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As part of a conventional controlled ovarian hyperstimulation (COH) regimen, final follicular maturation is usually triggered by a single bolus dose of human chorionic gonadotropin (hCG). COH, which combines GnRH antagonist co-treatment with GnRH agonist(GnRHa) trigger, is often used in attempts to eliminate severe early ovarian hyperstimulation syndrome and to improve oocyte/embryo yield and quality. Recently, the combination of GnRHa, with hCG trigger has also been implemented into clinical practice. Here, we analyze and discuss published studies on various ways of triggering final follicular maturation, seeking to elucidate the appropriateness of each approach for specific patient subgroups., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The author declares that he has no competing interests., (© 2025. The Author(s).)

This prospective study aimed to test the ability of follicular GnRH agonist challenge test (FACT) to predict suboptimal response to GnRH agonist trigger, assessed by LH levels post ovulation trigger in non-medical oocyte cryopreservation program. The study included 91 women that underwent non-medical fertility preservation. On day two to menstrual cycle, blood tests were drawn (basal Estradiol, basal FSH, basal LH, Progesterone) and ultrasound (US) was performed. On that evening, the women were instructed to inject 0.2 mg GnRH agonist (FACT) and arrive for repeated blood workup 10-12 h later in the next morning, followed by a flexible antagonist protocol. LH levels on the morning after ovulation trigger were compared to FACT LH levels. The results demonstrated that LH levels following agonist ovulation trigger below 15IU/L occurred in 1.09% of cycles and were predicted by FACT, r = 0.57, p < 0.001. ROC analysis demonstrated that FACT LH > 42.70 IU/L would predict LH post trigger of more than 30 IU/L with 75% sensitivity and 70% specificity, AUC = 0.81. LH levels post trigger also displayed significant positive correlation to basal FSH (r = 0.35, p = 0.002) and basal LH (r = 0.54, p < 0.001). LH levels post ovulation trigger were not associated with total oocytes number or maturity rate. The strongest correlation to the number of frozen oocytes was progesterone levels post agonist trigger (r = 0.746, p < 0.001). We concluded that suboptimal response to agonist trigger, as assessed by post trigger LH levels was a rare event. FACT could serve as an adjunct pre-trigger, intracycle tool to predict adequate LH levels elevation after agonist ovulation trigger. Future studies should focus on optimization of agonist trigger efficacy assessment and prediction, especially in high responders., (© 2024. The Author(s).)

Gonadotropin-releasing hormone agonist (GnRHa) for final oocyte maturation, along with vitrification of all usable embryos followed by transfer in a subsequent frozen-thawed cycle, is the most effective strategy to avoid ovarian hyperstimulation syndrome (OHSS). However, less is known about the ovulation induction triggers effect on early embryo development and blastocyst formation. This study is a secondary analysis of a multicenter, randomized controlled trial, with the aim to compare embryo development in normo-ovulatory women, randomized to GnRHa or human chorionic gonadotropin (hCG) trigger. In all, 4056 retrieved oocytes were observed, 1998 from the GnRHa group (216 women) and 2058 from the hCG group (218 women). A number of retrieved oocytes, mature and fertilized oocytes, and high-quality embryos and blastocysts were similar between the groups. A sub-analysis in 250 women enrolled at the main trial site including 2073 oocytes was conducted to compare embryo morphokinetics and cleavage patterns with EmbryoScope time-lapse system. In total, 1013 oocytes were retrieved from the GnRHa group (124 women) and 1060 oocytes were retrieved from the hCG group (126 women). Morphokinetic parameters and cleavage patterns were comparable between the groups. However, embryos derived from the GnRHa group were less likely to perform rolling during their development than the embryos from the hCG trigger group (OR = 0.41 (95%CI 0.25; 0.67), p-value 0.0003). The comparable results on embryo development and utilization rates between the GnRHa and hCG triggers is of clinical relevance to professionals and infertile patients, when GnRHa trigger and freeze-all is performed to avoid OHSS development. ClinicalTrials.gov Identifier: NCT02746562., (© 2021. Society for Reproductive Investigation.)

Objective: This study aimed to characterize those patients undergoing the stop gonadotropin-releasing hormone (GnRH)-agonist combined with multidose GnRH-antagonist protocol, with suboptimal response to GnRH-agonist trigger in in vitro fertilization (IVF) cycles., Design: This is a cohort study., Setting: The study was conducted in a university hospital., Patients: All consecutive women admitted to our IVF unit from February 2020 through November 2020 who reached the ovum pick-up stage were reviewed., Interventions: Triggering final oocyte maturation by GnRH-ag alone (GnRH-ag trigger group), or combined with hCG (dual trigger group), in patients undergoing the stop GnRH-agonist combined with multidose GnRH-antagonist protocol was performed., Main Outcome Measure: The main outcome measure was LH level 12 h after the trigger., Results: Five out of the 32 patients (15.6%) demonstrated suboptimal response as reflected by LH levels <15 IU/L 12 h after GnRH-agonist trigger. Moreover, while no differences were observed in oocyte recovery rate, maturity, or embryo quality between the different study groups (GnRH-ag trigger and dual trigger groups), those achieving a suboptimal response to the GnRH-agonist trigger (post-trigger LH <15 mIU/mL) demonstrated significantly higher number of follicles and peak estradiol levels at the day of trigger, compared to those with optimal response (post-trigger LH >15 mIU/mL)., Conclusions: The stop GnRH-agonist combined with GnRH-antagonist protocol enables the substitution of hCG with GnRH-ag for final oocyte maturation. However, caution should be taken in high responders, where the dual trigger with small doses of hCG (1,000-1,500 IU) should be considered, aiming to avoid suboptimal response (post-trigger LH levels <15 IU/L)., (© 2021 S. Karger AG, Basel.)

Purpose: Despite the increasing use of GnRHa to trigger final oocyte maturation in segmented IVF cycles, the effects of trigger modality on chromosomal competence and embryo quality remain controversial. Hence, the purpose of this study was to compare euploidy rates and pregnancy outcomes among hyper-responding women using hCG versus GnRHa trigger., Methods: This retrospective study included 333 hyper-responders, defined as >15 oocytes retrieved, who underwent preimplantation genetic testing (PGT-A) in segmented IVF cycles using either GnRHa or urinary hCG trigger. Live birth rate (LBR) was the primary outcome of interest. Implantation rate (IR), clinical pregnancy rate (CPR), and euploidy rate were secondary outcomes., Results: GnRH triggering was associated with improved IR (70.5 vs. 53.2%, p = 0.0475), LBR (51.3 vs. 33.8%, p = 0.0170) compared to hCG. A greater number of oocytes were retrieved (21.9 vs 18.4%, p < 0.001) and euploid embryos produced (2.8 vs. 2.1, p = 0.0109) after GnRHa triggering, while higher euploidy rates were only observed among women <35-years-old (62.0 vs. 51.7%, p = 0.0307) using GnRHa trigger. Higher OHSS rates were observed after hCG triggering (10.6 vs. 2.1%, p = 0.0009)., Conclusion: Hyper-responders who received GnRHa trigger experienced improved pregnancy outcomes and lower rates of OHSS compared to hCG triggering. The higher number of oocytes retrieved and euploid embryos produced may reflect an improved developmental competence using GnRHa triggering due to physiologic induction of both LH and FSH surge or other undefined mechanisms that improve embryo development. However, higher overall euploid rates were only observed among women <35-years-old using the GnRHa trigger. Further prospective studies are required to validate this observation and evaluate the specific influence of different ovulation triggers on gamete developmental competence among hyper-responder women.

The introduction of gonadotrophin-releasing hormone agonist (GnRHa) trigger greatly impacted modern IVF treatment. Patients at low risk of ovarian hyperstimulation syndrome (OHSS) development, undergoing fresh embryo transfer and GnRHa trigger can be offered a virtually OHSS-free treatment with non-inferior reproductive outcomes by using a modified luteal phase support in terms of small boluses of human chorionic gonadotrophin (hCG), daily recombinant luteinizing hormone LH (rLH) or GnRHa. In the OHSS risk patient, GnRHa trigger can safely be performed, followed by a 'freeze-all' policy with a minimal risk of OHSS development and high live birth rates in the subsequent frozen embryo transfer cycle. Importantly, GnRHa trigger opened the 'black box' of the luteal phase, promoting research in the most optimal steroid levels during the luteal phase. GnRHa trigger allows high-dose gonadotropin stimulation to achieve the optimal number of oocytes and embryos needed to ensure the highest chance of live birth. This review thoroughly discusses how the GnRHa trigger concept adds safety and efficacy to modern IVF in terms of OHSS prevention. Furthermore, the optimal luteal phase management after GnRHa trigger in fresh embryo transfer cycles is discussed.

In this review the advantages of the gonadotropin-releasing hormone agonist (GnRHa) trigger are discussed beyond those immediately associated with ovarian hyperstimulation syndrome (OHSS) prevention. The GnRHa trigger concept has sparked the development of novel protocols, enriching the assisted reproductive technology (ART) armamentarium for the benefit of present and future patients. Thus, GnRHa trigger already has a pivotal role, not only for the standard in vitro fertilisation (IVF) patient, but also for patient groups like oocyte donors, cancer patients, patients with poor ovarian reserve, and patients with immature oocyte syndrome and empty follicle syndrome. Herein, we discuss the importance of the GnRHa-elicited midcycle FSH surge and the potential improvement in oocyte yield and embryo competence.

Purpose: An alternative option to human chorionic gonadotropin (hCG) is GnRH agonist (GnRH-a) for ovulation trigger in intrauterine insemination (IUI) cycles. This study aims to compare the efficacy of GnRH-a with hCG in women with history of follicular-endometrial asynchrony after clomiphene in IUI cycles., Methods: This prospective observational study recruited 631 women with unexplained infertility and follicular-endometrial asynchrony (follicle ≥ 18 mm, endometrial thickness (ET) < 7 mm) in previous two failed clomiphene/IUI cycles. Overall 27 patients with synchronized follicular-endometrial relationship and 49 women with persistent ET < 7 mm and/or follicle > 26 mm were excluded. Remaining women (n = 555) were divided into two groups: Group A (n = 285) received GnRH-a and Group B (n = 270) received hCG ovulation trigger. Finally, 513 patients, who underwent IUI, were analysed., Results: Cancellation due to luteinized unruptured follicle was more in hCG group (P = 0.01). Higher clinical pregnancies (10.33 vs. 4.96%, P = 0.03) and live birth rates (8.86 vs. 4.13%, P = 0.03) were noted with GnRH-a trigger. Miscarriage rate was comparable in both the groups (10.71 and 16.67% in Group A and Group B, respectively)., Conclusion: In unexplained infertility, GnRH agonist is an useful alternative for triggering ovulation in women with follicular-endometrial asynchrony following clomiphene induction.

Objective: To investigate the reproductive outcomes after the use of GnRH agonist (GnRHa) compared with hCG for the induction of final oocyte maturation in GnRH antagonist cycles performed in hyper-responder women aged 35-40 years., Design: Retrospective study., Setting: Academic fertility center., Patient(s): Two hundred seventy-two hyper-responder women aged 35-40 years who underwent controlled ovarian stimulation under GnRH antagonist suppression were included. Final oocyte maturation was performed with GnRHa (n = 168) or hCG (n = 104). Embryos were cryopreserved at the blastocyst stage and transferred in subsequent warming cycles (n = 542). Subjects were included in the analysis until live birth was achieved, after which they were excluded from further analysis., Intervention(s): None., Main Outcome Measure(s): Cumulative live birth rate., Result(s): Subjects in the GnRHa group achieved a higher number of oocytes (22 vs. 21) and a higher number of mature oocytes (16 vs. 14). The number of cryopreserved blastocysts (median of five blastocysts in both groups) was similar. Women in the hCG group needed a lower number of warming cycles to achieve live birth (1.32 vs. 2.12), had higher embryo implantation rates (48% vs. 39%), and the proportion of embryos transferred until live birth was lower (33% vs. 57%). The cumulative live birth rate was similar between the groups (48.15% vs. 48%)., Conclusion(s): Although the cumulative live birth rate is similar, a single dose of GnRHa possibly results in suboptimal oocyte and embryo competence, as manifested by decreased embryo implantation rates and increased time needed to achieve live birth., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

Objective: To identify risk factors for a suboptimal response to gonadotropin-releasing hormone (GnRH) agonist trigger in in vitro fertilization (IVF) cycles., Design: Retrospective cohort study., Setting: Academic medical center., Patient(s): All 424 patients undergoing fresh IVF cycles (n = 500) between August 2007 and June 2013 in whom a GnRH agonist was used as all or part of the ovulation trigger., Intervention(s): GnRH-antagonist-based IVF cycles triggered with leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin., Main Outcome Measure(s): Suboptimal response to GnRH-agonist trigger, as defined by a serum luteinizing hormone (LH) level <15 mIU/mL on the morning after trigger., Result(s): The rate of suboptimal response to the GnRH-agonist trigger was 5.2%. Patients with a suboptimal hormone response had lower follicle-stimulating hormone (<0.1 vs. 3.48) and LH (<0.1 vs. 2.51) levels on day 2 of the cycle start, lower LH (0.109 vs. 0.596) on the day of trigger, and required longer stimulation and more gonadotropins than those with an adequate response. Suboptimal responders were also more likely to have irregular menses and be on long-term oral contraception. Patients with an undetectable LH on the day of trigger had a 25% chance of a suboptimal LH surge. In our study cohort, limiting the use of the GnRH-agonist trigger alone to patients with a trigger day LH ≥0.5 would have reduced the rate of suboptimal response from 5.2% to 0.2%., Conclusion(s): Long-term hormonal contraception use is an independent risk factor for suboptimal response to GnRH-agonist trigger. Patients with very low endogenous serum LH levels on the day of LH trigger are at increased risk for a suboptimal GnRH-agonist trigger response. Understanding the at-risk phenotype and using trigger day LH as a marker for increased risk of suboptimal GnRH-agonist trigger response can be helpful for individualizing treatment and selecting a safe and efficacious trigger medication for patients undergoing IVF., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Since the introduction of the gonadotrophin-releasing hormone analogues (GnRHa) protocol, it has become possible to trigger final oocyte maturation with a bolus of GnRHa. This leads to a significant reduction or complete elimination of ovarian hyperstimulation syndrome compared with human chorionic gonadotrophin (HCG) trigger. Early trials showed a severe luteal phase insufficiency after GnRHa trigger despite the application of standard luteal phase support protocols. Subsequent research has led to modifications of the luteal phase support, resulting in reproductive outcome comparable to that seen after HCG trigger in normal- and high-responders. GnRHa trigger facilitates a tailored approach to subsequent luteal phase support, taking into account the ovarian response to stimulation. In the future, GnRHa is likely to be used for trigger in all women co-treated with GnRH antagonists., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)