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Background A consensus has been reached on the preferred primary outcome of all infertility treatment trials, which is the cumulative live birth rate (CLBR). Some recent randomized controlled trials (RCTs) and retrospective studies have compared the effectiveness of GnRH-antagonist and GnRH-agonist protocols but showed inconsistent results. Studies commonly used conservative estimates and optimal estimates to described the CLBR of one incomplete assisted reproductive technology (ART) cycle and there are not many previous studies with data of the complete cycle to compare CLBRs in GnRH-antagonist versus GnRH-agonist protocols. Methods A total of 18,853 patients have completed their first IVF cycle including fresh and subsequent frozen-thawed cycles during 2016–2019, 16,827 patients were treated with GnRH-a long and 2026 patients with GnRH-ant protocol. Multivariable logistic analysis was used to evaluate the difference of GnRH-a and GnRH-ant protocol in relation to CLBR. Utilized Propensity Score Matching(PSM) for sampling by up to 1:1 nearest neighbor matching to adjust the numerical difference and balance the confounders between groups. Results Before PSM, significant differences were observed in baseline characteristics and the CLBR was 50.91% in the GnRH-a and 33.42% in the GnRH-ant (OR = 2.07; 95%CI: 1.88–2.28; P  < 0.001). Stratified analysis showed the CLBR of GnRH-ant was lower than GnRH-a in suboptimal responders(46.89 vs 27.42%, OR = 2.34, 95%CI = 1.99–2.74; P  < 0.001) and no differences of CLBR were observed in other patients between protocols. After adjusting for potential confounders, multivariable logistic analysis found the CLBR of GnRH-ant group was lower than that of GnRH-a group (OR = 2.11, 95%CI:1.69–2.63,  P  < 0.001). After PSM balenced the confounders between groups, the CLBR of GnRH-a group was higher than that of GnRH-ant group in suboptimal responders((38.61 vs 28.22%, OR = 1.60, 95%CI = 1.28–1.99; P  < 0.001) and the normal fertilization rate and number of available embryo in GnRH-a were higher than these of GnRH-ant groups in suboptimal responders (77.39 vs 75.22%; 2.86 ± 1.26 vs 2.61 ± 1.22; P  < 0.05). No significant difference was observed in other patients between different protocols. Conclusions It is crucial to optimize the utilization of protocols in different ovarian response patients and reconsider the field of application of GnRH-ant protocols in China.

Background Diminished ovarian reserve (DOR) is one of the obstacles affecting the reproductive outcomes of patients receiving assisted reproductive therapy. The purpose of this study was to investigate whether dual trigger, including gonadotropin‐releasing hormone agonist (GnRHa) and human chorionic gonadotropin (hCG), can improve pregnancy outcomes in patients with DOR undergoing in vitro fertilization (IVF) cycles using mild stimulation protocols. Methods A total of 734 patients with DOR were included in this retrospective study. Patients were divided into a recombinant hCG trigger group and a dual trigger group (hCG combined with GnRHa) according to the different trigger drugs used. The main outcome measures included the number of oocytes retrieved, the fertilization rate, the number of transferable embryos, the implantation rate, the clinical pregnancy rate, the miscarriage rate, the live birth rate (LBR), and the cumulative live birth rate (CLBR). Generalized linear model and logistic regression analyses were performed for confounding factors. Results There were 337 cycles with a single hCG trigger and 397 cycles with dual trigger. The dual trigger group demonstrated significantly higher numbers of retrieved oocytes [3.60 vs. 2.39, adjusted β = 0.538 (0.221–0.855)], fertilized oocytes [2.55 vs. 1.94, adjusted β = 0.277 (0.031–0.523)] and transferable embryos [1.22 vs. 0.95, adjusted β = 0.162 (-0.005–0.329)] than did the hCG trigger group, whereas no significant difference in the fertilization rate was observed between the two groups. Moreover, the embryo transfer cancellation rate (35.5% vs. 43.9%) was obviously lower in the dual trigger group. Among the fresh embryo transfer cycles, the implantation rate, clinical pregnancy rate, miscarriage rate and live birth rate were similar between the two groups. After controlling for potential confounding variables, the trigger method was identified as an independent factor affecting the number of oocytes retrieved but had no significant impact on the CLBR. Conclusions Dual triggering of final oocyte maturation with hCG combined with GnRHa can significantly increase the number of oocytes retrieved in patients with DOR but has no improvement effect on the implantation rate, clinical pregnancy rate or LBR of fresh cycles or on the CLBR.

Background To evaluate whether there was a difference in outcome between pulsatile gonadotropin releasing hormone (GnRH) therapy and human chorionic gonadotropin/human menopausal gonadotropin (hCG/HMG) therapy for induction of spermatogenesis in post-pubertal male patients with congenital hypogonadotropic hypogonadism (CHH). Methods This was a single-center retrospective cohort study conducted at the Andrology Center of a university hospital. A total of 155 postpubertal CHH patients who met the inclusion criteria underwent spermatogenic induction at the same andrology center. All patients used pulsatile GnRH therapy or hCG/HMG therapy for at least 6 months. The effects of spermatogenic induction therapy and testicular growth were evaluated. Logistic regression analysis was used to identify statistically significant factors which could predict the outcome of treatment. Results There was no difference in the efficiency of successfully inducing spermatogenesis between pulsatile GnRH therapy and hCG/HMG therapy (82.1% vs. 75.8%, P: 0.356), nor was there a difference in sperm concentration category (SCC) (P: 0.284). However, the mean time required for pulsatile GnRH therapy was shorter (12.34 vs. 14.74 months, P: 0.038). At the treatment endpoint, total testicular volume (TTV) was greater with pulsatile GnRH therapy compared with hCG/HMG therapy (15 vs. 12 ml, P: 0.010), and there was still no difference in SCC (P: 0.310). Multivariate logistic regression analysis showed that only baseline TTV was statistically significant predictor of induced spermatogenic success (odds ratio, OR: 1.156, 95% confidence interval, CI: 1.013, 1.319). The area under receiver operating characteristic curve was 0.635, a sensitivity of 0.661, and a specificity of 0.588. In addition, multiple linear regression analysis demonstrated that younger age at treatment initiation and higher baseline TTV were significantly associated with increased sperm concentration at the end of treatment. Conclusion Pulsatile GnRH therapy was similar to hCG/HMG therapy in inducing spermatogenesis in post-pubertal CHH patients, but it took less time and was more beneficial to testicular development. Larger baseline TTV may mean a better spermatogenic outcome. It was necessary for patients to have more information about spermatogenesis therapy in order to make reasonable medical decisions. Clinical trial registration number Chinese Clinical Trial Registry. ChiCTR2400086876. Retrospectively registered on July 5, 2024.

Embryo implantation is a complex process involving continuous molecular cross-talk between the embryo and the decidua. One of the key molecules during this process is human chorionic gonadotropin (HCG). HCG effectively modulates several metabolic pathways within the decidua contributing to endometrial receptivity. Herein, a brief overview of the molecular mechanisms regulated by HCG is presented. Furthermore, we summarize the existing evidence regarding the clinical impact on reproductive outcomes after endometrial priming with HCG prior to embryo transfer. Although promising, further evidence is needed to clarify the protocol that would lead to beneficial outcomes.

Background Traditionally, final follicular maturation is triggered by a single bolus of human chorionic gonadotropin (hCG). This acts as a surrogate to the naturally occurring luteinizing hormone (LH) surge to induce luteinization of the granulosa cells, resumption of meiosis and final oocyte maturation. More recently, a bolus of gonadotropin-releasing hormone (GnRH) agonist in combination with hCG (dual trigger) has been suggested as an alternative regimen to achieve final follicular maturation. Methods This study was a systematic review and meta-analysis of randomized trials evaluating the effect of dual trigger versus hCG trigger for follicular maturation on pregnancy outcomes in women undergoing in vitro fertilization (IVF). The primary outcome was the live birth rate (LBR) per started cycle. Results A total of 1048 participants were included in the analysis, with 519 in the dual trigger group and 529 in the hCG trigger group. Dual trigger treatment was associated with a significantly higher LBR per started cycle compared with the hCG trigger treatment (risk ratio (RR) = 1.37 [1.07, 1.76], I 2  = 0%, moderate evidence). There was a trend towards an increase in both ongoing pregnancy rate (RR = 1.34 [0.96, 1.89], I 2  = 0%, low evidence) and implantation rate (RR = 1.31 [0.90, 1.91], I 2  = 76%, low evidence) with dual trigger treatment compared with hCG trigger treatment. Dual trigger treatment was associated with a significant increase in clinical pregnancy rate (RR = 1.29 [1.10, 1.52], I 2  = 13%, low evidence), number of oocytes collected (mean difference (MD) = 1.52 [0.59, 2.46), I 2  = 53%, low evidence), number of mature oocytes collected (MD = 1.01 [0.43, 1.58], I 2  = 18%, low evidence), number of fertilized oocytes (MD = 0.73 [0.16, 1.30], I 2  = 7%, low evidence) and significantly more usable embryos (MD = 0.90 [0.42, 1.38], I 2  = 0%, low evidence). Conclusion Dual trigger treatment with GnRH agonist and HCG is associated with an increased live birth rate compared with conventional hCG trigger. Trial registration CRD42020204452 .

To evaluate pregnancy outcomes and the incidence of ovarian hyperstimulation syndrome (OHSS) using a sliding scale hCG protocol to trigger oocyte maturity and establish a threshold level of serum b-hCG associated with optimal oocyte maturity. Retrospective cohort. Academic medical center. Fresh IVF cycles from 9/2004-12/2011. 10,427 fresh IVF-ICSI cycles met inclusion criteria. hCG was administered according to E2 level at trigger: 10,000IU vs. 5,000IU vs. 4,000IU vs. 3,300IU vs. dual trigger (2mg leuprolide acetate + 1,500IU hCG). Serum absorption of hCG was assessed according to dose and BMI. Oocyte maturity was analyzed according to post-trigger serum b-hCG. Fertilization, clinical pregnancy, live birth and OHSS rates were examined by hCG trigger dose. Post-trigger serum b-hCG 20-30, 30-40, and 40-50 mIU/mL was associated with reduced oocyte maturity as compared b-hCG >50 (67.8% vs. 71.4% vs. 73.3% vs. 78.9%, respectively, P<0.05). b-hCG 20-50 mIU/mL was associated with a 40.1% reduction in live birth (OR 0.59, 95% CI 0.41-0.87). No differences in IVF outcomes per retrieval were seen for varying doses of hCG or dual trigger when controlling for patient age. The incidence of moderate to severe OHSS was 0.13% (n = 14) and severe OHSS was 0.03% (n = 4) of cycles. Moderate stimulation with sliding scale hCG at trigger and fresh transfer is associated with low rates of OHSS and favorable pregnancy rates. Doses as low as 3,300IU alone or dual trigger with 1,500IU are sufficient to facilitate oocyte maturity.

The final trigger of oocyte maturation is a pivotal step in assisted reproductive technology (ART). Different molecules and protocols-including human chorionic gonadotropin (hCG), gonadotropin-releasing hormone agonists (GnRHa), the dual trigger, the double trigger, and emerging agents such as kisspeptin-have been investigated to optimize oocyte competence, embryo development, and pregnancy outcomes while minimizing the risk of ovarian hyperstimulation syndrome (OHSS). HCG remains the most widely used trigger, but its pharmacological profile is associated with a significant risk of OHSS. GnRHa has emerged as an alternative in antagonist cycles, abolishing the risk of severe OHSS but often requiring tailored luteal phase support. Several strategies, including hCG, GnRHa, and combined approaches, have shown improvements in specific outcomes such as the oocyte maturity (MII) rate, fertilization rate, embryo development parameters, and, in selected contexts, a reduction in OHSS risk. Kisspeptin represents a promising option; however, its use remains predominantly within the research setting, with clinical application still limited to early-phase or highly selected studies. Beyond the choice of molecule, the timing of trigger administration-adjusted to follicle size, estradiol concentrations, and progesterone levels-also influences oocyte competence and subsequent clinical outcomes. Triggering final oocyte maturation remains a multifaceted decision that should be individualized according to patient characteristics, ovarian response, and risk of OHSS. Although hCG remains the historical reference standard, accumulating but heterogeneous evidence suggests that GnRHa-based strategies, including dual-trigger protocols, may improve specific outcomes in selected patient subgroups. However, results across trials are inconsistent, particularly in poor responders, and any exposure to hCG maintains a residual risk of OHSS. Kisspeptin represents a promising but still experimental option, with current data largely limited to early-phase clinical studies in highly selected high-risk populations. Well-designed randomized trials are required to clarify the true impact of these strategies on live birth, to refine timing and dosing, and to better define which patients are most likely to benefit.

Background The utilization of a double trigger, involving the co-administration of gonadotropin-releasing hormone agonist (GnRH-a) and human chorionic gonadotropin (hCG) for final oocyte maturation, is emerging as a novel approach in gonadotropin-releasing hormone antagonist (GnRH-ant) protocols during controlled ovarian hyperstimulation (COH). This protocol involves administering GnRH-a and hCG 40 and 34 h prior to ovum pick-up (OPU), respectively. This treatment modality has been implemented in patients with low/poor oocytes yield. This study aimed to determine whether the double trigger could improve the number of top-quality embryos (TQEs) in patients with fewer than three TQEs. Methods The stimulation characteristics of 35 in vitro fertilization (IVF) cycles were analyzed. These cycles were triggered by the combination of hCG and GnRHa (double trigger cycles) and compared to the same patients’ previous IVF attempt, which utilized the hCG trigger (hCG trigger control cycles). The analysis involved cases who were admitted to our reproductive center between January 2018 and December 2022. In the hCG trigger control cycles, all 35 patients had fewer than three TQEs. Results Patients who received the double trigger cycles yielded a significantly higher number of 2PN cleavage embryos (3.54 ± 3.37 vs. 2.11 ± 2.15, P  = 0.025), TQEs ( 2.23 ± 2.05 vs. 0.89 ± 0.99, P  < 0.001), and a simultaneously higher proportion of the number of cleavage stage embryos (53.87% ± 31.38% vs. 39.80% ± 29.60%, P  = 0.043), 2PN cleavage stage embryos (43.89% ± 33.01% vs. 27.22% ± 27.13%, P  = 0.014), and TQEs (27.05% ± 26.26% vs. 14.19% ± 19.76%, P  = 0.019) to the number of oocytes retrieved compared with the hCG trigger control cycles, respectively. The double trigger cycles achieved higher rates of cumulative clinical pregnancy (20.00% vs. 2.86%, P  = 0.031), cumulative persistent pregnancy (14.29% vs. 0%, P  < 0.001), and cumulative live birth (14.29% vs. 0%, P  < 0.001) per stimulation cycle compared with the hCG trigger control cycles. Conclusion Co-administration of GnRH-agonist and hCG for final oocyte maturation, 40 and 34 h prior to OPU, respectively (double trigger) may be suggested as a valuable new regimen for treating patients with low TQE yield in previous hCG trigger IVF/intracytoplasmic sperm injection (ICSI) cycles.

ProposeThe 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.MethodA 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).ResultsWe 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]).ConclusionThe 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.RelevanceAfter dual trigger, delaying ET due to the concern of endometrial receptivity might not be needed.

Research question Does luteinizing hormone (LH) levels on human chorionic gonadotropin (HCG) trigger day (LH HCG ) affect the clinical outcomes of patients with diminished ovarian reserve (DOR) undergoing gonadotropin-releasing hormone antagonist (GnRH-ant) protocol? Methods Retrospective analysis fresh embryo transfer cycles of DOR patients who underwent GnRH-ant protocol from August 2019 to June 2023. The participants were divided into different groups according to LH HCG level and age. The clinical data and outcomes were compared between groups. Results In patients with DOR, the HCG positive rate (59.3% versus 39.8%, P  = 0.005), embryo implantation rate (34.5% versus 19.7%, P  = 0.002), clinical pregnancy rate (49.2% versus 28.4%, P  = 0.003), live birth rate (41.5% versus 22.7%, P  = 0.005) in LH HCG < 2.58 IU/L group were significantly higher than LH HCG ≥ 2.58 IU/L group. There was no significant correlation between LH HCG level and clinical pregnancy in POSEIDON group 3. In POSEIDON group 4, the HCG positive rate (52.8% versus 27.0%, P  = 0.015), embryo implantation rate (29.2% versus 13.3%, P  = 0.023), clinical pregnancy rate (45.3% versus 18.9%, P  = 0.010) in LH HCG < 3.14 IU/L group were significantly higher than LH HCG ≥ 3.14 IU/L group. Logistic regression analysis indicated that LH HCG level was an independent influencing factor for clinical pregnancy in POSEIDON group 4 patients (OR = 3.831, 95% CI: 1.379–10.643, P  < 0.05). Conclusions LH HCG level is an independent factor affecting pregnancy outcome of fresh embryo transfer in DOR patients undergoing GnRH-ant protocol, especially for advanced-aged women. LH HCG had a high predictive value for POSEIDON group 4 patients, and LH HCG ≥ 3.14 IU/L predicts poor pregnancy outcomes.