Skip to main content

Advertisement

SpringerLink
Log in

Molecular Evidence for Differences in Endometrium in Severe Versus Mild Endometriosis

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

Abstract

Women with stage III/IV versus stage I/II endometriosis have lower implantation and pregnancy rates in natural and assisted reproduction cycles. To elucidate potential molecular mechanisms underlying these clinical observations, herein we investigated the transcriptome of eutopic endometrium across the menstrual cycle in the setting of severe versus mild endometriosis. Proliferative (PE), early secretory (ESE), and mid-secretory (MSE) endometrial tissues were obtained from 63 participants with endometriosis (19 mild and 44 severe). Purified RNA was subjected to microarray analysis using the Gene 1.0 ST Affymetrix platform. Data were analyzed with GeneSpring and Ingenuity Pathway Analysis and subsequently validated. Comparison of differentially regulated genes, analyzed by cycle phase, revealed dysregulation of progesterone and/or cyclic adenosine monophosphate (cAMP)-regulated genes and genes related to thyroid hormone action and metabolism. Also, members of the epidermal growth factor receptor (EGFR) signaling pathway were observed, with the greatest upregulation of EGFR in severe versus mild disease during the early secretory phase. The extracellular matrix proteoglycan versican (VCAN), which regulates cell proliferation and apoptosis, was the most highly expressed gene in severe versus mild disease. Upregulation of microRNA 21 (MIR21) and DICER1 transcripts suggests roles for microRNAs (miRNAs) in the pathogenesis of severe versus mild endometriosis, potentially through regulation of gene silencing and epigenetic mechanisms. These observed differences in transcriptomic signatures and signaling pathways may result in poorly programmed endometrium during the cycle, contributing to lower implantation and pregnancy rates in women with severe versus mild 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. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–1799.

    Article  PubMed  Google Scholar 

  2. Taylor RN, Yu J, Torres PB, et al. Mechanistic and therapeutic implications of angiogenesis in endometriosis. Reprod Sci. 2009;16(2):140–146.

    Article  PubMed  CAS  Google Scholar 

  3. The American Fertility Society. Revised American Fertility Society classification of endometriosis. Fertil Steril. 1985;43(3):351–352.

    Article  Google Scholar 

  4. Rock JA. The revised American Fertility Society classification of endometriosis: reproducibility of scoring. ZOLADEX Endometriosis Study Group. Fertil Steril. 1995;63(5):1108–1110.

    Article  PubMed  CAS  Google Scholar 

  5. Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril. 1997;68(4):585–596.

    Article  PubMed  CAS  Google Scholar 

  6. Donnez J, Nisolle M, Smoes P, Gillet N, Beguin S, Casanas-Roux F. Peritoneal endometriosis and “endometriotic” nodules of the rectovaginal septum are two different entities. Fertil Steril. 1996;66(3):362–368.

    Article  PubMed  CAS  Google Scholar 

  7. Matsuzaki S, Maleysson E, Darcha C. Analysis of matrix metalloproteinase-7 expression in eutopic and ectopic endometrium samples from patients with different forms of endometriosis. Hum Reprod. 2010;25(3):742–750.

    Article  PubMed  CAS  Google Scholar 

  8. D’Hooghe TM, Debrock S, Hill JA, Meuleman C. Endometriosis and subfertility: is the relationship resolved?. Semin Reprod Med. 2003;21(2):243–254.

    Article  PubMed  Google Scholar 

  9. Kuivasaari P, Hippelainen M, Anttila M, Heinonen S. Effect of endometriosis on IVF/ICSI outcome: stage III/IV endometriosis worsens cumulative pregnancy and live-born rates. Hum Reprod. 2005;20(11):3130–3135.

    Article  PubMed  Google Scholar 

  10. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002;77(5):1148–1155.

    Article  PubMed  Google Scholar 

  11. Matalliotakis IM, Cakmak H, Mahutte N, Fragouli Y, Arici A, Sakkas D. Women with advanced-stage endometriosis and previous surgery respond less well to gonadotropin stimulation, but have similar IVF implantation and delivery rates compared with women with tubal factor infertility. Fertil Steril. 2007;88(6):1568–1572.

    Article  PubMed  CAS  Google Scholar 

  12. 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  PubMed  CAS  Google Scholar 

  13. 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  15. Aghajanova L, Horcajadas JA, Weeks JL, et al. The protein kinase A pathway-regulated transcriptome of endometrial stromal fibroblasts reveals compromised differentiation and persistent proliferative potential in endometriosis. Endocrinology. 2010;151(3):1341–1355.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Talbi S, Hamilton AE, Vo KC, et al. Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women. Endocrinology. 2006;147(3):1097–1121.

    Article  PubMed  CAS  Google Scholar 

  17. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Fertil Steril. 1950;1:3–25.

    Article  Google Scholar 

  18. 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  PubMed  PubMed Central  CAS  Google Scholar 

  19. Russell DL, Ochsner SA, Hsieh M, Mulders S, Richards JS. Hormone-regulated expression and localization of versican in the rodent ovary. Endocrinology. 2003;144(3):1020–1031.

    Article  PubMed  CAS  Google Scholar 

  20. Kaplan F, Comber J, Sladek R, et al. The growth factor midkine is modulated by both glucocorticoid and retinoid in fetal lung development. Am J Respir Cell Mol Biol. 2003;28(1):33–41.

    Article  PubMed  CAS  Google Scholar 

  21. Bulmer JN, Thrower S, Wells M. Expression of epidermal growth factor receptor and transferrin receptor by human trophoblast populations. Am J Reprod Immunol. 1989;21(3–4):87–93.

    Article  PubMed  CAS  Google Scholar 

  22. Smith K, LeJeune S, Harris AH, Rees MC. Epidermal growth factor receptor in human uterine tissues. Hum Reprod. 1991;6(9):619–622.

    Article  PubMed  CAS  Google Scholar 

  23. Heiner JS, Cai L, Ding H, Rutgers JK. Myometrial expression of mRNA encoding epidermal growth factor receptor (EGFR) throughout the menstrual cycle. Am J Reprod Immunol. 1994;32(3):152–156.

    Article  PubMed  CAS  Google Scholar 

  24. Velarde MC, Aghajanova L, Nezhat CR, Giudice LC. Increased mitogen-activated protein kinase kinase/extracellularly regulated kinase activity in human endometrial stromal fibroblasts of women with endometriosis reduces 3,′5′-cyclic adenosine 5’-monophosphate inhibition of cyclin D1. Endocrinology. 2009;150(10):4701–4712.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Horcajadas JA, Pellicer A, Simón C. Wide genomic analysis of human endometrial receptivity: new times, new opportunities. Hum Reprod Update. 2007;13(1):77–86.

    Article  PubMed  CAS  Google Scholar 

  26. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5(5):341–354.

    Article  PubMed  CAS  Google Scholar 

  27. Earp HS, 3rd, Calvo BF, Sartor CI. The EGF receptor family—multiple roles in proliferation, differentiation, and neoplasia with an emphasis on HER4. Trans Am Clin Climatol Assoc. 2003;114:315–333.

    PubMed  PubMed Central  Google Scholar 

  28. Birchmeier C, Nave KA. Neuregulin-1, a key axonal signal that drives Schwann cell growth and differentiation. Glia. 2008;56(4):1491–1497.

    Article  PubMed  Google Scholar 

  29. Esper RM, Pankonin MS, Loeb JA. Neuregulins: versatile growth and differentiation factors in nervous system development and human disease. Brain Res Rev. 2006;51(2):161–175.

    Article  PubMed  CAS  Google Scholar 

  30. Xu Y, Li X, Zhou M. Neuregulin-1/ErbB signaling: a druggable target for treating heart failure. Curr Opin Pharmacol. 2009;9(2):214–219.

    Article  PubMed  CAS  Google Scholar 

  31. Imai T, Kurachi H, Adachi K, et al. Changes in epidermal growth factor receptor and the levels of its ligands during menstrual cycle in human endometrium. Biol Reprod. 1995;52(4):928–938.

    Article  PubMed  CAS  Google Scholar 

  32. Ejskjaer K, Sorensen BS, Poulsen SS, Mogensen O, Forman A, Nexo E. Expression of the epidermal growth factor system in human endometrium during the menstrual cycle. Mol Hum Reprod. 2005;11(8):543–551.

    Article  PubMed  CAS  Google Scholar 

  33. Aghajanova L, Bjuresten K, Altmae S, Landgren BM, Stavreus-Evers A. HB-EGF but not amphiregulin or their receptors HER1 and HER4 is altered in endometrium of women with unexplained infertility. Reprod Sci. 2008;15(5):484–492.

    Article  PubMed  CAS  Google Scholar 

  34. Ejskjaer K, Sorensen BS, Poulsen SS, Mogensen O, Forman A, Nexo E. Expression of the epidermal growth factor system in eutopic endometrium from women with endometriosis differs from that in endometrium from healthy women. Gynecol Obstet Invest. 2009;67(2):118–126.

    Article  PubMed  CAS  Google Scholar 

  35. Hynes NE, MacDonald G. ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol. 2009;21(2):177–184.

    Article  PubMed  CAS  Google Scholar 

  36. Wu YJ, La Pierre DP, Wu J, Yee AJ, Yang BB. The interaction of versican with its binding partners. Cell Res. 2005;15(7):483–494.

    Article  PubMed  CAS  Google Scholar 

  37. Sheng W, Wang G, Wang Y, et al. The roles of versican V1 and V2 isoforms in cell proliferation and apoptosis. Mol Biol Cell. 2005;16(3):1330–1340.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Wu Y, Chen L, Cao L, Sheng W, Yang BB. Overexpression of the C-terminal PG-M/versican domain impairs growth of tumor cells by intervening in the interaction between epidermal growth factor receptor and beta1-integrin. J Cell Sci. 2004;117(11):2227–2237.

    Article  PubMed  CAS  Google Scholar 

  39. Cattaruzza S, Schiappacassi M, Ljungberg-Rose A, et al. Distribution of PG-M/versican variants in human tissues and de novo expression of isoform V3 upon endothelial cell activation, migration, and neoangiogenesis in vitro. J Biol Chem. 2002;277(49):47626–47635.

    Article  PubMed  CAS  Google Scholar 

  40. Luo X, Prucha MS, Chegini N. The expression, regulation and function of miR-21 in the endometrium and endometriosis. Reprod Sci. 2010;17(3):349A.

    Google Scholar 

  41. Pan Q, Luo X, Chegini N. MicroRNA 21: response to hormonal therapies and regulatory function in leiomyoma, transformed leiomyoma and leiomyosarcoma cells. Mol Hum Reprod. 2010;16(3):215–227.

    Article  PubMed  CAS  Google Scholar 

  42. Zhang JG, Wang JJ, Zhao F, Liu Q, Jiang K, Yang GH. MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC). Clin Chim Acta. 2010;411(11–12):846–852.

    Article  PubMed  CAS  Google Scholar 

  43. Qi L, Bart J, Tan LP, et al. Expression of miR-21 and its targets (PTEN, PDCD4, TM1) in flat epithelial atypia of the breast in relation to ductal carcinoma in situ and invasive carcinoma. BMC Cancer. 2009;9:163.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Zhou X, Ren Y, Moore L, et al. Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Lab Invest. 2010;90(2):144–155.

    Article  PubMed  CAS  Google Scholar 

  45. Ran L, Arias P, Han D, Andreu-Vieyra C, Matzuk M, Hawkins S. Characterization of DICER gene expression in the human reproductive tract. Reprod Sci. 2010;17(2):137A.

    Google Scholar 

  46. Nagaraja AK, Andreu-Vieyra C, Franco HL, et al. Deletion of Dicer in somatic cells of the female reproductive tract causes sterility. Mol Endocrinol. 2008;22(10):2336–2352.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Asada S, Takahashi T, Isodono K, et al. Downregulation of Dicer expression by serum withdrawal sensitizes human endothelial cells to apoptosis. Am J Physiol Heart Circ Physiol. 2008;295(6):2512–2521.

    Article  CAS  Google Scholar 

  48. Zhang H, Zhao X, Liu S, Li J, Wen Z, Li M. 17betaE2 promotes cell proliferation in endometriosis by decreasing PTEN via NFkappaB-dependent pathway. Mol Cell Endocrinol. 2010;317(1–2):31–43.

    Article  PubMed  CAS  Google Scholar 

  49. Tokushige N, Markham R, Russell P, Fraser IS. High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis. Hum Reprod. 2006;21(3):782–787.

    Article  PubMed  CAS  Google Scholar 

  50. Tokushige N, Markham R, Russell P, Fraser IS. Different types of small nerve fibers in eutopic endometrium and myometrium in women with endometriosis. Fertil Steril. 2007;88(4):795–803.

    Article  PubMed  Google Scholar 

  51. Porpora MG, Koninckx PR, Piazze J, Natili M, Colagrande S, Cosmi EV. Correlation between endometriosis and pelvic pain. J Am Assoc Gynecol Laparosc. 1999;6(4):429–434.

    Article  PubMed  CAS  Google Scholar 

  52. Vercellini P, Fedele L, Aimi G, Pietropaolo G, Consonni D, Crosignani PG. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod. 2007;22(1):266–271.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Sciences, The Robert B. Jaffe, MD Endowed Professor in the Reproductive Sciences, University of California, San Francisco, 505 Parnassus Ave., M1496, Box 0132, San Francisco, CA, 94143, USA

    Lusine Aghajanova MD, PhD & Linda C. Giudice MD, PhD, MSc

Authors
  1. Lusine Aghajanova MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Linda C. Giudice MD, PhD, MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Linda C. Giudice MD, PhD, MSc.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aghajanova, L., Giudice, L.C. Molecular Evidence for Differences in Endometrium in Severe Versus Mild Endometriosis. Reprod. Sci. 18, 229–251 (2011). https://doi.org/10.1177/1933719110386241

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719110386241

Keywords

Search

Navigation