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Global Gene Expression Profiling of Proliferative Phase Endometrium Reveals Distinct Functional Subdivisions

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Abstract

The human endometrium follows a predictable pattern of development during the proliferative phase. Endometrial thickness increases after day 3 and then plateaus at days 9 to 10 of the menstrual cycle despite continued high serum levels of estrogen. We hypothesized that proliferative phase endometrium undergoes more than simple estrogen responsive growth, rather it is characterized by complex time-dependent functional activities reflected in differential gene expression. Nine endometrial RNA samples from healthy participants were subjected to microarray analysis and 15 samples were used for quantitative real-time polymerase chain reaction. The samples were divided into early, mid, or late proliferative phase. The early proliferative phase showed higher expression of genes including transforming growth factor β2, chemokine (C-C motif) ligand 18 (CCL18), and metallothionein 2A. The mid-proliferative phase was characterized by higher expression of heat shock proteins and implantation-associated genes including Indian hedgehog, secreted frizzled protein 4, and progesterone receptor. In the late proliferative phase, we identified increased angiotensin II receptor, type 2 and large decrease in expression of genes related to natural killer (NK) cell function. We demonstrate a unique gene expression signature at distinct time points within the proliferative phase. The early proliferative phase is characterized by tissue remodeling, angiogenesis, and modulation of inflammation; the mid-proliferative phase is characterized not only by proliferation in response to estrogens but also marks the onset of expression of genes required for endometrial receptivity and a dampening of estrogen responsiveness. In the late proliferative phase, changes in immune function and NK cells predominate. The proliferative phase is not simply a uniform period of estrogen responsive endometrial growth that can be considered as a single experimental time point when evaluating endometrial development; rather the proliferative phase is complex with differing functions and patterns of gene expression.

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References

  1. Milne SA, Critchley HO, Drudy TA, Kelly RW, Baird DT. Perivascular interleukin-8 messenger ribonucleic acid expression in human endometrium varies across the menstrual cycle and in early pregnancy decidua. J Clin Endocrinol Metab. 1999;84(7): 2563–2567.

    CAS  PubMed  Google Scholar 

  2. Seli MD, Senturk LM, Bahtiyar OM, Kayisli UA, Arici A. Expression of aminopeptidase N in human endometrium and regulation of its activity by estrogen. Fertil Steril. 2001;75(6): 1172–1176.

    Article  CAS  Google Scholar 

  3. Leon Speroff, Fritz MA. Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins, 2005.

    Google Scholar 

  4. Lobo SC, Huang ST, Germeyer A, et al. The immune environment in human endometrium during the window of implantation. Am J Reprod Immunol. 2004;52(4):244–251.

    Article  Google Scholar 

  5. Kao LC, Tulac S, Lobo S, et al. Global gene profiling in human endometrium during the window of implantation. Endocrinology. 2002;143(6):2119–2138.

    Article  CAS  Google Scholar 

  6. Fazleabas AT, Strakova Z. Endometrial function: cell specific changes in the uterine environment. Mol Cell Endocrinol. 2002; 186(2): 143–147.

    Article  CAS  Google Scholar 

  7. Noguchi Y, et al. Identification and characterization of extracellular matrix metalloproteinase inducer in human endometrium during the menstrual cycle in vivo and in vitro. J Clin Endocrinol Metab. 2003;88(12):6063-6072.

    Article  CAS  Google Scholar 

  8. Critchley Ho.OD, Saunders PTK. Hormone receptor dynamics in a receptive human endometrium. Reprod Sci. 2009; 16(2): 191–199.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Bromer JG, Aldad TS, Taylor HS. Defining the proliferative phase endometrial defect. Fertil Steril. 2009;91(3):698–704.

    Article  Google Scholar 

  11. Pepper MS. Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev. 1997;8(1):21–43.

    Article  CAS  Google Scholar 

  12. Chang CC, Hsieh YY, Hsu KH, Lin CS. Effects of a and b recombinant FSH (Gonal-F, Puregon) and progesterone upon human endometrial cell proliferation in-vitro: a preliminary study. Gynecol Endocrinol. 2011 ;27(2):110–116.

    Article  CAS  Google Scholar 

  13. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15(23): 3059–3087.

    Article  CAS  Google Scholar 

  14. Kang DH, Han ME, Song MH, et al. The role of hedgehog signaling during gastric regeneration. J Gastroenterol. 2009;44(5):372–379.

    Article  CAS  Google Scholar 

  15. Walterhouse DO, Lamm ML, Villavicencio E, Iannaccone PM. Emerging roles for hedgehog-patched-Gli signal transduction in reproduction. Biol Reprod. 2003;69(1):8–14.

    Article  CAS  Google Scholar 

  16. Tabibzadeh S, Broome J. Heat shock proteins in human endometrium throughout the menstrual cycle. Infect Dis Obstet Gynecol. 1999;7(1–2):5–9.

    Article  CAS  Google Scholar 

  17. Zheng WL, Sierra-Rivera E, Luan J, Osteen KG, Ong DE: Retinoic acid synthesis and expression of cellular retinol-binding protein and cellular retinoic acid-binding protein type II are concurrent with decidualization of rat uterine stromal cells. Endocrinology. 2000;141(2):802-808.

    Article  CAS  Google Scholar 

  18. Sidell N, Feng Y, Hao L, et al. Retinoic acid is a cofactor for translational regulation of vascular endothelial growth factor in human endometrial stromal cells. Mol Endocrinol. 2010;24(1): 148–160.

    Article  CAS  Google Scholar 

  19. Ferrara N, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996; 380(6573):439–442.

    Article  CAS  Google Scholar 

  20. Jauniaux E, Poston L, Burton GJ. Placental-related diseases of pregnancy: involvement of oxidative stress and implications in human evolution. Hum Reprod Update. 2006;12(6):747–755.

    Article  CAS  Google Scholar 

  21. Maruyama T, Yoshimura Y. Molecular and cellular mechanisms for differentiation and regeneration of the uterine endometrium. Endocr J. 2008;55(5):795–810.

    Article  CAS  Google Scholar 

  22. Li XF, Ahmed A. Dual role of angiotensin II in the human endometrium. Hum Reprod. 1996;11(2):95–108.

    Article  CAS  Google Scholar 

  23. Nissen NN, Polverini PJ, Koch AE, Volin MV, Gamelli RL, DiPietro LA. Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am J Pathol. 1998;152(6):1445–1452.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Penna G, Vulcano M, Sozzani S, Adorini L. Differential migration behavior and chemokine production by myeloid and plasma-cytoid dendritic cells. Hum Immunol. 2002;63(12): 1164–1171.

    Article  CAS  Google Scholar 

  25. Tranquilli AL, Landi B, Corradetti A, et al. Inflammatory cytokines patterns in the placenta of pregnancies complicated by HELLP (hemolysis, elevated liver enzyme, and low platelet) syndrome. Cytokine. 2007;40(2):82–88.

    Article  CAS  Google Scholar 

  26. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12(2):121–127.

    Article  CAS  Google Scholar 

  27. Baggiolini M, Dewald B, Moser B. Human chemokines: an update. Annu Rev Immunol. 1997;15:675–705.

    Article  CAS  Google Scholar 

  28. Schutyser E, Richmond A, Van Damme J. Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes. J Leukoc Biol. 2005;78(1):14–26.

    Article  CAS  Google Scholar 

  29. Dunk C, Smith S, Hazan A, Whittle W, Jones RL. Promotion of angiogenesis by human endometrial lymphocytes. Immunol Invest. 2008;37(5):583–610.

    Article  CAS  Google Scholar 

  30. Carmon KS, Loose DS. Secreted frizzled-related protein 4 regulates two Wnt7a signaling pathways and inhibits proliferation in endometrial cancer cells. Mol Cancer Res. 2008;6(6):1017–1028.

    Article  CAS  Google Scholar 

  31. Hrzenjak A, Tippl M, Kremser ML, et al. Inverse correlation of secreted frizzled-related protein 4 and beta-catenin expression in endometrial stromal sarcomas. J Pathol. 2004;204(1): 19–27.

    Article  CAS  Google Scholar 

  32. Sonderegger S, Pollheimer J, Knöfler M. Wnt Signalling in implantation, decidualisation and placental differentiation. Placenta. 2010;31(10):839–847.

    Article  CAS  Google Scholar 

  33. Komatsu T, Konishi I, Fukumoto M, et al. Messenger ribonucleic acid expression of heat shock proteins HSP70 and HSP90 in human endometrium and myometrium during the menstrual cycle. J Clin Endocrinol Metab. 1997;82(5): 1385–1389.

    CAS  PubMed  Google Scholar 

  34. Koshiyama M, Konishi I, Nanbu K, et al. Immunohistochemical localization of heat shock proteins HSP70 and HSP90 in the human endometrium: correlation with sex steroid receptors and Ki-67 antigen expression. J Clin Endocrinol Metab. 1995;80(4): 1106–1112.

    CAS  PubMed  Google Scholar 

  35. Klentzeris LD, Bulmer JN, Warren A, Morrison L, Li TC, Cooke ID. Endometrial lymphoid tissue in the timed endometrial biopsy: morphometric and immunohistochemical aspects. Am J Obstet Gynecol. 1992;167(3):667–674.

    Article  CAS  Google Scholar 

  36. Peel S. Granulated metrial gland cells. Adv Anat Embryol Cell Biol. 1989;115:1–112.

    Article  CAS  Google Scholar 

  37. Keskin DB, Allan DS, Rybalov B, et al. TGFbeta promotes conversion of CD16+ peripheral blood NK cells into CD16- NK cells with similarities to decidual NK cells. Proc Natl Acad Sci USA. 2007;104(9):3378–3383.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar St, 06520, New Haven, CT, USA

    Rafaella G. Petracco MD, Alice Kong BA, Olga Grechukhina MD, Graciela Krikun PhD & Hugh S. Taylor MD

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  1. Rafaella G. Petracco MD
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  2. Alice Kong BA
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  3. Olga Grechukhina MD
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  4. Graciela Krikun PhD
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  5. Hugh S. Taylor MD
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Correspondence to Hugh S. Taylor MD.

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Petracco, R.G., Kong, A., Grechukhina, O. et al. Global Gene Expression Profiling of Proliferative Phase Endometrium Reveals Distinct Functional Subdivisions. Reprod. Sci. 19, 1138–1145 (2012). https://doi.org/10.1177/1933719112443877

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