Journal of Assisted Reproduction and Genetics

, Volume 35, Issue 3, pp 449–455 | Cite as

HCG administration after endogenous LH rise negatively influences pregnancy rate in modified natural cycle for frozen–thawed euploid blastocyst transfer: a pilot study

  • Katarzyna Litwicka
  • Cecilia Mencacci
  • Cristiana Arrivi
  • Maria Teresa Varricchio
  • Alina Caragia
  • Maria Giulia Minasi
  • Ermanno Greco
Assisted Reproduction Technologies



The aim of the present study was to evaluate whether in a modified natural cycle (modified-NC) for a frozen-thawed single euploid blastocyst transfer, a critical LH value, above which human chorionic gonadotropin (hCG) administration should be avoided, may be defined.


One hundred and sixty-seven patients underwent modified natural cycle in order to transfer a single frozen-thawed euploid blastocyst. All embryos were obtained by intracytoplasmic sperm injection and were biopsied at the blastocyst stage and analyzed by means of array comparative genomic hybridization (aCGH). Ovulation was induced using 10.000 IU hCG when the mean follicle diameter was at least of 17 mm, independently from LH values. The primary end points were the hCG-positive test and clinical pregnancy. The interim analysis showed that LH value ≥ 13 mIU/ml on the day of hCG injection may negatively influence the clinical results, suggesting that in this condition, it should be advisable waiting for spontaneous ovulation.


Among patients who received hCG for ovulation induction, the hCG-positive test and clinical pregnancy rates in modified-NC were significantly lower in cycles with LH ≥ 13 mIU/ml in respect to those with LH < 13 mIU/ml (45.4 vs 73.3 and 36.4 vs 65.9%, in LH ≥ 13 and LH < 13 groups, respectively). In patients with LH value ≥ 13 mIU/ml, hCG administration led to significantly lower rates of hCG-positive test (45.4 vs 74.5% in hCG administration and spontaneous ovulation groups, respectively) and clinical pregnancy (36.4 vs 64.7% in hCG administration and spontaneous ovulation groups, respectively). The baseline patient characteristics were comparable in all groups.


The findings of this study highlight that LH elevation ≥ 13 mIU/ml prior to hCG administration may negatively affect clinical pregnancy rates in modified-NC for single euploid blastocyst transfer. The LH determination should be routinely performed during follicular monitoring. In the presence of LH level ≥ 13 mIU/ml, hCG administration should be avoided, and the embryo transfer should be planned only after spontaneous follicular rupture.


Frozen-thawed transfer Euploid blastocyst Modified-natural cycle Ovulation induction 


Compliance with ethical standards

The Institutional Review Boards of European Hospital and Genoma Laboratory approved the study before initiation. All participants gave written consent after having been informed on all the aspects of the study. All the clinical and biological procedures were conducted at the Center for Reproductive Medicine of European Hospital, Rome (Italy), whereas the genetic screenings were performed at the Genoma Laboratory, Rome (Italy). All procedures were performed according to the Helsinki Declaration of 1975 and its further modifications.


  1. 1.
    Weinerman R, Mainigi M. Why we should froze instead of fresh embryos: the translational rationale. Fertil Steril. 2014;102:10–8.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Thomas S. Large blastocyst diameter, early blastulation, and low preovulatory serum progesterone are dominant predictors of clinical pregnancy in fresh autologous cycles. Fertil Steril. 2008;90:302–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Check JH, Choe JK, Katsoff D, Summers-Chase D, Wilson C. Controlled ovarian hyperstimulation adversely affects implantation after in vitro fertilization-embryo transfer. J Assist Reprod Genet. 1999;16:416–20.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Haouzi D, Assou S, Mahmoud K, Tondeur S, Reme T, Hedon B, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Horcajadas JA, Dıaz-Gimeno P, Pellicer A, Simon C. Uterine receptivity and the ramifications of ovarian stimulation on endometrial function. Semin Reprod Med. 2007;25:454–60.CrossRefPubMedGoogle Scholar
  6. 6.
    Kolibianakis E, Bourgain C, Albano C, Osmanagaoglu K, Smitz J, Van Steirteghem A, et al. 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. 2002;78:1025–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Nikas G, Develioglu OH, Toner JP, Jones HW Jr. Endometrial pinopodes indicate a shift in the window of receptivity in IVF cycles. Hum Reprod. 1999;14:787–92.CrossRefPubMedGoogle Scholar
  8. 8.
    Papanikolaou EG, Bourgain C, Kolibianakis E, Tournaye H, Devroey P. Steroid receptor expression in late follicular phase endometrium in GnRH antagonist IVF cycles is already altered, indicating initiation of early luteal phase transformation in the absence of secretory changes. Hum Reprod. 2005;20:1541–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Hellani A, Abu-Amero K, Azouri J, El-Akoum S. Successful pregnancies after application of array-comparative genomic hybridization in PGS-aneuploidy screening. Reprod BioMed Online. 2008;17(6):841–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Murata Y, Oku H, Morimoto Y, Tokuda M, Murata T, Sugihara K, et al. Freeze-thaw programmes rescue the implantation of day 6 blastocyts. Reprod BioMed Online. 2005;1:428–33.CrossRefGoogle Scholar
  11. 11.
    Shapiro BS, Daneshmand ST, Restrepo H, Garner FC, Aguirre M, Hudson C. Matched-cohort comparison of single-embryo transfers in fresh and frozen-thawed embryo transfer cycles. Fertil Steril. 2013;99:389–92.CrossRefPubMedGoogle Scholar
  12. 12.
    Hill MJ, Miller A, Frattarelli JLA. GnRH agonist and exogenous hormone stimulation protocol has a higher live-birth rate than a natural endogenous hormone protocol for frozen-thawed blastocyst-stage embryo transfer cycles: an analysis of 1391 cycles. Fertil Steril. 2010;93:416–22.CrossRefPubMedGoogle Scholar
  13. 13.
    Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C, Thomas S. Evidence of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: a prospective randomized trial comparing fresh and frozen-thawed embryo transfer in normal responders. Fertil Steril. 2011;96:344–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Roque M, Lattes K, Serra S, Sola I, Geber S, Carreras R, et al. Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis. Fertil Steril. 2013;99:156–62.CrossRefPubMedGoogle Scholar
  15. 15.
    Ghobara T, Vandekerckhove P. Cycle regimens for frozen-thawed embryo transfer. Cochrane Database Syst Rev. 2008;1:CD003414.Google Scholar
  16. 16.
    Groenewoud ER, Cantineau AE, Kollen BJ, Macklon NS, Cohlen BJ. What is the optimal means of preparing the endometrium in frozen-thawed embryo transfer cycles? A systematic review and meta-analysis. Hum Reprod Update. 2013;19(5):458–70.CrossRefPubMedGoogle Scholar
  17. 17.
    Fatemi HM, Kyrou D, Bourgain C, Van den Abeel E, Griesunger 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):2054–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Groenewoud ER, Kollen BJ, Macklon NS, Cohlen BJ. Spontaneous LH surges prior to HCG administration in unstimulated-cycle frozen-thawed embryo transfer do not influence pregnancy rates. Reprod BioMed Online. 2012;24:191–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Weissman A, Horowitz E, Ravhon A, Steinfeld Z, Mutzafi R, Golan A, et al. Spontaneous ovulation versus HCG triggering for timing natural-cycle frozen-thawed embryo transfer: a randomized study. Reprod BioMed Online. 2011;23(4):484–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Lathi RB, Chi YY, Liu J, Saravanabavanandhan B, Hegde A, Baker VL. Frozen blastocyst embryo transfer using a supplemented natural cycle protocol has a similar live birth rate compared to a programmed cycle protocol. J Assist Reprod Genet. 2015;32(7):1057–62.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Groenewoud ER, Cohlen BJ, Al-Oraiby A, Brinkhuis EA, Broekmans FJ, de Bruin JP, et al. A randomized controlled, non-inferiority trial of modified natural versus artificial cycle for cryo-thawed embryo transfer. Hum Reprod. 2016;31(7):1483–92.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Groenewoud ER, Macklon NS, Cohlen BJ. Cryo-thawed embryo transfer: natural versus artificial cycle. A non-inferiority trial. (ANTARCTICA trial). ANTARCTICA trial study group. BMC Womens Health. 2012;12:27.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Greco E, Litwicka K, Arrivi C, Varricchio MT, Caragia A, Greco A, et al. The endometrial preparation for frozen-thawed euploid blastocysts transfer: a prospective randomized trial comparing clinical results from natural modified cycle and exogenous hormone stimulation with GnRH agonist. J Assist Reprod Genet. 2016;33(7):873–84.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Greco E, Litwicka K, Ferrero S, Baroni E, Sapienza F, Rienzi L. GnRH antagonists in ovarian stimulation for ICSI with oocyte restriction: a matched, controlled study. Reprod BioMed Online. 2008;14(5):572–8.CrossRefGoogle Scholar
  25. 25.
    Kuwayama M. Highly efficient vitrification for cryopreservation of human oocytes and embryos: the Cryotop method. Theriogenology. 2007;67(1):73–80.CrossRefPubMedGoogle Scholar
  26. 26.
    Segaloff DL, Ascoli M. The lutropin/choriogonadotropin receptor 4 years later. Endocr Rev. 1993;14:324–17.PubMedGoogle Scholar
  27. 27.
    Licht P, von Wolff M, Berkholz A, Wildt L. Evidence for cycle-dependent expression of full-length human chorionic gonadotropin/luteinizing hormone receptor mRNA in human endometrium and decidua. Fertil Steril. 2003;79 Suppl 1:718–23.CrossRefPubMedGoogle Scholar
  28. 28.
    Müller T, Gromoll J, Simoni M. Absence of exon 10 of the human luteinizing hormone (LH) receptor impairs LH, but not human chorionic gonadotropin action. J Clin Endocrinol Metab. 2003;88(5):2242–9.CrossRefPubMedGoogle Scholar
  29. 29.
    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. 2007;269(1–2):85–92. ReviewCrossRefPubMedGoogle Scholar
  30. 30.
    Krotz S, McKenzie LJ, Cisneros P, Buster J, Amato P, Carson S. Prevalence of premature urinary luteinizing hormone surges in women with regular menstrual cycles and its effect on implantation of frozen-thawed embryos. Fertil Steril. 2005;83(6):1742.CrossRefPubMedGoogle Scholar
  31. 31.
    Cantineau AE, Cohlen BJ. The prevalence and influence of luteinizing hormone surges in stimulated cycles combined with intrauterine insemination during a prospective cohort study. Fertile Steril. 2007;88(1):107–12.CrossRefGoogle Scholar
  32. 32.
    Weissman A, Levin D, Ravhon A, Eran H, Golan A, Levran D. What is the preferred method for timing natural cycle frozen-thawed embryo transfer? Reprod BioMed Online. 2009;19(1):66–71.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Katarzyna Litwicka
    • 1
  • Cecilia Mencacci
    • 1
  • Cristiana Arrivi
    • 1
  • Maria Teresa Varricchio
    • 1
  • Alina Caragia
    • 1
  • Maria Giulia Minasi
    • 1
  • Ermanno Greco
    • 1
  1. 1.Centre For Reproductive MedicineEuropean HospitalRomeItaly

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