This British Fertility Society (BFS) Policy and Practice guideline aims to support clinicians in preventing ovarian hyperstimulation syndrome (OHSS) in patients undergoing gonadotropin ovarian stimulation. A systematic literature search of the medical databases was performed. The Guideline Development Group (GDG) identified the risk factors of OHSS before and during ovarian stimulation. The relation of different pre-treatment measures and different ovarian stimulation protocols with OHSS was evaluated. The optimal monitoring during treatment was assessed. The current evidence on preventive strategies during and after ovarian stimulation and the available adjuvant preventive agents were examined. Based on this, the GDG developed evidence-based, graded recommendations for clinical practice. The evidence was evaluated within context, considering the effectiveness, cost and practical problems of assisted reproductive technology for patients and healthcare providers. Early identification and application of preventive measures identified in this guideline may reduce the incidence of OHSS or reduce its severity. Suggestions for future research on OHSS prevention are provided.

The PPOS (Progestin Primed Ovarian Stimulation) protocol has been evaluated and has proved its effectiveness in preventing the LH (luteinizing hormone) surge. This protocol is often used for cryopreservation for social reasons because it is simpler and more cost-effective. The objective of our study was to evaluate the efficacy and the convenience of the PPOS protocol in the context of oocyte cryopreservation for social reasons.

In this bicentric matched case‒control study, all PPOS cycles performed for nonmedical reasons between January 2021 and June 2023 were included. Each PPOS cycle was matched with 2 control cycles performed with the antagonist protocol on the basis of the antral follicle count (+/- 5), BMI (+/- 2 kg/cm2) and starting gonadotropin dose (+/- 75 UI). The primary endpoint was the number of mature oocytes. The secondary endpoints were other parameters and outcomes of COS. We evaluated the convenience of PPOS by analysing the frequency of monitoring sessions. Univariate analysis was performed via univariate conditional logistic regression. Multivariate analysis was performed via conditional multivariate logistic regression for significant parameters in the univariate analysis (p < 0.2).

The patient characteristics were comparable, except the median age, which was lower in the antagonist group (35.5 vs. 34.6 years, p < 0.001). Multivariate analysis revealed no statistically significant difference in the number of metaphase II (MII) oocytes between the groups (p = 0.91) or in the total number of COCs retrieved (0.94). There was no statistically significant difference between the groups in terms of the maturation rate or the OSI (p = 0.38 and p = 0.16). The number of monitoring sessions was significantly lower in the PPOS protocol group (p < 0.001).

The response to ovarian stimulation with the PPOS protocol for oocyte cryopreservation in patients with nonmedical indications does not differ statistically from that with the antagonist protocol in terms of the number of MII oocytes. This protocol offers the advantages of a more patient-friendly approach through oral administration, a significantly lower number of monitoring sessions with the same efficacy as the antagonist protocol and could be offered as a first line treatment.

NA.

NA.

The impact of oral GnRH antagonists on IVF treatment outcomes remains unclear. The aim of the study is to investigate the impact of GnRH antagonist over the outcomes of IVF.

We performed an electronic search using MEDLINE® with the OvidSP interface PUBMED, Embase, Web of Science, and Cochrane Library up to December 16, 2024. We included experimental and non-experimental studies, assessing the role of oral GnRH during controlled ovarian stimulation protocols. Our main outcomes were cycle cancelation rate and mean number of mature oocytes retrieved at oocyte pickup (OPU) day.

We included four studies comprising 813 patients, of whom 452 women received oral GnRH antagonists and 294 received injectable subcutaneous GnRH antagonists. No statistical differences were noted in the meta-analysis between each outcome measured (cycle cancelation, mean overall and mature oocytes, fertilization rate, and blastulation rate). Using the GRADE criteria, the overall quality of the existing evidence was determined as moderate.

This is the first systemic review and meta-analysis to examine the usage of oral GnRH antagonists for ovulation suppression during IVF treatments. Our findings suggest the use of oral GnRH antagonists may be beneficial in infertility treatments; however, caution should be taken, as robust establishment of their effectivity and safety in clinical practice is still pending.

Registration Number: PROSPERO study ID: CRD42024599730.

It is ambiguous whether the multiple COS with supraphysiologic hormonal doses impact ovarian reserve functions or pregnancy outcomes. The aim is to explore the effect of multiple COS during ART on ovarian reserve function and clinical pregnancy outcomes in infertile women.

The retrospective study included 45,555 IVF/ICSI fresh cycles enrolled between January 2015 and March 2021 and were segregated into 5 different cycle cohorts. The participants were retrospectively grouped according to the number of repeated cycles. The primary observables symbolizing ovarian reserve function were antral follicle count (AFC) and anti-Müllerian hormone (AMH). We analyzed clinical pregnancy rate (CPR), live birth rates (LBR), and early miscarriage rate (EMR) to explore clinical pregnancy outcomes.

Among populations with different numbers of COS cycles, regression analyses found that the number of COS cycles had no significant impact on pregnancy outcomes (p > 0.05) after adjusting for confounding factors. However, factors such as age, BMI, and embryo transfer parameters showed significant associations with pregnancy outcomes. Intra-group analysis within same population revealed that, basal FSH, basal LH, AMH, and AFC exhibit no significant distinction (P > 0.05). Cycle 2 in Group B (aOR = 8.29; 95% CI, 6.80-10.12; P = 0.000), Cycle 3 in Group C (aOR = 6.05; 95% CI, 3.28-11.15; P = 0.000) and Cycle 4 in Group D (aOR = 20.46; 95% CI, 3.05-137.24; P = 0.002) had the highest CPR within each group; Cycle 2 in Group B and Cycle 3 in Group C had the highest LBR and lowest EMR within each group, and the differences did not reached statistical significance in the remaining groups.

The number of COS cycles did not significantly adversely affect pregnancy outcomes across different populations. In self-controlled comparisons within the same population, repeated COS (≤ 5 cycles) may not impair ovarian reserve function, while repeated COS (≤ 4 cycles) positively influenced clinical pregnancy outcomes, suggesting a potential cumulative effect.

Ganirelix, a third-generation GnRH antagonist, is widely used in assisted reproductive technology (ART) for rapid pituitary suppression to prevent premature luteinizing hormone (LH) surges. Despite its extensive clinical use, real-world evidence on its safety in large populations remains scarce. This study aimed to evaluate the safety profile of ganirelix by comprehensively analyzing adverse drug events (ADEs) using real-world data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japan Adverse Drug Event Reporting (JADER) database.

We extracted ADE data from FAERS (Q1 2004-Q2 2024) and JADER (Q1 2009-Q1 2024). Disproportionality analyses, including reporting odds ratios (ROR), proportional reporting ratios (PRR), Bayesian Confidence Propagation Neural Networks (BCPNN), and Multi-item Gamma Poisson Shrinkage (MGPS), were employed to identify significant associations between ganirelix and ADEs.

In the FAERS database, we identified 1,096 ganirelix-related ADE reports, spanning 26 system organ classes (SOCs). A total of 65 positive signals were detected, including ADEs consistent with drug label such as ovarian hyperstimulation syndrome (OHSS) (n = 290, ROR 2462.76, PRR 2168.48, EBGM05 1655.59, IC025 9.18), injection site pain (n = 54, ROR 3.99, PRR 3.93, EBGM05 3.13, IC025 0.31), and fetal death (n = 6, ROR 21.05, PRR 21.00, EBGM05 10.72, IC025 2.72). Additionally, unexpected signals not listed in the drug label were identified, including ectopic pregnancy (n = 7, ROR 33.02, PRR 32.93, EBGM05 17.64, IC025 3.37), maternal exposure before pregnancy (n = 30, ROR 76.09, PRR 75.16, EBGM05 74.72, IC025 6.22), dermatitis allergic (n = 4, ROR 7.98, PRR 7.97, EBGM05 3.50, IC025 1.33), and bladder tamponade (n = 4, ROR 771.47, PRR 770.3, EBGM05 311.57, IC025 7.80). The median time to ADE onset was 13 days. External validation using the JADER database (62 ganirelix-related ADE reports) confirmed four signals, including abortion (n = 19), OHSS (n = 17), missed abortion (n = 9), and fetal death (n = 8), aligning with FAERS findings.

This study provides a robust real-world safety evaluation of ganirelix, with findings corroborated by two independent pharmacovigilance databases. While consistent with clinical observations, the identification of unexpected signals warrants further pharmacoepidemiological investigations to confirm these results.

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic complication of ovarian stimulation during in vitro fertilisation (IVF) treatment and is associated with significant morbidity and a small risk of mortality. Women with polycystic ovary syndrome (PCOS) are at a substantially increased risk of developing OHSS compared to those without. This paper reviews the current evidence for strategies to mitigate the risk of OHSS in this patient population. In order to minimise the risk of OHSS, clinicians should identify patients at high risk prior to commencing treatment and provide adequate pre-treatment counselling regarding the risks and benefits of IVF treatment, as well as alternative treatment options. Strategies that can reduce the risk of OHSS include co-treatment with metformin in gonadotropin releasing hormone (GnRH) agonist cycles, use of GnRH antagonist or PPOS protocols, appropriate gonadotropin dosing, the use of a GnRH agonist trigger for oocyte maturation in antagonist or PPOS protocols, cryopreservation of all embryos with deferred frozen embryo transfer, and treatment with dopamine-agonists after oocyte collection. In vitro maturation (IVM) offers an alternative with no risk of OHSS, however currently has a lower cumulative live birth rate than conventional IVF. These strategies can prevent significant early and late OHSS in women with PCOS and should be used to optimise the safety of IVF for this high-risk population, striving for OHSS-free treatment for all patients undergoing IVF.

To compare recombinant FSH (rFSH) with highly purified-human menopausal gonadotrophin (hp-hMG) on ovarian response in women undergoing elective fertility preservation (FP).

This retrospective study included 456 women who underwent elective FP with gonadotropin-releasing hormone (GnRH) antagonist or progestin-primed ovarian stimulation (PPOS) protocols between 01/2017-12/2021. Only the first treatment cycle of each woman was included. 341 women were stimulated with rFSH and 115 with hp-hMG, and the ovarian stimulation outcomes were compared. A multivariate linear regression assessed the impact of age, basal FSH, antral follicle count (AFC) and protocol and gonadotropin types on the outcomes.

Women in the rFSH group were significantly younger, and their AFC was significantly higher than those in the hp-hMG group (35.50±2.12 vs. 35.99±2.13years, p=0.034 and 13.76±6.08 vs. 11.84±6.06, p=0.002). There were no significant group differences in the amount (p=0.645) and duration (p=0.265) of FSH stimulation. The estradiol level was significantly lower for the rFSH group compared to the hp-hMG group (2547.18±1648.21pg/mL vs. 3468.02±2497.69pg/mL, p<0.001), while the progesterone level was significantly higher (1.33±0.75 ng/mL vs. 1.01±0.52ng/mL, p=0.001). The numbers of retrieved and MII oocytes were significantly higher for the rFSH group compared with the hp-hMG group (16.82±10.95 vs. 13.25±9.66, p=0.02, and 13.22±9.13 vs. 9.76±7.11, p=0.005), while the maturity rates were comparable (p=0.103).

Patients in the rFSH group had higher numbers of both retrieved and MII oocytes when undergoing elective FP.

Background: Progestin-primed ovarian stimulation (PPOS) stimulates ovaries to block the premature surge of luteinizing hormone (LH) by using micronized progesterone or a progestin during the follicular phase instead of the conventional gonadotropin-releasing hormone (GnRH) analogues or GnRH antagonists downregulating LH to obtain multi-follicle engagement. Current work aims to assess the influence of progestogen treatment on ovarian stimulation and the ability to control LH surge, its efficacy and suitability in retrieving oocytes, without affecting the embryo quality and its benefit among infertile women long-term outcomes on children compared to standard stimulation protocols. Materials and Methods: The literature review used the randomized control trials published in the Pubmed database from January 2015 to April 2021. To generate the citation list, the following keywords were used: 'progestin-primed ovarian stimulation', 'PPOS', 'micronized progesterone', 'medroxyprogesterone', and/or 'dydrogesterone'. The selected articles analyzed the cohort, intervention, and scheme of the progestin-primed ovarian stimulation protocol in controlled ovarian stimulation (COS) for in-vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI) used in Assisted Reproductive Technologies (ART). Results: Overall we concluded that PPOS for IVF/ICSI in ART results in a higher number of obtained embryos, lower incidence of OHSS, equal duration of stimulation, number of retrieved oocytes, and number of MII oocytes. It is also suggested that long-term safety in children shows no significant difference between the study and control groups. Conclusions: Despite the outcomes of progestin stimulation cycles among all cohorts, we concluded that poor ovarian responders, patients with PCOS, women of advanced age and oocyte donors benefit the most from using PPOS.

To disclose the relationships between serum LH and reproductive outcomes in Gonadotropin-releasing hormone (GnRH) antagonist protocol pretreated with luteal estradiol.

371 patients, pretreated with estradiol, followed the GnRH antagonist protocol. They were divided into four groups based on the quartiles of serum LH levels on the day of gonadotropin (Gn) initiation(LHGI) and trigger (LHtrigger). Data on various pregnancy outcomes were collected.

As serum LHGI increased, anti-Müllerian hormone (AMH) level, antral follicle count (AFC), LHtrigger, estradiol (E2) and P on the trigger day, E2/oocytes, and oocyte numbers increased and peaked in Q4, while Gn dose decreased. Good-quality embryo and blast formation rates increased and peaked in Q3. LHGI <3.93 mIU/ml impaired ongoing pregnancy rate and LBR. After adjusting for AMH and AFC, the impacts were not significant. As LHtrigger increased, E2/oocytes and good-quality embryo rate increased and peaked in T4 and implantation rate increased and peaked in T3. LHtrigger <1.49 mIU/ml independently influenced clinical pregnancy rate (CPR) after adjusting for AMH and AFC. LHGI was positively related to AMH, AFC, LHtrigger, blast formation rate and negatively related to BMI, age and Gn dose. LHtrigger was positively related to E2/oocytes and good quality embryo rate.

Lower serum LH represents as a potential indicator for embryo quality and reproductive outcomes in GnRH antagonist fixed protocol pretreated with estradiol. Early identification of excessive suppression of LH levels will benefit individuals with normal ovarian reserve more.

Increasing numbers of people are seeking assisted conception. In people with known cardiac disease or risk factors for cardiac disease, assisted conception may carry increased risks during treatment and any subsequent pregnancy. These risks should be assessed, considered and minimized prior to treatment.

To compare in vitro fertilization treatment outcomes for the oral gonadotropin-releasing hormone (GnRH) antagonist elagolix (E) to the conventionally used injectable GnRH antagonist ganirelix (G) for achieving pituitary gonadotropin suppression during a controlled ovarian stimulation (COS) cycle.

Retrospective cohort study.

Private university-affiliated fertility center.

One hundred and ninety-four infertility patients receiving either E or G for pituitary suppression during the COS cycle.

Use of E for ovulation suppression during the COS cycle.

Biochemical pregnancy, sustained implantation, and cycle cancellation rates were the primary outcome measures. Secondary outcomes included miscarriage, fertilization, and blastulation rates.

The groups did not differ in their baseline demographic characteristics (age, body mass index, hormone profiles, total dosage of gonadotropins, number of oocytes retrieved, and number of embryos transferred). The overall cycle cancellation rates were 7.0% and 4.9% for e and G, respectively, and the difference was not statistically significant. For the frozen embryo transfers, the biochemical pregnancy, sustained implantation, and miscarriage rates for E were 74.5%, 51.0%, and 31.6%, respectively. For G, these were 55.9%, 39.8%, and 28.8%. Out of these outcomes, only the biochemical pregnancy rates were significantly different. For the fresh embryo transfers, biochemical pregnancy, sustained implantation, and miscarriage rates for E were 33.3%, 33.3%, and 0.0%, and for G, they were 37.5%, 25.0%, and 33.3%. None of the differences reached significance.

The oral GnRH antagonist, E, may be as effective as the injected antagonist, G, regarding embryological and clinical outcomes and could offer a less invasive, more cost-effective, and "patient-friendly" approach to pituitary suppression for in vitro fertilization treatment.

Infertility related to polycystic ovary syndrome (PCOS) represents a significant challenge for women of reproductive age. Over the last few years, evidence-based medicine has driven new approaches for treating infertility in patients with PCOS, changing rapidly and deeply the clinical practice.

The authors provide an in-depth examination of recent developments in drug treatment strategies that have impacted the clinical practice and changed the previous approach to infertility in patients with PCOS.

The authors identify four primary areas of interest that have impacted clinical practice in the last few years. Specifically, they discuss the current role of metformin administration in women with PCOS and infertility, the choice for using clomiphene citrate or letrozole as first-line treatment for ovulation induction, the use of new gonadotropin formulations for in vitro fertilization (IVF) program, and the elective embryo transfer in IVF cycles as golden standard treatment for patients with PCOS at high-risk for ovarian hyperstimulation syndrome.

This study aimed to examine the correlation between different dominant follicle proportions (DFPs) and outcomes of in-vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) among patients classified under POSEIDON Groups 3 and 4, who underwent gonadotropin-releasing hormone antagonist (GnRH-ant) protocols. Additionally, it sought to determine the optimal DFP threshold for trigger timing.

A retrospective analysis was performed on patients classified under POSEIDON Groups 3 (n = 593) and 4 (n = 563) who underwent GnRH-ant protocols for controlled ovarian hyperstimulation (COH) between 2016 and 2022. These patients were categorized into two groups based on their DFPs, defined as the ratio of ≥ 18-mm dominant follicles to ≥ 12-mm follicles on the trigger day (DFP ≤ 40% and DFP ≥ 40%). Statistical analyses, including restricted cubic spline (RCS) and multivariate logistic regression, were employed to assess the relationship between DFP and IVF/ICSI outcomes.

Demographic characteristics of patients were similar across groups. In POSEIDON Groups 3 and 4, DFP > 40 was associated with a significant decrease in the number (No.) of oocytes retrieved, cleaved embryos, and available embryos. Moreover, following the GnRH-ant cycle, the clinical pregnancy and live birth rates in fresh embryo transfer (ET) were notably reduced in the DFP > 40 group compared with the DFP ≤ 40 group, whereas no significant differences were observed in the pregnancy outcomes of the first frozen-thawed embryo transfer (FET) between the groups. In POSEIDON Group 3, the cumulative clinical pregnancy rate (CCPR) and cumulative live birth rate (CLRB) were significantly higher in the DFP ≤ 40 subgroup than in the DFP > 40 subgroup, with a notable decrease in CLRB observed with increasing DFP levels. However, in POSEIDON Group 4, no significant differences in CCPR and CLRB were found between the groups. Logistic regression analysis identified age and the No. of oocytes retrieved as pivotal factors influencing CLRB in Group 4.

For patients in POSEIDON Group 3, maintaining a DFP ≤ 40 mm is crucial to achieve optimal laboratory and pregnancy outcomes by avoiding delayed triggering. However, for patients in POSEIDON Group 4, age remains a critical factor influencing CLRB regardless of DFP, although a higher No. of oocytes retrieved and available embryos with DFP ≤ 40 is beneficial.

This study aims to determine whether the live birth rates were similar between GnRH antagonist original reference product Cetrotide® and generic Ferpront®, in gonadotropin-releasing hormone (GnRH) antagonist protocol for controlled ovarian stimulation (COS).

This retrospective cohort study investigates COS cycles utilizing GnRH antagonist protocols. The research was conducted at a specialized reproductive medicine center within a tertiary care hospital, spanning the period from October 2019 to October 2021. Within this timeframe, a total of 924 cycles were administered utilizing the GnRH antagonist originator, Cetrotide® (Group A), whereas 1984 cycles were undertaken using the generic, Ferpront® (Group B).

Ovarian reserve markers, including anti-Mullerian hormone, antral follicle number, and basal follicular stimulating hormone, were lower in Group A compared to Group B. Propensity score matching (PSM) was performed to balance these markers between the groups. After PSM, baseline clinical features were similar, except for a slightly longer infertile duration in Group A versus Group B (4.43 ± 2.92 years vs. 4.14 ± 2.84 years, P = 0.029). The duration of GnRH antagonist usage was slightly longer in Group B than in Group A (6.02 ± 1.41 vs. 5.71 ± 1.48 days, P < 0.001). Group B had a slightly lower number of retrieved oocytes compared to Group A (14.17 ± 7.30 vs. 14.96 ± 7.75, P = 0.024). However, comparable numbers of usable embryos on day 3 and good-quality embryos were found between the groups. Reproductive outcomes, including biochemical pregnancy loss, clinical pregnancy, miscarriage, and live birth rate, did not differ significantly between the groups. Multivariate logistic regression analyses suggested that the type of GnRH antagonist did not independently impact the number of oocytes retrieved, usable embryos, good-quality embryos, moderate to severe OHSS rate, clinical pregnancy, miscarriage, or live birth rate.

The retrospective analysis revealed no clinically significant differences in reproductive outcomes between Cetrotide® and Ferpront® when used in women undergoing their first and second COS cycles utilizing the GnRH antagonist protocol.

The 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.

We 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.

438 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.

The GnRHa trigger to oocyte retrieval interval range in our cohort did not significantly affect oocyte yield and maturation rate.

Objective The objective of this study was to determine if gonadotropin-releasing hormone agonist (GnRH-a) or gonadotropin-releasing hormone antagonist (GnRH-ant) protocols during in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment in young infertile women improve their pregnancy outcomes. Methodology We retrospectively reviewed the records of 876 young infertile women aged 20-35 years who underwent fresh embryo transfer in IVF/ICSI cycles. The data were collected from their initial visits to the reproductive medicine center of the Second Affiliated Hospital of Zhengzhou University between January 2019 and December 2022. We divided them into two groups according to the controlled ovarian hyperstimulation (COH) protocols: GnRH-a (n = 580) and GnRH-ant (n = 296). The primary outcome assessed in this study was the live birth rate. The secondary observation indicators included the total dose and duration of gonadotropin (Gn), total embryo transfer, day three (D3) embryo transfer, total two pro-nuclei (2PN) cleavage count, number of fertilizations, and implantation rate. Results The live birth rate had no clinical significance (P > 0.05). The total dose and duration of Gn stimulation in the GnRH-ant group were lower than in the GnRH-a group (P  < 0.05). The total embryo transfer, D3 embryo transfer, total cleavage count, total 2PN cleavage count, number of fertilizations, transfer, and mature oocytes in metaphase II (MII) of D3 embryos in the GnRH-a group were higher than those in the GnRH-ant group (P  < 0.05). The clinical pregnancy rate and implantation rate of the GnRH-a group were higher than those of the control group. Conclusions The total embryo transfer, D3 embryo transfer, total cleavage count, total 2PN cleavage count, number of fertilizations, transfer and MII of D3 embryos, clinical pregnancy, and implantation rates were significantly higher in the GnRH-a protocol group. The total dosage of Gn and duration of Gn stimulation were lower in the GnRH-ant group than in the GnRH-a group. These findings provide the basis for the selection of the COH protocol in normal Chinese ovarian response patients undergoing IVF/ICSI.

How does a gonadotrophin-releasing hormone (GnRH) agonist versus a GnRH antagonist protocol affect ovarian response when using an individualized fixed daily dose of follitropin delta for ovarian stimulation?

The BEYOND trial data demonstrate thatindividualized fixed-dose follitropin delta is effective when used in a GnRH agonist protocol, compared with a GnRH antagonist protocol, in women with anti-Müllerian hormone (AMH) ≤35 pmol/l and no increased risk of ovarian hyperstimulation syndrome (OHSS).

The efficacy and safety of an individualized fixed daily dose of follitropin delta (based on body weight and AMH) have been established in randomized controlled trials (RCTs) using a GnRH antagonist protocol. Preliminary study data indicate that individualized follitropin delta is also efficacious in a GnRH agonist protocol (RAINBOW trial, NCT03564509). There are no prospective comparative data using individualized follitropin delta for ovarian stimulation in a GnRH agonist versus a GnRH antagonist protocol.

This is the first randomized, controlled, open-label, multi-centre trial exploring efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus a GnRH antagonist protocol in participants undergoing their first ovarian stimulation cycle for IVF/ICSI. A total of 437 participants were randomized centrally and stratified by centre and age. The primary endpoint was the number of oocytes retrieved. Secondary endpoints included ongoing pregnancy rates, adverse drug reactions (including OHSS), live births, and neonatal outcomes.

Participants (18-40 years; AMH ≤35 pmol/l) were enrolled at specialist reproductive health clinics in Austria, Denmark, Israel, Italy, the Netherlands, Norway, and Switzerland. The mean number of oocytes retrieved was compared between the GnRH agonist and antagonist protocols using a negative binomial regression model with age and AMH at screening as factors. Analyses were based on all randomized subjects, using a multiple imputation method for randomized subjects withdrawing before the start of stimulation.

Of the 437 randomized subjects, 221 were randomized to the GnRH agonist, and 216 were randomized to the GnRH antagonist protocol. The participants had a mean age of 32.3 ± 4.3 years and a mean serum AMH of 16.6 ± 7.8 pmol/l. A total of 202 and 204 participants started ovarian stimulation with follitropin delta in the GnRH agonist and antagonist groups, respectively. The mean number of oocytes retrieved was statistically significantly higher in the agonist group (11.1 ± 5.9) versus the antagonist group (9.6 ± 5.5), with an estimated mean difference of 1.31 oocytes (95% CI: 0.22; 2.40, P = 0.0185). The difference in number of oocytes retrieved was influenced by the patients' age and ovarian reserve, with a greater difference observed in patients aged <35 years and in patients with high ovarian reserve (AMH >15 pmol/l). Both the GnRH agonist and antagonist groups had a similar proportion of cycle cancellations (2.0% [4/202] versus 3.4% [7/204]) and fresh blastocyst transfer cancellations (13.4% [27/202] versus 14.7% [30/204]). The estimated ongoing pregnancy rate per started cycle was numerically higher in the GnRH agonist group (36.9% versus 29.1%; difference: 7.74% [95% CI: -1.49; 16.97, P = 0.1002]). The most commonly reported adverse events (≥1% in either group; headache, OHSS, nausea, pelvic pain, or discomfort and abdominal pain) were similar in both groups. The incidence of early moderate/severe OHSS was low (1.5% for the agonist group versus 2.5% for antagonist groups). Estimated live birth rates per started cycle were 35.8% and 28.7% in the GnRH agonist and antagonist groups, respectively (treatment difference 7.15%; 95% CI: -2.02; 16.31; P = 0.1265). The two treatment groups were comparable with respect to neonatal health data for singletons and twins and for incidence of congenital malformations (2.7% and 3.3% for the GnRH agonist versus antagonist groups, respectively).

All participants had AMH ≤35 pmol/l and were ≤40 years old. Clinicians should remain cautious when using a GnRH agonist protocol in patients with AMH >35 pmol/l (i.e. those with an increased OHSS risk). The incidence of OHSS in the GnRH antagonist group may have been lower if a GnRH agonist trigger had been allowed. Outcomes of transfers with cryopreserved blastocysts were not followed up, therefore the cumulative live birth rates and neonatal outcomes after cryotransfer are unknown.

In women with AMH ≤35 pmol/l, an individualized fixed daily dose of follitropin delta resulted in a significantly higher number of oocytes retrieved when used in a GnRH agonist protocol compared with a GnRH antagonist protocol, with no additional safety signals observed and no additional risk of OHSS. Live birth rates following ovarian stimulation with individualized follitropin delta were not statistically different between the GnRH protocols; however, the trial was not powered to assess this endpoint. There were no safety concerns with respect to neonatal health after ovarian stimulation with follitropin delta in either protocol.

The trial was funded by Ferring Pharmaceuticals. EE, EP, and MS have no competing interests. AP has received research support from Ferring, and Gedeon Richter, and honoraria or consultation fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, Merck A/S. BC has received consulting fees from Ferring and Merck, and his department received fees from Ferring to cover the costs of patient enrolment. MBS has received support to attend meetings and/or travel from Ferring, and was a board member for FertiPROTEKT e.V. until 2023. JS has received honoraria or consultation fees from Ferring and Merck, and support for attending meetings and/or travel from Ferring, Merck, and GoodLife. TS has received support/travel expenses from Ferring for attending a congress meeting, and participated in an advisory board for Merck. YS has received grants/research support from Ferring and support to attend a professional society congress meeting from Merck. RL and PP are employees of Ferring Pharmaceuticals. PP is a BOD member of PharmaBiome and owns stocks of Takeda Pharmaceuticals.

ClinicalTrials.gov identifier NCT03809429; EudraCT Number 2017-002783-40.

7 April 2019.

2 May 2019.

Progesterone can be used instead of GnRH agonists and antagonists in order to avert a premature LH surge during controlled ovarian stimulation (COS) protocol. Nonetheless, there is limited knowledge regarding its utilization. Thus, this study compared the effects of progesterone and GnRH antagonists (GnRH-ant) on premature LH surges and assisted reproductive technology (ART) results in infertile women undergoing ART.

In this clinical trial, the progesterone protocol (study group) and GnRH-ant protocol (control group) were tested in 300 infertile individuals undergoing IVF/ICSI. The main outcome was the number of oocytes retrieved. The secondary outcomes included premature LH rise/surge, the quantity of follicles measuring ≥ 10 and 14 mm, oocyte maturity and fertilization rate, the number of viable embryos, high-quality embryo rate and pregnancy outcomes.

The study group exhibited a statistically significant increase in the number of retrieved oocytes, follicles measuring 14 mm or greater, and viable embryos compared to the control group (P < 0.05). The study group also increased oocyte maturity, chemical pregnancy rate, and clinical pregnancy rate (P < 0.05). Both groups had similar mean serum LH, progesterone, and E2 levels on trigger day. The control group had more premature LH rise than the study group, although this difference was not statistically significant.

In conclusion, it can be stated that the progesterone protocol and the GnRH-ant protocol exhibit similar rates of sudden premature LH surge in infertile patients. However, it is important to note that the two regiments differ in their outcomes in ART.

This study was retrospectively registered in the Iranian website ( www.irct.ir ) for clinical trials registration ( http://www.irct.ir : IRCT-ID: IRCT20201029049183N, 2020-11-27).

Endometriosis is a complex and chronic gynaecological disorder that affects millions of women worldwide, leading to significant morbidity and impacting reproductive health. This condition affects up to 10% of women of reproductive age and is characterised by the presence of endometrial-like tissue outside the uterus, potentially leading to symptoms such as chronic pelvic pain, dysmenorrhoea, dyspareunia, and infertility. The Montreux summit brought a number of experts in this field together to provide a platform for discussion and exchange of ideas. These proceedings summarise the six main topics that were discussed at this summit to shed light on future directions of endometriosis classification, diagnosis, and therapeutical management. The first question addressed the possibility of preventing endometriosis in the future by identifying risk factors, genetic predispositions, and further understanding of the pathophysiology of the condition to develop targeted interventions. The clinical presentation of endometriosis is varied, and the correlation between symptoms severity and disease extent is unclear. While there is currently no universally accepted optimal classification system for endometriosis, several attempts striving towards its optimisation - each with its own advantages and limitations - were discussed. The ideal classification should be able to reconcile disease status based on the various diagnostic tools, and prognosis to guide proper patient tailored management. Regarding diagnosis, we focused on future tools and critically discussed emerging approaches aimed at reducing diagnostic delay. Preserving fertility in endometriosis patients was another debatable aspect of management that was reviewed. Moreover, besides current treatment modalities, potential novel medical therapies that can target underlying mechanisms, provide effective symptom relief, and minimise side effects in endometriotic patients were considered, including hormonal therapies, immunomodulation, and regenerative medicine. Finally, the question of hormonal substitution therapy after radical treatment for endometriosis was debated, weighing the benefits of hormone replacement.

Progestin can inhibit the pituitary luteinising hormone (LH) surge during ovarian stimulation for in vitro fertilisation (IVF) and studies show progestin-primed ovarian stimulation (PPOS) is effective in blocking the LH surge in IVF. More and more centres are using PPOS because this regimen appears simpler and cheaper. This study aims to compare the euploidy rate of blastocysts following the PPOS protocol and the gonadotropin-releasing hormone antagonist protocol in women undergoing preimplantation genetic testing for aneuploidy (PGT-A).

This is a randomised trial. A total of 400 women undergoing PGT-A will be enrolled and randomised according to a computer-generated randomisation list to either (1) the antagonist group: an antagonist given once daily from day 6 of ovarian stimulation till the day of the ovulation trigger; or (2) the PPOS group: dydrogesterone from the first day of ovarian stimulation till the day of ovulation trigger. The primary outcome is the euploidy rate of blastocysts.

An ethical approval was granted from the ethics committee of assisted reproductive medicine in Shanghai JiAi Genetics and IVF institute (JIAIE2020-03). A written informed consent will be obtained from each woman before any study procedure is performed, according to good clinical practice. The results of this randomised trial will be disseminated in a peer-reviewed journal.

NCT04414748.

Several studies have compared the effects of fixed and flexible gonadotropin releasing hormone antagonist (GnRH-ant) protocols during in vitro fertilization and embryo transfer (IVF-ET). However, which GnRH-ant initiation strategy is better remains controversial. Moreover, no studies have assessed the optimal timing of GnRH-ant initiation in women of advanced maternal age (AMA).

In this retrospective cohort study, a total of 472 infertile women aged ≥ 35 years old undergoing their first IVF cycle from August 2015 to September 2021 at a tertiary academic medical center were recruited, of whom 136 followed fixed GnRH-ant protocol and 336 followed flexible GnRH-ant protocol. The primary outcomes measured were the cumulative live birth rate (CLBR) per IVF cycle and the time to live birth (TTLB) from the date of oocyte retrieval. Cox proportional models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) of CLBR regarding GnRH-ant timing.

No significant difference in CLBR was found between the fixed and flexible GnRH-ant groups (27.9% vs 20.5%, p=0.105). The TTLB was also comparable between groups (10.56 vs 10.30 months, p=0.782). The Kaplan-Meier analysis for CLBR also showed comparable results between groups (P=0.351, HR=0.83; 95%CI: 0.56-1.23). After establishing a multiple Cox proportional hazard model, the fixed GnRH-ant group still had comparable CLBR with the flexible GnRH-ant group (HR=0.85; 95%CI: 0.53-1.38; P=0.518). Subgroup and sensitivity analyses also demonstrated similar results.

GnRH-ant protocols can be tailored to the needs of AMA women, and timing of GnRH-ant initiation can be adjusted flexibly.

Ovarian reactivity to gonadotrophin stimulation varies, and individual adjustments to the timing and dose of gonadotrophin-releasing hormone (GnRH) antagonist administration are necessary to prevent excessive increases and decreases in luteinizing hormone (LH) levels in patients with different ovarian response following the GnRH antagonist (GnRH-A) protocol. The present study aims to investigate optimal LH suppression thresholds for patients with normal ovarian response (NOR), high ovarian response (HOR), and poor ovarian response (POR) following the GnRH-A protocol respectively.

A total of 865 in vitro fertilization (IVF) cycles using a flexible or fixed GnRH-A protocol were included. Patients were categorized into the HOR, NOR, or POR group according to their anti-Müllerian hormone (AMH) levels. Then, patients in each group were stratified into one of four subgroups according to the quartile (Q1-Q4) of the basal LH level to LH on triggering day ratio (bLH/hLH). The primary outcomes were the clinical pregnancy and live birth rates, and the secondary outcomes were the number of oocytes retrieved, MII oocytes, two pronucleus (2PN) embryos, and good-quality embryos.

There were 526 patients with NOR, 180 with HOR, and 159 with POR. Basal LH level, LH on triggering day and bLH/hLH were identified as independent predictors of clinical pregnancy rate and live birth rate by logistics regression analysis. Compared to those with NOR, patients with POR had the lowest embryo implantation rate (22.6% vs. 32.8%, P < 0.05), clinical pregnancy rate (32.3% vs. 47.3%, P < 0.05) and live birth rate (22.6 vs. 37.8%, P < 0.05) of fresh embryo transfer (ET). The embryo implantation, clinical pregnancy and live birth rates of frozen embryo transfer (FET) were not significantly different among the three groups. In the subgroup analysis, patients with HOR had the highest embryo implantation rate (51.6%, P < 0.05), clinical pregnancy rate (68.4%, P < 0.05) and live birth rate (52.6%, P < 0.05) of ET in Q3, with a bLH/hLH ratio of 2.40-3.69. In the NOR group, the embryo implantation rate (41.9%, P < 0.05), clinical pregnancy rate (61.5%, P < 0.05) and live birth rate (50.8%, P < 0.05) of ET and live birth rate (53.1%, P < 0.05) of FET were highest in Q2, with a bLH/hLH ratio of 1.29-2.05. Patients with POR had the highest clinical pregnancy rate (57.1%, P < 0.05) and live birth rate (42.9%, P < 0.05) of ET in Q2, with a bLH/hLH ratio of 0.86-1.35.

In the present study, the bLH/hLH ratio represented the LH suppression threshold. The subgroup analysis of HOR, NOR and POR showed that, the LH suppression threshold varies according to ovarian response. We recommend LH suppression thresholds of 2.40-3.69 for HOR, 1.29-2.05 for NOR, and 0.86-1.35 for POR to obtain the highest clinical pregnancy rate and live birth rate. This study provides comprehensive and precise references for clinicians to monitor LH levels individually during controlled ovarian stimulation (COS) according to the patient's ovarian response following the GnRH-A protocol.

Follitropin δ may be an alternative to conventional follitropin α/β for controlled ovarian stimulation (COS) within assisted reproductive treatment (ART), but its efficacy and safety remain unknown. We performed a random-effects meta-analysis to compare the efficacy and safety of follitropin δ and follitropin α/β.

We searched randomized controlled trials comparing follitropin δ and follitropin α/β using MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and WHO-ITCRP on December 14, 2022. The primary outcomes were the live birth rate and the incidence of moderate or severe ovarian hyperstimulation syndrome (OHSS). The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation approach. The protocol was registered on the Open Science Framework.

Three studies involving 2682 participants were included in our meta-analysis. The results indicated that follitropin δ may result in little to no difference in live birth rates (risk ratio [RR], 1.12; 95% confidence interval [CI], 0.91-1.38; low certainty) and the incidence of moderate or severe OHSS (RR, 0.78; 95% CI, 0.48-1.26; low certainty) compared with follitropin α/β.

Follitropin δ may result in little to no difference in COS compared with follitropin α/β, especially in terms of live births and safety.

Anti-Mullerian hormone is a robust marker of ovarian reserve and ovarian response in in vitro fertilisation (IVF). However, its role extends beyond improving the safety of IVF by aiding in choosing appropriate protocols and dosing. This review looks at the value of pre-treatment anti-Mullerian hormone (AMH) value in choosing the appropriate modality of treatment and its predictive ability for the outcomes of such treatment. It briefly addresses the factors that may modulate AMH levels and make clinical decision-making challenging.

Ovarian stimulation is a fundamental step in assisted reproductive technology (ART) with the intention of inducing ovarian follicle development prior to timed intercourse or intra-uterine insemination and facilitating the retrieval of multiple oocytes during a single in vitro fertilization (IVF) cycle. The basis of ovarian stimulation includes the administration of exogenous gonadotropins, with or without pre-treatment with oral hormonal therapy. Gonadotropin-releasing hormone agonist or antagonist is given in addition to the gonadotropins to prevent a premature rise of endogenous luteinizing hormone that would in turn lead to premature ovulation. With the advancement in technology, various stimulation protocols have been devised to cater for different patient needs. However, ovarian hyperstimulation syndrome and its serious complications may occur following ovarian stimulation. It is also evident that suboptimal ovarian stimulation strategies may have a negative impact on oogenesis, embryo quality, endometrial receptivity, and reproductive outcomes over recent years. This review describes the various forms of pre-treatment for ovarian stimulation and stimulation protocols, and aims to provide clinicians with the latest available evidence.

For patients with polycystic ovary syndrome (PCOS) to undergo in vitro fertilization (IVF) and embryo transfer (ET), there has been no consensus regarding which protocol is the most optimal for live birth rate in fresh cycles. We sought to evaluate depot gonadotropin-releasing hormone (GnRH) agonist protocol versus GnRH antagonist protocol in IVF outcomes for PCOS patients in a single fertility center.

In this retrospective cohort, PCOS patients who visited the Second Hospital of Hebei Medical University reproductive center between February 2012 and December 2019 were screened, and 533 PCOS infertility patients were included undergoing their first IVF cycle, with 470 in the depot GnRH agonist group and 63 in the GnRH antagonist group. The primary of this study outcome was the fresh live birth rate (LBR).

PCOS women in the depot GnRH agonist group had a higher LBR (49.79%) than those in the GnRH antagonist group (34.92%, p = 0.027). The multivariable logistic regression also confirmed that women in the depot GnRH agonist group had a higher LBR than those in the GnRH antagonist group (OR = 1.83, 95% CI 1.05~3.18, p = 0.032). After propensity score matching (PSM), the LBR in the depot GnRH agonist group was higher (50.32%) than that of the GnRH antagonist group (35.48%), p = 0.033. The ovarian hyperstimulation syndrome (OHSS) rates were similar between the two groups, with 35 in the depot GnRH group and 6 in the GnRH antagonist group (p = 0.561).

For PCOS patients in fresh embryo transfer cycles, the depot GnRH agonist protocol may lead to a higher LBR than the antagonist protocol with satisfied lower OHSS rates.

The addition of antagonists is mainly based on estrogen level and follicle size, while LH level has not received sufficient attention.In this study, LH Level on the antagonist administration day was used as the main research objective to explore its relationship with laboratory indicators and pregnancy outcomes.

We enrolled 854 patients with normal ovarian function undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) between May 2021 to May 2022 at the Reproductive Center of Shandong University of Traditional Chinese Medicine.We used the quartile method to group LH levels on the antagonist administration day. There were four groups: Q1 (0.53IU/L≤LH ≤ 1.89IU/L); Q2 (1.89IU/L

Result

There were significant differences among the four groups in terms of total Gn dosage, E2, P and LH on trigger day, number of retrieved oocytes, number of 2PN embryos, number of blastocysts, Number of ET and fresh ETR.There is a significant correlation between LH on antagonist administration day and Basal LH Level,LH on trigger day,number of oocytes retrieved,number of 2PN embryos,number of blastocysts, number of ET.Using Fresh ETR,Fresh CPR,OHSS and Cumulative CPR as the criterion respectively, the optimal cut-off value for evaluating LH on antagonist administration day was 4.18IU/L,3.99IU/L,4.63IU/L,4.66IU/L.

Conclusion

There was a significant positive correlation between LH on the antagonist administration day and number of oocytes retrieved,number of 2PN embryos,number of blastocysts.LH on the antagonist administration day could predict Fresh CPR,OHSS and Cumulative CPR to some extent.

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For high responders with polycystic ovary syndrome (PCOS), there is no clear recommendation for the initial follicle-stimulating hormone (FSH) dosage to ensure an optimal number of retrieved oocytes and avoid ovarian hyperstimulation syndrome (OHSS). The aim of this study was to determine the ideal initial FSH dosage of in patients with PCOS undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) using the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol to obtain the optimal number of retrieved oocytes and minimize the risk of OHSS.

The data of 1898 patients with PCOS aged 20-40 years from January 2017 to December 2020 were retrospectively analyzed to explore the factors related to the number of retrieved oocytes. Statistically significant variables were used to construct a dose nomogram and it was then validated using an independent cohort of patients with PCOS from January 2021 to December 2021.

Multivariate analyses demonstrated that body mass index (BMI) was the most significant factor to predict the number of retrieved oocytes compared to body weight (BW) and body surface area (BSA). Among patients with PCOS aged 20-40 years undergoing their first IVF cycles with the GnRH-ant protocol, age was not a significant predictor of the initial FSH dosage. We developed a nomogram based on BMI, basal FSH, basal luteinizing hormone (bLH), anti-Müllerian hormone (AMH), and antral follicle count (AFC) to calculate the ideal initial FSH dosage for patients with PCOS undergoing IVF/ICSI using the GnRH-ant protocol. In addition, low BMI and high bLH and AMH levels and AFC appear to be risk factors for OHSS.

We clearly demonstrated that the initial FSH dosage for patients with PCOS undergoing IVF/ICSI with the GnRH-ant protocol may be calculated on the basis of the woman's BMI and ovarian reserve markers. The nomogram will help guide clinicians in the selection of the most appropriate initial FSH dose in the future.

There is no agreement on which of the 2 gonadotropin-releasing hormone (GnRH) agonist protocols are the most efficient, neither there is any consensus on which one yields a better clinical pregnancy percentage.

The present study aims to compare the effectiveness of reduced dosages of long- and short-acting GnRH agonists on pregnancy outcomes.

In this randomized controlled clinical trial, 400 women were randomly assigned to 2 groups (n = 200/group): the reduced dosage of long-acting GnRH agonist group (group 1, 1.25 mg Decapeptyl) and the short-acting GnRH agonist group (group 2, 0.5 mg/day Buserelin Acetate). The study was conducted at Mehr Medical Institute, Rasht, Iran between July 2019 and July 2020. Biochemical and clinical pregnancy were compared between groups.

No significant differences were observed in the endometrial lining, the total number of retrieved and metaphase-II oocytes, progesterone, and serum estradiol levels on human chorionic gonadotropin day, fertilization rate, and top-quality embryos between the groups. The duration of induction (10.8 ± 1.7 vs. 10 ± 2.1, p < 0.001) and the total dosage of gonadotropins (2939.4 ± 945.9 vs. 2441 ± 1247.1, p < 0.001) were significantly greater in group 2 than in group 1. No significant differences were observed between the 2 groups in terms of implantation rate, chemical pregnancy rate, and clinical pregnancy rate. A higher percentage of ovarian hyperstimulation syndrome was observed in group 2 (p = 0.005).

Due to a lower percentage of ovarian hyperstimulation syndrome in group 1 and similar assisted reproductive technology outcomes in both groups, the long protocol was found to be superior to the short protocol.

The number of oocytes retrieved does not always coincide with the number of follicles aspirated in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment. Patients with high expectation of retrieval sometimes obtain few oocytes, which may be induced by improper operation or therapeutic factors. The purpose of this study was to evaluate the distribution data of oocyte retrieval rate (ORR) and to explore the risk factors for low ORR in patients with polycystic ovary syndrome (PCOS) undergoing IVF/ICSI.

A total of 2478 patients with PCOS undergoing IVF/ICSI were involved in this retrospective case-control study from March 2016 to October 2021. The oocyte retrieval rate was calculated as the ratio of the number of obtained oocytes to the number of follicles (≥ 12 mm) on the trigger day. Patients were divided into a low ORR and a normal ORR group with the boundary of one standard deviation from the mean value of ORR. The patient characteristics, treatment protocols, serum hormone levels, and embryonic and pregnancy outcomes were analyzed.

The ORR exhibited a non-normal distribution, with a median of 0.818. The incidence of complete empty follicle syndrome was 0.12% (3/2478). The proportion of patients in the low ORR group who received the progestin-primed protocol was significantly higher than that in the normal ORR group (30.30% vs. 17.69%). A logistic regression analysis showed that the serum estradiol level/follicle (≥ 12 mm) ratio (OR: 0.600 (0.545-0.661)) and progesterone level (OR: 0.783 (0.720-0.853)) on the trigger day were significant factors in the development of a low ORR, with optimal cutoff values of 172.85 pg/ml and 0.83 ng/ml, respectively, as determined by receiver operating curve. Fewer high-quality embryos (2 vs. 5) and more cycles with no available embryos (5.42% vs. 0.43%) were found in the low ORR group.

For patients with PCOS, low estradiol levels/follicles (≥ 12 mm) and progesterone levels on the trigger day and the use of the progestin-primed protocol could be risk factors for low ORR, which leads to a limited number of embryos and more cycle cancellations.

To investigate whether serum LH levels on hCG trigger day are associated with live birth rate (LBR) after fresh embryo transfer with GnRH antagonist regimen in different populations.

This study was a retrospective study. A total of 3059 fresh embryo transfers were divided into three populations: predicted normal ovarian responders (NOR) (n=2049), patients with PCOS (n=533), and predicted poor ovarian responders (POR) (n=477). Each population was stratified into three groups based on LH levels: < 25th percentile, 25-75th percentile, and > 75th percentile. The primary outcome of the study was LBR, and secondary outcomes included implantation, clinical pregnancy, and early pregnancy loss rates. Univariable and multivariable regression analyses were performed to adjust for potential confounders.

In NOR, compared to the reference group (>75th percentile), LBR was significantly lower in the < 25th percentile group (adjusted OR=0.662; 95%CI, 0.508-0.863) and 25-75th percentile group (adjusted OR=0.791; 95%CI, 0.633-0.988). In PCOS patients, LBR decreased significantly in the < 25th percentile group (41.4%) compared to the 25-75th percentile group (53.7%) and > 75th percentile group (56.1%). In addition, the LBR was lower in the < 25th percentile group (33.6%) compared with the 25-75th percentile group (43.4%) and the>75th percentile group (42.0%) in POR, but this was not statistically significant.

High serum LH levels are associated with increased LBR after fresh embryo transfer in GnRH antagonist cycles, which may be attributable to higher implantation rate. LH may be a predictor of whether to schedule fresh embryo transfer in IVF cycles for better clinical outcomes.

To compare the neonatal outcomes of progestin-primed ovarian stimulation (PPOS) and flexible gonadotropin-releasing hormone (GnRH) antagonist protocols.

This was a retrospective propensity score-matched (PSM) cohort study. Women who underwent their first frozen embryo transfer (FET) cycle with freezing of all embryos followed by PPOS or GnRH antagonist protocols between January 2016 and January 2022 were included. Patients using PPOS were matched with the patients using GnRH antagonist at a 1:1 ratio. The main focus of this study was the neonatal outcomes of singleton live births, including preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), macrosomia and large for gestational age (LGA).

After 1:1 PSM, a total of 457 PPOS and 457 GnRH antagonist protocols were included for analysis. The average starting dose of gonadotropin (275.1 ± 68.1 vs. 249.3 ± 71.3, P<0.01) and total dose of gonadotropin (2799.6 ± 579.9 vs. 2634.4 ± 729.1, P<0.01) were significantly higher in the PPOS protocol than in the GnRH antagonist protocol. The other baseline and cycle characteristics were comparable between the two protocols. The rates of PTB (P=0.14), LBW (P=0.11), SGA (P=0.31), macrosomia (P=0.11) and LGA (P=0.49) did not differ significantly between the two groups. A total of 4 patients in the PPOS group and 3 patients in the GnRH antagonist group qualified as having congenital malformations.

PPOS resulted in singleton neonatal outcomes similar to those of a GnRH antagonist protocol. The application of the PPOS protocol is a safe option for infertility patients.

Gonadotropin-releasing hormone antagonists (GnRH-ant) are widely used in current in vitro fertilization-embryo transfer (IVF-ET), however, whether the lowest daily dose of GnRH-ant is individualized remains unknown. Due to the negative effect of GnRH-ant on endometrial receptivity, lessening the amount of GnRH-antagonists used during controlled ovarian stimulation may be helpful for embryo implantation. As such, a randomized controlled study is essential to validate the feasibility and efficacy of daily GnRH-ant dose reduction to 0.125 mg geared towards providing scientific evidence for guidance in clinical practice.

In total, 620 infertile women undergoing in vitro fertilization will be enrolled in the multicentered, randomized, parallel controlled trial. Based on a computer-generated random list, they will be randomly and equally subdivided into half-dose GnRH-ant group or conventional-dose GnRH-ant group. The primary outcome is ongoing pregnancy ie, intrauterine pregnancy diagnosed by pelvic ultrasonography at more than 12 weeks of gestation accompanied by normal fetal heartbeats. Secondary outcomes include cycle cancellation, premature luteinizing hormone surge, positive pregnancy, embryo implantation rate, clinical pregnancy, early spontaneous abortion, and live birth. The intention-to-treat and per protocol analyses will be used to initially analyze the difference in ongoing pregnancy rate between the two groups, while the multiple imputation method was used to handle missing values in the data.

At present, no randomized controlled trials (RCTs) have been performed on the use of the half-dose GnRH-ant protocol (0.125mg/d) to improve reproductive outcomes of IVF-ET in predicted normal responder, compared to conventional-dose GnRH-ant protocol (0.25mg/d). Half-dose GnRH-ant protocol might provide a suitable clinical solution for predicted normal responder undergoing IVF treatment. Thus, it is critical to conduct a well-designed RCT to evaluate the impact of a half-dose GnRH-ant protocol on the reproductive outcomes of IVF-ET in predicted normal responder.

This study was registered in the Chinese Clinical Trials Registry Platform on August 29, 2020. (chictr.org.cn; identifier: ChiCTR2000037629). This trial is version 1.3.

To explore the efficacy and safety of individualized follitropin delta dosing, based on serum anti-Müllerian hormone (AMH) concentration and bodyweight, in a long gonadotropin-releasing hormone (GnRH) agonist protocol.

Clinical outcomes after one treatment cycle are reported in women with AMH: 5-35 pmol/L. Oocytes were inseminated by intracytoplasmic sperm injection, blastocyst transfer was on Day 5 and remaining blastocysts were cryopreserved. Data collection included live births and neonatal health follow-up for all fresh/frozen transfers performed within one year after treatment allocation.

In total, 104 women started stimulation, of whom 101 had oocyte recovery and 92 had blastocyst transfer. The average daily dose of follitropin delta was 11.0 ± 1.6 µg and the duration of stimulation was 10.3 ± 1.6 days. The mean number of oocytes was 12.5 ± 6.4, the mean number of blastocysts was 5.1 ± 3.4, and 85% had at least one good-quality blastocyst. Following mostly single blastocyst transfer (95%), the ongoing pregnancy rate was 43%, the live-birth rate was 43%, and the cumulative live-birth rate was 58% per started stimulation. There were 6 cases of early OHSS (5.8%) graded as mild (n = 3) and moderate (n = 3) and 6 cases of late OHSS (5.8%) graded as moderate (n = 3) and severe (n = 3).

In this first evaluation of the individualized follitropin delta dosing in a long GnRH agonist protocol, the cumulative live-birth rate was high. A randomized trial comparing follitropin delta in a long GnRH agonist protocol versus in a GnRH antagonist protocol should provide further insight into the efficacy and safety of this treatment option.

NCT03564509; June 21, 2018.

Infertility is increasing worldwide, and many couples seek IVF. Clinical management and laboratory work are fundamental in the IVF journey. Therefore, the definition of reliable key performance indicators (KPIs) based on clinical and laboratory parameters, is essential for internal quality control (IQC). Laboratory performance indicators have been identified and a first attempt to also determine clinical ones has been recently published. However, more detailed indicators are required.

An Italian group of experts in Reproductive Medicine from both public and private clinics on behalf of SIFES-MR and SIERR was established to define IVF indicators to monitor clinical performance.

The working group built a consensus on a list of KPIs, performance indicators (PIs) and recommendation indicators (RIs). When deemed necessary, the reference population was stratified by woman age, response to ovarian stimulation and adoption of preimplantation genetic testing for aneuploidies (PGT-A). Each indicator was scored with a value from 1 to 5 and a weighted average formula - considering all the suggested parameters-was defined. This formula generates a center performance score, indicating low, average, good, or excellent performance.

This study is intended to provide KPIs, PIs and RIs that encompass several essential aspects of a modern IVF clinic, including quality control and constant monitoring of clinical and embryological features. These indicators could be used to assess the quality of each center with the aim of improving efficacy and efficiency in IVF.

Follitropin alfa (FA) is one of the most widely used exogenous gonadotropins in both agonist and antagonist protocols for controlled ovarian stimulation (COS) and in vitro fertilization (IVF). However, reports of its effectiveness are limited, particularly in terms of its impact on overall IVF outcomes and ovarian hyperstimulation syndrome (OHSS). Therefore, in this study, FA competency was investigated by evaluating its effect on IVF outcomes and OHSS, administering agonist and antagonist COS protocols.

A retrospective study with 120 subjects was conducted. Outcomes comprising the number of retrieved and fertilized oocytes, quality of embryos, and clinical pregnancies were assessed. Statistical correlation between FA dose, IVF outcomes, and the incidence of OHSS was also analyzed. All statistical analyses were performed at 95% confidence level.

There was no significant difference in both protocols regarding retrieved oocytes (p=0.604), fertilized oocytes (p=0.761), embryo quality including good, average, poor embryo (p=0.875, p=0.565, p=0.785), and clinical pregnancy (p= 0.844). However, FA doses in the agonist protocol were shown notably higher (p= 0.001). Negative correlations were also observed between FA dose and the number of retrieved oocytes (r=-0.255, p<0.01), fertilized oocytes (r=-0.296, p<0.01), and good quality embryos (r=-0.231, p<0.05).

Our study suggested that FA yields similar outcomes in both COS protocols, but agonist protocols require higher doses of FA and evaluation of its effect on OHSS is an important area of research for further investigation.

Oocyte maturation is affected by various patient and cycle parameters and has a key effect on treatment outcome. A prediction model for oocyte maturation rate formulated by using machine learning and neural network algorithms has not yet been described. A retrospective cohort study that included all women aged ≤ 38 years who underwent their first IVF treatment using a flexible GnRH antagonist protocol in a single tertiary hospital between 2010 and 2015. 462 patients met the inclusion criteria. Median maturation rate was approximately 80%. Baseline characteristics and treatment parameters of cycles with high oocyte maturation rate (≥80%, n = 236) were compared to cycles with low oocyte maturation rate (<80%, n = 226). We used an XGBoost algorithm that fits the training data using decision trees and rates factors according to their influence on the prediction. For the machine training phase, 80% of the cohort was randomly selected, while rest of the samples were used to evaluate our model's accuracy. We demonstrated an accuracy rate of 75% in predicting high oocyte maturation rate in GnRH antagonist cycles. Our model showed an operating characteristic curve with AUC of 0.78 (95% CI 0.73-0.82). The most predictive parameters were peak estradiol level on trigger day, estradiol level on antagonist initiation day, average dose of gonadotropins per day and progesterone level on trigger day. A state-of-the-art machine learning algorithm presented promising ability to predict oocyte maturation rate in the first GnRH antagonist flexible protocol using simple parameters before final trigger for ovulation. A prospective study to evaluate this model is needed.

To compare cumulative live birth rate (LBR) between progestin-primed ovarian stimulation (PPOS) and GnRH antagonist protocols of preimplantation genetic testing (PGT) cycles in different populations.

This was a retrospective cohort study. A total of 865 patients were enrolled and separate analyses were performed for three populations: 498 patients with predicted normal ovarian response (NOR), 285 patients with PCOS, and 82 patients with predicted poor ovarian response (POR). The primary outcome was cumulative LBR for one oocyte retrieval cycle. The results of response to ovarian stimulation were also investigated, including numbers of oocytes retrieved, MII oocytes, 2PN, blastocysts, good-quality blastocysts, and usable blastocysts after biopsy, as well as rates of oocyte yield, blastocyst formation, good-quality blastocysts, and moderate or severe OHSS. Univariable and multivariable logistic regression analyses were used to identify potential confounders that may be independently associated with cumulative live birth.

In NOR, the cumulative LBR of PPOS protocol was significantly lower than that of GnRH antagonists (28.4% vs. 40.7%; P=0.004). In multivariable analysis, the PPOS protocol was negatively associated with cumulative LBR (adjusted OR=0.556; 95% CI, 0.377-0.822) compared to GnRH antagonists after adjusting for potential confounders. The number and ratio of good-quality blastocysts were significantly reduced in PPOS protocol compared to GnRH antagonists (2.82 ± 2.83 vs. 3.20 ± 2.79; P=0.032 and 63.9% vs. 68.5%; P=0.021), while numbers of oocytes, MII oocytes and 2PN did not show any significant difference between GnRH antagonist and PPOS protocols. PCOS patients had similar outcomes as NOR. The cumulative LBR of PPOS group appeared to be lower than that of GnRH antagonists (37.4% vs. 46.1%; P=0.151), but not significantly. Meanwhile, the proportion of good-quality blastocysts in PPOS protocol was also lower compared to GnRH antagonists (63.5% vs. 68.9%; P=0.014). In patients with POR, the cumulative LBR of PPOS protocol was comparable to that of GnRH antagonists (19.2% vs. 16.7%; P=0.772). There was no statistical difference in the number and rate of good-quality blastocysts between the two protocols in POR, while the proportion of good-quality blastocysts appeared to be higher in PPOS group compared to GnRH antagonists (66.7% vs. 56.3%; P=0.182). In addition, the number of usable blastocysts after biopsy was comparable between the two protocols in three populations.

The cumulative LBR of PPOS protocol in PGT cycles is lower than that of GnRH antagonists in NOR. In patients with PCOS, the cumulative LBR of PPOS protocol appears to be lower than that of GnRH antagonists, albeit lacking statistical difference, whereas in patients with diminished ovarian reserve, the two protocols were comparable. Our findings suggest the need for caution when choosing PPOS protocol to achieve live births, especially for normal and high ovarian responders.

To evaluate different starting doses of recombinant human follicle-stimulating hormone (rhFSH) on pregnancy outcomes for patients with normal ovarian reserve during gonadotropin- releasing hormone antagonist (GnRH-ant) protocol-controlled ovarian stimulation of in vitro fertilization (IVF) cycles.

In this retrospective study, a total of 1138 patients undergoing IVF cycles following the GnRH-ant protocol were enrolled. Patients were divided into two groups according to the starting dose of rhFSH. 617 patients received a starting dose of rhFSH of 150 IU, and 521 patients received a starting dose of rhFSH of 225 IU. We compared demographic characteristics, ovarian stimulation and embryological characteristics, and pregnancy and birth outcomes between the two groups. Multivariate logistic regression analysis was performed to examine the possible effects of the known potential confounding factors on pregnancy outcomes.

The number of oocytes retrieved in the 150 IU rhFSH group was significantly lower than those in the 225 IU rhFSH group. There was no significant difference between the two groups referring to embryological characteristics. The proportion of fresh embryo transfer in the 150 IU rhFSH group was significantly higher than that in the 225 IU rhFSH group (48.30% vs. 40.90%), and there was no difference in the risk of ovarian hyperstimulation syndrome and pregnancy outcomes between the two groups.

In conclusion, the starting dose of rhFSH of 150 IU for ovarian stimulation has a similar pregnancy outcome as starting dose of rhFSH of 225 IU in GnRH-ant protocol for patients with normal ovarian reserve. Considering the potential cost-effectiveness and shorter time to live birth, the starting dose of rhFSH of 150 IU may be more suitable than 225 IU.

Controlled ovarian hyperstimulation (COH) is essential for the success of in vitro fertilization (IVF). Evidence showing the comparison of different COH protocols remains predominantly of low certainty and derives from unspecified infertile and highly heterogeneous populations. Thus, personalized approaches to examine the response of patients to the various COH protocols need to be investigated. Data from in vitro and animal studies have identified the mechanistic target of rapamycin (mTOR) and Hippo signaling pathways play a key role in follicular homeostasis and oocyte quality. To be specific, current data indicate the controlled activation of mTOR and the controlled inhibition of the Hippo pathway within the ovarian granulosa cells (GC). Both are reported to lead to a nurturing follicular microenvironment, increase oocyte quality, and potentially improve reproductive outcomes. As intracellular markers, phosphorylated/unphosphorylated levels of the pathways' main downstream mediators could be included among the candidate "personalized" predictors of patients' response to COH protocols and final IVF outcomes. Based on these hypotheses, we make a preliminary attempt to investigate their validity: We propose a prospective cohort study to compare the levels of certain phosphorylated/unphosphorylated components of the investigated pathways (mTOR, ribosomal protein S6 kinase beta-1 (p70S6K-1), yes-associated protein-1 (YAP-1), and transcriptional coactivator with PDZ-binding motif (TAZ)) within the follicular fluid-isolated GC between women undergoing gonadotropin-releasing hormone (GnRH) antagonist/"short" protocols and those receiving GnRH agonist/"long 21" protocols. A case-control design comparing these levels between women achieving pregnancy and those who did not is further planned. Additional analyses addressing the population's expected heterogeneity are planned after the completion of the pilot phase, during which 100 participants undergoing IVF are intended to be recruited. At this stage, these hypotheses are solely based on in vitro/animal data, and thus, similar studies on humans in this respect are necessary for the investigation of their potential validity.