometriosis as a model for inflammation-hormone interactions in ovarian and breast cancers. Eur J Cancer. 2006;42(6):691–703.

    CAS  PubMed  Google Scholar 

  18. Berkkanoglu M, Arici A. Immunology and endometriosis. Am J Reprod Immunol. 2003;50(1):48–59.

    PubMed  Google Scholar 

  19. Berbic M, Fraser IS. Immunology of normal and abnormal menstruation. Womens Health (Lond Engl). 2013;9(4):387–395.

    CAS  Google Scholar 

  20. Malutan AM, Drugan T, Costin N, et al. Pro-inflammatory cytokines for evaluation of inflammatory status in endometriosis. Cent Eur J Immunol. 2015;40(1):96–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Kocbek V, Vouk K, Bersinger NA, Mueller MD, Lanišnik Rižner T. Panels of cytokines and other secretory proteins as potential biomarkers of ovarian endometriosis. J Mol Diagn. 2015;17(3): 325–334.

    CAS  PubMed  Google Scholar 

  22. Králíčková M, Vetvicka V. Immunological aspects of endometriosis: a review. Ann Transl Med. 2015;3(11):153.

    PubMed  PubMed Central  Google Scholar 

  23. Cakmak H, Taylor HS. Implantation failure: molecular mechanisms and clinical treatment. Hum Reprod Update. 2011;17(2): 242–253.

    CAS  PubMed  Google Scholar 

  24. Cakmak H, Taylor HS. Molecular mechanisms of treatment resistance in endometriosis: the role of progesterone-hox gene interactions. Semin Reprod Med. 2010;28(1):69–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gupta S, Goldberg JM, Aziz N, Goldberg E, Krajcir N, Agarwal A. Pathogenic mechanisms in endometriosis-associated infertility. Fertil Steril. 2008;90(2):247–257.

    CAS  PubMed  Google Scholar 

  26. 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.

    PubMed  PubMed Central  Google Scholar 

  27. Giudice LC. Genes associated with embryonic attachment and implantation and the role of progesterone. J Reprod Med. 1999; 44(2):165–171.

    CAS  PubMed  Google Scholar 

  28. Rackow BW, Taylor HS. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil Steril. 2010;93(6):2027–2034.

    CAS  PubMed  Google Scholar 

  29. Doherty LF, Taylor HS. Leiomyoma-derived transforming growth factor-β impairs bone morphogenetic protein-2-mediated endometrial receptivity. Fertil Steril. 2015;103(3):845–852.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Rackow BW, Jorgensen E, Taylor HS. Endometrial polyps affect uterine receptivity. Fertil Steril. 2011;95(8):2690–2692.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Franasiak JM, Holoch KJ, Yuan L, Schammel DP, Young SL, Lessey BA. Prospective assessment of midsecretory endometrial leukemia inhibitor factor expression versus ανβ3 testing in women with unexplained infertility. Fertil Steril. 2014;101(6): 1724–1731.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Naqvi H, Ilagan Y, Krikun G, Taylor HS. Altered genome-wide methylation in endometriosis. Reprod Sci. 2014;21(10):1237–1243.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Taylor HS, Vanden Heuvel GB, Igarashi P. A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes. Biol Reprod. 1997;57(6):1338–1345.

    CAS  PubMed  Google Scholar 

  34. Akbas GE, Taylor HS. HOXC and HOXD gene expression in human endometrium: lack of redundancy with HOXA paralogs. Biol Reprod. 2004;70(1):39–45.

    CAS  PubMed  Google Scholar 

  35. 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.

    CAS  PubMed  Google Scholar 

  36. Zanatta A, Rocha AM, Carvalho FM, et al. The role of the Hoxa10/HOXA10 gene in the etiology of endometriosis and its related infertility: a review. J Assist Reprod Genet. 2010; 27(12):701–710.

    PubMed  PubMed Central  Google Scholar 

  37. Du H, Taylor HS. Molecular regulation of mullerian development by Hox genes. Ann N Y Acad Sci. 2004;1034:152–165.

    CAS  PubMed  Google Scholar 

  38. Bagot CN, Troy PJ, Taylor HS. Alteration of maternal Hoxa10 expression by in vivo gene transfection affects implantation. Gene Ther. 2000;7(16):1378–1384.

    CAS  PubMed  Google Scholar 

  39. Taylor HS, Igarashi P, Olive DL, Arici A. Sex steroids mediate HOXA11 expression in the human peri-implantation endometrium. J Clin Endocrinol Metab. 1999;84(3):1129–1135.

    CAS  PubMed  Google Scholar 

  40. Taylor HS, Arici A, Olive D, Igarashi P. HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium. J Clin Invest. 1998;101(7):1379–1384.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Eun Kwon H, Taylor HS. The role of HOX genes in human implantation. Ann N Y Acad Sci. 2004;1034:1–18.

    PubMed  Google Scholar 

  42. Wu Y, Halverson G, Basir Z, Strawn E, Yan P, Guo S-W. Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis. Am J Obstet Gynecol. 2005;193(2):371–380.

    CAS  PubMed  Google Scholar 

  43. Lydon JP, DeMayo FJ, Funk CR, et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 1995;9(18):2266–2278.

    CAS  PubMed  Google Scholar 

  44. Zhang X-L, Zhang D, Michel FJ, Blum JL, Simmen FA, Simmen RCM. Selective interactions of Kruppel-like factor 9/basic transcription element-binding protein with progesterone receptor isoforms A and B determine transcriptional activity of progesterone-responsive genes in endometrial epithelial cells. J Biol Chem. 2003;278(24):21474–21482.

    CAS  PubMed  Google Scholar 

  45. Simmen RC, Eason RR, McQuown JR, et al. Subfertility, uterine hypoplasia, and partial progesterone resistance in mice lacking the Kruppel-like factor 9/basic transcription element-binding protein-1 (Bteb1) gene. J Biol Chem. 2004;279(28):29286–29294.

    CAS  PubMed  Google Scholar 

  46. Du H, Sarno J, Taylor HS. HOXA10 inhibits Kruppel-like factor 9 expression in the human endometrial epithelium. Biol Reprod. 2010;83(2):205–211.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Nayak NR, Giudice LC. Comparative biology of the IGF system in endometrium, decidua, and placenta, and clinical implications for foetal growth and implantation disorders. Placenta. 2003; 24(4):281–296.

    CAS  PubMed  Google Scholar 

  48. Rutanen E-M. Insulin-like growth factors in endometrial function. Gynecol Endocrinol. 1998;12(6):399–406.

    CAS  PubMed  Google Scholar 

  49. Ghazal S, McKinnon B, Zhou J, 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 

  50. Kim H, Ku S-Y, Kim SH, Choi YM, Kim JG. Association between endometriosis and polymorphisms in insulin-like growth factor binding protein genes in Korean women. Eur J Obstet Gynecol Reprod Biol. 2012;162(1):96–101.

    CAS  PubMed  Google Scholar 

  51. Kim JJ, Taylor HS, Lu Z, et al. Altered expression of HOXA10 in endometriosis: potential role in decidualization. Mol Hum Reprod. 2007;13(5):323–332.

    CAS  PubMed  Google Scholar 

  52. Weiss G, Goldsmith LT, Taylor RN, Bellet D, Taylor HS. Inflammation in reproductive disorders. Reprod Sci. 2009;16(2): 216–229.

    CAS  PubMed  Google Scholar 

  53. Cho S, Mutlu L, Grechukhina O, Taylor HS. Circulating micro-RNAs as potential biomarkers for endometriosis. Fertil Steril. 2015;103(5):1252–1260.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Santamaria X, Taylor H. MicroRNA and gynecological reproductive diseases. Fertil Steril. 2014;101(6):1545–1551.

    CAS  PubMed  Google Scholar 

  55. Petracco R, Grechukhina O, Popkhadze S, Massasa E, Zhou Y, Taylor HS. MicroRNA 135 regulates HOXA10 expression in endometriosis. J Clin Endocrinol Metab. 2011;96(12): e1925–e1933.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Sakr S, Naqvi H, Komm B, Taylor HS. Endometriosis impairs bone marrow-derived stem cell recruitment to the uterus whereas bazedoxifene treatment lead to endometriosis regression and improved uterine stem cell engraftment. Endocrinology. 2014; 155(4):1489–1497.

    PubMed  PubMed Central  Google Scholar 

  57. Zhou Y, Gan Y, Taylor HS. Cigarette smoke inhibits recruitment of bone-marrow-derived stem cells to the uterus. Reprod Toxicol. 2011;31(2):123–127.

    CAS  PubMed  Google Scholar 

  58. Santamaria X, Massasa EE, Taylor HS. Migration of cells from experimental endometriosis to the uterine endometrium. Endocrinology. 2012;153(11):5566–5574.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Cruz CD, Del Puerto HL, Rocha AL, et al. Expression of Nodal, Cripto, SMAD3, phosphorylated SMAD3, and SMAD4 in the proliferative endometrium of women with endometriosis. Reprod Sci. 2015;22(5):527–533.

    PubMed  PubMed Central  Google Scholar 

  60. Governini L, Carrarelli P, Rocha AL, et al. FOXL2 in human endometrium: hyperexpressed in endometriosis. Reprod Sci. 2014;21(10):1249–1255.

    CAS  PubMed  Google Scholar 

  61. Lessey BA, Lebovic DI, Taylor RN. Eutopic endometrium in women with endometriosis: ground zero for the study of implantation defects. Semin Reprod Med. 2013;31(2):109–124.

    PubMed  Google Scholar 

  62. Afshar Y, Hastings J, Roqueiro D, Jeong JW, Giudice LC, Fazleabas AT. Changes in eutopic endometrial gene expression during the progression of experimental endometriosis in the baboon, Papio anubis. Biol Reprod. 2013;88(2):44.

    PubMed  PubMed Central  Google Scholar 

  63. Kim JJ, Fazleabas AT. Uterine receptivity and implantation: the regulation and action of insulin-like growth factor binding protein-1 (IGFBP-1), HOXA10 and forkhead transcription factor-1 (FOXO-1) in the baboon endometrium. Reprod Biol Endocrinol. 2004;2:34.1–6.

    Google Scholar 

  64. Pabona JM, Simmen FA, Nikiforov MA, et al. Krüppel-like factor 9 and progesterone receptor coregulation of decidualizing endometrial stromal cells: implications for the pathogenesis of endometriosis. J Clin Endocrinol Metab. 2012;97(3):e376–e392.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Aghajanova L, Giudice LC. Molecular evidence for differences in endometrium in severe versus mild endometriosis. Reprod Sci. 2011;18(3):229–251.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Heard ME, Velarde MC, Giudice LC, Simmen FA, Simmen RC. Krüppel-like factor 13 deficiency in uterine endometrial cells contributes to defective steroid hormone receptor signaling but not lesion establishment in a mouse model of endometriosis. Biol Reprod. 2015;92(6):140.

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, PO Box: 208063, 06510, New Haven, CT, USA

    Hanyia Naqvi MS, Ramanaiah Mamillapalli PhD, Graciela Krikun PhD & Hugh S. Taylor MD

Authors
  1. Hanyia Naqvi MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ramanaiah Mamillapalli PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Graciela Krikun PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hugh S. Taylor MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ramanaiah Mamillapalli PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Naqvi, H., Mamillapalli, R., Krikun, G. et al. Endometriosis Located Proximal to or Remote From the Uterus Differentially Affects Uterine Gene Expression. Reprod. Sci. 23, 186–191 (2016). https://doi.org/10.1177/1933719115613449

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719115613449

Keywords

Search

Navigation