Skip to main content
SpringerLink
Log in

Endometrial Receptivity in Natural and Controlled Ovarian-Stimulated Cycles

  • Chapter
  • First Online:
Biennial Review of Infertility

Abstract

The development of endometrial receptivity is a prerequisite for successful embryonic implantation in mammals. The receptive status is reached only during a short period of time in the midluteal phase, this being maximal 7 days after the endogenous peak of LH (LH+7), named as the window of implantation (WOI). At this time, the endometrial epithelium acquires the functional ability to support blastocyst adhesion. In ART, controlled ovarian stimulation (COS) induces lower implantation rates per embryo transferred than natural or ovum donation cycles, suggesting suboptimal endometrial development due to the abnormal endocrine/paracrine milieu. Researchers have investigated the functional genomics of endometrial receptivity in natural cycles and the impact of COS on the gene expression pattern of the endometrium, even with the use of different drugs such as gonadotrophin-releasing hormone (GnRH) agonists or antagonists. This paper reviews results obtained in different studies to elucidate the changes induced by the different clinical protocols with the objective to introduce a new molecular objective tool to analyze the endometrial receptivity status in natural cycles and to understand the impact of COS in the human endometrium.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. American Society for Reproductive Medicine. Assisted reproductive technology in the United States and Canada: 1999 results generated from the American Society for Reproductive Medicine/Assisted Reproductive Technology Registry. Fertil Steril. 2002;78:5.

    Google Scholar 

  2. Simón C, Cano F, Valbuena D, et al. Clinical evidence for a detrimental effect on uterine receptivity of high serum estradiol levels in high and normal responder patients. Hum Reprod. 1995;10:2432–4.

    PubMed  Google Scholar 

  3. Simón C, García-Velasco J, Valbuena D, et al. Increasing uterine receptivity by decreasing estradiol levels during the preimplantation period in high responders with the use of a follicle-stimulating hormone step-down regimen. Fertil Steril. 1998;70:234–9.

    Article  PubMed  Google Scholar 

  4. Simón C, Domínguez F, Valbuena D, et al. The role of estrogen in uterine receptivity and blastocyst implantation. Trends Endocrinol Metabol. 2003;14:197–9.

    Article  Google Scholar 

  5. Pellicer A, Valbuena D, Cano F, et al. Lower implantation rates in high responders: evidence for an altered endocrine milieu during the preimplantation period. Fertil Steril. 1996;65:1190–5.

    PubMed  CAS  Google Scholar 

  6. Ma WG, Song H, Das SK, et al. Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation. Proc Natl Acad Sci U S A. 2003;100:2963–8.

    Article  PubMed  CAS  Google Scholar 

  7. Paulson RJ, Sauer MV, Lobo RA. Embryo implantation after human in vitro fertilization: importance of endometrial receptivity. Fertil Steril. 1990;53:870–4.

    PubMed  CAS  Google Scholar 

  8. Seif MW, Pearson JM, Ibrahim ZH, et al. Endometrium in in-vitro fertilization cycles: morphological and functional differentiation in the implantation phase. Hum Reprod. 1992;7:6–11.

    PubMed  CAS  Google Scholar 

  9. Psychoyos A. The implantation window; basic and clinical aspects. In: Mori T, Aono T, Tominaga T, Hiroi M, editors. Perspectives on assisted reproduction. Ares-Serono symposium, vol. 4. Roma; 1994. p. 57–63.

    Google Scholar 

  10. Kolb BA, Paulson RJ. The luteal phase of cycles ­utilizing controlled ovarian hyperstimulation and the possible impact of this hyperstimulation on embryo implantation. Am J Obstet Gynecol. 1997;176:1262–7.

    Article  PubMed  CAS  Google Scholar 

  11. Kolibianakis EM, Bourgain C, Platteau P, et al. Abnormal endometrial development occurs during the luteal phase of nonsupplemented donor cycles treated with recombinant follicle stimulating hormone and gonadotropin-releasing hormone antagonists. Fertil Steril. 2003;80:464–6.

    Article  PubMed  Google Scholar 

  12. Nikas G, Develioglu OH, Toner JP, et al. Endometrial pinopodes indicate a shift in the window of receptivity in IVF cycles. Hum Reprod. 1999;14:787–92.

    Article  PubMed  CAS  Google Scholar 

  13. Giudice LC. Elucidating endometrial function in the postgenomic era. Hum Reprod Update. 2003;9:223–35.

    Article  PubMed  CAS  Google Scholar 

  14. Develioglu OH, Hsiu JG, Nikas G, et al. Endometrial estrogen and progesterone receptor and pinopode expression in stimulated cycles of oocyte donors. Fertil Steril. 1999;71:1040–7.

    Article  PubMed  CAS  Google Scholar 

  15. Simón C, Mercader A, Francés A, et al. Hormonal regulation of serum and endometrial IL-1α, IL-1β and IL-1Ra: IL-1 endometrial microenvironment of the human embryo at the apposition phase under physiological and supraphysiological steroid level conditions. J Reprod Immunol. 1996;31:165–84.

    Article  PubMed  Google Scholar 

  16. Okada H, Nakajima T, Yoshimura T, et al. Microarray analysis of genes controlled by progesterone in human endometrial stromal cells in vitro. Gynecol Endocrinol. 2003;17:271–80.

    PubMed  CAS  Google Scholar 

  17. Rossi M, Sharkey AM, Vigano P, et al. Identification of genes regulated by interleukin-1beta in human endometrial stromal cells. Reproduction. 2005;130:721–9.

    Article  PubMed  CAS  Google Scholar 

  18. White CA, Dimitriadis E, Sharkey AM, Salamonsen LA. Interleukin-11 inhibits expression of insulin-like growth factor binding protein-5 mRNA in decidualizing human endometrial stromal cells. Mol Hum Reprod. 2005;11:649–58.

    Article  PubMed  CAS  Google Scholar 

  19. Krikun G, Schatz F, Taylor R, et al. Endometrial endothelial cell steroid receptor expression and steroid effects on gene expression. J Clin Endocrinol Metabol. 2005;90:1812–8.

    Article  CAS  Google Scholar 

  20. Dockery B, Burke MJ. The fine structure of mature human endometrium. In: Aplin JD, Fazleabas AT, Glasser SR, Giudice LC, editors. The endometrium: molecular, cellular and clinical perspectives. 2nd ed. London: Informa Healthcare; 2008. p. 46–65.

    Chapter  Google Scholar 

  21. Wynn RM. The human endometrium: cyclic and gestational changes. In: Wynn RM, Jollie WP, editors. Biology of the uterus. 2nd ed. New York: Plenum; 1989. p. 289–332.

    Google Scholar 

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

    Google Scholar 

  23. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122:262–3.

    PubMed  CAS  Google Scholar 

  24. Ponnampalam AP, Weston GC, Trajstman AC, et al. Molecular classification of human endometrial cycle stages by transcriptional profiling. Mol Hum Reprod. 2004;10:879–93.

    Article  PubMed  CAS  Google Scholar 

  25. 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;147:1097–121.

    Article  PubMed  CAS  Google Scholar 

  26. Schena M, Shalon D, Davis RW, Brown PO. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science. 1995;270:467–70.

    Article  PubMed  CAS  Google Scholar 

  27. Popovici RM, Kao LC, Giudice LC. Discovery of new inducible genes in in vitro decidualized human endometrial stromal cells using microarray technology. Endocrinology. 2000;141:3510–3.

    Article  PubMed  CAS  Google Scholar 

  28. Brar AK, Handwerger S, Kessler CA, Aronow BJ. Gene induction and categorical reprogramming during in vitro human endometrial fibroblast decidualization. Physiol Genomics. 2001;7:135–48.

    PubMed  CAS  Google Scholar 

  29. Tierney EP, Tulac S, Huang STJ, Giudice LC. Sequential induction of gene expression during human endometrial stromal cell decidualization using microarray expression profile analysis. In: Proceedings of the 84th annual meeting of the endocrine society, vol. 537. San Francisco; 2002, p. P3–192.

    Google Scholar 

  30. Carson DD, Lagow E, Thathiah A, et al. Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening. Mol Hum Reprod. 2002;8:871–9.

    Article  PubMed  CAS  Google Scholar 

  31. Kao LC, Tulac S, Lobo S, et al. Global gene profiling in human endometrium during the window of implantation. Endocrinology. 2002;143:2119–38.

    Article  PubMed  CAS  Google Scholar 

  32. Borthwick JM, Charnock-Jones DS, Tom BD, et al. Determination of the transcript profile of human endometrium. Mol Hum Reprod. 2003;9:19–33.

    Article  PubMed  CAS  Google Scholar 

  33. Riesewijk A, Martin J, van Os R, et al. Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology. Mol Hum Reprod. 2003;9:253–64.

    Article  PubMed  CAS  Google Scholar 

  34. Mirkin S, Arslan M, Churikov D, et al. In search of candidate genes critically expressed in the human endometrium during the window of implantation. Hum Reprod. 2005;20:2104–17.

    Article  PubMed  CAS  Google Scholar 

  35. Horcajadas JA, Riesewijk A, Martin J, et al. Global gene expression profiling of human endometrial receptivity. J Reprod Immunol. 2004;63:41–9.

    Article  PubMed  CAS  Google Scholar 

  36. Horcajadas JA, Pellicer A, Simon C. Wide genomic analysis of human endometrial receptivity: new times, new opportunities. Hum Reprod Update. 2007;13:77–86.

    Article  PubMed  CAS  Google Scholar 

  37. Aplin J. Embryo implantation: the molecular mechanisms remain elusive. RBM Online. 2006;13:833–9.

    PubMed  CAS  Google Scholar 

  38. Horcajadas JA, Riesewijk A, Polman J, et al. Effect of controlled ovarian hyperstimulation in IVF on endometrial gene expression profiles. Mol Hum Reprod. 2005;11:195–205.

    Article  PubMed  CAS  Google Scholar 

  39. Mirkin S, Nikas G, Hsiu JG, et al. Gene expression profiles and structural/functional features of the peri-implantation endometrium in natural and gonadotropin-stimulated cycles. J Clin Endocrinol Metab. 2004;89:5742–52.

    Article  PubMed  CAS  Google Scholar 

  40. Simón C, Bellver J, Vidal C, et al. Similar endometrial development in oocyte donors treated with high- or low-dose GnRH-antagonist compared to GnRH-agonist treatment and natural cycles. Hum Reprod. 2005;12:3318–27.

    Article  Google Scholar 

  41. Lee Y-L, Liu Y, Ng P-Y, et al. Aberrant expression of angiopoietins-1 and -2 and vascular growth factor-A in peri-implantation endometrium after gonadotrophin stimulation. Hum Reprod. 2008;23:894–903.

    Article  PubMed  CAS  Google Scholar 

  42. Liu Y, Lee K-F, Ng E H-Y, et al. Gene expression profiling of human peri-implantation endometria between natural and stimulated cycles. Fertil Steril. 2008;90:2152–64.

    Article  PubMed  CAS  Google Scholar 

  43. Haouzi D, Assou S, Mahmoud K, et al. Gene expression profile of human endometrial receptivity: comparison between natural and stimulated cycles for the same patients. Hum Reprod. 2009;24:1436–45.

    Article  PubMed  CAS  Google Scholar 

  44. Haouzi D, Assou S, Dechanet C, et al. Controlled ovarian hyperstimulation for in vitro fertilization alters endometrial receptivity in humans: protocol effects. Biol Reprod. 2010;82:679–86.

    Article  PubMed  CAS  Google Scholar 

  45. Horcajadas JA, Mínguez P, Dopazo J, et al. Controlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications. J Clin Endocrinol Metab. 2008;93:4500–10.

    Article  PubMed  CAS  Google Scholar 

  46. Al-Shahrour F, Diaz-Uriarte R, Dopazo J. FatiGO: a web tool for finding significant associations of gene ontology terms with groups of genes. Bioinformatics. 2004;20:578–80.

    Article  PubMed  CAS  Google Scholar 

  47. Bourgain C, Devroey P. Histologic and functional aspects of the endometrium in the implantatory phase. Gynecol Obstet Invest. 2007;64:131–3.

    Article  PubMed  Google Scholar 

  48. Boomsma CM, Kavelaars A, Eijkemans MJ, et al. Cytokine profiling in endometrial secretions: a non-invasive window on endometrial receptivity. Reprod Biomed Online. 2009;18:85–94.

    Article  PubMed  CAS  Google Scholar 

  49. Murray MJ, Meyer WR, Zaino RJ, et al. A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. Fertil Steril. 2004;81:1333–43.

    Article  PubMed  Google Scholar 

  50. Coutifaris C, Myers ER, Guzick DS, et al. Histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril. 2004;82:1264–72.

    Article  PubMed  Google Scholar 

  51. Díaz-Gimeno P, Horcajadas JA, Martínez-Conejero JA, et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril. 2011;95:50–60.

    Article  PubMed  Google Scholar 

  52. Landgren BM, Johannisson E, Stavreus-Evers A, et al. A new method to study the process of implantation of a human blastocyst in vitro. Fertil Steril. 1996;65:1067–70.

    PubMed  CAS  Google Scholar 

  53. Martin JC, Jasper D, Valbuena D, et al. Increased adhesiveness in cultured endometrial-derived cells is related to the absence of moesin expression. Biol Reprod. 2000;63:1370–6.

    Article  PubMed  CAS  Google Scholar 

  54. Simón C, Mercader A, Garcia-Velasco J, et al. Coculture of human embryos with autologous human endometrial epithelial cells in patients with implantation failure. J Clin Endocrinol Metab. 1999;84:2638–46.

    Article  PubMed  Google Scholar 

  55. Barmat LI, Liu HC, Spandorfer SD, et al. Autologous endometrial co-culture in patients with repeated failures of implantation after in vitro fertilization-embryo transfer. J Assist Reprod Genet. 1999;16:121–7.

    Article  PubMed  CAS  Google Scholar 

  56. Mardon H, Grewal S, Mills K. Experimental models for investigating implantation of the human embryo. Semin Reprod Med. 2007;25:410–7.

    Article  PubMed  Google Scholar 

  57. Dey SK, Lim H, Das SK, et al. Molecular cues to implantation. Endocr Rev. 2004;25:341–73.

    Article  PubMed  CAS  Google Scholar 

  58. Yoshinaga K. Review of factors essential for blastocyst implantation for their modulating effects on the maternal immune system. Semin Cell Dev Biol. 2008;19:161–9.

    Article  PubMed  CAS  Google Scholar 

  59. Martínez-Conejero JA, Simón C, Pellicer A, Horcajadas JA. Is ovarian stimulation detrimental to the endometrium? RBM Online. 2007;15:45–50.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Fundación IVI-Instituto Universitario IVI-University of Valencia, Valencia, 46015, Spain

    Carlos Simón

  2. Valencia Stem Cell Bank, Centro de Investigaciones Príncipe Felipe, Valencia, 46012, Spain

    Carlos Simón

Authors
  1. José A. Horcajadas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. José A. Martínez-Conejero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlos Simón
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlos Simón .

Editor information

Editors and Affiliations

  1. Brigham & Women's Hospital, Dept. Obstetrics & Gynecology, Harvard Medical School, Francis St. 75, Boston, 02115, Massachusetts, USA

    Catherine Racowsky

  2. Weill Cornell Medical Center, Dept. Urology, New York Presbyterian Hospital, East 68th St. 525, New York, 10021, New York, USA

    Peter N. Schlegel

  3. , Department of Reproductive Medicine, University Medical Center Utrecht, PO Box 85500, Utrecht, 3508 GA, Netherlands

    Bart C. Fauser

  4. Departments of Surgery (Urology), Obstetrics & Gynecology & Physiology, Andrology and IVF Laboratories, Arapeen Dr. 675, Salt Lake City, 84108, Utah, USA

    Douglas T. Carrell

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Horcajadas, J.A., Martínez-Conejero, J.A., Simón, C. (2011). Endometrial Receptivity in Natural and Controlled Ovarian-Stimulated Cycles. In: Racowsky, C., Schlegel, P., Fauser, B., Carrell, D. (eds) Biennial Review of Infertility. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8456-2_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-8456-2_5

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4419-8455-5

  • Online ISBN: 978-1-4419-8456-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation