Recombinant Human Follicle-stimulating Hormone Research Articles

Recombinant Human Follicle-Stimulating Hormone in Controlled Ovarian Hyperstimulation with Assisted Reproductive Technology in China: A Cost-Effectiveness Analysis.

To compare the cost-effectiveness of originator (reference) recombinant human follicle stimulating hormone alfa (rhFSH-α) (follitropin alfa, GONAL-f) and its biosimilar (rhFSH, JinSaiHeng) in assisted reproductive technology (ART) from a Chinese patient perspective. A decision tree model was developed to simulate the treatment pathway of infertile women undergoing ART using GONAL-f or JinSaiHeng. Published clinical and cost data were used to evaluate the cost-effectiveness of the rhFSH-α. The cumulative live birth rate (CLBR), direct medical costs and costs per cumulative live birth were estimated via an analytic decision-tree model. CLBR of GONAL-f was higher than JinSaiHeng preparation (88.3% vs 84.4%), while the cost per cumulative live birth was lower (51,475 vs 52,095 CNY). The originator rhFSH-α was associated with higher CLBR and lower cost per cumulative live birth, with incremental cost per additional live birth of 38,096 CNY (Chinese Yuan).

Differential effects of follicle-stimulating hormone glycoforms on the transcriptome profile of cultured rat granulosa cells as disclosed by RNA-seq.

It has been documented that variations in glycosylation on glycoprotein hormones, confer distinctly different biological features to the corresponding glycoforms when multiple in vitro biochemical readings are analyzed. We here applied next generation RNA sequencing to explore changes in the transcriptome of rat granulosa cells exposed for 0, 6, and 12 h to 100 ng/ml of four highly purified follicle-stimulating hormone (FSH) glycoforms, each exhibiting different glycosylation patterns: a. human pituitary FSH18/21 (hypo-glycosylated); b. human pituitary FSH24 (fully glycosylated); c. Equine FSH (eqFSH) (hypo-glycosylated); and d. Chinese-hamster ovary cell-derived human recombinant FSH (recFSH) (fully-glycosylated). Total RNA from triplicate incubations was prepared from FSH glycoform-exposed cultured granulosa cells obtained from DES-pretreated immature female rats, and RNA libraries were sequenced in a HighSeq 2500 sequencer (2 x 125 bp paired-end format, 10-15 x 106 reads/sample). The computational workflow focused on investigating differences among the four FSH glycoforms at three levels: gene expression, enriched biological processes, and perturbed pathways. Among the top 200 differentially expressed genes, only 4 (0.6%) were shared by all 4 glycoforms at 6 h, whereas 118 genes (40%) were shared at 12 h. Follicle-stimulating hormone glycocoforms stimulated different patterns of exclusive and associated up regulated biological processes in a glycoform and time-dependent fashion with more shared biological processes after 12 h of exposure and fewer treatment-specific ones, except for recFSH, which exhibited stronger responses with more specifically associated processes at this time. Similar results were found for down-regulated processes, with a greater number of processes at 6 h or 12 h, depending on the particular glycoform. In general, there were fewer downregulated than upregulated processes at both 6 h and 12 h, with FSH18/21 exhibiting the largest number of down-regulated associated processes at 6 h while eqFSH exhibited the greatest number at 12 h. Signaling cascades, largely linked to cAMP-PKA, MAPK, and PI3/AKT pathways were detected as differentially activated by the glycoforms, with each glycoform exhibiting its own molecular signature. These data extend previous observations demonstrating glycosylation-dependent distinctly different regulation of gene expression and intracellular signaling pathways triggered by FSH in granulosa cells. The results also suggest the importance of individual FSH glycoform glycosylation for the conformation of the ligand-receptor complex and induced signalling pathways.

230 The use of recombinant human follicle-stimulating hormone in comparison to pituitary-derived follicle-stimulating hormone prior to ovum pickup in vitro embryo production in cattle

230 The use of recombinant human follicle-stimulating hormone in comparison to pituitary-derived follicle-stimulating hormone prior to ovum pickup in vitro embryo production in cattle

#394 : The Efficacy of an Individualized Dose of Follitropin Delta on Ovary Reproductive Stimulation and Clinical Outcomes

Background and Aims: Follitropin delta is the third recombinant human follicle-stimulating hormone (r-hFSH) expressed in a host cell line of human fetal retinal origin that currently emphasizes that the actual tendency of administration is a personalized dosing algorithm based on the anti-Mullerian hormone (AMH) and body mass index (BMI) for ovarian stimulation. Methods: In this present manuscript, we aimed to gather all available data published between 2018–2022 regarding the co-administration and administration of follitropin delta and the clinical outcomes reported following an in vitro fertilization (IVF). Results: Follitropin delta is non-inferior in contrast to its previously launched agents for ovarian stimulation, enhancing a similar-to-superior response reflected by both the reproductive and pregnancy outcomes in parallel with a low risk of ovarian hyperstimulation syndrome (OHSS), being well tolerated. The body weight and AMH level are factors that may influence the outcome in a patient. Despite controversy and results that refute these arguments on several occasions, follitropin delta exceeds the benefits of conventional dosing with either follitropin alfa or follitropin beta. Therefore, all post hoc derived analyzes and subgroups of patients who participated in subsequent studies support this statement. Conclusion: Despite the relatively limited range of data in the current literature, most authors provide strong evidence to support the later use of this drug according to patient profiles and overcoming ethnic limitations. Others disagree with these observations, but this topic and this drug have great potential. As such, additional research is needed to fill existing knowledge gaps and extend this experience to a larger scale. Demonstrate overcoming all limitations.

Oral follicle-stimulating hormone receptor agonist affects granulosa cells differently than recombinant human FSH

To determine whether TOP5300, a novel oral follicle-stimulating hormone (FSH) receptor (FSHR) allosteric agonist, elicits a different cellular response than recombinant human FSH (rh-FSH) in human granulosa cells from patients undergoing invitro fertilization. Basic science research with a preclinical allosteric FSHR agonist. University hospital. Patients with infertility at a single academic fertility clinic were recruited under an Institutional Review Board-approved protocol. Primary granulosa cell cultures were established for 41 patients, of whom 8 had normal ovarian reserve (NOR), 17 were of advanced reproductive age (ARA), 12 had a diagnosis of polycystic ovary syndrome (PCOS), and 4 had a combination of diagnoses, such as ARA and PCOS. Primary granulosa-lutein (GL) cell cultures were treated with rh-FSH, TOP5300, or vehicle. Estradiol (E2) production using enzyme-linked immunosorbent assay, steroid pathway gene expression of StAR and aromatase using quantitative polymerase chain reaction, and FSHR membrane localization using immunofluorescence were measured in human GL cells. TOP5300 consistently stimulated E2 production among patients with NOR, ARA, and PCOS. Recombinant FSH was the more potent ligand in GL cells from patients with NOR but was ineffective in cells from patients with ARA or PCOS. The lowest level of FSHR plasma membrane localization was seen in patients with ARA, although FSHR localization was more abundant in cells from patients with PCOS; the highest levels were present in cells from patients with NOR. The localization of FSHR was not affected by TOP5300 relative to rh-FSH in any patient group. TOP5300 stimulated greater expression of StAR and CYP19A1 across cells from all patients with NOR, ARA, and PCOS combined, although rh-FSH was unable to stimulate StAR and aromatase (CYP19A1) expression in cells from patients with PCOS. TOP5300-induced expression of StAR and CYP19A1 mRNA among patients with ARA and NOR was consistently lower than that observed in cells from patients with PCOS. TOP5300 appears to stimulate E2 production and steroidogenic gene expression from GL cells more than rh-FSH in PCOS, relative to patients with ARA and NOR. It does not appear that localization of FSHR at cell membranes is a limiting step for TOP5300 or rh-FSH stimulation of steroidogenic gene expression and E2 production.

Withdrawal notice to: ‘Effectiveness of recombinant human follicle-stimulating hormone (r-hFSH): recombinant human luteinizing hormone versus r-hFSH alone in assisted reproductive technology treatment cycles among women aged 35–40 years: A German database study’ [YBEOG 89C (2023) 102350

Withdrawal notice to: ‘Effectiveness of recombinant human follicle-stimulating hormone (r-hFSH): recombinant human luteinizing hormone versus r-hFSH alone in assisted reproductive technology treatment cycles among women aged 35–40 years: A German database study’ [YBEOG 89C (2023) 102350

WITHDRAWN:Â Effectiveness of recombinant human follicle-stimulating hormone (r-hFSH): recombinant human luteinizing hormone versus r-hFSH alone in assisted reproductive technology treatment cycles among women aged 35–40 years: A German database study

This non-interventional study compared the effectiveness of recombinant human follicle-stimulating hormone (r-hFSH) and recombinant human luteinizing hormone (r-hLH) (2:1 ratio) versus r-hFSH alone for ovarian stimulation (OS) during assisted reproductive technology treatment in women aged 35–40 years, using real-world data from the Deutsches IVF-Register (D·I·R). Numerically higher clinical pregnancy (29.8% [95% CI 28.2, 31.6] vs. 27.8% [26.5, 29.2]) and live birth (20.3% [18.7, 21.8] vs. 18.0% [16.6, 19.4]) rates were observed with r-hFSH:r-hLH versus r-hFSH alone. The treatment effect was consistently higher for r-hFSH:r-hLH compared with r-hFSH alone in terms of clinical pregnancy (relative risk [RR] 1.16 [1.05, 1.26]) and live birth (RR 1.16 [1.02, 1.31]) in a post-hoc analysis of women with 5–14 oocytes retrieved (used as a surrogate for normal ovarian reserve), highlighting the potential benefits of r-hFSH:r-hLH for OS in women aged 35–40 years with normal ovarian reserve.

A semi-automated hybrid HPLC-MS approach for in-depth characterization of intact non-covalent heterodimer glycoforms of gonadotropin biopharmaceuticals

BackgroundGonadotropins are a class of heavily glycosylated protein hormones, thus extremely challenging to characterize by mass spectrometry. As biopharmaceuticals, gonadotropins are prescribed for the treatment of infertility and are derived from different sources: either from pooled urine of pregnant women or upon production in genetically modified Chinese Hamster Ovary cells. Human chorionic gonadotropin (hCG) is sold as a biopharmaceutical under the name Pregnyl® (urinary hCG, u-hCG) and Ovitrelle® (recombinant hCG, r-hCG), and recombinant human follicle stimulating hormone (r-hFSH) is marketed as Gonal-f®. Recently, we reported the exhaustive characterization of r-hCG at different structural levels. ResultsWe implement size exclusion (SE) HPLC-MS to automatize the acquisition of native mass spectra of r-hCG dimer, but also u-hCG and r-hFSH, comparing the drug products up to intact heterodimer level. A hybrid HPLC-MS approach was employed for the characterization of r-hCG, u-hCG and r-hFSH drug products at different structural levels. Released glycans were analyzed by porous graphitized carbon (PGC)-HPLC-MS/MS, glycopeptides by reversed-phase (RP)-HPLC-MS/MS, subunits by RP-HPLC-MS and finally the intact native heterodimers by semi-automated online buffer exchange SE-HPLC-MS. The data were integrated using bioinformatic tools, to finally unravel the composition of 1481 co-existing dimeric glycoforms for r-hCG, 1167 glycoforms for u-hCG, and 1440 glycoforms for r-hFSH, and to compare critical quality attributes of the different drug products such as their degree of sialylation and O-glycosylation. Significance and noveltyThe strong alliance of bioanalytics and bioinformatics data integration at the different structural levels allowed the identification of more than thousand different glycoforms of r-hCG, u-hCG, and r-hFSH. The results showed that these biopharmaceuticals differ considerably in their glycosylation patterns and highlight the importance of in-depth characterization of biopharmaceuticals for quality control.© 2017 Elsevier Inc. All rights reserved.

Correction for: Efficacy and safety of recombinant human follicle-stimulating hormone in patients undergoing in vitro fertilization-embryo transfer.

Correction for: Efficacy and safety of recombinant human follicle-stimulating hormone in patients undergoing in vitro fertilization-embryo transfer.

P-630 Comparison of follitropin delta versus follitropin alfa in progestin-primed ovarian stimulation in IVF

Abstract Study question Is there a difference in a clinical outcome between using follitropin delta and follitropin alfa undergoing a progestin primed ovarian stimulation (PPOS) protocol? Summary answer There was no difference between follitropin delta and follitropin alfa in terms of pregnancy rates. What is known already Follitropin delta (REKOVELLE, Ferring Pharmaceuticals, Switzerland) is the first recombinant human follicle-stimulating hormone (FSH) using the algorithm-based individualized dosing regimen while reducing the risk of ovarian hyperstimulation syndrome (OHSS) as compared with conventional dosing strategies. The efficacy and safety of follitropin delta has been demonstrated in randomized controlled trials (RCTs). Study design, size, duration We performed a retrospective analysis of 645 patients who underwent ovarian stimulation by a PPOS protocol using follitropin delta or follitropin alfa between April 2022 and August 2022. (325 patients using follitropin delta and 320 patients using follitropin alfa, respectively.) Participants/materials, setting, methods 325 cycles of women who used follitropin delta were compared to 320 cycles of women who used follitropin alfa. The following outcomes were analysed; fertilized rate, 2 pronuclear embryo rate, good quality embryo rate, blastocyst rate, good quality blastocyst rate. A total of 499 women who underwent embryo transfer in cryo cycles using natural cycle or hormone replacement cycle were analysed about biochemical pregnancy rate, clinical pregnancy rate. Main results and the role of chance Baseline demographics for 325 women in follitropin delta group and 320 women in follitropin alfa were: age, 35.1±4.3 years and 35.2±4.3 years; number of previous IVF cycles, 1.6±1.6 and 1.7±1.7, respectively. The laboratory data were: fertilization rate, 81.4% and 80.1%, 2 pronuclear embryo rate, 73.9% and 71.5%, good quality cleavage stage embryo rate, 59.4% and 55.9%, blastocyst rate, 58.9% and 55.7%, good quality blastocyst rate, 41.3% and 38.7%, respectively. Only good quality cleavage stage embryo rate and good quality blastocyst rate were significantly higher (P < 0.05) in follitropin delta group. A vitrified-warmed embryo transfer was performed for 257/325 women (79.1%) and 242/320 women (75.6%) and subsequent positive β-human chorionic gonadotropin (βhCG) reported for 218/621 cycles (35.1%) and 194/570 cycles (34.0%), respectively. Ongoing pregnancy rate after embryo transfer were 19.2% (n = 119) and 19.6% (n = 112) and cumulative ongoing pregnancy rate were both 46.3%. Mild OHSS was reported for 131 women (40.3%) and 170 women (53.1%), respectively (P = 0.07). Limitations, reasons for caution This is a non-controlled, retrospective study. Wider implications of the findings The present study shows that in addition to reducing the OHSS risk, follitropin delta in its individualised fixed-dose regimen has the potential to improve the quality of embryos although there was no significant difference in clinical outcomes. Trial registration number not applicable

POvaStim: An online tool for directing individualized FSH doses in ovarian stimulation

POvaStim: An online tool for directing individualized FSH doses in ovarian stimulation

Comparison of two different starting dose of rhFSH in GnRH antagonist protocol for patients with normal ovarian reserve.

To evaluate different starting doses of recombinant human follicle-stimulating hormone (rhFSH) on pregnancy outcomes for patients with normal ovarian reserve during gonadotropin- releasing hormone antagonist (GnRH-ant) protocol-controlled ovarian stimulation of in vitro fertilization (IVF) cycles. In this retrospective study, a total of 1138 patients undergoing IVF cycles following the GnRH-ant protocol were enrolled. Patients were divided into two groups according to the starting dose of rhFSH. 617 patients received a starting dose of rhFSH of 150 IU, and 521 patients received a starting dose of rhFSH of 225 IU. We compared demographic characteristics, ovarian stimulation and embryological characteristics, and pregnancy and birth outcomes between the two groups. Multivariate logistic regression analysis was performed to examine the possible effects of the known potential confounding factors on pregnancy outcomes. The number of oocytes retrieved in the 150 IU rhFSH group was significantly lower than those in the 225 IU rhFSH group. There was no significant difference between the two groups referring to embryological characteristics. The proportion of fresh embryo transfer in the 150 IU rhFSH group was significantly higher than that in the 225 IU rhFSH group (48.30% vs. 40.90%), and there was no difference in the risk of ovarian hyperstimulation syndrome and pregnancy outcomes between the two groups. In conclusion, the starting dose of rhFSH of 150 IU for ovarian stimulation has a similar pregnancy outcome as starting dose of rhFSH of 225 IU in GnRH-ant protocol for patients with normal ovarian reserve. Considering the potential cost-effectiveness and shorter time to live birth, the starting dose of rhFSH of 150 IU may be more suitable than 225 IU.

Optimizing a therapeutic humanized follicle-stimulating hormone-blocking antibody formulation by protein thermal shift assay.

Biopharmaceutical products are formulated using several Food and Drug Administration (FDA) approved excipients within the inactive ingredient limit to maintain their storage stability and shelf life. Here, we have screened and optimized different sets of excipient combinations to yield a thermally stable formulation for the humanized follicle-stimulating hormone (FSH)-blocking antibody, MS-Hu6. We used a protein thermal shift assay in which rising temperatures resulted in the maximal unfolding of the protein at the melting temperature (Tm ). To determine the buffer and pH for a stable solution, four different buffers with a pH range from 3 to 8 were screened. This resulted in maximal Tm s at pH 5.62 for Fab in phosphate buffer and at pH 6.85 for Fc in histidine buffer. Upon testing a range of salt concentrations, MS-Hu6 was found to be more stable at lower concentrations, likely due to reduced hydrophobic effects. Molecular dynamics simulations revealed a higher root-mean-square deviation with 1mM than with 100mM salt, indicating enhanced stability, as noted experimentally. Among the stabilizers tested, Tween 20 was found to yield the highest Tm and reversed the salt effect. Among several polyols/sugars, trehalose and sucrose were found to produce higher thermal stabilities. Finally, binding of recombinant human FSH to MS-Hu6 in a final formulation (20mM phosphate buffer, 1mM NaCl, 0.001% w/v Tween 20, and 260mM trehalose) resulted in a thermal shift (increase in Tm ) for the Fab, but expectedly not in the Fc domain. Given that we used a low dose of MS-Hu6 (1μM), the next challenge would be to determine whether 100-fold higher, industry-standard concentrations are equally stable.

A Narrative Review Discussing the Efficiency of Personalized Dosing Algorithm of Follitropin Delta for Ovarian Stimulation and the Reproductive and Clinical Outcomes.

Background: Follitropin delta is the third recombinant human follicle-stimulating hormone (r-hFSH) expressed in a host cell line of human fetal retinal origin that currently emphasizes that the actual tendency of administration is a personalized dosing algorithm based on the anti-Müllerian hormone (AMH) and body mass index (BMI) for ovarian stimulation. Methods: In this context, we aimed, in the present manuscript, to gather all available data published between 2018-2022 regarding the co-administration and administration of follitropin delta and the clinical outcomes reported following an in vitro fertilization (IVF). Results: Follitropin delta is non-inferior in contrast to its previously launched agents for ovarian stimulation, enhancing a similar-to-superior response reflected by both the reproductive and pregnancy outcomes in parallel with a low risk of ovarian hyperstimulation syndrome (OHSS), being well tolerated. The body weight and AMH level are factors that may influence the outcome in a patient. Despite controversy and results that refute these arguments on several occasions, follitropin delta exceeds the benefits of conventional dosing with either follitropin alfa or follitropin beta. Thus, all post hoc, derived analyses and subsets of patients that participated in subsequent studies support this statement. Conclusions: Despite the relatively limited spectrum of data in the current literature, most authors brought potent proof, supporting the subsequent use of this drug depending on the patient's profile and overcoming ethnic-related limitations. Although others contradict these observations, this topic and drug possess substantial potential, which is why additional studies are mandatory to fill the existing gaps in our knowledge and expand these experiences at a larger scale supported by the obtained reproductive and clinical outcomes that clearly indicate an overcoming of all limitations.

Use of a recombinant human follicle-stimulating hormone:recombinant human luteinizing hormone (r-hFSH:r-hLH) 2:1 combination for controlled ovarian stimulation during assisted reproductive technology treatment: A real-world study of routine practice in the Russian Federation.

Two observational studies in the Russian Federation described patient demographics/clinical decision for treatment with recombinant human follicle-stimulating hormone:recombinant human luteinizing hormone (r-hFSH:r-hLH) 2:1 combination for ovarian stimulation (OS) during assisted reproductive technology (ART) and outcomes, respectively. The first (prospective) study enrolled 500 patients. After post-hoc regrouping to assign patients to discrete groups, 378 (75.6%) met the local Russian label for an r-hFSH:r-hLH 2:1 combination, 105 (21%) were treated according to other physician preference, and 17 (3.4%) met only the ESHRE Bologna criteria for a poor ovarian response. The clinical pregnancy rate per cycle was 30.4%. A total of 158/175 (90.3%) women achieving clinical pregnancy in the prospective study participated in the second (retrospective) study. The live birth rate per cycle was 25.8%. No new safety concerns were reported. These results support the use of the r-hFSH:r-hLH 2:1 combination in patients with a poor/suboptimal response to OS for ART treatment in the Russian Federation.

Cost-effectiveness analysis of recombinant human follicle-stimulating hormone alfa(r-hFSH) and urinary highly purified menopausal gonadotropin (hMG) based on data from a large German registry.

This was a retrospective real-world evidence analysis of the costs per live birth for reference recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) versus highly purified urinary human menopausal gonadotropin (hMG-HP), based on data from a German invitro fertilization registry (RecDate). Pregnancy and live birth rates from the RecDate real-world evidence study over three complete assisted reproductive technology (ART) cycles using the same gonadotropin drug were used as clinical inputs. Costs related to ART treatment and to drugs were obtained from public sources. Treatment with r-hFSH-alfa resulted in higher adjusted cumulative live birth rates versus hMG-HP after one (25.3% vs. 22.3%), two (30.9% vs. 27.5%), and three (31.9% vs. 28.6%) ART cycles. Costs per live birth were lower with r-hFSH-alfa versus hMG-HP after one (€17,938 vs. €20,054), two (€18,251 vs. €20,437), and three (€18,473 vs. €20,680) ART cycles. r-hFSH-alfa was found to be a cost-effective strategy compared with hMG-HP over three cycles.

Originator recombinant human follitropin alfa versus recombinant human follitropin alfa biosimilars in Spain: A cost-effectiveness analysis of assisted reproductive technology related to fresh embryo transfers.

This study compared the cost per live birth and cost-effectiveness of the originator recombinant human follicle-stimulating hormone follitropin alfa (r-hFSH-alfa) and r-hFSH-alfa biosimilars for ovarian stimulation prior to assisted reproductive technology treatment in Spain. A decision tree model was developed, comprising pregnancy and live birth for one treatment cycle with fresh embryo transfer. Clinical inputs were based on a recent meta-analysis by Chua etal. [4]. Cost inputs were extracted from publicly available Spanish sources. The costs per live birth were lower with originator r-hFSH-alfa (€18,138) versus r-hFSH-alfa biosimilars (€20,377). The incremental cost-effectiveness ratio was €7208 for originator r-hFSH-alfa versus biosimilars. Drug acquisition costs for originator r-hFSH-alfa represented 10.5% of total costs in the base case analysis, and 6.2% in a treatment cycle resulting in live birth with one fresh embryo transfer. Results from the sensitivity analyses confirmed the robustness of the findings.

The effect of a single escalating dose of long-acting recombinant human follicle-stimulating hormone Fc fusion protein (KN015) on healthy, pituitary-suppressed women: first-in-human and randomized study on its pharmacokinetics, pharmacodynamics, and tolerability

ABSTRACT Objective KN015 is a long-acting, recombinant human follicle-stimulating hormone Fc fusion protein that induces follicle development. This first-in-human study evaluated the effect of KN015 on healthy, pituitary-suppressed women and examined its pharmacokinetics, pharmacodynamics, and tolerability. Methods This phase I study was a double-blind, randomized, and placebo-controlled design with a single ascending dose (20, 40, and 60 μg, respectively). Results After subcutaneous administration of a single dose, the maximum serum KN015 concentrations reached 1.57, 2.78, and 3.62 ng/mL, respectively, after baseline adjustment. Over this dose range, the median Tmax occurred at 240–312 h, and the half-life (t½) was 752–1160 h. Dose proportionality was shown across the studied dose range. In most subjects, follicular growth was observed, and the number and diameter of the follicles increased with an increasing dose. In the 40-μg and 60-μg groups, the mean numbers of follicles with a diameter of ≥17 mm were 3 and 4, respectively. There was no significant difference in adverse events between the KN015 and placebo groups. KN015 antibody was not detected in any of the dosage groups. Conclusion The administration of a single ascending dose of KN015 was tolerated and able to induce follicular growth. Trial registration This trial is registered at the Chinese Clinical Trials website (http://www.chinadrugtrials.org.cn/index.html # CTR20160741) and ClinicalTrials.gov (https://clinicaltrials.gov/ # NCT03192527).

A retrospective, matched case-control study of recombinant LH versus hMG supplementation on FSH during controlled ovarian hyperstimulation in the GnRH-antagonist protocol.

BackgroundThe role of luteinizing hormone (LH) in controlled ovarian hyperstimulation (COH) requires more evidence for its efficacy. Several studies compared recombinant human LH (r-hLH) or human menopausal gonadotropin (hMG) in combination with recombinant human follicle-stimulating hormone (r-hFSH) but lack the results with GnRH-antagonist protocol and in Asians.MethodsThis is a retrospective, single-center study inspecting women receiving GnRH antagonist protocol and r-hFSH+hMG or r-hFSH+r-hLH regimen for over five days for COH in the in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle in Taiwan from 2013 to 2018. The outcomes of IVF/ICSI cycles were analyzed after propensity score matching between the two groups. A subgroup analysis was conducted in cycles in which women underwent their first embryo transfer (ET), including fresh ET and frozen ET (FET).ResultsWith a total of 503 cycles, the results revealed that the r-hFSH+r-hLH group performed better in terms of numbers of oocytes retrieved (r-hFSH+hMG vs. r-hFSH+r-hLH, 11.7 vs. 13.7, p=0.014), mature oocytes (8.7 vs. 10.9, p=0.001), and fertilized oocytes (8.3 vs. 9.8, p=0.022), while other outcomes were comparable. The analysis of first ET cycles also showed similar trends. Although the implantation rate (39% vs. 43%, p=0.37), pregnancy rate (52% vs. 53%, p=0.90), and live birth rate (39% vs. 45%, p=0.19) were not significantly different, the miscarriage rate was higher in the r-hFSH+hMG group than the r-hFSH+r-hLH group (26% vs. 15%, p<0.05) in first ET cycles. The cumulative pregnancy rate was significantly higher in the r-hFSH+r-hLH group (53% vs. 64%, p=0.02). No significant difference in rates of ovarian hyperstimulation syndrome (OHSS) was observed.ConclusionThe results support the hypothesis that the treatment of r-hLH+r-hFSH improves COH clinical outcomes in the IVF/ICSI cycle.

O-011 A prospective multicentre, non-interventional, real-world study to assess the pattern of use, effectiveness and safety of follitropin delta in routine clinical practice (the PROFILE study)

Abstract Study question To observe real-world utilization of algorithm-based dosing of follitropin delta in women naïve to ovarian stimulation (OS) and undergoing either in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Summary answer Individualized dosing of follitropin delta in real-world clinical practice results in predictable ovarian response while minimizing risk of ovarian hyperstimulation syndrome (OHSS). What is known already Follitropin delta (REKOVELLE, Ferring Pharmaceuticals, Switzerland), is the first recombinant human follicle-stimulating hormone (FSH) to be produced in a human cell line. The algorithm-based individualized dosing regimen for follitropin delta was developed to target an ovarian response of 8–14 oocytes while reducing the risk of extreme ovarian hypo- and hyper-response as compared with conventional dosing strategies. The efficacy and safety of follitropin delta has been demonstrated in randomized controlled trials (RCTs) compared with a standard daily starting dose of 150 IU recombinant FSH. Real-world implementation of individualized follitropin delta dosing using the algorithm in OS cycles is currently unknown. Study design, size, duration PROFILE was a prospective, open-label, non-interventional, multinational study conducted between March 2018 and October 2020 in which 1258 women were screened, 1013 met the inclusion/exclusion criteria and 944 women initiated their first OS cycle. No study drugs were reimbursed or provided by the study sponsor. All IVF/ICSI treatment protocols were conducted according to routine clinical practice, including how to prescribe follitropin delta and undertaking fresh/frozen transfers. Participants were followed for up to three OS cycles. Participants/materials, setting, methods All participants met inclusion criteria: ≥18 years, were naïve to IVF/ICSI treatment and the decision had made before enrolment to use follitropin delta for OS. Main exclusion criteria were any contraindication(s) preventing prescription of follitropin delta, and undergoing OS for oocyte donation or fertility preservation. The main outcomes were use of dosing algorithm, follitropin delta dosing patterns, ovarian response and pregnancy for first OS cycle, and adverse drug reactions (ADRs) for up to three cycles. Main results and the role of chance Baseline demographics for 944 women who initiated Cycle 1 were: age, 33.5±4.7 years; bodyweight, 67.1±13.6 kg; anti-Müllerian hormone, 20.3±16.1 pmol/L (2.84 ng/mL) (mean±standard deviation). Cycles 2 and 3 were initiated by 156 and 29 women, respectively. In Cycle 1, clinicians used the dosing algorithm to calculate the follitropin delta starting dose for 893/944 women (94.5%), although some clinicians adjusted the prescribed daily starting dose. The difference between the calculated and prescribed daily dose was small (0.2±1.40 µg); most women (822/944, 87.1%) were prescribed a daily dose of follitropin delta within 0.33 µg (1 click of pen) of the algorithm-calculated dose. The mean daily starting dose was 10.4 µg and mean total dose administered was 104 µg over 10.1 days. A mean of 10.1±7.03 oocytes were retrieved per woman. A fresh transfer was performed for 592/944 women (62.7%) and subsequent positive β-human chorionic gonadotropin (βhCG) reported for 352/944 women (37.3%). Ongoing pregnancy rate after fresh transfer was 27.0% (n = 255) and cumulative ongoing pregnancy rate after fresh/frozen transfer was 36.4% (n = 344). Four women discontinued follitropin delta due to ADRs. OHSS was reported for 37 women (3.9%); 12 (1.3%) OHSS events were reported as serious ADRs. No new safety signals were reported. Limitations, reasons for caution There may be bias towards IVF/ICSI treatment protocols used in countries with highest enrolment. Reasons for prescribing follitropin delta as part of a mixed FSH regimen in 33/944 women (3.5%) were not reported. Wider implications of the findings In real-world clinical practice, nearly all clinicians use the dosing algorithm to calculate individualized daily follitropin delta dose. Despite some women being prescribed dose deviations, first cycle ovarian response was predictable with good ongoing pregnancy rates. OHSS incidence was within expected range. PROFILE confirms efficacy and safety from pivotal RCTs. Trial registration number NCT03393780