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Global Transcriptome Abnormalities of the Eutopic Endometrium From Women With Adenomyosis

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Abstract

Objective

Adenomyosis is a clinical disorder defined by the presence of endometrial glands and stroma within the myometrium, the pathogenesis of which is poorly understood. We postulate that dysregulation of genes and pathways in eutopic endometrium may predispose to ectopic implantation. No study, to our knowledge, has examined the global transcriptome of isolated eutopic endometrium from women with clinically significant adenomyosis.

Design

Laboratory-based study with full institutional review board approval and consents.

Materials and Methods

Endometrial sampling was performed on hysterectomy specimens (proliferative phase) from symptomatic women with pathologically confirmed diffuse adenomyosis (n = 3). Controls (n = 5) were normo-ovulatory patients without adenomyosis. All patients were free from leiomyoma, endometriosis, and hormonal exposures. Isolated purified total RNA was subjected to microarray analysis using the Gene 1.0 ST Affymetrix platform. Data were analyzed with GeneSpring and Ingenuity Pathway analysis. Validation of several genes was undertaken by quantitative real-time reverse transcriptase polymerase chain reaction.

Results

Comparison of transcriptomes of proliferative endometrium from women with and without adenomyosis revealed 140 upregulated and 884 downregulated genes in samples from women with adenomyosis compared to controls. Highly differentially expressed genes include those involved in regulation of apoptosis, steroid hormone responsiveness, and proteins involved in extracellular matrix remodeling as well as microRNAs of unknown significance. Affected canonical pathways included eukaryotic initiation factor 2 signaling, oxidative phosphorylation, mitochondrial dysfunction, estrogen receptor signaling, and mammalian target of rapamycin signaling.

Conclusion

The eutopic endometrium in patients with adenomyosis has fundamental abnormalities that may predispose to invasion and survival beyond the myometrial interface.

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References

  1. Tomassetti, C, Meuleman, C, Timmerman, D, D’Hooghe, T Ade-nomyosis and subfertility: evidence of association and causation. Semin Reprod Med. 2013;31(2):101–108.

    Article  PubMed  Google Scholar 

  2. Benagiano, G, Habiba, M, Brosens, I The pathophysiology of uter-ine adenomyosis: an update. Fertil Steril. 2012;98(3):572–579.

    Article  CAS  PubMed  Google Scholar 

  3. Bird, CC, McElin, TW, Manalo- Estrella, P The elusive adenomyo-sis of the uterus–revisited. Am J Obstet Gynecol. 1972;112(5): 583–593.

    Article  CAS  PubMed  Google Scholar 

  4. Fischer, CP, Kayisili, U, Taylor, HS HOXA10 expression is decreased in endometrium of women with adenomyosis. Fertil Steril. 2011;95(3):1133–1136.

    Article  CAS  PubMed  Google Scholar 

  5. Burney, RO, Talbi, S, Hamilton, AE, et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinol. 2007;148(8):3814–3826.

    Article  CAS  Google Scholar 

  6. 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. Endo-crinol. 2003;144(7):2870–2881.

    CAS  Google Scholar 

  7. Matsumoto, Y, Iwasaka, T, Yamasaki, F, Sugimori, H Apoptosis and Ki-67 expression in adenomyotic lesions and in the corre-sponding eutopic endometrium. Obstet Gynecol. 1999;94(1):71.

    CAS  PubMed  Google Scholar 

  8. Yang, JH, Wu, MY, Chen, CD, Chen, MJ, Yang, YS, Ho, HN Altered apoptosis and proliferation in endometrial stromal cells of women with adenomyosis. Hum Reprod. 2007;22(4):945–952.

    Article  CAS  PubMed  Google Scholar 

  9. Goteri, G, Lucarini, G, Montik, N, et al. Expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1a (HIF-1a), and microvessel density in endometrial tissue in women with adenomyosis. Int J Gynecol Path. 2009;28(2):157–163.

    Article  Google Scholar 

  10. Nie, J, Lu, Y, Liu, X, Guo S-W. Immunoreactivity of progesterone receptor isoform, B, nuclear factor kB, and IkBa in adenomyosis. Fertil Steril. 2009;92(3):886–889.

    Article  CAS  PubMed  Google Scholar 

  11. Ota, H, Igarashi, S, Kato, N, Tanaka, T Aberrant expression of glutathione peroxidase in eutopic and ectopic endometrium in endometriosis and adenomyosis. Fertil Steril. 2000;74(2): 313–318.

    Article  CAS  PubMed  Google Scholar 

  12. Ota, H Xanthine oxidase in eutopic and ectopic endometrium in endometriosis and adenomyosis. Fertil Steril. 2001;75(4): 785–790.

    Article  CAS  PubMed  Google Scholar 

  13. Xiaoyu, L, Weiyuan, Z, Ping, J, Anxia, W, Liane, Z Serum differ-ential proteomic analysis of endometriosis and adenomyosis by iTRAQ technique. Eur J Obstet Gynecol Reprod Biol. 2014;182: 62–65.

    Article  PubMed  CAS  Google Scholar 

  14. Hever, A, Roth, RB, Hevezi, PA, et al. Molecular characterization of human adenomyosis. Mol Hum Reprod. 2006;12(12):737–748.

    Article  CAS  PubMed  Google Scholar 

  15. Benagiano, G, Brosens, I The endometrium in adenomyosis. Women’s Health 2012;8(3):301–312.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Noyes, RW, Hertig, AT, Rock, J Dating the endometrial biopsy. Fertil Steril. 1950;1(0):3–25.

    Article  Google Scholar 

  18. 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. Endocrinol. 2006;147(3):1097–1121.

    Article  CAS  Google Scholar 

  19. Kiss-László Z, Henry, Y, Kiss, T Sequence and structural ele-ments of methylation guide snoRNAs essential for site-specific ribose methylation of pre-rRNA. EMBO, J 1998;17(3): 797–807.

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Mehasseb, MK, Panchal, R, Taylor, AH, Brown, L, Bell, SC, Habiba, M Estrogen and progesterone receptor isoform distribution through the menstrual cycle in uteri with and without adenomyo-sis. Fertil Steril. 2011;95(7):2228–2235.e1.

    Article  CAS  PubMed  Google Scholar 

  22. Mohammed, H, D’Santos, C, Serandour, AA, et al. Endogenous purification reveals GREB1 as a key estrogen receptor regulatory factor. Cell Reports. 2013;3(2):342–349.

    Article  CAS  PubMed  Google Scholar 

  23. Chand, AL, Wijayakumara, DD, Knower, KC, et al. The orphan nuclear receptor LRH-1 and ERa activate GREB1 expression to induce breast cancer cell proliferation. PLoS ONE. 2012;7(2): e31593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pellegrini, C, Gori, I, Achtari, C, et al. The expression of estrogen receptors as well as GREB1, c-MYC, and cyclin D1, estrogen-regulated genes implicated in proliferation, is increased in peritoneal endometriosis. Fertil Steril. 2012;98(5):1200–1208.

    Article  CAS  PubMed  Google Scholar 

  25. Leyendecker, G, Wildt, L, Mall, G The pathophysiology of endo-metriosis and adenomyosis: tissue injury and repair. Arch Gynecol Obstet. 2009;280(4):529–538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yamamoto, T, Noguchi, T, Tamura, T, Kitawaki, J, Okada, H Evi-dence for estrogen synthesis in adenomyotic tissues. Am J Obstet Gynecol. 1993;169(3):734–738.

    Article  CAS  PubMed  Google Scholar 

  27. Chen Y-J, Li H-Y, Huang, CH, et al. Oestrogen-induced epithe-lial–mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis. J Pathol. 2010; 222(3):261–270.

    Article  CAS  PubMed  Google Scholar 

  28. Huang T-S, Chen Y-J, Chou T-Y, et al. Oestrogen-induced angio-genesis promotes adenomyosis by activating the Slug-VEGF axis in endometrial epithelial cells. J Cell Mol Med. 2014;18(7): 1358–1371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gonzalez, G, Behringer, RR Dicer is required for female repro-ductive tract development and fertility in the mouse. Mol Reprod Dev. 2009;76(7):678–688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Marsh, EE, Lin, Z, Yin, P, Milad, M, Chakravarti, D, Bulun, SE Differential expression of microRNA species in human uterine leiomyoma versus normal myometrium. Fertil Steril. 2008;89(6): 1771–1776.

    Article  CAS  PubMed  Google Scholar 

  31. Pan, Q, Luo, X, Chegini, N Differential expression of microRNAs in myometrium and leiomyomas and regulation by ovarian ster-oids. J Cell Mol Med. 2008;12(1):227–240.

    Article  CAS  PubMed  Google Scholar 

  32. Santamaria, X, Taylor, H MicroRNA and gynecological reproduc-tive diseases. Fertil Steril. 2014;101(6):1545–1551.

    Article  CAS  PubMed  Google Scholar 

  33. Burney, RO, Hamilton, AE, Aghajanova, L, et al. MicroRNA expression profiling of eutopic secretory endometrium in women with versus without endometriosis. Mol Hum Reprod. 2009;15(10):625–631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yuva-Aydemir, Y, Simkin, A, Gascon, E, Gao F-B. MicroRNA-9. RNA Biol. 2014;8(4):557–564.

    Article  CAS  Google Scholar 

  35. Sa, R, Song, J Relationship between ultrastructural features with the expression of connexin 43 in the uterine junction zone and pathogenesis of adenomyosis. Zhonghua Fu Chan Ke Za Zhi. 2010;45(10):762–766.

    PubMed  Google Scholar 

  36. Jones, RK, Searle, RF, Bulmer, JN Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis. Hum Reprod. 1998;13(12):3496–3502.

    Article  CAS  PubMed  Google Scholar 

  37. Makker, A, Goel, MM, Das, V, Agarwal, A PI3K-Akt-mTOR and MAPK signaling pathways in polycystic ovarian syndrome, uter-ine leiomyomas and endometriosis: an update. Gynecol Endocri-nol. 2012;28(3):175–181.

    Article  CAS  Google Scholar 

  38. Erikson, D, Chen, JC, Piltonen, TT, Conti, M, Irwin, JC, Giudice, LC Inhibition of epidermal growth factor receptor restores deciduali-zation markers in stromal fibroblasts from women with endome-triosis. JEPPD. 2014;6(4):196–211.

    Google Scholar 

  39. Sabatini, DM mTOR and cancer: insights into a complex relation-ship. Nat Rev Cancer. 2006;6(9):729–734.

    Article  CAS  PubMed  Google Scholar 

  40. Fasolo, A, Sessa, C mTOR inhibitors in the treatment of cancer. Expert Opin Investig Drugs. 2008;17(11):1717–1734.

    Article  CAS  PubMed  Google Scholar 

  41. deGraffenried, LA, Friedrichs, WE, Russell, DH, et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity. Clin Cancer Res. 2004;10(23): 8059–8067.

    Article  CAS  PubMed  Google Scholar 

  42. Meric-Bernstam, F, Gonzalez-Angulo, AM Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27(13): 2278–2287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Khan, KN, Kitajima, M, Hiraki, K, et al. Cell proliferation effect of GnRH agonist on pathological lesions of women with endome-triosis, adenomyosis and uterine myoma. Hum Reprod. 2010;25(11):2878–2890.

    Article  CAS  PubMed  Google Scholar 

  44. Mehasseb, MK, Taylor, AH, Pringle, JH, Bell, SC, Habiba, M Enhanced invasion of stromal cells from adenomyosis in a three-dimensional coculture model is augmented by the presence of myocytes from affected uteri. Fertil Steril. 2010;94(7):2547–2551.

    Article  CAS  PubMed  Google Scholar 

  45. Li, T, Li, YG, Pu, DM Matrix metalloproteinase-2 and -9 expres-sion correlated with angiogenesis in human adenomyosis. Gyne-col Obstet Invest. 2006;62(4):229–235.

    Article  CAS  Google Scholar 

  46. Yang J-H, Wu M-Y, Chen M-J, Chen S-U, Yang Y-S, Ho H-N. Increased matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 secretion but unaffected invasiveness of endometrial stromal cells in adenomyosis. Fertil Steril. 2009; 91(5):2193–2198.

    Article  CAS  PubMed  Google Scholar 

  47. Symington, BE, Takada, Y, Carter, WG Interaction of integrins alpha 3 beta 1 and alpha 2 beta 1: potential role in keratinocyte intercellular adhesion. J Cell Biol. 1993;120(2):523–535.

    Article  CAS  PubMed  Google Scholar 

  48. Prifti, S, Zourab, Y, Koumouridis, A, Bohlmann, M, Strowitzki, T, Rabe, T Role of integrins in invasion of endometrial cancer cell lines. Gynecol Oncol. 2002;84(1):12–20.

    Article  PubMed  Google Scholar 

  49. Qiu, F, XM, G, GL, L, et al. Expression of matrix metalloproteinase and tissue inhibitor of metalloproteinase in adenomyosis. Sichuan Da Xue Xue Bao Yi Xue Ban. 2006;37(1):118–122.

    CAS  PubMed  Google Scholar 

  50. Tokyol, C, Aktepe, F, Dilek, FH, Sahin, O, Arioz, DT Expression of cyclooxygenase-2 and matrix metalloproteinase-2 in adenomyo-sis and endometrial polyps and its correlation with angiogenesis. Int J Gynecol Path. 2009;28(2):148–156.

    Article  Google Scholar 

  51. Aghajanova, L, Shen, S, Rojas, AM, Fisher, SJ, Irwin, JC, Giudice, LC Comparative transcriptome analysis of human trophectoderm and embryonic stem cell-derived trophoblasts reveal key partici-pants in early implantation. Biol Reprod. 2011;86(1):1–21.

    Google Scholar 

  52. Yu, J, Boicea, A, Barrett, KL, et al. Reduced connexin 43 in eutopic endometrium and cultured endometrial stromal cells from subjects with endometriosis. Mol Hum Reprod. 2014;20(3):260–270.

    Article  CAS  PubMed  Google Scholar 

  53. Regidor, PA, Regidor, M, Schindler, AE, Winterhager, E Aberrant expression pattern of gap junction connexins in endometriotic tissues. Mol Hum Reprod. 1997;3(5):375–381.

    Article  CAS  PubMed  Google Scholar 

  54. Aghajanova, L, Giudice, LC Molecular evidence for differences in endometrium in severe versus mild endometriosis. Reprod Sci. 2010;18(3):229–251.

    Article  PubMed  CAS  Google Scholar 

  55. McElin, TW, Bird, CC Adenomyosis of the uterus. Obstet Gynecol Annu. 1974;3(0):425–441.

    CAS  PubMed  Google Scholar 

  56. Gonzales, M, de Matos, LA, da Costa Gonçalves, MO, et al. Patients with adenomyosis are more likely to have deep endome-triosis. Gynecol Surg. 2012;9(3):259–264.

    Article  Google Scholar 

  57. Kunz, G, Beil, D, Huppert, P, Noe, M, Kissler, S, Leyendecker, G Adenomyosis in endometriosis–prevalence and impact on ferti-lity. Evidence from magnetic resonance imaging. Hum Reprod. 2005;20(8):2309–2316.

    Article  CAS  PubMed  Google Scholar 

  58. Larsen, SB, Lundorf, E, Forman, A, Dueholm, M Adenomyosis and junctional zone changes in patients with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2011;157(2):206–211.

    Article  CAS  PubMed  Google Scholar 

  59. Sheldon, E, Vo, KC, McIntire, RA, et al. Biobanking human endometrial tissue and blood specimens: standard operating procedure and importance to reproductive biology research and diagnostic development. Fertil Steril. 2011;95(6): 2120–2122. e12.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, 550 16th Street, 7th Floor, Box 0132, CA, 94143, USA

    Christopher N. Herndon MD, Lusine Aghajanova MD PhD, Shaina Balayan BS MSc, Fatima Barragan BS, Gabriel Goldfien BS, Kim Chi Vo BS & Linda C. Giudice MD, PhD, MSc

  2. Endocrine Technologies Support Core, Oregon National Primate Research Center, Beaverton, OR, USA

    David Erikson PhD

  3. Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA

    Shannon Hawkins MD, PhD

Authors
  1. Christopher N. Herndon MD
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  2. Lusine Aghajanova MD PhD
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  3. Shaina Balayan BS MSc
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  4. David Erikson PhD
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  6. Gabriel Goldfien BS
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  8. Shannon Hawkins MD, PhD
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  9. Linda C. Giudice MD, PhD, MSc
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Corresponding author

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

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Herndon, C.N., Aghajanova, L., Balayan, S. et al. Global Transcriptome Abnormalities of the Eutopic Endometrium From Women With Adenomyosis. Reprod. Sci. 23, 1289–1303 (2016). https://doi.org/10.1177/1933719116650758

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