Gonadotropin-releasing Hormone Antagonist Protocol Research Articles

Gonadotropin Versus Gonadotropin/Letrozole Protocol in Previously Failed Antagonist Cycles in Patients with Low Prognosis

Objective: Letrozole is an aromatase inhibitor which has been used for ovulation induction. Our aim is to evaluate the effectiveness of adding letrozole to gonadotropins in the early follicular phase of gonadotropin-releasing hormone antagonist (GnRH-a) protocol in patients with poor ovarian response who had failed in the preceding GnRH-a cycle.
 Materials and Method: Ninety-eight patients with poor ovarian response who had previously failed GnRH-a cycle were included. Patients (n; 58) who were treated with letrozole plus gonadotropins (LzGA) were compared with patients (n; 40) who received gonadotropins (GT). The number of total oocytes retrieved, the number of MII oocytes and fertilized oocytes, fertilization and implantation ratios, the rate of cycle cancellation as well as clinical pregnancy and live birth rates
 Results: The LzGA group had a significantly shorter duration of GnRH-a stimulation and higher progesterone level at trigger day (p=0.005, p=0.049 respectively). Although letrozole administration demonstrated lower estradiol levels at trigger day and the total dose of gonadotropins used were lower in LzGA group, this was statistically non-significant (p=0.13, p=0.13 respectively).
 Conclusion: Adding letrozole to gonadotropins in GnRH-a protocol in patients with poor prognosis did not improve pregnancy outcomes. But it seems to decrease IVF costs by reducing the GnRH-antagonist and gonadotropin dosage.

Luteinizing Hormone/Human Chorionic Gonadotropin Receptor N312S Single-Nucleotide Polymorphism and Its Impact on Clinical and Reproductive Outcomes in Assisted Reproductive Technology: A Prospective Cohort Study.

Objective The aim of this study was to determine the genotypic distribution of luteinizing hormone/human chorionic gonadotropin receptor (LHCGR) N312S single-nucleotide polymorphism (SNP) and to investigate its impact on clinical and reproductive outcomes in infertile Indian women undergoing assisted reproductive technology (ART). Study design and settings This was a prospective cohort study conducted at a tertiary care university hospital. Subjects and methods Infertile women aged between 21 and 40 years undergoing ART with an antagonist protocol were enrolled in this study. A 2-ml sample of peripheral venous blood was collected from each woman and genotyped for the LHCGR N312S SNP. Participants were divided into three groups based on their SNP: NN, NS, and SS. All subjects underwent controlled ovarian hyperstimulation (COH) through a gonadotropin-releasing hormone (GnRH) antagonist protocol and intracytoplasmic sperm injection (ICSI). Of the 140 women recruited based on selection criteria, 128 underwent embryo transfer. We compared the genotypic distribution of the LHCGR N312S SNP, baseline characteristics, clinical outcomes, and reproductive outcomes in ART among the three groups. Data were analyzed using IBM SPSS Statistics for Windows, Version 29 (Released 2022; IBM Corp., Armonk, New York, United States). The chi-square test and Fisher-Irwin test were employed to evaluate significant differences among the qualitative categorical variables. A p-value of less than 0.05 was considered statistically significant. Results Among the test subjects, 19.3% were homozygous for the LHCGR N312 SNP (NN group), 38.6% were heterozygous (NS group), and 42.1% were homozygous for the LHCGR S312 SNP (SS group). Baseline characteristics were similar among the three groups. In terms of ovarian reserve tests, significantly lower anti-Müllerian hormone (AMH) levels were observed in the SS group compared to the NS and NN groups (2.8 ± 2.1 vs. 3.2 ± 2.5 vs. 4.3 ± 3.3; p=0.03). No significant differences were observed in COH outcomes such as duration of stimulation, total gonadotropin requirement, oocyte yield, or the number of good-quality embryos among the three groups. The cumulative pregnancy rate (82.9% vs. 50.0% vs. 38.2%, p=0.0005), cumulative clinical pregnancy rate (78.8% vs. 44.7% vs. 34.5%, p = 0.0005), and cumulative live birth rate (50.0% vs. 20.2% vs. 20.0%, p=0.005) were significantly higher in the NN group than in the NS and SS groups. Conclusion The study's findings suggest that LHCGR N312 may help predict reproductive outcomes in ART, which may aid in providing better counseling to infertile couples. We need more studies on individualized/personalized COH using pharmacogenomics for follicle-stimulating hormone (FSH) and luteinizing hormone (LH) supplementation based on combined FSH and LH receptor SNP and to assess their effects on ART outcomes.

Predictors for persistent endometrial cavity fluid from fresh to subsequent frozen embryo transfer

Introduction: During the process of assisted reproductive technology, clinicians are always faced with the problem of endometrial cavity fluid (ECF) interfering with pregnancy outcomes, especially those patients with ECF. The aim of this study was to identify which characteristics of those patients with ECF during the preparation of fresh embryo transfer would predict their recurrent ECF when they were to undergo this cycle of frozen embryo transfer due to cancellation of fresh embryo transfer or failure to obtain a live birth after fresh embryo transfer. Methods: We collected relevant clinical information of those patients receiving assisted reproduction therapy at Reproductive Hospital affiliated with Shandong University between January 2014 and December 2020, including those patients who developed ECF before fresh embryo transfer and canceled fresh embryo transfer for different reasons or did not obtain pregnancy after transfer. Patients were divided into persistent and transient ECF groups according to whether they still had ECF before the current cycle of frozen embryo transfer. We compared relevant data that may influence the persistence of ECF and performed logistic regression analysis to examine whether these variables were associated with the persistence of ECF. Results: The proportion of continued existence of ECF was 14.13% (276/1953). The variables related to the persistence of ECF were as follows: polycystic ovarian syndrome status, previous hysteroscopic adhesiolysis history, history of cesarean section, controlled ovarian hyperstimulation protocol, and endometrial thickness on human chorionic gonadotropin trigger day. Conclusions: It is recommended to inform those patients who present with a thin endometrium on human chorionic gonadotropin trigger day, the diagnosis of polycystic ovarian syndrome, a history of hysteroscopic adhesiolysis, cesarean section history, or were treated with gonadotropin-releasing hormone antagonist protocol that the ECF is less likely to resolve spontaneously, and early intervention based on the corresponding high-risk factors should be recommended.

In Vitro Fertilization Outcomes With a Dual Trigger in Normoresponders in Antagonist Cycles.

Objectives To evaluate whether the dual trigger of ovulation with a gonadotropin-releasing hormone (GnRH) agonist and the standard dose of recombinant human chorionic gonadotropin (hCG) (dual trigger) is better than hCG alone in in vitro fertilization (IVF) cycles of patients who responded well to ovarian stimulation. Methods Between January 2013 and December 2021, 5593 antagonist cycles of patients were reviewed. This study included women who had an antral follicle count of 5 or more and exhibited a normoresponse to ovarian stimulation using the GnRH antagonist protocol, as determined by the follicular output rate (FORT).The primary outcome indicators consisted of the quantities of retrieved oocytes and mature oocytes. The secondary outcome markers included live birth rates, clinical pregnancy rates, and continued pregnancy rates. Results A total of 1244 normoresponder women who met the inclusion criteria were identified from the scanned files and subsequently enrolled in the GnRH antagonist protocol. A total of 383 cycles were observed in the group that was given the standard hCG triggerwhile 861 cycles were observed in the group that was given the dual trigger. The number of mature oocytes and top-quality embryos was significantly higher in the dual trigger group. The maturation rate in the hCG group was 74.8%while it was 76.9% in the dual trigger group (p=0.018). The dual trigger group exhibited an ongoing pregnancy rate of 37.6%, whereas the hCG group had a rate of 30.1% (p = 0.02). The dual trigger group exhibited a slightly higher live birth rate (34.3% vs 29.2%, p = 0.11), although this difference did not reach statistical significance. Conclusion Dual trigger of ovulation was superior to hCG alone in terms of the number of mature oocytes yielded, top quality of embryos, maturation rates, andongoing pregnancy in IVF cycles of normoresponders having ovarian stimulation on the GnRH antagonist protocol.

The efficacy of GnRH agonist trigger followed by hCG add-back in normal responders for fresh embryo transfer: a case-control analysis from Vietnam

Aim: to assess the effects of a dual trigger by gonadotrophin-releasing hormone (GnRH) agonist and low-dose human chorionic gonadotropin (hCG) on in vitro fertilization (IVF) outcomes in women with normal ovarian response.Materials and Methods. This case-control analysis comprised 118 patients who responded normally to ovarian stimulation with a GnRH antagonist protocol at Hue Center for Reproductive Endocrinology and Infertility, Vietnam, between January 2018 and October 2019. Recruitment was achieved through case-control matching: a case (with Dual trigger – group A) was paired with control (with hCG trigger – group B) in a 1:1 ratio. The primary markers of success were the retrieval of oocytes and embryological data, the pregnancy rate, and the incidence of ovarian hyperstimulation syndrome (OHSS).Results. 59 patients in group A and 59 women in group B were recruited. Two groups had comparable patient characteristics and ovarian reserve. The initial dose, total dose, duration of gonadotropin administration, and peak of estradiol level were not statistically different across groups. The number of recovered oocytes (10.3 ± 4.2 vs. 10.0 ± 3.3; p = 0.663), mature oocytes (8.6 ± 3.7 vs.8.1 ± 2.8; p = 0.346), and high-quality embryos (56.2 ± 28.9 vs. 59.8 ± 35.9; p = 0.555) was equivalent. Fertilization, clinical pregnancy, and live birth rates were comparable between the dual trigger and hCG groups. In neither group were any occurrences of OHSS seen.Conclusion. Dual trigger may substitute hCG for final oocyte maturation and fresh embryo transfer in patients with normal responses to GnRH antagonist protocol-induced ovarian stimulation without compromising IVF outcomes.

Live Birth Outcomes for PCOS Patients Under the Follicular-Phase Long-Acting GnRH Agonist Protocol or Antagonist Protocol - A Retrospective Chinese Cohort.

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.

Human chorionic gonadotropin levels after ovulation triggering as predictors of clinical pregnancy after intracytoplasmic sperm injection: a prospective cohort study

ABSTRACT This study aimed to assess the correlation between human chorionic gonadotropin (HCG) levels after ovulation triggering and clinical pregnancy following intracytoplasmic sperm injection (ICSI), affected by HCG formulation and dose. The study was a prospective cohort study of 100 women who underwent ICSI and controlled ovarian stimulation (COS) using a fixed gonadotropin-releasing hormone (GnRH) antagonist protocol. Women were divided according to the type of ovulation triggering into three groups: (1) urinary HCG (uHCG) group (n = 33); (2) recombinant HCG (rHCG) group (n = 33); and (3) dual trigger group (n = 34). The three groups were compared to each other taking into consideration the HCG levels and their correlations to clinical pregnancy following ICSI. Clinical pregnancy could be predicted by serum HCG levels 34 h after ovulation triggering by uHCG, rHCG and dual trigger at cutoff levels of 73.72, 57.35 and 22.37 mIU/ml, respectively, with sensitivities of 95%, 94.7% and 87%, and specificities of 76.9%, 92.9% and 90.9%, respectively. Follicular fluid (FF) HCG levels could predict clinical pregnancy after ovulation triggering by uHCG, rHCG and dual trigger at cutoff levels of 21.58 mIU/ml, 20.82 mIU/ml and 8.66 mIU/ml, respectively, with sensitivities of 95%, 94.7% and 91.3%, and specificities of 92.3%, 92.9% and 90.9%, respectively. In conclusion, serum and FF HCG levels after ovulation triggering could predict clinical pregnancy following ICSI at variable cutoff levels according to HCG formulation and dose.

The role of serum vitamin D in patients with normal ovarian reserve undergoing the first IVF/ICSI cycle.

The debate over the impact of vitamin D in assisted reproduction continues. The purpose of our study was to assess embryo quality and pregnancy outcomes among groups with different levels of vitamin D after the first in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle in patients with normal ovarian reserve (NOR). Patients in this retrospective cohort study were divided into three groups: severe vitamin D deficiency group (25OH-D < 10 ng/ml), vitamin D deficiency group (10 ng/ml ≤ 25OH-D < 20 ng/ml), and non-vitamin D deficiency group (25OH-D ≥ 20 ng/ml). The primary outcome was clinical pregnancy, while the secondary outcomes were mature oocytes, oocyte fertilization, available cleavage embryos, available blastocysts, biochemical pregnancy, early abortion, and embryo implantation. A modified Poisson regression model and multiple linear regression analysis were conducted for the multivariate analysis. 264 NOR patients undergoing the first IVF/ICSI cycles were included. For the primary outcome, there was no significant difference in clinical pregnancy between the severe vitamin D deficiency group and the other two groups (vitamin D deficiency group: adjusted RR = 1.026; 0.780 - 1.350; P = 0.854; non-vitamin D deficiency group: adjusted RR = 1.092; 0.743 - 1.605; P = 0.652). For all secondary outcomes, no significant differences were observed among the severe vitamin D deficiency, vitamin D deficiency, and non-vitamin D deficiency groups (P > 0.05). Exploratory subgroup analyses concerning the season of embryo transfer, phase of embryo transferred, and endometrial thickness, as well as the sensitivity analysis using logistic regression models for the primary outcome, revealed comparable clinical pregnancy rates among the groups (P > 0.05). Subgroup analysis concerning ovarian stimulation protocol indicated that in the subgroup of gonadotrophin-releasing hormone (GnRH) antagonist protocol, the clinical pregnancy rate of the non-vitamin D deficiency group was significantly higher than that of the other two groups (P < 0.05). Serum vitamin D level was not associated with embryo quality and pregnancy outcomes for patients with NOR. Further studies with greater sample sizes and a longer follow-up period are needed to elucidate the relationships between vitamin D levels and IVF outcomes.

Oral Contraceptive Pill Pretreatment in Polycystic Ovary Syndrome Patients Undergoing IVF/ICSI Using the Gonadotrophin Releasing Hormone Antagonist Protocol (A Randomized Controlled Trial)

Abstract 700 women with PCOS undergoing IVF/ICSI using flexible GnRH antagonist protocol, were included in the study, and randomized to either OCP pretreatment (n = 350), or no pretreatment (n = 350). The latter group received OCP pretreatment in the form of 30µg ethinyl estradiol / 3mg drospirenone (Yasmin®, Bayer AG, Berlin, Germany) pills for an interval of 21 to 28 days; after which COH was started following a 5-day pill wash-out period. OCP-pretreated PCOS women had more retrieved oocytes, albeit, on the expense of increased gonadotropin consumption. However, this increased oocyte yield did not translate to a significant effect on conception rates among intended-to-treat PCOS woman receiving OCP pretreatment. Conversely, it shifted among OCP-pretreated women who actually started COH cycle, to a significant 18% reduction in the probability of successful pregnancy.

Progestin Primed Ovarian Stimulation (PPOS) protocol yields lower euploidy rate in older patients undergoing IVF

BackgroundTo explore if exogenous progestin required for progestin primed ovarian stimulation (PPOS) protocol compromises the euploidy rate of patients who underwent preimplantation genetic testing cycles when compared to those who received the conventional gonadotropin-releasing hormone (GnRH) antagonist protocol.MethodsThis retrospective cohort study analyzed 128 preimplantation genetic testing for aneuploidy (PGT-A) cycles performed from January 2018 to December 2021 in a single university hospital-affiliated fertility center. Infertile women aged 27 to 45 years old requiring PGT-A underwent either PPOS protocol or GnRH-antagonist protocol with in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) for fertilization. Frozen embryo transfers were performed following each PGT-A cycle. Data regarding the two groups were analyzed using the Statistical Package for Social Sciences (SPSS) version 22.0 (SPSS Inc., Chicago, IL).ResultsPatients who underwent PPOS treatment had significantly reduced blastocyst formation rate and euploidy rate compared to those who received the GnRH antagonist protocol. Subgroup-analysis was performed by stratifying patients’ age into elder and young subgroups (elder: ≥ 38-year-old, young: < 38-year-old). In the elder sub-population, the blastocyst formation rate of the PPOS group was significantly lower than that of the GnRH-antagonist group (45.8 ± 6.1% vs. 59.9 ± 3.8%, p = 0.036). Moreover, the euploidy rate of the PPOS group was only about 20% of that of the GnRH-antagonist group (5.4% and 26.7%, p = 0.006). In contrast, no significant differences in blastocyst formation rate (63.5 ± 5.7% vs. 67.1 ± 3.2%, p = 0.45) or euploidy rate (30.1% vs. 38.5%, p = 0.221) were observed in the young sub-population. Secondary outcomes, which included implantation rate, biochemical pregnancy rate, clinical pregnancy rate, live birth rate, and miscarriage rate, were comparable between the two treatment groups, regardless of age.ConclusionWhen compared to the conventional GnRH-antagonist approach, PPOS protocol could potentially reduce the euploidy rate in aging IVF patients. However, due to the retrospective nature of this study, the results are to be interpreted with caution. Before the PPOS protocol is widely implemented, further studies exploring its efficacy in larger populations are needed to define the optimal patient selection suitable for this method.Trial registrationHuman Investigation and Ethical Committee of Chang Gung Medical Foundation (202200194B0).

Dose Nomogram of Individualization of the Initial Follicle-Stimulating Hormone Dosage for Patients with Polycystic Ovary Syndrome Undergoing IVF/ICSI with the GnRH-Ant Protocol: A Retrospective Cohort Study.

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 20-40years 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 20-40years 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.

Pregnancy outcomes following supplementation of single dose GnRH agonist to sustain the luteal phase in antagonist fresh embryo transfer cycles: A multicentric prospective cohort study

Objective: To determine whether a single dose of gonadotropin-releasing hormone (GnRH) agonist administered subcutaneously in addition to the regular progesterone supplementation could provide a better luteal support in antagonist protocol fresh embryo transfer cycles. Methods: This prospective, multicentric, cohort study included total 140 women, 70 in each group. Controlled ovarian stimulation was carried out as per fixed GnRH antagonist protocol. The trigger was given with hCG. In vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) was performed and day-3 embryos were transferred. Patients were divided into groups 1 and 2 based on computer generated randomization sheet. Six days following oocyte retrieval, group 1 received 0.2 mg decapeptyl subcutaneously in addition to regular progesterone support while group 2 received progesterone only. Luteal support was given for 14 days to both groups; if pregnancy was confirmed luteal support was continued till 12 weeks of gestation. The clinical pregnancy rate was the primary outcome. The implantation rate, miscarriage rate, live birth delivery rate, and multiple pregnancy rates were the secondary outcomes. Results: A total of 140 patients were analysed, 70 in each group. Clinical pregnancy rates (47.1% vs. 35.7%; P=0.17), implantation rates (23.4% vs. 18.1%, P=0.24), live birth delivery rates (41.4% vs. 27.1%, P=0.08), and multiple pregnancy rates (21.2% vs. 16.0%, P=0.74) were higher in group 1 than in group 2. Group 1 had a lower miscarriage rate than group 2 (5.7% vs. 8.6%; P=0.75). However, these differences were not statistically significant between the two groups. Conclusions: Administration of a single dose of GnRH agonist in addition to regular natural micronized vaginal progesterone as luteal support in GnRH antagonist protocol cycles marginally improves implantation rates, clinical pregnancy rates, and live birth delivery rates. However, more studies with higher sample sizes are needed before any conclusive statements about GnRH agonist as luteal phase support can be made.

Guideline No. 315: Prevention of Ovarian Hyperstimulation Syndrome

Summary Statements1.The particular follicle-stimulating hormone formulation used for ovarian stimulation does not affect the incidence of ovarian hyperstimulation syndrome. (I)2.Coasting may reduce the incidence of severe ovarian hyperstimulation syndrome. (III)3.Coasting for longer than 3 days reduces in vitro fertilization pregnancy rates. (II-2)4.The use of either luteinizing hormone or human chorionic gonadotropin for final oocyte maturation does not influence the incidence of ovarian hyperstimulation syndrome. (I)5.There is no clear published evidence that lowering the human chorionic gonadotropin dose will result in a decrease in the rate of ovarian hyperstimulation syndrome. (III)6.Cabergoline starting from the day of human chorionic gonadotropin reduces the incidence of ovarian hyperstimulation syndrome in patients at higher risk and does not appear to lower in vitro fertilization pregnancy rates. (II-2)7.Avoiding pregnancy by freezing all embryos will prevent severe prolonged ovarian hyperstimulation syndrome in patients at high risk. (II-2)8.Pregnancy rates are not affected when using gonadotropin-releasing hormone (GnRH) agonists in GnRH antagonist protocols for final egg maturation when embryos are frozen by vitrification for later transfer. (II-2) Recommendations1.The addition of metformin should be considered in patients with polycystic ovarian syndrome who are undergoing in vitro fertilization because it may reduce the incidence of ovarian hyperstimulation syndrome. (I-A)2.Gonadotropin dosing should be carefully individualized, taking into account the patient’s age, body mass, antral follicle count, and previous response to gonadotropins. (II-3B)3.Cycle cancellation before administration of human chorionic gonadatropin is an effective strategy for the prevention of ovarian hyperstimulation syndrome, but the emotional and financial burden it imposes on patients should be considered before the cycle is cancelled. (III-C)4.Gonadotropin-releasing hormone (GnRH) antagonist stimulation protocols are recommended in patients at high risk for ovarian hyperstimulation syndrome (OHSS). The risk of severe OHSS in patients on GnRH antagonist protocols who have a very robust ovarian stimulation response can be reduced by using a GnRH agonist as a substitute for human chorionic gonadotropin to trigger final oocyte maturation. (I-B)5.A gonadotropin-releasing hormone (GnRH) antagonist protocol with a GnRH agonist trigger for final oocyte maturation is recommended for donor oocyte and fertility preservation cycles. (III-C)6.Albumin or other plasma expanders at the time of egg retrieval are not recommended for the prevention of ovarian hyperstimulation syndrome. (I-E)7.Elective single embryo transfer is recommended in patients at high risk for ovarian hyperstimulation syndrome. (III-C)8.Progesterone, rather than human chorionic gonadotropin, should be used for luteal phase support. (I-A)9.Outpatient culdocentesis should be considered for the prevention of disease progression in severe ovarian hyperstimulation syndrome. (II-2B)

P-205 comparison of GnRH antagonist protocol versus progestin-primed protocol in high ovarian responders: a propensity score-matched study

Abstract Study question To compare the clinical outcomes and cost-efficiency between gonadotropin-releasing hormone (GnRH) antagonist and progestin-primed ovarian stimulation (PPOS) protocol in high ovarian responders. Summary answer Comparing with PPOS protocol, GnRH antagonist protocol was associated with shorter time to live birth, higher OHSS rate and less cost in high responders. What is known already For high ovarian responders prone to develop ovarian hyperstimulation syndrome (OHSS), the best option should be the GnRH antagonist, as it has been shown to significantly reduce the incidence of OHSS. By applying ovarian stimulation using the combination of antagonist with agonist trigger and embryos freezing, OHSS can be erased. PPOS protocol in combination with a freeze-all strategy has proved to be a valid alternative to the conventional stimulation protocols. Recent studies showed that comparing with antagonist protocol, a lower cumulative live birth rate (CLBR) was associated with PPOS in general population, with no data available in high responders. Study design, size, duration This was a propensity score-matched retrospective cohort study. From Jan. 2016 to Jan. 2023, 5810 patients with AMH &amp;gt; 3.67ng/ml undergoing IVF treatment with antagonist or PPOS protocol at the Sixth Affiliated Hospital of Sun Yat-sen University were screened. Participants/materials, setting, methods Two-to-one propensity score matching was performed with a caliper of 0.2. After matching, 540 patients in GnRH antagonist group and 270 patients in PPOS group were included. Generalized estimated equation regression was applied to evaluate the impact of independent variables on the CLBR. Main results and the role of chance No significant difference in baseline characteristics was found in two groups. The OHSS (moderate to severe) rate was significantly higher in the GnRH antagonist group than in the PPOS group (7% vs. 3%). The clinical pregnancy rate and live birth rate per transfer were comparable between the two groups. After excluding patients who didn't achieve live birth but had surplus embryos, the CLBR was comparable between the antagonist and PPOS group (67.4% vs. 61.0%; Risk ratio = 1.106; 95% confidence interval [CI], 0.973-1.256, P = 0.109), and the generalized estimated equation regression analysis also showed that protocol selection had no significant impact on CLBR. The average time to live birth (TTLB) in the antagonist group was significantly shorter than the PPOS group (11.45 months vs. 12.13 months, P &amp;lt; 0.05). Besides, the average cost in the antagonist group was about $4933, while it was about $5465 in the PPOS group. Limitations, reasons for caution Although we recruited a large sample size and the sophisticate statistical analysis method, this was a retrospective study with an intrinsic limitation, besides more patients in the PPOS group had surplus embryos than in the antagonist group (24.1% vs. 19.8%). Further prospective RCTs are required to confirm our findings. Wider implications of the findings For infertile patients with high ovarian reserve, the clinical outcomes were comparable between GnRH antagonist and PPOS group. The antagonist group was associated with a shorter TTLB and more cost-effective, while the PPOS was associated with a lower OHSS rate. Trial registration number Not Applicable

P-611 Progestin-Primed Ovarian Stimulation is a non-inferior alternative to the GnRH Antagonist Protocol in patients undergoing ovarian stimulation: a propensity score weighting analysis

Abstract Study question To evaluate the effectiveness of the progestin-primed ovarian stimulation (PPOS) protocol versus the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol in ovarian stimulation. Summary answer The PPOS protocol with dydrogesterone provided similar embryo outcomes to the GnRH-ant protocol. The serum LH concentration during ovarian stimulation using PPOS was well-controlled. What is known already Since Yanping Kuang's proposal PPOS in 2015, several studies on the effectiveness of this treatment regimen have been published. Although it has been suggested that outcomes of the PPOS regimen were comparable to those of GnRH-ant regimen, the findings were limited due to differences in study design, patient characteristics, dosage and type of progestins. While medroxyprogesterone acetate is often used in PPOS studies, dydrogesterone has seen far less popularity. Additionally, dydrogesterone is a relatively weak LH inhibitor compared to MPA, leading to concern about the increased incidence of unexpected LH surge Study design, size, duration We conducted a retrospective study among women who underwent In Vitro Fertilization at the Assisted Reproduction Center, Tam Anh General Hospital, Vietnam from January 1st, 2022 to October 10th, 2022. Participants/materials, setting, methods We included 804 patients who underwent ovarian stimulation, among which 208 used the PPOS protocol with dydrogesterone (30 mg dydrogesteron per day from the beginning of stimulation until the trigger-day) and 598 women used the GnRH-ant protocol (cetrorelix 0.25 daily, from day 6 of ovarian stimulation until the trigger-day). In addition to unadjusted analysis, we used propensity score weighting to account for confounding that might possibly remain. Main results and the role of chance Baseline characteristics were comparable in both groups. In both unadjusted and adjusted analysis, the mean number of good cleavage embryos in PPOS (6.33) was non-inferior to GnRH-ant (6.44; unadjusted ratio of two means 1.02, 95%CI 0.92, 1.13). The trigger-day estradiol level in patients with PPOS was higher (4,420 vs 3,830 pmol/L in GnRH-ant) despite similar total follicle stimulating hormone dose and fewer days of ovarian stimulation. The overall number of oocytes retrieved, the number of MII oocytes, the number of cleavage embryos, the number of blastocysts, and the number of good blastocysts were comparable between the two protocols. None of the PPOS patients had an unexpected LH surge, and serum LH levels decreased slightly during ovarian stimulation. Limitations, reasons for caution Due to the nature of the retrospective study design, we did not record the progesterone level on the trigger-day in the PPOS regimen; therefore, identifying LH surge based on LH and progesterone levels is not feasible. Furthermore, we did not study the outcomes of embryo transfer. Wider implications of the findings These results supported the use of PPOS with dydrogesterone as a cheap and effective alternative for clinicians in clinical practice. In patients with an indication for freeze-all embryo, the PPOS protocol could be recommended. Trial registration number Not Applicable

P-638 Impact of amphiregulin on oocyte maturation and embryo quality in patients with the polycystic ovarian syndrome.

Abstract Study question Does the concentration of amphiregulin in the follicular fluid affect oocyte maturation and embryo quality in patients with polycystic ovarian syndrome? Summary answer The concentration of amphiregulin affects oocyte maturity and embryo quality in patients with polycystic ovarian syndrome and can be used as a predictive biomarker. What is known already Polycystic ovary syndrome (PCOS) is a common metabolic dysfunction and heterogeneous endocrine disorder in women of reproductive age. Epidermal growth factor receptors and their ligands, such as amphiregulin, which are expressed in female reproductive tissues, have been shown to regulate various important reproductive functions. Amphiregulin is reportedly involved in oocyte maturation through autocrine and paracrine mechanisms, however, the impact of amphiregulin on oocyte maturity end embryo quality in patients diagnosed with POCS which goes under controlled ovarian stimulation remains unknown. Determination of potential biomarkers might be the key to successful IVF outcomes. Study design, size, duration The study consisted of a total of 87 oocytes obtained from 30 patients who underwent ICSI at UKS Homburg (Germany) between October 2021 and March 2022. Fifteen patients were diagnosed with polycystic ovary syndrome while the other fifteen were fertile without any diagnosis. For the study purpose, follicles were aspirated separately, and the follicular fluid was centrifuged for 5 min at 1,500×g. After the preparation, the supernatant was removed and stored at -20 °C until analysis. Participants/materials, setting, methods Concentrations of amphiregulin in follicular fluid were determined by using a commercially available sandwich ELISAkit (Duo Set; R&amp;D Systems Inc., Minneapolis) in accordance with the manufacturer’s instructions. Good embryo quality (GQE) on day 3 was defined as a 7-9 cell stage embryo with less than 25% of fragmentation and with equally sized blastomeres. Between-group comparisons were conducted with a Mann-Whitney test. Logistic regression analysis was used to determine the influence of amphiregulin on studied parameters. Main results and the role of chance The mean age of all patients was 33.5 (±5.2) years. Patients included in the study were stimulated according to a gonadotropin-releasing hormone (GnRH) antagonist protocol. Out of the 87 oocytes, 59 (67.8%) were at MII stadium, 13 (14.9%) were at MI and 8 (9.1%) were at GV stadium. ICSI was done only with MII and MI oocytes and the fertilization rate was 70.1% (61 oocytes were fertilized out of 72). Obtained results showed that concentrations of amphiregulin were significantly lower in follicular fluid of PCOS patients [(107.00(51.95-131.00) ng/mL vs 115.27(43.19-209.51) ng/mL) respectively; p = 0.024]. Data comparisons between mature and immature oocytes indicated that amphiregulin concentration was significantly higher in follicles where mature oocytes were developed [(117.50 (65.99-209.51) ng/mL vs 81.75(43.19-128.20) ng/mL) respectively; p &amp;lt; 0.0001]. Additionally, logistic regression analysis confirmed the positive effect of amphiregulin concentration on oocyte maturity (p &amp;lt; 0.001). Out of the 61 fertilized oocytes, 36 (59.0%) formed good-quality embryos. Additional analysis indicated that oocytes that developed into good-quality embryos came from follicles where amphiregulin concentrations were significantly higher compared to those that developed into poor-quality embryos [(124.05 (91.88-209.51) ng/mL. vs 86.72(43.19-109.40) ng/mL) respectively; p &amp;lt; 0.001]. Logistic regression analysis confirmed the positive effect of amphiregulin concentration on embryo quality (p &amp;lt; 0.01). Limitations, reasons for caution The limitation of the presented study was the relatively small patient cohort. Although the pregnancy rate in the presented study was 27.8 % , single embryo transfer was not performed, therefore further research should link amphiregulin concentrations with the pregnancy rate as well. Wider implications of the findings Results obtained in the study might be useful for further handling of PCOS patients since the literature already confirmed that PCOS patients produce an increased number of mature oocytes, so culture medium-containing amphiregulin might be a future solution for those patients. Trial registration number 146/19

Elevated follicular cortisone level is a negative predictor of clinical pregnancy in women undergoing fresh embryo transfer

BackgroundAlthough numerous studies have investigated the potential correlation between follicular fluid (FF) steroid concentrations and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes, few have accounted for the effect of controlled ovarian hyperstimulation regimes on FF steroid concentrations. ObjectiveTo comprehensively compare follicular steroid concentrations between women stimulated with gonadotropin-releasing hormone agonist (GnRHa) and antagonist (GnRHant) protocols and to explore the associations between FF steroid concentrations and IVF/ICSI outcomes. MethodsA total of 295 infertile women undergoing IVF/ICSI from January 2018 to May 2020 were enrolled. Eighty-four and 211 women received GnRHa and GnRHant protocols, respectively. Seventeen steroids in FF were quantified by liquid chromatography tandem mass spectrometry (LC–MS/MS), and the correlation of follicular steroids with clinical pregnancy was explored. ResultsFollicular steroid concentrations were similar between the GnRHa and GnRHant groups. Follicular cortisone levels were adversely associated with clinical pregnancy in fresh embryo transfers. Receiver operating characteristic (ROC) analysis revealed an area under the ROC curve (AUC) of 0.639 (95% confidence interval = 0.527–0.751, p = 0.025) for predicting non-pregnancy, with an optimal cutoff value of 15.81 ng/mL (sensitivity = 33.3%, specificity = 94.1%). Women with FF cortisone concentrations ≥15.81 ng/mL were fifty times less likely to achieve clinical pregnancy in fresh embryo transfers than those with FF cortisone levels below this threshold (adjusted OR = 0.019, 95% confidence interval = 0.002–0.207, p = 0.001) after adjusting for age, body mass index, baseline serum progesterone levels, serum levels of luteinizing hormone, estradiol and progesterone on human chorionic gonadotropin day, ovarian stimulation protocols, and the number of transferred embryos. ConclusionsThere was no significant difference in intrafollicular steroid levels between GnRHa and GnRHant protocols, and intrafollicular cortisone level ≥15.81 ng/mL was found to be a strong negative predictor of clinical pregnancy in fresh embryo transfers with high specificity.

High anti-Mullerian hormone level is adversely associated with cumulative live birth rates of two embryo transfers after the first initiated cycle in patients with polycystic ovary syndrome.

Anti-Mullerian hormone (AMH) has been recently identified as a potential predictor of live birth rates (LBRs) following assisted reproductive technology (ART) treatment. This study aimed to investigate the association between AMH levels and the outcomes of in vitro fertilization (IVF) in patients with polycystic ovary syndrome (PCOS). Patients with PCOS initiating their first ovarian stimulation under the gonadotropin-releasing hormone antagonist protocol at the Guangdong Women and Children Hospital, China, were enrolled from November 2014 to September 2018.A total of 157 patients who underwent fresh embryo transfer (ET) cycles were included in group A, whereas 187 patients who underwent frozen-thawed ET cycles were included in group B. After the failure of the first ET cycle, 94 patients underwent the second ET cycle with frozen-thawed embryos. Of these 94 patients, 52 had failed the first fresh ET cycle (group C) and 42 had failed the first frozen-thawed ET cycle (group D). Successful embryo transfer was defined as live birth. This retrospective cohort study addressed the association between AMH levels and pregnancy outcomes using logistic regression approaches. After adjusting for age, body mass index, antral follicle counts, baseline follicle-stimulating hormone levels and baseline progesterone levels, LBRs were compared among the four groups and the cumulative live birth rate after two embryo transfers (TCLBR) was calculated. The LBRs showed no differences among the four groups. Higher serum AMH levels were found to be associated with a lower TCLBR [adjusted OR 0.937 (0.888-0.987), P = 0.015]. In patients who underwent the second ET cycle, LBRs were inversely proportional to AMH levels [crude OR 0.904 (0.828-0.986), P = 0.022 versus adjusted OR 0.845 (0.754-0.946), P = 0.004, respectively]. In addition, the LBR was approximately 61%-78% lower in the group with AMH levels of >12 ng/mL [crude OR 0.391 (0.168-0.912), P = 0.030 versus adjusted OR 0.217 (0.074-0.635), P = 0.005, respectively]. Among PCOS patients high AMH level (>12 ng/ml) is found to be associated with low TCLBR and low LBR of the second embryo transfer cycles. The results provide limited clinical inferences and warrant further investigation.

Effect of oral contraceptives pretreatment on cumulative clinical pregnancy of oocyte retrieval cycle in polycystic ovary syndrome women with gonadotropin releasing hormone antagonist protocol

Objective: To investigate the effect of pretreatment with oral contraceptives (OC) on cumulative clinical pregnancy of oocyte retrieval cycle in polycystic ovary syndrome (PCOS) women with gonadotropin releasing hormone (GnRH) antagonist protocol. Methods: A retrospective cohort study was conducted to analyze PCOS women who underwent in vitro fertilization-embryo transfer (IVF-ET)/intracytoplasmic sperm injection (ICSI) treatment with GnRH antagonist in the Reproductive Medical Center of Peking University First Hospital from January 2017 to December 2020. A total of 225 patients were divided into OC pretreatment group (119 patients) and non-pretreatment group (106 patients), according to whether they received OC before GnRH antagonist protocol. The baseline information, IVF, and pregnancy outcomes of the two groups were compared. A multivariate logistic regression model was used to analyze the effect of OC pretreatment on cumulative clinical pregnancy of the oocyte retrieval cycle. Results: The age of 225 patients was (31.1±3.3) years old. The ages of patients in the OC pretreatment group and non-pretreatment group were (31.0±3.3) and (31.2±3.3) years old (P>0.05), respectively. The cumulative clinical pregnancy rate of oocyte retrieval cycle was significantly higher in the OC pretreatment group than that in the non-pretreatment group (79.8%, 95 patients; 67.0%, 71 patients; P=0.029). Age <35 years old (OR=3.199, 95%CI: 1.200-8.531, P=0.020), OC pretreatment (OR=3.129, 95%CI: 1.305-7.506, P=0.011), number of oocytes retrieved (OR=1.102, 95%CI: 1.007-1.206, P=0.035) and number of high-quality embryos (OR=1.536, 95%CI: 1.205-1.957, P=0.001) were related factors for the cumulative clinical pregnancy of oocyte retrieval cycle. Conclusions: OC pretreatment before GnRH antagonist protocol can significantly increase the cumulative clinical pregnancy rate of oocyte retrieval cycle in women with PCOS. Age <35 years old, OC pretreatment, the number of oocytes retrieved, and the number of high-quality embryos were related factors for the cumulative clinical pregnancy of oocyte retrieval cycle.

Correlation between the number of oocytes and the increase of polyspermy rate in IVF cycles

Aims: To investigate the association between the number of oocytes and the polyspermy rate following in vitro fertilization (IVF) treatment. Materials and methods: 376 IVF cycles with gonadotropin-releasing hormone (GnRH) antagonist protocol in the reproductive center of our hospital were retrospectively included in the analysis, which were divided into five groups according to the number of oocytes retrieved. Group A (78 cases):1–5 oocytes, group B (118 cases): 6–10 oocytes, group C (94 cases): 11–15 oocytes, group D (55 cases): 16–20 oocytes, group E (31 cases): ≥21 oocytes. According to polyspermy rate, 376 IVF cycles were then divided into two groups. Normal level polyspermy group (170 cases): polyspermy rate<6%, and high level polyspermy group (206 cases): polyspermy rate ≥ 6%. The variables with p < .10 in univariate analysis were incorporated into the multiple logistic regression model to control the confounding, and the effect of the number of oocytes on the increase of polyspermy rate was analyzed. Results: Multiple logistic regression analysis showed that after adjustment for confounding factor, the increase risk of polyspermy rate in group B, C, D and E was 1.763, 3.804, 2.021 and 3.208 times of that in group A respectively (OR = 1.763, p = .085; OR = 3.804, p = .001; OR = 2.021, p = .158; OR = 3.208, p = .068, respectively). Conclusion: This result demonstrated that when the oocyte number is 15 or less, the more the oocyte number, the greater the increase risk of polyspermy rate. While, there appears to be little increase risk of polyspermy rate when the oocyte number is more than 15.