Single-chain human follicle-stimulating hormone with a di-N-glycosylated linker.

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.

Conventional ovarian stimulation vs. delayed single dose corifollitropin alfa ovarian stimulation in oocyte donors: a prospective randomized study. Tail trial.

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.

Low responders may benefit from undergoing ovarian stimulation with a long GnRH agonist protocol with corifollitropin alfa followed by hMG.

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.

Corifollitropin Alfa for Controlled Ovarian Stimulation in Assisted Reproductive Technologies: State of the Art / Alfacorifolitropina para estimulação ovariana controlada em tecnologias de reprodução assistida: Estado da arte

Abstract Physical and emotional burdens during the journey of infertile people through assisted reproductive technologies are sufficient to justify the efforts in developing patient-friendly treatment strategies. Thus, shorter duration of ovarian stimulation protocols and the need for less injections may improve adherence, prevent mistakes, and reduce financial costs. Therefore, the sustained follicle-stimulating action of corifollitropin alfa may be the most differentiating pharmacokinetic characteristic among available gonadotropins. In this paper, we gather the evidence on its use, aiming to provide the information needed for considering it as a first choice when a patient-friendly strategy is desired.

Resumo O desgaste físico e emocional durante a jornada de pessoas inférteis pelas tecnologias de reprodução assistida é suficiente para justificar esforços no desenvolvimento de estratégias de tratamento compassivas. Desta forma, a menor duração dos protocolos de estimulação ovariana e a necessidade de menos injeções podem melhorar a adesão, prevenir erros e reduzir custos financeiros. Portanto, a estimulação folicular sustentada da alfacorifolitropina parece ser a característica farmacocinética que melhor a diferencia das gonadotrofinas atualmente disponíveis no mercado. No presente artigo, reunimos evidências sobre seu uso, com o objetivo de fornecer as informações necessárias para considerá-la como primeira escolha quando se deseja uma estratégia amigável ao paciente.

Corifollitropin Alfa Combined With Human Chorionic Gonadotropin in Adolescent Boys With Hypogonadotropic Hypogonadism.

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).

Patient burden and healthcare resource utilization of regimens for ovarian stimulation.

RESEARCH QUESTION: 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? DESIGN: 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. RESULTS: 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. CONCLUSIONS: Treatment with corifollitropin alfa resulted in similar or numerically small differences in psychological impact and lower clinic service use compared with daily gonadotrophin regimens.

Comparison of the number of oocytes obtained after ovarian stimulation between Chinese and Caucasian women undergoing in vitro fertilization using a standardized stimulation regime.

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.

IVF protocol efficacy in women with expected suboptimal response depending on ovary stimulation mode.

INVESTIGATION OBJECTIVE: IVF protocol efficacy estimation in women with expected suboptimal response depending on ovary stimulation mode. MATERIALS AND TECHNIQUE: 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. RESULTS: 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. CONCLUSION: 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.

Corifollitropin alfa for poor responders patients, a prospective randomized study.

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).

Evaluation of the safety and efficacy of corifollitropin alfa combined with GnRH agonist triggering in oocyte donation cycles. A prospective longitudinal study.

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<0.001). No significant differences were identified in the clinical pregnancy rate per donor (p=0.13), the delivery rates, the number of oocytes (p=0.35), the number of MII oocytes (p=0.50) and the number of transferred embryos, between the two protocols. However, the luteal phase duration was significantly shorter (p<0.001) in the corifollitropin alpha + GnRH agonist-triggering protocol. Moreover, three cases of moderate OHSS (3.75%) were identified after hCG triggering, whereas no case of OHSS occurred after GnRH agonist ovulation induction (p=0.25). CONCLUSION: The use of corifollitropin alpha combined with a GnRH agonist for triggering is a safe, effective and acceptable protocol for oocyte donors.

Corifollitropin alfa versus follitropin beta: an economic analysis alongside a randomized controlled trial in women undergoing IVF/ICSI.

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

The performance of the Elecsys® anti-Müllerian hormone assay in predicting extremes of ovarian response to corifollitropin alfa.

RESEARCH QUESTION: 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)? DESIGN: 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. RESULTS: 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%. CONCLUSIONS: 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.

A pilot study comparing corifollitropin alfa associated with hp-HMG versus high dose rFSH antagonist protocols for ovarian stimulation in poor responders.

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.

A novel strategy of using corifollitropin alfa in the ultrashort gonadotropin-releasing hormone agonist (GnRHa) protocol in unselected patients: A patient-friendly alternative.

OBJECTIVE: To compare the outcomes of in vitro fertilization (IVF) and fresh embryo transfer (ET) using corifollitropin alfa in ultrashort gonadotropin-releasing hormone agonist (GnRHa) protocol and GnRH antagonist protocol. MATERIALS AND METHODS: A total of 245 unselected patients undergoing IVF/fresh ET were enrolled between January 1 and December 31, 2017, including 135 treated with ultrashort GnRHa protocol and 110 treated with antagonist protocol. The primary outcomes were number of total injections and outpatient department (OPD) visits before ovulation triggering. The secondary outcomes were the duration of stimulation, dosage of additional gonadotropin for ovarian hyperstimulation, rates of pregnancy, clinical pregnancy, live birth, ovarian response, and ovarian hyperstimulation syndrome (OHSS) rate. RESULTS: Patients treated with ultrashort GnRHa required less additional gonadotropin, fewer total injections, but had better ovarian responses, including more oocytes retrieved, more metaphase II oocytes, and more blastocysts than those treated with antagonist did. A premature LH surge occurred only in six patients treated with antagonist protocol. The rates of pregnancy (37.0% vs. 43.6%), clinical pregnancy (25.2% vs. 34.6%), and live birth (19.3% vs. 30.0%) did not differ significantly between the two groups. The OHSS rate was similar in the two groups. CONCLUSION: In unselected patients using corifollitropin alfa, the ultrashort GnRHa protocol needed lower dose of additional gonadotropin and fewer injections but produced similar pregnancy outcomes than antagonist protocol did, suggesting that the ultrashort GnRHa protocol could be an alternative.

Corifollitropin- α compared to daily r-FSH in for patients undergoing intracytoplasmic sperm injection: Clinical trial study.

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.

Is corifollitropin alfa effective in controlled ovarian stimulation among all poor ovarian responders? A retrospective comparative study.

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.

Cumulative Live Birth Rates Following Stimulation With Corifollitropin Alfa Compared With hp-hMG in a GnRH Antagonist Protocol in Poor Ovarian Responders.

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.

Corifollitropin alfa for ovarian stimulation in in vitro fertilization: a systematic review and meta-analysis of randomized controlled trials.

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.

Pituitary suppression protocol among Bologna poor responders undergoing ovarian stimulation using corifollitropin alfa: does it play any role?

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.

Gene expression profiles of human granulosa cells treated with bioequivalent doses of corifollitropin alfa (CFA) or recombinant human follicle-stimulating hormone (recFSH).

Using recombinant DNA technologies, a chimeric gene containing the coding sequences of follicle stimulating hormone (FSH) ß-subunit and C-terminal peptide of the human chorionic gonadotrophin (hCG) ß-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.