Abstract
Purpose
To assess whether the GnRH-agonist or urinary-hCG ovulation triggers affect oocyte competence in a setting entailing vitrified-warmed euploid blastocyst transfer.
Methods
Observational study (April 2013–July 2018) including 2104 patients (1015 and 1089 in the GnRH-a and u-hCG group, respectively) collecting ≥1 cumulus-oocyte-complex (COC) and undergoing ICSI with ejaculated sperm, blastocyst culture, trophectoderm biopsy, comprehensive-chromosome-testing, and vitrified-warmed transfers at a private clinic. The primary outcome measure was the euploid-blastocyst-rate per inseminated oocytes. The secondary outcome measure was the maturation-rate per COCs. Also, the live-birth-rate (LBR) per transfer and the cumulative-live-birth-delivery-rate (CLBdR) among completed cycles were investigated. All data were adjusted for confounders.
Results
The generalized-linear-model adjusted for maternal age highlighted no difference in the mean euploid-blastocyst-rate per inseminated oocytes in either group. The LBR per transfer was similar: 44% (n=403/915) and 46% (n=280/608) in GnRH-a and hCG, respectively. On the other hand, a difference was reported regarding the CLBdR per oocyte retrieval among completed cycles, with 42% (n=374/898) and 25% (n=258/1034) in the GnRh-a and u-hCG groups, respectively. Nevertheless, this variance was due to a lower maternal age and higher number of inseminated oocytes in the GnRH-a group, and not imputable to the ovulation trigger itself (multivariate-OR=1.3, 95%CI: 0.9–1.6, adjusted p-value=0.1).
Conclusion
GnRH-a trigger is a valid alternative to u-hCG in freeze-all cycles, not only for patients at high risk for OHSS. Such strategy might increase the safety and flexibility of controlled-ovarian-stimulation with no impact on oocyte competence and IVF efficacy.
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References
Iussig B, Maggiulli R, Fabozzi G, Bertelle S, Vaiarelli A, Cimadomo D, et al. A brief history of oocyte cryopreservation: arguments and facts. Acta Obstet Gynecol Scand. 2019;98(5):550–8. https://doi.org/10.1111/aogs.13569.
Rienzi L, Gracia C, Maggiulli R, LaBarbera AR, Kaser DJ, Ubaldi FM, et al. Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance. Hum Reprod Update. 2017;23(2):139–55. https://doi.org/10.1093/humupd/dmw038.
Cha KY, Chian RC. Maturation in vitro of immature human oocytes for clinical use. Hum Reprod Update. 1998;4(2):103–20. https://doi.org/10.1093/humupd/4.2.103.
Coticchio G, Dal Canto M, Mignini Renzini M, Guglielmo MC, Brambillasca F, Turchi D, et al. Oocyte maturation: gamete-somatic cells interactions, meiotic resumption, cytoskeletal dynamics and cytoplasmic reorganization. Hum Reprod Update. 2015;21(4):427–54. https://doi.org/10.1093/humupd/dmv011.
Dosouto C, Haahr T, Humaidan P. Advances in ovulation trigger strategies. Panminerva Med. 2019;61(1):42–51. https://doi.org/10.23736/S0031-0808.18.03537-1.
Ortega I, Garcia-Velasco JA, Pellicer A. Ovarian manipulation in ART: going beyond physiological standards to provide best clinical outcomes. J Assist Reprod Genet. 2018;35(10):1751–62. https://doi.org/10.1007/s10815-018-1258-6.
Olivennes F, Fanchin R, Bouchard P, Taieb J, Frydman R. Triggering of ovulation by a gonadotropin-releasing hormone (GnRH) agonist in patients pretreated with a GnRH antagonist. Fertil Steril. 1996;66(1):151–3. https://doi.org/10.1016/s0015-0282(16)58404-0.
Gonen Y, Balakier H, Powell W, Casper RF. Use of gonadotropin-releasing hormone agonist to trigger follicular maturation for in vitro fertilization. J Clin Endocrinol Metab. 1990;71(4):918–22. https://doi.org/10.1210/jcem-71-4-918.
Tay CC. Use of gonadotrophin-releasing hormone agonists to trigger ovulation. Hum Fertil (Camb). 2002;5(1):G35–7; discussion G8-9, G41-8. https://doi.org/10.1080/1464727992000199811.
Eppig JJ. FSH stimulates hyaluronic acid synthesis by oocyte-cumulus cell complexes from mouse preovulatory follicles. Nature. 1979;281(5731):483–4. https://doi.org/10.1038/281483a0.
Andersen CY. Possible new mechanism of cortisol action in female reproductive organs: physiological implications of the free hormone hypothesis. J Endocrinol. 2002;173(2):211–7. https://doi.org/10.1677/joe.0.1730211.
Lamb JD, Shen S, McCulloch C, Jalalian L, Cedars MI, Rosen MP. Follicle-stimulating hormone administered at the time of human chorionic gonadotropin trigger improves oocyte developmental competence in in vitro fertilization cycles: a randomized, double-blind, placebo-controlled trial. Fertil Steril. 2011;95(5):1655–60. https://doi.org/10.1016/j.fertnstert.2011.01.019.
Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF treatment. Hum Reprod. 2011;26(10):2593–7. https://doi.org/10.1093/humrep/der251.
Fauser BC, de Jong D, Olivennes F, Wramsby H, Tay C, Itskovitz-Eldor J, et al. Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization. J Clin Endocrinol Metab. 2002;87(2):709–15. https://doi.org/10.1210/jcem.87.2.8197.
Humaidan P, Kol S, Papanikolaou EG, Copenhagen Gn RHATWG. GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Hum Reprod Update. 2011;17(4):510–24. https://doi.org/10.1093/humupd/dmr008.
Engmann L, DiLuigi A, Schmidt D, Nulsen J, Maier D, Benadiva C. The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertil Steril. 2008;89(1):84–91. https://doi.org/10.1016/j.fertnstert.2007.02.002.
Hernandez ER, Gomez-Palomares JL, Ricciarelli E. No room for cancellation, coasting, or ovarian hyperstimulation syndrome in oocyte donation cycles. Fertil Steril. 2009;91(4 Suppl):1358–61. https://doi.org/10.1016/j.fertnstert.2008.03.077.
Cerrillo M, Rodriguez S, Mayoral M, Pacheco A, Martinez-Salazar J, Garcia-Velasco JA. Differential regulation of VEGF after final oocyte maturation with GnRH agonist versus hCG: a rationale for OHSS reduction. Fertil Steril. 2009;91(4 Suppl):1526–8. https://doi.org/10.1016/j.fertnstert.2008.08.118.
Nevo O, Eldar-Geva T, Kol S, Itskovitz-Eldor J. Lower levels of inhibin A and pro-alphaC during the luteal phase after triggering oocyte maturation with a gonadotropin-releasing hormone agonist versus human chorionic gonadotropin. Fertil Steril. 2003;79(5):1123–8. https://doi.org/10.1016/s0015-0282(03)00177-8.
Griesinger G, Berndt H, Schultz L, Depenbusch M, Schultze-Mosgau A. Cumulative live birth rates after GnRH-agonist triggering of final oocyte maturation in patients at risk of OHSS: a prospective, clinical cohort study. Eur J Obstet Gynecol Reprod Biol. 2010;149(2):190–4. https://doi.org/10.1016/j.ejogrb.2009.12.030.
Acevedo B, Gomez-Palomares JL, Ricciarelli E, Hernandez ER. Triggering ovulation with gonadotropin-releasing hormone agonists does not compromise embryo implantation rates. Fertil Steril. 2006;86(6):1682–7. https://doi.org/10.1016/j.fertnstert.2006.05.049.
Erb TM, Vitek W, Wakim AN. Gonadotropin-releasing hormone agonist or human chorionic gonadotropin for final oocyte maturation in an oocyte donor program. Fertil Steril. 2010;93(2):374–8. https://doi.org/10.1016/j.fertnstert.2008.12.015.
Galindo A, Bodri D, Guillen JJ, Colodron M, Vernaeve V, Coll O. Triggering with HCG or GnRH agonist in GnRH antagonist treated oocyte donation cycles: a randomised clinical trial. Gynecol Endocrinol. 2009;25(1):60–6. https://doi.org/10.1080/09513590802404013.
Oktay K, Turkcuoglu I, Rodriguez-Wallberg KA. GnRH agonist trigger for women with breast cancer undergoing fertility preservation by aromatase inhibitor/FSH stimulation. Reprod BioMed Online. 2010;20(6):783–8. https://doi.org/10.1016/j.rbmo.2010.03.004.
Garcia-Velasco JA. Agonist trigger: what is the best approach? Agonist trigger with vitrification of oocytes or embryos. Fertil Steril. 2012;97(3):527–8. https://doi.org/10.1016/j.fertnstert.2011.12.010.
Griesinger G, Schultz L, Bauer T, Broessner A, Frambach T, Kissler S. Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a “freeze-all” strategy: a prospective multicentric study. Fertil Steril. 2011;95(6):2029–33, 33 e1. https://doi.org/10.1016/j.fertnstert.2011.01.163.
Youssef MA, Van der Veen F, Al-Inany HG, Mochtar MH, Griesinger G, Nagi Mohesen M, et al. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology. Cochrane Database Syst Rev. 2014;10:CD008046. https://doi.org/10.1002/14651858.CD008046.pub4.
Kolibianakis EM, Schultze-Mosgau A, Schroer A, van Steirteghem A, Devroey P, Diedrich K, et al. A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists. Hum Reprod. 2005;20(10):2887–92. https://doi.org/10.1093/humrep/dei150.
Humaidan P, Bredkjaer HE, Bungum L, Bungum M, Grondahl ML, Westergaard L, et al. GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study. Hum Reprod. 2005;20(5):1213–20. https://doi.org/10.1093/humrep/deh765.
Griesinger G, Kolibianakis EM, Papanikolaou EG, Diedrich K, Van Steirteghem A, Devroey P, et al. Triggering of final oocyte maturation with gonadotropin-releasing hormone agonist or human chorionic gonadotropin. Live birth after frozen-thawed embryo replacement cycles. Fertil Steril. 2007;88(3):616–21. https://doi.org/10.1016/j.fertnstert.2006.12.006.
Griesinger G, Berndt H, Schultz L, Schultze-Mosgau A, Diedrich K, von Otte S. Intensified ovarian stimulation in a GnRH antagonist protocol with agonist triggering: a prospective, clinical feasibility study. Reprod BioMed Online. 2011;22(2):133–9. https://doi.org/10.1016/j.rbmo.2010.10.017.
Eldar-Geva T, Zylber-Haran E, Babayof R, Halevy-Shalem T, Ben-Chetrit A, Tsafrir A, et al. Similar outcome for cryopreserved embryo transfer following GnRH-antagonist/GnRH-agonist, GnRH-antagonist/HCG or long protocol ovarian stimulation. Reprod BioMed Online. 2007;14(2):148–54. https://doi.org/10.1016/s1472-6483(10)60781-x.
Melo M, Busso CE, Bellver J, Alama P, Garrido N, Meseguer M, et al. GnRH agonist versus recombinant HCG in an oocyte donation programme: a randomized, prospective, controlled, assessor-blind study. Reprod BioMed Online. 2009;19(4):486–92. https://doi.org/10.1016/j.rbmo.2009.06.001.
Mazzilli R, Cimadomo D, Vaiarelli A, Capalbo A, Dovere L, Alviggi E, et al. Effect of the male factor on the clinical outcome of intracytoplasmic sperm injection combined with preimplantation aneuploidy testing: observational longitudinal cohort study of 1,219 consecutive cycles. Fertil Steril. 2017;108:961–972.e3. https://doi.org/10.1016/j.fertnstert.2017.08.033.
Rienzi L, Ubaldi FM, Iacobelli M, Minasi MG, Romano S, Ferrero S, et al. Significance of metaphase II human oocyte morphology on ICSI outcome. Fertil Steril. 2008;90(5):1692–700. https://doi.org/10.1016/j.fertnstert.2007.09.024.
Ubaldi F, Vaiarelli A, D’Anna R, Rienzi L. Management of poor responders in IVF: is there anything new? Biomed Res Int. 2014;2014:352098. https://doi.org/10.1155/2014/352098.
Capalbo A, Rienzi L, Cimadomo D, Maggiulli R, Elliott T, Wright G, et al. Correlation between standard blastocyst morphology, euploidy and implantation: an observational study in two centers involving 956 screened blastocysts. Hum Reprod. 2014;29(6):1173–81. https://doi.org/10.1093/humrep/deu033.
Cimadomo D, Capalbo A, Levi-Setti PE, Soscia D, Orlando G, Albani E, et al. Associations of blastocyst features, trophectoderm biopsy and other laboratory practice with post-warming behavior and implantation. Hum Reprod. 2018;33:1992–2001. https://doi.org/10.1093/humrep/dey291.
Maggiulli R, Cimadomo D, Fabozzi G, Papini L, Dovere L, Ubaldi FM, et al. The effect of ICSI-related procedural timings and operators on the outcome. Hum Reprod. 2020;35(1):32–43. https://doi.org/10.1093/humrep/dez234.
Treff NR, Tao X, Ferry KM, Su J, Taylor D, Scott RT Jr. Development and validation of an accurate quantitative real-time polymerase chain reaction-based assay for human blastocyst comprehensive chromosomal aneuploidy screening. Fertil Steril. 2012;97(4):819–24. https://doi.org/10.1016/j.fertnstert.2012.01.115.
Vera-Rodriguez M, Michel CE, Mercader A, Bladon AJ, Rodrigo L, Kokocinski F, et al. Distribution patterns of segmental aneuploidies in human blastocysts identified by next-generation sequencing. Fertil Steril. 2016;105(4):1047–55 e2. https://doi.org/10.1016/j.fertnstert.2015.12.022.
Vaiarelli A, Cimadomo D, Patrizio P, Venturella R, Orlando G, Soscia D, et al. Biochemical pregnancy loss after frozen embryo transfer seems independent of embryo developmental stage and chromosomal status. Reprod BioMed Online. 2018;37(3):349–57. https://doi.org/10.1016/j.rbmo.2018.05.019.
Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, et al. The International Glossary on Infertility and Fertility Care, 2017. Hum Reprod. 2017;32(9):1786–801. https://doi.org/10.1093/humrep/dex234.
Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, et al. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril. 2017;108(3):393–406. https://doi.org/10.1016/j.fertnstert.2017.06.005.
Toftager M, Bogstad J, Bryndorf T, Lossl K, Roskaer J, Holland T, et al. Risk of severe ovarian hyperstimulation syndrome in GnRH antagonist versus GnRH agonist protocol: RCT including 1050 first IVF/ICSI cycles. Hum Reprod. 2016;31(6):1253–64. https://doi.org/10.1093/humrep/dew051.
Ubaldi FM, Capalbo A, Colamaria S, Ferrero S, Maggiulli R, Vajta G, et al. Reduction of multiple pregnancies in the advanced maternal age population after implementation of an elective single embryo transfer policy coupled with enhanced embryo selection: pre- and post-intervention study. Hum Reprod. 2015;30(9):2097–106. https://doi.org/10.1093/humrep/dev159.
Capalbo A, Ubaldi FM, Cimadomo D, Maggiulli R, Patassini C, Dusi L, et al. Consistent and reproducible outcomes of blastocyst biopsy and aneuploidy screening across different biopsy practitioners: a multicentre study involving 2586 embryo biopsies. Hum Reprod. 2016;31(1):199–208. https://doi.org/10.1093/humrep/dev294.
Cimadomo D, Scarica C, Maggiulli R, Orlando G, Soscia D, Albricci L, et al. Continuous embryo culture elicits higher blastulation but similar cumulative delivery rates than sequential: a large prospective study. J Assist Reprod Genet. 2018;35:1329–38. https://doi.org/10.1007/s10815-018-1195-4.
Thorne J, Loza A, Kaye L, Nulsen J, Benadiva C, Grow D, et al. Euploidy rates between cycles triggered with gonadotropin-releasing hormone agonist and human chorionic gonadotropin. Fertil Steril. 2019;112(2):258–65. https://doi.org/10.1016/j.fertnstert.2019.03.040.
Vuong TN, Ho MT, Ha TD, Phung HT, Huynh GB, Humaidan P. Gonadotropin-releasing hormone agonist trigger in oocyte donors co-treated with a gonadotropin-releasing hormone antagonist: a dose-finding study. Fertil Steril. 2016;105(2):356–63. https://doi.org/10.1016/j.fertnstert.2015.10.014.
Pabuccu EG, Pabuccu R, Caglar GS, Yilmaz B, Yarci A, et al. J Hum Reprod Sci. 2015;8(1):25–9. https://doi.org/10.4103/0974-1208.153123.
Zarcos SM, Mejia PV, Stefani CD, Martin PS, Martin FS. Comparison of two different dosage of GnRH agonist as ovulation trigger in oocyte donors: a randomized controled trial. JBRA Assist Reprod. 2017;21(3):183–7. https://doi.org/10.5935/1518-0557.20170036.
Makhijani R, Thorne J, Bartels C, Bartolucci A, Nulsen J, Grow D, et al. Pregnancy outcomes after frozen-thawed single euploid blastocyst transfer following IVF cycles using GNRH agonist or HCG trigger for final oocyte maturation. J Assist Reprod Genet. 2020;37(3):611–7. https://doi.org/10.1007/s10815-019-01646-z.
Humaidan P, Nelson SM, Devroey P, Coddington CC, Schwartz LB, Gordon K, et al. Ovarian hyperstimulation syndrome: review and new classification criteria for reporting in clinical trials. Hum Reprod. 2016;31(9):1997–2004. https://doi.org/10.1093/humrep/dew149.
Humaidan P, Engmann L, Benadiva C. Luteal phase supplementation after gonadotropin-releasing hormone agonist trigger in fresh embryo transfer: the American versus European approaches. Fertil Steril. 2015;103(4):879–85. https://doi.org/10.1016/j.fertnstert.2015.01.034.
Kummer NE, Feinn RS, Griffin DW, Nulsen JC, Benadiva CA, Engmann LL. Predicting successful induction of oocyte maturation after gonadotropin-releasing hormone agonist (GnRHa) trigger. Hum Reprod. 2013;28(1):152–9. https://doi.org/10.1093/humrep/des361.
Youssef MA, Abou-Setta AM, Lam WS. Recombinant versus urinary human chorionic gonadotrophin for final oocyte maturation triggering in IVF and ICSI cycles. Cochrane Database Syst Rev. 2016;4:CD003719. https://doi.org/10.1002/14651858.CD003719.pub4.
Madani T, Mohammadi Yeganeh L, Ezabadi Z, Hasani F, Chehrazi M. Comparing the efficacy of urinary and recombinant hCG on oocyte/follicle ratio to trigger ovulation in women undergoing intracytoplasmic sperm injection cycles: a randomized controlled trial. J Assist Reprod Genet. 2013;30(2):239–45. https://doi.org/10.1007/s10815-012-9919-3.
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DC, AV, LR, and FMU conceived the study. DC and AV analyzed the data and drafted the manuscript. All authors contributed to data collection and discussion of the results.
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Danilo Cimadomo and Alberto Vaiarelli are co-first authors.
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Supplementary Figure 1
Flowchart of the study. COS, controlled ovarian stimulation; COC, cumulus oocyte complex; MII, metaphase II. (PNG 221 kb)
Supplementary Figure 2
Distribution of the PGT-A cycles in the two groups under investigation (i.e. GnRH-agonist and urinary-hCG trigger) according to maternal age (A) and number of follicles with a mean diameter >15 mm on the day of trigger (B). Figure (C) shows the percentage of administration of GnRH-agonist and urinary-hCG trigger according to the ranges of number of follicles with a mean diameter >15 mm on the day of trigger, across the observational period (April 2013 to July 2018). The prevalence of severe and moderate-OHSS (ovarian hyperstimulation syndrome) is also reported. Statistically significant differences were assessed with Mann-Whitney U tests. (PNG 428 kb)
Supplementary Figure 3
Distribution of the PGT-A cycles in the two groups under investigation (i.e. GnRH-agonist and urinary-hCG trigger), according to the number of cumulus oocyte complexes (COCs) retrieved after oocyte pick-up. Statistically significant difference was assessed with Mann-Whitney U test. (PNG 182 kb)
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Cimadomo, D., Vaiarelli, A., Petriglia, C. et al. Oocyte competence is independent of the ovulation trigger adopted: a large observational study in a setting that entails vitrified-warmed single euploid blastocyst transfer. J Assist Reprod Genet 38, 1419–1427 (2021). https://doi.org/10.1007/s10815-021-02124-1
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DOI: https://doi.org/10.1007/s10815-021-02124-1