Suboptimal Mature Oocyte Yield in Antagonist Icsi Cycles: Any Impact of the Ovulation Triggering Agent?

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Chloé Maignien, Rami El Hachem, Mathilde Bourdon, Ahmed Chargui, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8939235/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract PURPOSE OF RESEARCH: To evaluate the impact of ovulation-triggering agents on suboptimal mature oocyte yield in antagonist ICSI cycles. DESIGN: We conducted a retrospective cohort study of 2,129 antagonist ICSI cycles at a tertiary university hospital from October 2013 to October 2022. The primary outcome was suboptimal response to triggering, defined as a mature oocyte yield below the 75th percentile. Mature oocyte yield was calculated as the number of mature oocytes retrieved divided by the number of mature follicles (mean diameter ≥ 15 mm) on the trigger day. Prognostic factors for suboptimal response were analyzed using univariate and multivariate methods. RESULTS: Of the cycles, 909 (42.7%) were triggered with GnRHa, 845 (39.7%) with hCG, and 375 (17.6%) with both. The mean mature follicle count was 7.9 ± 4.3, the average number of mature oocytes was 7.0 ± 5.0, and the mean mature oocyte yield was 92.3 ± 55.2%. The 75th percentile for mature oocyte yield was 117%. Mature oocyte yield was significantly higher with GnRHa versus hCG (96.7 ± 59.1% vs. 87.6 ± 48.8%), with no significant difference compared to dual trigger (92.2 ± 58.0%; p = 0.017). Suboptimal yield was lower with GnRHa (71.6%) than hCG (80%), but not dual trigger (76.8%), p = 0.017. Multivariate analysis showed GnRHa triggering was associated with lower risk of suboptimal yield (p < 0.001). CONCLUSION: GnRHa triggering is associated with a reduced risk of suboptimal mature oocyte yield compared to hCG Sexual & Reproductive Medicine Antagonist protocol GnRH agonist hCG Mature oocyte yield Ovulation triggering Figures Figure 1 INTRODUCTION One of the most significant advancements in assisted reproductive technology (ART) over the past few decades has been the use of gonadotropin-releasing hormone agonists (GnRHa) to induce ovulation in antagonist protocols. This development has notably reduced the incidence of ovarian hyperstimulation syndrome (OHSS) [ 1 , 2 ]. OHSS is an iatrogenic complication associated with controlled ovarian hyperstimulation (COH) in IVF/ICSI cycles, triggered by either exogenous or endogenous human chorionic gonadotropin (hCG). This hormone activates the luteinizing hormone (LH)/hCG receptor in the ovaries, leading to the release of vascular endothelial growth factor (VEGF) and increased capillary permeability [ 3 ]. By employing a bolus of GnRHa instead of standard hCG to trigger ovulation, there is a physiological-like surge of endogenous LH, albeit shorter in duration and lower in amplitude [ 4 , 5 ]. This approach results in the rapid regression of the corpus luteum within a few days, effectively reducing VEGF expression and consequently lowering the risk of OHSS. Despite the clear safety advantages of using GnRHa over hCG for triggering ovulation, the debate over their clinical efficacy remains unresolved. Some studies indicate that GnRHa leads to improved outcomes, including a higher number of retrieved and mature oocytes, as well as an increased number of embryos [ 2 ]. Conversely, other research highlights the risk of suboptimal responses to GnRHa, ranging from suboptimal LH levels post-trigger to insufficient oocyte recovery or even empty follicle syndrome [ 6 – 13 ]. However, these studies often lack a control group using hCG, making it difficult to differentiate between intrinsic ovarian issues and those related to the triggering method itself. Given this context of conflicting data, we aimed to compare patients based on their ovulation triggering method to identify clinical factors associated with suboptimal mature oocyte yields in a large cohort undergoing COH for ICSI in a GnRH antagonist protocol. MATERIALS AND METHODS Study population and inclusion criteria We conducted a retrospective cohort study of patients who underwent COH with a GnRH antagonist protocol for ICSI at our university-based reproductive medicine center from October 2013 to October 2022. Inclusion criteria were: (i) age < 43 years at the time of oocyte retrieval; (ii) indication for ICSI, including male factor infertility, previous fertilization failure after conventional IVF, unexplained infertility, and low number of oocytes retrieved [ 14 ]; (iii) COH using a GnRH antagonist protocol; and (iv) final COH monitoring conducted on the day of ovulation triggering. Exclusion criteria included: (i) use of other COH protocols, such as long and short agonist protocols or natural cycles; (ii) IVF cycles that did not allow for the assessment of oocyte maturity on retrieval day; (iii) cycles canceled prior to oocyte retrieval; and (iv) oocyte cryopreservation or donation cycles. General Characteristics The study analysis was based on a prospectively managed database. Data were collected for each patient prior to ART treatment, encompassing personal history and fertility investigation results. The recorded information included: age at retrieval (years), smoking status (active or non-smoker), body mass index (BMI) calculated as weight (kg)/height (m 2 ), and country of birth/geographic origin (European, Asian, African-Caribbean) [ 15 ]. Additional variables included gravidity, parity, type of infertility (primary or secondary), duration of infertility (years), IVF/ICSI cycle rank, and serum levels of day-3 FSH (IU/mL), estradiol (pg/mL), and LH (IU/mL). Also documented were the antral follicle count (AFC), anti-Müllerian hormone (AMH) levels (ng/mL), ovulation status according to the WHO classification [ 16 ], and infertility causes (e.g., male factor, female factor, including ovulatory dysfunction, tubal factor, endometriosis, uterine factor, diminished ovarian reserve/premature ovarian insufficiency, or idiopathic infertility). ICSI cycles: clinical and laboratory procedures Before starting COH, a pre-treatment was administered for scheduling purposes, using either antigonadotropic medication (estro-progestin or progestin pill) or estradiol (0.2 mg/day via two simultaneous Vivelledot® 100 systems; Novartis Pharma SA, France). Ovarian stimulation commenced after a wash-out period of five days for antigonadotropic medication and two days for estradiol. COH was conducted using recombinant follicle-stimulating hormone (FSH; Bemfola®; Gedeon Richter, France) and human menopausal gonadotropin (hMG; Menopur®; Ferring Pharmaceuticals, France), with no adjustments to the gonadotropin dose during stimulation. The initial gonadotropin dose ranged from 150 to 450 IU/day and was determined based on patient age, BMI, AFC, AMH level, and previous responses to gonadotropins. A GnRH antagonist at a daily dose of 0.25 mg was introduced on the 6th day of stimulation. Monitoring of COH occurred every 48–72 hours from the 8th day, involving blood sampling for E2, LH, and progesterone levels, along with transvaginal ultrasonography, according to a standardized protocol at our institution. Final oocyte maturation was triggered when at least three ovarian follicles measuring 17 mm or larger were visible on ultrasound, and E2 levels were at least 1000 pg/mL. For deferred embryo transfer (ET), final oocyte maturation was achieved with a single injection of 0.2 mg of GnRH agonist (Triptorelin, Decapeptyl®; Ipsen, Boulogne-Billancourt, France). The decision to implement a freeze-all strategy was made either before stimulation or during the stimulation phase, based on specific indications as outlined in previous research by our team [ 17 ]. For fresh ET, final oocyte maturation was induced using rhCG (rhCG; Ovitrelle®; Merck Serono, France) or a dual trigger combining rhCG and GnRHa. Oocyte retrieval (OR) was performed by transvaginal aspiration under ultrasound guidance by qualified senior gynecologists [ 18 ]. Semen samples were collected through masturbation following a sexual abstinence period of two to five days. Upon receiving the follicular fluid tubes, cumulo-oocyte complexes (COCs) were identified using a binocular magnifying glass. COCs were placed in universal IVF medium® (CooperSurgical) in incubators set at 37°C, with 5.5% CO2 and 5% O2. Between one and two hours after retrieval, the COCs underwent denudation via enzymatic treatment (hyaluronidase 80 UI/ml, Fujifilm Irvine Scientific) and mechanical stripping (Stripper®, Origio). Oocyte maturity was assessed, and mature (MII) oocytes were microinjected with a single spermatozoon. The precise methods for embryo culture and selection, as well as the vitrification and thawing protocols, have been described in detail previously [ 19 – 21 ]. Briefly, ET was performed on day 2 or at the blastocyst stage, depending on the study period, with exclusive extended embryo culture implemented since 2018. Luteal phase support for fresh and frozen ET was provided according to our institutional protocols [ 22 ]. Outcome variables The primary outcome of the study was the suboptimal response to triggering characterized as a mature oocyte yield below the 75th percentile [ 13 ]. The mature oocyte yield was defined as the number of mature oocytes retrieved divided by the number of mature follicles (mean diameter ≥ 15 mm) on the day of triggering [ 11 ]. Secondary endpoints included the fertilization rate, calculated as the number of 2PN oocytes divided by the total number of mature oocytes, and the blastocyst formation rate, determined by the number of blastocysts divided by the total number of embryos cultured. Furthermore, the following reproductive outcomes for fresh embryo transfers were recorded: (i) clinical pregnancies [ 23 ]; (ii) live births [ 23 ]; (iii) early miscarriages [ 24 ]; and (iv) ectopic pregnancies [ 23 ]. Statistical analysis Data were compiled into a digital database and analyzed using SPSS version 23.0 software (SPSS Inc., Chicago, Illinois, USA). A p-value < 0.05 was considered statistically significant. Continuous data were presented as means with standard deviation (SD), while categorical data were reported as numbers and percentages. The characteristics of women and ICSI cycles were compared based on the type of ovulation triggering and mature oocyte yield to identify prognostic factors for suboptimal mature oocyte yield. For univariate statistical analysis, the Pearson χ 2 test was used for qualitative variables, and the Kruskal-Wallis or Mann-Whitney tests were employed for quantitative variables, as appropriate. Variables associated with a suboptimal mature oocyte yield at a threshold of < 0.1 in univariate analysis were subsequently tested in a multiple logistic regression model. The correlation between variables was assessed, and in cases of high correlation, only one variable was retained in the model. For instance, AMH and AFC, as well as mean starting and mean total gonadotropin doses, and LH and E2 levels at triggering were evaluated (Spearman correlations 0.602, 0.87, and 0.403, respectively), with the last parameters excluded from the model. The final model included the following variables: age, cause of infertility, day 3 FSH and LH levels, AMH level, mean starting gonadotropin dose, type of ovulation triggering, and LH level at triggering. The final model was constructed using all selected significant variables via the "Enter" method. Additionally, a supplementary analysis was conducted in a subgroup of patients with AMH levels ≥ 75th percentile (i.e., 3.8 ng/mL) to evaluate the impact of the type of ovulation triggering on mature oocyte yield in women with high ovarian reserve. RESULTS Study population The cohort selection process is illustrated in Fig. 1 . Between October 2013 and October 2022, a total of 2,129 ICSI cycles utilizing a GnRH antagonist protocol were included, with last COH monitoring conducted on the day of ovulation triggering at our tertiary care center. The characteristics of the overall population are summarized in Table 1 . The mean age of participants was 35.0 ± 4.1 years, with an average infertility duration of 4.3 ± 2.7 years and a mean ICSI cycle rank of 1.4 ± 0.8. The characteristics and outcomes of the ICSI cycles are detailed in Table 2 and Supplemental Table 1. Among the cycles, 909 (42.7%) were triggered with GnRHa, 845 (39.7%) with hCG, and 375 (17.6%) with both. On average, patients had 7.9 ± 4.3 mature follicles on the day of triggering, resulting in a mean number of mature oocytes of 7.0 ± 5.0, and an average mature oocyte yield of 92.3 ± 55.2%. The 75th percentile for mature oocyte yield was 117%. Table 1 General characteristics of the study population (n = 2,129) Characteristics * Values Age (years) 35.0 ± 4.1 Body mass index (kg/m 2 ) 23.8 ± 4.4 Smoking status* 269 (13.1%) Geographic Origin* European 1724 (84.6%) African-Caribbean 215 (10.5%) Asian 100 (4.9%) Gravidity 0.7 ± 1.0 Parity 0.4 ± 0.6 Type of infertility Primary 1412 (66.3%) Secondary 717 (33.7%) Duration of infertility (years) 4.3 ± 2.7 ICSI cycle rank 1.4 ± 0.8 Ovarian reserve Day 3 FSH (IU/L) 7.2 ± 2.4 Day 3 LH (IU/L) 5.4 ± 2.6 Day 3 estradiol (pg/mL) 50.5 ± 36.6 AMH (ng/mL) 3.0 ± 2.8 AFC 17.8 ± 11.7 Ovulation status* Normal ovulation 1861 (89.9%) WHO I 16 (0.8%) WHO II 182 (8.8%) WHO III 12 (0.5%) Infertility cause* Male factors 759 (37.0%) Female factors 1060 (51.7%) DOR/POI 228 (21.5%) Ovulatory dysfunction 147 (13.9%) Endometriosis 469 (44.2%) Tubal factor 213 (20.1%) Uterine factor 3 (0.3%) Idiopathic 231 (11.3%) Note: ICSI = intracytoplasmic sperm injection; FSH = follicle-stimulating hormone; LH = luteinizing hormone; AMH = anti-Müllerian hormone; AFC = antral follicle count; WHO = world health organization (“Agents stimulating gonadal function in the human. Report of a WHO scientific group,” 1973); DOR = diminished ovarian reserve; POI = premature ovarian insufficiency * Continuous data are presented as mean ± standard deviation. Categorical data are presented as number (percentage). Missing data: smoking status (n = 75), geographic origin (n = 90), ovulation status (n = 58), infertility cause (n = 79) Table 2 ICSI cycle characteristics (n = 2,129) ICSI cycle characteristics * Values Synchronization by OCP 1200 (56.4%) Mean starting gonadotropin dose (IU) 285.0 ± 86.8 Mean total gonadotropin dose (IU) 2553.8 ± 984.0 Mean cycle duration (days) 9.3 ± 1.5 Type of ovulation triggering GnRH agonist 909 (42.7%) hCG 845 (39.7%) Dual trigger 375 (17.6%) Triggering day characteristics LH level (IU/L) 1.5 ± 1.6 Estradiol level (pg/mL) 2278.4 ± 1473.6 Progesterone level (ng/mL) 0.76 ± 1.2 Endometrial thickness (mm) 10.0 ± 2.5 Mean mature follicle count (> 15 mm) 7.9 ± 4.3 Mean number of oocytes 9.5 ± 7.1 Mean number of mature oocytes 7.0 ± 5.0 Mean mature oocyte yield (%) $ 92.3 ± 55.2 Mean number of fertilized oocytes 4.6 ± 3.8 Mean number of blastocysts 2.4 ± 2.7 Note: ICSI = intracytoplasmic sperm injection; OCP = oral contraceptive pill; GnRH = gonadotropin-releasing hormone; hCG = human chorionic gonadotropin; LH = luteinizing hormone * Continuous data are presented as mean ± standard deviation and categorical data are presented as number (percentage) $ Mature oocyte yield = number of mature oocytes retrieved/number of mature follicles (≥ 15 mm) Patient and cycle characteristics according to the type of ovulation triggering The results of the univariate analysis comparing patient and cycle characteristics based on the type of ovulation triggering are presented in Supplemental Table 2. The mean mature oocyte yield was significantly higher in cycles triggered by GnRHa compared to those triggered by hCG, although it did not differ significantly from the dual trigger group (96.7 ± 59.1% vs. 87.6 ± 48.8% vs. 92.2 ± 58.0%, respectively; p = 0.017). Additionally, the rate of suboptimal mature oocyte yield was significantly lower with GnRHa triggering compared to hCG, but not compared to the dual trigger (71.6% vs. 80% vs. 76.8%, respectively; p = 0.017). Prognostic factors of suboptimal mature oocyte yield The results of the univariate analysis comparing patients with optimal versus suboptimal mature oocyte yields are detailed in Supplemental Table 3. Women with suboptimal oocyte yields were older (35.1 ± 4.1 vs. 34.7 ± 4.1 years; p = 0.028) and had a higher incidence of female factors as the cause of infertility (52.8% vs. 48.6; p = 0.030). Their ovarian reserve was significantly lower, indicated by higher day 3 FSH levels (7.3 ± 2.5 vs. 6.9 ± 2.2 IU/L; p = 0.008), lower AMH levels (2.8 ± 2.7 vs 3.5 ± 3.1 ng/mL; p < 0.001) and a lower AFC (17.3 ± 11.4 vs. 19.6 ± 12.4; p < 0.001). In terms of ICSI cycle characteristics, women with suboptimal yields required higher mean starting gonadotropin doses (277.2 ± 81.0 vs. 260.0 ± 77.1 IU; p < 0.001), had higher LH levels at triggering (1.6 ± 1.7 vs. 1.4 ± 1.5 IU/L, p = 0.034), and lower E2 levels at triggering (2063.4 ± 1336.1 vs. 2425.4 ± 1727.1 pg/mL; p < 0.001). Furthermore, GnRHa was used less frequently for ovulation triggering in this subgroup (40.3% vs. 50.2%; p < 0.001). Multivariate analysis revealed that GnRHa triggering was the only factor significantly associated with a reduced risk of suboptimal oocyte yield (OR 0.58, 95% CI (0.44–0.78); p < 0.001), as shown in Table 3 . Table 3 Prognostic factors for suboptimal mature oocyte yield. α Multivariate analysis. Characteristics OR (95% CI) a P-value Age 1.01 (0.98–1.04) 0.517 Infertility cause Male factor Reference Female factor 1.20 (0.91–1.58) 0.190 Idiopathic 0.98 (0.65–1.48) 0.925 Day-3 FSH 1.02 (0.97–1.09) 0.432 Day-3 LH 0.97 (0.92–1.02) 0.229 AMH 0.97 (0.93–1.02) 0.279 Mean starting gonadotropin dose 1.00 (0.99–1.01) 0.479 Type of ovulation triggering hCG Reference GnRH agonist 0.58 (0.44–0.78) < 0.001 Dual trigger 0.73 (0.52–1.05) 0.087 LH level at triggering 1.03 (0.94–1.12) 0.529 Note: FSH = follicle-stimulating hormone; LH = luteinizing hormone; AMH = anti-Müllerian hormone; hCG = human chorionic gonadotropin; GnRH = gonadotropin-releasing hormone a Odds Ratio (95% Confidence Interval) α Suboptimal mature oocyte yield = mature oocyte yield (number of mature oocytes retrieved/number of mature follicles (≥ 15 mm)) < 75th percentile (< 117%) To further investigate the impact of ovarian reserve, a subgroup analysis was conducted focusing on patients with AMH levels ≥ 75th percentile (i.e., 3.8 ng/mL). This analysis confirmed the association between GnRHa triggering and a lower risk of suboptimal mature oocyte yield compared to hCG and dual trigger (66.1% vs. 76.9% vs. 86.0%; p < 0.001) (Supplemental Table 4). DISCUSSION This observational cohort study, encompassing 2,129 antagonist ICSI cycles, aimed to investigate the impact of ovulation triggering on oocyte maturity and to analyze risk factors associated with suboptimal outcomes, defined by mature oocyte yield. Our findings indicate that the mean mature oocyte yield was significantly higher in the GnRHa triggering group compared to the hCG group, while the rate of suboptimal mature oocyte yield (below the 75th percentile) was significantly lower with GnRHa. Multivariate analysis confirmed that GnRHa triggering was the sole significant prognostic factor associated with a reduced risk of suboptimal outcomes in antagonist ICSI cycles. The strengths of this study include: i) to our knowledge, it is the largest study to date comparing the efficacy of GnRHa and hCG triggering in antagonist ICSI cycles, utilizing a novel and clinically relevant endpoint; ii) all COH protocols adhered to our institutional guidelines, and transvaginal ultrasounds were performed consistently at our ART center, minimizing the risk of comparison bias regarding protocols and mature follicle counts, which could impact oocyte maturity; iii) a comprehensive array of epidemiological and clinical variables was prospectively collected to analyze a broad range of factors potentially associated with suboptimal mature oocyte yield. The main limitation of this study is its retrospective design, which introduces a risk of confounding bias that cannot be entirely eliminated, despite our efforts through multivariable analysis. Additionally, GnRHa triggering is frequently employed in younger, high-responder patients to mitigate the risk of OHSS, leading to differences in patient characteristics between the GnRHa and hCG groups, particularly concerning age and ovarian reserve. To address this selection bias, we conducted a subgroup analysis of patients with AMH levels ≥ 75th percentile (3.8 ng/mL) and still observed a reduced risk of suboptimal mature oocyte yield with GnRHa. This reinforces the notion that GnRHa positively impacts oocyte maturity, independent of patient profile. Concerns surrounding the use of GnRHa for ovulation triggering have persisted due to findings from uncontrolled studies utilizing various endpoints [ 6 – 9 , 12 , 13 ]. Some studies evaluated biological markers such as suboptimal LH or progesterone levels post-triggering [ 8 , 9 , 12 ], which may not accurately reflect oocyte recovery or maturity. Furthermore, these investigations primarily focused on potential suboptimal outcomes following GnRHa triggering without comparing this risk to that of hCG triggering, even though suboptimal outcomes can occur with any triggering method [ 25 ]. This publication bias may have contributed to a misleading perception of GnRHa triggering’s efficacy. In our study, we focused on a clinically relevant outcome that directly reflects the efficacy of ovulation triggering by comparing the number of mature oocytes retrieved to the expected number based on the mature follicle count at triggering. This approach differs from the traditional oocyte maturation rate used in previous studies [ 11 , 13 ], which calculates the maturation rate using the total number of retrieved oocytes. This method can be influenced by how oocyte retrieval is performed, particularly if clinicians aspirates smaller or intermediate follicles containing less mature oocytes [ 26 ]. Such practices can lead to a lower maturation rate that does not accurately reflect the effectiveness of the triggering agent. Our analysis of mature oocyte yield in a large cohort revealed that GnRHa outperformed hCG. This finding is consistent with a recent meta-analysis by Bourdon et al. [ 2 ], which reported higher total numbers of retrieved oocytes, mature oocytes, and embryos following GnRHa triggering compared to hCG. The enhanced performance of GnRHa may be attributed to the additional FSH surge it induces, which plays a critical role in final oocyte and follicular maturation in natural cycles. For instance, FSH facilitates the resumption of meiosis, enhances communication between the oocyte and cumulus cells, promotes cumulus expansion, and stimulates the release of proteolytic enzymes—all vital for successful follicular maturation and ovulation [ 27 – 31 ]. Furthermore, the more physiological LH surge produced by GnRHa may also contribute to its positive effects, as emerging evidence suggests that LH and hCG, despite binding to the same receptor, can activate distinct downstream signaling pathways that may influence the ovulation profile [ 32 ]. Given the effectiveness and safety profile of GnRHa triggering, clinicians should consider routinely offering this strategy in antagonist cycles. When a fresh embryo transfer is planned, a dual trigger with hCG can be used to ensure sufficient LH support for the corpora lutea. In our study, we found no significant difference in mature oocyte yield between dual triggering and hCG alone, likely due to the small sample size. However, recent literature has reported favorable outcomes with the dual trigger approach, highlighting improvements in the number of oocytes retrieved, mature oocytes, and blastocysts [ 33 , 34 ]. Additionally, pregnancy outcomes such as implantation rates, clinical pregnancies, and live births have shown significant enhancement [ 2 , 35 , 36 ], which may be attributed to the positive effects of GnRHa on endometrial receptivity during fresh embryo transfer cycles [ 37 ]. In conclusion, our findings indicate that GnRHa triggering is associated with a lower risk of suboptimal mature oocyte yield compared to hCG, suggesting that its systematic use could enhance ART outcomes. This approach may be effective when used alone for deferred embryo transfers or in combination with hCG for fresh transfers. However, further studies are needed to validate these benefits, especially regarding the dual trigger strategy. Caution should be exercised with the dual trigger approach, as the inclusion of hCG poses a risk of OHSS, which is not alleviated by adding GnRHa. Using GnRHa alone mitigates the risk of OHSS, underscoring the importance of carefully assessing OHSS risk at the time of ovulation triggering before implementing this strategy in clinical practice. Declarations COMPETING INTERESTS The authors have no relevant financial or non-financial interests to disclose. ETHICS APPROVAL This study received approval for publication from the Ethics Review Committee of Cochin University Hospital (CLEP) (No. AAA-2024-10007). All participants provided written informed consent. FUNDING The authors did not receive support from any organization for the submitted work. DATA AVAILABILITY Data will be made available on request. ACKNOWLEDGEMENTS The authors extend their gratitude to the staff members of our department for their expert assistance with data collection, especially Valérie Blanchet, Julia Gonnot, Emmanuelle Laviron, Célie Cervantes, and Audrey Houliat at the ART unit. 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Arch Gynecol Obstet 299:559–564 McCulloh DH, Kutchukhidze N, Charkviani T, Zhorzholadze T, Barbakadze T, Munné S et al (2020) Follicle size indicates oocyte maturity and blastocyst formation but not blastocyst euploidy following controlled ovarian hyperstimulation of oocyte donors. Hum Reprod Oxf Engl 35:545–556 Yding Andersen C, Leonardsen L, Ulloa-Aguirre A, Barrios-De-Tomasi J, Moore L, Byskov AG (1999) FSH-induced resumption of meiosis in mouse oocytes: effect of different isoforms. Mol Hum Reprod 5:726–731 D’Alessandris C, Canipari R, Di Giacomo M, Epifano O, Camaioni A, Siracusa G et al (2001) Control of mouse cumulus cell-oocyte complex integrity before and after ovulation: plasminogen activator synthesis and matrix degradation. Endocrinology 142:3033–3040 Yding Andersen C (2002) Effect of FSH and its different isoforms on maturation of oocytes from pre-ovulatory follicles. Reprod Biomed Online 5:232–239 Dell’Aquila ME, Caillaud M, Maritato F, Martoriati A, Gérard N, Aiudi G et al (2004) Cumulus expansion, nuclear maturation and connexin 43, cyclooxygenase-2 and FSH receptor mRNA expression in equine cumulus-oocyte complexes cultured in vitro in the presence of FSH and precursors for hyaluronic acid synthesis. Reprod Biol Endocrinol RBE 2:44 Godard NM, Pukazhenthi BS, Wildt DE, Comizzoli P (2009) Paracrine factors from cumulus-enclosed oocytes ensure the successful maturation and fertilization in vitro of denuded oocytes in the cat model. Fertil Steril 91:2051–2060 Choi J, Smitz J (2014) Luteinizing hormone and human chorionic gonadotropin: origins of difference. Mol Cell Endocrinol 383:203–213 González VG, Triana AM, García IS, Nieto SO, Urrutia MC, García IC et al (2023) Dual trigger vs. Conventional trigger outcomes in In Vitro Fertilization. Systematic review and meta-analysis. JBRA Assist Reprod 27:112–119 He F-F, Hu W, Yong L, Li Y-M (2023) Triggering of ovulation for GnRH-antagonist cycles in normal and low ovarian responders undergoing IVF/ICSI: A systematic review and meta-analysis of randomized trials. Eur J Obstet Gynecol Reprod Biol 289:65–73 Haas J, Bassil R, Samara N, Zilberberg E, Mehta C, Orvieto R et al (2020) GnRH agonist and hCG (dual trigger) versus hCG trigger for final follicular maturation: a double-blinded, randomized controlled study. Hum Reprod Oxf Engl 35:1648–1654 Hsia L-H, Lee T-H, Lin Y-H, Huang Y-Y, Chang H-J, Liu Y-L (2023) Dual trigger improves the pregnancy rate in fresh in vitro fertilization (IVF) cycles compared with the human chorionic gonadotropin (hCG) trigger: a systematic review and meta-analysis of randomized trials. J Assist Reprod Genet 40:2063–2077 Liu J, Maccalman CD, Wang Y, Leung PCK (2009) Promotion of human trophoblasts invasion by gonadotropin-releasing hormone (GnRH) I and GnRH II via distinct signaling pathways. Mol Endocrinol Baltim Md 23:1014–1021 Additional Declarations The authors declare no competing interests. Supplementary Files SUPPLEMENTALTABLE.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8939235","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":595131681,"identity":"44ae5cb4-36f8-4ec8-a341-e9b95a3d36c3","order_by":0,"name":"Chloé Maignien","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Chloé","middleName":"","lastName":"Maignien","suffix":""},{"id":595131682,"identity":"cd2261e8-f87a-418b-b19a-040f8c7c8f7e","order_by":1,"name":"Rami El Hachem","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Rami","middleName":"El","lastName":"Hachem","suffix":""},{"id":595131683,"identity":"5ba38f04-9d58-4286-bb0f-2272a1917806","order_by":2,"name":"Mathilde Bourdon","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Mathilde","middleName":"","lastName":"Bourdon","suffix":""},{"id":595131684,"identity":"4887fca1-2d48-481c-bfa9-eeb5d512ccec","order_by":3,"name":"Ahmed Chargui","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"","lastName":"Chargui","suffix":""},{"id":595131685,"identity":"70f1daa7-010e-4bdc-bd65-2d9acee7b085","order_by":4,"name":"Catherine Patrat","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Catherine","middleName":"","lastName":"Patrat","suffix":""},{"id":595131686,"identity":"a8c734cf-daf7-4dbf-9339-e5164c559a1f","order_by":5,"name":"Charles Chapron","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Charles","middleName":"","lastName":"Chapron","suffix":""},{"id":595131687,"identity":"be58be94-8d67-4d05-b3ae-941a0c5b66e5","order_by":6,"name":"Pietro Santulli","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIiWNgGAWjYDACZgST8cADA5sEMDOhAK8WxgYwg42B4UCCQVoCiMGQYIDXHmQtDIchWhjwaDFnZz7+uKKiTt5cvsfgQELB+Tx++e7EDw8MGOT5xQ5g1WLZzJbYeObMYcOdbTxALQa3iyXbeDdLAB1mOHN2AlYtBod5DBsb2w4wbjgG0ZK44RjvBpAWIBuXFv6PQC119lAt50BaNv/Ar4WHEaiFORGq5QBIyza8tgD9Yjiz4czh5A3H0gqAWpITZ7blbrNIMJDA6Rdz/sMPPjZU1NluOHx444MPf+wS+5nPbr75o8JGnl8ah8OwigKBBC4JfFE2CkbBKBgFowAKAORoZOcDqlrUAAAAAElFTkSuQmCC","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Pietro","middleName":"","lastName":"Santulli","suffix":""}],"badges":[],"createdAt":"2026-02-22 13:00:00","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8939235/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8939235/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103338378,"identity":"1739ee1c-c694-4164-890b-bf857d78ad5e","added_by":"auto","created_at":"2026-02-24 15:02:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":53053,"visible":true,"origin":"","legend":"\u003cp\u003ePatient inclusion flowchart\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNote: GnRH = gonadotropin-releasing hormone; hCG = human chorionic gonadotropin\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8939235/v1/3642db729aba0a109e339db8.png"},{"id":103510045,"identity":"59aca00a-a163-42a6-a29f-541b223d2ebb","added_by":"auto","created_at":"2026-02-26 14:03:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":575432,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8939235/v1/88532535-db7c-4b1b-81de-e2f83e4be4ac.pdf"},{"id":103506656,"identity":"16cb2593-91ff-497e-ad5f-96ced9737246","added_by":"auto","created_at":"2026-02-26 13:38:29","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":34015,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTALTABLE.docx","url":"https://assets-eu.researchsquare.com/files/rs-8939235/v1/8cc64ac4d143d001a61ed156.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eSuboptimal Mature Oocyte Yield in Antagonist Icsi Cycles: Any Impact of the Ovulation Triggering Agent?\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eOne of the most significant advancements in assisted reproductive technology (ART) over the past few decades has been the use of gonadotropin-releasing hormone agonists (GnRHa) to induce ovulation in antagonist protocols. This development has notably reduced the incidence of ovarian hyperstimulation syndrome (OHSS) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. OHSS is an iatrogenic complication associated with controlled ovarian hyperstimulation (COH) in IVF/ICSI cycles, triggered by either exogenous or endogenous human chorionic gonadotropin (hCG). This hormone activates the luteinizing hormone (LH)/hCG receptor in the ovaries, leading to the release of vascular endothelial growth factor (VEGF) and increased capillary permeability [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. By employing a bolus of GnRHa instead of standard hCG to trigger ovulation, there is a physiological-like surge of endogenous LH, albeit shorter in duration and lower in amplitude [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This approach results in the rapid regression of the corpus luteum within a few days, effectively reducing VEGF expression and consequently lowering the risk of OHSS.\u003c/p\u003e \u003cp\u003eDespite the clear safety advantages of using GnRHa over hCG for triggering ovulation, the debate over their clinical efficacy remains unresolved. Some studies indicate that GnRHa leads to improved outcomes, including a higher number of retrieved and mature oocytes, as well as an increased number of embryos [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Conversely, other research highlights the risk of suboptimal responses to GnRHa, ranging from suboptimal LH levels post-trigger to insufficient oocyte recovery or even empty follicle syndrome [\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, these studies often lack a control group using hCG, making it difficult to differentiate between intrinsic ovarian issues and those related to the triggering method itself.\u003c/p\u003e \u003cp\u003eGiven this context of conflicting data, we aimed to compare patients based on their ovulation triggering method to identify clinical factors associated with suboptimal mature oocyte yields in a large cohort undergoing COH for ICSI in a GnRH antagonist protocol.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eStudy population and inclusion criteria\u003c/p\u003e \u003cp\u003eWe conducted a retrospective cohort study of patients who underwent COH with a GnRH antagonist protocol for ICSI at our university-based reproductive medicine center from October 2013 to October 2022. Inclusion criteria were: (i) age\u0026thinsp;\u0026lt;\u0026thinsp;43 years at the time of oocyte retrieval; (ii) indication for ICSI, including male factor infertility, previous fertilization failure after conventional IVF, unexplained infertility, and low number of oocytes retrieved [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]; (iii) COH using a GnRH antagonist protocol; and (iv) final COH monitoring conducted on the day of ovulation triggering. Exclusion criteria included: (i) use of other COH protocols, such as long and short agonist protocols or natural cycles; (ii) IVF cycles that did not allow for the assessment of oocyte maturity on retrieval day; (iii) cycles canceled prior to oocyte retrieval; and (iv) oocyte cryopreservation or donation cycles.\u003c/p\u003e \u003cp\u003eGeneral Characteristics\u003c/p\u003e \u003cp\u003eThe study analysis was based on a prospectively managed database. Data were collected for each patient prior to ART treatment, encompassing personal history and fertility investigation results. The recorded information included: age at retrieval (years), smoking status (active or non-smoker), body mass index (BMI) calculated as weight (kg)/height (m\u003csup\u003e2\u003c/sup\u003e), and country of birth/geographic origin (European, Asian, African-Caribbean) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Additional variables included gravidity, parity, type of infertility (primary or secondary), duration of infertility (years), IVF/ICSI cycle rank, and serum levels of day-3 FSH (IU/mL), estradiol (pg/mL), and LH (IU/mL). Also documented were the antral follicle count (AFC), anti-M\u0026uuml;llerian hormone (AMH) levels (ng/mL), ovulation status according to the WHO classification [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], and infertility causes (e.g., male factor, female factor, including ovulatory dysfunction, tubal factor, endometriosis, uterine factor, diminished ovarian reserve/premature ovarian insufficiency, or idiopathic infertility).\u003c/p\u003e \u003cp\u003eICSI cycles: clinical and laboratory procedures\u003c/p\u003e \u003cp\u003eBefore starting COH, a pre-treatment was administered for scheduling purposes, using either antigonadotropic medication (estro-progestin or progestin pill) or estradiol (0.2 mg/day via two simultaneous Vivelledot\u0026reg; 100 systems; Novartis Pharma SA, France). Ovarian stimulation commenced after a wash-out period of five days for antigonadotropic medication and two days for estradiol. COH was conducted using recombinant follicle-stimulating hormone (FSH; Bemfola\u0026reg;; Gedeon Richter, France) and human menopausal gonadotropin (hMG; Menopur\u0026reg;; Ferring Pharmaceuticals, France), with no adjustments to the gonadotropin dose during stimulation. The initial gonadotropin dose ranged from 150 to 450 IU/day and was determined based on patient age, BMI, AFC, AMH level, and previous responses to gonadotropins. A GnRH antagonist at a daily dose of 0.25 mg was introduced on the 6th day of stimulation. Monitoring of COH occurred every 48\u0026ndash;72 hours from the 8th day, involving blood sampling for E2, LH, and progesterone levels, along with transvaginal ultrasonography, according to a standardized protocol at our institution.\u003c/p\u003e \u003cp\u003eFinal oocyte maturation was triggered when at least three ovarian follicles measuring 17 mm or larger were visible on ultrasound, and E2 levels were at least 1000 pg/mL. For deferred embryo transfer (ET), final oocyte maturation was achieved with a single injection of 0.2 mg of GnRH agonist (Triptorelin, Decapeptyl\u0026reg;; Ipsen, Boulogne-Billancourt, France). The decision to implement a freeze-all strategy was made either before stimulation or during the stimulation phase, based on specific indications as outlined in previous research by our team [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. For fresh ET, final oocyte maturation was induced using rhCG (rhCG; Ovitrelle\u0026reg;; Merck Serono, France) or a dual trigger combining rhCG and GnRHa. Oocyte retrieval (OR) was performed by transvaginal aspiration under ultrasound guidance by qualified senior gynecologists [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Semen samples were collected through masturbation following a sexual abstinence period of two to five days. Upon receiving the follicular fluid tubes, cumulo-oocyte complexes (COCs) were identified using a binocular magnifying glass. COCs were placed in universal IVF medium\u0026reg; (CooperSurgical) in incubators set at 37\u0026deg;C, with 5.5% CO2 and 5% O2. Between one and two hours after retrieval, the COCs underwent denudation via enzymatic treatment (hyaluronidase 80 UI/ml, Fujifilm Irvine Scientific) and mechanical stripping (Stripper\u0026reg;, Origio). Oocyte maturity was assessed, and mature (MII) oocytes were microinjected with a single spermatozoon.\u003c/p\u003e \u003cp\u003eThe precise methods for embryo culture and selection, as well as the vitrification and thawing protocols, have been described in detail previously [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Briefly, ET was performed on day 2 or at the blastocyst stage, depending on the study period, with exclusive extended embryo culture implemented since 2018. Luteal phase support for fresh and frozen ET was provided according to our institutional protocols [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOutcome variables\u003c/p\u003e \u003cp\u003eThe primary outcome of the study was the suboptimal response to triggering characterized as a mature oocyte yield below the 75th percentile [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The mature oocyte yield was defined as the number of mature oocytes retrieved divided by the number of mature follicles (mean diameter \u0026ge; 15 mm) on the day of triggering [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Secondary endpoints included the fertilization rate, calculated as the number of 2PN oocytes divided by the total number of mature oocytes, and the blastocyst formation rate, determined by the number of blastocysts divided by the total number of embryos cultured. Furthermore, the following reproductive outcomes for fresh embryo transfers were recorded: (i) clinical pregnancies [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]; (ii) live births [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]; (iii) early miscarriages [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]; and (iv) ectopic pregnancies [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData were compiled into a digital database and analyzed using SPSS version 23.0 software (SPSS Inc., Chicago, Illinois, USA). A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Continuous data were presented as means with standard deviation (SD), while categorical data were reported as numbers and percentages.\u003c/p\u003e \u003cp\u003eThe characteristics of women and ICSI cycles were compared based on the type of ovulation triggering and mature oocyte yield to identify prognostic factors for suboptimal mature oocyte yield. For univariate statistical analysis, the Pearson χ\u003csup\u003e2\u003c/sup\u003e test was used for qualitative variables, and the Kruskal-Wallis or Mann-Whitney tests were employed for quantitative variables, as appropriate. Variables associated with a suboptimal mature oocyte yield at a threshold of \u0026lt;\u0026thinsp;0.1 in univariate analysis were subsequently tested in a multiple logistic regression model. The correlation between variables was assessed, and in cases of high correlation, only one variable was retained in the model. For instance, AMH and AFC, as well as mean starting and mean total gonadotropin doses, and LH and E2 levels at triggering were evaluated (Spearman correlations 0.602, 0.87, and 0.403, respectively), with the last parameters excluded from the model. The final model included the following variables: age, cause of infertility, day 3 FSH and LH levels, AMH level, mean starting gonadotropin dose, type of ovulation triggering, and LH level at triggering. The final model was constructed using all selected significant variables via the \"Enter\" method.\u003c/p\u003e \u003cp\u003eAdditionally, a supplementary analysis was conducted in a subgroup of patients with AMH levels\u0026thinsp;\u0026ge;\u0026thinsp;75th percentile (i.e., 3.8 ng/mL) to evaluate the impact of the type of ovulation triggering on mature oocyte yield in women with high ovarian reserve.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eStudy population\u003c/p\u003e \u003cp\u003eThe cohort selection process is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Between October 2013 and October 2022, a total of 2,129 ICSI cycles utilizing a GnRH antagonist protocol were included, with last COH monitoring conducted on the day of ovulation triggering at our tertiary care center. The characteristics of the overall population are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean age of participants was 35.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1 years, with an average infertility duration of 4.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 years and a mean ICSI cycle rank of 1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8. The characteristics and outcomes of the ICSI cycles are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Supplemental Table\u0026nbsp;1. Among the cycles, 909 (42.7%) were triggered with GnRHa, 845 (39.7%) with hCG, and 375 (17.6%) with both. On average, patients had 7.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3 mature follicles on the day of triggering, resulting in a mean number of mature oocytes of 7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0, and an average mature oocyte yield of 92.3\u0026thinsp;\u0026plusmn;\u0026thinsp;55.2%. The 75th percentile for mature oocyte yield was 117%.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGeneral characteristics of the study population (n\u0026thinsp;=\u0026thinsp;2,129)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValues\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking status*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e269 (13.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeographic Origin*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1724 (84.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAfrican-Caribbean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e215 (10.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100 (4.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGravidity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of infertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1412 (66.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e717 (33.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of infertility (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICSI cycle rank\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvarian reserve\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay 3 FSH (IU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay 3 LH (IU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay 3 estradiol (pg/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.5\u0026thinsp;\u0026plusmn;\u0026thinsp;36.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAMH (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.8\u0026thinsp;\u0026plusmn;\u0026thinsp;11.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvulation status*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNormal ovulation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1861 (89.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWHO I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (0.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWHO II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e182 (8.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWHO III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (0.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfertility cause*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale factors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e759 (37.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale factors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1060 (51.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDOR/POI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e228 (21.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvulatory dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e147 (13.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometriosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e469 (44.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTubal factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e213 (20.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUterine factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (0.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIdiopathic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e231 (11.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cem\u003eNote: ICSI\u0026thinsp;=\u0026thinsp;intracytoplasmic sperm injection; FSH\u0026thinsp;=\u0026thinsp;follicle-stimulating hormone; LH\u0026thinsp;=\u0026thinsp;luteinizing hormone; AMH\u0026thinsp;=\u0026thinsp;anti-M\u0026uuml;llerian hormone; AFC\u0026thinsp;=\u0026thinsp;antral follicle count; WHO\u0026thinsp;=\u0026thinsp;world health organization\u003c/em\u003e (\u0026ldquo;Agents stimulating gonadal function in the human. Report of a WHO scientific group,\u0026rdquo; 1973); \u003cem\u003eDOR\u0026thinsp;=\u0026thinsp;diminished ovarian reserve; POI\u0026thinsp;=\u0026thinsp;premature ovarian insufficiency\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e\u003cem\u003e*\u003c/em\u003e\u003c/sup\u003e \u003cem\u003eContinuous data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Categorical data are\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cem\u003epresented as number (percentage). Missing data: smoking status (n\u0026thinsp;=\u0026thinsp;75), geographic origin (n\u0026thinsp;=\u0026thinsp;90), ovulation status (n\u0026thinsp;=\u0026thinsp;58), infertility cause (n\u0026thinsp;=\u0026thinsp;79)\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eICSI cycle characteristics (n\u0026thinsp;=\u0026thinsp;2,129)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICSI cycle characteristics\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValues\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSynchronization by OCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1200 (56.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean starting gonadotropin dose (IU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e285.0\u0026thinsp;\u0026plusmn;\u0026thinsp;86.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean total gonadotropin dose (IU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2553.8\u0026thinsp;\u0026plusmn;\u0026thinsp;984.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean cycle duration (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of ovulation triggering\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGnRH agonist\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e909 (42.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehCG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e845 (39.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDual trigger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e375 (17.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriggering day characteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLH level (IU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstradiol level (pg/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2278.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1473.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgesterone level (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.76\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrial thickness (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean mature follicle count (\u0026gt;\u0026thinsp;15 mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean number of oocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean number of mature oocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean mature oocyte yield (%)\u003csup\u003e\u003cem\u003e$\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e92.3\u0026thinsp;\u0026plusmn;\u0026thinsp;55.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean number of fertilized oocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean number of blastocysts\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cem\u003eNote: ICSI\u0026thinsp;=\u0026thinsp;intracytoplasmic sperm injection; OCP\u0026thinsp;=\u0026thinsp;oral contraceptive pill; GnRH\u0026thinsp;=\u0026thinsp;gonadotropin-releasing hormone; hCG\u0026thinsp;=\u0026thinsp;human chorionic gonadotropin; LH\u0026thinsp;=\u0026thinsp;luteinizing hormone\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e\u003cem\u003e*\u003c/em\u003e\u003c/sup\u003e \u003cem\u003eContinuous data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation and categorical data are\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cem\u003epresented as number (percentage)\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e\u003cem\u003e$\u003c/em\u003e\u003c/sup\u003e \u003cem\u003eMature oocyte yield\u0026thinsp;=\u0026thinsp;number of mature oocytes retrieved/number of mature follicles (\u0026ge;\u0026thinsp;15 mm)\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePatient and cycle characteristics according to the type of ovulation triggering\u003c/p\u003e \u003cp\u003eThe results of the univariate analysis comparing patient and cycle characteristics based on the type of ovulation triggering are presented in Supplemental Table\u0026nbsp;2. The mean mature oocyte yield was significantly higher in cycles triggered by GnRHa compared to those triggered by hCG, although it did not differ significantly from the dual trigger group (96.7\u0026thinsp;\u0026plusmn;\u0026thinsp;59.1% vs. 87.6\u0026thinsp;\u0026plusmn;\u0026thinsp;48.8% vs. 92.2\u0026thinsp;\u0026plusmn;\u0026thinsp;58.0%, respectively; p\u0026thinsp;=\u0026thinsp;0.017). Additionally, the rate of suboptimal mature oocyte yield was significantly lower with GnRHa triggering compared to hCG, but not compared to the dual trigger (71.6% vs. 80% vs. 76.8%, respectively; p\u0026thinsp;=\u0026thinsp;0.017).\u003c/p\u003e \u003cp\u003ePrognostic factors of suboptimal mature oocyte yield\u003c/p\u003e \u003cp\u003eThe results of the univariate analysis comparing patients with optimal versus suboptimal mature oocyte yields are detailed in Supplemental Table\u0026nbsp;3. Women with suboptimal oocyte yields were older (35.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1 vs. 34.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1 years; p\u0026thinsp;=\u0026thinsp;0.028) and had a higher incidence of female factors as the cause of infertility (52.8% vs. 48.6; p\u0026thinsp;=\u0026thinsp;0.030). Their ovarian reserve was significantly lower, indicated by higher day 3 FSH levels (7.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5 vs. 6.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2 IU/L; p\u0026thinsp;=\u0026thinsp;0.008), lower AMH levels (2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 vs 3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1 ng/mL; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and a lower AFC (17.3\u0026thinsp;\u0026plusmn;\u0026thinsp;11.4 vs. 19.6\u0026thinsp;\u0026plusmn;\u0026thinsp;12.4; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In terms of ICSI cycle characteristics, women with suboptimal yields required higher mean starting gonadotropin doses (277.2\u0026thinsp;\u0026plusmn;\u0026thinsp;81.0 vs. 260.0\u0026thinsp;\u0026plusmn;\u0026thinsp;77.1 IU; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), had higher LH levels at triggering (1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 vs. 1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 IU/L, p\u0026thinsp;=\u0026thinsp;0.034), and lower E2 levels at triggering (2063.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1336.1 vs. 2425.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1727.1 pg/mL; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Furthermore, GnRHa was used less frequently for ovulation triggering in this subgroup (40.3% vs. 50.2%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eMultivariate analysis revealed that GnRHa triggering was the only factor significantly associated with a reduced risk of suboptimal oocyte yield (OR 0.58, 95% CI (0.44\u0026ndash;0.78); p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), as shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrognostic factors for suboptimal mature oocyte yield.\u003csup\u003eα\u003c/sup\u003e Multivariate analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR (95% CI)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.01 (0.98\u0026ndash;1.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.517\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfertility cause\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.20 (0.91\u0026ndash;1.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.190\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIdiopathic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.98 (0.65\u0026ndash;1.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.925\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay-3 FSH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.02 (0.97\u0026ndash;1.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.432\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay-3 LH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.97 (0.92\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.229\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAMH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.97 (0.93\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.279\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean starting gonadotropin dose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.00 (0.99\u0026ndash;1.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.479\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of ovulation triggering\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehCG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGnRH agonist\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.58 (0.44\u0026ndash;0.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDual trigger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.73 (0.52\u0026ndash;1.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.087\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLH level at triggering\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.03 (0.94\u0026ndash;1.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.529\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cem\u003eNote: FSH\u0026thinsp;=\u0026thinsp;follicle-stimulating hormone; LH\u0026thinsp;=\u0026thinsp;luteinizing hormone; AMH\u0026thinsp;=\u0026thinsp;anti-M\u0026uuml;llerian hormone; hCG\u0026thinsp;=\u0026thinsp;human chorionic gonadotropin; GnRH\u0026thinsp;=\u0026thinsp;gonadotropin-releasing hormone\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e \u003cem\u003eOdds Ratio (95% Confidence Interval)\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003eα\u003c/sup\u003e \u003cem\u003eSuboptimal mature oocyte yield\u0026thinsp;=\u0026thinsp;mature oocyte yield (number of mature oocytes retrieved/number of mature follicles (\u0026ge;\u0026thinsp;15 mm)) \u0026lt; 75th percentile (\u0026lt;\u0026thinsp;117%)\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTo further investigate the impact of ovarian reserve, a subgroup analysis was conducted focusing on patients with AMH levels\u0026thinsp;\u0026ge;\u0026thinsp;75th percentile (i.e., 3.8 ng/mL). This analysis confirmed the association between GnRHa triggering and a lower risk of suboptimal mature oocyte yield compared to hCG and dual trigger (66.1% vs. 76.9% vs. 86.0%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Supplemental Table\u0026nbsp;4).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis observational cohort study, encompassing 2,129 antagonist ICSI cycles, aimed to investigate the impact of ovulation triggering on oocyte maturity and to analyze risk factors associated with suboptimal outcomes, defined by mature oocyte yield. Our findings indicate that the mean mature oocyte yield was significantly higher in the GnRHa triggering group compared to the hCG group, while the rate of suboptimal mature oocyte yield (below the 75th percentile) was significantly lower with GnRHa. Multivariate analysis confirmed that GnRHa triggering was the sole significant prognostic factor associated with a reduced risk of suboptimal outcomes in antagonist ICSI cycles.\u003c/p\u003e \u003cp\u003e The strengths of this study include: i) to our knowledge, it is the largest study to date comparing the efficacy of GnRHa and hCG triggering in antagonist ICSI cycles, utilizing a novel and clinically relevant endpoint; ii) all COH protocols adhered to our institutional guidelines, and transvaginal ultrasounds were performed consistently at our ART center, minimizing the risk of comparison bias regarding protocols and mature follicle counts, which could impact oocyte maturity; iii) a comprehensive array of epidemiological and clinical variables was prospectively collected to analyze a broad range of factors potentially associated with suboptimal mature oocyte yield.\u003c/p\u003e \u003cp\u003eThe main limitation of this study is its retrospective design, which introduces a risk of confounding bias that cannot be entirely eliminated, despite our efforts through multivariable analysis. Additionally, GnRHa triggering is frequently employed in younger, high-responder patients to mitigate the risk of OHSS, leading to differences in patient characteristics between the GnRHa and hCG groups, particularly concerning age and ovarian reserve. To address this selection bias, we conducted a subgroup analysis of patients with AMH levels\u0026thinsp;\u0026ge;\u0026thinsp;75th percentile (3.8 ng/mL) and still observed a reduced risk of suboptimal mature oocyte yield with GnRHa. This reinforces the notion that GnRHa positively impacts oocyte maturity, independent of patient profile.\u003c/p\u003e \u003cp\u003eConcerns surrounding the use of GnRHa for ovulation triggering have persisted due to findings from uncontrolled studies utilizing various endpoints [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Some studies evaluated biological markers such as suboptimal LH or progesterone levels post-triggering [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], which may not accurately reflect oocyte recovery or maturity. Furthermore, these investigations primarily focused on potential suboptimal outcomes following GnRHa triggering without comparing this risk to that of hCG triggering, even though suboptimal outcomes can occur with any triggering method [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This publication bias may have contributed to a misleading perception of GnRHa triggering\u0026rsquo;s efficacy.\u003c/p\u003e \u003cp\u003eIn our study, we focused on a clinically relevant outcome that directly reflects the efficacy of ovulation triggering by comparing the number of mature oocytes retrieved to the expected number based on the mature follicle count at triggering. This approach differs from the traditional oocyte maturation rate used in previous studies [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], which calculates the maturation rate using the total number of retrieved oocytes. This method can be influenced by how oocyte retrieval is performed, particularly if clinicians aspirates smaller or intermediate follicles containing less mature oocytes [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Such practices can lead to a lower maturation rate that does not accurately reflect the effectiveness of the triggering agent.\u003c/p\u003e \u003cp\u003eOur analysis of mature oocyte yield in a large cohort revealed that GnRHa outperformed hCG. This finding is consistent with a recent meta-analysis by Bourdon et al. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], which reported higher total numbers of retrieved oocytes, mature oocytes, and embryos following GnRHa triggering compared to hCG. The enhanced performance of GnRHa may be attributed to the additional FSH surge it induces, which plays a critical role in final oocyte and follicular maturation in natural cycles. For instance, FSH facilitates the resumption of meiosis, enhances communication between the oocyte and cumulus cells, promotes cumulus expansion, and stimulates the release of proteolytic enzymes\u0026mdash;all vital for successful follicular maturation and ovulation [\u003cspan additionalcitationids=\"CR28 CR29 CR30\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Furthermore, the more physiological LH surge produced by GnRHa may also contribute to its positive effects, as emerging evidence suggests that LH and hCG, despite binding to the same receptor, can activate distinct downstream signaling pathways that may influence the ovulation profile [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the effectiveness and safety profile of GnRHa triggering, clinicians should consider routinely offering this strategy in antagonist cycles. When a fresh embryo transfer is planned, a dual trigger with hCG can be used to ensure sufficient LH support for the corpora lutea. In our study, we found no significant difference in mature oocyte yield between dual triggering and hCG alone, likely due to the small sample size. However, recent literature has reported favorable outcomes with the dual trigger approach, highlighting improvements in the number of oocytes retrieved, mature oocytes, and blastocysts [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Additionally, pregnancy outcomes such as implantation rates, clinical pregnancies, and live births have shown significant enhancement [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], which may be attributed to the positive effects of GnRHa on endometrial receptivity during fresh embryo transfer cycles [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn conclusion, our findings indicate that GnRHa triggering is associated with a lower risk of suboptimal mature oocyte yield compared to hCG, suggesting that its systematic use could enhance ART outcomes. This approach may be effective when used alone for deferred embryo transfers or in combination with hCG for fresh transfers. However, further studies are needed to validate these benefits, especially regarding the dual trigger strategy. Caution should be exercised with the dual trigger approach, as the inclusion of hCG poses a risk of OHSS, which is not alleviated by adding GnRHa. Using GnRHa alone mitigates the risk of OHSS, underscoring the importance of carefully assessing OHSS risk at the time of ovulation triggering before implementing this strategy in clinical practice.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e \u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e \u003ch2\u003eETHICS APPROVAL\u003c/h2\u003e \u003cp\u003e This study received approval for publication from the Ethics Review Committee of Cochin University Hospital (CLEP) (No. AAA-2024-10007). All participants provided written informed consent.\u003c/p\u003e \u003ch2\u003eFUNDING\u003c/h2\u003e \u003cp\u003eThe authors did not receive support from any organization for the submitted work.\u003c/p\u003e \u003ch2\u003eDATA AVAILABILITY\u003c/h2\u003e \u003cp\u003eData will be made available on request.\u003c/p\u003e\u003ch2\u003eACKNOWLEDGEMENTS\u003c/h2\u003e \u003cp\u003eThe authors extend their gratitude to the staff members of our department for their expert assistance with data collection, especially Val\u0026eacute;rie Blanchet, Julia Gonnot, Emmanuelle Laviron, C\u0026eacute;lie Cervantes, and Audrey Houliat at the ART unit.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYoussef MAFM, Van der Veen F, Al-Inany HG, Mochtar MH, Griesinger G, Nagi Mohesen M et al (2014) Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology. 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J Clin Endocrinol Metab 71:918\u0026ndash;922\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eItskovitz J, Boldes R, Levron J, Erlik Y, Kahana L, Brandes JM (1991) Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist. Fertil Steril 56:213\u0026ndash;220\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen S-L, Ye D-S, Chen X, Yang X-H, Zheng H-Y, Tang Y et al (2012) Circulating luteinizing hormone level after triggering oocyte maturation with GnRH agonist may predict oocyte yield in flexible GnRH antagonist protocol. Hum Reprod Oxf Engl 27:1351\u0026ndash;1356\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKummer NE, Feinn RS, Griffin DW, Nulsen JC, Benadiva CA, Engmann LL (2013) Predicting successful induction of oocyte maturation after gonadotropin-releasing hormone agonist (GnRHa) trigger. Hum Reprod Oxf Engl 28:152\u0026ndash;159\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeyer L, Murphy LA, Gumer A, Reichman DE, Rosenwaks Z, Cholst IN (2015) Risk factors for a suboptimal response to gonadotropin-releasing hormone agonist trigger during in vitro fertilization cycles. Fertil Steril 104:637\u0026ndash;642\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChang FE, Beall SA, Cox JM, Richter KS, DeCherney AH, Levy MJ (2016) Assessing the adequacy of gonadotropin-releasing hormone agonist leuprolide to trigger oocyte maturation and management of inadequate response. Fertil Steril 106:1093\u0026ndash;1100e3\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeepika K, Sindhuma D, Kiran B, Ravishankar N, Gautham P, Kamini R (2018) Empty Follicle Syndrome Following GnRHa Trigger in PCOS Patients Undergoing IVF Cycles. 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World Health Organ Tech Rep Ser 514:1\u0026ndash;30\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBourdon M, Maignien C, Pocate-Cheriet K, Plu Bureau G, Marcellin L, Patrat C et al (2021) The freeze-all strategy after IVF: which indications? Reprod Biomed Online 42:529\u0026ndash;545\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eESHRE Working Group on Ultrasound in ART, D\u0026rsquo;Angelo A, Panayotidis C, Amso N, Marci R, Matorras R et al (2019) Recommendations for good practice in ultrasound: oocyte pick up\u0026dagger;. Hum Reprod Open 2019:hoz025\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBourdon M, Santulli P, Marcellin L, Lamau MC, Maignien C, Chapron C (2017) [Bowel endometriosis and infertility: Do we need to operate?]. Gynecol Obstet Fertil Senol 45:486\u0026ndash;490\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBourdon M, Santulli P, Chen Y, Patrat C, Pocate-Cheriet K, Maignien C et al (2019) The Deferred Embryo Transfer Strategy Seems Not to be a Good Option After Repeated IVF/ICSI Cycle Failures. Reprod Sci Thousand Oaks Calif 26:1210\u0026ndash;1217\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerreux L, Bourdon M, Sallem A, Santulli P, Barraud-Lange V, Le Foll N et al (2018) Live birth rate following frozen-thawed blastocyst transfer is higher with blastocysts expanded on Day 5 than on Day 6. Hum Reprod Oxf Engl 33:390\u0026ndash;398\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaignien C, Bourdon M, Parpex G, Ferreux L, Patrat C, Bordonne C et al (2024) Endometriosis-related infertility: severe pain symptoms do not impact assisted reproductive technology outcomes. 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Arch Gynecol Obstet 299:559\u0026ndash;564\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcCulloh DH, Kutchukhidze N, Charkviani T, Zhorzholadze T, Barbakadze T, Munn\u0026eacute; S et al (2020) Follicle size indicates oocyte maturity and blastocyst formation but not blastocyst euploidy following controlled ovarian hyperstimulation of oocyte donors. Hum Reprod Oxf Engl 35:545\u0026ndash;556\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYding Andersen C, Leonardsen L, Ulloa-Aguirre A, Barrios-De-Tomasi J, Moore L, Byskov AG (1999) FSH-induced resumption of meiosis in mouse oocytes: effect of different isoforms. Mol Hum Reprod 5:726\u0026ndash;731\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD\u0026rsquo;Alessandris C, Canipari R, Di Giacomo M, Epifano O, Camaioni A, Siracusa G et al (2001) Control of mouse cumulus cell-oocyte complex integrity before and after ovulation: plasminogen activator synthesis and matrix degradation. Endocrinology 142:3033\u0026ndash;3040\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYding Andersen C (2002) Effect of FSH and its different isoforms on maturation of oocytes from pre-ovulatory follicles. Reprod Biomed Online 5:232\u0026ndash;239\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDell\u0026rsquo;Aquila ME, Caillaud M, Maritato F, Martoriati A, G\u0026eacute;rard N, Aiudi G et al (2004) Cumulus expansion, nuclear maturation and connexin 43, cyclooxygenase-2 and FSH receptor mRNA expression in equine cumulus-oocyte complexes cultured in vitro in the presence of FSH and precursors for hyaluronic acid synthesis. Reprod Biol Endocrinol RBE 2:44\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGodard NM, Pukazhenthi BS, Wildt DE, Comizzoli P (2009) Paracrine factors from cumulus-enclosed oocytes ensure the successful maturation and fertilization in vitro of denuded oocytes in the cat model. 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Eur J Obstet Gynecol Reprod Biol 289:65\u0026ndash;73\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaas J, Bassil R, Samara N, Zilberberg E, Mehta C, Orvieto R et al (2020) GnRH agonist and hCG (dual trigger) versus hCG trigger for final follicular maturation: a double-blinded, randomized controlled study. Hum Reprod Oxf Engl 35:1648\u0026ndash;1654\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHsia L-H, Lee T-H, Lin Y-H, Huang Y-Y, Chang H-J, Liu Y-L (2023) Dual trigger improves the pregnancy rate in fresh in vitro fertilization (IVF) cycles compared with the human chorionic gonadotropin (hCG) trigger: a systematic review and meta-analysis of randomized trials. J Assist Reprod Genet 40:2063\u0026ndash;2077\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu J, Maccalman CD, Wang Y, Leung PCK (2009) Promotion of human trophoblasts invasion by gonadotropin-releasing hormone (GnRH) I and GnRH II via distinct signaling pathways. Mol Endocrinol Baltim Md 23:1014\u0026ndash;1021\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Assistance Publique – Hôpitaux de Paris","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Antagonist protocol, GnRH agonist, hCG, Mature oocyte yield, Ovulation triggering","lastPublishedDoi":"10.21203/rs.3.rs-8939235/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8939235/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePURPOSE OF RESEARCH: To evaluate the impact of ovulation-triggering agents on suboptimal mature oocyte yield in antagonist ICSI cycles.\u003c/p\u003e \u003cp\u003eDESIGN: We conducted a retrospective cohort study of 2,129 antagonist ICSI cycles at a tertiary university hospital from October 2013 to October 2022. The primary outcome was suboptimal response to triggering, defined as a mature oocyte yield below the 75th percentile. Mature oocyte yield was calculated as the number of mature oocytes retrieved divided by the number of mature follicles (mean diameter\u0026thinsp;\u0026ge;\u0026thinsp;15 mm) on the trigger day. Prognostic factors for suboptimal response were analyzed using univariate and multivariate methods.\u003c/p\u003e \u003cp\u003eRESULTS: Of the cycles, 909 (42.7%) were triggered with GnRHa, 845 (39.7%) with hCG, and 375 (17.6%) with both. The mean mature follicle count was 7.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3, the average number of mature oocytes was 7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0, and the mean mature oocyte yield was 92.3\u0026thinsp;\u0026plusmn;\u0026thinsp;55.2%. The 75th percentile for mature oocyte yield was 117%. Mature oocyte yield was significantly higher with GnRHa versus hCG (96.7\u0026thinsp;\u0026plusmn;\u0026thinsp;59.1% vs. 87.6\u0026thinsp;\u0026plusmn;\u0026thinsp;48.8%), with no significant difference compared to dual trigger (92.2\u0026thinsp;\u0026plusmn;\u0026thinsp;58.0%; p\u0026thinsp;=\u0026thinsp;0.017). Suboptimal yield was lower with GnRHa (71.6%) than hCG (80%), but not dual trigger (76.8%), p\u0026thinsp;=\u0026thinsp;0.017. Multivariate analysis showed GnRHa triggering was associated with lower risk of suboptimal yield (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eCONCLUSION: GnRHa triggering is associated with a reduced risk of suboptimal mature oocyte yield compared to hCG\u003c/p\u003e","manuscriptTitle":"Suboptimal Mature Oocyte Yield in Antagonist Icsi Cycles: Any Impact of the Ovulation Triggering Agent?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-24 15:02:39","doi":"10.21203/rs.3.rs-8939235/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bb2f878d-c47d-421b-ad0c-5b3e94918d41","owner":[],"postedDate":"February 24th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":63458831,"name":"Sexual \u0026 Reproductive Medicine"}],"tags":[],"updatedAt":"2026-02-24T15:02:39+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-24 15:02:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8939235","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8939235","identity":"rs-8939235","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}