OBJECTIVE: 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?
CONCLUSIONS: 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.
BACKGROUND: 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.
METHODS: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
CONCLUSIONS: 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.
BACKGROUND: 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.
BACKGROUND: The RCT was registered in the Chinese Clinical Trial Registry; Study Number: ChiCTR2100053453.
UNASSIGNED: 21 November 2021.
UNASSIGNED: 23 November 2021.

OBJECTIVE: 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?
CONCLUSIONS: 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).
BACKGROUND: 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.
METHODS: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
CONCLUSIONS: 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.
BACKGROUND: 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.
BACKGROUND: ClinicalTrials.gov identifier NCT03809429; EudraCT Number 2017-002783-40.
UNASSIGNED: 7 April 2019.
UNASSIGNED: 2 May 2019.

UNASSIGNED: Progesterone-primed cycles effectively suppress the pituitary LH surge during ovarian stimulation in oocyte donors and in the infertile population. Particularly in oocyte donors, the use of synthetic progesterone (progestins) has been explored in prospective clinical trials, showing mixed results. This trial was designed to determine whether the use of micronized natural progesterone is as effective as the GnRH-antagonist protocol in terms of the number of mature oocytes (MII) retrieved in oocyte donation cycles as a primary outcome, and it also aims to explore the corresponding results in recipients as a secondary outcome.
UNASSIGNED: We propose a prospective, open-label, non-inferiority clinical trial to compare a novel approach for oocyte donors with a control group, which follows the standard ovarian stimulation protocol used in our institution. A total of 150 donors (75 in each group) will be recruited and randomized using a computer algorithm. After obtaining informed consent, participants will be randomly assigned to one of two ovarian stimulation protocols: either the standard GnRH antagonist or the oral micronized natural progesterone protocol. Both groups will receive recombinant gonadotropins tailored to their antral follicle count and prior donation experiences, if any. The primary outcome is the number of mature metaphase II (MII) oocytes. Secondary measures include treatment duration, pregnancy outcomes in recipients, as well as the economic cost per MII oocyte obtained in each treatment regimen. Analyses for the primary outcome will be conducted in both the intention-to-treat (ITT) and per-protocol (PP) populations. Each donor can participate only once during the recruitment period. The estimated duration of the study is six months for the primary outcome and 15 months for the secondary outcomes.
UNASSIGNED: The outcomes of this trial have the potential to inform evidence-based adjustments in the management of ovarian stimulation protocols for oocyte donors.
UNASSIGNED: ClinicalTrials.gov, identifier, NCT05954962.

The 29-year-old participant in the case study has been grappling with infertility for the last six years. Following an assessment of her symptoms, hormone profile, and ultrasound results, she received a diagnosis of polycystic ovarian syndrome (PCOS). PCOS is a multifaceted endocrine and metabolic disorder characterized by symptoms such as obesity, insulin resistance, anovulation, and polycystic ovaries. Various factors, including heredity, intestinal dysbiosis, obesity, environmental pollutants, lifestyle choices, and neuroendocrine abnormalities, contribute to the susceptibility of women to PCOS. In planning polycystic ovarian stimulation, it is crucial to consider parameters such as antral follicle count (AFC), luteinizing hormone (LH), and anti-Müllerian hormone (AMH). Careful planning of the gonadotrophin dose is essential to achieve an optimal response during a gonadotropin-releasing hormone antagonist (GnRH-ant) cycle. In our case, the brief antagonist protocol was used, resulting in a favorable outcome with minimal risk of ovarian hyperstimulation syndrome (OHSS). Despite multiple unsuccessful attempts at natural conception, the patient successfully conceived with the help of intracytoplasmic sperm injection (ICSI), leading to a positive pregnancy outcome. In addition to incorporating mechanical hatching to promote implantation, we diligently selected the most beneficial medications for the patient.

To compare the effects of recombinant FSH alfa (rFSH-alfa), rFSH-beta, highly purified human menopausal gonadotropin (HP-hMG) and urinary FSH (uFSH) in women with polycystic ovarian syndrome who have undertaken the GnRH antagonist protocol during IVF/ICSI treatment.
A single-center retrospective cohort study including women with PCOS who received the GnRH antagonist protocol from January 2019 to July 2022 was conducted. Patients were divided into rFSH-alfa group, HP-hMG group, uFSH group, and rFSH-beta group, and the number of oocytes retrieved, clinical pregnancy rate of the fresh cycle (primary outcomes), embryo quality, and severe OHSS rate (secondary outcomes) were compared.
No statistical differences were found among the four groups in fresh cycle clinical pregnancy rate (p=0.426), nor in the subgroup analyses. The HP-hMG group had a smaller number of oocytes retrieved and a higher high-quality D3 embryo rate than the three FSH groups (p<0.05). No statistical differences were found among the four groups in the severe OHSS rate (p=0.083).
For women with PCOS undergoing the GnRH antagonist protocol, the clinical pregnancy rates of fresh IVF/ICSI-ET cycle are similar for all four types of Gn. With a lower risk of OHSS and a similar number of high-quality and available embryos, HP-hMG may have an advantage in the PCOS population.

The present study was designed to establish and validate a prediction model for high ovarian response (HOR) in the GnRH antagonist protocol.
In this retrospective study, the data of 4160 cycles were analyzed following the in vitro fertilization (IVF) at our reproductive medical center from June 2018 to May 2022. The cycles were divided into a training cohort (n=3121) and a validation cohort (n=1039) using a random sampling method. Univariate and multivariate logistic regression analyses were used to screen out the risk factors for HOR, and the nomogram was established based on the regression coefficient of the relevant variables. The area under the receiver operating characteristic curve (AUC), the calibration curve, and the decision curve analysis were used to evaluate the performance of the prediction model.
Multivariate logistic regression analysis revealed that age, body mass index (BMI), follicle-stimulating hormone (FSH), antral follicle count (AFC), and anti-mullerian hormone (AMH) were independent risk factors for HOR (all P< 0.05). The prediction model for HOR was constructed based on these factors. The AUC of the training cohort was 0.884 (95% CI: 0.869-0.899), and the AUC of the validation cohort was 0.884 (95% CI:0.863-0.905).
The prediction model can predict the probability of high ovarian response prior to IVF treatment, enabling clinicians to better predict the risk of HOR and guide treatment strategies.

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/LThere 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.
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.

OBJECTIVE: The aim of this study was to investigate the influence of ratio of serum luteinizing hormone (LH) on gonadotropin-releasing hormone antagonist (GnRH-ant) day to basal LH (hLH/bLH) on in-vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) outcome in polycystic ovary syndrome (PCOS) women who received GnRH-ant protocol for controlled ovarian hyperstimulation (COH).
METHODS: This retrospective study was conducted in women with PCOS (n = 1116) who underwent the GnRH-ant protocol for COH between 2015 and 2022 and were stratified as group A (hLH/bLH < 1, n = 489) and group B (hLH/bLH ≥ 1, n = 627) according to the variation of serum LH. The outcomes of COH and the first frozen embryo transfer (FET) cycle were compared between group A, B and the linear relationship between hLH/bLH ratio and IVF/ICSI outcomes were studied by multivariate linear regression analysis and restricted cubic spline (RCS) models.
RESULTS: There were significant differences in baseline characteristics and outcomes between group A and B. Group A had higher levels of bLH, AMH, estradiol (E2) on GnRH-ant start day and lower levels of LH on GnRH-ant start day. Group B has better ovulation induction outcomes: more retrieved oocytes, normally fertilized oocytes (2PN), cleavage embryos, available embryos and high-quality blastocysts. Multivariate linear regression analysis found no statistically significant connection between hLH/bLH and clinical outcomes. RCS models showed hLH/bLH had nonlinear association with outcomes, including number of oocytes retrieved, 2PN, available embryos, incidence of OHSS, chemical pregnancy, clinical pregnancy, abortion and live birth.
CONCLUSIONS: hLH/bLH ratio could be a more forward-looking indicator of clinical outcome in women with PCOS undergoing GnRH-ant protocols than LH on trigger day and the ratio of LH level on trigger day to basal LH. hLH/bLH = 1 may be the best condition for higher live birth rate and lower OHSS rate.

Several strategies have been proposed for ovarian stimulation in older women, such as using an increased daily dose of gonadotropins (300-450 IU per day) with GnRH agonist (long or micro dose flare protocols), or using GnRH antagonist protocols. The objective of this study is to compare the efficacy of flexible GnRH antagonist protocol and GnRH agonist flare - pituitary block protocols for ovarian stimulation in women above 40 years old undergoing IVF.
This study was performed between January 2016 and February 2019. One hundred and fourteen women aged between 40 and 42 years who underwent IVF were divided into two groups; group I were treated by Flexible GnRH antagonist protocol (Antagonist group, n=68); and group II were treated by Flare GnRH agonist protocol (Flare group, n=46).
Patients treated with the antagonist protocol had a significantly lower cancellation rate when compared with patients treated with flare agonist protocol (10.3% vs. 21.7%, p value 0.049). The other parameters evaluated did not show statistically significant differences.
Our finding showed that both Flexible antagonist and Flare agonist protocols had comparable outcomes, with lower cycle cancellation rates for older patients treated with the antagonist protocol.

The aim of this study is to compare the ART (assisted reproductive technology) outcomes and cancellation rates between GnRH antagonist protocol and GnRH agonist short protocol in POSEIDON (Patient-Oriented Strategy Encompassing IndividualizeD Oocyte Number) groups 3 and 4. It is a retrospective cohort study conducted in the Department of Reproductive Medicine and Surgery of a tertiary-level hospital. Women who underwent ART treatment with either GnRH antagonist or GnRH agonist short protocol with fresh embryo transfer, between January 2012 and December 2019 belonging to POSEIDON 3 and 4 groups, were included. Among the 295 women who belonged to the POSEIDON groups 3 or 4, 138 women received GnRH antagonist and 157 women received GnRH agonist short protocol. The median total dose of gonadotropin in the GnRH antagonist protocol was not significantly different from GnRH agonist short protocol [3000, IQR (2481-3675) vs. 3175, IQR (2643-3993), p = 0.370]. There was a significant difference in the duration of stimulation between the GnRH antagonist and GnRH agonist short protocol [10, IQR (9-12) vs. 10, IQR (8-11), p = 0.002]. The median number of mature oocytes retrieved was significantly different in the cohort of women receiving GnRH antagonist protocol compared to GnRH agonist short protocol [3, IQR (2-5) vs. 3, IQR (2-4), p = 0.029]. There was no significant difference in the clinical pregnancy rate (24% vs. 20%, p = 0.503) and cycle cancellation rate (29.7% vs. 36.3%, p = 0.290) between the GnRH antagonist and agonist short protocols respectively. Live birth rate was not significantly different between the GnRH antagonist protocol (16.7%) and GnRH agonist short protocol (14.0%) [OR 1.23, 95% CI (0.56-2.68), p = 0.604]. After adjusting for the significant confounding factors, the live birth rate was not significantly associated with the antagonist protocol compared with the short protocol [aOR 1.08, 95% CI (0.44-2.63), p = 0.870]. Though GnRH antagonist protocol results in higher mature oocyte yield when compared with GnRH agonist short protocol, it does not translate into an increase in live birth in POSEIDON groups 3 and 4.