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  • Review Article
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Fertile ground: human endometrial programming and lessons in health and disease

Nature Reviews Endocrinology volume 12, pages 654–667 (2016)Cite this article

Subjects

Key Points

  • The human endometrium is a unique, dynamic tissue that is cyclically shed, repaired, regenerated and remodelled, in preparation for embryo implantation

  • Decidualization in women occurs spontaneously (regardless of the presence of an embryo) during the mid-to-late luteal phase, necessitating endometrial shedding and subsequent regeneration in the absence of conception

  • Endometrial remodelling occurs primarily under the orchestration of oestrogen and progesterone, but is influenced by many factors, including epigenetic signals and stem/progenitor cells

  • Abnormalities in endometrial remodelling lead to pathologies including infertility, endometriosis and pregnancy disorders

  • Understanding the processes that operate in the endometrium could provide information that is applicable to nonreproductive pathologies such as cancer and wound healing

Abstract

The human endometrium is a highly dynamic tissue that is cyclically shed, repaired, regenerated and remodelled, primarily under the orchestration of oestrogen and progesterone, in preparation for embryo implantation. Humans are among the very few species that menstruate and that, consequently, are equipped with unique cellular and molecular mechanisms controlling these cyclic processes. Many reproductive pathologies are specific to menstruating species, and studies in animal models rarely translate to humans. Abnormal remodelling and regeneration of the human endometrium leads to a range of reproductive complications. Furthermore, the processes regulating endometrial remodelling and implantation, including those controlling hormonal impact, breakdown and repair, stem/progenitor cell activation, inflammation and cell invasion have broad applications to other fields. This Review presents current knowledge regarding the normal and abnormal function of the human endometrium. The development of biomarkers for prediction of uterine diseases and pregnancy disorders and future avenues of investigation to improve fertility and enhance endometrial function are also discussed.

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Figure 1: The pre-receptive, receptive and post-receptive endometrium.
Figure 2: Endometrial decidualization, menstruation, repair and regeneration.

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References

  1. Finn, C. A. Menstruation: a nonadaptive consequence of uterine evolution. Q. Rev. Biol. 73, 163–173 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Lynch, V. J. et al. Ancient transposable elements transformed the uterine regulatory landscape and transcriptome during the evolution of mammalian pregnancy. Cell Rep. 10, 551–561 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Brosens, I. et al. The perinatal origins of major reproductive disorders in the adolescent: research avenues. Placenta 36, 341–344 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Brosens, J. J., Parker, M. G., McIndoe, A., Pijnenborg, R. & Brosens, I. A. A role for menstruation in preconditioning the uterus for successful pregnancy. Am. J. Obstet. Gynecol. 200, 615.e1–e6 (2009).

    Article  Google Scholar 

  5. Al-Sabbagh, M., Lam, E. W. & Brosens, J. J. Mechanisms of endometrial progesterone resistance. Mol. Cell. Endocrinol. 358, 208–215 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Murphy, C. R. Uterine receptivity and the plasma membrane transformation. Cell Res. 14, 259–267 (2004).

    Article  PubMed  Google Scholar 

  7. Li, Y., Sun, X. & Dey, S. K. Entosis allows timely elimination of the luminal epithelial barrier for embryo implantation. Cell Rep. 11, 358–365 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Revel, A. Defective endometrial receptivity. Fertil. Steril. 97, 1028–1032 (2012).

    Article  PubMed  Google Scholar 

  9. Davidson, L. M. & Coward, K. Molecular mechanisms of membrane interaction at implantation. Birth Defects Res. C Embryo Today 108, 19–32 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Dimitriadis, E. et al. Interleukin-11, IL-11 receptorα and leukemia inhibitory factor are dysregulated in endometrium of infertile women with endometriosis during the implantation window. J. Reprod. Immunol. 69, 53–64 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Yap, J., Foo, C. F., Lee, M. Y., Stanton, P. G. & Dimitriadis, E. Proteomic analysis identifies interleukin 11 regulated plasma membrane proteins in human endometrial epithelial cells in vitro. Reprod. Biol. Endocrinol. 9, 73–87 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Haouzi, D., Dechaud, H., Assou, S., De Vos, J. & Hamamah, S. Insights into human endometrial receptivity from transcriptomic and proteomic data. Reprod. Biomed. Online 24, 23–34 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Heng, S., Hannan, N. J., Rombauts, L. J., Salamonsen, L. A. & Nie, G. PC6 levels in uterine lavage are closely associated with uterine receptivity and significantly lower in a subgroup of women with unexplained infertility. Hum. Reprod. 26, 840–846 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Heng, S. et al. Posttranslational removal of α-dystroglycan N terminus by PC5/6 cleavage is important for uterine preparation for embryo implantation in women. FASEB J. 29, 4011–4022 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. Croxatto, D. et al. Stromal cells from human decidua exert a strong inhibitory effect on NK cell function and dendritic cell differentiation. PLoS ONE 9, e89006 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Murakami, K. et al. Decidualization induces a secretome switch in perivascular niche cells of the human endometrium. Endocrinology 155, 4542–4553 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Teklenburg, G. et al. Natural selection of human embryos: decidualizing endometrial stromal cells serve as sensors of embryo quality upon implantation. PLoS ONE 5, e10258 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Brosens, J. J., Hayashi, N. & White, J. O. Progesterone receptor regulates decidual prolactin expression in differentiating human endometrial stromal cells. Endocrinology 140, 4809–4820 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Popovici, R. M. et al. Gene expression profiling of human endometrial-trophoblast interaction in a coculture model. Endocrinology 147, 5662–5675 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Garrido-Gomez, T. et al. Modeling human endometrial decidualization from the interaction between proteome and secretome. J. Clin. Endocrinol. Metab. 96, 706–716 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Estella, C. et al. miRNA signature and Dicer requirement during human endometrial stromal decidualization in vitro. PLoS ONE 7, e41080 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Gellersen, B. & Brosens, J. J. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr. Rev. 35, 851–905 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Kuroda, K. et al. Induction of 11β-HSD 1 and activation of distinct mineralocorticoid receptor- and glucocorticoid receptor-dependent gene networks in decidualizing human endometrial stromal cells. Mol. Endocrinol. 27, 192–202 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Filant, J. & Spencer, T. E. Endometrial glands are essential for blastocyst implantation and decidualization in the mouse uterus. Biol. Reprod. 88, 93 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Filant, J. & Spencer, T. E. Uterine glands: biological roles in conceptus implantation, uterine receptivity and decidualization. Int. J. Dev. Biol. 58, 107–116 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Plaks, V. et al. Uterine DCs are crucial for decidua formation during embryo implantation in mice. J. Clin. Invest. 118, 3954–3965 (2008).

    PubMed  PubMed Central  CAS  Google Scholar 

  27. Ashkar, A. A., Di Santo, J. P. & Croy, B. A. Interferon γ contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J. Exp. Med. 192, 259–270 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Gong, X. et al. Insights into the paracrine effects of uterine natural killer cells. Mol. Med. Rep. 10, 2851–2860 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Nancy, P. et al. Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface. Science 336, 1317–1321 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Slayden, O. D. & Brenner, R. M. A critical period of progesterone withdrawal precedes menstruation in macaques. Reprod. Biol. Endocrinol. 4 (Suppl. 1), S6 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Garry, R., Hart, R., Karthigasu, K. A. & Burke, C. A re-appraisal of the morphological changes within the endometrium during menstruation: a hysteroscopic, histological and scanning electron microscopic study. Hum. Reprod. 24, 1393–1401 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Mote, P. A., Balleine, R. L., McGowan, E. M. & Clarke, C. L. Heterogeneity of progesterone receptors A and B expression in human endometrial glands and stroma. Hum. Reprod. 15 (Suppl. 3), 48–56 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Evans, J. & Salamonsen, L. A. Decidualized human endometrial stromal cells are sensors of hormone withdrawal in the menstrual inflammatory cascade. Biol. Reprod. 90, 14 (2014).

    PubMed  Google Scholar 

  34. Sugino, N., Karube-Harada, A., Taketani, T., Sakata, A. & Nakamura, Y. Withdrawal of ovarian steroids stimulates prostaglandin F2α production through nuclear factor-κB activation via oxygen radicals in human endometrial stromal cells: potential relevance to menstruation. J. Reprod. Dev. 50, 215–225 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Evans, J. & Salamonsen, L. A. Inflammation, leukocytes and menstruation. Rev. Endocr. Metab. Disord. 13, 277–288 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Gaide Chevronnay, H. P. et al. Spatiotemporal coupling of focal extracellular matrix degradation and reconstruction in the menstrual human endometrium. Endocrinology 150, 5094–5105 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Evans, J., Kaitu'u-Lino, T. & Salamonsen, L. A. Extracellular matrix dynamics in scar-free endometrial repair: perspectives from mouse in vivo and human in vitro studies. Biol. Reprod. 85, 511–523 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Maybin, J. A. & Critchley, H. O. Steroid regulation of menstrual bleeding and endometrial repair. Rev. Endocr. Metab. Disord. 13, 253–263 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Cousins, F. L. et al. Evidence from a mouse model that epithelial cell migration and mesenchymal-epithelial transition contribute to rapid restoration of uterine tissue integrity during menstruation. PLoS ONE 9, e86378 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Evans, J. et al. Endometrial CRISP3 is regulated throughout the mouse estrous and human menstrual cycle and facilitates adhesion and proliferation of endometrial epithelial cells. Biol. Reprod. 92, 99 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Evans, J. et al. Galectin-7 is important for normal uterine repair following menstruation. Mol. Hum. Reprod. 20, 787–798 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Fan, X. et al. Dynamic regulation of Wnt7a expression in the primate endometrium: implications for postmenstrual regeneration and secretory transformation. Endocrinology 153, 1063–1069 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Gargett, C. E., Schwab, K. E. & Deane, J. A. Endometrial stem/progenitor cells: the first 10 years. Hum. Reprod. Update 22, 137–163 (2016).

    Article  CAS  PubMed  Google Scholar 

  44. Gargett, C. E., Schwab, K. E., Zillwood, R. M., Nguyen, H. P. & Wu, D. Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol. Reprod. 80, 1136–1145 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Schwab, K. E. & Gargett, C. E. Co-expression of two perivascular cell markers isolates mesenchymal stem-like cells from human endometrium. Hum. Reprod. 22, 2903–2911 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Masuda, H., Anwar, S. S., Bühring, H. J., Rao, J. R. & Gargett, C. E. A novel marker of human endometrial mesenchymal stem-like cells. Cell Transplant. 21, 2201–2214 (2012).

    Article  PubMed  Google Scholar 

  47. Spitzer, T. L. et al. Perivascular human endometrial mesenchymal stem cells express pathways relevant to self-renewal, lineage specification, and functional phenotype. Biol. Reprod. 86, 58 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Masuda, H. et al. Endometrial side population cells: potential adult stem/progenitor cells in endometrium. Biol. Reprod. 93, 84 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Cervelló, I. et al. Reconstruction of endometrium from human endometrial side population cell lines. PLoS ONE 6, e21221 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Miyazaki, K. et al. Stem cell-like differentiation potentials of endometrial side population cells as revealed by a newly developed in vivo endometrial stem cell assay. PLoS ONE 7, e50749 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Masuda, H. et al. Stem cell-like properties of the endometrial side population: implication in endometrial regeneration. PLoS ONE 5, e10387 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Ulrich, D. et al. Human endometrial mesenchymal stem cells modulate the tissue response and mechanical behavior of polyamide mesh implants for pelvic organ prolapse repair. Tissue Eng. Part A 20, 785–798 (2014).

    CAS  PubMed  Google Scholar 

  53. Salamonsen, L. A., Evans, J., Nguyen, H. P. & Edgell, T. A. The microenvironment of human implantation: determinant of reproductive success. Am. J. Reprod. Immunol. 75, 218–225 (2016).

    Article  PubMed  Google Scholar 

  54. Hannan, N. J. et al. Analysis of fertility-related soluble mediators in human uterine fluid identifies VEGF as a key regulator of embryo implantation. Endocrinology 152, 4948–4956 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Robertson, S. A., Chin, P. Y., Glynn, D. J. & Thompson, J. G. Peri-conceptual cytokines—setting the trajectory for embryo implantation, pregnancy and beyond. Am. J. Reprod. Immunol. 66 (Suppl. 1), 2–10 (2011).

    Article  PubMed  Google Scholar 

  56. Vilella, F. et al. Hsa-miR-30d, secreted by the human endometrium, is taken up by the pre-implantation embryo and might modify its transcriptome. Development 142, 3210–3221 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Wira, C. R., Rodriguez-Garcia, M. & Patel, M. V. The role of sex hormones in immune protection of the female reproductive tract. Nat. Rev. Immunol. 15, 217–230 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Gardner, D. K., Wale, P. L., Collins, R. & Lane, M. Glucose consumption of single post-compaction human embryos is predictive of embryo sex and live birth outcome. Hum. Reprod. 26, 1981–1986 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Kermack, A. J. et al. Amino acid composition of human uterine fluid: association with age, lifestyle and gynaecological pathology. Hum. Reprod. 30, 917–924 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Van Sinderen, M., Menkhorst, E., Winship, A., Cuman, C. & Dimitriadis, E. Preimplantation human blastocyst-endometrial interactions: the role of inflammatory mediators. Am. J. Reprod. Immunol. 69, 427–440 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Butler, S. A. et al. Human chorionic gonadotropin (hCG) in the secretome of cultured embryos: hyperglycosylated hCG and hCG-free beta subunit are potential markers for infertility management and treatment. Reprod. Sci. 20, 1038–1045 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Evans, J. et al. Prokineticin 1 mediates fetal-maternal dialogue regulating endometrial leukemia inhibitory factor. FASEB J. 23, 2165–2175 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Licht, P., Fluhr, H., Neuwinger, J., Wallwiener, D. & Wildt, L. Is human chorionic gonadotropin directly involved in the regulation of human implantation? Mol. Cell. Endocrinol. 269, 85–92 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Paiva, P. et al. Human chorionic gonadotrophin regulates FGF2 and other cytokines produced by human endometrial epithelial cells, providing a mechanism for enhancing endometrial receptivity. Hum. Reprod. 26, 1153–1162 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Sherwin, J. R. et al. Identification of novel genes regulated by chorionic gonadotropin in baboon endometrium during the window of implantation. Endocrinology 148, 618–626 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Gardner, D. K. Lactate production by the mammalian blastocyst: manipulating the microenvironment for uterine implantation and invasion? Bioessays 37, 364–371 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Cuman, C. et al. Preimplantation human blastocysts release factors that differentially alter human endometrial epithelial cell adhesion and gene expression relative to IVF success. Hum. Reprod. 28, 1161–1171 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Cuman, C. et al. Human blastocyst secreted microRNA regulate endometrial epithelial cell adhesion. EBioMedicine 2, 1528–1535 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Cano, A. & Gomez, R. Mir-661: a key factor in embryo-maternal dialog with potential clinical application to predict implantation outcome? EBioMedicine 2, 1312–1313 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Sampson, J. A. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am. J. Pathol. 3, 93–110 (1927).

    PubMed  PubMed Central  CAS  Google Scholar 

  71. Han, S. J. et al. Estrogen receptor β modulates apoptosis complexes and the inflammasome to drive the pathogenesis of endometriosis. Cell 163, 960–974 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Rahmioglu, N. et al. Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets. Hum. Reprod. Update 20, 702–716 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Chan, R. W., Ng, E. H. & Yeung, W. S. Identification of cells with colony-forming activity, self-renewal capacity, and multipotency in ovarian endometriosis. Am. J. Pathol. 178, 2832–2844 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Gargett, C. E. et al. Potential role of endometrial stem/progenitor cells in the pathogenesis of early-onset endometriosis. Mol. Hum. Reprod. 20, 591–598 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Burney, R. O. et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 148, 3814–3826 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Aghajanova, L. et al. Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol. Reprod. 84, 801–815 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Salker, M. et al. Natural selection of human embryos: impaired decidualization of endometrium disables embryo-maternal interactions and causes recurrent pregnancy loss. PLoS ONE 5, e10287 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Savaris, R. F. et al. Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles. J. Clin. Endocrinol. Metab. 96, 1737–1746 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Aghajanova, L. & Giudice, L. C. Molecular evidence for differences in endometrium in severe versus mild endometriosis. Reprod. Sci. 18, 229–251 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Garcia-Velasco, J. A. et al. Is endometrial receptivity transcriptomics affected in women with endometriosis? A pilot study. Reprod. Biomed. Online 31, 647–654 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Rai, P., Kota, V., Deendayal, M. & Shivaji, S. Differential proteome profiling of eutopic endometrium from women with endometriosis to understand etiology of endometriosis. J. Proteome Res. 9, 4407–4419 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Díaz, I. et al. Impact of stage III-IV endometriosis on recipients of sibling oocytes: matched case-control study. Fertil. Steril. 74, 31–34 (2000).

    Article  PubMed  Google Scholar 

  83. Budak, E. et al. Improvements achieved in an oocyte donation program over a 10-year period: sequential increase in implantation and pregnancy rates and decrease in high-order multiple pregnancies. Fertil. Steril. 88, 342–349 (2007).

    Article  PubMed  Google Scholar 

  84. Polat, M., Boynukalin, F. K., Yarali, I., Esinler, I. & Yarali, H. Endometriosis is not associated with inferior pregnancy rates in in vitro fertilization: an analysis of 616 patients. Gynecol. Obstet. Invest. 78, 59–64 (2014).

    Article  PubMed  Google Scholar 

  85. Vernaeve, V. et al. Endometrial receptivity after oocyte donation in recipients with a history of chemotherapy and/or radiotherapy. Hum. Reprod. 22, 2863–2867 (2007).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  87. Harb, H. M., Gallos, I. D., Chu, J., Harb, M. & Coomarasamy, A. The effect of endometriosis on in vitro fertilisation outcome: a systematic review and meta-analysis. BJOG 120, 1308–1320 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Hadfield, R. M., Mardon, H. J., Barlow, D. H. & Kennedy, S. H. Endometriosis in monozygotic twins. Fertil. Steril. 68, 941–942 (1997).

    Article  CAS  PubMed  Google Scholar 

  89. Dyson, M. T. et al. Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLoS Genet. 10, e1004158 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Fassbender, A. et al. Update on biomarkers for the detection of endometriosis. Biomed. Res. Int. 2015, 130854 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Fassbender, A. et al. World endometriosis research foundation endometriosis phenome and biobanking harmonisation project: IV. Tissue collection, processing, and storage in endometriosis research. Fertil. Steril. 102, 1244–1253 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Kupka, M. S. et al. Assisted reproductive technology in Europe, 2010: results generated from European registers by ESHRE†. Hum. Reprod. 29, 2099–2113 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Evans, J. et al. Fresh versus frozen embryo transfer: backing clinical decisions with scientific and clinical evidence. Hum. Reprod. Update 20, 808–821 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Fauser, B. C. & Devroey, P. Reproductive biology and IVF: ovarian stimulation and luteal phase consequences. Trends Endocrinol. Metab. 14, 236–242 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Evans, J., Hannan, N. J., Hincks, C., Rombauts, L. J. & Salamonsen, L. A. Defective soil for a fertile seed? Altered endometrial development is detrimental to pregnancy success. PLoS ONE 7, e53098 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Wilcox, A. J., Baird, D. D. & Weinberg, C. R. Time of implantation of the conceptus and loss of pregnancy. N. Engl. J. Med. 340, 1796–1799 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. Macklon, N. S., van der Gaast, M. H., Hamilton, A., Fauser, B. C. & Giudice, L. C. The impact of ovarian stimulation with recombinant FSH in combination with GnRH antagonist on the endometrial transcriptome in the window of implantation. Reprod. Sci. 15, 357–365 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Shapiro, B. S. et al. Matched-cohort comparison of single-embryo transfers in fresh and frozen-thawed embryo transfer cycles. Fertil. Steril. 99, 389–392 (2013).

    Article  PubMed  Google Scholar 

  99. Edgell, T. A., Rombauts, L. J. & Salamonsen, L. A. Assessing receptivity in the endometrium: the need for a rapid, non-invasive test. Reprod. Biomed. Online 27, 486–496 (2013).

    Article  PubMed  Google Scholar 

  100. Vilella, F. et al. PGE2 and PGF2α concentrations in human endometrial fluid as biomarkers for embryonic implantation. J. Clin. Endocrinol. Metab. 98, 4123–4132 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Ruiz-Alonso, M. et al. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil. Steril. 100, 818–824 (2013).

    Article  PubMed  Google Scholar 

  102. Sirmans, S. M. & Pate, K. A. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin. Epidemiol. 6, 1–13 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Teede, H., Deeks, A. & Moran, L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med. 8, 41 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Bellver, J. et al. Endometrial gene expression in the window of implantation is altered in obese women especially in association with polycystic ovary syndrome. Fertil. Steril. 95, 2335–2341 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Li, X., Feng, Y., Lin, J. F., Billig, H. & Shao, R. Endometrial progesterone resistance and PCOS. J. Biomed. Sci. 21, 2 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Piltonen, T. T. et al. Endometrial stromal fibroblasts from women with polycystic ovary syndrome have impaired progesterone-mediated decidualization, aberrant cytokine profiles and promote enhanced immune cell migration in vitro. Hum. Reprod. 30, 1203–1215 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Matteo, M. et al. Reduced percentage of natural killer cells associated with impaired cytokine network in the secretory endometrium of infertile women with polycystic ovary syndrome. Fertil. Steril. 94, 2222–2227 (2010).

    Article  CAS  PubMed  Google Scholar 

  108. Piltonen, T. T. et al. Mesenchymal stem/progenitors and other endometrial cell types from women with polycystic ovary syndrome (PCOS) display inflammatory and oncogenic potential. J. Clin. Endocrinol. Metab. 98, 3765–3775 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Chang, E. M. et al. Insulin resistance does not affect early embryo development but lowers implantation rate in in vitro maturation-in vitro fertilization-embryo transfer cycle. Clin. Endocrinol. (Oxf.) 79, 93–99 (2013).

    Article  Google Scholar 

  110. Ujvari, D. et al. Lifestyle intervention up-regulates gene and protein levels of molecules involved in insulin signaling in the endometrium of overweight/obese women with polycystic ovary syndrome. Hum. Reprod. 29, 1526–1535 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Jakubowicz, D. J., Iuorno, M. J., Jakubowicz, S., Roberts, K. A. & Nestler, J. E. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 87, 524–529 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Palomba, S. et al. Uterine effects of metformin administration in anovulatory women with polycystic ovary syndrome. Hum. Reprod. 21, 457–465 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Mohsen, I. A., Elkattan, E., Nabil, H. & Khattab, S. Effect of metformin treatment on endometrial vascular indices in anovulatory obese/overweight women with polycystic ovarian syndrome using three-dimensional power doppler ultrasonography. J. Clin. Ultrasound 41, 275–282 (2013).

    Article  PubMed  Google Scholar 

  114. Ito-Yamaguchi, A. et al. Effects of metformin on endocrine, metabolic milieus and endometrial expression of androgen receptor in patients with polycystic ovary syndrome. Gynecol. Endocrinol. 31, 44–47 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Palomba, S. et al. Six weeks of structured exercise training and hypocaloric diet increases the probability of ovulation after clomiphene citrate in overweight and obese patients with polycystic ovary syndrome: a randomized controlled trial. Hum. Reprod. 25, 2783–2791 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Hulchiy, M., Nybacka, A., Sahlin, L. & Hirschberg, A. L. Endometrial expression of estrogen receptors and the androgen receptor in women with polycystic ovary syndrome: a lifestyle intervention study. J. Clin. Endocrinol. Metab. 101, 561–571 (2016).

    Article  CAS  PubMed  Google Scholar 

  117. Li, X. et al. Reversing the reduced level of endometrial GLUT4 expression in polycystic ovary syndrome: a mechanistic study of metformin action. Am. J. Transl. Res. 7, 574–586 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  118. Kollmann, M. et al. Strategies to improve the outcomes of assisted reproduction in women with polycystic ovarian syndrome: a systematic review and meta-analysis. Ultrasound Obstet. Gynecol. http://dx.doi.org/10.1002/uog.15898 (2016).

  119. Feng, L., Lin, X. F., Wan, Z. H., Hu, D. & Du, Y. K. Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: a meta-analysis. Gynecol. Endocrinol. 31, 833–839 (2015).

    Article  CAS  PubMed  Google Scholar 

  120. Al-Biate, M. A. Effect of metformin on early pregnancy loss in women with polycystic ovary syndrome. Taiwan J. Obstet. Gynecol. 54, 266–269 (2015).

    Article  PubMed  Google Scholar 

  121. Gonzalez, D. et al. Loss of WT1 expression in the endometrium of infertile PCOS patients: a hyperandrogenic effect? J. Clin. Endocrinol. Metab. 97, 957–966 (2012).

    Article  CAS  PubMed  Google Scholar 

  122. Gargett, C. E. & Ye, L. Endometrial reconstruction from stem cells. Fertil. Steril. 98, 11–20 (2012).

    Article  PubMed  Google Scholar 

  123. Singh, N. et al. Autologous stem cell transplantation in refractory Asherman's syndrome: a novel cell based therapy. J. Hum. Reprod. Sci. 7, 93–98 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Gargett, C. E. & Healy, D. L. Generating receptive endometrium in Asherman's syndrome. J. Hum. Reprod. Sci. 4, 49–52 (2011).

    PubMed  PubMed Central  Google Scholar 

  125. Lensen, S., Sadler, L. & Farquhar, C. Endometrial scratching for subfertility: everyone's doing it. Hum. Reprod. 31, 1241–1244 (2016).

    Article  CAS  PubMed  Google Scholar 

  126. Nastri, C. O. et al. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database Syst. Rev. http://dx.doi.org/10.1002/14651858.CD009517.pub2 (2012).

  127. Barash, A. et al. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization. Fertil. Steril. 79, 1317–1322 (2003).

    Article  PubMed  Google Scholar 

  128. Werner, M. D. et al. Endometrial disruption does not improve implantation in patients who have failed the transfer of euploid blastocysts. J. Assist. Reprod. Genet. 32, 557–562 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Dain, L. et al. Effect of local endometrial injury on pregnancy outcomes in ovum donation cycles. Fertil. Steril. 102, 048–1054 (2014).

    Article  Google Scholar 

  130. Yeung, T. W. et al. The effect of endometrial injury on ongoing pregnancy rate in unselected subfertile women undergoing in vitro fertilization: a randomized controlled trial. Hum. Reprod. 29, 2474–2481 (2014).

    Article  CAS  PubMed  Google Scholar 

  131. Hayashi, T. et al. Single curettage endometrial biopsy injury in the proliferative phase improves reproductive outcome of subsequent in vitro fertilization-embryo transfer cycle in infertile patients with repeated embryo implantation failure. Clin. Exp. Obstet. Gynecol. 40, 323–326 (2013).

    CAS  PubMed  Google Scholar 

  132. Kitaya, K. et al. Clinical background affecting pregnancy outcome following local endometrial injury in infertile patients with repeated implantation failure. Gynecol. Endocrinol. http://dx.doi.org/10.3109/09513590.2016.1144742 (2016).

  133. Tada, Y. et al. A pilot survey on obstetric complications in pregnant women with a history of repeated embryo implantation failure and those undergoing single local endometrial injury. Clin. Exp. Obstet. Gynecol. 42, 176–178 (2015).

    CAS  PubMed  Google Scholar 

  134. Simón, C. & Bellver, J. Scratching beneath 'The Scratching Case': systematic reviews and meta-analyses, the back door for evidence-based medicine. Hum. Reprod. 29, 1618–1621 (2014).

    Article  PubMed  Google Scholar 

  135. Gibreel, A. et al. Endometrial scratching for women with previous IVF failure undergoing IVF treatment. Gynecol. Endocrinol. 31, 313–316 (2015).

    Article  PubMed  Google Scholar 

  136. Verstraelen, H. et al. Characterisation of the human uterine microbiome in non-pregnant women through deep sequencing of the V1–2 region of the 16S rRNA gene. PeerJ 4, e1602 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Mitchell, C. M. et al. Colonization of the upper genital tract by vaginal bacterial species in nonpregnant women. Am. J. Obstet. Gynecol. 212, 611.e1–611.e9 (2015).

    Article  Google Scholar 

  138. King, A. E., Critchley, H. O. & Kelly, R. W. Presence of secretory leukocyte protease inhibitor in human endometrium and first trimester decidua suggests an antibacterial protective role. Mol. Hum. Reprod. 6, 191–196 (2000).

    Article  CAS  PubMed  Google Scholar 

  139. Fahey, J. V. et al. Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture. Mucosal Immunol. 1, 317–325 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. King, A. E., Critchley, H. O. & Kelly, R. W. Innate immune defences in the human endometrium. Reprod. Biol. Endocrinol. 1, 116 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Fahey, J. V. & Wira, C. R. Effect of menstrual status on antibacterial activity and secretory leukocyte protease inhibitor production by human uterine epithelial cells in culture. J. Infect. Dis. 185, 1606–1613 (2002).

    Article  CAS  PubMed  Google Scholar 

  142. Fung, K. Y. et al. Interferon-ε protects the female reproductive tract from viral and bacterial infection. Science 339, 1088–1092 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Jirtle, R. L. & Skinner, M. K. Environmental epigenomics and disease susceptibility. Nat. Rev. Genet. 8, 253–262 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Munro, S. K., Farquhar, C. M., Mitchell, M. D. & Ponnampalam, A. P. Epigenetic regulation of endometrium during the menstrual cycle. Mol. Hum. Reprod. 16, 297–310 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Taft, R. J., Pang, K. C., Mercer, T. R., Dinger, M. & Mattick, J. S. Non-coding RNAs: regulators of disease. J. Pathol. 220, 126–139 (2010).

    Article  CAS  PubMed  Google Scholar 

  146. Galliano, D. & Pellicer, A. MicroRNA and implantation. Fertil. Steril. 101, 1531–1544 (2014).

    Article  CAS  PubMed  Google Scholar 

  147. Hull, M. L. & Nisenblat, V. Tissue and circulating microRNA influence reproductive function in endometrial disease. Reprod. Biomed. Online 27, 515–529 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Siristatidis, C. et al. Review: microRNAs in assisted reproduction and their potential role in IVF failure. In Vivo 29, 169–175 (2015).

    CAS  PubMed  Google Scholar 

  149. Kang, Y. J. et al. MiR-145 suppresses embryo-epithelial juxtacrine communication at implantation by modulating maternal IGF1R. J. Cell Sci. 128, 804–814 (2015).

    Article  CAS  PubMed  Google Scholar 

  150. Zhang, Q. et al. MicroRNA-181a is involved in the regulation of human endometrial stromal cell decidualization by inhibiting Kruppel-like factor 12. Reprod. Biol. Endocrinol. 13, 23 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Ghazal, S. et al. H19 lncRNA alters stromal cell growth via IGF signaling in the endometrium of women with endometriosis. EMBO Mol. Med. 7, 996–1003 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Wang, H. et al. LncRNA-regulated infection and inflammation pathways associated with pregnancy loss: genome wide differential expression of lncRNAs in early spontaneous abortion. Am. J. Reprod. Immunol. 72, 359–375 (2014).

    Article  CAS  PubMed  Google Scholar 

  153. Raposo, G. & Stoorvogel, W. Extracellular vesicles: exosomes, microvesicles, and friends. J. Cell Biol. 200, 373–383 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Mathivanan, S., Ji, H. & Simpson, R. J. Exosomes: extracellular organelles important in intercellular communication. J. Proteom. 73, 1907–1920 (2010).

    Article  CAS  Google Scholar 

  155. Simons, M. & Raposo, G. Exosomes—vesicular carriers for intercellular communication. Curr. Opin. Cell Biol. 21, 575–581 (2009).

    Article  CAS  PubMed  Google Scholar 

  156. Greening, D. W., Gopal, S. K., Xu, R., Simpson, R. J. & Chen, W. Exosomes and their roles in immune regulation and cancer. Semin. Cell Dev. Biol. 40, 72–81 (2015).

    Article  CAS  PubMed  Google Scholar 

  157. Ng, Y. H. et al. Endometrial exosomes/microvesicles in the uterine microenvironment: a new paradigm for embryo-endometrial cross talk at implantation. PLoS ONE 8, e58502 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Braundmeier, A. G., Dayger, C. A., Mehrotra, P., Belton, R. J. Jr & Nowak, R. A. EMMPRIN is secreted by human uterine epithelial cells in microvesicles and stimulates metalloproteinase production by human uterine fibroblast cells. Reprod. Sci. 19, 1292–1301 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Greening, D. W., Nguyen, H. P., Elgass, K., Simpson, R. J. & Salamonsen, L. A. Human endometrial exosomes contain hormone-specific cargo modulating trophoblast adhesive capacity: insights into endometrial-embryo interactions. Biol. Reprod. 94, 38 (2016).

    Article  CAS  PubMed  Google Scholar 

  160. Gore, A. C. et al. Executive summary to EDC-2: The Endocrine Society's second scientific statement on endocrine-disrupting chemicals. Endocr. Rev. 36, 593–602 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Newbold, R. R. Prenatal exposure to diethylstilbestrol (DES). Fertil. Steril. 89 (Suppl. 2), e55–e56 (2008).

    Article  PubMed  Google Scholar 

  162. Taylor, H. S. Endocrine disruptors affect developmental programming of HOX gene expression. Fertil. Steril. 89 (Suppl. 2), e57–e58 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Rein, D. T., Breidenbach, M. & Curiel, D. T. Current developments in adenovirus-based cancer gene therapy. Future Oncol. 2, 137–143 (2006).

    Article  PubMed  CAS  Google Scholar 

  164. Rein, D. T. et al. Treatment of endometriosis with a VEGF-targeted conditionally replicative adenovirus. Fertil. Steril. 93, 2687–2694 (2010).

    Article  PubMed  Google Scholar 

  165. Lu, X. Y., Wu, D. C., Li, Z. J. & Chen, G. Q. Polymer nanoparticles. Prog. Mol. Biol. Transl. Sci. 104, 299–323 (2011).

    Article  CAS  PubMed  Google Scholar 

  166. Abd Ellah, N. et al. Development of non-viral, trophoblast-specific gene delivery for placental therapy. PLoS ONE 10, e0140879 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Kolonin, M. G. et al. Synchronous selection of homing peptides for multiple tissues by in vivo phage display. FASEB J. 20, 979–981 (2006).

    Article  CAS  PubMed  Google Scholar 

  168. Menkhorst, E. et al. Vaginally administered PEGylated LIF antagonist blocked embryo implantation and eliminated non-target effects on bone in mice. PLoS ONE 6, e19665 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. White, C. et al. Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy. Proc. Natl Acad. Sci. USA 104, 19357–19362 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Hufnagel, D., Li, F., Cosar, E., Krikun, G. & Taylor, H. S. The role of stem cells in the etiology and pathophysiology of endometriosis. Semin. Reprod. Med. 33, 333–340 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Hubbard, S. A. & Gargett, C. E. A cancer stem cell origin for human endometrial carcinoma? Reproduction 140, 23–32 (2010).

    Article  CAS  PubMed  Google Scholar 

  172. Chan, R. W., Kaitu'u-Lino, T. & Gargett, C. E. Role of label retaining cells in estrogen-induced endometrial regeneration. Reprod. Sci. 19, 102–114 (2012).

    Article  CAS  PubMed  Google Scholar 

  173. Chan, R. W. & Gargett, C. E. Identification of label-retaining cells in mouse endometrium. Stem Cells 24, 1529–1538 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful for funding from National Health and Medical Research Council (NHMRC) of Australia Project Grants to J.E., L.A.S., C.E.G., E.D. and E.M. (grants 1081944, 1085435, 1098321 and 1098332), a Senior Principal Research Fellowship to L.A.S. (grant 1002028), Senior Research Fellowships to E.D. (grant 1019826), G.N. (grant 494808) and C.E.G. (grant 1042298), a Cancer Council of Victoria Fellowship to A.W. and the Victorian Infrastructure Support Program and Australian Government NHMRC Independent Research Institute Infrastructure Support Scheme.

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Authors and Affiliations

  1. Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, 3168, Australia

    Jemma Evans, Lois A. Salamonsen, Amy Winship, Ellen Menkhorst, Guiying Nie & Eva Dimitriadis

  2. Department of Molecular and Translational Medicine, Monash University, Clayton, 3800, Australia

    Jemma Evans, Lois A. Salamonsen, Amy Winship, Ellen Menkhorst, Guiying Nie & Eva Dimitriadis

  3. Department of Physiology, Monash University, Clayton, 3800, Australia

    Jemma Evans

  4. Department of Obstetrics and Gynaecology, Monash University, Clayton, 3800, Australia

    Lois A. Salamonsen & Caroline E. Gargett

  5. Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3800, Australia

    Guiying Nie

  6. The Ritchie Centre, Hudson Institute of Medical Research, Clayton, 3168, Australia

    Caroline E. Gargett

  7. Department of Anatomy and Developmental Biology, Monash University, Clayton, 3800, Australia

    Eva Dimitriadis

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All authors researched data for the article. J.E., L.A.S., G.N., C.E.G. and E.D. provided substantial contributions to discussions of the content. All authors contributed to writing the article and to review and/or editing of the manuscript before submission.

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Evans, J., Salamonsen, L., Winship, A. et al. Fertile ground: human endometrial programming and lessons in health and disease. Nat Rev Endocrinol 12, 654–667 (2016). https://doi.org/10.1038/nrendo.2016.116

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