Skip to main content
SpringerLink
Log in

Aktueller Wissensstand zum Zeitfenster der Implantation – wie lange steht es wirklich offen?

Current state of knowledge on the time window of implantation—How long does it really stay open?

  • Leitthema
  • Published:
Gynäkologische Endokrinologie Aims and scope

Zusammenfassung

Die Implantation eines Embryos im Endometrium ist ein komplexer Prozess. In der Lutealphase des Menstruationszyklus besteht nur ein begrenztes Zeitfenster, in dem die Nidation stattfinden kann: das sogenannte Implantationsfenster. Die Veränderungen des Endometriums um den Zeitpunkt der Implantation sind bereits in vielen Aspekten verstanden. Doch ist es bisher nicht gelungen, dieses Wissen auch in valide klinische Tests zur Bestimmung der Rezeptivität zu übersetzen und Behandlungsmethoden für die suboptimale Endometriumrezeptivität zu entwickeln. Viele Surrogatparameter der endometrialen Rezeptivität wurden vorgeschlagen, sie besitzen jedoch insgesamt eine schlechte prognostische Genauigkeit für den Eintritt einer klinischen Schwangerschaft in Frisch- und Auftauzyklen. Es gilt zu berücksichtigen, dass eine ovarielle Stimulation die endometriale Rezeptivität beeinflusst. Auch ist der Zeitpunkt der Embryoübertragung in Abhängigkeit vom angewendeten Protokoll möglicherweise von Bedeutung. Daneben müssen Störungen des Uterus berücksichtigt werden, die die endometriale Rezeptivität beeinflussen und mit Implantationsversagen assoziiert sein können. Generell sind verlässlichere Marker der endometrialen Rezeptivität und robustere klinische Studien notwendig.

Abstract

The implantation of an embryo in the endometrium is a complex process. In the luteal phase of the menstrual cycle there is only a limited time window in which nidation can take place, the so-called implantation window. The changes in the endometrium around the time of implantation are already known in many aspects; however, it has not yet been possible to convert this knowledge into valid clinical tests to determine receptivity and to develop treatment methods for suboptimal endometrial receptivity. Many surrogate parameters for endometrial receptivity have been proposed, all of which have a poor prognostic accuracy for the onset of a clinical pregnancy in fresh and thaw cycles. It must be considered that ovarian stimulation influences the endometrial receptivity. The timing of the embryo transfer depending on the protocol used is also possibly crucial for success. In addition, disorders of the uterus which influence the endometrial receptivity and could be associated with failure of implantation must also be considered. In general, reliable markers of endometrial receptivity and more robust clinical studies are necessary.

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

Abb. 1

Literatur

  1. Karsch FJ, Weick RF, Butler WR, Dierschke DJ, Krey LC, Weiss G et al (1973) Induced LH surges in the rhesus monkey: strength-duration characteristics of the estrogen stimulus. Endocrinology 92(6):1740–1747

    Article  CAS  PubMed  Google Scholar 

  2. Frydman R, Testart J, Fernandez H, Arvis P, Belaisch JC (1982) Prediction of ovulation. J Gynecol Obstet Biol Reprod 11(7):793–799

    CAS  Google Scholar 

  3. Testart J, Frydman R, Feinstein MC, Thebault A, Roger M, Scholler R (1981) Interpretation of plasma luteinizing hormone assay for the collection of mature oocytes from women: definition of a luteinizing hormone surge-initiating rise. Fertil Steril 36(1):50–54. https://doi.org/10.1016/S0015-0282(16)45617-7

    Article  CAS  PubMed  Google Scholar 

  4. Groenewoud ER, Macklon NS, Cohlen BJ, Al-Oraiby A, Brinkhuis EA, Broekmans FJM et al (2017) The effect of elevated progesterone levels before HCG triggering in modified natural cycle frozen-thawed embryo transfer cycles. Reprod Biomed Online 34(5):546–554. https://doi.org/10.1016/j.rbmo.2017.02.008

    Article  CAS  PubMed  Google Scholar 

  5. Kosmas IP, Tatsioni A, Fatemi HM, Kolibianakis EM, Tournaye H, Devroey P (2007) Human chorionic gonadotropin administration vs. luteinizing monitoring for intrauterine insemination timing, after administration of clomiphene citrate: a meta-analysis. Fertil Steril 87(3):607–612

    Article  CAS  PubMed  Google Scholar 

  6. Andersen AG, Als-nielsen B, Hornnes PJ, Andersen LF (1995) Time interval from human chorionic gonadotrophin (HCG) injection to follicular rupture. Hum Reprod 10(12):3202–3205

    Article  CAS  PubMed  Google Scholar 

  7. Hoff JD, Quigley ME, Yen SSC (1983) Hormonal dynamics at midcycle: a reevaluation. J Clin Endocrinol Metab 57(4):792–796

    Article  CAS  PubMed  Google Scholar 

  8. Direito A, Bailly S, Mariani A, Ecochard R (2013) Relationships between the luteinizing hormone surge and other characteristics of the menstrual cycle in normally ovulating women. Fertil Steril. https://doi.org/10.1016/j.fertnstert.2012.08.047

    Article  PubMed  Google Scholar 

  9. Alliende ME (2002) Mean versus individual hormonal profiles in the menstrual cycle. Fertil Steril 78(1):90–95

    Article  PubMed  Google Scholar 

  10. Park SJ, Goldsmith LT, Skurnick JH, Wojtczuk A, Weiss G (2007) Characteristics of the urinary luteinizing hormone surge in young ovulatory women. Fertil Steril 88(3):684–690

    Article  CAS  PubMed  Google Scholar 

  11. Evans J, Salamonsen LA, Winship A, Menkhorst E, Nie G, Gargett CE et al (2016) Fertile ground: human endometrial programming and lessons in health and disease. Nat Rev Endocrinol 12(11):654–667. https://doi.org/10.1038/nrendo.2016.116

    Article  CAS  PubMed  Google Scholar 

  12. Shahbazi MN (2020) Mechanisms of human embryo development: from cell fate to tissue shape and back. Development. https://doi.org/10.1242/dev.190629

    Article  PubMed  PubMed Central  Google Scholar 

  13. Macklon NS, Brosens JJ (2014) Minireview the human endometrium as a sensor of embryo quality 1. Biol Reprod 91:1–8

    Article  Google Scholar 

  14. Weimar CHE, Macklon NS, Uiterweer EDP, Brosens JJ, Gellersen B (2013) The motile and invasive capacity of human endometrial stromal cells : implications for normal and impaired reproductive function. Hum Reprod Update 19(5):542–557

    Article  CAS  PubMed  Google Scholar 

  15. Weimar CHE, Kavelaars A, Brosens JJ, Gellersen B, de Vreeden-Elbertse JMT, Heijnen CJ et al (2012) Endometrial stromal cells of women with recurrent miscarriage fail to discriminate between high- and low-quality human embryos. PLoS One 7(7):1–8

    Article  Google Scholar 

  16. Diedrich K, Fauser BCJM, Devroey P, Griesinger G (2007) The role of the endometrium and embryo in human implantation. Hum Reprod Update 13(4):365–377

    Article  CAS  PubMed  Google Scholar 

  17. Wilcox AJ, Baird DD, Weinberg CR (1999) Time of implantation of the conceptus and loss of pregnancy. Obstet Gynecol Surv 54(11):705

    Article  Google Scholar 

  18. Navot D, Scott RT, Droesch K, Veeck LL, Liu HC, Rosenwaks Z (1991) The window of embryo transfer and the efficiency of human conception in vitro. Fertil Steril 55(1):114–118

    Article  CAS  PubMed  Google Scholar 

  19. Kolibianakis E, Bourgain C, Albano C, Osmanagaoglu K, Smitz J, Van Steirteghem A et al (2002) Effect of ovarian stimulation with recombinant follicle-stimulating hormone, gonadotropin releasing hormone antagonists, and human chorionic gonadotropin on endometrial maturation on the day of oocyte pick-up. Fertil Steril 78(5):1025–1029

    Article  PubMed  Google Scholar 

  20. Ubaldi F, Bourgain C, Tournaye H, Smitz J, Van Steirteghem A, Devroey P (1997) Endometrial evaluation by aspiration biopsy on the day of oocyte retrieval in the embryo transfer cycles in patients with serum progesterone rise during the follicular phase. Fertil Steril 67(3):521–526

    Article  CAS  PubMed  Google Scholar 

  21. Craciunas L, Gallos I, Chu J, Bourne T, Quenby S, Brosens JJ et al (2019) Conventional and modern markers of endometrial receptivity: a systematic review and meta-analysis. Hum Reprod Update 25(2):202–223

    Article  CAS  PubMed  Google Scholar 

  22. Karlsson B, Granberg S, Ridell B, Wikland M (1994) Endometrial thickness as measured by transvaginal sonography: interobserver variation. Ultrasound Obstet Gynecol 4(4):320–325

    Article  CAS  PubMed  Google Scholar 

  23. Kasius A, Smit JG, Torrance HL, Eijkemans MJC, Mol BW, Opmeer BC et al (2014) Endometrial thickness and pregnancy rates after IVF: a systematic review and meta-analysis. Hum Reprod Update 20(4):530–541

    Article  PubMed  Google Scholar 

  24. Weiss NS, van Vliet MN, Limpens J, Hompes PGA, Lambalk CB, Mochtar MH et al (2017) Endometrial thickness in women undergoing IUI with ovarian stimulation. How thick is too thin? A systematic review and meta-analysis. Hum Reprod 32(5):1009–1018

    Article  CAS  PubMed  Google Scholar 

  25. Hershko-Klement A, Tepper R (2016) Ultrasound in assisted reproduction: a call to fill the endometrial gap. Fertil Steril 105(6):1394–1402.e4. https://doi.org/10.1016/j.fertnstert.2016.04.012

    Article  PubMed  Google Scholar 

  26. Wang J, Xia F, Zhou Y, Wei X, Zhuang Y, Huang Y (2018) Association between endometrial/ subendometrial vasculature and embryo transfer outcome: a meta-analysis and subgroup analysis. J Ultrasound Med 37(1):149–163

    Article  PubMed  Google Scholar 

  27. Santi A, Felser R, Bersinger NA, Wunder DM, McKinnon B, Mueller MD (2012) The hysteroscopic view of infertility: the mid-secretory endometrium and treatment success towards pregnancy. Gynecol Surg 9(2):147–150

    Article  Google Scholar 

  28. Li S, Pan P, Yao S, Feng M, Wu J, Su Y et al (2010) Hysteroscopic appearence of midsecretory endometrium in relation to pinopodes expression and the reproductive outcome in infertile women. J Reprod Contracept 21(1):17–26. https://doi.org/10.1016/S1001-7844(10)60010-7

    Article  Google Scholar 

  29. Sakumoto T, Inafuku K, Miyara M, Takamiyagi N, Miyake A, Shinkawa T et al (1992) Hysteroscopic assessment of midsecretory-phase endometrium, with special reference to the luteal-phase defect. Horm Res 37(1):48–52

    Article  PubMed  Google Scholar 

  30. Masamoto H, Nakama K, Kanazawa K (2000) Hysteroscopic appearance of the mid-secretory endometrium: relationship to early phase pregnancy outcome after implantation. Hum Reprod 15(10):2112–2118

    Article  CAS  PubMed  Google Scholar 

  31. Kliman HJ (2020) Noyes, Hertig, and Rock revisited. F S Rep 1(1):2–4

    PubMed  PubMed Central  Google Scholar 

  32. Murray MJ, Meyer WR, Zaino RJ, Lessey BA, Novotny DB, Ireland K et al (2004) A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. Fertil Steril 81(5):1333–1343

    Article  PubMed  Google Scholar 

  33. Usadi RS, Murray MJ, Bagnell RC, Fritz MA, Kowalik AI, Meyer WR et al (2003) Temporal and morphologic characteristics of pinopod expression across the secretory phase of the endometrial cycle in normally cycling women with proven fertility. Fertil Steril 79(4):970–974

    Article  PubMed  Google Scholar 

  34. Stavreus-Evers A, Nikas G, Sahlin L, Eriksson H, Landgren BM (2001) Formation of pinopodes in human endometrium is associated with the concentrations of progesterone and progesterone receptors. Fertil Steril 76(4):782–791

    Article  CAS  PubMed  Google Scholar 

  35. Sudoma I, Goncharova Y, Zukin V (2011) Optimization of cryocycles by using pinopode detection in patients with multiple implantation failure: preliminary report. Reprod Biomed Online 22(6):590–596. https://doi.org/10.1016/j.rbmo.2011.02.004

    Article  CAS  PubMed  Google Scholar 

  36. Nikas G, Develioglu OH, Toner JP, Jones HW (1999) Endometrial pinopodes indicate a shift in the window of receptivity in IVF cycles. Hum Reprod 14(3):787–792

    Article  CAS  PubMed  Google Scholar 

  37. Nikas G, Drakakis P, Loutradis D, Mara-skoufari C, Koumantakis E, Michalas S et al (1995) Implantation: uterine pinopodes as markers of the „nidation window“ in cycling women receiving exogenous oestradiol and progesterone. Hum Reprod 10(5):1208–1213

    Article  CAS  PubMed  Google Scholar 

  38. Quinn C, Ryan E, Claessens EA, Greenblatt E, Hawrylyshyn P, Cruickshank B et al (2007) The presence of pinopodes in the human endometrium does not delineate the implantation window. Fertil Steril 87(5):1015–1021

    Article  PubMed  Google Scholar 

  39. Quinn CE, Casper RF (2009) Pinopodes: a questionable role in endometrial receptivity. Hum Reprod Update 15(2):229–236

    Article  CAS  PubMed  Google Scholar 

  40. Pantos K, Nikas G, Makrakis E, Stavrou D, Karantzis P, Grammatis M (2004) Clinical value of endometrial pinopodes detection in artificial donation cycles. Reprod Biomed Online 9(1):86–90. https://doi.org/10.1016/S1472-6483(10)62115-3

    Article  PubMed  Google Scholar 

  41. Jin XY, Zhao LJ, Luo DH, Liu L, Dai YD, Hu XX et al (2017) Pinopode score around the time of implantation is predictive of successful implantation following frozen embryo transfer in hormone replacement cycles. Hum Reprod 32(12):2394–2403

    Article  CAS  PubMed  Google Scholar 

  42. Díaz-Hernández I, Alecsandru D, García-Velasco JA, Domínguez F (2021) Uterine natural killer cells: from foe to friend in reproduction. Hum Reprod Update 27(4):720–746

    Article  PubMed  Google Scholar 

  43. Kuon RJ, Weber M, Heger J, Santillán I, Vomstein K, Bär C et al (2017) Uterine natural killer cells in patients with idiopathic recurrent miscarriage. Am J Reprod Immunol 78(4):1–4

    Article  Google Scholar 

  44. El-Azzamy H, Dambaeva SV, Katukurundage D, Salazar Garcia MD, Skariah A, Hussein Y et al (2018) Dysregulated uterine natural killer cells and vascular remodeling in women with recurrent pregnancy losses. Am J Reprod Immunol 80(4):1–9

    Article  Google Scholar 

  45. Michimata T, Ogasawara MS, Tsuda H, Suzumori K, Aoki K, Sakai M et al (2002) Distributions of endometrial NK cells, B cells, T cells, and Th2/Tc2 cells fail to predict pregnancy outcome following recurrent abortion. Am J Reprod Immunol 47(4):196–202

    Article  PubMed  Google Scholar 

  46. Shimada S, Kato EH, Morikawa M, Iwabuchi K, Nishida R, Kishi R et al (2004) No difference in natural killer or natural killer T‑cell population, but aberrant T‑helper cell population in the endometrium of women with repeated miscarriage. Hum Reprod 19(4):1018–1024

    Article  CAS  PubMed  Google Scholar 

  47. Tuckerman E, Laird SM, Prakash A, Li TC (2007) Prognostic value of the measurement of uterine natural killer cells in the endometrium of women with recurrent miscarriage. Hum Reprod 22(8):2208–2213

    Article  CAS  PubMed  Google Scholar 

  48. Díaz-Gimeno P, Ruiz-Alonso M, Blesa D, Bosch N, Martínez-Conejero JA, Alamá P et al (2013) The accuracy and reproducibility of the endometrial receptivity array is superior to histology as a diagnostic method for endometrial receptivity. Fertil Steril 99(2):508–517

    Article  PubMed  Google Scholar 

  49. Hashimoto T, Koizumi M, Doshida M, Toya M, Sagara E, Oka N et al (2017) Efficacy of the endometrial receptivity array for repeated implantation failure in Japan: a retrospective, two-centers study. Reprod Med Biol 16(3):290–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bassil R, Casper R, Samara N, Hsieh TB, Barzilay E, Orvieto R et al (2018) Does the endometrial receptivity array really provide personalized embryo transfer? J Assist Reprod Genet 35(7):1301–1305

    Article  PubMed  PubMed Central  Google Scholar 

  51. Koot YEM, van Hooff SR, Boomsma CM, van Leenen D, Groot Koerkamp MJA, Goddijn M et al (2016) An endometrial gene expression signature accurately predicts recurrent implantation failure after IVF. Sci Rep 6:1–12

    Article  Google Scholar 

  52. Evans J, Hannan NJ, Edgell TA, Vollenhoven BJ, Lutjen PJ, Osianlis T et al (2014) Fresh versus frozen embryo transfer: backing clinical decisions with scientific and clinical evidence. Hum Reprod Update 20(6):808–821

    Article  CAS  PubMed  Google Scholar 

  53. Jones HWJ (1996) What has happened? Where are we? Hum Reprod 11(1):7–31

    Article  PubMed  Google Scholar 

  54. van der Linden M, Buckingham K, Farquhar C, Kremer JAM, Metwally M (2015) Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev 2015(7):CD9154

    PubMed  PubMed Central  Google Scholar 

  55. Kolibianakis EM, Devroey P (2002) The luteal phase after ovarian stimulation. Reprod Biomed Online 5(1):26–35. https://doi.org/10.1016/S1472-6483(11)60214-9

    Article  PubMed  Google Scholar 

  56. Sohn SH, Penzias AS, Emmi AM, Dubey AK, Layman LC, Reindollar RH et al (1999) Administration of progesterone before oocyte retrieval negatively affects the implantation rate. Fertil Steril 71(1):11–14

    Article  CAS  PubMed  Google Scholar 

  57. Zaat T, Zagers M, Mol F, Goddijn M, van Wely M, Mastenbroek S (2021) Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.cd011184.pub3

    Article  PubMed  PubMed Central  Google Scholar 

  58. Bosch E, Labarta E, Crespo J, Simón C, Remohí J, Jenkins J et al (2010) Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles. Hum Reprod 25(8):2092–2100

    Article  CAS  PubMed  Google Scholar 

  59. Glujovsky D, Pesce R, Sueldo C, Quinteiro Retamar AM, Hart RJ, Ciapponi A (2020) Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.cd006359.pub3

    Article  PubMed  PubMed Central  Google Scholar 

  60. Mumusoglu S, Polat M, Ozbek IY, Bozdag G, Papanikolaou EG, Esteves SC, Humaidan P, Yarali H (2021) Preparation of the endometrium for frozen embryo transfer: a systematic review. Front Endocrinol 12:688237. https://doi.org/10.3389/fendo.2021.688237

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sektion für gynäkologische Endokrinologie und Reproduktionsmedizin, Universitäres Kinderwunschzentrum Lübeck und Manhagen, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Deutschland

    R. A. F. Hiller, A. Schultze-Mosgau, M. Depenbusch, T. K. Eggersmann & G. Griesinger

  2. Sektion für gynäkologische Endokrinologie und Reproduktionsmedizin, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Deutschland

    R. A. F. Hiller

Authors
  1. R. A. F. Hiller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Schultze-Mosgau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Depenbusch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. K. Eggersmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Griesinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. A. F. Hiller.

Ethics declarations

Interessenkonflikt

R.A.F. Hiller erhielt Honorare und/oder nichtfinanzielle Unterstützung von Merck Serono, Gedeon Richter und Organon. A. Schultze-Mosgau erhielt Honorare und/oder nichtfinanzielle Unterstützung von MSD, Ferring, Merck Serono, TEVA, Gedeon Richter und Theramex. M. Depenbusch erhielt Honorare und/oder nichtfinanzielle Unterstützung von Merck Serono. T.K. Eggersmann erhielt Honorare und/oder nichtfinanzielle Unterstützung von Ferring, Merck Serono, Gedeon Richter, Abbott, Besins Healthcare und IBSA. G. Griesinger erhielt nichtfinanzielle Unterstützung von Abbott, MSD, Ferring, Merck Serono, IBSA, Finox, TEVA, Glycotope und Gedeon Richter sowie persönliche Honorare von MSD, Ferring, Merck Serono, IBSA, Finox, TEVA, Glycotope, Vitrolife, Cooper, NMC Healthcare, ReprodWissen GmbH, Biosilu, Gedeon Richter und ZIVA.

Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Additional information

Redaktion

Georg Griesinger, Lübeck

Wolfgang Küpker, Baden-Baden

Hinweis des Verlags

Der Verlag bleibt in Hinblick auf geografische Zuordnungen und Gebietsbezeichnungen in veröffentlichten Karten und Institutsadressen neutral.

figure qr

QR-Code scannen & Beitrag online lesen

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hiller, R.A.F., Schultze-Mosgau, A., Depenbusch, M. et al. Aktueller Wissensstand zum Zeitfenster der Implantation – wie lange steht es wirklich offen?. Gynäkologische Endokrinologie 22, 102–110 (2024). https://doi.org/10.1007/s10304-024-00562-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10304-024-00562-5

Schlüsselwörter

Keywords

Search

Navigation