A repeated gonadotropin-releasing hormone agonist trigger improves pregnancy outcomes of frozen-thawed embryo transfer in GnRH antagonist cycles: a retrospective propensity-matched score analysis.

Purpose To evaluate whether co-treatment of repeated GnRHa triggers with GnRH antagonist protocols can improve the clinical outcomes in in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) procedures.

In this retrospective study, 712 Chinese Han women aged 20–42 undergoing autologous IVF/ICSI-ET with a flexible GnRH antagonist protocol were analyzed. The 735 cycles were split into the single (n = 238) and the repeated (n = 497) GnRHa groups. In the single GnRHa group, 0.2 mg of triptorelin was given for oocyte maturation, whereas in the repeated GnRHa group, two doses of 0.2 mg were administered 12 h apart. PSM design was used for a fair comparison. The main study outcomes included the clinical pregnancy rate (CPR), live birth rate (LBR), good-quality embryo rate, and fertilization rate. Multivariate logistic regression analyses were used to identify all potential factors affecting clinical outcomes.

Post-PSM, analysis of 159 cycles per group showed the repeated GnRHa group outperforming the single GnRHa group in IVF fertilization rates (71.5% vs. 67.7%, P < 0.05) and good-quality embryo rate (47.1% vs. 43.7%, P < 0.05). Furthermore, the repeated GnRHa group achieved higher CPR (72.6% vs. 53.4%, P < 0.05) and LBR (59.7% vs. 43.8%, P < 0.05) in FET cycles. Multivariate logistic regression indicated a significant negative correlation between the use of a single GnRHa trigger and both clinical pregnancy (OR = 0.382, P < 0.05) and live birth (OR = 0.518, P < 0.05).

Our study reported that individuals who received a repeated GnRHa trigger exhibited higher CPR and LBR during FET cycles compared to those who received a single dose GnRHa trigger. Similar content being viewed by others Data availability The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Mills G, Dahan MH. Gonadotropin releasing hormone (GnRH) antagonist administration to decrease the risk of ovarian hyperstimulation syndrome in GNRH agonist cycles triggered with human chorionic gonadotropin. Arch Gynecol Obstet. 2022;306(5):1731–7. Najdecki R, et al. Agonist triggering in oocyte donation programs-mini review. Front Endocrinol. 2022;13:838236. Martazanova BMN, et al. Angiogenic cytokine and interleukin 8 levels in early luteal phase after triggering ovulation with gonadotropin-releasing hormone agonist in high-responder patients. Am J Reprod Immunol. 2021;85(6):e13381. Tannus S, et al. Reproductive outcomes after a single dose of gonadotropin-releasing hormone agonist compared with human chorionic gonadotropin for the induction of final oocyte maturation in hyper-responder women aged 35–40 years. Fertil Steril. 2017;107(6):1323–8. Humaidan PKS. Suboptimal response to GnRH agonist trigger causes and practical management. Curr Opin Obstet Gynecol. 2021;33(3):213–7. Popovic-Todorovic B, et al. Predicting suboptimal oocyte yield following GnRH agonist trigger by measuring serum LH at the start of ovarian stimulation. Hum Reprod. 2019;34(10):2027–35. Deepika K, et al. Empty follicle syndrome following GnRHa trigger in PCOS patients undergoing IVF cycles. J Reprod Infertil. 2018;19(1):16–25. Martazanova B, et al. Hormonal profile in early luteal phase after triggering ovulation with gonadotropin-releasing hormone agonist in high-responder patients. Front Endocrinol. 2022;13:834627. Engmann LL, et al. Low dose human chorionic gonadotropin administration at the time of gonadotropin releasing-hormone agonist trigger versus 35 h later in women at high risk of developing ovarian hyperstimulation syndrome - a prospective randomized double-blind clinical trial. J Ovarian Res. 2019;12(1):8. Humaidan P, Kol S, Papanikolaou EG. GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Hum Reprod Update. 2011;17(4):510–24. Vuong TN, et al. 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. Deepika K, et al. Repeat dose of gonadotropin-releasing hormone agonist trigger in polycystic ovarian syndrome undergoing in vitro fertilization cycles provides a better cycle outcome - a proof-of-concept study. J Hum Reprod Sci. 2017;10(4):271–80. Aflatoonian A, et al. Does the repeat dose of gonadotropin-releasing hormone agonist trigger in polycystic ovarian syndrome improve in vitro fertilization cycles outcome? A clinical trial study. Int J Reprod Biomed. 2020;18(7):485–90. Zhou X, et al. Comparison of dual trigger with combination GnRH agonist and hCG versus hCG alone trigger of oocyte maturation for normal ovarian responders. Int J Gynaecol Obstet. 2018;141(3):327–31. Embryology ASiRMaESIGo. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011; 26(6): 1270–1283. Gardner DK, Schoolcraft WB. Culture and transfer of human blastocysts. Curr Opin Obstet Gynecol. 1999;11(3):307–11. Casper RF. Basic understanding of gonadotropin-releasing hormone-agonist triggering. Fertil Steril. 2015;103(4):867–9. Lamb JD, et al. 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. Casarini L, et al. LH and hCG action on the same receptor results in quantitatively and qualitatively different intracellular signalling. PLoS ONE. 2012;7(10):e46682. Haas J, et al. GnRH agonist vs. hCG for triggering of ovulation–differential effects on gene expression in human granulosa cells. PLoS One. 2014;9(3):e90359. O’neill KE, Senapati S, Dokras A. Use of gonadotropin-releasing hormone agonist trigger during in vitro fertilization is associated with similar endocrine profiles and oocyte measures in women with and without polycystic ovary syndrome. Fertil Steril. 2015;103(1):264–9. Dosouto C, Haahr T, Humaidan P. Gonadotropin-releasing hormone agonist (GnRHa) trigger - state of the art. Reprod Biol. 2017;17(1):1–8. Zelinski-Wooten MB, et al. Titrating luteinizing hormone surge requirements for ovulatory changes in primate follicles. I. Oocyte maturation and corpus luteum function. J Clin Endocrinol Metab. 1991;73(3):577–83. Meyer L, et al. Risk factors for a suboptimal response to gonadotropin-releasing hormone agonist trigger during in vitro fertilization cycles. Fertil Steril. 2015;104(3):637–42. Seibel MM, et al. The temporal relationship between the luteinizing hormone surge and human oocyte maturation. Am J Obstet Gynecol. 1982;142(5):568–72. Zelinski-Wooten MB, et al. Administration of human luteinizing hormone (hLH) to macaques after follicular development: further titration of LH surge requirements for ovulatory changes in primate follicles. J Clin Endocrinol Metab. 1992;75(2):502–7. Castillo JC, et al. Gonadotropin-releasing hormone agonist ovulation trigger-beyond OHSS prevention. Ups J Med Sci. 2020;125(2):138–43. O’Neill KE, Coutifaris C. Gonadotropin-releasing hormone agonist trigger in clinical in vitro fertilization: can the suboptimal candidate be defined? Fertil Steril. 2015;104(3):555–6. Barbotin AL, et al. Hypothalamic neuroglial plasticity is regulated by anti-Müllerian hormone and disrupted in polycystic ovary syndrome. EBioMedicine. 2023;90:104535. Cheung AP, Chang RJ. Pituitary responsiveness to gonadotrophin-releasing hormone agonist stimulation: a dose-response comparison of luteinizing hormone/follicle-stimulating hormone secretion in women with polycystic ovary syndrome and normal women. Hum Reprod. 1995;10(5):1054–9. Ye X, et al. Semen parameters’ mediation effect on the association between advanced paternal age and IVF clinical outcomes: a 10-year retrospective cohort study. Maturitas. 2023;173:20–7. Shi Y, et al. Transfer of fresh versus frozen embryos in ovulatory women. N Engl J Med. 2018;378(2):126–36.

We gratefully acknowledge all the staff of the Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, for their support and cooperation. Funding This study was funded by the Clinical Research Program of Nanfang Hospital, Southern Medical University (grant numbers: 2018CR016), and the Guangdong Basic and Applied Basic Research Foundation (grant number: 2021A1515011061). Author information Authors and Affiliations Corresponding authors Ethics declarations Ethics approval and consent to participate All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethics committee of Nanfang Hospital (2012–021) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Due to the retrospective design, informed consent was not necessary, which is in accordance with the ethics committee of the Nanfang Hospital. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Wang, A., Zhou, XY., Lai, YH. et al. A repeated gonadotropin-releasing hormone agonist trigger improves pregnancy outcomes of frozen-thawed embryo transfer in GnRH antagonist cycles: a retrospective propensity-matched score analysis. J Assist Reprod Genet 41, 3433–3443 (2024). https://doi.org/10.1007/s10815-024-03269-5 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s10815-024-03269-5