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Research question The cost of IVF treatment remains high, among other factors because of the medication needed for ovarian stimulation. This study investigated the effect of using low-dose human chorionic gonadotrophin (HCG) for the second phase of follicular maturation after corifollitropin alfa induction, to replace the more expensive, either recombinant or human menopausal gonadotrophin (HMG), on the cost of ovarian stimulation. Design One hundred and five patients were randomly divided into two groups: patients in the HCG group (n = 50) received low-dose HCG from Day 7 until the diameter of at least three follicles reached 17 mm or more, while patients in the FSH group (n = 55) received conventional ovarian stimulation with highly purified HMG injections. Results The clinical pregnancy rate in the HCG group was 38% higher than in the FSH group (number needed to treat, NNT = 13). The cost per pregnancy needed for ovarian stimulation was reduced from €4902 in the FSH group to €2684 in the HCG group. Hence, the cost of ovarian stimulation medication to obtain 10 pregnancies using the conventional FSH protocol is sufficient to attain 18 pregnancies when applying the low-dose HCG protocol. Conclusion This study provides evidence that using HCG instead of HMG/FSH for ovarian stimulation results in a significant reduction in the cost of IVF with, at least, an equivalent pregnancy rate.

Study question How machine learning assisted in generating patient-friendly corifollitropin alfa protocol in normal responders? Summary answer In retrospective experiments, our machine learning model integrated physiological measurements of patients and clinical experience to generate a patient-friendly corifollitropin alfa protocol. What is known already Long-acting corifollitropin alfa can simplify the regimen, minimizing injections during the whole cycle. The previous study has described the patient-friendly protocol using corifollitropin alfa without routine pituitary suppression in normal responder can result in non-compromised clinical outcomes. Some studies showed machine learning can help with making clinical decisions and have the ability to learn from physiological measurements. Those methods effectuate certain points throughout short-acting menotropin protocols, however, there are still no robust AI tools for long-acting corifollitropin alfa protocols. Study design, size, duration 1,309 cycles were collected at Stork Fertility Center from November 2016 to October 2019, and 1,221 cycles were available after data cleaning and applying exclusion criteria, which Anti-Mullerian Hormone (AMH) is lower than 2. The data from electronic medical records (EMRs) consisted of age, AMH, body weight, luteinizing hormone (LH), and estradiol (E2) concentrations measured on revisit. Evaluation is performed by one physician who has more than 20 years of experience in IVF. Participants/materials, setting, methods: The protocol generator consisted of 5 parts: doses of Elonva, trigger type, doses of recombinant follicle-stimulating hormone (rFSH), doses of recombinant luteinizing hormone (rLH), and day of oocyte retrieval. The protocol was predicted by age, AMH, and weight firstly, then fine-tuned by LH and E2 after the first revisit. We used the gradient boosting decision tree algorithm to learn the protocol. The dataset was randomly split into 80% for training and 20% for testing. Main results and the role of chance In classification, the model predicted the dose of Elonva achieved an accuracy of 0.913 and an AUC of 0.946, and trigger type got an accuracy of 0.901 and AUC of 0.852 only using features on stimulation day (SD) 1 and gained 0.012 and 0.056 in accuracy and AUC correspondingly after adding features on the first revisit day. In regression, the mean absolute error (MAE) of rFSH dose, rLH dose, and oocytes retrieved day was 156.30 IU, 232.75 IU, and 0.80 days respectively, and after refining, the MAE dropped to 92.37 IU, 100.07 IU, and 0.46 days. The error of predictions in rFSH and rLH was almost equal to half increments of rFSH (150 IU) and one increment rLH (75 IU). This indicated that our model could provide a better prediction of these clinical decisions with one revisit only. Limitations, reasons for caution The present study was a single-center retrospective, and only analyzed the data from normal responders, whose AMH was equal or greater than 2. Though, the recommendations of our system act as references, the physician will make the final decision. Wider implications of the findings: Our result showed the potential of machine learning in generating protocols is promising. Recommendations generated by our model can provide the junior clinical teams to optimize the clinical plans and learn from the experience of experts. We look forward to applying our machine learning model to different protocols. Trial registration number Not applicable

Background: Corifollitropin alfa in GnRH antagonist protocol could provide a friendly treatment for IVF patients. There is limited evidence regarding the outcomes of corifollitropin alfa in ovarian hyperstimulation in Asian population. Methods: This was a retrospective study conducted on IVF women from July 2012 to July 2018. The recruited patients were expected normal responders, expected poor responders and oocyte donors. The patients underwent GnRH antagonist protocol with corifollitropin alfa. Results: There were 804 IVF patients included in the study. The patients were analyzed into: normal ovarian reserve-autologous cycles ([Formula: see text] 36 years and [Formula: see text] 60 kg, n = 33; [Formula: see text] 36 years and [Formula: see text] 60 kg, n [Formula: see text] 9; [Formula: see text] 36 years and [Formula: see text] 50 kg, n [Formula: see text] 204; [Formula: see text] 36 years and [Formula: see text] 50 kg, n [Formula: see text] 52), normal ovarian reserve-donor cycles ([Formula: see text] 60 kg, n [Formula: see text] 234; [Formula: see text] 60 kg, n [Formula: see text] 104) and diminished ovarian reserve cycles (n [Formula: see text] 168). In each group of patients, the pregnancy outcomes of fresh embryo transfer were comparable to those of frozen embryo transfer. Conclusions: Corifollitropin alfa could offer an effective and simple treatment option for all groups of patients without PCOS.

During the last decade, increased attention has been paid to the development of new treatment approaches in assisted reproduction. It is crucial to establish a safe, effective and comfortable stimulation regimen to increase acceptability and reduce patients’ treatment stress and the high dropout rate that occurs after a failed treatment. The present study aimed to describe the acceptance and results of a novel treatment regimen, consisting of Corifollitropin alfa (CFT) for ovarian stimulation (OS) and oral Desogestrel (DSG) for control of endogenous LH rise in oocyte donors (OD) who had a previous OS cycle with CFT and GnRH-antagonist (ANT) for LH suppression. This retrospective, cohort study, was performed in a private infertility clinic including 42 oocyte donors between April 1st 2016 and April 1st 2017. To evaluate the degree of acceptability of the DSG treatment cycle, a satisfaction questionnaire was used (EFESO questionnaire). When analyzing results, the degree of satisfaction observed with the novel stimulation protocol was high, without finding significant differences between both groups of treatment related to clinical variables.

Background Poor ovarian response remains one of the biggest challenges for reproductive endocrinologists. The introduction of corifollitropin alpha (CFA) offered an alternative option to other gonadotropins for its longer half-life, its more rapid achievement of the threshold and higher FSH levels. We compared two different protocols with CFA, a long agonist and a short antagonist, and a no-CFA protocol. Methods Patients enrolled fulfilled at least two of the followings: AFC 40 years. Ovarian stimulation with an antagonist protocol was performed either with 300 UI rFSH and 150 UI rLH or 300UI HMG. In the long agonist group, after pituitary suppression with triptorelin, CFA was given the 1-2th day of cycle and 300 UI rFSH and 150 UI rLH the 5th day. In the short antagonist group CFA was given the 1-2th day of cycle and 300 UI rFSH and 150 UI rLH the 5th day. The primary objective was the effect on the number of oocytes and MII oocytes. Secondary objective were pregnancy rates, ongoing pregnancies and ongoing pregnancies per intention to treat. Results The use of CFA resulted in a shorter lenght of stimulation and a lower number of suspended treatments. Both the CFA protocols were significantly different from the no-CFA group in the number of retrieved oocytes (p p p Conclusions The long agonist protocol with the addition of rFSH and rLH showed the best results in all the parameters. A short antagonist protocol with CFA was less effective, but not significantly, although provided better results compared to the no-CFA group. We suggest that a long agonist protocol with CFA and recombinant gonadotropins might be a valuable option for poor responders. Trial registration The study was approved by the local Ethics Committee (EudraCT2015–002817-31).

Objective: In order to help make the dream of parenthood come true for oocyte acceptors, it is essential that the procedure is not dangerous or unpleasant for oocyte donors. The aim of this study was to identify differences in safety, efficacy and patient acceptability between a traditional stimulation antagonist protocol with recombinant-FSH (rFSH) with hCG-triggering, compared with an innovative antagonist protocol with corifollitropin alfa (Elonva®) plus GnRH agonist triggering in oocyte donors. Methods: A prospective longitudinal study was conducted at an in vitro fertilization center in Greece. The same eighty donors underwent two consecutive antagonist stimulation schemes. Primary outcomes were patient satisfaction (scored by a questionnaire) and delivery rate per donor. Secondary outcomes were mean number of cumulus-oocyte-complexes, metaphase II (MII) oocytes and ovarian hyperstimulation syndrome (OHSS) rate. Results: Donors reported better adherence and less discomfort with the corifollitropin alpha + GnRH agonist-triggering protocol (p

Objective: The aim of this study was to compare the effect of corifollitropin alfa (CFA) and recombinant follicle-stimulating hormone (rFSH) in poor-responder patients undergoing antagonist cycles. Materials and Methods: The study was a retrospective analysis of the treatment results of 214 poor responder patients who had been admitted to the In Vitro Fertilization Unit of İzmir Medical Park Hospital between November 2014 and November 2016. Intracytoplasmic sperm injections were performed in 38 patients (group 1) with CFA, and the remaining 176 (group 2) with rFSH for controlled ovarian hyperstimulation. Results: The age, body mass index, anti-müllerian hormone level, duration of infertility, duration of induction and antral follicle number were similar in the two groups. There was no difference in the total aspirated oocyte counts, mature oocyte ratio, fertilization rate, implantation rate, and clinical pregnancy rates between the two groups. The implantation rate was 9/38 (23.6%) in group 1 and 42/176 (23.8%) in group 2, whereas the clinical pregnancy rates were 16.3% and 17.2%, respectively. Conclusion: No difference was found in terms of oocyte count, fertilization rate, implantation rate, and clinical pregnancy rates of CFA or rFSH use in the antagonist cycles in poor-responder patients. © 2017 by Turkish Society of Obstetrics and Gynecology.

Recombinant DNA technologies have produced Corifollitropin alfa (CFa) used during IVF/ICSI in order to keep the circulating FSH levels above the threshold necessary to support multi-follicular growth for a week. In this prospective case-control study, we compared 70 participants treated with 150 μg CFa combined with 150 IU of follitropin beta (study group) with 70 subfertile participants with matching baseline characteristics, conforming with the same inclusion criteria and treated with an antagonist protocol using follitropin beta (control group). Live birth was the primary outcome, while secondary outcome measures were IVF/ICSI cycles characteristics, including adverse events and complications. Live birth was determined in reduced rates in the study compared to the control group, reaching statistical significance [6/70 versus 20/70, p = 0.002], as also in the respective number of clinical pregnancies [9/70 versus 23/70, p = 0.005], although the incidence of miscarriage was similar for both groups [6/70 versus 5/70, p 0.99]. Most of the secondary parameters examined were similar between groups. Logistic regression revealed that protocol and AFC had a direct impact on live birth. Ovarian stimulation with CFa does not seem to constitute an equally effective method as compared with follitropin beta to be offered in a general subfertile population seeking IVF/ICSI treatments.

Resume Objectifs Demontrer que la corifollitropine alpha est aussi efficace que la FSH quotidienne dans la stimulation ovarienne controlee des donneuses d’ovocytes. Methodes De janvier 2013 a octobre 2015, 77 cycles de stimulation ovarienne controlee, issus d’une cohorte continue de 77 donneuses d’ovocytes, ont ete analyses. Apres une synchronisation par œstroprogestatifs ou œstrogenes, la stimulation ovarienne a ete initiee par de la corifollitropine alpha (groupe corifollitropine alpha) ou par de la FSH quotidienne (groupe FSH quotidienne). Un antagoniste a la GnRH a ete utilise pour la prevention du pic premature de l’hormone luteinisante (LH). Le declenchement de l’ovulation a ete realise par un agoniste de la GnRH. La duree du traitement, le taux d’œstradiol, le nombre d’ovocytes matures, le taux de fecondation, le taux de grossesses cliniques et evolutives ont ete evalues dans les deux groupes. Resultats Il n’y a pas de difference concernant l’âge, les marqueurs de la reserve ovarienne et la duree du traitement. Le taux moyen d’œstradiol au huitieme jour de la stimulation est plus bas pour le groupe corifollitropine alpha (845 ± 694,5 vs 1742 ± 1177,3, p p = 0,979), avec un taux de fertilisation significativement plus eleve dans le groupe corifollitropine alpha (59,8 % vs 49,3 %, p p = 0,277). Conclusion La corifollitropine alpha utilisee chez les donneuses d’ovocytes offre des avantages en termes de facilite d’emploi avec une efficacite identique compare a la FSH quotidienne.

Research question: Does the type of pituitary suppression protocol influence cumulative live birth rate (LBR) in Bologna poor responders treated with corifollitropin alfa (CFA)? Design: Retrospective cohort analysis including poor responder patients fulfilling the Bologna criteria who underwent their first intracytoplasmic sperm injection cycle using a CFA-based ovarian stimulation protocol between 2011 and 2017. The starting dose of CFA was 150 µg. The primary outcome was cumulative LBR, defined as the first delivery of a live born resulting from the fresh and all the subsequent frozen embryo transfers. Results: A total of 717 cycles were divided into three groups: A (gonadotrophin-releasing hormone [GnRH] antagonist protocol, n = 407), B (long GnRH agonist protocol, n = 224) and C (short GnRH agonist protocol, n = 86). Cumulative LBR did not significantly differ between groups (20.1% versus 17.4% versus 14.0%; P = 0.35). Significantly more patients in Group A had supernumerary embryos cryopreserved (28.3% versus 18.4% versus 11.6%; P < 0.001). Days of additional highly purified human menopausal gonadotrophin 300 IU injections following CFA were significantly different between Groups A, B and C (3 versus 5 versus 3 days; P < 0.001). Multivariate logistic regression analysis showed that the number of oocytes retrieved remained an independent predictive factor (odds ratio 1.23, 95% confidence interval 1.16–1.31) for cumulative LBR. Conclusions: Poor responders according to the Bologna criteria in whom CFA is used for ovarian stimulation had comparable cumulative LBR, irrespective of the type of pituitary suppression. An increase in number of oocytes retrieved is an independent variable related to cumulative LBR., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Bologna criteria poor ovarian responders have a very low prognosis. Although, it has been proposed that LH supplementation could be beneficial in women with previous hypo-response to FSH. There are no studies comparing the cumulative live birth rates (LBRs) between corifollitropin alfa (CFA) and highly purified human menopausal gonadotrophin (hp-hMG). Objective: To compare cumulative LBRs in Bologna poor ovarian responders undergoing ovarian stimulation with CFA followed by hp-hMG vs. hp-hMG alone in a GnRH antagonist protocol. Design: This is a retrospective cohort study. We included in total 917 poor responders fulfilling the Bologna criteria for poor ovarian response (POR) at a university-affiliated tertiary center from January 2011 until March 2017. Patients were administered either fixed daily doses of 300–450 IU of hp-hMG (group A) or a single dose of 150 μg of CFA followed by daily injections of ≥300 IU of hp-hMG from Day 8 of stimulation until the day of ovulation trigger (group B), in a fixed GnRH antagonist protocol. Results: LBRs after fresh embryo transfer (ET) were similar in group A 71/510 (14%) and B 42/407 (10%). Cumulative LBR per cycle was significantly higher in group A (16.9%) compared to group B (11.8%); (P = 0.03). However, logistic regression analysis showed no association between the type of gonadotropin administered and cumulative LBR. Only age was significantly associated with cumulative LBR (OR = 0.93, P = 0.007). Conclusion: Cumulative LBRs are similar in Bologna poor responders stimulated with CFA followed by hp-hMG compared to hp-hMG monotreatment in an antagonist protocol.

Using recombinant DNA technologies, a chimeric gene containing the coding sequences of follicle stimulating hormone (FSH) β-subunit and C-terminal peptide of the human chorionic gonadotrophin (hCG) β-subunit have been designed to generate a new gonadotrophin named corifollitropin alfa (CFA). CFA has longer elimination half-life and slower rate of absorption compared with FSH, which makes CFA a long-acting hormone employed as a substitute of the recombinant FSH (recFSH) in the controlled ovarian stimulation (COS). The purpose of this study is to compare the gene expression profiles elicited by bioequivalent doses of CFA or recFSH in primary cultures of human granulosa cells (hGCs). Gonadotrophins exert their functions by binding FSH receptors (FSHRs), activating signaling pathways that increase the cyclic adenosine monophosphate (cAMP) intracellular content. Bioequivalence has been defined as the dose/duration of gonadotrophin treatment able to promote the same amount of intracellular cAMP. hGCs were treated with different doses of either gonadotrophin and the cAMP was measured after different incubation times to establish the bioequivalence. Results obtained by comparing the bioequivalent treatments, showed that CFA is more effective than recFSH in inducing aromatase gene expression after 6 and 24 h from the initial stimulation in agreement with its long-acting characteristic.

Several studies have compared the effectiveness of corifollitropin alfa versus daily gonadotropins in poor ovarian responders (PORs) undergoing controlled ovarian stimulation (COS), showing conflicting results in terms of IVF outcomes. Given the heterogeneity of patients included in the classification of POR according to 'Bologna criteria', the aim of this study was to evaluate the impact of corifollitropin alfa in two different categories of POR distinguished according to patients' antral follicle count (AFC). We retrospectively evaluated 104 infertile POR, split into two groups according to AFC (Group A ≤ 5; Group B 5) and subgroups according to the ovarian stimulation regimen (corifollitropin alfa plus daily gonadotropins (Subgroup 1) versus daily gonadotropins alone (Subgroup 2)). Outcome measures were total oocytes, MII oocytes, total embryos, follicular output rate (FORT), implantation rate (IR), clinical pregnancy rate (CPR), miscarriage rate (MR), and live birth rate (LBR). Subgroup A1 experienced a lower number of total oocytes, MII oocytes, total embryos, and FORT (

Objective: Corifollitropin alfa is a good choice for assisted reproductive technology (ART) cycles because fewer injections are needed than with other agents. In this retrospective cohort, we analyzed luteal injected half-dose depot gonadotropin hormone-releasing hormone (GnRH) agonist cycles in women who received corifollitropin alfa and those who underwent a conventional corifollitropin alfa cycle with a GnRH antagonist. Material and Methods: In this retrospective cohort, we analyzed luteal injected half-dose depot GnRH agonist cycles in women who received corifollitropin alfa and those who underwent a conventional corifollitropin alfa cycle with a GnRH antagonist at the Division of Reproductive Endocrinology and IVF Unit, Obstetrics and Gynecology Department, Baskent University School of Medicine, Adana, Turkey, from March 2014 to August 2015. The patient's baseline characteristics were similar between the two groups. Forty-five patients underwent the long protocol, in which a half-dose of depot GnRH agonist was administered on day 21 of the preceding cycle. Forty-nine patients underwent the GnRH-antagonist protocol. Corifollitropin alfa was administered on the menstrual cycle day 3. Results: The mean ages of the two groups were similar (32.77+/-5.55 vs. 34.2+/-4.51 years ["for the long-and antagonist-protocol groups, respectively"]). The total number of retrieved oocytes, the fertilization rate, and the number of transferred embryos were similar between the two groups. The only significant difference between the two protocols was the number of injections during the controlled ovarian stimulation (COH) cycle, which included the depot-agonist injection in the long-protocol group (4.46+/-1.64 vs. 5.71+/-2.51, p=0.006). The clinical pregnancy and implantation rates were similar in the two protocols (16/45 [35.6%] vs. 16/49 [32.7%] for the intention to treat and 32.5+/-6.82% vs. 36.25+/-8.58%, respectively). Conclusion: Our results show that ART cycles could be performed with fewer injections using corifollitropin alfa and a half-dose of depot GnRH agonist.

Aim The aim of the present study was to characterize the pharmacokinetic profile of corifollitropin alfa and examine the relationships between dose, intrinsic factors [body weight, body mass index (BMI), age and race] and corifollitropin alfa pharmacokinetics. Methods Data from five phase II and III clinical trials of corifollitropin alfa were evaluated. All subjects included in the analysis received 60 – 180 μg corifollitropin alfa for controlled ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol followed by daily recombinant follicle stimulating hormone (rFSH) from day 8 onwards. Serum corifollitropin alfa levels (across the entire range of treatment) and total follicle stimulating hormone immunoreactivity levels (up to the start of rFSH treatment) were indicators of drug exposure. The analyses were performed using a nonlinear mixed-effects modelling approach. Results A total of 2630 subjects were treated with corifollitropin alfa, and 2557 subjects were evaluable for analysis. Body weight, BMI and race (Asian and Black vs. Caucasian) were significant determinants of corifollitropin alfa exposure. Dose-normalized corifollitropin alfa exposure was ~89% higher in women with a body weight of 50 kg vs. 90 kg (in subjects with a similar BMI of 24 kg m−2); 14% higher in women with a BMI of 18 kg m−2 vs. 32 kg m−2 (provided they were of similar body weight); and ~15.7% lower in Asian subjects and 13% higher in Black subjects vs. Caucasian subjects. Conclusions Body weight was the major determinant of corifollitropin alfa exposure; BMI and race (Asian and Black) were also determinants but to a lesser extent and without associated effects on clinical outcomes. Corifollitropin alfa dose adjustment is indicated, based on body weight but not for BMI or race. These recommendations are consistent with the product label.

There are controversial data about the effect of different controlled ovarian hyperstimulation (COS) protocols on embryological stage and in vitro fertilization (ivf) outcomes. The aim of our study was to evaluate embryological and clinical outcomes according to COS protocol.Material and methods. This prospective cohort study included 521 patients treated with ivf. The patients were divided into the following 5 groups: group 1 - women treated with gonadotrophin-releasing hormone (GnRH) antagonists: subgroup 1a (n=143) - triggering of final oocyte maturation with human chorionic gonadotropin, subgroup 1b (n=85) - with GnRH agonist. Group 2 (n=119) - women treated with GnRH agonists, group 3 (n=82) - women treated in «modified» natural cycle, group 4 (n=92) - women treated with GnRH antagonists and corifollitropin alfa.Results. The lowest percent of empty follicles (78.9%) was observed in group 2. The proportion of mature oocytes (number of mature oocytes|number of cumulus-oocyte complexes) was highest in groups 1a and 2 in comparison with groups 1b and 4 (87.9 and 87.2% vs. 84.0 and 81.9%, respectively). The fertilization rate was maximal in group of women with «modified» natural cycle. The proportion of embryos with different morphological quality was similar in the groups. A clinical pregnancy was observed in 48 (33.6%) cases in group 1a, in 26 (30.6%) patients in group 1b, in 39 (32.8%) casesin group 2 in 7 (8.5%) cases in group 3 and in 17 (18.5%) cases in group 4 (p

Objective To evaluate the effectiveness of corifollitropin alfa in improving the success of IVF. Design Systematic review and meta-analysis. Setting Not applicable. Patient(s) Infertile women undergoing conventional IVF or intracytoplasmic sperm injection (ICSI). Intervention(s) Randomized controlled trials (RCTs) of infertile women undergoing a single IVF/ICSI cycle with either corifollitropin alfa or a conventional ovarian stimulation protocol based on daily injections. The review protocol was registered in PROSPERO before starting the data extraction (CRD42018088605). Main Outcome Measure(s) Primary outcomes were live birth rate and/or ongoing pregnancy rate. Clinical pregnancy rate, miscarriage rate, multiple pregnancies, number of oocytes and embryos obtained, cancellation rate, and rate of ovarian hyperstimulation syndrome and ectopic pregnancy were considered as secondary outcomes. Result(s) Eight randomized controlled trials were included; 2,345 women were assigned to the intervention group and 1,995 to the control group. The analysis of 4,340 IVF cycles did not reveal any difference in live birth rate and/or ongoing pregnancy rate between groups (risk ratio [RR], 0.92; 95% confidence interval [CI], 0.80–1.05). Similarly, no difference was found in clinical pregnancy rate (RR, 0.96; 95% CI, 0.88–1.05; I2 = 0%), miscarriage rate (RR, 0.94; 95% CI, 0.71–1.25; I2 = 0%), or multiple pregnancy rate (RR, 1.22; 95% CI, 0.99–1.50; I2 = 0%). Also, the rates of cycle cancellation, ovarian hyperstimulation syndrome, and ectopic pregnancy were similar in both groups. Sensitivity and subgroup analyses did not provide statistical changes to pooled results. Conclusion(s) Corifollitropin alfa seems to be an alternative for daily recombinant FSH injections in normal and poor responder patients undergoing ovarian stimulation in IVF/ICSI treatment cycles.

International audience; Does corifollitropin alfa associated with hp-HMG protocol from the beginning of ovarian stimulation perform better than high dose rFSH alone for ovarian stimulation with GnRH antagonist in poor responders? This retrospective, monocentric, case-control pilot study was conducted in 65 poor responders (Bologna criteria) undergoing 2 consecutive IVF cycles. All patients underwent a first ovarian stimulation cycle with high dose rFSH (≥300 IU/day) alone in antagonist protocol, unfortunately leading to poor ovarian response and no pregnancy. The following cycle was performed with 150 μg of corifollitropin alfa associated with daily injections of hp-HMG from the beginning of the cycle. The primary outcome was the number of mature oocytes retrieved. The secondary outcomes were ovarian stimulation cancellation and embryo transfer rate per initiated cycle. The number of mature oocytes was not significantly different between the 2 groups. However, cycle cancellation rate was significantly lower and the proportion of cycles with embryo transfer was significantly higher with corifollitropin + hp-HMG protocol, leading to an encouraging clinical pregnancy rate of 24.1% per oocyte retrieval. This pilot study based on corifollitropin alfa associated with hp-HMG from the onset of stimulation appears to be promising for ovarian stimulation in poor responders.

Objective: To compare the results of two ovarian stimulation protocols for IVF in patients at risk of poor ovarian response: corifollitropin alfa followed by hp-hMG versus daily administration of hp-hMG. We intended to demonstrate the non-inferiority of the protocol with corifollitropin alfa. Study design: This is a prospective, randomized, non-inferiority, controlled study. We compared two ovarian stimulation protocols for IVF in 234 patients, under 40 years of age and at risk of poor ovarian response. First protocol was a single injection of 150 mu g corifollitropin alfa and the second, a daily injection of 300 IU of hp-hMG during the first week of ovarian stimulation. In both groups, if necessary, a daily injection of 300 Ill of hp-hMG was dispensed until the criteria for hCG administration are met. For the primary and secondary outcomes, results were analysed by using a one-sided chi-square test or a Fisher exact test, as appropriate, with a level of significance of 0.05. For continuous variables, parametric (independent t-test) or non-parametric (Mann-Whitney test) tests were used depending on the normality of the distribution. Statistical significance was set at P < 0.05. Results: The ongoing pregnancy rate, live birth rate (15.2 vs 20.2) (P = 0.33), and the cumulative live birth rate (15.2 vs 22.0) (P = 0.19) per started cycle did not show significant differences between the corifollitropin alfa and hp-hMG groups, and the difference estimated between treatments was -5% [95% CI: (-15.1, 5.0)]. Conclusions: It was not possible to probe non-inferiority of the protocol with corifollitropin alfa followed by hp-hMG compared to hp-hMG in patients at risk of poor ovarian response undergoing ICSI. (C) 2018 Elsevier B.V. All rights reserved.

This study presents an economic assessment of controlled ovarian stimulation in assisted reproductive technology procedures in Spain, comparing the use of corifollitropin alfa and various forms of recombinant follicle-stimulating hormone (rFSH) in women of advanced maternal age. A cost-minimization analysis (CMA) was performed to assess the cost per cycle of controlled controlled ovarian stimulation, including only direct costs associated with the stimulation phase. The CMA was based on the population characteristics, the protocol, and the results obtained from the PURSUE study, taking into account 9 days of controlled controlled ovarian stimulation and 300 IU rFSH/day. The primary analysis included pharmacological costs alone. Different scenarios were evaluated including various doses and possible additional days (0–5) for rFSH. For the alternative analyses, the total costs (direct pharmacological costs, costs of visits and follow-up tests, and any additional pharmacological costs) were considered in both the private and public sectors. Treatment with corifollitropin alfa resulted in a lower pharmacological cost compared with rFSH (€757.25 and €950.30, respectively), creating a saving of approximately -20%. The results of the scenario analyses showed that corifollitropin alfa reduced the pharmacological cost of controlled ovarian stimulation in comparison with daily administration of doses ≥ 250 IU rFSH (considering same daily dose for all days), regardless of the additional days required (7–12 days) (average -€223; range -€488 to -€44). In conclusion, in addition to the efficacy shown in the PURSUE study, the use of corifollitropin alfa results in a decrease in the direct costs associated with controlled ovarian stimulation in older women in Spain., Highlights • Treatment with corifollitropin alfa in advanced maternal age women created a mean saving of -20% in the pharmacological cost of COS. • 7 days of COS with corifollitropin alfa + 2 additional days with recombinant FSH in older women presented a total cost saving of -11% from the private perspective. • Corifollitropin alfa had lower pharmacological costs relative to doses of 250 IU or higher of daily FSH pharmacological cost of COS regardless the duration of treatment (7-12 days), taking into account older women. • Corifollitropin reduced the cost when considering women aged between 35 and 42 years treated with a rFSH dose of daily 300 UI for the first 7 days and changes in rFSH dose (range 200-375 UI) for the additional days.

Background The current treatment regimen for ovarian stimulation in Intracytoplasmic sperm injection (ICSI) patients is daily injections of Gonadotropins. Recombinant DNA technologies have produced a new recombinant molecule that is a long-acting Follicle Stimulating Hormone (FSH), named corifollitropin alfa. A single injection of long-acting FSH can replace seven daily FSH injections during the first week of controlled ovarian stimulation (COS) and can make assisted reproduction more patients-friendly. There is limited data with different results in this area. Objective To compare the effectiveness of long-acting FSH vs. daily r-FSH in terms of pregnancy and safety outcomes in women undergoing ICSI cycles. Materials and Methods In this clinical trial study, 109 women who were the candidates for ICSI at azzahra hospital were divided in two groups. The first group received 150 units of daily Gonal-f from second or third day of menstruation. The second group received a 150IU corifollitropin alfa on the second or third day of mensuration, and the treatment continued from day eighth of stimulation with Gonal-f based on the ultrasound finding. Both the groups received GnRH antagonist from fifth day of stimulation. Two groups were compared in terms of number of dominant follicles, number of oocytes, stimulation duration, total number of embryos, number of transferred embryos, and success rate of pregnancy. Results No significant difference was found between the two groups in terms of stimulation duration, number of follicles, number of oocytes, total number of embryos, and number of transferred embryos. Moreover, pregnancy outcomes including chemical pregnancy rate (positive pregnancy test), clinical pregnancy rate (detection of fetal heart), the rate of ovarian hyper-stimulation syndrome, multiple-pregnancy, ectopic pregnancy, and miscarriage didn't have a significant difference between the two groups. Conclusion As corifollitropin alfa was as effective as r-FSH, it could be used as an alternative to ovulation stimulation method in patients undergoing ICSI.

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.

Objective This study aimed to compare the outcomes of controlled ovarian stimulation (COS) with corifollitropin alfa versus daily recombinant follicle-stimulating hormone (rRFSH) or highly purified human menopausal gonadotropin (HP-HMG) in patients undergoing in vitro fertilization (IVF) cycles based on gonadotropin-releasing hormone (GnRH) antagonist protocols. The primary endpoints were total number of oocytes and mature oocytes. Methods This retrospective study looked into 132 controlled ovarian stimulation cycles from IVF or oocyte cryopreservation performed in a private human reproduction center between January 1 and December 31, 2014. Enrollment criteria: women aged < 40 years submitted to COS with corifollitropin alfa 100µg or 150µg (n = 26) and rFSH or HP-HMG in the first seven days of treatment with daily doses of 150-225 IU (n = 106); all subjects were on GnRH antagonist protocols. Results The groups had similar mean ages and duration of stimulation. The mean number ± standard deviation of total aspirated oocytes and MII oocytes was 11.9±10 and 10.3±7.9 in the corifollitropin alfa group, and 10.9±7.2 and 8.6±5.7 in the group on rFSH or HMG (p>0.05). There were no significant differences in fertilization (76.9% vs. 76.8%, p=1.0), biochemical pregnancy (66.7% vs. 47.2%, p=0.1561) or embryo implantation rates (68.7% vs. 50%, p=0.2588) between the groups using corifollitropin alfa and rFSH or HMG, respectively. Conclusions Corifollitropin alfa seems to be as effective as rFSH or HP-HMG when used in the first seven days of ovulation induction for patients undergoing assisted reproduction in GnRH antagonist protocols.

To evaluate whether a short follicular phase of ovarian stimulation compromises the chance of pregnancy, subjects from a double-blind, randomized trial treated with a single dose of corifollitropin alfa (n=756) or daily recombinant FSH (n=750) were categorized as early responders if three follicles ⩾17mm were reached and human chorionic gonadotrophin (HCG) was administered prior to or on stimulation day 8, and as normal responders if three follicles ⩾17mm were reached and HCG was administered after stimulation day 8. In the corifollitropin alfa and recombinant FSH groups, 23.2% and 29.1%, respectively, were early responders (P=0.01). Regardless of the treatment group, the initial ovarian response was higher in early responders, but with two extra days of stimulation, the number and size of follicles on the day of HCG in the normal responders was similar to those of the early responders. The number of oocytes was similar in both response groups following corifollitropin alfa treatment (13.6 versus 14.5) and recombinant FSH treatment (12.8, both groups). The ongoing pregnancy rates were comparable for early and normal responders regardless of the treatment group, supporting successful outcome following a stimulation period of only 1week. During ovarian stimulation for assisted reproduction, some women respond earlier than others to treatment with follicle-stimulating agents and require fewer days of treatment. To evaluate whether such short stimulation jeopardizes the chance of pregnancy, clinical outcomes of early responders and normal responders were compared in women aged 18–36years treated with either a single dose of corifollitropin alfa (756 women) or daily recombinant FSH (750 women) for the first 7days of stimulation. On average, about 25% of the evaluated women were early responders. The initial ovarian response was higher in early responders than in normal responders but the number of eggs retrieved and the ongoing pregnancy rates in early and normal responders were similar regardless of the treatment group. This study shows that the chance of ongoing pregnancy was not compromised in women requiring only 1week of stimulation compared with women who required a longer duration of stimulation.

Objective This study evaluated the use of Corifollitropin alfa in patients with previous poor response to recombinant follicle stimulating hormone in long-term protocols using gonadotropin-releasing hormone. Methods Twenty-seven poor responders to previous treatment with the long term protocol using the recombinant follicle stimulating hormone (Group 1) were selected and then submitted to a second attempt using the same long term protocol with Corifollitropin alfa instead of the recombinant follicle stimulating hormone (Group 2).Ovarian down-regulation was achieved using subcutaneous administration of Leuprolide Acetate. Ovarian stimulation was performed with recombinant follicle stimulating hormone until the administration of human chorionic gonadotropin, followed by follicular aspiration (Group 1). Group 2 was submitted to this same protocol using Corifollitropin alfa instead of recombinant follicle stimulating hormone. Results There were significant differences in the number of aspirated oocytes, percentage of mature oocytes, amount of injected oocytes and transferred embryos - with all of these parameters being increased in the Corifollitropin alfa group. In addition, the rates of pregnancy and ongoing pregnancy were also significantly higher in the Corifollitropin alfa group. Conclusion The present study demonstrated that the use of Corifollitropin alfa in the long-term protocol could be a highly effective alternative for patients with poor ovarian response, who were unsuccessful in a previous treatment with In Vitro Fertilization - Intracytoplasmic Sperm Injection.

Corifollitropin alfa ist ein neuartiges Hybridmolekul, das durch Fusion der β-Kette des follikelstimulierenden Hormons (FSH) in der Wildtypvariante mit dem sog. C-terminalen Peptid der β-Kette des humanen Choriongonadotropins gewonnen wird. Aufgrund einer verzogerten Absorption vom Injektionsort und einer verlangerten Halbwertszeit kann Corifollitropin alfa eine multifollikulare Reaktion im Rahmen der ovariellen Stimulation induzieren und uber eine Woche aufrechterhalten. In mehreren Phase-III-Studien wurden Sicherheit und Effektivitat von Corifollitropin alfa uberpruft. Der Wirkstoff ist dem herkommlichen Vorgehen – tagliche Einzelinjektionen von rekombinantem FSH – in Bezug auf die Schwangerschaftswahrscheinlichkeit, die Zahl der Eizellen nach Stimulation sowie das Risiko eines ovariellen Uberstimulationssyndroms ebenburtig. Eine Immunreaktion auf Corifollitropin alfa konnte in Phase-III-Studien nicht beobachtet werden.

Corifollitropin alfa (also referred to originally as follicle-stimulating hormone [FSH]–carboxi terminal peptide and Org-36286) is a new artificial gonadotropin commercially available for women undergoing controlled ovarian follicle stimulation for IVF or intracytoplasmic sperm injection procedures. It is an artificial chimeric recombinant FSH analog, and its development has taken more than 20 years in order to show its functionality, safety and efficacy. Corifollitropin alfa has a similar functionality to natural FSH but with a longer half-life, among different pharmacokinetic parameters. This has allowed for the development of a new protocol with gonadotropin-releasing hormone antagonists, where the first seven daily injections of 150 IU recombinant have been substituted by a single initial 100 or 150 µg Corifollitropin alfa dose with no safety or efficacy differences, measured by either the number of retrieved oocytes or pregnancy rates.

Die ovarielle Stimulation ist integraler Bestandteil der In-vitro-Fertilisation- (IVF-)Behandlung und tragt wesentlich zur Effizienz des Verfahrens bei. Sie ist eine komplexe und haufig fur die Patientin als Belastung empfundene Modalitat der IVF-Behandlung, da sie gewohnlich die tagliche Selbstinjektion von follikelstimulierendem Hormon (FSH) beinhaltet. Das jungst entwickelte FSH-Praparat, FSH-CTP (Corifollitropin alfa), ist ein rekombinantes, lang wirksames Derivat des FSH-Molekuls. Es besteht aus der α-Untereinheit des humanen FSH und einer hybridisierten Untereinheit, die sich aus dem CTP (Carboxy-terminales Peptid) der β-Untereinheit des humanen Choriongonadotropins (hCG) gekoppelt mit der FSH-β-Untereinheit zusammensetzt. Phase-III-Daten zeigen, dass das FSH-CTP uber mehrere Tage wirkt und ahnlich effektiv und sicher ist wie die tagliche FSH-Verabreichung im Rahmen der ovariellen Stimulation zur IVF. Somit ist es geeignet, die Anzahl der fur die Stimulation notwendigen Selbstinjektionen deutlich zu senken und damit die Behandlungsbelastung fur die Patientin zu reduzieren. Dies konnte die Akzeptanz bei Patientinnen erhohen, die sich der kontrollierten Ovarstimulation unterziehen.

The present study offers a meta-analysis of published randomized controlled trials (RCTs) evaluating the outcomes of in vitro fertilization (IVF) cycles using corifollitropin alfa for controlled ovarian stimulation (COS) in comparison with daily recombinant FSH (rFSH). The study examined seven RCTs including 2138 patients receiving corifollitropin alfa and 1788 women receiving daily rFSH for COS. As a novel aspect, this meta-analysis included two specific subpopulations of IVF patients, i.e. egg donors and poor responders. There were no significant differences between corifollitropin alfa and rFSH with respect to the majority of the clinical parameters considered, and comparable were the outcomes in terms of live birth rate, ongoing pregnancy rate, and clinical pregnancy rate. Women receiving corifollitropin alfa had a significantly higher number of metaphase II oocytes at ovum pick-up, and number of formed embryos, in comparison to rFSH. The risk of cycle cancellation due to overstimulation was significantly higher in the corifollitropin alfa group. Ovarian hyperstimulation syndrome (OHSS) incidence was statistically comparable between patients receiving long lasting or daily rFSH. Nevertheless, in view of the fact that corifollitropin alfa resulted in a higher number of metaphase II oocytes collected and a higher number of cycles cancelled due to overstimulation, corifollitropin alfa should be cautiously considered in women with the potential of being hyper responders.

To investigate efficacy and safety of a controlled ovarian stimulation (COS) protocol in which a single dose of Corifollitropin-alfa (CFα) was administered on day 4 of a GnRH-antagonist cycle.Cohort case-control study.University Hospital.One hundred twenty-two normally cycling women expected to be normal responders to COS.In 61 patients, CFα (100-150 μg) was injected subcutaneously on day 4 of a spontaneous menstrual cycle; a GnRH-antagonist was added from day 8 (fixed protocol; 0.25 mg/day). If needed to complete follicular maturation, recombinant FSH (rFSH) daily injections (150/200 IU/day) were given from day 11. A control group of 61 matched women was stimulated with daily subcutaneous injections of rFSH (100-150 U/day) from day 4 of the cycle, and received GnRH-antagonist (0.25 mg/day) from day 8. IVF or ICSI was performed according to the sperm characteristics, and 1-2 embryos were transferred in utero under US guidance on day 2.Number of retrieved cumulus-oocyte complexes (COCs), clinical pregnancy rate (PR), implantation rate (IR), ongoing PR at 10 weeks, number of injections/cycle, ovarian hyperstimulation syndrome (OHSS) rate.No cycle was cancelled and the mean number of retrieved COCs was comparable in patients and controls. About 60% of CF-alfa treated women had no need of daily rFSH addition, and the mean number of injections/cycle was significantly lower in the CF-alfa group than in controls (p 0.05). The ongoing PR/transfer was 36.8% in CF-alfa group and 37.5% in controls. No patient developed severe OHSS, and the incidence of moderate OHSS was similar in cases and controls.CFα may be started on day 4 of the cycle obtaining results comparable to those of a COS using day 4-start daily rFSH, with significantly less injections and a similar risk of OHSS.

Background This secondary analysis aimed to identify predictors of low (18 oocytes retrieved) in IVF patients undergoing controlled ovarian stimulation with corifollitropin alfa in a gonadotropin-releasing hormone (GnRH) antagonist protocol. Methods Statistical model building for high and low ovarian response was based on the 150 μg corifollitropin alfa treatment group of the Pursue trial in infertile women aged 35–42 years (n = 694). Results Multivariable logistic regression models were constructed in a stepwise fashion (P

Objective To determine whether individual subject variation in ovarian response between repeated cycles with the same ovarian stimulation protocol can be predicted. Design Retrospective data analysis. Setting Multicenter, open-label, uncontrolled clinical trial. Patient(s) Women aged 18–39 from a phase 3, open-label, uncontrolled trial with complete data across all cycles (n = 176). Intervention(s) Up to three cycles of a single injection of 150 μg corifollitropin alfa for 7 days, then daily recombinant FSH/hMG until three follicles reached ≥17 mm. Gonadotropin-releasing hormone antagonist from stimulation day 5 until day of hCG administration. Main Outcome Measure(s) Numbers of follicles ≥11 mm on day of hCG in cycles 1–3, transition in ovarian response type between cycles from low (0– Result(s) The mean (SD) numbers of follicles ≥11 mm on day of hCG were 13.4 (6.2), 13.3 (5.4), and 13.8 (6.4) in cycles 1, 2 and 3, respectively. Between cycles 1 and 2, 11.9% switched from normal to low or high response, and 12.5% switched from low or high to normal response; 75.6% remained in the same category. Between cycles 2 and 3, 15.9% switched from normal to low or high response, and 10.2% switched from low or high to normal response; 73.9% remained in the same category. These shifts are symmetrical in nature, in that the percentage of subjects who shift from normal to low or high response is comparable to the percentage of subjects who shift from low or high to normal response. Baseline FSH and AFC did not significantly predict transition in ovarian response. Conclusion(s) The variability in ovarian responses between repeated cycles using the same protocol was not explained by baseline FSH and AFC. Clinical Trial Registration Number NCT00696878 Protocol P05714.

Controlled ovarian stimulation (COS) has been recognized as a painstaking process for many people. It involves the maintenance of extended control over endogenous reproductive hormones and continuous dosing with exogenous hormones via abdominal injection.