Customized Frozen Embryo Transfer after Identification of the Receptivity Window with a Transcriptomic Approach Improves the Implantation and Live Birth Rates in Patients with Repeated Implantation Failure

Delphine Haouzi, Frida Entezami, Antoine Torre, Charlène Innocenti, Yannick Antoine, Charlotte Mauries, Claire Vincens, Sophie Bringer-Deutsch, Anna Gala, Alice Ferrieres-Hoa, Jeanine Ohl, Beatriz Gonzalez Marti, Sophie Brouillet, Samir Hamamah, Delphine Haouzi, Frida Entezami, Antoine Torre, Charlène Innocenti, Yannick Antoine, Charlotte Mauries, Claire Vincens, Sophie Bringer-Deutsch, Anna Gala, Alice Ferrieres-Hoa, Jeanine Ohl, Beatriz Gonzalez Marti, Sophie Brouillet, Samir Hamamah

Abstract

The aim of this prospective study was to evaluate outcome benefits expected in repeated implantation failure (RIF) patients (n = 217) after customized embryo transfer based upon identification of the receptivity window by transcriptomic approach using the Win-Test. In this test, the expression of 11 endometrial genes known to be predictive of endometrial receptivity is assessed by RT-PCR in biopsies collected during the implantation window (6-9 days after the spontaneous luteinizing hormone surge during natural cycles, 5-9 days after progesterone administration during hormone replacement therapy cycles). Then, patients underwent either customized embryo transfer (cET, n = 157 patients) according to the Win-Test results or embryo transfer according to the classical procedure (control group, n = 60). Pregnancy and live birth rates were compared in the two groups. The Win-Test showed that in 78.5% of women, the receptivity window lasted less than 48 h, although it could be shorter (< 24 h, 9.5%) or longer (> 48 h, 12%). This highlighted that only in 20% of patients with RIF the endometrium would have been receptive if the classical embryo transfer protocol was followed. In the other 80% of patients, the receptivity window was delayed by 1-3 days relative to the classical timing. This suggests that implantation failure could be linked to inadequate timing of embryo transfer. In agreement, both implantation (22.7% vs. 7.2%) and live birth rates per patient (31.8% vs. 8.3%) were significantly higher in the cET group than in the control group. cET on the basis of the Win-Test results could be proposed to improve pregnancy and live birth rates.ClinicalTrials.gov ID: NCT04192396; December 5, 2019, retrospectively registered.

Keywords: Implantation window; Receptivity window; Transcriptome; Win-Test.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Outline of the Win-Test procedure. HRT, hormone replacement therapy; LH, luteinizing hormone; Pg, progesterone; cET, customized embryo transfer
Fig. 2
Fig. 2
a Percentage of patients with RIF in whom the endometrial receptivity window (RW) was or was not identified in function of the number of endometrial biopsy performed. b RW duration in patients with RIF who had at least two endometrial biopsies
Fig. 3
Fig. 3
(a) Endometrial receptivity status according to the Win-Test performed at LH + 6/LH + 7 (natural cycles) and at Pg + 5/Pg + 6 (HRT cycles with or without GnRHa). (b) Percentage of patients with receptive endometrium (Win-Test) at different time points during natural and HRT cycles with or without GnRHa. GnRHa, GnRH analogue; HRT, hormone replacement therapy; LH, luteinizing hormone; N, natural cycle; Pg, progesterone
Fig. 4
Fig. 4
Receptivity window timing in the 157 patients with RIF (n = 46 in natural cycles; n = 73 in HRT cycles; n = 38 in HRT with GnRHa cycles) who underwent cET according to the Win-Test results. The receptivity window was considered delayed relative to the classical embryo transfer strategy for natural and HRT cycles. Bl, blastocyst; cET, customized embryo transfer; GnRHa, GnRH analogue; LH, luteinizing hormone; Pg, progesterone; RIF, repeated implantation failure

References

    1. Enquête nationale périnatale Rapport 2016—Epopé Inserm. 2016. . Accessed 31 Jan 2020.
    1. Observatoire épidemiologique de la fertilité en France. 2015. . Accessed 31 Jan 2020.
    1. Le nouveau rapport d'activité de l'Agence de la biomédecine. 2017. . Accessed 31 Jan 2020.
    1. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Fertil Steril. 1950;1:3–25.
    1. Friedler S, Schenker JG, Herman A, Lewin A. The role of ultrasonography in the evaluation of endometrial receptivity following assisted reproductive treatments: a critical review. Hum Reprod Update. 1996;2(4):323–335.
    1. Murray MJ, Meyer WR, Zaino RJ, Lessey BA, Novotny DB, Ireland K, Zeng D, Fritz MA. A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. Fertil Steril. 2004;81(5):1333–1343.
    1. Haouzi D, Dechaud H, Assou S, De Vos J, Hamamah S. Insights into human endometrial receptivity from transcriptomic and proteomic data. Reprod BioMed Online. 2012;24(1):23–34.
    1. Díaz-Gimeno P, Horcajadas JA, Martínez-Conejero JA, Esteban FJ, Alamá P, Pellicer A, et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril. 2011;95(1):50–60.
    1. Enciso M, Carrascosa JP, Sarasa J, Martínez-Ortiz PA, Munné S, Horcajadas JA, Aizpurua J. Development of a new comprehensive and reliable endometrial receptivity map (ER map/ER grade) based on RT-qPCR gene expression analysis. Hum Reprod. 2018;33(2):220–228.
    1. Haouzi D, Mahmoud K, Fourar M, Bendhaou K, Dechaud H, De Vos J, et al. Identification of new biomarkers of human endometrial receptivity in the natural cycle. Hum Reprod. 2009;24(1):198–205.
    1. Haouzi D, Assou A, Mahmoud K, Tondeur S, Rème T, Hedon B, et al. Gene expression profile of the human endometrial receptivity: comparison between natural and stimulated cycles for the same patients. Hum Reprod. 2009;24(6):1436–1445.
    1. Haouzi D, Assou S, Dechanet C, Anahory T, Dechaud H, De Vos J, et al. Controlled ovarian hyperstimulation for in vitro fertilization alters endometrial receptivity in humans: protocol effects. Biol Reprod. 2010;82(4):679–686.
    1. Haouzi D, Dechaud H, Assou S, Monzo C, de Vos J, Hamamah S. Transcriptome analysis reveals dialogues between human trophectoderm and endometrial cells during the implantation period. Hum Reprod. 2011;26(6):1440–1449.
    1. Bissonnette L, Drissennek L, Antoine Y, Tiers L, Hirtz C, Lehmann S, Perrochia H, Bissonnette F, Kadoch IJ, Haouzi D, Hamamah S. Human S100A10 plays a crucial role in the acquisition of the endometrial receptivity phenotype. Cell Adhes Migr. 2016;10(3):282–298.
    1. Haouzi D, Bissonnette L, Gala A, Assou S, Entezami F, Perrochia H, et al. Endometrial receptivity profile in patients with premature progesterone elevation on the day of HCG administration. Biomed Res Int. 2014;2014:951937.
    1. Hamamah S, Haouzi D (2011) Methods for assessing endometrium receptivity of a patient. Patent application number PCT/EP2011/058757
    1. Polanski LT, Baumgarten MN, Quenby S, Brosens J, Campbell BK, Raine-Fenning NJ. What exactly do we mean by ‘recurrent implantation failure’? A systematic review and opinion. Reprod BioMed Online. 2014;28(4):409–423.
    1. Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A. 2001;98(9):5116–5121.
    1. Rème T, Hose D, De Vos J, Vassal A, Poulain PO, Pantesco V, et al. A new method for class prediction based on signed-rank algorithms applied to Affymetrix microarray experiments. BMC Bioinformatics. 2008;11(9):16.
    1. Drissennek L, Baron C, Brouillet S, Entezami F, Hamamah S, Delphine Haouzi D (2020) Endometrial miRNome profile according to the receptivity status and implantation failure. Hum Fertil
    1. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44(3):837–845.
    1. Kalma Y, Granot I, Gnainsky Y, Or Y, Czernobilsky B, Dekel N, et al. Endometrial biopsy-induced gene modulation: first evidence for the expression of bladder-transmembranal uroplakin Ib in human endometrium. Fertil Steril. 2009;4:1042–1049.
    1. Psychoyos A. Uterine receptivity for nidation. Ann N Y Acad Sci. 1986;476:36–42.
    1. Navot D, Scott RT, Droesch K, Veeck LL, Liu HC, Rosenwaks Z. The window of embryo transfer and the efficiency of human conception in vitro. Fertil Steril. 1991;55(1):114–118.
    1. Prapas Y, Prapas N, Jones EE, Duleba AJ, Olive DL, Chatziparasidou A, Vlassis G. The window for embryo transfer in oocyte donation cycles depends on the duration of progesterone therapy. Hum Reprod. 1998;13(3):720–723.
    1. Lessey BA, Young SL. What exactly is endometrial receptivity? Fertil Steril. 2019;111(4):611–617.
    1. Fatemi HM, Kyrou D, Bourgain C, Van den Abbeel E, Griesinger G, Devroey P. Cryopreserved-thawed human embryo transfer: spontaneous natural cycle is superior to human chorionic gonadotropin-induced natural cycle. Fertil Steril. 2010;94(6):2054–2058.
    1. Xiao Z, Zhou X, Xu W, Yang J, Xie Q. Natural cycle is superior to hormone replacement therapy cycle for vitrificated-preserved frozen-thawed embryo transfer. Syst Biol Reprod Med. 2012;58(2):107–112.
    1. Cardellicchio L, Reschini M, Paffoni A, Guarneri C, Restelli L, Somigliana E, Vegetti W. Frozen-thawed blastocyst transfer in natural cycle: feasibility in every day clinical practice. Arch Gynecol Obstet. 2017;295(6):1509–1514.
    1. Gelbaya TA, Nardo LG, Hunter HR, Fitzgerald CT, Horne G, Pease EE, et al. Cryopreserved-thawed embryo transfer in natural or down-regulated hormonally controlled cycles: a retrospective study. Fertil Steril. 2006;85(3):603–609.
    1. Mackens S, Santos-Ribeiro S, van de Vijver A, Racca A, Van Landuyt L, Tournaye H, et al. Frozen embryo transfer: a review on the optimal endometrial preparation and timing. Hum Reprod. 2017;13(11):2234–2242.
    1. van de Vijver A, Drakopoulos P, Polyzos NP, Van Landuyt L, Mackens S, Santos-Ribeiro S, et al. Vitrified-warmed blastocyst transfer on the 5th or 7th day of progesterone supplementation in an artificial cycle: a randomised controlled trial. Gynecol Endocrinol. 2017;33(10):783–786.
    1. Devine K, Richter KS, Widra EA, McKeeby JL. Vitrified blastocyst transfer cycles with the use of only vaginal progesterone replacement with Endometrin have inferior ongoing pregnancy rates: results from the planned interim analysis of a three-arm randomized controlled non inferiority trial. Fertil Steril. 2018;109(2):266–275.
    1. Ruiz-Alonso M, Blesa D, Díaz-Gimeno P, Gómez E, Fernández-Sánchez M, Carranza F, Carrera J, Vilella F, Pellicer A, Simón C. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil Steril. 2013;100(3):818–824.
    1. Cho K, Tan S, Buckett W, Dahan MH. Intra-patient variability in the endometrial receptivity assay (ERA) test. J Assist Reprod Genet. 2018;35(5):929–930.
    1. Tan J, Kan A, Hitkari J, Taylor B, Tallon N, Warraich G, Yuzpe A, Nakhuda G. The role of the endometrial receptivity array (ERA) in patients who have failed euploid embryo transfers. J Assist Reprod Genet. 2018;35(4):683–692.
    1. Bassil R, Casper R, Samara N, Hsieh TB, Barzilay E, Orvieto R, Haas J. Does the endometrial receptivity array really provide personalized embryo transfer? J Assist Reprod Genet. 2018;35(7):1301–1305.
    1. Valde CT, Schutt A, Simon C. Implantation failure of endometrial origin: it is not pathology, but our failure to synchronize the developing embryo with a receptive endometrium. Fertil Steril. 2017;108(1):15–18.
    1. Bashiri A, Halper KI, Orvieto R. Recurrent implantation failure—update overview on etiology, diagnosis, treatment and future directions. Reprod Biol Endocrinol. 2018;16(1):121.
    1. Haouzi D, Bissonnette L, Leture H, Entezami F, Chahine H, Olivennes F, Hamamah S Endometrial receptivity under hormone replacement therapy in oocyte-donation recipient patients: transcriptomic approach. Med Res Arch. 2015;2(1).
    1. Ruiz-Alonso M, Galindo N, Pellicer A, Simón C. What a difference two days make: “personalized” embryo transfer (pET) paradigm: a case report and pilot study. Hum Reprod. 2014;29(6):1244–1247.
    1. Hashimoto T, Koizumi M, Doshida M, Toya M, Sagara E, Oka N, Nakajo Y, Aono N, Igarashi H, Kyono K. Efficacy of the endometrial receptivity array for repeated implantation failure in Japan: a retrospective, two-centers study. Reprod Med Biol. 2017;16(3):290–296.

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