Low dose hCG supplementation in a Gn-RH-agonist trigger protocol is associated with worse pregnancy outcomes: a retrospective cohort study

Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders

Background: the purpose of this study was to compare rates of ovarian hyperstimulation syndrome (OHSS) and the pregnancy outcome after using gonadotropin-releasing hormone agonists (GnRHa) alone and GnRHa in combination with low-dose human chorionic gonadotropin (hCG, dual trigger) for final oocyte maturation in women undergoing controlled ovarian hyperstimulation (COH). Patients and Methods: the study included 150 female patients with high risk of OHSS occurrence who were allocated by the Computer-based randomization method into two groups with 75 patients in each arm, Group I received GnRHa trigger and Group II received dual trigger (GnRHa + low-dose (1500 IU) hCG trigger). Results: Our study showed that the incidence of OHSS was higher after dual trigger than GnRHa trigger but with no statistically significant difference (8.0 vs 1.33 %, p >0.05). There were 6 cases of OHSS developed with dual trigger group (Group II) (3 were mild early OHSS, 2 were moderate early and one case was severe late OHSS). In contrast, there was only one case of severe late OHSS seen in Group I. Conclusion: Dual trigger for final oocyte maturation using GnRHa and low-dose hCG is associated with increased the incidence of early OHSS compared to GnRH alone. However, dual trigger appears to be a safe approach with a satisfactory pregnancy outcome. Also, the dual trigger improves the oocyte maturation, the number of yield embryos and the quality of embryos.

Is a dual ovulation trigger with a combination of GnRH agonist (GnRHa) and hCG superior to single hCG and/or single GnRHa trigger in improving treatment outcomes in advanced-age women (aged ≥ 35 years) undergoing IVF/ICSI treatment? Co-administration of GnRHa and hCG as a dual trigger increases the number of good-quality embryos but it is not associated with a higher number of oocytes retrieved, compared with single hCG or GnRHa trigger. Many studies have demonstrated that a dual trigger has positive impact on oocyte maturation, retrieval rate and pregnancy rate without increasing the risk of ovarian hyperstimulation syndrome (OHSS) in some groups of IVF patients, when compared with single hCG trigger. Few studies have however been conducted to compare a dual trigger with a single GnRHa trigger, and insufficient evidence exists to support which trigger can achieve the best outcomes in IVF patients aged ≥35 years. This was an open-label randomized controlled trial of 510 participants conducted at single reproductive medical center from January 2019 to December 2021. After a sample size calculation performed by retrospectively analyzing our previous clinical data, we planned to recruit 170 patients in each group and 510 patients in total for the study. Women aged ≥35 years undergoing IVF/ICSI treatment, receiving a non-pituitary down-regulation protocol, and with low risk of OHSS, were enrolled in this trial. On the trigger day, patients were randomized into three groups: hCG alone (who received 6000 IU of hCG), GnRHa alone (who received 0.2 mg of triptorelin) and dual trigger (who received 0.2 mg of triptorelin plus 2000 IU of hCG) groups. The primary outcome parameter was the number of retrieved oocytes. The secondary outcome parameters included, among others, the number and rates of mature oocytes, two pronuclei (2PN) embryos and good-quality embryos, as the rates of OHSS, clinical pregnancy, miscarriage and live birth. There were no significant differences in the baseline demographic characteristics among the three groups. The dual trigger was associated with a higher retrieval rate (87.9% vs 84.1% in the hCG group, P = 0.031; 87.9% vs 83.6% in the GnRHa group, P = 0.014). However, the number of retrieved oocytes in the dual trigger group was comparable with those in the hCG group (4.08 ± 2.79 vs 3.60 ± 2.71, P = 0.080) and the GnRHa group (4.08 ± 2.79 vs 3.81 ± 3.38, P = 0.101); comparable data between the groups were also found when analyzing the number of 2PN embryos and the 2PN rate. In the dual trigger group, the numbers of good-quality embryos and viable embryos were both significantly higher than in the hCG group (1.74 ± 1.90 vs 1.19 ± 1.45, P = 0.016 and 2.19 ± 2.11 vs 1.56 ± 1.66, P = 0.008, respectively) and the GnRHa group (1.74 ± 1.90 vs 1.20 ± 1.67, P = 0.003 and 2.19 ± 2.11 vs 1.45 ± 1.75, P = 0.001, respectively). Pregnancy outcomes after fresh embryo transfer (ET) were comparable between the groups. The live birth rate and ongoing pregnancy rate after frozen ET in the dual trigger group were significantly higher than those in the GnRHa group (32.6% vs 14.1%, P = 0.007 and 34.8% vs 17.6%, P = 0.013, respectively), but not superior to those in the hCG group (32.6% vs 27.9%, P = 0.537 and 34.8% vs 27.9%, P = 0.358, respectively). Women of advanced age are quite a heterogeneous population and overlap with poor ovarian responders or patients with diminished ovarian reserve. We therefore could not entirely exclude selection biases or confounding factors. This study was also not a double-blinded trial; the patients in the GnRHa and dual trigger groups could have been affected by the placebo effect. The results of this study suggest that in advanced-age women with low risk of OHSS, a dual trigger or even a single hCG trigger may be a better choice than a single GnRHa trigger. This study was supported by the Shanghai Municipal Health Commission of Science and Research Fund (20184Y0289). The authors declare no conflict of interest. This trial was registered in the Chinese Clinical Trial Registry (ChiCTR-1800016285). 24 May 2018. 2 January 2019.

Agonist and antagonist coast

Preventing ovarian hyperstimulation with gonadotropin-releasing hormone agonist trigger: is anything perfect?

Risk of severe ovarian hyperstimulation syndrome in GnRH antagonist versus GnRH agonist protocol: RCT including 1050 first IVF/ICSI cycles.

Gonadotropin-releasing hormone agonist to induce final oocyte maturation prevents the development of ovarian hyperstimulation syndrome in high-risk patients and leads to improved clinical outcomes compared with coasting

This study compared, in high responders undergoing IVF treatment, GnRH agonist-only trigger and dual trigger on oocyte retrieval rate and cumulative live birth rate (LBR). The aim was to determine if the GnRH agonist-only triggers had provided outcomes comparable to dual trigger, while minimizing the risk of ovarian hyperstimulation syndrome (OHSS). A retrospective, matched case-control study was conducted at Taichung Veterans General Hospital, Taiwan, including women who underwent IVF/ICSI between January 1, 2014, and December 31, 2022. Inclusion criteria were: GnRH antagonist protocol and estrogen level >3,000 pg/ml on trigger day. Exclusion criteria were: immune/metabolic diseases, donated oocytes, and mixed stimulation cycles. Propensity score matching was applied to balance age, AMH level, and oocyte number between the GnRH agonist-only and dual trigger groups. Outcomes were analyzed for patients who had complete treatment cycles, focusing on oocyte retrieval rate and cumulative LBR. We analyzed 116 cycles in the agonist-only group, and 232 cycles in the dual trigger group. No inter-group difference was found in their age, BMI, and AMH levels. The dual trigger group had a higher oocyte retrieval rate (93% vs. 80%; p <0.05), while fertilization rates, blastocyst formation rates, and cumulative LBR were comparable. Notably, no OHSS cases had been reported in the GnRH agonist-only group, compared with 7 cases in the dual trigger group. GnRH agonist-only triggers resulted in a lower oocyte retrieval rate compared to dual triggers but did not significantly affect cumulative LBR in high responders. This approach effectively reduces OHSS risk without compromising pregnancy outcomes, making it a preferable option in freeze-all strategies, despite a longer oocyte pick-up duration and a medium cost. GnRH agonist-only trigger, however, may not be suitable for fresh embryo transfers or patients with low serum LH levels on trigger day.

Low-dose human chorionic gonadotropin versus estradiol/progesterone luteal phase support in gonadotropin-releasing hormone agonist–triggered assisted reproductive technique cycles: understanding a new approach

Study question Does dual trigger with co-administration of GnRH agonist and Human Chorionic Gonadotropin (hCG) increase the outcome of Intrauterine Insemination (IUI) compared to hCG alone? Summary answer using the dual trigger for final oocyte maturation increases the clinical pregnancy rate compared to triggering with hCG alone in IUI cycle. What is known already Various techniques are performed to increase the success rates of Intrauterine Insemination (IUI) including sperm preparation, ovarian stimulation, ovulation trigger, and endometrial preparation. The dual trigger of final oocyte maturation with a GnRH-agonist and a standard dosage of hCG increase the outcome of in vitro fertilization (IVF) cycles significantly but this dual trigger has not been used in IUI. Study design, size, duration A single center, retrospective observational study between January 2016 and October 2018 was performed in 639 IUI cycles in Halim Fertility Center (HFC), Division of Reproductive Endocrinology and Infertility, Faculty of Medicine, Universitas Sumatera Utara, Indonesia. Participants/materials, setting, methods Six hundred and thirty-nine IUI cycles were divided into two groups: group I received recombinant hCG alone as the single trigger and group II received GnRH agonist plus recombinant hCG as dual-trigger. Data on patients age,FSH, AMH, total amount of rFSH, sperm quality, endometrial thickness, number of basal antral follicles, number of follicles &amp;gt; 17 mm, clinical pregnancy rate, multiple pregnancy rate and Ovarian hyperstimulation syndrome (OHSS) were assessed and compared between the two groups. Main results and the role of chance Our study included 639 IUI cycles with a dual trigger group (334 IUI cycles) and a single trigger (305 IUI cycles). The age of participants (32 years versus 32 years, P = 0.945), FSH (6.3 mIU/mL versus 6.5 mIU/mL, P = 0.411), AMH (2.7 ng/mL versus 2.4 ng/mL), P = 0.340), total amount of rFSH (900 IU versus 900 IU, P = 0.873), sperm concentration (17.2x106/mL versus 17.3x106/mL, P = 0.488), sperm motility (35% versus 35%, P = 0.847), sperm morphology (5%normal versus 5%normal, P = 0.916), TMSC (13.9x106/ejaculate versus 12.6x106/ejaculate, P = 0.545) were comparable between the two groups. The endometrial thickness (9 mm versus 9 mm, P = 0.337), the number of basal antral follicles (7 versus 7, P = 0.587) and the number of follicles &amp;gt;17mm (2 versus 2, P = 0.974) were also comparable between the two groups. The clinical pregnancy rate (14.1% versus 28.7%, P &amp;lt; 0.001) with RR value 2.524 (95%CI RR 1.681-3.790) was significantly higher in the dual trigger compared to the single trigger group. The multiple pregnancy rate (7% versus 7.3%), P = 0.627) and OHSS rate (2.6% versus 2.7%, P = 0.576) were no significantly difference between the two groups. Limitations, reasons for caution This study is a retrospective study so that data sampling was not well controlled. Data recruitment is based on a period because we modified the ovulation trigger from a single trigger to dual trigger after almost one year then we evaluated the outcome of IUI between the two groups. Wider implications of the findings This is the first study to evaluate the outcome of the dual trigger on ovulation trigger in intrauterine insemination (IUI) in Indonesia. The present study indicates a potential dual trigger might lead to better IUI outcomes and it can be used more widely. Trial registration number Not applicable

The purpose of this study was to assess whether the implementation of a "dual trigger" approach, utilizing gonadotropin-releasing hormone agonist (GnRHa) and human chorionic gonadotropin (hCG) in the GnRH antagonist protocol for in vitro fertilization (IVF), leads to improved pregnancy outcomes compared to the conventional hCG trigger alone. Previous meta-analyses have not provided sufficient evidence to support the superiority of the dual trigger over the hCG trigger in fresh or frozen embryo transfer cycles. Thus, a systematic review and meta-analysis of randomized trials were conducted to provide a comprehensive evaluation of the impact of the dual trigger on pregnancy outcomes in fresh or frozen embryo transfer cycles. A systematic review and meta-analysis of randomised controlled trials (RCTs) were conducted. We searched the Medline and Embase databases for articles up to 2023 by using search terms: "dual trigger," "GnRHa," "hCG," "IVF." Eligible RCTs comparing the dual trigger with the hCG trigger were included. The primary outcome was the live birth rate (LBR) per cycle. The secondary outcomes were the number of oocytes retrieved, number of mature oocytes retrieved, implantation rate, biochemical pregnancy rate, CPR, miscarriage rate and ovarian hyperstimulation syndrome (OHSS) rate per started cycle We compared the oocyte maturation and pregnancy outcomes in the dual trigger and hCG trigger groups. In patients undergoing fresh embryo transfer (ET) and frozen-thawed ET, we also conducted a subgroup analysis to evaluate whether dual trigger improves the clinical pregnancy rate (CPR). We included 10 randomised studies, with 825 participants in the dual trigger group and 813 in the hCG trigger group. Compared with the hCG trigger, dual trigger was associated with a significant increase in the LBR per cycle (odds ratio (OR) = 1.61[1.16, 2.25]), number of oocytes retrieved (mean difference [MD] = 1.05 [0.43, 1.68]), number of mature oocytes retrieved (MD = 0.82 [0. 84, 1.16]), and CPR (OR = 1.48 [1.08, 2.01]). Subgroup analyses revealed that dual trigger was associated with a significantly increased CPR in patients who received fresh ET (OR = 1.68 [1.14, 2.48]). By contrast, the dual trigger was not associated with an increased CPR in the patient group with frozen-thawed ET (OR = 1.15 [0.64, 2.08]). The dual trigger was associated with a significantly higher number of retrieved oocytes, number of mature oocytes, CPR, and LBR in IVF than the hCG trigger. The beneficial effect for fresh ET cycles compared with frozen-thawed ET might be associated with increased endometrial receptivity. After dual trigger, delaying ET due to the concern of endometrial receptivity might not be needed.

PurposeThis study was designed to evaluate the effects of dual trigger (GnRH agonist and hCG) compared with hCG trigger alone on oocyte quality, embryo development, and pregnancy outcomes in elderly women (aged≥35 years) who underwent IVF treatment with an antagonist stimulation protocol, aiming to identify the more optimal triggering strategy.MethodsThis retrospective cohort study analyzed 449 elderly infertile women (≥35 years) who underwent antagonist stimulation protocols, including 236 patients in the hCG trigger group and 213 patients in the dual trigger group. The study compares the age, gravidity, parity, body mass index (BMI),anti-Müllerian hormone (AMH),gonadotropin (Gn) days, Gn dosage, trigger day luteinizing hormone (LH), trigger day estradiol (E2), trigger day progesterone (P), number of follicles ≥14mm on trigger day, number of oocytes retrieved, two pronuclei (2PN) fertilization rate, cleavage-stage embryo number, blastocyst number, embryo implantation rate (IR), clinical pregnancy rate (CPR), live birth rate (LBR), and miscarriage rate between the two groups. Multivariate logistic regression was used to analyze the influencing factors of CPR in patients.ResultsThere were no significant differences in baseline and cycle data between the two groups. In terms of oocyte and embryo outcomes, the number of oocytes retrieved (P=0.018), 2PN fertilization rate (P=0.046), and cleavage-stage embryo number (P=0.032) were significantly higher in the dual trigger group than in the hCG trigger group. There was no significant difference in the number of blastocysts obtained in the cycles of the two groups (P=0.689). In terms of pregnancy outcomes, the CPR per embryo transfer (ET) cycle (P=0.010),the CPR per frozen embryo transfer (FET) cycle (P=0.011), total embryo IR (P<0.001), total CPR (P<0.001), CPR per patient (P=0.003), total LBR (P<0.001), and LBR per patient (P=0.001) were all significantly higher in the dual trigger group than in the hCG trigger group. There was no significant difference in the miscarriage rate between the two groups (P=0.841). No cases of ovarian hyperstimulation syndrome (OHSS) occurred in either group.ConclusionFor elderly women undergoing antagonist stimulation protocols, the use of dual trigger, is more effective than hCG trigger alone in improving oocyte quality, embryo outcomes, and pregnancy outcomes.

The aim of this study was to compare clinical and laboratory outcomes between GnRHa, dual and HCG triggers in altruistic oocyte donation cycles. Normal or high responders were given either gonadotropin releasing hormone agonist (GnRHa) or a dual trigger of GnRHa and a low dose of human chorionic gonadotropin (HCG). Low responders were given HCG trigger. In 333 cycles, 232 (69.7%) received GnRHa trigger, 59 (17.7%) received dual trigger and 42 (12.6%) had HCG trigger. The total number of mature oocytes retrieved and cryopreserved were significantly higher in the GnRHa and dual trigger groups, compared to the HCG group (p < 0.001). However, the ovarian hyperstimulation syndrome (OHSS) rate was significantly higher in the dual trigger group (n = 5 (8.5%)), compared to the GnRH agonist (n = 1 (0.4%)) and HCG groups (n = 0 (0%)) (p = 0.001). GnRHa trigger maximises mature oocyte yields in oocyte donors suspected of normal and high response but offers a significant reduction in OHSS risk compared to dual trigger. As such, dual trigger should not be used in oocyte donation. HCG trigger can also be used with a very low risk of OHSS at low risk of OHSS in carefully selected donors where GnRHa is unlikely to be effective.

The study aimed to evaluate the impact of the dual trigger with the combination of GnRH agonist and standard dose of recombinant hCG on IVF outcomes in poor ovarian responders with GnRH antagonist protocol. 1283 cycles of 1010 poor responder patients according to Bologna criteria were retrospectively analysed in terms of final oocyte maturation: dual trigger group (250 μg hCG + 0.2 mg triptorelin) or standard group (250 μg hCG). Primary outcome measures were the number of retrieved and mature oocytes. The secondary outcome measures were clinical pregnancy rates and live birth rates. The number of retrieved oocytes, mature oocytes, and the top-quality embryos transferred were significantly higher in the dual trigger group (p < .001). Fertilisation rates (73.6% vs 69.6%, p = .009), implantation rates (18.7% vs 14.6, p = .039), clinical pregnancy rate per embryo transfer (27.5% vs. 19.9%, p = .010) and live birth rate per embryo transfer (21.6% vs. 14.9%, p = .011) were also significantly higher in the dual trigger group as compared to the hCG trigger group. The usage of dual trigger with a GnRH agonist and a standard dosage of hCG could improve clinical pregnancy rates and live birth rates in poor ovarian responders undergoing GnRH antagonist IVF/ICSI cycles. IMPACT STATEMENT What is already known on this subject? Dual trigger with standard dose of hCG has been the subject of trials in normal responders to optimise IVF outcomes. The results of these studies showed significant improvements in implantation and pregnancy rates with an increase in the number of mature oocytes retrieved. As a result, dual trigger has become a popular ovulation trigger option in GnRH antagonist cycles. What do the results of this study add? There is limited data about the use of dual trigger in poor ovarian responders (PORs). According to our study, increasing the number of retrieved oocytes, mature oocytes, the number of fertilised oocytes, the number of transferred embryos and top quality embryos transferred by using dual trigger in patients with PORs have a positive impact on pregnancy outcomes. What are the implications of these findings for clinical practice and/or further research? These findings implies potential advantages of dual trigger usage for improving IVF outcomes in PORs. With large sample sized prospective randomised trials, dual trigger with combination of GnRHa and a standard dose of hCG might replace the traditional ovulation trigger with hCG in PORs.

The aim of this study was to evaluate whether dual trigger with leuprolide acetate plus recombinant human chorionic gonadotropin (hCG) improves in vitro fertilization outcome in gonadotropin-releasing hormone antagonist cycles. A total of 156 patients diagnosed with mild male factor, unexplained or tubal factor infertility were enrolled in the study. All subjects were allocated into one of two groups: the dual trigger group (leuprolide acetate 500μg + recombinant hCG 250μg) and the standard group (recombinant hCG 250μg) according to the selected trigger method. Oocyte trigger was performed when at least three follicles >17 mm were observed. Pregnancy rate, number of collected oocytes, number of metaphase II oocytes, number of grade-A embryos, cycle cancellation rate, and ovarian hyperstimulation syndrome rate were the main outcome measures for the study. The mean number of grade-A embryos (1.6 ± 1.5 vs 1.1 ± 1.4, P=0.01) and of metaphase II oocytes (7.9 ± 4.6 vs 6.3 ± 5.8, P=0.02) was significantly higher in the dual-trigger group. Pregnancy rate was significantly higher in the dual-trigger group than in the standard group (54.8 vs 37.5%, P=0.006). Two cases of mild ovarian hyperstimulation syndrome were observed in each group. This novel and more physiological trigger approach using 500μg leuprolide acetate plus 250μg recombinant hCG may lead to an increase in the number of metaphase II oocytes, grade-A embryos, and may improve pregnancy rates.