Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial

Andersen, Anders Nyboe; Nelson, Scott M.; Fauser, Bart C.J.M.; García-Velasco, Juan A.; Klein, Bjarke M.; Arce, Joan‐Carles; Tournaye, Herman; Sutter, Petra De; Decleer, W; Petracco, Álvaro; Borges, Edson; Barbosa, Caio Parente; Havelock, Jon; Claman, Paul; Yuzpe, A. Albert; Višňová, Hana; Ventruba, Pavel; Uher, Petr; Mrazek, Milan; Knudsen, Ulla Breth; Dewailly, Didier; Leveque, Anne Guivarc'h; Marca, Antonio La; Papaleo, Enrico; Kuczyński, Waldemar; Kozioł, Katarzyna; Anshina, M. B.; Zazerskaya, Irina E.; Gzgzyan, Alexander M.; Bulychova, Elena; Verdú, Victoria; Barri, Pedro N.; Sánchez, Manuel Fernández; Martín, Fernando Sánchez; Bosch, Ernesto; Serna, J.; Castillon, G; Bernabéu, Rafael; Ferrando, Marcos; Lavery, Stuart; Gaudoin, Marco; Helmgaard, L.; Mannaerts, Bernadette

doi:10.1016/j.fertnstert.2016.10.033

Cited by 224 publications

(312 citation statements)

References 26 publications

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“…In addition, follitropin delta displays a noninferior pregnancy rate and live birth rate compared to follitropin alfa, with a reduced rate of complications such as OHSS (39). The differences observed clinically between the two rFSH proteins might be caused by differences in their glycosylation (14) since variations in glycosylation have been reported to affect FSH pharmacokinetics and pharmacodynamics (15, 16, 17, 18, 19).…”

Section: Discussionmentioning

confidence: 99%

Comparative pharmacology of a new recombinant FSH expressed by a human cell line

Koechling

Plaksin²,

Croston³

et al. 2017

Endocrine Connections

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Recombinant FSH proteins are important therapeutic agents for the treatment of infertility, including follitropin alfa expressed in Chinese Hamster Ovary (CHO) cells and, more recently, follitropin delta expressed in the human cell line PER.C6. These recombinant FSH proteins have distinct glycosylation, and have distinct pharmacokinetic and pharmacodynamic profiles in women. Comparative experiments demonstrated that follitropin delta and follitropin alfa displayed the same in vitro potency at the human FSH receptor, but varied in their pharmacokinetics in mouse and rat. While follitropin delta clearance from serum depended in part on the hepatic asialoglycoprotein receptor (ASGPR), follitropin alfa clearance was unaffected by ASGPR inhibition in rat or genetic ablation in mice. The distinct properties of follitropin delta and follitropin alfa are likely to contribute to the differing pharmacokinetic and pharmacodynamic profiles observed in women and to influence their efficacy in therapeutic protocols for the treatment of infertility.

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Section: Discussionmentioning

confidence: 99%

Comparative pharmacology of a new recombinant FSH expressed by a human cell line

Koechling

Plaksin²,

Croston³

et al. 2017

Endocrine Connections

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“…Several algorithms incorporating biomarkers of ovarian reserve have been developed to individualize dosing of different gonadotropin preparations . Two of these, which incorporate anti‐Müllerian hormone (AMH) concentrations as a biomarker of ovarian reserve, have been externally validated in randomized controlled clinical trials …”

Section: Introductionmentioning

confidence: 99%

Anti‐Müllerian hormone variability and its implications for the number of oocytes retrieved following individualized dosing with follitropin delta

Nelson

Mannaerts

Andersen

et al. 2019

Clinical Endocrinology

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Summary Objective The stability of anti‐Müllerian hormone (AMH) across and between menstrual cycles has been the subject of debate. The objective of this analysis was to study the inter‐ and intracycle variability in repeated measurements and assess the impact on an individualized gonadotropin dosing algorithm and predicted oocyte yield. Design Retrospective analysis of repeat AMH measures from a randomized controlled trial. Patients A total of 1326 women aged 18‐40 years. Measurements Serum AMH levels at screening and at cycle day 2‐3 in up to three ovarian stimulation cycles. AMH variability and its impact on gonadotropin dose and the predicted number of oocytes. Results Repeat serum AMH measurements were strongly correlated within individual women (correlation coefficient 0.92). AMH exhibited limited within‐subject variation (coefficient of variation 23%), a small time‐related decline (mean 6% decrease/y), but no systematic variation across the menstrual cycle. Irrespective of whether the AMH screening value or the AMH at the initiation of ovarian stimulation was used, for women with an AMH level <15 pmol/L, 93% would receive the same gonadotropin dose and attain an identical number of oocytes in 97% of cases. For women with an AMH level ≥15 pmol/L, 80% would receive an individualized dose within ±1.5 μg and 90% would attain ±1 oocyte. Conclusion AMH variability had limited impact on individualized gonadotropin dosing, with 95% of women predicted to obtain an oocyte yield that does not vary beyond 1 oocyte count, irrespective of whether a random or early follicular AMH measurement was used to determine the individualized gonadotropin dose.

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“…Recently, a large trial evaluated individualized vs standard FSH dosing, and used a dosing algorithm that contained both anti‐Müllerian hormone and body weight with more gradual FSH dose reductions for predicted hyper responders. Designed specifically for a new recombinant FSH (follitropin δ), with a different pharmacokinetic and pharmacodynamic profile than the conventional follitropin α or β, the generalizability of this algorithm has to be demonstrated first before application in daily practice can be considered.…”

Section: Discussionmentioning

confidence: 99%

Do female age and body weight modify the effect of individualized FSH dosing in IVF/ICSI treatment? A secondary analysis of the OPTIMIST trial

Leijdekkers

Tilborg

Torrance

et al. 2019

Acta Obstet Gynecol Scand

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Introduction The OPTIMIST trial revealed that for women starting in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment, no substantial differences exist in first cycle and cumulative live birth rates between an antral follicle count (AFC)‐based individualized follicle‐stimulating hormone (FSH) dose and a standard dose. Female age and body weight have been suggested to cause heterogeneity in the effect of FSH dose individualization. The objective of the current study is to evaluate whether these patient characteristics modify the effect of AFC‐based individualized FSH dosing in IVF/ICSI treatment. Material and methods A secondary data‐analysis of the OPTIMIST trial. Women initiating IVF/ICSI treatment were classified as predicted poor (AFC 0‐7), suboptimal (AFC 8‐10) or hyper responders (AFC >15), and randomly allocated to a standard FSH dose (150 IU/d) or an individualized FSH dose (450, 225 or 100 IU/d for predicted poor, suboptimal and hyper responders, respectively). In each predicted response category, logistic regression models with interaction terms were used to evaluate the presence of effect modification. The first cycle was analyzed, and the primary outcomes were first complete cycle live birth rate (including fresh plus frozen‐thawed embryo transfers) and ovarian hyperstimulation syndrome (OHSS) risks. Results No effect modification was revealed in the predicted poor (n = 234) and suboptimal (n = 277) responders. In the predicted hyper responders (n = 521), the effect of the individualized FSH dose on the first cycle live birth rate was modified by female age (P = 0.02) and the effect on OHSS risks was modified by body weight (P = 0.02). A dose reduction from 150 to 100 IU/d generally decreased the OHSS risks in predicted hyper responders, but also reduced the chance of a live birth in young women, and had no beneficial impact on OHSS risks in women with a relatively low body weight. Conclusions In women with a predicted hyper response undergoing IVF/ICSI treatment, female age and body weight seem to modify the effect of FSH dose individualization. Although a reduced FSH starting dose generally decreases the OHSS risks, it may also reduce the chance of a live birth, specifically for young women. Future studies could consider these findings when investigating the optimal approach to reduce OHSS risks while maintaining the probability of a live birth for predicted hyper responders in IVF/ICSI treatment.

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Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial

Abstract: NCT01956110.

Cited by 224 publications

References 26 publications

Comparative pharmacology of a new recombinant FSH expressed by a human cell line

Comparative pharmacology of a new recombinant FSH expressed by a human cell line

Anti‐Müllerian hormone variability and its implications for the number of oocytes retrieved following individualized dosing with follitropin delta

Do female age and body weight modify the effect of individualized FSH dosing in IVF/ICSI treatment? A secondary analysis of the OPTIMIST trial

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