GnRH Agonist Protocol Research Articles

#304 : Comparing GnRH Agonist and GnRH Antagonist Protocols for IVF-ET Outcomes in Patients with Endometriosis: A Meta-Analysis

Background and Aims: Endometriosis is known to have detrimental effects on fertility, but there is no consensus on the optimal stimulation protocol for IVF-ET in patients with endometriosis. The study aimed to compare the IVF outcomes of gonadotropin-releasing hormone (GnRH) agonist protocols versus antagonist protocols in patients diagnosed with endometriosis. Method: We performed a meta-analysis of studies that compared IVF outcomes of GnRH agonist versus antagonist protocols in patients with endometriosis. Through literature search, we retrieved 222 articles, and the last search date was April 7, 2023. Among them, six studies which met inclusion criteria were eligible for final analysis. The primary outcome was clinical pregnancy. Random effects and fixed effects models were applied according to I2 statistics. Results: The use of GnRH agonist was associated with higher clinical pregnancy rate (Odds ratio (OR) 1.61, 95% CI 1.35–1.93, 6 studies, [Formula: see text]<0.00001, I2=16%), higher live birth rate (OR 1.75, 95% CI 1.32–2.33, 3 studies, [Formula: see text]<0.0001, I2=12%), and similar miscarriage rate. The total dose of gonadotropin did not differ between the two methods, but the GnRH agonist protocol had a longer duration of stimulation (WMD 1.34, 95% CI 0.44–2.24, 5 studies, I2=98%), retrieved more oocytes (WMD 2.23, 95% CI 0.58–3.88, 3 studies, [Formula: see text]=0.0008, I2=97%), more MII oocytes (WMD 2.81, 95% CI 2.34–3.28, 3 studies, [Formula: see text]<0.00001, I2=0), and more embryos (WMD 1.90, 95%CI 1.13–2.67, 3 studies, [Formula: see text]<0.00001, I2=68%). Conclusion: Patients with endometriosis may benefit from using GnRH agonist protocol in the IVF-ET cycle, as it may be associated with a higher clinical pregnancy rate and live birth rate. Even though the stimulation duration is longer, more oocytes, mature oocytes, and embryos may be expected. Although the findings of this study may be potentially beneficial for clinicians, it is crucial to conduct additional randomized prospective trials with larger cohorts to further validate the results.

#21 : Letrozole Can Be a Good Adjuvant for In Vitro Fertilization (IVF) Procedure in Patient with Ovarian Endometriosis

Background and Aims: To evaluation the pregnancy rate in IVF procedure with letrozole in patient with ovarian endometrioma. Method: Prospective study performed by single physician at primary fertility center. From August 2016 to November 2019, 109 cycles of IVF were performed from couples who were diagnosed as endometrioma. 40 women were diagnosed during ovarian cystectomy, 69 were by transvaginal ultrasonography. In 64 cycles, gonadotrophic releasing hormone (GnRH) antagonist protocol was used, and in another 45 cycles, gonadotrophin releasing hormone agonist (GnRHa) protocol were applied. In every cycle, 10 mg of letrozole was added from the start of gonadotrophin till the end of ovarian stimulation. Results: Women’s age was 36.10±3.67, and the number of their previous IVF cycle was 2.66±1.63. AMH was 2.30±2.31, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) on the third day of menstruation were 9.40±5.26, 7.81±4.60 and 54.1±44.2. Start dosages and total dosages of recombinant FSH were 314.32±74.99 and 2541.37±992.77, and serum E2 and progesterone on trigger day were 1220.06±1072.49 and 0.92±0.79. The endometrial thickness was 9.20±1.46. The number of obtained oocytes was 9.05±5.94 and metaphase II(M2) oocytes were 6.71±4.12. 1.91±0.42 embryos were transferred to the uterine cavity and 2.68±2.58 surplus embryos were cryopreserved. Pregnancy rate was diagnosed if serum beta human chorionic gonadotrophin (hCG) level was above 5 ng/ml on 14th day after oocyte retrieval, and the result was 44.95% (49/109). Clinical pregnancy rate which was defined if gestational sac was visualized by transvaginal ultrasonography after at least 21st days after oocyte retrieval, and the result was 24.77% (27/109). Conclusion: In IVF procedure for the patients with ovarian endometrioma, just adding letrozole to conventional controlled ovarian hyperstimulation protocol can reduce serum peak E2 level without make harmful effect on uterine endometrium, and result in comparable pregnancy rate.

#20 : Follitropin Delta Can Play a Good Role in Both Patients with High Serum AMH Level and Patients with Low Serum AMH Level in IVF

Background and Aims: To evaluation clinical efficacy of follitropin delta in IVF procedure for Korean. Method: This is a prospective study performed by single physician at primary fertility center. From December 2020 to November 2021, total 82 cycles of IVF were performed. 70% of total cycles was performed using gonadotrophic releasing hormone (GnRH) antagonist protocol, and another 30% of cycles were gonadotrophin releasing hormone agonist (GnRHa) protocol. Results: Average duration of infertility was 2.2± 1.5 years. AMH levels were 2.4± 2.4 ng/ml. The number of obtained oocytes were 8.9± 5.0. Mean daily dose of follitropin delta were 10.3± 2.5 mcg, and total dosage were 121.8± 25.5 mcg. Duration of stimulation were 9.9± 2.0 days. Biochemical pregnancy rate was 38% and clinical pregnancy rate was 27%. No cases of severe ovarian hyperstimulation syndrome were developed. Conclusion: For both patients with good ovarian reserve, and the patients with poor ovarian reserve, follitropin delta can play a good role. With its discriminative fixed dosing protocol, follitropin delta gives more convenient way for both physicians and patients with minimal risk of OHSS, without having detrimental effect on pregnancy rate.

#265 : Oocyte Outcome After Laparoscopy Cyst Drainage Procedure Before IVF Stimulation in Endometriosis Patients

Background: Endometriosis is the presence of endometrial-like tissue outside the uterine cavity. In late years, in order to control endometriosis, we often performed cystectomy either laparoscopy or laparotomy. However, cystectomy done in endometriosis patient undergoing IVF can decrease the AMH also the quality of the oocytes, thus cyst drainage procedures (with the insertion of hemostate agent) was considered as a replacement for cystectomy in endometriosis patients before they begin the IVF stimulations. Aims: To see the effect of laparoscopic cyst drainage with the insertion of an absorbable hemostate towards the quality of the oocytes in endometriosis patient Method: A retrospective cohort study took place at Center of Reproductive Medicine and Andrology Bocah Indonesia in Primaya Hospital, Tangerang between January 2021 and December 2022. Patients with endometriosis cysts before IVF stimulations were all included. Excluded were those declining to participate and with incomplete case notes. All of the subjects used ultra-long GnRH agonist protocols. A medical committee approved the study and all women provided written informed consent. Results: 18 patients were included in the analysis (11 undergoing laparoscopy cyst drainage and insertion absorbable hemostatic agent’s vs 7 undergoing only cystectomy). There was a statistically significant difference in AMH values in patients with cystectomy vs drainage with an absorbable hemostatic agent in AMH values 1.002 ± 0.76 to 0.77 ± 0.76 vs 1 (0.30 – 3.31) to 1 (0.30 – 4.00) (p=0.003 vs p =0.678). Among those, there was no significant difference between cystectomy and drainage with the maturation of oocyte (p=0.231 vs p=0.381). On the other side, there was a significant difference between cyst drainage and cystectomy resulting in good embryos in cleavage (p=0.038). One of the patients has a naturally conceive pregnancy after a cyst drainage procedure. Conclusion: Endometriosis with laparoscopic cyst drainage procedure can maintain AMH level, reduce inflammation, and proliferation of lesions so it can maintain better quality of oocytes.

Analysis of controlled ovarian hyperstimulation protocols in women over 35 years old with poor ovarian response: a real-world study

The objective of this study was to investigate the optimal controlled ovarian hyperstimulation (COH) protocol for patients aged 35 and above with poor ovarian response (POR), utilizing real-world data. This retrospective cohort study examined clinical information from a total of 4256 patients between January 2017 and November 2022. The patients were categorized into three groups: modified GnRH agonist protocol (2116 patients), GnRH antagonist protocol (1628 patients), and Mild stimulation protocol (512 patients). Comparative analysis was conducted on clinical variables and pregnancy outcomes across the three groups. The GnRH agonist protocol was associated with a higher number of oocyte number (4.02 ± 2.25 vs. 3.15 ± 1.52 vs. 2.40 ± 1.26, p < 0.001), higher number of transferable embryos (1.73 ± 1.02 vs. 1.35 ± 1.22 vs. 1.10 ± 0.86, p = 0.016), higher cumulative live birth rate 28.50(603/2116) vs. 24.94(406/1628) vs. 20.51(105/512), p < 0.001) than GnRH antagonist protocol and Mild stimulation protocol, the Mild stimulation protocol was associated with a higher miscarriage rates 16.27(62/381) vs. 16.61(48/289) vs. 32.22(29/90), p = 0.001) than the other two groups. Therefore, it can be concluded that all three protocols can be used in patients over 35 years old with poor ovarian response. However, if patients require more frozen-thawed embryo transfers to achieve better cumulative live birth rates, the modified GnRH agonist protocol may be the preferable option.

Comparison between the modified long gonadotropin-releasing hormone agonist protocol and the non-downregulation protocol in POSEIDON groups: a propensity score matching retrospective cohort study.

In vitro fertilization (IVF) is the main technique to address the infertility issue in the patient-oriented strategy encompassing individualized oocyte number (POSEIDON) population. Adopting appropriate protocols for assisted reproduction technologies (ART) cycles in the POSEIDON group may attain more favorable pregnancy outcomes. This study aimed to compare the effectiveness of modified long gonadotropin-releasing hormone agonist protocol and non-downregulation protocol in POSEIDON patients undergoing ART, and to identify the factors affecting the pregnancy outcomes in this group. This study was designed as a propensity score-matched (PSM) retrospective analysis. The study cohort consisted of 910 patients diagnosed with ovarian hyporesponsiveness and treated by IVF from January 2020 to June 2022. They were followed up until the transfer of the last embryo of the IVF cycle and/or pregnancy at 12 weeks. The study was conducted at the Center of Reproductive Medicine, Tongji Medical College, Wuhan Union Hospital, Huazhong University of Science and Technology. The patients were divided into Group I and Group II. Group I was treated with modified long gonadotropin-releasing hormone agonist protocol while Group II was put on a non-downregulation protocol. Propensity score matching (PSM) was used to select patients for each group. The subjects were compared in terms of the baseline level, process of controlled ovarian hyperstimulation, and pregnancy outcomes. Binary logistic regression analysis was performed to assess the difference in the cumulative pregnancy rate between the two groups. Of the 910 POSEIDON patients who underwent IVF, 213 received the modified long gonadotropin-releasing hormone agonist protocol and 697 were subjected to the non-downregulation protocol. From the original cohort, PSM matched 174 pairs of patients. No statistically significant difference was found in total gonadotropin (Gn) dose between the two PSM groups, but the average daily Gn dose was lower in Group I and the duration of Gn lasted longer. The number of retrieved oocytes, the number of metaphase II (MII) ooctyes retrieved, normal fertilization, and normal cleavage embryos was significantly higher in Group I than in Group II, but there existed no significant difference in the number of high-quality embryos between the two groups. The single-cycle CPR (cumulative pregnancy rate) was higher in Group I than in Group II (for Group I: before PSM, CPR = 52.6%; after PSM, CPR = 51.7%; for Group II: before PSM, CPR = 34.0%; after PSM, CPR = 34.5%), and the difference was statistically significant. A binary logistic regression analysis in the unmatched patients showed that the CPR of Group II was 0.486 times that of Group I (95% CI: 0.303 to 0.779). The modified long gonadotropin-releasing hormone agonist protocol can be used as an optimal protocol for IVF or ICSI (Intracytoplasmic sperm injection) in POSEIDON patients. Level III.

Clinical evidence of growth hormone for infertile women with diminished ovarian reserve undergoing IVF: a systematic review and meta-analysis.

To appraise the current randomized clinical trials (RCTs) for evidence of the association of growth hormone (GH) with improved outcomes in infertile women with diminished ovarian reserve (DOR) undergoing in vitro fertilization (IVF). Relevant RCTs published in Chinese or English were identified through a comprehensive search of nine databases from the period of database inception to April 20, 2023. We included trials investigating adjuvant GH during ovarian stimulation and reported the subsequent outcomes. The group with adjuvant GH treatment and the group without adjuvant GH treatment were set up as the trial and control groups, respectively. The quality of RCTs was measured according to the Cochrane Collaboration Handbook. Of the 579 studies initially identified, 10 RCTs comprising 852 infertile women with DOR were included. The GH dose of individual trials ranged between 3 and 5 IU/day. Overall, we judged the trials to be at high risk of bias in the blinding domain. Pooled results showed that GH was associated with an increased clinical pregnancy rate (RR = 1.63, 95%CI [1.31, 2.03], p < 0.0001) and a greater number of oocytes retrieved (MD = 0.91, 95%CI [0.47, 1.35], p < 0.0001). Favorable associations were also observed when ovarian stimulation was combined with GH therapy for improving the optimal embryos rate (RR = 1.84, 95%CI [1.30, 2.59], p = 0.0005) and the number of optimal embryos (MD = 0.28, 95%CI [0.08, 0.48], p = 0.005) along with reducing the cycle cancellation rate (RR = 0.46, 95%CI [0.24, 0.89], p = 0.02). Moreover, GH resulted in an increase in the fertilization rate (RR = 1.33, 95%CI [1.18, 1.50], p < 0.00001) and the embryo implantation rate (RR = 1.56, 95%CI [1.21, 2.01], p = 0.0006). In addition, there was a significant enhancement in estradiol levels (SMD = 1.18, 95%CI [0.46, 1.91], p = 0.001) and endometrial thickness (MD = 0.75, 95%CI [0.41, 1.09], p < 0.0001) on the day of hCG. With regard to the total number of days and total dose of gonadotrophins used, GH treatment was correlated with shorter days (MD = -0.26, 95%CI [-0.46, -0.06], p = 0.01) and lower dose (MD = -460.97, 95%CI [-617.20, -304.73], p < 0.00001) of gonadotrophins applied during ovarian stimulation. Furthermore, GH in conjunction with the GnRH antagonist protocol was more conducive to improving the number of oocytes retrieved when compared with the GnRH agonist protocol (p < 0.0001). Moreover, a notable association was also seen in IVF combined with GH more than or equal to 4.5 IU/day to increase the number of optimal embryos and estradiol levels on the day of hCG (p < 0.05). For infertile women with DOR undergoing IVF, adjuvant treatment with GH during ovarian stimulation protocols showed better clinical outcomes, shorter days and lower dosages of gonadotrophin required. Furthermore, well-designed RCTs are needed to verify our results in the future. https://www.crd.york.ac.uk PROSPERO (CRD42023421739).

Pregnancy outcome in long- versus short-acting gonadotropin-releasing hormone agonist cycles in participants with normal ovarian reserve: An RCT.

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.

Young obese patients may benefit from GnRH-a long protocol contributing to higher implantation rate and live birth rate of fresh IVF-ET cycles

IntroductionObesity has detrimental influences on women reproductive health. There is little experience in optimizing controlled ovarian hyperstimulation (COH) protocols to treat Chinese obese patients who are undergoing in vitro fertilization and embryo transfer (IVF-ET) therapy. MethodsThe clinical outcome differences were retrospectively analyzed among obese patients who received gonadotrophin-releasing hormone agonist (GnRH-a), GnRH antagonist (GnRH-ant), micro dose GnRH-a (mGnRH-a) and GnRH-a long protocol in IVF-ET cycle at Chengdu Jinjiang Hospital for Women's and Children's Health from January 2014 to December 2019. ResultsThe transplantation rate of the GnRH-a long protocol group (59.1%) was higher than that of the GnRH-ant (25.9%) and mGnRH-a (36.7%) groups. The total live birth rate of the GnRH-a long protocol group (46.2%) was higher than that of the GnRH-a group (25.9%) and GnRH-ant group (40.3%). The total number of frozen embryos in the GnRH-ant group was higher than in the other groups (P < 0.05). After adjusting for confounding factors, the logistic regression analysis showed that the GnRH-a long protocol group had higher probabilities of biochemical pregnancy, clinical pregnancy, and live birth than the GnRH-a protocol group. The Gn dose in the mGnRH-a group was higher than the other three groups. Whether single or twin, there were similar neonatal outcomes among the four groups including premature birth rate, Apgar score, newborn weight, and length. ConclusionFor young obese patients undergoing IVF-ET, the GnRH-a long protocol for COH gives better pregnancy outcomes.

Presence of Adenomyosis Impairs Clinical Outcomes in Women Undergoing Frozen Embryo Transfer: A Retrospective Cohort Study.

(1) Background: The presence of adenomyosis among pregnant patients has been associated with a higher incidence of miscarriage and pregnancy complications. Although the role of adenomyosis in women undergoing in vitro fertilization (IVF) was investigated in several studies and demonstrated a potentially detrimental effect on live birth rates following IVF, most of them were small studies in which the adenomyosis diagnosis was not confirmed based on solid ultrasonographic criteria. (2) Methods: 3503 patients undergoing their first blastocyst frozen transfer through a hormonal replacement (HRT) FET cycle. Among them, 140 women had a confirmed diagnosis of adenomyosis based on the MUSA criteria. (3) Results: Adenomyosis patients were more likely to proceed with deferred FET compared with no-adenomyosis women (p = 0.002) and were significantly more likely to be treated with GnRH agonist pre-treatment (2 months) (p < 0.001). The presence of adenomyosis significantly decreased the clinical pregnancy rates (aOR 0.62, 95% CI: 0.39-0.98, p = 0.040) and live birth rates (aOR 0.46, 95% CI: 0.27-0.75, p = 0.003) and significantly increased the miscarriage rates (aOR 2.13, 95% CI: 0.98-4.37, p = 0.045). Multivariable logistic regression adjusting for age, autologous or donor oocytes, PGT-A, deferred FET, serum progesterone levels the day before FET, GnRH agonist pre-treatment, number of embryos transferred, and adenomyosis demonstrated that the use of the GnRH agonist protocol did not decrease or increase the miscarriage rate, clinical pregnancy rate, or live birth rate. (4) Conclusions: The presence of adenomyosis had a significant negative impact on the clinical outcomes of patients undergoing FET and was associated with higher miscarriage, lower clinical pregnancy, and live birth rates. GnRH agonist pre-treatment does not appear to improve clinical 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.

O-131 BEYOND: a randomised controlled trial comparing efficacy and safety of individualised follitropin delta dosing in GnRH agonist versus antagonist protocols for first ovarian stimulation cycle

Abstract Study question How does a long GnRH agonist versus a GnRH antagonist protocol affect ovarian response when using individualised fixed daily follitropin delta dose for ovarian stimulation? Summary answer BEYOND trial data demonstrates that individualised follitropin delta dosing is safe and effective in a long GnRH agonist protocol in women with AMH ≤35 pmol/L. What is known already Efficacy and safety of a fixed daily dose of follitropin delta, individualised based on bodyweight and anti-Müllerian (AMH), have been established in RCTs using a GnRH antagonist protocol. Preliminary study data shows that individualised follitropin delta is efficacious when used with a long GnRH agonist protocol (RAINBOW trial). There is no comparative data for efficacy and safety of individualised follitropin delta in a long GnRH agonist versus an antagonist protocol. Study design, size, duration This was a randomised, controlled, open-label, multi-centre trial comparing efficacy and safety of individualised follitropin delta dosing in a long GnRH agonist versus an antagonist protocol in participants undergoing their first ovarian stimulation for IVF/ICSI conducted between May 2019 and February 2022. The primary endpoint was the number of oocytes retrieved. Important secondary endpoints included ongoing pregnancy rates and adverse drug reactions, with a special focus on OHSS. A total of 437 participants were randomised. Participants/materials, setting, methods Participants, 18–40 years old with 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 agonist and antagonist protocols using a negative binomial regression model with age and AMH at screening as factors. The analyses were based on all randomised subjects, using a multiple imputation method for randomised subjects withdrawing before start of stimulation. Main results and the role of chance Of the 437 randomised subjects, 202 and 204 initiated ovarian stimulation with follitropin delta in the agonist and antagonist groups, respectively. Baseline mean data were: age, 32.3±4.3 years; AMH, 16.6±7.8 pmol/L, respectively. The number of oocytes retrieved was statistically significantly higher in the agonist (11.1±5.9) versus antagonist (9.6±5.5) group, 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 &amp;lt;35 years and patients with high ovarian reserve (AMH &amp;gt;15 pmol/L). Cycle cancellations (2.0% versus 3.4%) and transfer cancellations (13.7% versus 14.7%) were similar in both groups. Ongoing pregnancy rate (36.9% vs 29.1%; estimated difference: 7.74% [95% CI: –1.49; 16.97, p = 0.1002]) and other pregnancy outcomes were higher in the agonist versus antagonist protocol group, but the differences were not statistically significant. The most commonly reported adverse events (≥1% in either group) were similar in both groups (headache, OHSS, nausea, pelvic pain or discomfort, and abdominal pain). Incidence of early moderate/severe OHSS was low (1.5% versus 2.5%). Early pregnancy loss was similar between the groups (20% vs 24% of subjects with positive beta-hCG test, respectively). Limitations, reasons for caution Subjects with AMH &amp;gt;35 pmol/L were not enrolled. Clinicians should remain cautious when using a GnRH agonist protocol in patients with AMH &amp;gt;35 pmol/L (greater OHSS risk). OHSS incidence in the GnRH antagonist group may have been lower if a GnRH agonist trigger had been allowed. Wider implications of the findings In women with AMH ≤35 pmol/L, a fixed daily dose of follitropin delta (individualised according to bodyweight and AMH) showed similar efficacy when used in a long GnRH agonist protocol with no additional safety signals observed and no additional risk of OHSS versus follitropin delta used in an antagonist protocol. Trial registration number ClinicalTrials.gov identifier: NCT03809429; EudraCT number: 2017-002783-40

P-761 Live-birth and neonatal outcomes from BEYOND, a randomised controlled trial comparing efficacy and safety of individualised follitropin delta dosing in GnRH agonist versus antagonist protocols

Abstract Study question What are the live birth and neonatal outcomes following an individualised follitropin delta dosing regimen in either a long GnRH agonist or GnRH antagonist protocol? Summary answer Live birth rates and neonatal outcomes were similar, supporting the efficacy and safety of follitropin delta in both GnRH agonist and antagonist protocols. What is known already Follitropin delta is used for ovarian stimulation and is administered as a fixed daily dose, individualised based on bodyweight and anti-Müllerian (AMH) levels. Registrational trials for follitropin delta used a GnRH antagonist protocol. Preliminary study data shows that individualized follitropin delta is efficacious when used with a long GnRH agonist protocol (RAINBOW trial); however, there is no comparative data for the effects on live birth rates and neonatal outcomes with individualised follitropin delta in a long GnRH agonist versus an antagonist protocol. Study design, size, duration This RCT compared the efficacy and safety of individualised follitropin delta dosing using a long GnRH agonist versus an antagonist protocol and was conducted between May 2019 and February 2022. The trial was designed to describe potential differences in the number of oocytes retrieved between the two GnRH analogue protocols (reported separately). A total of 437 participants were randomised, with a post-trial follow-up period to 4 weeks after birth to record birth and neonatal outcomes. Participants/materials, setting, methods Participants were 18–40 years old with AMH ≤35 pmol/L, undergoing their first ovarian stimulation cycle for IVF/ICSI at specialist reproductive health clinics in Austria, Denmark, Israel, Italy, the Netherlands, Norway and Switzerland.Live birth rates were compared using a logistic regression model with age and AMH at screening as factors. Multiple imputation was used for randomised subjects withdrawing before start of stimulation. Subjects with transfer cancellation due to COVID-19 related reasons were excluded. Main results and the role of chance All participants had a single blastocyst transferred, except two participants ≥38 years in the agonist group who received a double transfer resulting in one dichorionic diamniotic pregnancy for one subject, complicated by maternal hypertension and preterm birth at 33 weeks. All 133 participants with ongoing pregnancies (138 fetuses) were included in this post-trial follow-up analysis. Late pregnancy losses (after confirmed ongoing pregnancy) were similar in the agonist and antagonist groups (2.7% and 1.7%). There were 130 live births (agonist group: 75 neonates [67 singletons; 4 sets of twins]; antagonist group: 60 neonates [58 singletons; 1 set of twins]). Estimated live-birth rates were 35.8% and 28.7% in the agonist and antagonist groups, respectively, per started cycle (treatment difference 7.15%; 95% CI: –2.02; 16.31; p = 0.1265). There were two neonatal deaths in the agonist group – a set of monochorionic twins born at gestational age 24 weeks + 2 days died shortly after birth due to prematurity. The two treatment groups were comparable with respect to neonatal health data for singletons and twins, and incidence of congenital malformations (2.7% and 3.3%, respectively). Neonatal admissions to intensive care units were similar for both groups (10 and six neonates, respectively). Limitations, reasons for caution Double blastocyst transfer was permitted for participants ≥38 years with no good-quality blastocysts. Neonatal health is dependent on singleton/twin status. Outcomes of transfers with cryopreserved blastocysts were not followed up – the cumulative live birth rates and neonatal outcomes after cryo-transfer are not known. Wider implications of the findings The safety profile of individualised follitropin delta dosing was similar in GnRH agonist and antagonist protocols. Live birth rates following individualised follitropin delta were also similar for both GnRH protocols. There were no safety concerns with respect to the neonatal health after ovarian stimulation with follitropin delta. Trial registration number ClinicalTrials.gov identifier: NCT03809429; EudraCT number: 2017-002783-40

P-671 Comparing clomiphene citrate/ flexible GnRH antagonist vs ultrashort flare GnRH agonist protocols for controlled ovarian stimulation in poor ovarian reserve patients

Abstract Study question How do Clomiphene citrate (CC)/ flexible GnRH antagonist and ultrashort flare GnRH agonist protocols compare in poor ovarian reserve patients (POSEIDON groups 3 &amp; 4)? Summary answer In poor ovarian reserve patients, irrespective of age, use of CC / flexible antagonist vs ultrashort flare protocol significantly reduces gonadotrophin consumption and stimulation duration. What is known already Poor responders constitute 47% of ART patients and up to 65% of these have diminished ovarian reserve. Despite the various treatment options available, lack of good quality evidence to enable recommendation of a particular protocol or adjuvant continues to pose a challenge to their effective management. The need for multiple stimulations for pooling up embryos also makes effective cost of treatment an added concern in them. Study design, size, duration An open label, multi centric, randomized controlled study was conducted over a period of 1 year recruiting 116 women having AMH &amp;lt;1.2ng/dl and antral follicle count (AFC) &amp;lt;5 who were further analysed in POSEIDON 3 and 4 subgroups. Patients were randomized to 1 of 2 groups for controlled ovarian stimulation. Those with severe endometriosis, adenomyosis, autoimmune or metabolic disorders, sustained hyperprolactinaemia, congenital uterine malformations and with male partners having severe oligoasthenoteratozoospermia were excluded. Participants/materials, setting, methods Group A (55 women) received CC 100mg from D1-D5 with 300 IU human menopausal gonadotrophin (hMG) in a flexible GnRH antagonist protocol. Group B (61 women) underwent ultrashort flare protocol. 1mg leuprolide was administered from D1-D4 and 300 IU hMG given D2 onwards followed by flexible GnRH antagonist administration. Dual trigger with triptorelin and recombinant hCG was administered 35-36 hours before oocyte retrieval. Embryos cultured till D5 were vitrified for transfer at a later stage. Main results and the role of chance The two groups were well matched for baseline characteristics like age, BMI, AMH, duration of infertility, D2 AFC, estradiol and FSH levels. The mean total gonadotrophin consumption (3387.29 + 1082.5 vs 4407 + 1224.2, p value &amp;lt;0.01) and the duration of stimulation (10.71 + 2.52 vs 11.95 + 2.43, p value &amp;lt;0.01) were significantly lower in group A vs group B. The primary outcomes of median number of oocytes retrieved (4 vs 4, p value- 0.71) , M2 rate (3 vs 3, p value-0.91), fertilisation rate were similar in the two groups. The secondary outcomes of oocyte retrieval rate (103.05 + 42.97 vs 97.14 + 42.96, p value- 0.63), FORT (0.81 +0.68 vs 0.96 + 0.48, p value- 0.37) FOI (0.91 + 0.55 vs 0.92+ 0.54, p value 0.92), top quality embryo rate (0.53 + 1.1 vs 0.41 + 0.84, p value 0.61), cycle cancellation rate (26.22% vs 29.09%), implantation rate (23.63% vs 24.59%) and clinical pregnancy rate (21.31% vs 20%) were also similar in group A vs B respectively. A subgroup analysis of POSEIDON 3 versus POSEIDON 4 patients revealed similar outcomes with both the protocols in the two groups. Limitations, reasons for caution Small sample size of the cases limits the current statistical power of the study. Wider implications of the findings CC /flexible GnRH antagonist protocol is an effective alternative to ultrashort flare protocol in patients with poor ovarian reserve irrespective of their age. The lower gonadotrophin dosage required and shorter duration of stimulation observed make it a viable option in patients who might need multiple stimulations for pooling up embryos. Trial registration number Not applicable

O-268 Presence of adenomyosis impairs clinical outcomes in women undergoing frozen embryo transfer

Abstract Study question Does the presence of adenomyosis impact the clinical outcomes of patients undergoing frozen embryo transfer (FET)? Summary answer Presence of adenomyosis is associated with higher miscarriage and lower clinical pregnancy and live birth rates. GnRH agonist pre-treatment does not increase clinical outcomes. What is known already Presence of adenomyosis among pregnant patients has been associated with a higher incidence of miscarriage and pregnancy complications. Although the role of adenomyosis in women undergoing in vitro fertilization (IVF) has been investigated in several studies demonstrating a potential detrimental effect on live birth rates following IVF, most of them were small studies in which adenomyosis diagnosis was not confirmed based on solid ultrasonographic criteria. Considering the fragmented evidence up to date, we decided to perform a large retrospective study including women with adenomyosis undergoing FET which has been confirmed based on solid ultrasonographic criteria. Study design, size, duration Retrospective cohort study of 3503 patients undergoing their first cycle of blastocyst frozen transfer in a university-affiliated fertility center between January 2017 and December 2021. Participants/materials, setting, methods Overall, 3503 patients undergoing their first blastocyst frozen transfer through a hormonal replacement (HRT) FET cycle. Patients were categorized as adenomyosis when fulfilling to the Morphological Uterus Sonographic Assessment (MUSA) criteria and as non-adenomyosis when no-adenomyosis was identified. Among them 140 women had a confirmed diagnosis of adenomyosis based on MUSA criteria. Clinical information was retrospectively collected from medical records. Main results and the role of chance Comparisons between adenomyosis and non-adenomyosis groups revealed similar baseline characteristics in terms of patients’ weight, parity, smoking status, and age. Similarly, endometrial thickness and mean serum progesterone levels the day before FET as well as the number of embryos transferred were comparable between groups. Adenomyosis patients were more likely to proceed with a deferred FET (freeze-all protocol) as compared with no-adenomyosis women (p = 0.002) and were significantly more likely to be treated with GnRH agonist pre-treatment (2 injections) (P &amp;lt; 0.001). Multivariable logistic regression, adjusting for age, autologous or donor oocytes, PGT-A, deferred FET, serum progesterone levels the day before FET, GnRH agonist pre-treatment, number of embryos transferred, and adenomyosis, demonstrated that the use of GnRH agonist protocol did not affect miscarriage, clinical pregnancy rate or live birth rate. However, the presence of adenomyosis significantly decreased clinical pregnancy rates (OR 0.62, 95% CI: 0.39-0.98, P = 0.040) and live birth rates (OR 0.46, 95% CI: 0.27-0.75, P = 0.003) and significantly increased miscarriage rates (OR 2.13, 95% CI 0.98-4.37, p = 0.045). PGT-A was the only factor associated with a significative reduction in miscarriage rate. Limitations, reasons for caution The main limitation of this study is the single-center retrospective approach. Furthermore, due to the limited number of cases with adenomyosis focal and diffuse adenomyosis were analyzed together although this may be clinically distinct entities. Wider implications of the findings The results of this study demonstrate that presence of adenomyosis has significant negative impact on the clinical outcomes of patients undergoing FET. Future prospective studies are needed to create a consensus on the optimal ET technique for these patients. Trial registration number Not Applicable

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.

Effects of changing the COS protocol in patients without a transplantable embryo in the previous IVF/ICSI cycle

Objective: Some patients fail to obtain an embryo for transplantation during previous in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles, and require multiple reproductive treatments. This study aimed to evaluate whether changing the control ovarian stimulation (COS) protocol during the subsequent stimulation cycle could improve laboratory and clinical outcomes in these patients. Methods: Patients without a transplantable embryo (TE) in the previous IVF/ICSI cycles were recruited during their second cycles. They were classified into two groups according to their first cycle protocol: Group A, patients treated with a gonadotropin-releasing hormone agonist (GnRH-a), and Group B, patients treated with a gonadotropin-releasing hormone antagonist (GnRH-ant). The study group included patients whose stimulation protocols were changed, whereas the control group consisted of patients who used the same stimulation protocol in the second cycle. We then compared the numbers of oocytes collected (OC) and TE, the incidence of non-TE, the pregnancy rate (PR), and the live birth rate (LBR). Results: In Group A, the numbers of OC and TE were significantly lower (6.0±4.7 vs. 9.4±6.4, 2.±2.2 vs. 4.5±3.8, P&lt;0.05) in the study group compared with those in the control group. In Group B, the numbers of OC and TE were higher (7.0±5.5 vs. 4.0±4.3, 3.5±3.4 vs. 1.8±2.1, P&lt;0.05) in the study group. There was a significant increase in the incidence of non-TE (AOR=2.12, 95% CI:1.04–4.69) of the study group in Group A but not in Group B. No significant differences in the PR or LBR were found between the study and control groups in either Group A or B. Conclusions: Changing the COS protocol from GnRH-ant to GnRH-a or continuing the GnRH-a protocol can improve laboratory outcomes in patients with no TE in the previous IVF/ICSI cycle.

Live birth rates following individualized dosing algorithm of follitropin delta in a long GnRH agonist protocol

PurposeTo 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.MethodsClinical 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.ResultsIn 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).ConclusionIn 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.Trial registration numberNCT03564509; June 21, 2018.

Morphokinetic analysis of early human embryonic development and its relationship to endometriosis resection: a retrospective time-lapse study using the KIDScore™ D3 and D5 implantation data algorithm

Research questionDoes complete resection of endometriosis improve embryo quality as assessed by morphokinetic parameters using time-lapse microscopy?DesignFor this retrospective study we analysed 237 fertilised, cultured and transferred embryos from 128 fresh IVF and/ or ICSI transfer cycles. Endometriosis was confirmed or excluded by laparoscopy. Patients were stimulated with recombinant FSH using GnRH agonist and antagonist protocols. After fertilisation, a time-lapse incubation system was used for observation. Embryo quality was assessed using the KIDScore™ D3 and D5 implantation data algorithm.ResultsThe analysis showed a median KIDScore™ D5 of 2.6 (on a scale of 1 to 9.9) for embryos from patients with endometriosis without complete resection. The control group without endometriosis achieved a score of 6.8 (p = 0.003). The median score for embryos from endometriosis patients with complete resection was 7.2, which was a significant increase compared to embryos from patients without complete resection (p = 0.002). We observed an effect size of r = 0.4 for complete resection versus no resection of endometriosis using the KIDScore™ D5. There were no differences in KIDScore™ D3 between the three patient groups. Pregnancy and miscarriage rates showed the same clinical trends. In three of our four case series of patients who underwent IVF/ ICSI cycles before and after complete resection, we found a marked improvement in embryo quality after complete resection.ConclusionsComplete resection of endometriosis could significantly improve the otherwise poor embryo quality of patients undergoing IVF-procedures. The data, therefore, strongly support recommending surgery to patients with endometriosis prior to assisted reproduction.

Effect of hyperandrogenism on pregnancy outcomes in women with polycystic ovary syndrome undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer

Objective: To explore the effects of hyperandrogenism (HA) on pregnancy outcomes in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET). Methods: A retrospective study was conducted on infertile women with PCOS undergoing IVF/ICSI-ET from January 2017 to June 2021 in our center. Patients were divided into HA group and NON-HA group according to the levels of testosterone. Propensity score matching (PSM) was used to balance the influence of female age and IVF/ICSI-ET for patients with gonadotropin-releasing hormone (GnRH)antagonist protocol and GnRH agonist protocol, separately. After the PSM procedure, 191 cases in HA group and 382 cases in NON-HA group, were included. Hormone levels and pregnancy outcomes were compared in the two groups. Results: The female age was comparable in two groups [HA: (29.6±3.7) vs NON-HA: (29.5±3.6), P=0.665]. The basal luteinizing hormone [(10.82±6.73) vs (7.76±5.30) IU/L], testosterone [(3.27±0.97) vs (1.60±0.59) nmol/L], free androgen index (7.13 vs 2.77), anti-mullerian hormone [(11.37±5.74) vs (9.67±4.67) ng/ml], fasting glucose [(5.18±0.49) vs (5.06±0.42) mmol/L], 1h glucose [(9.34±2.42) vs (7.99±2.21) nmol/L], 2 h glucose [(7.66±2.17) vs (6.64±1.84) nmol/L], 2 h insulin [(129.81±145.49) vs (97.51±86.92) mU/L], total cholesterol [(5.35±0.89) vs (4.92±0.92) mmol/L], triglycerides [(1.55±1.28) vs (1.33±0.77) mmol/L], and low density lipoprotein cholesterol levels [(3.38±0.66) vs (3.14±0.71) mmol/L] were significantly higher in HA group, compared with NON-HA group (P<0.05). The initiated gonadotropin dose was higher in HA group than that in NON-HA group [(126.96±33.65) vs (137.60±38.12) U, P=0.001], but moderate-severe ovarian hyperstimulation syndrome (OHSS) rate was similar in two groups (P>0.05). The rates of implantation, clinical pregnancy, miscarriage, and live birth were comparable between the two groups (P>0.05). Also, in the subgroups, the rates of implantation, clinical pregnancy, live birth, and miscarriage were similar in HA group and NON-HA group. Conclusions: The risks of hormonal abnormality and glucose-lipid metabolic disorder were higher in PCOS women with HA, whereas satisfactory pregnancy outcomes could be achieved under proper ovarian stimulation undergoing IVF/ICSI-ET.