BEYOND: a randomized controlled trial comparing efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus antagonist protocol during the first ovarian stimulation cycle.

How does a gonadotrophin-releasing hormone (GnRH) agonist versus a GnRH antagonist protocol affect ovarian response when using an individualized fixed daily dose of follitropin delta for ovarian stimulation? The BEYOND trial data demonstrate thatindividualized fixed-dose follitropin delta is effective when used in a GnRH agonist protocol, compared with a GnRH antagonist protocol, in women with anti-Müllerian hormone (AMH) ≤35 pmol/l and no increased risk of ovarian hyperstimulation syndrome (OHSS). The efficacy and safety of an individualized fixed daily dose of follitropin delta (based on body weight and AMH) have been established in randomized controlled trials (RCTs) using a GnRH antagonist protocol. Preliminary study data indicate that individualized follitropin delta is also efficacious in a GnRH agonist protocol (RAINBOW trial, NCT03564509). There are no prospective comparative data using individualized follitropin delta for ovarian stimulation in a GnRH agonist versus a GnRH antagonist protocol. This is the first randomized, controlled, open-label, multi-centre trial exploring efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus a GnRH antagonist protocol in participants undergoing their first ovarian stimulation cycle for IVF/ICSI. A total of 437 participants were randomized centrally and stratified by centre and age. The primary endpoint was the number of oocytes retrieved. Secondary endpoints included ongoing pregnancy rates, adverse drug reactions (including OHSS), live births, and neonatal outcomes. Participants (18-40 years; AMH ≤35 pmol/l) were enrolled at specialist reproductive health clinics in Austria, Denmark, Israel, Italy, the Netherlands, Norway, and Switzerland. The mean number of oocytes retrieved was compared between the GnRH agonist and antagonist protocols using a negative binomial regression model with age and AMH at screening as factors. Analyses were based on all randomized subjects, using a multiple imputation method for randomized subjects withdrawing before the start of stimulation. Of the 437 randomized subjects, 221 were randomized to the GnRH agonist, and 216 were randomized to the GnRH antagonist protocol. The participants had a mean age of 32.3 ± 4.3 years and a mean serum AMH of 16.6 ± 7.8 pmol/l. A total of 202 and 204 participants started ovarian stimulation with follitropin delta in the GnRH agonist and antagonist groups, respectively. The mean number of oocytes retrieved was statistically significantly higher in the agonist group (11.1 ± 5.9) versus the antagonist group (9.6 ± 5.5), with an estimated mean difference of 1.31 oocytes (95% CI: 0.22; 2.40, P = 0.0185). The difference in number of oocytes retrieved was influenced by the patients' age and ovarian reserve, with a greater difference observed in patients aged <35 years and in patients with high ovarian reserve (AMH >15 pmol/l). Both the GnRH agonist and antagonist groups had a similar proportion of cycle cancellations (2.0% [4/202] versus 3.4% [7/204]) and fresh blastocyst transfer cancellations (13.4% [27/202] versus 14.7% [30/204]). The estimated ongoing pregnancy rate per started cycle was numerically higher in the GnRH agonist group (36.9% versus 29.1%; difference: 7.74% [95% CI: -1.49; 16.97, P = 0.1002]). The most commonly reported adverse events (≥1% in either group; headache, OHSS, nausea, pelvic pain, or discomfort and abdominal pain) were similar in both groups. The incidence of early moderate/severe OHSS was low (1.5% for the agonist group versus 2.5% for antagonist groups). Estimated live birth rates per started cycle were 35.8% and 28.7% in the GnRH agonist and antagonist groups, respectively (treatment difference 7.15%; 95% CI: -2.02; 16.31; P = 0.1265). The two treatment groups were comparable with respect to neonatal health data for singletons and twins and for incidence of congenital malformations (2.7% and 3.3% for the GnRH agonist versus antagonist groups, respectively). All participants had AMH ≤35 pmol/l and were ≤40 years old. Clinicians should remain cautious when using a GnRH agonist protocol in patients with AMH >35 pmol/l (i.e. those with an increased OHSS risk). The incidence of OHSS in the GnRH antagonist group may have been lower if a GnRH agonist trigger had been allowed. Outcomes of transfers with cryopreserved blastocysts were not followed up, therefore the cumulative live birth rates and neonatal outcomes after cryotransfer are unknown. In women with AMH ≤35 pmol/l, an individualized fixed daily dose of follitropin delta resulted in a significantly higher number of oocytes retrieved when used in a GnRH agonist protocol compared with a GnRH antagonist protocol, with no additional safety signals observed and no additional risk of OHSS. Live birth rates following ovarian stimulation with individualized follitropin delta were not statistically different between the GnRH protocols; however, the trial was not powered to assess this endpoint. There were no safety concerns with respect to neonatal health after ovarian stimulation with follitropin delta in either protocol. The trial was funded by Ferring Pharmaceuticals. EE, EP, and MS have no competing interests. AP has received research support from Ferring, and Gedeon Richter, and honoraria or consultation fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, Merck A/S. BC has received consulting fees from Ferring and Merck, and his department received fees from Ferring to cover the costs of patient enrolment. MBS has received support to attend meetings and/or travel from Ferring, and was a board member for FertiPROTEKT e.V. until 2023. JS has received honoraria or consultation fees from Ferring and Merck, and support for attending meetings and/or travel from Ferring, Merck, and GoodLife. TS has received support/travel expenses from Ferring for attending a congress meeting, and participated in an advisory board for Merck. YS has received grants/research support from Ferring and support to attend a professional society congress meeting from Merck. RL and PP are employees of Ferring Pharmaceuticals. PP is a BOD member of PharmaBiome and owns stocks of Takeda Pharmaceuticals. ClinicalTrials.gov identifier NCT03809429; EudraCT Number 2017-002783-40. 7 April 2019. 2 May 2019.

Lobo R ，Soerdal T ，Ekerhovd E ，Cohlen B ，Porcu E ，Schenk M ，Shufaro Y ，Smeenk J ，Suerdieck MB ，Pinton P ，Pinborg A ，BEYOND Investigators ... -  《-》

Biosimilars versus the originator of follitropin alfa for ovarian stimulation in ART: a systematic review and meta-analysis.

Is the probability of pregnancy different between women using biosimilars versus the originator of follitropin alfa for ovarian stimulation in ART? Meta-analysis of eight randomized clinical trials (RCTs) suggests that live birth, clinical, and ongoing pregnancy rates are significantly lower with biosimilars of follitropin alfa compared to the originator. All biosimilars of follitropin alfa have received regulatory approval by demonstrating non-inferiority in the number of retrieved oocytes compared to the originator. Nevertheless, the most clinically relevant outcome in ART for both clinicians and patients is live birth. A meta-analysis published in 2021 suggested that biosimilars of follitropin alfa are associated with lower live birth rates compared to the originator. Since then, more relevant RCTs have been published, and thus an updated critical synthesis of the available evidence is urgently warranted. A systematic review and meta-analysis were performed to compare biosimilars versus the originator of follitropin alfa in women undergoing ovarian stimulation for ART. A literature search was conducted until January 2024 in MEDLINE, Embase, Cochrane CENTRAL, Scopus, Web of Science, WHO, Clinicaltrials.gov, and others to identify eligible RCTs. The primary outcome was live birth. Secondary outcomes included clinical and ongoing pregnancy, duration of gonadotrophin administration and total FSH dose, number of oocytes retrieved, and ovarian hyperstimulation syndrome (OHSS). Data were extracted independently by two reviewers. Quality was assessed using the RoB-2 Tool by Cochrane, and a sensitivity analysis was performed by excluding studies having high risk of bias. Meta-analysis was performed using the random or fixed effects model depending on the presence or not of significant (>50%) statistical heterogeneity (I2). Results were combined using the intention-to-treat principle and are reported as risk ratio (RR) or weighted-mean-difference (WMD) with 95% CIs. Eight RCTs (n = 2987) (published between 2015 and 2023) were identified, assessing seven biosimilar products of follitropin alfa. The number of patients included in the eligible studies ranged from 100 to 1100. Three of the RCTs were deemed to be at high risk of bias. The duration of gonadotrophin administration was shorter in the biosimilars group (WMD: -0.19 days, 95% CI: -0.34 to -0.05; I2 = 0%, 5 studies, n = 2081), while no difference was observed in the total dose of FSH (WMD: -34.69 IUs, 95% CI: -74.54 to 5.16; I2 = 15.53%, 5 studies, n = 2081). No difference was observed in the number of oocytes retrieved (WMD: 0.27, 95% CI: -0.43 to 0.96; I2 = 10.7%, 6 studies, n = 1527) and OHSS rates (RR: 1.17, 95% CI: 0.90-1.52; I2 = 0%, 8 studies, n = 2986) between the two groups. A significantly lower live birth rate was observed using the biosimilars of follitropin alfa compared to the originator in women undergoing ovarian stimulation for ART (RR: 0.83, 95% CI: 0.72-0.96; I2 = 0%, 6 studies, n = 2335; moderate certainty of evidence). Similarly, clinical pregnancy (RR: 0.82, 95% CI: 0.73-0.92; I2 = 0%, 7 studies, n = 2876; low certainty of evidence) and ongoing pregnancy rates (RR: 0.81, 95% CI: 0.70-0.94; I2 = 0%, 7 studies, n = 1886; low certainty of evidence) were lower in the biosimilars group. These results were not materially altered in the sensitivity analyses performed where studies deemed at high risk of bias were excluded. This meta-analysis included RCTs evaluating seven different biosimilars of follitropin alfa; however, pooled data appeared to be homogeneous. No data were available comparing biosimilars of follitropin alfa with the originator regarding cumulative live birth rate per aspiration or the probability of live birth in frozen thawed cycles. The population examined in the eligible RCTs includes mainly normal responders and no RCTs were identified focusing on poor or high responders. Clinicians should be informed that although biosimilars of follitropin alfa produce similar number of oocytes with the originator, pregnancy rates after a fresh transfer are likely to be lower. Future research should focus on optimizing the production and use of biosimilars of follitropin alfa, so that they lead to pregnancy rates comparable to the originator. No external funding was used for this study. K.I.K. and A.S. have no competing interest to disclose. E.M.K. reports personal fees and non-financial support from Merck, Ferring, IBSA, and Vianex. B.W.M. has been supported by an investigator grant from NHMRC, has received consulting fees from Organon, Merck, and Norgine, research support and non-financial support from Merck KGaA, Darmstadt, Germany. B.W.M. also reports having stocks from OBsEva. C.A.V. reports grants, personal fees, and non-financial support from Merck KGaA, Darmstadt, Germany, personal fees, and non-financial support from Merck, Sharpe and Dohme, personal fees and non-financial support from Organon, grants and non-financial support from Ferring, personal fees from IBSA, and personal fees and non-financial support from Gedeon Richter and Vianex. Protocol for the systematic review registered in The International Prospective Register of Systematic Reviews (PROSPERO; CRD42024498237).

Kiose KI ，Storr A ，Kolibianakis EM ，Mol BW ，Venetis CA ... -  《-》

Erratum: Eyestalk Ablation to Increase Ovarian Maturation in Mud Crabs.

《Jove-Journal of Visualized Experiments》

Psychosocial and physical wellbeing in women and male partners undergoing immediate versus postponed modified natural cycle frozen embryo transfer after ovarian stimulation and oocyte pick-up: a sub-study of a randomized controlled trial.

Are there differences in psychosocial and physical wellbeing among women and male partners undergoing modified natural cycle (mNC) frozen embryo transfer (FET) in immediate compared to postponed cycles after ovarian stimulation (OS) and oocyte pick-up (OPU)? Significantly more women in the immediate group reported physical symptoms than women in the postponed group whilst fewer were emotionally affected by waiting time, although the latter difference lost statistical significance after adjustment for multiple testing. Infertility and fertility treatment are known to cause psychosocial distress in women and couples longing for a child. The treatment may be long-term and delayed for various reasons, such as the elective postponement of FET after a fresh transfer without pregnancy or an elective freeze-all cycle, possibly further increasing the level of distress. Sub-study of an ongoing multicentre randomized controlled, non-inferiority trial assessing the optimal timing for mNC-FET treatment after OS and OPU. Participants were randomized 1:1 to mNC-FET in the cycle immediately following OS or mNC-FET in a subsequent cycle. The study is based on data from the first women (N = 300) and male partners (N = 228) invited to answer a self-reported questionnaire assessing psychosocial and physical wellbeing. Data were collected from April 2021 to March 2024. Questionnaires were distributed to all randomized women and their male partners on cycle day 2-5 of mNC-FET cycles and returned before the administration of ovulation trigger. The questionnaire consisted of validated items originating from the Copenhagen Multicentre Psychosocial Infertility-Fertility Problem Stress Scale (COMPI-FPSS) and Marital Benefit Measure (COMPI-MBM). Emotional reactions to waiting time in fertility treatment, mental health, general quality-of-life, and physical symptoms were also assessed. Questionnaire response rates were 90.3% for women and 80.0% for male partners in the immediate group, and 82.3% for women and 57.3% for male partners in the postponed group. Approximately 90% of all women worried to some or a great extent about whether the treatment would be successful. More women in the postponed group reported that they were emotionally affected by the waiting time from OPU to blastocyst transfer to some or to a great extent (57.4% versus 73.9% in the immediate versus postponed group, P = 0.014), but the results were not significant after adjustment for multiple testing (P = 0.125). For male partners, no difference in emotional reactions to waiting time between groups was found. There was no significant difference in total infertility-related stress or symptoms of severe depression between the immediate and the postponed group for women or male partners, but women were generally more distressed than their partners. There was a significantly higher incidence of stomach and/or pelvic pain (24.0% versus 9.4%, adjusted P = 0.013), feeling of being bloated (33.8% versus 15.1%, adjusted P = 0.010) and swollen or tender breasts (24.8% versus 0.9%, P < 0.001) in the immediate group. All items were self-reported. No assessment of psychosocial or physical wellbeing was performed before participant enrolment. The sample size of male partners was relatively small, and female partners were not included in this sub-study due to a very small number of participants in this group. If immediate mNC-FET proves to be effective, physical and emotional factors may play a key role in choosing treatment strategy for the individual patient. This study demonstrated more physical symptoms related to OS in the immediate cycles. The RCT was supported by Rigshospitalet's Research Foundation and an independent research grant from Merck A/S (MS200497_0024). Merck A/S had no role in the design of this study and will not have any role during its execution, analyses, interpretation of data, or decision to submit results. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors. A.P. received grants from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S and Cryos as payment to the institution. A.P. received consulting fees from IBSA, Ferring Pharmaceuticals, Gedeon Richter, Cryos and Merck A/S, and honoraria from Organon, Ferring Pharmaceuticals, Gedeon Richter and Merck A/S. A.P. received support for meeting attendance from Gedeon Richter. M.S. benefitted from a grant from Gedeon Richter. S.B. and C.C. benefitted from a grant from Merck A/S. S.B. is currently employed by Novo Nordisk. N.C.F. received grants from Gedeon Richter, Merck A/S and Cryos as payment to the institution. N.C.F. received consulting fees from Merck A/S and support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, IBSA, and Gedeon Richter. N.C.F. is chair of the steering committee for the guideline groups for The Danish Fertility Society. E.L. received a radiometer contract on blood gas validation as a payment to the institution. E.L. received honoraria from Pfizer and support for meeting attendance from Astella. B.N. received grants from IBSA, Ferring Pharmaceuticals, Merck A/S, and Gedeon Richter as payment to the institution. B.N. received honoraria from Merck A/S and Organon and support for meeting attendance from IBSA and Gedeon Richter. B.N. and L.P. participate in an Advisory Board at Ferring Pharmaceuticals. L.P. received support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, and Gedeon Richter. L.P. declare stocks in Novo Nordisk. ClinicalTrials.gov NCT04748874.

Bergenheim S ，Saupstad M ，Colombo C ，Møller JE ，Bogstad JW ，Freiesleben NC ，Behrendt-Møller I ，Prætorius L ，Oxlund B ，Nøhr B ，Husth M ，Løkkegaard E ，Sopa N ，Pinborg A ，Løssl K ，Schmidt L ... -  《-》

Empirical use of growth hormone in IVF is useless: the largest randomized controlled trial.

Does adjuvant growth hormone (GH) therapy in GnRH antagonist cycles improve reproductive outcomes in the general IVF population? Empiric adjuvant GH therapy in GnRH antagonist cycles does not improve IVF stimulation results or reproductive outcomes, including implantation, miscarriage, and clinical pregnancy rates. Previous evidence regarding the benefits of GH therapy in IVF cycles has been inconclusive due to the lack of well-designed, large-scale randomized controlled trials (RCTs) in the general IVF population. This is a phase III open-label RCT involving 288 patients undergoing antagonist IVF cycles at the Ovo clinic in Montreal, Canada, between June 2014 and January 2020. Patients were randomly assigned at a 1:1 ratio to either the GH or control group. The intervention group received daily 2.5 mg subcutaneous injections of GH from Day 1 of ovarian stimulation until the day of oocyte retrieval, while the control group received standard ovarian stimulation without any adjuvant therapy. Patients were expected normal responders. All embryo transfers, both fresh and frozen, resulting from the studied IVF cycle were included in an intention-to-treat and per-protocol analyses. The primary outcome was the clinical pregnancy rate, while secondary outcomes included the number of retrieved oocytes, good-quality embryos, maturation, fertilization, implantation, and miscarriage rates. A total of 288 patients were recruited and randomly assigned at a 1:1 ratio to either the GH or the control group. After excluding cycle cancellations and patients who did not undergo transfer, 105 patients remained in each group. The overall mean age was 38.0 years, the mean BMI was 25.11 kg/m2 and the mean anti-Müllerian hormone was 2.51 ng/ml. The cycle characteristics were similar between both groups. No differences were observed regarding the total dose of gonadotropins (4600 versus 4660 IU for the GH and control groups, respectively, P = 0.752), days of stimulation (11.4 versus 11.7 days, P = 0.118), and endometrial thickness (10.63 versus 10.94 mm, P = 0.372). Both the intention to treat (ITT) and per protocol analyses yielded similar results for stimulation outcomes. In the ITT analysis, no differences were found in the number of follicles ≥15 mm (7.8 versus 7.1, P = 0.212), retrieved oocytes (11.7 versus 11.2, P = 0.613), mature oocytes (8.5 versus 8.6, P = 0.851), maturation rate (73.8 versus 78.4%, P = 0.060), fertilization rate (64.3 versus 67.2%, P = 0.388), and good quality embryos (2.5 versus 2.6, P = 0.767). Reproductive outcomes in fresh embryo transfer showed no difference for implantation rate (38.2 versus 39.5%, P = 0.829), miscarriage rate (26.5 versus 31.1%, P = 0.653), clinical pregnancy rate (43.6 versus 50.0%, P = 0.406, rate difference, 95% CI: -0.06 [-0.22, 0.09]), and live birth rate (32.1 versus 33.3%, P = 0.860). The number of embryos needed to achieve a clinical pregnancy was 3.0 versus 2.5 in the GH and control groups, respectively. Similarly, reproductive outcomes in first frozen embryo transfer showed no difference for implantation rate (31.6 versus 45.3%, P = 0.178), miscarriage rate (28.6 versus 26.3%, P = 0.873), clinical pregnancy rate (35.1 versus 44.2%, P = 0.406, P = 0.356, rate difference, 95% CI: -0.09 [-0.28, 0.10]), and live birth rate (22.8 versus 32.6%, P = 0.277). The number of embryos needed to achieve a clinical pregnancy was 3.1 versus 2.4 in the GH and control groups, respectively. The study focused on expected normal responders, limiting its applicability to other patient populations such as poor responders. These findings suggest that adding GH therapy to ovarian stimulation in GnRH antagonist cycles may not benefit the general IVF population. Additional high-quality RCTs are warranted to identify subgroups of patients who might benefit from this treatment. EMD Serono Inc., Mississauga, Canada, supplied Saizen® for the study, free of charge. In addition, they provided funding for the statistical analysis. I-J.K. declares grants or contracts from Ferring Pharmaceuticals, consulting fees from Ferring Pharmaceuticals, honoraria from Ferring Pharmaceuticals and EMD Serono, support for attending meetings or travel from Ferring Pharmaceuticals and EMD Serono, participation on a Data Safety Monitoring Board or Advisory Board for Ferring Pharmaceuticals, and stock or stock options from The Fertility Partners; W.J. declares support for attending meetings or travel from EMD Serono; and S.P. declares stock or stock options from The Fertility Partners. All other authors have no conflicts of interest to disclose. NCT01715324. 25 October 2012. 25 June 2014.

Mourad A ，Jamal W ，Hemmings R ，Tadevosyan A ，Phillips S ，Kadoch IJ ... -  《-》