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Jing-Xian Cao,1 Jing-Yan Song2,3 1Gynecology, Binzhou Hospital of Traditional Chinese Medicine, Binzhou, People’s Republic of China; 2The First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 3Reproductive Center of Integrated Medicine, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of ChinaCorrespondence: Jing-Yan Song, The First Clinical College, Shandong University of Traditional Chinese Medicine, Reproductive Center of Integrated Medicine, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 42, Wen Hua Xi Road, Lixia District, Jinan, 250011, People’s Republic of China, Tel +86-0531-68617921, Email hanlingjuzei91@126.comPurpose: The purpose of this study was to compare the efficacy of Follitropin alpha (Gonal-F) and Follitropin beta (Puregon) on cumulative live birth rate (CLBR), defined as the percentage of the number of patients who delivered for the first time in a single ovarian stimulation cycle and the number of patients in all oocyte retrieval cycles.Methods: A retrospective cohort study including 2864 infertile patients who underwent ovarian stimulation with Puregon (group A, n=1313) and Gonal-F (group B, n=1551) was conducted between July 2015 and June 2021 at a university-affiliated reproductive medicine center. Reduce potential confounding factors between groups, propensity scores and multivariable logistic regression analyses were estimated to obtain unbiased estimates of outcomes. The primary outcome was the difference in CLBR between the two groups.Results: Each group identified 1160 individuals after propensity score matching (PSM). Baseline characteristics were similar between groups after PSM. The total gonadotrophin (Gn) dose (2400 vs 2325), p=0.038) and cost of Gn usage (5327.9¥ vs 7547.2¥, p< 0.001) between the Puregon and Gonal-F groups were statistically significant. Nevertheless, the pregnancy outcomes between the two groups were comparable after fresh embryo transfer and subsequent frozen-thawed embryo transfer. Additionally, there was also no difference observed in the primary outcome of CLBR (52.8% vs 55.7%, p=0.169). Multivariable regression analysis revealed that the type of Gn was not associated with CLBR (p = 0.912).Conclusion: Gonal-F may be a reasonable option for infertile patients who are hesitant to receive more Gn dosage injections. Furthermore, Puregon can eliminate unneeded anxiety and expenses while also administering more flexibility. Taken together, these findings could well be utilized in everyday clinical practice to better inform patients when deciding on an ovarian stimulation strategy.Keywords: cumulative live birth rate, follitropin alpha, follitropin beta, in vitro fertilization, propensity score matching

Are cumulative live birth rates (CLBR) after follitropin alpha (Ovaleap®) and follitropin beta (Puregon®) similar when used for ovarian stimulation with ICSI (intracytoplasmic sperm injection) in a first-rank gonadotrophin-releasing hormone (GnRH) antagonist protocol? Retrospective single-centre cohort study including 832 infertile patients undergoing ovarian stimulation with a daily dose of 150–225 IU FSH in their first ICSI cycle at a tertiary referral centre between July 2016 and July 2019. Of those, 349 patients used Ovaleap and 483 patients received Puregon. Baseline characteristics were not statistically different between the groups. The duration of stimulation was slightly longer in the Ovaleap group (10.6 ± 1.7 versus 10.3 ± 1.6 days; P = 0.012). The number of mature oocytes was not statistically different and there was no significant difference in fertilization rate or embryo utilization rate between the two groups. After fresh embryo transfer, biochemical pregnancy rate (137/349 [39.3%] versus 186/483 [38.5%]) as well as clinical pregnancy rate (105/349 [30.1%] versus 152/483 [31.5%]) were comparable (P = 0.83 and 0.67, respectively). Live birth rate (LBR) after fresh embryo transfer (94/349 [26.9%] versus 141/483 [29.2%]; P = 0.48) and CLBR (199/349 [57.0%] versus 287/483 [59.4%]; P = 0.49) were not significantly different. Multivariable regression analysis revealed that the type of gonadotrophin was not associated with CLBR (P = 0.28). This retrospective study shows no significant difference in CLBR between Ovaleap and Puregon in patients undergoing their first GnRH antagonist ICSI cycle. [ABSTRACT FROM AUTHOR]

STUDY QUESTION: Does substituting 150 µg corifollitropin alfa for 450 IU follitropin beta during the first 7 days of ovarian stimulation in proven poor responders, result in retrieval of a non-inferior number (<1.5 fewer) of cumulus oocyte complexes (COCs)? SUMMARY ANSWER: A single s.c. dose of 150 µg corifollitropin alfa on the first day of ovarian stimulation, followed if necessary, from Day 8 onwards, with 450 IU of follitropin beta/day, is not inferior to daily doses of 450 IU follitropin beta. The 95% CI of the difference between medians in the number of oocytes retrieved was -1 to +1 within the safety margin of 1.5. WHAT IS KNOWN ALREADY: Recent data from retrospective studies suggest that the use of corifollitropin alfa in poor responders is promising since it could simplify ovarian stimulation without compromising its outcome. STUDY DESIGN, SIZE, DURATION: Seventy-nine women with previous poor ovarian response undergoing ICSI treatment were enrolled in this open label, non-inferiority, randomized clinical trial (RCT). PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were: previous poor response to ovarian stimulation (≤4 COCs) after maximal stimulation, age <45 years, regular spontaneous menstrual cycle, body mass index: 18-32 kg/m(2) and basal follicle stimulating hormone ≤20 IU/l. On Day 2 of the menstrual cycle, patients were administered either a single s.c dose of 150 µg corifollitropin alfa (n = 40) or a fixed daily dose of 450 IU of follitropin beta (n = 39). In the corifollitropin alfa group, 450 IU of follitropin beta were administered from Day 8 of stimulation until the day of human chorionic gonadotrophin (hCG) administration, if necessary. To inhibit premature luteinizing hormone surge, the gonadotrophin releasing hormone antagonist ganirelix was used. Triggering of final oocyte maturation was performed using 250 µg of recombinant hCG, when at least two follicles reached 17 mm in mean diameter. MAIN RESULTS AND THE ROLE OF CHANCE: The number of COCs retrieved was not statistically different between the corifollitropin alfa and the follitropin beta groups [Median 3 versus 2, 95% CI 2-4, 2-3, respectively, P = 0.26]. The 95% CI of the difference between medians in the number of oocytes retrieved was -1 to +1. A multivariable analysis adjusting for all the potential baseline differences confirmed this finding. No significant difference was observed regarding the probability of live birth between the corifollitropin alfa and the follitropin beta group (live birth per patient reaching oocyte retrieval: 7.9 versus 2.6%, respectively, difference +5.3%, 95% CI: -6.8 to +18.3). LIMITATIONS, REASONS FOR CAUTION: The present study was not powered to test a smaller difference (e.g. 1 COC) in terms of COCs retrieved as well as to show potential differences in the probability of pregnancy. Moreover, it would be interesting to assess whether the continuation of stimulation in the long acting FSH arm, where necessary, with 200 IU instead of 450 IU of follitropin beta would have altered the direction or the magnitude of the effect of the type of FSH, observed on the number of COCs retrieved. WIDER IMPLICATIONS OF THE FINDINGS: Corifollitropin alfa simplifies IVF treatment because it is administered in a GnRH antagonist protocol and replaces seven daily FSH injections with a single one of a long acting FSH without compromising the outcome. It could greatly reduce the burden of treatment for poor responders and this deserves further investigation. STUDY FUNDING/COMPETING INTERESTS: No external funding was used for this study. None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER: NCT02046655. [ABSTRACT FROM AUTHOR]

Purpose: To prevent multiple pregnancies the goal of ovulation induction by gonadotropins is to achieve only mono-follicular development. The most important issue is therefore to determine the starting dose. The aim of this study is to compare three different starting doses of follitropin beta to assess the lowest effective dose. Methods: We evaluated 92 cycles with ovarian stimulation for patients with unexplained infertility, anovulatory disorder or mild male factor. We prospectively divided patients into 50, 75 and 100 IU groups based on patients' response to clomiphene citrate treatment. Results: We performed 87 intrauterine inseminations (95 % of cycles with ovulation induction). Five cycles were cancelled. We achieved 15 pregnancies; total pregnancy rate was 18 %. Pregnancy rate was 22, 10 and 28 % in 50, 75 and 100 IU follitropin beta groups. The average number of follicles was 2.0 ± 0.8, 2.2 ± 1.1 and 2.5 ± 1.8 (ns), total dose of gonadotropins (IU) 483 ± 192, 600 ± 151 and 830 ± 268 ( p < 0.001), respectively. We observed one case of twins in 75 and 100 IU treatment group, as well (25 % risk). Conclusions: This study suggests that based on the dose which was chosen according to clomiphene citrate response, all treatment regimes were effective for ovulation induction. 50 IU of follitropin beta daily is the appropriate starting dose to support ovulation for clomiphene citrate-sensitive women. The disadvantage may be an increased risk of cycle cancellation due to low ovarian response. Daily doses 75 or 100 IU of rFSH increase total consumption of gonadotropins. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of follitropin alfa and beta on the myoelectrical activity of rat myometrium using signal-processing techniques. Design: Prospective, placebo-controlled study. Setting: Animal and pharmacology laboratory at Inonu University. Animal(s): Forty-five female Wistar albino rats. Intervention(s): Thirty of 45 animals involved in the experiment were registered as the superovulation group. After two successive normal estrous cycles, these animals were put into three equal subgroups. Group 1 was the control; animals were given 0.9% saline. Groups 2 and 3 were treated with follitropin alfa (Gonal-f) and follitropin beta (Puregon), respectively. The other 15 animals were ovariectomized (OVX) and subjected to the same protocol. The uterine myoelectrical signals were recorded and analyzed using a Matlab environment. Main Outcome Measure(s): Power/second, variance, and the effects of recombinant human follicle-stimulating hormone (FSH) on myoelectrical signals were assessed through temporal, spectral, and joint time-frequency analysis. The uterine endometrium and ovarian morphology were also assessed concerning primary follicles, antral follicles, and corpora lutea. Result(s): The power and some characteristic spectral components of myoelectrical signal were reduced with the administration of follitropin alfa and beta. No statistically significant difference was detected between endometrial and ovarian histology of the rats treated with these follitropins. Conclusion(s): Uterine myoelectrical signals change with administration of recombinant human FSH preparations. Follitropin beta and, more precisely, follitropin alfa suppress the spectral components and power of the myoelectrical signals, which provides uterine quiescence. [Copyright &y& Elsevier]

Gonadotrophins are injected daily over several days in follicular stimulation protocols. To facilitate self-injection, various injection or reconstitution devices are available. It was investigated whether injection training enabled patients to choose their preferred device. Patients and their partners received nurse-led training about: powdered urofollitropin (Bravelle®) with needle-free reconstitution (Q-Cap™) and conventional needles and syringes for administration; follitropin beta (Follistim® AQ) in a premixed, prefilled cartridge (Follistim® AQ Cartridge) with a reusable injection device (Follistim Pen®); or follitropin alfa (GONAL-f®) in a disposable, premixed, prefilled injection device (GONAL-f® RFF Pen). A total of 123 participants (81 women) attended the training and were asked to complete a questionnaire after training. More participants expressed a preference for a pen injection device than the needle-free reconstitution and conventional syringe (84.6% versus 5.7%: P < 0.0001). Of the 94 participants who preferred a particular device, more preferred the follitropin alfa prefilled pen (68.1%) than the follitropin beta cartridge and pen (24.5%; P < 0.0001) or urofollitropin with needle-free reconstitution device and conventional syringe (7.4%; P < 0.0001). It was concluded that nurse-led training classes empowered participants to choose a device that they considered most suitable to their needs. [ABSTRACT FROM AUTHOR]

: ObjectiveTo evaluate controlled ovarian stimulation cycles using the GnRH antagonist ganirelix in combination with the recombinant FSH, follitropin-β, in women with polycystic ovary syndrome (PCOS).: DesignProspective, nonrandomized clinical study.: SettingHospital-based infertility practice.: Patient(s)Twenty women with PCOS planning to undergo ovarian stimulation.: Intervention(s)Fasting glucose and insulin levels were used to calculate insulin resistance ratios (FG/I). After pretreatment with oral contraceptives, serum LH levels were determined, and 250 μg ganirelix was administered on cycle day 2. Upon suppression of LH, concurrent ganirelix and follitropin-β therapy (morning ganirelix and evening follitropin-β) was started and continued until the day of hCG.: Main outcome measuresDays of stimulation, dose of follitropin-β, pregnancy, and ongoing pregnancy were compared based on FG/I ratios.: ResultsOne dose of ganirelix effectively suppressed LH levels in all patients. All patients ovulated as documented by a rise in progesterone. Significant differences were observed between the insulin-resistant and non–insulin-resistant groups for both days of stimulation and dose of follitropin-β. The overall clinical pregnancy rate was 44.4%, with an ongoing pregnancy rate of 27.8%.: ConclusionsIn this preliminary study, we demonstrate the effectiveness of a concurrent ganirelix and follitropin-β therapy for ovarian stimulation in women with PCOS. [Copyright &y& Elsevier]

Résumé Une patiente souffrant de stérilité anovulatoire a suivi un traitement à base de clomifène. Celui-ci n’ayant pas donné les résultats escomptés, son médecin a choisi d’y associer des injections de gonadotrophine chorionique humaine. Summary A patient suffering from anovulatory infertility has followed a treatment based on clomifene. As this has not produced the expected results, her doctor has chosen to combine it with injections of human chorionic gonadotropin. [ABSTRACT FROM AUTHOR]

This cost-effectiveness analysis was conducted from the patient's perspective alongside a randomized controlled trial comparing corifollitropin alfa with follitropin beta for a single stimulation cycle. Only unit costs paid by patients are included in this analysis. The incremental cost-effectiveness ratio was calculated. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) were also performed. Baseline characteristics (except for the number of follicles and frozen embryos), treatment outcomes and complications were similar in the two groups. The live birth rate was comparable between the two groups, but the mean total cost per patient was higher for the corifollitropin alfa strategy (€4293) compared with the follitropin beta strategy (€4086). Costs per live birth were €13,726 and €12,511, respectively. The difference in effect between corifollitropin alfa and collitropin beta was three fewer live births, and the difference in costs was €24,048. The probability of live birth after the first and second embryo transfers and the proportion of patients who had no more frozen embryos available after non-achievement of live birth in the first or second transfer influenced the comparative cost-effectiveness of the two strategies. PSA showed that a corifollitropin alfa strategy would be rejected in up to 27.4% of scenarios. Follitropin beta 300 IU/day was more cost-effective than corifollitropin alfa 150 μg in women aged 35-42 years weighing ≥ 50 kg undergoing in-vitro fertilzation/intracytoplasmic sperm injection., (© 2020 The Authors.)

Study Question: Is corifollitropin alfa 150 μg equivalent to follitropin beta 300 IU/day for controlled ovarian hyperstimulation (COS) in older women weighing ≥50 kg undergoing IVF and/or ICSI in Vietnam?, Summary Answer: Corifollitropin alfa 150 μg was equivalent to follitropin beta 300 IU/day with respect to the number of oocytes retrieved, the ongoing, cumulative and live birth rates and obstetric outcomes., What Is Known Already: Corifollitropin alfa is a recombinant FSH (rFSH) preparation with slow absorption and a long half-life allowing administration of a single dose for COS lasting 7 days. Several randomized, controlled clinical trials have reported that COS with corifollitropin alfa is associated with similar outcomes compared with COS using daily rFSH. However, limited data are available in Asian patients., Study Design Size Duration: This randomized controlled trial was conducted at a single large IVF centre in Vietnam from June 2015 to August 2016. A total of 400 patients were included, 200 in each treatment group. The primary outcome measure was the number of oocytes retrieved. Patients were followed for 1 year after randomization., Participants /materials Setting Methods: Participants aged 35-42 years with a body weight ≥50 kg who were undergoing an IVF cycle were randomized to undergo COS with a single dose of corifollitropin alfa 150 μg on Day 2 or 3 of the menstrual cycle, or follitropin beta 300 IU/day for 7 days starting on Day 2 or 3 of the menstrual cycle. All underwent ICSI according to standard institutional protocols. A beta hCG test was performed 17 days after ovum pick-up, and positive tests were confirmed on vaginal and/or abdominal ultrasound at 5-6 weeks after embryo transfer (clinical pregnancy) and at ≥10 weeks (ongoing pregnancy). Rates of ovarian hyperstimulation syndrome, and maternal and foetal outcomes after one cycle of ICSI were monitored over 12 months., Main Results and the Role of Chance: Patients in the corifollitropin alfa and follitropin beta groups were well matched at baseline (mean age 37.5 ± 1.9 vs 37.7 ± 2.0 years, mean body weight 53.7 ± 5.4 vs 52.5 ± 4.8 kg). There was no significant difference between the corifollitropin alfa and follitropin beta groups in the number of oocytes retrieved (11.4 ± 5.9 vs 10.8 ± 5.8; P = 0.338). The ongoing pregnancy rate (31.5 vs 32.0%; P = 0.99) and live birth rate (30.5 vs 32.0%; P = 0.83) (both per initiated cycle at 12 months after randomization) were also similar in the two treatment groups. Complication rates were low and similar in the corifollitropin alfa and follitropin beta groups, and there were no significant between-group differences in obstetric outcomes., Limitations Reasons for Caution: This study had an open-label design, and therefore, the potential for bias cannot be excluded. The findings are only applicable to patient populations with similar characteristics to those enroled in the study., Wider Implications of the Findings: This study adds to the body of evidence supporting the equivalence of corifollitropin alfa and follitropin beta for COS in a variety of patients undergoing IVF and/or ICSI. The ability to provide COS with corifollitropin alfa has the potential to reduce the burden of treatment for patients., Study Funding/competing Interests: This study was supported by Merck Sharp and Dohme. The authors state that they have no financial or commercial conflicts of interest., Trial Registration Number: The trial was registered with clinicaltrials.gov (NCT02466204)., Trial Registration Date: 2 June 2015., Date of First Patient’s Enrolment: 19 June 2015.

Anovulation is a common cause of female subfertility. Treatment of anovulation is aimed at induction of ovulation. In women with clomiphene-citrate resistant WHO group II anovulation, one of the treatment options is ovulation induction with exogenous follicle-stimulating hormone (FSH or follitropin). FSH is derived from urine or is produced as recombinant FSH. Two forms of recombinant FSH are available - follitropin alpha and follitropin beta. To evaluate the efficacy, safety, costs and acceptability of recombinant FSH, we performed a review to compare recombinant FSH with urinary-derived FSH products. Follitropin alpha, beta and urinary FSH products appeared to be equally effective in terms of pregnancy rates. Patient safety was also found to be comparable, as the incidence of side effects including multiple pregnancies was similar for all FSH products. In practice follitropin alpha and beta may be more convenient to use due to the ease of self-administration, but they are also more expensive than the urinary products.