Antagonist Cycles Research Articles

Comparative analysis of pregnancy outcomes in different time intervals following GnRH antagonist stimulation and modified natural frozen-thawed embryo transfers

To evaluate whether the interval between oocyte retrieval and frozen-thawed embryo transfer (FET) affects clinical outcomes using modified natural cycle (mNC) regimen following freeze-all GnRH antagonist stimulation. A total of 542 patients underwent first mNC-FET were divided into two groups: immediate (FET conducted in the first menstrual cycle after freeze-all) and delayed (FET performed in the second or subsequent menstrual cycle) groups. The immediate group was associated with a notably reduced duration between oocyte retrieval and transfer day (35.5 ± 5.8 vs. 88.7 ± 35.5 d, P < 0.001). Regarding pregnancy results, the immediate cycles resulted in comparable implantation rate (55.3% vs. 57.2%, P = 0.624), clinical pregnancy rate (66.9% vs. 72.2%, P = 0.236), abortion rate (16.1% vs. 12.7%, P = 0.402), ongoing pregnancy rate (59.0% vs. 65.0%, P = 0.204), and live birth rate (56.1% vs. 63.0%, P = 0.149) with the delayed cycles. After the multivariable logistic regression analysis, the difference in live birth outcome between the two regimens remained insignificant (immediate vs. delayed protocol: adjusted odds ratio = 0.87, 95% confidence interval= 0.56–1.33). Immediate mNC-FET following a freeze-all antagonist cycle displayed promising clinical outcomes and significantly shortened the time to conception compared to delayed FET.

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

To evaluate whether co-treatment of repeated GnRHa triggers with GnRH antagonist protocols can improve the clinical outcomes in in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) procedures. In this retrospective study, 712 Chinese Han women aged 20-42 undergoing autologous IVF/ICSI-ET with a flexible GnRH antagonist protocol were analyzed. The 735 cycles were split into the single (n = 238) and the repeated (n = 497) GnRHa groups. In the single GnRHa group, 0.2mg of triptorelin was given for oocyte maturation, whereas in the repeated GnRHa group, two doses of 0.2mg were administered 12h apart. PSM design was used for a fair comparison. The main study outcomes included the clinical pregnancy rate (CPR), live birth rate (LBR), good-quality embryo rate, and fertilization rate. Multivariate logistic regression analyses were used to identify all potential factors affecting clinical outcomes. Post-PSM, analysis of 159 cycles per group showed the repeated GnRHa group outperforming the single GnRHa group in IVF fertilization rates (71.5% vs. 67.7%, P < 0.05) and good-quality embryo rate (47.1% vs. 43.7%, P < 0.05). Furthermore, the repeated GnRHa group achieved higher CPR (72.6% vs. 53.4%, P < 0.05) and LBR (59.7% vs. 43.8%, P < 0.05) in FET cycles. Multivariate logistic regression indicated a significant negative correlation between the use of a single GnRHa trigger and both clinical pregnancy (OR = 0.382, P < 0.05) and live birth (OR = 0.518, P < 0.05). Our study reported that individuals who received a repeated GnRHa trigger exhibited higher CPR and LBR during FET cycles compared to those who received a single dose GnRHa trigger.

Inter-cycle variability of anti-Müllerian hormone: implications for predicting controlled ovarian stimulation cycle outcomes

BackgroundAnti-Müllerian hormone (AMH) is a widely used marker for estimating ovarian reserve, and it may predict response to ovarian stimulation. While AMH is considered a stable, cycle-independent marker, studies have shown it can exhibit significant fluctuations based on factors like age, reproductive stage, and menstrual cycle phase. The fluctuations in AMH levels can make it challenging to predict individual responses accurately, particularly when the AMH is not measured in the COS cycle. The aim of this study was to assess the inter-cycle variability of serum AMH levels in two consecutive menstrual cycles and their correlation with response to controlled ovarian stimulation outcome in the latter.MethodsIn this single-centre retrospective cohort study, data of normal and low responder patients who underwent intracytoplasmic sperm injection following a GnRH antagonist cycle at a university hospital infertility clinic between January 2022 and December 2023 were reviewed. Serum AMH levels were measured in the early follicular phase of two consecutive menstrual cycles with Elecsys-AMH Roche® system (Roche Diagnostics, Meylan, France). Correlations between AMH levels and controlled ovarian stimulation outcomes, including total oocyte and mature oocyte (MII) counts, were assessed. The study included normal and poor responder women to maintain data integrity.ResultsA total of 79 patients were included in the final analyses. Significant cycle-to-cycle variation in serum AMH levels was observed, with a median variation of 44.3%. Normal responders exhibited a mean change of 0.60 ± 0.46 ng/ml, while poor responders had a mean change of 0.28 ± 0.28 ng/ml. Approximately 20% of patients were reclassified between normal and poor responder categories based on the second AMH measurement. The controlled ovarian stimulation cycle AMH levels showed a stronger correlation with both total oocyte count (r = 0.871, P < 0.001) and MII oocyte count (r = 0.820, P < 0.001) compared to preceding cycle AMH levels.ConclusionAMH levels can exhibit significant variations between consecutive cycles, potentially leading to misclassification of patients. Measuring AMH in the early follicular phase of the COS cycle provides a more accurate prediction of the numbers of total and MII oocytes collected. Consistent and repeated AMH measurements can help clinical decision-making.

Prediction of Assisted Reproductive Technology Outcome by Day 5 Estradiol (E2) Levels in Antagonist Cycles

Prediction of Assisted Reproductive Technology Outcome by Day 5 Estradiol (E2) Levels in Antagonist Cycles

Effect of progesterone concentration on hCG trigger day on clinical outcomes after high-quality single blastocyst transfer in GnRH antagonist cycles.

To investigate whether progesterone levels on the human chorionic gonadotropin (hCG) trigger day are associated with clinical outcomes in fresh cycles and the first frozen-thawed cycles (the freeze-all strategy) following the transfer of a high-quality single blastocyst. This single-center retrospective analysis was conducted on patients undergoing in vitro fertilization with the gonadotropin-releasing hormone (GnRH) antagonist protocol from January 2017 to December 2023. The study included the first and second oocyte retrieval cycles with progesterone levels ≤2 ng/ml on hCG trigger day. Clinical pregnancy rates and early miscarriage rates were compared among groups using curve fitting, threshold effect analysis, and multivariable regression. When progesterone levels were between 1 and 2 ng/ml, the pregnancy rate in fresh cycles was only 51% of that in cycles with progesterone levels ≤1 ng/ml (95% CI: 0.33, 0.79, p = 0.0028). And the pregnancy rate decreased by 25% (95% CI: 0.51, 1.09) for frozen cycles, although there was no statistically significant (p = 0.1273). When cycle types were used as a binary variable in multivariate regression analysis, it was found that the clinical pregnancy rate in frozen cycles was 1.84 times higher than in fresh cycles (OR = 1.84, 95% CI: 1.38-2.47). For progesterone levels between 1 and 2 ng/ml, the clinical pregnancy rate in frozen cycles was 2.90 times that of fresh cycles (OR = 2.90, 95% CI: 1.59, 5.29, p = 0.0015). Progesterone levels on hCG day had no impact on the clinical pregnancy rate in thaw cycles, nor did they affect miscarriage rates in fresh or thaw cycles (p > 0.05). When progesterone levels on hCG trigger day were between 1 and 2 ng/ml, the clinical pregnancy rate for frozen-thawed cycles of high-quality single blastocyst transfer using an GnRH antagonist protocol significantly surpasses that of fresh cycles, thus elective frozen embryo transfer after the freeze-all strategy is recommended.

Exposure of antral follicles to medroxyprogesterone acetate during stimulation does not cause molecular perturbations in gonadotropin-responsiveness and steroidogenic function of granulosa cells in progestin-primed cycles.

Does medroxyprogesterone acetate (MPA) exposure in progestin-primed ovarian stimulation (PPOS) cycles cause molecular perturbations in the steroidogenic function and gonadotropin responsiveness of the granulosa cells? PPOS cycles are identical to traditional GnRH antagonist cycles not only for clinical IVF characteristics but also for gonadotropin receptor expression, response to gonadotropins, and steroidogenic function at the molecular level. PPOS is increasingly used as an alternative to GnRH antagonists due to the inhibitory effect of progesterone on LH release by reducing GnRH pulsatility at the hypothalamic level. Although a growing body of evidence from clinical studies did not indicate significant differences between PPOS and antagonist protocols for IVF cycle characteristics and obstetrical outcomes, it is still unknown whether exposure of the antral follicle cohort to progesterone or its synthetic derivatives during ovarian stimulation causes any subtle molecular aberrations in terms of steroidogenesis and gonadotropin responsiveness. To address this issue, detailed comparative molecular analyses were conducted in the luteinized mural granulosa cells (GCs) obtained from normal responding IVF patients undergoing PPOS and antagonist cycles. A clinical translational research study was conducted with IVF patients. This study included 55 normal responding IVF patients who underwent ovarian stimulation with either PPOS using MPA (5 mg twice daily) or GnRH antagonist cetrorelix acetate. Recombinant forms of FSH and hCG were used for ovarian stimulation and ovulation triggering, respectively. Luteinized mural GCs obtained during the oocyte retrieval procedure were used for the experiments. Cell culture, quantitative real-time PCR, immunoblotting, confocal time-lapse live cell imaging, and hormone assays were used. Demographic and IVF cycle characteristics of the patients undergoing ovarian stimulation with PPOS and GnRH antagonist were similar, including ovarian response, mature oocyte yield, and fertilization rates. Molecular analyses revealed that the expression of the enzymes involved in sex-steroid synthesis (StAR, SCC, 3β-HSD, 17β-HSD, aromatase) and the uptake/storage/utilization of cholesterol (LDL receptor, Hormone-sensitive lipase, hydroxy-methyl glutaryl Co-enzyme-A reductase, and Sterol O-acyltransferase1) in the GCs of the PPOS cycles were comparable to those of the antagonist cycles. The expression of the receptors for gonadotropins, estrogen, and progesterone hormones was also similar. Basal and hCG-induced increases in 3β-HSD expression and progesterone production and basal and FSH-induced increases in aromatase expression and E2 output of the GCs from PPOS patients did not exhibit any meaningful differences when compared with GCs from antagonist cycles. Furthermore, basal and hCG-induced up-regulation in the LDL receptor expression and cholesterol uptake did not differ between the groups. Confocal imaging also revealed similar patterns of expression for the steroidogenic enzymes and their co-localization with mitochondria. Lastly, the expression of the other important genes regulating cumulus expansion, ovulation, and luteal function [Relaxin, ADAMTS-1, and epidermal growth factor (EGF)-like growth factor amphiregulin] in the GCs of the PPOS and antagonist cycles were similar. N/A. Caution should be exercised when interpreting our data which was derived from normally responding patients whose ovulation was triggered with hCG. It is unclear whether the molecular parameters assessed vary according to infertility etiologies, magnitude of ovarian response, mode of trigger, and any other underlying ovarian pathologies or systemic diseases. MPA was the progestin used for PPOS and whether these findings can be generalized to other progestins is unknown. This study provides reassuring molecular evidence that exposure of antral follicle cohorts to MPA during the follicular growth phase does not have any detrimental effects on steroidogenic, ovulatory, and luteal functions when compared with GnRH antagonist cycles. This study was funded by the School of Medicine, the Graduate School of Health Sciences of Koc University and Koç University Research Center for Translational Medicine (KUTTAM), and equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. All authors declare no conflict of interest. N/A.

Pretreatment with luteal estradiol for programming antagonist cycles compared to no pretreatment in advanced age women stimulated with corifollitropin alfa: a non-inferiority randomized controlled trial.

Pretreatment with luteal estradiol for programming antagonist cycles compared to no pretreatment in advanced age women stimulated with corifollitropin alfa: a non-inferiority randomized controlled trial.

Can We Harvest More Mature Oocytes by Repeating Gonadotropin-Releasing Hormone Agonist Doses in Polycystic Ovarian Syndrome Patients at Risk of OHSS in Antagonist Cycles? A Randomised Clinical Trial.

There is an ongoing debate about the optimal dosage of gonadotropin-releasing hormone (GnRH) agonist for oocyte triggering in polycystic ovarian syndrome (PCOS) patients at risk for ovarian hyperstimulation syndrome (OHSS). In this study, we intend to ascertain whether the use of repeated doses of a GnRH agonist for oocyte triggering in these patients can enhance the outcomes of controlled ovarian stimulation (COS) for in vitro fertilization/ intracytoplasmic sperm injection (IVF/ICSI) cycles. This randomised clinical trial enrolled 70 PCOS women candidates for IVF/ICSI with the standard antagonist protocol at Royan Institute (Tehran, Iran) from May 2020 to June 2022. Patients at risk of OHSS with oestradiol (E2) levels >3000 pg/ml on the day of trigger were randomly assigned to a control or experimental group. Group A (control group) patients received 0.2 mg triptorelin (Decapeptyl®) for final oocyte maturation. Group B (experimental group) patients received a second dose of 0.1 mg Decapeptyl®12 hours after their first dose, for a total dose of 0.3 mg. IVF/ICSI outcomes were compared between the groups. Ultimately, 35 women from the study group and 33 from the control group completed the treatment cycle. Both groups were comparable in terms of demographic characteristics, baseline hormonal profiles, and PCOS phenotypes. The dosage of gonadotropin, stimulation duration, number of retrieved oocytes, oocyte maturation rate, and oocyte recovery ratio did not significantly differ between the groups. No significant differences were found in terms of the number of blastocyst and cleavage embryos, nor the quality of obtained embryos between the groups. The mild to moderate OHSS rate was significantly lower in the study group (P=0.038). A second dose of GnRH agonist 12 hours after the first dose did not improve the number and maturity of oocytes, or pregnancy outcomes in PCOS patients (registration number: NCT04600986).

O-299 Exposure of antral follicles to progestins during stimulation does not cause molecular perturbations in gonadotropin-responsiveness and steroidogenic function of granulosa cells in progestin-primed IVF cycles

Abstract Study question Does progestin exposure cause any molecular perturbations in the steroidogenic features and gonadotropin responsiveness of the granulosa cells in progestin-primed ovarian stimulation (PPOS) cycles? Summary answer No. PPOS cycles are identical to antagonist cycles for gonadotropin receptor expression, response to gonadotropins, steroidogenic function at molecular level in normal responding IVF patients. What is known already PPOS is commonly used in IVF cycles as an alternative to antagonist cycles. Although accumulating evidence from clinical studies did not indicate any particular differences between these two types of stimulation protocol for IVF cycle characteristics, it is still unknown if exposure of antral follicle cohorts to synthetic progesterone derivatives during ovarian stimulation causes any subtle molecular aberrations in PPOS cycles in terms of steroidogenesis and gonadotropin responsiveness. To address this issue, detailed molecular analyses were conducted in the luteinized mural granulosa cells (GCs) obtained from the normal responding patients undergoing PPOS vs. antagonist IVF cycles. Study design, size, duration A translational research study in IVF patients. Participants/materials, setting, methods 55 normal responding IVF patients underwent ovarian stimulation either with PPOS using medroxy progesterone acetate (5mg twice daily) or, with GnRH antagonist cetrorelix acetate were included in the study. Recombinant forms of FSH and hCG were used for ovarian stimulation and ovulation trigger, respectively. Luteinized mural granulosa cells obtained during oocyte retrieval procedure were used for the experiments. Cell culture, quantitative real-time PCR, immunoblotting, confocal time-lapse live cell imaging and hormone assays were used. Main results and the role of chance Demographic and IVF characteristics of the patients undergoing ovarian stimulation with PPOS vs. GnRH antagonist were similar including ovarian-response, mature oocyte yield and fertilization rates. Molecular analyses revealed that the expression of the enzymes involved in sex-steroid synthesis (StAR, aromatase, 3B-HSD, 17B-HSD) and uptake/storage/utilization of cholesterol (LDL receptor, Hormone-sensitive lipase, hydroxy-methyl glutaryl Co-enzyme-A reductase and Sterol O-acyltransferase1) in the GCs of the PPOS cycles were comparable to the antagonist IVF cycles. Both cycles were also similar for the expression of FSH and LH receptors at transcriptional and translational level. Basal and hCG-induced increases in 3B-HSD expression and P4 production, and basal and FSH-induced increases in aromatase expression and E2 output of the GCs of the PPOS patients did not show any meaningful differences from the antagonist cycles. Similarly, basal and hCG-induced up-regulation in the LDL receptor expression and cholesterol uptake rate did not differ between the groups. Confocal imaging also revealed similar patterns of expression for the steroidogenic enzymes and their co-localization with mitochondria. Lastly, the expression of the other genes regulating cumulus expansion, ovulation and luteal function (Relaxin, ADAMTS-1 and EGF-like growth factor amphiregulin (AREG)) in the GCs of the PPOS cycles were comparable to the antagonist cycles. Limitations, reasons for caution Caution should be exercised when interpreting our data, which was produced in normal responders. It is unclear if the molecular parameters assessed here vary according to infertility etiologies, ovarian response type, mode of trigger and any other underlying ovarian pathology or systemic diseases that are concomitantly present. Wider implications of the findings This study provides reassuring molecular evidence that exposure of antral cohorts to progestins follicular growth phase does not appear to have any detrimental effect on their steroidogenic, ovulatory and luteal functions, suggesting that PPOS IVF cycles are not different from traditional antagonist cycles. Trial registration number not applicable

P-396 Comparison of luteal support protocols in fresh IVF/ICSI cycles: A network meta-analysis

Abstract Study question What is the optimal LPS in fresh cycles in agonist and antagonist cycles? Summary answer Vaginal progesterone, with the addition of SCGnRH-a results in improved clinical pregnancy and live birth events in both GnRH-agonist and antagonist ovarian stimulation protocols. What is known already Despite the proven superiority of various Luteal Phase Support protocols (LPS) over placebo in view of improved pregnancy rates in fresh cycles of IVF (in vitro fertilization) and ICSI (intracytoplasmic sperm injection) cycles, there is ongoing controversy over specific LPS protocol selection, dosage, and duration. Study design, size, duration Network Meta-analysis. Twelve databases, namely Embase (OVID), MEDLINE (R) (OVID), GlobalHealth (Archive), GlobalHealth, Health and Psychosocial Instruments, Maternity &amp; Infant Care Database (MIDIRS), APA PsycTests, ClinicalTrials.gov, HMIC Health Management Information Consortium, CENTRAL, Web of Science, Scopus and two prospective registers, MedRxiv, Research Square were searched from inception to Aug.1st, 2023.The study was prospectively registered under the PROSPERO database. Participants/materials, setting, methods Only RCTs were included. Primary outcomes included clinical pregnancy and live birth events, while secondary outcomes included biochemical pregnancy, miscarriage, multiple pregnancy and OHSS events. Bayesian network meta-analysis (NMA) model was employed for outcome analysis, presenting fixed effects, odds ratios (ORs) with 95% credibility intervals (CrIs). Vaginal Progesterone (VP) was considered the reference LPS for the purposes of the NMA given its’ clinical relevance. Main results and the role of chance Seventy-six RCTs, comparing 22 interventions, and including 26536 participants were included in the present NMA.Combinatorial regimens, with subcutaneous GnRH-a (SCGnRH-a) on a vaginal progesterone base and oral oestrogen (OE) appeared to overall improve clinical pregnancy events; VP+OE+SCGnRH-a [OR 1.57 (95% CrI 1.11 to 2.22)], VP+SCGnRH-a [OR 1.28 (95% CrI 1.05 to 1.55)] as well as live pregnancy events, VP+OE+SCGnRH-a [OR 8.81 (95% CrI 2.35 to 39.1)], VP+SCGnRH-a [OR 1.76 (95% CrI 1.45 to 2.15)]. Equally, the progesterone free LPS, intramuscular human chorionic gonadotrophin, [OR 9.67 (95%CrI 2.34, 73.2)] was also found to increase live birth events, however was also associated with an increased probability of ovarian hyperstimulation, [OR 1.64 (95%CrI 0.75, 3.71)]. Of all LPS protocols, VP+SC GnRH-a was found to significantly reduce miscarriage events, OR 0.54 (95% CrI 0.37 to 0.80). Subgroup analysis according to ovarian stimulation (OS) protocol revealed that the optimal LPS across both long and short OS, taking into account increase in live birth and reduction in miscarriage as well as OHSS events, was VP+SCGnRH-a, with an OR 2.89 [95%CrI 1.08, 2.96] and OR 2.84 [95%CrI 1.35, 6.26] respectively. Limitations, reasons for caution Given the anticipated diversity of measured outcomes, a Bayesian meta-synthesis approach has been adopted to account for the expected heterogeneity and to incorporate modelling flexibility by allowing for posterior distributions interpreted as SUCRA probabilities with the later enabling crisper communication of the uncertainty in the treatment effects estimates. Wider implications of the findings Overall, NMA data suggest that combinatorial treatments, with the addition of SCGnRH-a on a VP base result in improved clinical pregnancy and live birth events in both GnRH-agonist and antagonist ovarian stimulation protocols. Trial registration number Not applicable

O-219 Explainable artificial intelligence (XAI) to determine the follicle sizes on trigger day that maximize mature oocyte yield

Abstract Study question Which follicle sizes on trigger day (TD) are key to obtaining mature oocytes, embryos, and blastocysts, thereby enhancing live birth rates? Summary answer Follicles sized 13-18mm are most likely to yield mature oocytes. Live birth rate (LBR) was increased with a greater proportion of follicles in this range. What is known already At the time of oocyte retrieval, follicles that are either too small or too large are less likely to yield mature oocytes. However, there is only limited data examining which follicle sizes on TD administration are optimally sized to yield mature oocytes, nor any data examining whether live birth rates are impacted. Explainable artificial intelligence (XAI) offers a valuable opportunity to leverage clinical data to determine the range of follicle sizes that are most likely to yield mature oocytes and lead to improved downstream outcomes. Study design, size, duration A retrospective study incorporating 19,082 patients undergoing their first IVF/ICSI cycle (2005-2023) across 11 European clinics. Follicle sizes on TD were related to oocyte maturity (14,140 patients), fertilization (17,822 patients), high-quality blastocyst development (17,488 patients), and pregnancy outcomes (12,672 patients). Secondary analyses included stratification by age (&amp;gt;35 years: 4,717 patients; ≤35 years: 5,707), and suppressant protocol (GnRH agonist: n = 5,420 patients; GnRH antagonist: n = 3,982). Participants/materials, setting, methods An ensemble-based XAI model, developed through ‘internal-external validation’, was trained, Bayesian optimized, and independently iteratively tested on hold-out clinic datasets. The model determined follicle sizes contributing most to successful laboratory outcomes by harnessing permutation importance and ‘SHAP’ values. Model performance was evaluated and optimized for mean absolute error (MAE). The top 50% contiguous cohort of influential follicle sizes on TD were identified, and further validated through analysis of follicle sizes on preceding days. Main results and the role of chance XAI analysis revealed that follicles sized 13-18mm on TD were most influential in yielding mature oocytes, especially those sized 15-18mm (MAE: 3.60 ±0.35). Predictive follicle sizes from scans 1-2 days preceding TD administration were consistent with expected mean follicle growth rates. For high-quality blastocysts, follicles sized 14-20mm were contributory, narrowing to 15-18mm in the subset of patients where oocytes had been confirmed to be mature. In hCG-triggered cycles, follicles sized 12-19mm were most likely to yield mature oocytes in GnRH antagonist cycles, whereas follicles sized 14-20mm were most contributory in GnRH agonist cycles. In patients ≤35 years, follicles 13-18mm were most contributory, whereas a wider range of follicles (11-20mm) were contributory in patients &amp;gt;35 years. In line with current practice, having three lead follicles ≥17mm on TD was associated with a median improvement in mature oocyte yield of 10% versus those that did not (p &amp;lt; 0.0001). By comparison, maximizing the proportion of follicles on TD within the optimal size range could better improve mature oocyte yield, for example, by 42% when at least 70% of follicles were sized 15-18mm (p &amp;lt; 0.0001). Likewise, LBR improved as the proportion of follicles sized 13-18mm was increased (&amp;lt;10%: 23.3%; 10-20%: 25.7%; 20-30%: 28.8%; 30-40%: 31.6%). Limitations, reasons for caution These data could help guide when to administer the trigger to optimize clinical outcomes, however prospective assessment of different TD strategies based on the proportion of follicles within the optimal follicle size ranges identified in comparison to current practice based on lead follicle size is required prior to clinical adoption. Wider implications of the findings These findings provide a data-driven approach to personalizing ovarian stimulation in IVF. The findings generated by applying an XAI model could assist clinicians in optimizing TD timing, potentially enhancing clinical outcomes by moving beyond the conventional focus on lead follicle size. Trial registration number not appicable

P-608 Cumulative live birth rates after 3 consecutive embryo transfers in freeze-all cycles following gonadotropin-releasing hormone antagonist protocol versus progesterone-primed ovarian stimulation

Abstract Study question Do cumulative live birth rates in freeze-all cycles differ between gonadotropin-releasing hormone (GnRH) antagonist protocol and progesterone-primed ovarian stimulation (PPOS)? Summary answer GnRH antagonist and PPOS protocols have similar cumulative live birth rates in freeze-all cycles. What is known already GnRH antagonists and progesterone have been used for pituitary suppression in ovarian stimulation cycles. While PPOS protocol has the advantage of oral usage and lower cost, data regarding the laboratory and clinical outcome is limited and confounding. Freeze-all cycles might provide a better model to assess the impact of PPOS protocol and GnRH antagonist protocol on laboratory, clinical outcomes and cumulative live birth rates. Study design, size, duration A retrospective cohort study on IVF cycles performed (n = 568) between January 2020 and May 2022.The entire cohort of embryos were cryopreserved at the blastocyst stage.Inclusion criteria were 18-42 years of age,ICSI for severe male factor infertility.Exclusion criteria were PGD and severe endometriosis.Indications for cryopreservation in the antagonist group were high ovarian response (n:102),endometrial polyps (n:34),high follicular phase P4(n:48) and elective purposes(n:260).PPOS was used due to a transient shortage of GnRH antagonist in the market (n:124). Participants/materials, setting, methods 568 women (GnRH antagonist:444; PPOS:124) were included in the analysis.The primary outcome was the cumulative live birth rate (CLBR) after 3 consecutive embryo transfer cycle, and the secondary outcome parameters were the number of M-II oocytes, fertilization rate and blastocyst utilization rate. Student’s t-test was used for normally distributed continuous data and Fisher’s exact tests for categorical data were used. A generalized estimating equation model and logistic regression analysis were performed to adjust for confounding factors. Main results and the role of chance The mean age of the GnRH antagonist group was 34.1 ± 5.3 and 34.5 ± 5.7 years in PPOS group (p = 0.38). The baseline characteristics including BMI, serum AMH levels, duration of infertility, duration of stimulation and gonadotropin ampules used were similar in both groups. Estradiol and progesterone levels at the time of ovulation trigger were higher in GnRH antagonist cycles (2383.5 ± 1375.4 vs 2034.5 ± 1218.3, p = 0.02 and 0.7 ± 0.6 vs 0.5 ± 0.4, p = 0.01, respectively) The mean number of cumulus-oophorus complexes (12.9 ± 7.4 vs 11.5± 10.0, p = 0.61), M-II oocytes (10.0± 6.1 vs 9.1± 6.1, p = 0.14), frozen blastocysts (4.8± 3.5 vs 4.7± 3.6, p = 0.71) were similar between GnRH antagonist and PPOS groups, respectively. Fertilization rates (84.4% vs 87.2%, p = 0.12) and blastocyst utilization rates (63.4% vs 65.9%, p = 0.34) were also similar between GnRH antagonist and PPOS groups, respectively. The number of transferred embryos and the number of unused blastocysts were similar between groups. The CLBRs after one IVF cycle and 3 consecutive frozen-thawed blastocyst transfers were comparable in GnRH antagonist and PPOS cycles (56.8% and 53.2%, p = 0.37, respectively). Limitations, reasons for caution This was a retrospective study with relatively small sample size performed at a single fertility center, which may limit the generalizability of our findings. Wider implications of the findings If the fresh embryo transfer is not intended, PPOS protocol can be used in all patient types with cost-effective and patient-friendly manner. Trial registration number 2024.013.IRB2.012

P-793 New approaches for treating diminished ovarian reserve: MSC-derived extracellular vesicles and autologous platelet rich plasma

Abstract Study question Does intraovarian injection of MSC-Derived Extracellular Vesicles (EVs) and autologous platelet rich plasma (PRP) improves the outcome of IVF in women with Diminished Ovarian reserve? Summary answer EVs and PRP therapies increse Antral follicle count (AFC), lower FSH level and result in higher amount of mature oocytes and blastocysts What is known already Diminished ovarian reserve (DOR) and premature ovarian insufficiency (POI) are significant impediments to the success of in vitro fertilization (IVF). Current strategies for ovarian stimulation primarily affects only the growth of antral follicles. Even in scenarios where ovarian ovulatory function is compromised, a reservoir of dormant follicles persists, which could potentially be activated by stem cells. Mesenchymal stem cells (MSCs), owing to their multipotent differentiation capabilities and paracrine signaling properties, have emerged as leading candidates for innovative therapeutic approaches. Recent scientific inquiries have highlighted the paracrine impact of EVs secreted by stem cells, underscoring their prospective therapeutic relevance. Study design, size, duration This prospective interventional study was conducted at the V.I. Kulakov Scientific Research Center for Obstetrics, Gynecology, and Perinatology in Russia. It involved 60 infertile female participants aged 20 to 38 years, each with DOR and a history of at least two unsuccessful IVF cycles. These participants were enrolled in the study during their subsequent IVF cycle. Prior to inclusion, all patients provided written informed consent. Participants/materials, setting, methods Patients in group 1 (n = 30) received treatment with exosomes derived from human umbilical cord mesenchymal stem cells (HUC-MSCs-Exos) prior to initiating their in vitro fertilization (IVF) cycle. In contrast, participants in group 2 (n = 30) underwent intraovarian therapy with autologous platelet-rich plasma (PRP) in preparation for their IVF cycle. The comparative analysis encompassed antral follicle count (AFC), anti-Müllerian hormone (AMH) levels, follicle-stimulating hormone (FSH) levels, ovarian stimulation outcomes, and the primary characteristics of oogenesis and embryogenesis. Main results and the role of chance After transplantation of EVs and PRP the ovarian function-related hormone levels and the AFC returned to nearly normal parameteres.Meanwhile, after exosomal treatment the improvement in reproductive outcomes was more significant. FSH concentration was significantly different before and 30 days after the procedure in both groups. In group 1 FSH values were less than the initial data In 95% of cases, in group 2 – in 72% of cases. AMH levels did not change significantly in both groups. The AFC increased in group 1 compared to group 2. All Patients underwent an IVF antagonist cycle after 3 months from the treatment. The number of obtained oocytes in group 1 ranged from 2 to 8, MII from 1 to 6; in group 2: from 0-5, MII – 0-5. The number of blastocysts in group 1 ranged from 1 to 5, in group 2 – from 0 to 3. In group 1, pregnancy occurred in 9 patients (30%): 1 women ( 3,3%) conceived spontaneously in the cycle of procedures, 8 (26,7%) attempted IVF, in group 2 pregnancy occurred in 4 patients (13,3%): 4 attempted IVF. EVs and PRP injections improve outcomes of IVF results in women with low ovarian reserve. Limitations, reasons for caution Limitations may include the fact that the study is single-center and has a rather small amount of patients enrolled in the study. Fundamental approaches to further research in this area are also required to better understand the obtained results. Wider implications of the findings EVs and PRP therapies appear to enhance ovarian reserve metrics and the success rates of IVF programs in patients with DOR. The clinical implementation of these interventions may offer improved reproductive prospects for patients whose sole option was previously oocyte donation. Trial registration number 121040600410-7

O-089 Association of pituitary suppression method with euploid blastocyst yield in preimplantation genetic testing for aneuploidy (PGT-A) cycles

Abstract Study question Do progestin primed ovarian stimulation (PPOS) cycles have lower euploidy yield compared to pituitary suppression with gonadotropin releasing hormone (GnRH) antagonists? Summary answer The choice of pituitary suppression method has no bearing on euploid retrieval per blastocyst tested. What is known already Progestin primed ovarian stimulation cycles are an alternative to GnRH antagonists when fresh embryo transfer is not a priority. While the two approaches have been shown to be similar in terms of conventional stimulation outcomes such as mature oocyte retrieval, and blastulation rates, there is still some lingering controversy regarding cumulative pregnancy rates and the effects of progestins on embryo genetic constitution. Study design, size, duration This was a multicenter retrospective cohort study including data from two tertiary-level treatment centers. Participants/materials, setting, methods Infertile women undergoing ovarian stimulation with either progestin primed or GnRH antagonist pituitary suppression with the intention of transfer after PGT-A embryo testing with next-generation sequencing. The main outcome parameter was euploid embryo count per blastocyst tested and was modeled with mixed-effects log-binomial regression models. Results were adjusted for patient age and laboratory performing the PGT-A tests while they were not adjusted for embryo quality to avoid collider bias. Main results and the role of chance A total of 1425 PGT-A tested blastocysts from 383 cycles of 365 patients were included in the analysis. 243 cycles (63.4%) received GnRH antagonists for pituitary suppression while 140 (36.5%) received progestins. The overall euploidy rates per blastocyst tested in the GnRH antagonist and PPOS groups were 38.8% vs. 31.1%, 30.2% vs. 29.4%, 27.0% vs. 25.2%, and 13.8% vs. 14.5% for the age categories &amp;lt;35, 35-37, 38-40, and &amp;gt;40, respectively. After adjusting for the effect of female age at testing and the laboratory performing the PGT-A test, the type of pituitary suppression was not significantly associated with euploid retrieval per blastocyst tested (adjusted risk ratio: 0.94, 95% CI: 0.70 - 1.28, P = 0.701). After testing, 191 women received 233 embryo transfers. Human chorionic gonadotropin (hCG) positivity per transferred embryo was not significantly different between progestin primed and GnRH antagonist cycles (RR: 0.89, 95% CI: 0.71 – 1.08, P = 0.268). Limitations, reasons for caution This is a retrospective study with data from multiple centers with a non-standardized selection of blastocysts to be tested. In addition, the sample size and retrospective nature of the data may have biased the estimates. Wider implications of the findings The choice of pituitary suppression method does not appear to have a significant effect on euploid embryo retrieval rates or hCG positivity per transfer. The choice of medication can be based on the needs of the individual case without concern for suboptimal PGT-A outcomes. Trial registration number Not Applicable

Effect of body mass index on progesterone level on trigger day in gonadotropin-releasing hormone antagonist cycles

Objective To investigate the effect of body mass index (BMI) on progesterone (P) level on trigger day in gonadotropin-releasing hormone antagonist (GnRH-ant) cycles. Methods This study was a retrospective cohort study. From October 2017 to April 2022, 412 in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) patients who were treated with GnRH-ant protocol for controlled ovarian hyperstimulation (COH) in the reproductive center of our hospital were selected as the research objects. Patients were divided into three groups according to BMI level: normal weight group (n = 230):18.5 kg/m2≤BMI < 24 kg/m2; overweight group (n = 122): 24 kg/m2≤BMI < 28 kg/m2; Obesity group (n = 60): BMI ≥ 28 kg/m2. Variables with p < .10 in univariate analysis (BMI, basal FSH, basal P, FSH days, Gn starting dose and E2 level on trigger day) and variables that may affect P level on trigger day (infertility factors, basal LH, total FSH, HMG days and total HMG) were included in the multivariate logistic regression model to analyze the effect of BMI on P level on trigger day of GnRH-ant protocol. Results After adjustment for confounding factors, compared with that in normal weight patients, the risk of serum P elevation on trigger day was significantly lower in overweight and obese patients (OR = 0.434 and 0.199, respectively, p < .05). Conclusion The risk of P elevation on trigger day in GnRH-ant cycles decreased with the increase of BMI, and BMI could be used as one of the predictors of P level on trigger day in GnRH-ant cycles.

A modified flexible GnRH antagonist protocol using antagonist early cessation and a gonadotropin step-down approach improves live birth rates in fresh cycles: a randomized controlled trial.

Can pregnancy outcomes following fresh elective single embryo transfer (eSET) in gonadotropin-releasing hormone (GnRH) antagonist protocols increase using a gonadotropin (Gn) step-down approach with cessation of GnRH antagonist on the day of hCG administration (hCG day) in patients with normal ovarian response? The modified GnRH antagonist protocol using the Gn step-down approach and cessation of GnRH antagonist on the hCG day is effective in improving live birth rates (LBRs) per fresh eSET cycle. Currently, there is no consensus on optimal GnRH antagonist regimens. Studies have shown that fresh GnRH antagonist cycles result in poorer pregnancy outcomes than the long GnRH agonist (GnRHa) protocol. Endometrial receptivity is a key factor that contributes to this phenomenon. An open label randomized controlled trial (RCT) was performed between November 2021 and August 2022. There were 546 patients allocated to either the modified GnRH antagonist or the conventional antagonist protocol at a 1:1 ratio. Both IVF and ICSI cycles were included, and the sperm samples used were either fresh or frozen from the partner, or from frozen donor ejaculates. The primary outcome was the LBRs per fresh SET cycle. Secondary outcomes included rates of implantation, clinical and ongoing pregnancy, miscarriage, and ovarian hyperstimulation syndrome (OHSS), as well as clinical outcomes of ovarian stimulation. Baseline demographic features were not significantly different between the two ovarian stimulation groups. However, in the intention-to-treat (ITT) population, the LBRs in the modified antagonist group were significantly higher than in the conventional group (38.1% [104/273] vs. 27.5% [75/273], relative risk 1.39 [95% CI, 1.09-1.77], P = 0.008). Using a per-protocol (PP) analysis which included all the patients who received an embryo transfer, the LBRs in the modified antagonist group were also significantly higher than in the conventional group (48.6% [103/212] vs. 36.8% [74/201], relative risk 1.32 [95% CI, 1.05-1.66], P = 0.016). The modified antagonist group achieved significantly higher implantation rates, and clinical and ongoing pregnancy rates than the conventional group in both the ITT and PP analyses (P < 0.05). The two groups did not show significant differences between the number of oocytes retrieved or mature oocytes, two-pronuclear zygote (2PN) rates, the number of embryos obtained, blastocyst progression and good-quality embryo rates, early miscarriage rates, or OHSS incidence rates (P > 0.05). A limitation of our study was that the subjects were not blinded to the treatment allocation in the RCT trial. Only women under 40 years of age who had a good prognosis were included in the analysis. Therefore, use of the modified antagonist protocol in older patients with a low ovarian reserve remains to be investigated. In addition, the sample size for Day 5 elective SET was small, so larger trials will be required to strengthen these findings. The modified GnRH antagonist protocol using the Gn step-down approach and cessation of GnRH antagonist on hCG day improved the LBRs per fresh eSET cycle in normal responders. This project was funded by grant 2022YFC2702503 from the National Key Research & Development Program of China and grant 2021140 from the Beijing Health Promotion Association. The authors declare no conflicts of interest. The RCT was registered in the Chinese Clinical Trial Registry; Study Number: ChiCTR2100053453. 21 November 2021. 23 November 2021.

Trade-off between double cleavage-stage embryos transfer and single blastocyst-stage embryo transfer in patients with few good quality embryos in antagonist cycles: a retrospective study using a propensity score matching analysis

ObjectiveThis study aimed to compare the per OPU clinical outcomes for transfer of Day 3 double cleavage-stage embryos (DET) and Day 5 single blastocyst-stage (SBT) in patients with five or fewer good quality embryos on day 3 per occyte pick-up cycle (OPU) in antagonist cycles with consideration of blastocyst formation failure.MethodsThis was a retrospective, observational cohort study of 2,116 cases of OPU treated with antagonist protocol in the affiliated Chenggong Hospital of Xiamen University between January 2013 and December 2020. DET was performed in 1,811cycles and SBT was performed in 305 cycles. The DET group was matched to the SBT group by propensity score (PS) matching according to multiple maternal baseline covariates. After PS matching, there were 303 ET cycles in each group. The primary outcomes were the cumulative live birth rate (CLBR), cumulative multiple pregnancy rate(CMPR)per OPU and the number of ET to achieve live birth per OPU. Secondary outcomes were the percentage of clinical pregnancy(CPR), live birth rate(LBR), multiple pregnancy rate(MPR).ResultsFollowing PS mating, the CLBR was slightly higher (48.8% versus 40.3% ; P = 0.041) and the CMPR was significantly higher in the DET group compared to SBT group(44.2% versus 7.9%, P < 0.001). The CPR, LBR and MPR per fresh transfer were higher in DET group compared to SBT group(50.2% versus 28.7%; 41.3% versus 21.5%;29.6% versus 0%, P < 0.001). The number of ET to achieve live birth per OPU in SBT group was obiviously more than in DET group(1.48 ± 0.578 versus 1.22 ± 0.557 ,P < 0.001).ConclusionWith a marginal difference cumulative live birth rate, the lower live birth rate per fresh transfer and higher number of ET per OPU in the SBT group suggested that it might take longer time to achieve a live birth with single blastocyst strategy. A trade-off decision should be made between efficiency and safety.

Ovarian response and embryo ploidy following oral micronized progesterone-primed ovarian stimulation versus GnRH antagonist protocol. A prospective study with repeated ovarian stimulation cycles.

Is there any difference in ovarian response and embryo ploidy following progesterone-primed ovarian stimulation (PPOS) using micronized progesterone or GnRH antagonist protocol? Pituitary downregulation with micronized progesterone as PPOS results in higher number of oocytes retrieved and a comparable number of euploid blastocysts to a GnRH antagonist protocol. Although the GnRH antagonist is considered by most the gold standard protocol for controlling the LH surge during ovarian stimulation (OS) for IVF/ICSI, PPOS protocols are being increasingly used in freeze-all protocols. Still, despite the promising results of PPOS protocols, an early randomized trial reported potentially lower live births in recipients of oocytes resulting following downregulation with medroxyprogesterone acetate as compared with a GnRH antagonist protocol. The scope of the current prospective study was to investigate whether PPOS with micronized progesterone results in an equivalent yield of euploid blastocysts to a GnRH antagonist protocol. In this prospective study, performed between September 2019 to January 2022, 44 women underwent two consecutive OS protocols within a period of 6 months in a GnRH antagonist protocol or in a PPOS protocol with oral micronized progesterone. Overall, 44 women underwent two OS cycles with an identical fixed dose of rFSH (225 or 300 IU) in both cycles. Downregulation in the first cycles was performed with the use of a flexible GnRH antagonist protocol (0.25 mg per day as soon as one follicle of 14 mm) and consecutively, after a washout period of 1 month, control of LH surge was performed with 200 mg of oral micronized progesterone from stimulation Day 1. After the completion of both cycles, all generated blastocysts underwent genetic analysis for aneuploidy screening (preimplantation genetic testing for aneuplody, PGT-A). Comparisons between protocols did not reveal differences between the duration of OS. The hormonal profile on the day of trigger revealed statistically significant differences between protocols in all the tested hormones except for FSH: with significantly higher serum E2 levels, more elevated LH levels and higher progesterone levels in PPOS cycles as compared with antagonist cycles, respectively. Compared with the GnRH antagonist protocol, the PPOS protocol resulted in a significantly higher number of oocytes (12.7 ± 8.09 versus 10.3 ± 5.84; difference between means [DBM] -2.4 [95% CI -4.1 to -0.73]), metaphase II (9.1 ± 6.12 versus 7.3 ± 4.15; DBM -1.8 [95% CI -3.1 to -0.43]), and 2 pronuclei (7.1 ± 4.99 versus 5.7 ± 3.35; DBM -1.5 [95% CI -2.6.1 to -0.32]), respectively. Nevertheless, no differences were observed regarding the mean number of blastocysts between the PPOS and GnRH antagonist protocols (2.9 ± 2.11 versus 2.8 ± 2.12; DBM -0.07 [95% CI -0.67 to 0.53]) and the mean number of biopsied blastocysts (2.9 ± 2.16 versus 2.9 ± 2.15; DBM -0.07 [95% CI -0.70 to 0.56]), respectively. Concerning the euploidy rates per biopsied embryo, a 29% [95% CI 21.8-38.1%] and a 35% [95% CI 26.6-43.9%] were noticed in the PPOS and antagonist groups, respectively. Finally, no difference was observed for the primary outcome, with a mean number of euploid embryos of 0.86 ± 0.90 versus 1.00 ± 1.12 for the comparison of PPOS versus GnRh antagonist. The study was powered to detect differences in the mean number of euploid embryos and not in terms of pregnancy outcomes. Additionally, per protocol, there was no randomization, the first cycle was always a GnRH antagonist cycle and the second a PPOS with 1 month of washout period in between. In case of a freeze-all protocol, clinicians may safely consider oral micronized progesterone to control the LH surge and patients could benefit from the advantages of a medication of oral administration, with a potentially higher number of oocytes retrieved at a lower cost, without any compromise in embryo ploidy rates. This research was supported by an unrestricted grant from Theramex. N.P.P. has received Research grants from Merck Serono, Organon, Ferring Pharmaceutical, Roche, Theramex, IBSA, Gedeon Richter, and Besins Healthcare; honoraria for lectures from: Merck Serono, Organon, Ferring Pharmaceuticals, Besins International, Roche Diagnostics, IBSA, Theramex, and Gedeon Richter; consulting fees from Merck Serono, Organon, Besins Healthcare, and IBSA. M.d.M.V., F.M., and I.R. declared no conflicts of interest. The study was registered at Clinical Trials Gov. (NCT04108039).

Is there a preferred time interval between gonadotropin-releasing hormone (GnRH) agonist trigger and oocyte retrieval in GnRH antagonist cycles? A retrospective cohort of planned fertility preservation cycles

BackgroundThe ideal time frame between gonadotropin-releasing hormone (GnRH) agonist (GnRHa) trigger administration and oocyte retrieval in GnRH antagonist cycles has not been well studied. Our goal was to evaluate the effect of this time interval on oocyte yield and oocyte maturation rate in GnRH antagonist cycles designated for non-medical (“planned”) oocyte cryopreservation.MethodsWe conducted a retrospective cohort study including patients who underwent elective fertility preservation, using the GnRH antagonist protocol and exclusively triggered by GnRH-agonist. We focused on the effect of the trigger-to-retrieval time interval on oocyte yield and maturation rate, while also incorporating age, body mass index (BMI), anti-Müllerian hormone (AMH) levels, basal Follicle-Stimulating Hormone (FSH) levels, as well as the type and dosage of gonadotropin FSH medication.Results438 cycles were included. Trigger-to-retrieval time interval ranged from 32.03 to 39.92 h. The mean oocyte yield showed no statistically significant difference when comparing retrievals < 36 h (n = 240, 11.86 ± 8.6) to those triggered at ≥ 36 h (n = 198, 12.24 ± 7.73) (P = 0.6). Upon dividing the cohort into four-time quartiles, no significant differences in the number of retrieved oocytes were observed (P = 0.54). Multivariate regression analysis failed to reveal any significant associations between the interval and the aforementioned variables.ConclusionsThe GnRHa trigger to oocyte retrieval interval range in our cohort did not significantly affect oocyte yield and maturation rate.

Effect of trigger day serum luteinising hormone levels on the in-vitro fertilization outcome: an observational study.

Controlled ovarian stimulation leads to profound changes in the endocrine characteristics of the ovarian cycle. Serum luteinising hormone (LH) levels on the day of trigger have been shown to correlate with oocyte quality and pregnancy rate in antagonist cycles. This is an observational study of 86 women undergoing an antagonist in-vitro fertilisation cycle. Oocyte maturation trigger used was either Inj. human chorionic gonadotropin or Inj. triptorelin 0.2 mg s/c or a combination of both. Women were categorised into four groups based on serum LH levels on the day of trigger i.e., LH ≤0.5 (n=8), LH=0.6- 1.0 international units (IU)/L (n=12), LH=1.0-1.5 IU/L (n=13), and LH >1.6 IU/L (n=53) and the subgroup analysis was done based on type of trigger used. Mature oocyte (MII) retrieval rate did not show a significant relation with serum LH levels (87%, 89%, 77%, and 76% in groups with LH <0.5, 0.5-1.0, 1.0-1.5, and >1.5 IU/L respectively; P-value=0.243). There was no significant difference in the clinical pregnancy rate either when women were split according to the type of trigger given or according to trigger day LH levels. Women with low LH levels (<0.5 IU/L) required significantly more doses of gonadotropins compared to women with LH levels of 1.0-1.5 IU/L. (3,531+1,133 vs. 2,281+938; P-value=0.01). Based on the observation from the current study, there was no significant association of serum LH levels with MII retrieval rate and clinical pregnancy rate. The group with low LH levels required slightly longer days of stimulation.