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Objectives: The high prevalence of poor ovarian response in women undergoing ovarian stimulation is a main therapeutic challenge that affects pregnancy outcomes in such patients. The current clinical trial aimed to compare the pregnancy outcome of corifollitropin alfa (CFA) versus recombinant follicle-stimulating hormone (rFSH) used in the gonadotropin-realizing hormone (GnRH) antagonist protocol in poor ovarian response patients. Materials and Methods: We performed an open-label balanced block randomized clinical trial on 117 Iranian women with poor ovarian responses who were seeking treatment for infertility. Reporting followed the CONSORT 2010 guidelines for parallel group randomized trials. Patients were randomly assigned to the CFA group (a single injection of 150 µg CFA) or the rFSH group (300 IU rFSH on a daily basis). To avoid premature luteinizing hormone (LH) surges, treatment continued with a daily subcutaneous injection of 0.25 ganirelix, starting from day 6 of stimulation up to the hCG administration day. The primary investigated outcomes were the number of obtained oocytes and the number of metaphase II oocytes. Implantation rate, chemical pregnancy, and clinical pregnancy were the secondary outcomes examined, and study participants were followed up to ascertain the interested outcome. Results: The average number of mature follicles in CFA was 5.0±2.1, which was significantly higher than the rFSH group (4.2±1.7) (P = 0.021). The average number of puncture follicles and the number of embryos were significantly higher in the CFA group than in the rFSH group (P < 0.05). Chemical pregnancy was observed in 32.2% and 30.5% of patients in the CFA and recombinant-FSH groups, respectively, and the observed difference was not statistically significant (P = 0.748). We observed no statistically significant difference despite a relatively higher clinical pregnancy in the CFA group (P = 0.398). Conclusions: A single injection of CFA and a daily injection of rFSH could improve pregnancy outcomes in women with poor ovarian responses who underwent IVF. These two alternative treatments could be used interchangeably, and we highlighted no superiority between CFA and rFSH. [ABSTRACT FROM AUTHOR]

Objectives: The high prevalence of poor ovarian response in women undergoing ovarian stimulation is a main therapeutic challenge that affects pregnancy outcomes in such patients. The current clinical trial aimed to compare the pregnancy outcome of corifollitropin alfa (CFA) versus recombinant follicle-stimulating hormone (rFSH) used in the gonadotropin-realizing hormone (GnRH) antagonist protocol in poor ovarian response patients. Materials and Methods: We performed an open-label balanced block randomized clinical trial on 117 Iranian women with poor ovarian responses who were seeking treatment for infertility. Reporting followed the CONSORT 2010 guidelines for parallel group randomized trials. Patients were randomly assigned to the CFA group (a single injection of 150 µg CFA) or the rFSH group (300 IU rFSH on a daily basis). To avoid premature luteinizing hormone (LH) surges, treatment continued with a daily subcutaneous injection of 0.25 ganirelix, starting from day 6 of stimulation up to the hCG administration day. The primary investigated outcomes were the number of obtained oocytes and the number of metaphase II oocytes. Implantation rate, chemical pregnancy, and clinical pregnancy were the secondary outcomes examined, and study participants were followed up to ascertain the interested outcome. Results: The average number of mature follicles in CFA was 5.0±2.1, which was significantly higher than the rFSH group (4.2±1.7) (P=0.021). The average number of puncture follicles and the number of embryos were significantly higher in the CFA group than in the rFSH group (P

The classic way to produce single-chain (sc) glycoprotein hormones is to fuse their two subunits through the carboxy-terminal peptide (CTP) from human Choriogonadotropin (hCG). The CTP confers a longer half-life to single-chain hormones thanks to its four O-glycosyl side chains. However, unlike syncytiotrophoblastic cells, most cells used for recombinant protein production do not transfer O-glycosyl chains efficiently. We thus choose to fuse the hFSH subunits with a linker comprising two N -glycosyl side chains (sc-hFSH LNN) or none (sc-hFSH L0N), that were generated using two expression systems, HEK293 and CHO K1 cells. Their production levels and biological activities were tested and compared. Both expression systems successfully produced biologically active sc-hFSH, but, in our hands, CHO K1 cells yielded about 30-fold higher amounts of recombinant protein than HEK293 cells. Moreover, sc-hFSH L0N was considerably less expressed than sc-hFSH LNN in both cell types. Our data show that sc-hFSH L0N and sc-hFSH LNN produced from both cell lines stimulate cAMP and progesterone production in mLTC cells expressing hFSH receptors and exhibit similar B/I (in vitro Bioactivity/Immuno activity) ratios. Finally, the ratio of in vivo / in vitro bioactivities for sc-hFSH LNN relative to natural pituitary heterodimeric hFSH increased 8-fold, most likely because of a longer half-life in the blood. [ABSTRACT FROM AUTHOR]

Reproductive medicine is actively developing, and new methods, drugs, and protocols are being developed and introduced for the treatment of infertility. Assisted reproductive technologies (ART) are the most effective methods. In ART protocols, ovarian stimulation (OS) is based on gonadotropin use. The choice of the starting dose of gonadotropin is a critical factor in the successful OS and the effectiveness of ART programs. The article describes the development history of gonadotropins and provides current data on their use in ART programs. The use of biosimilars of follitropin alfa in OS is discussed, and the effectiveness of its Russian biosimilar is also addressed. TRANSLATE with x English Arabic Hebrew Polish Bulgarian Hindi Portuguese Catalan Hmong Daw Romanian Chinese Simplified Hungarian Russian Chinese Traditional Indonesian Slovak Czech Italian Slovenian Danish Japanese Spanish Dutch Klingon Swedish English Korean Thai Estonian Latvian Turkish Finnish Lithuanian Ukrainian French Malay Urdu German Maltese Vietnamese Greek Norwegian Welsh Haitian Creole Persian TRANSLATE with COPY THE URL BELOW Back EMBED THE SNIPPET BELOW IN YOUR SITE Enable collaborative features and customize widget: Bing Webmaster Portal Back

The present study compares two protocols for ovarian controlled stimulation in terms of number of cumulus-oocyte complexes and metaphase II oocytes. We employed a single injection of 150mcg of corifollitropin alfa after a 7-day oral contraceptive pill-free interval for TAIL group and a conventional administration of corifollitropin alfa after a 5-day OCP-free interval with additional rFSH from 8th of ovarian controlled stimulation. Prospective, randomized, comparative, non-inferiority, opened and controlled trial carried out in 180 oocyte donors 31 were excluded, 81 were randomized to the control group and 68 to the TAIL group. No differences were found in the number of follicles larger than 14 and 17 mm at triggering day. However, a lower number of cumulus-oocyte complexes and metaphase II oocytes were obtained in TAIL group compared to the control group, expressed as median (interquartile range): 10.5 (5.5-19) vs. 14 [11-21] and 9 (4-13) vs. 12 (9-17) respectively. Additionally, the incidence of failed retrieval or metaphase II oocytes = 0 was higher in TAIL group 7(10.3%) vs. 1(1.2%) p = 0.024. The use of a single injection of corifollitropin alfa after a 7-day oral contraceptive pill-free interval in oocyte donors resulted in a lower number of cumulus-oocyte complexes and metaphase II oocytes. No additional rFSH was administered in this group. [ABSTRACT FROM AUTHOR]

The present study compares two protocols for ovarian controlled stimulation in terms of number of cumulus-oocyte complexes and metaphase II oocytes. We employed a single injection of 150mcg of corifollitropin alfa after a 7-day oral contraceptive pill-free interval for TAIL group and a conventional administration of corifollitropin alfa after a 5-day OCP-free interval with additional rFSH from 8th of ovarian controlled stimulation. Prospective, randomized, comparative, non-inferiority, opened and controlled trial carried out in 180 oocyte donors 31 were excluded, 81 were randomized to the control group and 68 to the TAIL group. No differences were found in the number of follicles larger than 14 and 17 mm at triggering day. However, a lower number of cumulus-oocyte complexes and metaphase II oocytes were obtained in TAIL group compared to the control group, expressed as median (interquartile range): 10.5 (5.5–19) vs. 14 [11–21] and 9 (4–13) vs. 12 (9–17) respectively. Additionally, the incidence of failed retrieval or metaphase II oocytes = 0 was higher in TAIL group 7(10.3%) vs. 1(1.2%) p = 0.024. The use of a single injection of corifollitropin alfa after a 7-day oral contraceptive pill-free interval in oocyte donors resulted in a lower number of cumulus-oocyte complexes and metaphase II oocytes. No additional rFSH was administered in this group.Clinical Trial Registration:https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-001343-44/results.

Abstract Background In vitro fertilization (IVF) is a well-established method to treat various causes of infertility. Some previous retrospective studies suggested a lower ovarian response in Asian women compared to Caucasian women. However, the ovarian stimulation regimens were not standardized, potentially confounding the findings. The objective of this study is to compare the number of oocytes obtained after ovarian stimulation between Chinese and Caucasian women undergoing IVF using a standardized stimulation regimen. Methods This is a prospective cohort study conducted in two tertiary IVF units in Hong Kong, China and Sydney, Australia from October 2016 to August 2019. A total of 192 women aged 18–42 years with a body weight > 60 kg underwent IVF with a standard ovarian stimulation regimen of 150 micrograms corifollitropin alfa (Elonva®) followed by 200 IU follitropin beta (Puregon®) per day. The number of oocytes retrieved in Chinese women treated in the Hong Kong center was compared to that of Caucasian women treated in the Australian center. Results Serum AMH levels were similar between the two groups. Although women in the Chinese cohort were older and had a higher body mass index (BMI), longer duration of infertility and lower antral follicle count (AFC) than those in the Caucasian cohort in this study, no differences in the number of oocytes retrieved [11 (8–17) vs. 11 (6–17), p=0.29], total dosage and duration of stimulation and number of follicles aspirated were noted between the two ethnic cohorts. The peak estradiol level was greater in Chinese women than in Caucasian women. After controlling for age, BMI and AFC, ethnicity was a significant independent determinant of the number of oocytes obtained. Conclusions Chinese women had a higher number of oocytes after ovarian stimulation using a standardized stimulation regimen compared with Caucasian women undergoing IVF after controlling for age, BMI, AFC and AMH despite presenting later after a longer duration of infertility. Trial registration number: NCT02748278

Context: Adolescent males with hypogonadotropic hypogonadism (HH) have traditionally been treated with exogenous testosterone (T) or human chorionic gonadotropin (hCG) to produce virilization; however, those modalities do not result in growth of the testes and may promote premature maturation and terminal differentiation of Sertoli cells prior to their proliferation, which may impact future fertility. Another option is to use gonadotropins in those individuals to induce testicular growth, proliferation and maturation of Sertoli cells, and production of endogenous T with consequent virilization. Objective: We examined the efficacy and safety of corifollitropin alfa (CFA) combined with hCG for the induction of testicular growth and pubertal development in adolescent boys with HH. Methods: This was a 64-week, multicenter, open-label, single-group study of CFA in adolescent boys, aged 14 to younger than 18 years, with HH. Seventeen participants initiated a 12-week priming period with CFA (100 μg if weight ≤ 60 kg, or 150 μg if weight > 60 kg) given subcutaneously once every 2 weeks, after which they entered a 52-week combined treatment period with CFA, once every 2 weeks, and subcutaneous hCG, twice-weekly (hCG dose adjusted between 500 IU and 5000 IU to keep total T and estradiol levels within protocol-specified ranges). The primary efficacy end point was change from baseline in testicular volume (TV), measured as the sum of volumes of left and right testes by ultrasound. Results: After 64 weeks of therapy with CFA/CFA combined with hCG, geometric mean fold increase from baseline in TV was 9.43 (95% CI, 7.44-11.97) (arithmetic mean of change from baseline at week 64, 13.0 mL). Hormonal, Tanner stage, and growth velocity changes were consistent with initiation and progression of puberty. Treatment was generally well tolerated. No participant developed anti-CFA antibodies. Conclusion: Treatment of adolescent boys with HH with CFA alone for 12 weeks followed by CFA combined with hCG for 52 weeks induced testicular growth accompanied by pubertal progression, increased T, and a pubertal growth spurt (EudraCT: 2015-001878-18). [ABSTRACT FROM AUTHOR]

This literature review focuses on the use of corifollitropin alfa for ovarian stimulation in assisted reproductive technology (ART) programmes in different groups of patients. Corifollitropin alfa is a gonadotropin drug with prolonged FSH activity. The main difference between corifollitropin alfa and other gonadotropins is the higher level of peak FSH, which leads to the recruitment of more follicles. Another feature is the inability to adjust the gonadotropin dose during the first days of ovarian stimulation. In contrast to traditional indications/contraindications for gonadotropins, the use of cortifollitropin is not recommended in combination with GnRH agonists or in patients with polycystic ovary syndrome.Evidence for the feasibility and efficacy of using corifollitropin alfa in patients with various ovarian response variants in ART programmes has been analysed. Most researchers agree that the use of corifollitropin alfa can be recommended for patients with a presumed poor or normal ovarian response. The use of corifollitropin alfa in patients with a presumed excessive response to ovarian timulation is possible when embryo transfer is not expected: in oocyte donation/oocyte vitrification cycles or in "freeze-all" cycles.A significant advantage of using corifollitropin alfa for oocyte donor patients is the single administration of the drug, which can be done in a medical facility, which reduces the risk of prescription non-compliance.The use of corifollitropin alfa in protocols with GnRH agonists requires further research: firstly, corifollitropin alfa has no LH component and secondly, there is no possibility of ovulation trigger replacement in this protocol if there is a high risk of early ovarian hyperstimulation syndrome.

• Ovarian stimulation protocols may contribute to women's stress during IVF treatment • The psychological impact was less with corifollitropin alfa than daily gonadotrophins • The psychological impact of ovarian stimulation increases with treatment intensity Do women receiving corifollitropin alfa with a gonadotrophin-releasing hormone (GnRH) antagonist experience less emotional and/or physical exhaustion than women receiving standard of care gonadotrophin with daily administration of GnRH agonist or antagonist? The CoRifollitropin EvAluation in PracTicE (CREATE) study was a prospective observational study of fertility clinics in 17 countries in Europe and the Asia-Pacific region. Women undergoing IVF were categorized by treatment. Group A received single-dose corifollitropin alfa plus a GnRH antagonist; group B received usual care daily gonadotrophin regimens with a GnRH agonist or antagonist; and group B1i received daily GnRH agonist injections. For the primary analysis, two items from the Controlled Ovarian Stimulation Impact questionnaire were used to assess the level of emotional and physical exhaustion associated with ovarian stimulation. Secondary end-points included the impact of ovarian stimulation-related healthcare resource use. No statistical difference was found between the percentage of participants reporting emotional exhaustion in group A (11.6%) and B (13.1%) or the percentage reporting being 'often' or 'always' physically exhausted. More participants in group B1i (16.4%) reported being emotionally exhausted 'often' or 'always' during ovarian stimulation compared with group A (11.6%; P = 0.026). Patient questionnaire scores for psychological impact were higher in group A compared with group B, indicating less negative impact (72.7 versus 70.9; P = 0.004). Group A had fewer clinic visits, physician consultations, nurse contacts and transvaginal ultrasound scans (all P < 0.001) than group B1. Treatment with corifollitropin alfa resulted in similar or numerically small differences in psychological impact and lower clinic service use compared with daily gonadotrophin regimens. [ABSTRACT FROM AUTHOR]

Abstract 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

Background: Corifollitropin alfa (CFA) is a long-acting recombinant follicle-stimulating hormone (rFSH) used for controlled ovarian stimulation (COS). Several studies analyzing the clinical efficacy and safety of CFA compared to daily rFSH during COS have been carried out. The present study offers a meta-analysis of the randomized controlled trials (RCTs) on this topic. Methods: A computerized search of the published literature was carried out using PubMed, MEDLINE, Science direct and Google Scholar databases. The comparison between CFA and daily rFSH treatments during COS were investigated only in RCTs. The primary endpoint of the study is represented by the number of total oocytes retrieved at ovum pick-up. The studies included in the analysis were pooled together in order to estimate the log odds ratio (OR) or the mean difference (MD) along with the corresponding 95% confidence intervals (CI) by using a random effects model. The heterogeneity between the studies was evaluated with the Higgins and Chi-square tests. Results: The study examined a total of twelve RCTs published from 2004 to date and included a total of 4980 patients, with 2664 receiving CFA and 2316 patients receiving daily rFSH for COS. Women treated with CFA had higher number of total oocytes retrieved at ovum pick-up (MD 0.91, 95% CI [0.34, 1.49], p = 0.001), and higher number of metaphase II (MII) oocytes (MD 1.00, 95% CI [0.37, 1.62], p = 0.002) compared to those receiving daily rFSH. There were no significant differences between the two study groups regarding the other outcomes analyzed. The subgroup analysis performed comparing “normal” versus “poor” responders revealed that normal responders receiving CFA showed an higher cancellation rate, with respect to those receiving rFSH. Conclusions: This study shows that COS with CFA results in a higher number of oocytes retrieved at ovum pick-up in comparison with daily rFSH.

Background: In vitro fertilization (IVF) is a well-established method to treat various causes of infertility. Some previous retrospective studies suggested a lower ovarian response in Asian women compared to Caucasian women. However, the ovarian stimulation regimens were not standardized, potentially confounding the findings. The objective of this study is to compare the number of oocytes obtained after ovarian stimulation between Chinese and Caucasian women undergoing IVF using a standardized stimulation regimen. Methods: This is a prospective cohort study conducted in two tertiary IVF units in Hong Kong, China and Sydney, Australia from October 2016 to August 2019. A total of 192 women aged 18–42 years with a body weight > 60 kg underwent IVF with a standard ovarian stimulation regimen of 150 micrograms corifollitropin alfa (Elonva®) followed by 200 IU follitropin beta (Puregon®) per day. The number of oocytes retrieved in Chinese women treated in the Hong Kong center was compared to that of Caucasian women treated in the Australian center. Results: Serum AMH levels were similar between the two groups. Although women in the Chinese cohort were older and had a higher body mass index (BMI), longer duration of infertility and lower antral follicle count (AFC) than those in the Caucasian cohort in this study, no differences in the number of oocytes retrieved [11 (8–17) vs. 11 (6–17), p=0.29], total dosage and duration of stimulation and number of follicles aspirated were noted between the two ethnic cohorts. The peak estradiol level was greater in Chinese women than in Caucasian women. After controlling for age, BMI and AFC, ethnicity was a significant independent determinant of the number of oocytes obtained. Conclusions: Chinese women had a higher number of oocytes after ovarian stimulation using a standardized stimulation regimen compared with Caucasian women undergoing IVF after controlling for age, BMI, AFC and AMH despite presenting later after a longer duration of infertility. Trial registration number: NCT02748278 [ABSTRACT FROM AUTHOR]

IVF protocol efficacy estimation in women with expected suboptimal response depending on ovary stimulation mode. A randomized controlled study embracing results of 51 IVF cycle in women with ovary suboptimal response. The suboptimal response prognostic analysis was performed basing on ≤9 oocyte cumulus complexes obtained in previous IVF programs, the presence of no less than 5–9 antral follicles in both oocytes and amount of anti-Mullerian Hormone ≥0,8 ng/mL. In Group I (n = 25), the stimulation was performed by recombinant corifollitropin alfa combined with highly purified urinary gonadotropin, while in Group II (n = 26) it was made by means of recombinant follitropin/lutropin alfa within the protocol of applying gonadotropin-releasing hormone antagonists. The total gonadotropin dose in Group II patients was authentically lower compared to Group I (p˂,01). No statistical difference between the two studied groups was detected concerning the number of obtained oocytes, 2pn zygote, good-quality transferred embryos and clinical pregnancy rate (p>.05). Embryo cryopreservation was performed only for group-II patients. Corifollitropin alfa administration combined with highly purified menotropin in IVF cycles for suboptimal responders is quite effective, however, this strategy has no preference over other stimulation modes. The strategy of using recombinant follitropin/lutropin alfa can be promotive to IVF outcomes for suboptimal responders by means of embryo banking. ClinicalTrials.gov Identifier: NCT03177538 [ABSTRACT FROM AUTHOR]

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 ( ≤ 36 years and ≤ 60 kg, n = 33; ≤ 36 years and > 60 kg, n = 9; > 36 years and ≥ 50 kg, n = 204; > 36 years and < 50 kg, n = 52), normal ovarian reserve-donor cycles ( ≤ 60 kg, n = 234; > 60 kg, n = 104) and diminished ovarian reserve cycles (n = 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.

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.

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 < 5, AMH < 1,1 ng/ml, less than three oocytes in a previous cycle, age > 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 < 0,05), with a non-significant difference in favour of the long agonist protocol. Both CFA groups yielded higher pregnancy rates, especially the long protocol, due to the higher number of oocytes retrieved (p < 0,05), as implantation rates did not differ. The cumulative pregnancy rate was also different, due to the higher number of cryopreserved blastocysts (p < 0,02). 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). [ABSTRACT FROM AUTHOR]

What is the performance of anti-Müllerian hormone (AMH) as measured by the Elecsys® AMH assay in predicting ovarian response in women treated with 150 µg corifollitropin alfa (CFA)? Multicentre, prospective study conducted between December 2015 and April 2018. Women were aged 18–43 years, had regular menstrual bleeding, a body mass index of 17–35 kg/m2 and weighed 60 kg or over. Exclusion criteria: previous oophorectomy, history of ovarian hyperstimulation syndrome, a previous IVF and intracytoplasmic sperm injection cycle producing over 30 follicles measuring 11 mm or wider, basal antral follicle count (AFC) over 20 or polycystic ovarian syndrome. All women were treated with 150 μg CFA followed by recombinant FSH (150–300 IU/day) in a fixed gonadotrophin releasing hormone antagonist protocol. Of the 219 patients enrolled, 22.8% had low ovarian response (three or fewer oocytes), 66.2% had normal response and 11% had high ovarian response (15 or more oocytes). The AMH and AFC presented an area under the curve of 0.883 (95% CI 0.830 to 0.936) and 0.879 (95% CI 0.826 to 0.930), respectively, for low ovarian response; and an AUC of 0.865 (95% CI 0.793 to 0.935) and 0.822 (95% CI 0.734 to 0.909) for high ovarian response. An AMH cut-off of 1.0 ng/ml provided a sensitivity of 92.0% and a specificity of 66.9% in the prediction of low ovarian response; a cut-off of 2.25 ng/ml predicted high ovarian response with a sensitivity of 54.2% and a specificity of 91.8%. The automated Elecsys® AMH assay predicts ovarian response in a CFA antagonist protocol. The best predictors of ovarian response in CFA-treated patients were AMH and AFC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose. To define the schemes of induction of superovulation, what are the most pharmacoeconomical founded. Methods. Pharmacoeconomic analysis was performed using the cost minimization analysis on the assumption of equal effectiveness compared schemes of hormonal stimulation, which was confirmed in the review of clinical trials and meta-analysis. To estimate the cost of drugs for ovulation induction we used registered VED rates and recommended in the instructions for medical use and the standard of care for infertility using assisted reproductive technologies dosing regimens. Results. The results of the pharmacoeconomic analysis in according to all scenarios of the initial data, confirmed the pharmacoeconomic advantage of using corifollitropin alfa in comparison with the rFSH (follitropin alfa): 1) 1 732.22 rubles, approximately 5%; 2) 3 269.44 rubles, approximately 7%; 3) 14 955.83 rubles, approximately 30%. Conclusions. The scheme of hormonal stimulation using corifollitropin alfa in according to all scenarios of the initial data is more pharmacoeconomical reasonable, since it economizes the direct of medical costs with comparable efficacy, fewer subcutaneous injections, and the possibility to decrease the duration of stimulation cycle as compared with daily rFSH.

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.

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 (p <.05) in comparison to Subgroup A2, while no difference was found when comparing Subgroups B1 and B2. No difference was found between subgroups even in terms of IR, CPR, MR, and LBR. In conclusion, corifollitropin alfa may be as effective as daily gonadotropins in POR with AFC > 5 undergoing COS, while it might be inferior to daily gonadotropins in POR with AFC ≤ 5. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Does the type of pituitary suppression protocol influence cumulative live birth rate (LBR) in Bologna poor responders treated with corifollitropin alfa (CFA)? 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. 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. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To compare the Follicular Output Rate (FORT) between corifollitropin alfa (CFA) and recombinant follicle-stimulating hormone (rFSH) during controlled ovarian stimulation (COS).Study Design: This retrospective analysis compared FORT between women treated with CFA or rFSH from three clinical trials: ENGAGE (N = 1476; ages 18-36, >60 kg), ENSURE (N = 395; ages 18-36, ≤60 kg), and PURSUE (N = 1388; ages 35-42, ≥50 kg). Women underwent COS in a GnRH antagonist protocol followed by hCG trigger prior to IVF. Antral follicle count (AFC; <11 mm) and pre-ovulatory follicle count (>15 mm) were used for FORT, defined as [pre-ovulatory follicles/AFCx100].Results: For CFA and rFSH, respectively, mean FORT (adjusted for trial and age) was 85.0 versus 76.8 (p < 0.001) in the combined cohort, 86.0 versus 75.0 in ENGAGE (p < 0.001), 96.2 versus 79.2 in ENSURE (p = 0.070), and 74.1 versus 71.2 in PURSUE (p = 0.180); mean oocyte output (oocytes retrieved/AFCx100, adjusted for age) was 121.9 versus 107.3 in ENGAGE (p = 0.001), 133.5 versus 102.3 in ENSURE (p < 0.001), and 100.6 versus 98.1 in PURSUE (p = 0.463). FORT and oocyte output were consistent with the number of metaphase II oocytes retrieved for CFA and rFSH: 10.4 versus 8.8 in ENGAGE (p < 0.001), 10.3 versus 7.6 in ENSURE (p < 0.001), and 7.5 versus 7.2 in PURSUE (p = 0.37). No differences in pregnancy rates based on FORT were observed.Conclusions: FORT was significantly higher in CFA-stimulated cycles and accurately predicted oocyte output. No association of FORT with pregnancy likelihood was found. [ABSTRACT FROM AUTHOR]

Helmy Selman, Leonardo Rinaldi One Day Medical Center–IVF Unit, Roma, Italy Purpose: To evaluate the efficiency and efficacy of corifollitropin alfa (follicle-stimulating hormone–carboxy terminal peptide) in the treatment of poor responder patients. Methods: A total of 85 poor responder patients with a mean age 40.2±3.9 years entered our assisted fertilization program. The patients were prospectively randomized into two groups based on the ovarian stimulation regimen used: group A (study group) (n=42) received clomiphene citrate and corifollitropin alfa for the first 7 days of stimulation followed by recombinant follicle stimulating hormone (rFSH) in a gonadotropin-releasing hormone antagonist protocol, and group B (control group) (n=43) received clomiphene citrate and a daily injection of rFSH in a gonadotropin-releasing hormone antagonist protocol. We analyzed the stimulation outcome, the number of retrieved oocytes, cleaving embryos, and pregnancy and implantation rates as well. Results: Comparable results were observed between the two groups in terms of demographic data, stimulation outcome, and the number of canceled cycles. There were no differences evident between groups A and B with respect to the number of retrieved oocytes (3.0±0.8 and 2.7±0.7, respectively) and the number of cleaving embryos (1.8±0.6 and 1.7±0.7, respectively). Higher, though not statistically significant, differences were observed in favor of group A compared to group B in terms of pregnancy rate per cycle (19% and 16.3%, respectively), pregnancy rate per transfer (21.6% and 17.9%, respectively), and implantation rate (14.7% and 13.4%, respectively). Also, miscarriage rate was similar between patients treated with corifollitropin alfa and those treated with daily rFSH injection (12.5% and 14.2%, respectively). Conclusion: The results show that ovarian stimulation with corifollitropin alfa appears to be as efficacious and efficient as daily injection rFSH regimen to treat patients with poor ovarian response. Keywords: Long-acting FSH, recombinant FSH, ovarian stimulation, ovarian response, pregnancy

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 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 μg 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 IU 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. [ABSTRACT FROM AUTHOR]

Study Question: What is the performance of previously established regression models in predicting low and high ovarian response to 150 μg corifollitropin alfa/GnRH-antagonist ovarian stimulation in an independent dataset?Summary Answer: The outcome of ovarian stimulation with 150 μg corifollitropin alfa in a fixed, multiple dose GnRH-antagonist protocol can be validly predicted using logistic regression models with AMH being of paramount importance.What Is Known Already: Predictors of ovarian response have been identified in FSH/GnRH agonist protocols as well as ovarian stimulation with corifollitropin alfa/GnRH-antagonist. Multivariable response models have been established already, however, external validation of model performance has so far been lacking.Study Design, Size, Duration: Data from a prospective, multi-centre (n = 5), multi-national, investigator-initiated, observational cohort study were analysed. Infertile women (n = 211), body weight >60 kg, were undergoing ovarian stimulation with 150 μg corifollitropin alfa in a GnRH-antagonist multiple dose protocol for transvaginal oocyte retrieval for IVF. Demographic, sonographic and endocrine parameters were prospectively assessed on cycle Day 2 or 3 of spontaneous menstruation before ovarian stimulation. Main outcomes were low (<6 oocytes) and high (>18 oocytes) ovarian response.Participants/materials, Setting, Methods: Firstly, previously established prediction models for low ovarian response (LOR) and high ovarian response (HOR) were tested using the original parameters. Secondly, re-estimated parameters generated from the present data were tested on the established models. Thirdly, for the development of new predictive models of both LOR and HOR, several logistic regression models were estimated. Resulting prediction models were compared by means of the area under the receiver operating characteristic curve (AUC) and bias-corrected Akaike's Information Criterion (AICc) to identify the most reasonable model for each scenario.Main Results and the Role Of Chance: The previously established prediction models for low and high response performed remarkably well on this dataset (low response AUC 0.8879 (95% CI: 0.8185-0.9573) and high response AUC 0.8909 (95% CI: 0.8251-0.9568)). A newly developed simplified model for LOR with log-transformed AMH values and only age as another covariate showed an AUC of 0.8920 (95% CI: 0.8237-0.9603) with the lowest AICc of all models compared. For predicting HOR, we suggest a simplified model using AMH, FSH and AFC (AUC of 0.8976, 95% CI: 0.8206-0.9746).Limitations, Reasons For Caution: All analyses were done on data from women with a body weight >60 kg. The newly developed simplified models may suffer from overfitting and need to be tested in further independent data sets.Wider Implications Of the Findings: Patient selection for ovarian stimulation with corifollitropin alfa should utilize established response prediction models. The clinical impact of this needs to be evaluated in future studies.Study Funding/competing Interest(s): The study was funded by university funds. M.O.S., T.L. and I.R.K. have nothing to declare. G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, IBSA, Glycotope, Abbott, Marckryl Pharma, VitroLife, NMC Healthcare, ReprodWissen, ZIVA and BioSilu.Trial Registration Number: Not applicable. [ABSTRACT FROM AUTHOR]

Background/purpose: The long-acting corifollitropin alfa is comparable to FSH in terms of pregnancy outcomes in normal responders and poor responders. Corifollitropin alfa has never been studied in polycystic ovary syndrome (PCOS) patients because of concerns of excessive ovarian stimulation and ovarian hyperstimulation syndrome (OHSS). The purpose of the study was to evaluate if corifollitropin alfa can be used in PCOS patients.Methods: Forty PCOS patients who were going to undergo in vitro fertilization were enrolled in this study. A single injection of corifollitropin alfa was administered on cycle day 2 or day 3. From stimulation day 8 onwards, daily FSH was administered until the day of final oocyte maturation. Cetrorelix was administered from stimulation day 5 to prevent premature LH surge. Final oocyte maturation was triggered by: acetate. All embryos were cryopreserved and replaced in subsequent cycles.Results: All 40 patients were subjected to oocyte retrieval, and none developed moderate or severe ovarian hyperstimulation syndrome (0%, 95% CI 0-0.088). For each patient, an average of 23.4 (±7.4; 95% CI 21.0-25.7) oocytes were retrieved and a mean of 11.7 (±6.4; 95% CI 9.6-13.8) embryos were frozen. Mean serum estradiol level on the day of GnRHa triggering was 7829.9 pg/ml (±3297; 95% CI 6775-8885). The cumulated ongoing pregnancy rate after 3 frozen-thawed embryo transfers was 75.0% (95% CI 61.6%-88.4%).Conclusion: The results suggest that corifollitropin alfa/GnRH antagonist protocol can be used in PCOS patients, in combination with GnRHa triggering and embryo cryopreservation. [ABSTRACT FROM AUTHOR]

The role of the IVF clinician is to make the ART treatment safe, patient-friendly, cost effective and at the same time offer good and high quality treatment. IVF protocols are a burden for women and are one of the potential reasons why women don′t return for subsequent cycles. Frequent injections may increase stress and also result in high error rates. Simple short treatment regimen with optimal recovery of good quality oocytes results in development of good quality embryos followed by SET in treatment and cryopreservation cycles are a less burden and result in related lesser discontinuation, side effects, treatment cycles in time and are more cost-effective. Development of FSH analogues with longer terminal t1/2 and slower absorption to peak serum levels will increase the efficiency, decrease the side effects and also is easy to administer. This makes it convenient for the patients increasing the compliance. A certain minimum LH concentration is necessary for adequate thecal cell function and subsequent oestradiol synthesis in the granulosa cells. Adjuvant r-HLH gives clinician′s precise control over the dose of LH bioactivity administered to target the therapeutic window. New parenteral, transdermal, inhaled and oral fertility drugs and regimens are currently under research and development with the objective to further simplify treatment for ART.

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. [ABSTRACT FROM AUTHOR]

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Study Question: Does administration of corifollitropin alfa followed by highly purified (hp) HMG result in higher ongoing pregnancy rates compared with daily recombinant FSH (rFSH) in young poor responders?Summary Answer: Corifollitropin alfa followed by hp-HMG does not increase ongoing pregnancy rates compared with rFSH in young poor responders, although more supernumerary cryopreserved embryos were obtained with corifollitropin alfa and hp-HMG.What Is Known Already: Poor ovarian response remains one of the main therapeutic challenges in women undergoing ovarian stimulation, given that very low live birth rates of 6% have been reported in this particular group of infertile patients. Nevertheless, concerns have been raised that a degree of heterogeneity remains, as the prognostic effect of individual factors is still unclear, particularly for the young poor responder group. The rationale for conducting the current randomized trial was based on the results of a previous pilot study demonstrating promising results with the administration of hp-HMG following corifollitropin alpha in women younger than 40 years of age, fulfilling the 'Bologna' criteria.Study Design, Size, Duration: A multicenter, phase III, superiority, randomized trial was conducted using a parallel two-arm design. The study included 152 patients younger than 40 years old and fulfilling the 'Bologna' criteria for poor ovarian response, from one tertiary referral centre in Europe and one tertiary referral centre in Asia. Enrolment was performed from March 2013 to May 2016.Participants/materials, Setting, Methods: Eligible patients were randomized to either administration of 150 μg corifollitropin alfa followed by 300 IU hp-HMG (Group A) or to 300 IU of daily recombinant FSH (Group B) in a fixed GnRH antagonist protocol. The randomization sequence was created using a computer generated randomization list stratified by centre, using 1:1 allocation. The primary outcome was ongoing pregnancy rate (defined as the presence of an intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 9-10 weeks of gestation). Secondary outcomes included embryo cryopreservation rates, clinical and biochemical pregnancy rates and number of oocytes retrieved.Main Results and the Role Of Chance: Overall, 152 poor ovarian responders defined by the 'Bologna' criteria were included in the study. Using an intention-to treat analysis, the ongoing pregnancy rates did not differ significantly between Group A 11/77 (14.3%) and Group B 11/70 (15.7%), absolute difference: -0.4 (-11.5 to 10.8), OR = 0.9 (0.4-2.4). Biochemical and clinical pregnancy rates, live birth rates and the number of oocytes retrieved were also comparable between the two groups. Nevertheless, more patients in the corifollitropin alfa group had cryopreserved embryos compared to the rFSH group [22 (28.6%) versus 10 (14.3%), OR = 2.4 (1.01-5.5)]. Incidentally, Asian patients had significantly lower cancellation rates compared to European poor responders [2/64 (3.1%) versus 17/83 (20.4%), OR = 0.12 (0.03-0.5)]. This discrepancy could be explained by the fact that Asian women were better prognosis patients than European patients, with significantly lower FSH [9.8 (5.3) versus 11.5 (5.4), P = 0.017] and significantly higher AMH [1.1 (0.9) versus 0.4 (0.3), P-value <0.001] levels.Limitations, Reasons For Caution: Ongoing pregnancy rates close to 14% for both treatment groups differ significantly from the hypothesized primary outcome rates used in the power calculation. Therefore, our randomized trial might have been underpowered to detect smaller differences. The use of multiple secondary outcomes and multiple comparisons could have increased a Type 1 error. Finally, although the chance of selection biases remains low given the nature of the infertile population, the open-label design could have been a limitation.Wider Implications Of the Findings: Poor ovarian response represents a challenge and although a specific protocol may have increased the number of cryopreserved embryos, no difference was observed in ongoing pregnancy rates. Our study, being one of the largest RCTs in 'Bologna' criteria poor responders, highlights that baseline characteristics may play a crucial role in clinical prognosis of this population. Given that ovarian stimulation using novel protocols does not seem to significantly increase pregnancy rates even in young women, we suggest that future clinical research should focus on increasing the number of recruitable follicles and on oocyte quality rather than evaluating different stimulation protocols.Study Funding/competing Interests: No external funding was used for this study. P.D., N.L.V., N.A.V.H., A.V., M.T.H., M.C., A.T.L. and A.V.V. have no conflict of interest to report. C.B. has received unrestricted research grants from MSD and Ferring as well as honoraria for lectures from Abbott, MSD, Merck and Ferring. P.H has received unrestricted research grants from MSD, Merck and Ferring as well as honoraria for lectures from Merck, MSD and IBSA. H.T. has received unrestricted research grants from MSD, Merck, Ferring, Cook, Roche Diagnostics, Besins International and Goodlife as well as consultation fees for research project in female infertility from Merck Finox, Abbott and ObsEva. N.P.P. has received unrestricted research grants from MSD, Ferring, Roche Diagnostics and Besins International as well as honoraria for lectures from MSD, Merck and Ferring.Trial Registration Number: The EUDRACT number of the trial was 2013-000583-29 and the study was registered at clinicaltrials.gov (NCT01816321).Trial Registration Date: 19 February 2013.Date Of First Patient Enrolment: 28 February 2013. [ABSTRACT FROM AUTHOR]

In this prospective cohort study, oocyte donors were recruited prospectively and assigned to receive corifollitropin alfa: 5 days after pill discontinuation (group D5; 42 donors), or 7 days after pill discontinuation (group D7; 50 donors) in a gonadotrophin-releasing hormone antagonist protocol. Fixed additional daily doses of 200 IU recombinent FSH (rFSH) were started after 7 days of corifollitropinalfa, until triggering. No significant differences in basal characteristics were observed between both groups. In group D5, mean (SD) total additional rFSH dose was 659 (452) IU; in group D7, total rFSH dose was 459 (356) IU ( P = 0.022). Duration of stimulation was significantly longer in group D5 compared with group D7 ( P = 0.002). No differences were found in total number of oocytes obtained. Total number of injections was significantly lower in group D7 compared with group D5 (9.8 [3.2] versus 11.9 [3.9], respectively; P = 0.004). Total cost of medication used for donor treatment was significantly higher in group D5 than in group D7 ( P = 0.015). After more than 22 days of pill-taking, extending the pill-free interval to 7 days significantly reduces the total dose of gonadotrophins, duration of stimulation, total cost of medication and total number of injections. [ABSTRACT FROM AUTHOR]

Assisted reproductive technologies are well-established treatments for many types of subfertility representing substantial economic and healthcare implications for patients, healthcare providers and society as a whole. In order to optimize outcomes according to the type of gonadotrophins within an oocyte donor programme, we performed an economic evaluation based on data collected in a multicentre, prospective, randomized study within three private clinics belonging to the IVI Group. Results showed no relevant between-group differences in the clinical variables. According to the economic analysis, ovarian stimulation with corifollitropin alfa increased the overall cost of the treatment as well as the cost per retrieved and effective oocyte, although the differences were not statistically significant. In conclusion, cost savings can be achieved using cheaper gonadotrophins during ovarian stimulation. The cost of corifollitropin alfa compared with recombinant FSH and highly purified human menopausal gonadotrophin should be considered when making treatment decisions. [ABSTRACT FROM AUTHOR]

The incidence of low (<6 oocytes) and high (>18 oocytes) ovarian response to 150 µg corifollitropin alfa in relation to anti-Müllerian hormone (AMH) and other biomarkers was studied in a multi-centre ( n = 5), multi-national, prospective, investigator-initiated, observational cohort study. Infertile women ( n = 212), body weight >60 kg, underwent controlled ovarian stimulation in a gonadotrophin-releasing hormone-antagonist multiple-dose protocol. Demographic, sonographic and endocrine parameters were prospectively assessed on cycle day 2 or 3 of a spontaneous menstruation before the administration of 150 µg corifollitropin alfa. Serum AMH showed the best correlation with the number of oocytes obtained among all predictor variables. In receiver-operating characteristic analysis, AMH at a threshold of 0.91 ng/ml showed a sensitivity of 82.4%, specificity of 82.4%, positive predictive value 52.9%and negative predictive value 95.1% for predicting low response (area under the curve [AUC], 95% CI; P -value: 0.853, 0.769–0.936; <0.0001). For predicting high response, the optimal threshold for AMH was 2.58 ng/ml, relating to a sensitivity of 80.0%, specificity 82.1%, positive predictive value 42.5% and negative predictive value 96.1% (AUC, 95% CI; P -value: 0.871, 0.787–0.955; <0.0001). In conclusion, patients with serum AMH concentrations between approximately 0.9 and 2.6 ng/ml were unlikely to show extremes of response. [ABSTRACT FROM AUTHOR]

Background: Hypogonadotropic hypogonadism (HH) in men results in insufficient testicular function and deficiencies in testosterone and spermatogenesis. Combinations of human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) have been successful in the treatment of HH. Corifollitropin alfa is a long-acting FSH-analog with demonstrated action in women seeking infertility care. The aim of this study was to investigate the efficacy and safety of corifollitropin alfa combined with hCG to increase testicular volume and induce spermatogenesis in men with HH. Methods: This was a Phase III, multi-center, open-label, single-arm trial of corifollitropin alfa in azoospermic men aged 18 to 50 years with HH. After 16 weeks of pretreatment of 23 subjects with hCG alone, 18 subjects with normalized testosterone (T) levels who remained azoospermic entered the 52-week combined treatment phase with hCG twice-weekly and 150 μg corifollitropin alfa every other week. The increase in testicular volume (primary efficacy endpoint) and induction of spermatogenesis resulting in a sperm count ≥1 × 106/mL (key secondary efficacy endpoint) during 52 weeks of combined treatment were assessed. Safety was evaluated by the presence of anti-corifollitropin alfa antibodies and the occurrence of adverse events (AEs). Results: Mean (±SD) testicular volume increased from 8.6 (±6.09) mL to 17.8 (±8.93) mL (geometric mean fold increase, 2.30 [95% CI: 2.03, 2.62]); 14 (77.8%) subjects reached a sperm count ≥1 × 106/mL. No subject developed confirmed anti-corifollitropin alfa antibodies during the trial. Treatment was generally well tolerated. Conclusions: Corifollitropin alfa 150 μg administrated every other week combined with twice-weekly hCG for 52 weeks increased testicular volume significantly, and induced spermatogenesis in >75% of men with HH who had remained azoospermic after hCG treatment alone. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the outcomes of a long GnRH agonist protocol with corifollitropin alfa followed by hMG in low responders., Methods: Retrospective cohort study. Patients with a suboptimal previous ovarian response (<9 oocytes) and a normal ovarian reserve (Poseidon groups 1 and 2) were classified in 1) Group 1 (n=88), submitted to a second cycle with a GnRH antagonist protocol using rFSH/hMG; 2) Group 2 (n=66), submitted to a long GnRH agonist protocol with corifollitropin alfa followed by hMG (named as simplified long protocol). Clinical outcomes were compared between groups and between the first/second cycle of each group., Results: Clinical outcomes were similar between groups. There were no differences in the number of oocytes [7(5-11.75) versus 7(5-10), p=0.802], clinical pregnancy (19.3% versus 18.2%, p=0.858) and live birth rates (18.2% versus 15.2%, p=0.619). However, baseline characteristics were different, decoding a poor prognosis among women in group 2. Both groups (1 and 2) had significantly higher number of oocytes, pregnancy, and live birth rates in the second cycle. In group 2, there was a higher rate of embryo transfer (56.1% versus 27.3%, p<0.001). In group 1, despite the similar rate of embryo transfer, there was a higher positive hCG (23.9% versus 8.0%, p=0.004)., Conclusions: Both simplified long protocol and GnRH antagonist protocol are suitable for low responders. The best second cycle clinical outcomes experienced in a population with worse prognosis (group 2) suggests that the simplified long protocol may be a better option, although prospective well-conducted studies must explore this hypothesis.

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, Başkent 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A meta-analysis was conducted of individual patient data ( n = 3292) from three randomized controlled trials of corifollitropin alfa versus rFSH: Engage (150 µg corifollitropin alfa n = 756; 200 IU rFSH n = 750), Ensure (100 µg corifollitropin alfa n = 268; 150 IU rFSH n = 128), and Pursue (150 µg corifollitropin alfa n = 694; 300 IU rFSH n = 696). Women with regular menstrual cycles aged 18–36 and body weight >60 kg (Engage) or ≤60 kg (Ensure), or women aged 35–42 years and body weight ≥50 kg (Pursue), received a single injection (100 µg or 150 µg) of corifollitropin alfa (based on body weight and age) or daily rFSH. The difference (corifollitropin alfa minus rFSH) in the number of oocytes retrieved was +1.0 (95% CI: 0.5–1.5); vital pregnancy rate: −2.2% (95% CI: −5.3%–0.9%); ongoing pregnancy rate: −1.7% (95% CI: −4.7%–1.4%); and live birth rate: −2.0% (95% CI: −5.0%–1.1%). The odds ratio for overall OHSS was 1.15 (95% CI: 0.82–1.61), and for moderate-to-severe OHSS: 1.29 (95% CI: 0.81–2.05). A single dose of corifollitropin alfa for the first 7 days of ovarian stimulation is a generally well-tolerated and similarly effective treatment compared with daily rFSH. [ABSTRACT FROM AUTHOR]