Follicular and endocrine dose responses according to anti‐Müllerian hormone levels in <scp>IVF</scp> patients treated with a novel human recombinant <scp>FSH</scp> (<scp>FE</scp> 999049)

Bosch, Ernesto; Andersen, Anders Nyboe; Barri, Pedro N.; García-Velasco, Juan A.; Sutter, Petra De; Fernández‐Sánchez, Manuel; Višňová, Hana; Klein, Bjarke M.; Mannaerts, Bernadette; Arce, Joan‐Carles

doi:10.1111/cen.12864

Cited by 17 publications

(18 citation statements)

References 27 publications

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“…A subsequent dose-increase would recruit another wave of follicles that would therefore result in increased variability of follicle size by the end of stimulation. We observed that a lower starting rFSH dose reduced the proportion of follicles sized 12–19 mm at the end of stimulation in keeping with data using a novel human rFSH (39) and with our previous data (22). Furthermore, the need to increase the mean dose of rFSH by more than 5% of the starting dose reduced the proportion of follicles of 12–19 mm at the end of stimulation, and this was associated with 5 fewer mature oocytes.…”

Section: Discussionsupporting

confidence: 91%

FSH Requirements for Follicle Growth During Controlled Ovarian Stimulation

et al. 2019

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Introduction: Ovarian follicle growth is a key step in the success of assisted reproductive treatment, but limited data exists to directly relate follicle growth to recombinant FSH (rFSH) dose. In this study, we aim to evaluate FSH requirements for follicular growth during controlled ovarian stimulation. Method: Single center retrospective cohort study of 1,034 IVF cycles conducted between January 2012–January 2016 at Hammersmith Hospital IVF unit, London, UK. Median follicle size after 5 days of stimulation with rFSH and the proportion of antral follicles recruited were analyzed in women treated with rFSH alone to induce follicular growth during IVF treatment. Results: Starting rFSH dose adjusted for body weight (iU/kg) predicted serum FSH level after 5 days of rFSH ( r 2 = 0.352, p < 0.0001), median follicle size after 5 days of rFSH, and the proportion of antral follicles recruited by the end of stimulation. Day 5 median follicle size predicted median follicle size on subsequent ultrasound scans ( r 2 = 0.58–0.62; p < 0.0001), and hence time to oocyte maturation trigger ( r 2 = 0.22, P < 0.0001). Insufficient rFSH starting dose that required >5% dose-increase was associated with increased variability in follicle size on the day of oocyte maturation trigger, and negatively impacted the number of mature oocytes retrieved. Conclusion: Weight-adjusted rFSH dose correlates with follicular growth during ovarian stimulation. Early recruitment of follicles using a sufficient dose of rFSH from the start of stimulation was associated with reduced variability in follicle size at time of oocyte maturation trigger and an increased number of mature oocytes retrieved.

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Section: Discussionsupporting

confidence: 91%

FSH Requirements for Follicle Growth During Controlled Ovarian Stimulation

et al. 2019

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“…Dosing follitropin delta according to mass rather than bioactivity measured in rat is important as a result. This principle is being pursued in follitropin delta clinical development, with individualized dosing by mass optimized for each patient based on their AMH level and weight (11, 12). The differences between the pharmacology of follitropin delta and follitropin alfa also suggest that one should not be directly substituted for the other in one clinical procedure.…”

Section: Discussionmentioning

confidence: 99%

“…Recently follitropin delta has been described (FE 999049), the first recombinant FSH protein in clinical development that is expressed in a human cell line (PER.C6), with individualized dosing optimized based on each patient’s weight and anti-Mullerian hormone (AMH) level (10, 11, 12). In female volunteers, follitropin delta displayed distinct pharmacokinetics and pharmacodynamics, with higher exposure and lower serum clearance than follitropin alfa (13).…”

Section: Introductionmentioning

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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“…Individualised ovarian stimulation with follitropin delta relies on very narrow categories of AMH to stratify women to the appropriate gonadotropin dose to achieve a target ovarian response of 8–14 oocytes ( Arce et al , 2014 ; Bosch et al , 2015 ; Nyboe Andersen et al , 2017 ). That a large number of women would be classified differently if an alternative assay was used, in part reflects the small AMH categories that were used in the original dosing algorithm.…”

Section: Discussionmentioning

confidence: 99%

Non-equivalence of anti-Müllerian hormone automated assays—clinical implications for use as a companion diagnostic for individualised gonadotrophin dosing

et al. 2017

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STUDY QUESTIONCan anti-Müllerian hormone (AMH) automated immunoassays (Elecsys® and Access) be used interchangeably as a companion diagnostic for individualisation of follitropin delta dosing?SUMMARY ANSWERThe Access assay gives systematically higher AMH values than the Elecsys® assay which results in over 29% of women being misclassified to a different follitropin delta dose.WHAT IS KNOWN ALREADYFollitropin delta is the first gonadotrophin to be licenced with a companion diagnostic, the Roche Elecsys® AMH Plus assay. Alternative automated AMH assays including the Beckman Coulter Access immunoassay are considered to provide similar results, but clarification of their suitability as an off-licence companion diagnostic for follitropin delta is required.STUDY DESIGN, SIZE, DURATIONWe systematically searched the existing literature for studies that had measured AMH using both automated assays in the same cohort of women. Individual paired patient data were acquired from each author and combined with unpublished data.PARTICIPANTS/MATERIALS, SETTING, METHODSWe identified five eligible prospective published studies and one additional unpublished study. A 100% response from the authors was achieved. We collected paired AMH data on samples from 848 women. Passing–Bablok regression and Bland–Altman plots were used to compare the analytical performance of the two assays. The degree of misclassification to different treatment categories was estimated should the Access AMH be used as a companion diagnostic instead of the Elecsys AMH in determining the dosing of follitropin delta.MAIN RESULTS AND THE ROLE OF CHANCEThe Passing–Bablok regression shows a linear relationship (Access = −0.05 + 1.10 × Elecsys). The Access assay systematically gave higher values by an average of 10% compared with the Elecsys assay (slope = 1.10, 95% CI: 1.09 to 1.12). The average of the difference between the two assays was 2.7 pmol/l. The 95% limits of agreement were −11.7 to 6.3. Overall 253 (29.3%) women would have received an inappropriate follitropin delta dose if the Beckman Coulter Access assay was used. Specifically, a substantial proportion of women (ranging from 49% to 90% depending on the AMH category) would receive a lower dose of follitropin delta based on the Access AMH assay. Up to 10% (ranging from 2.5% to 10%) of women with high ovarian reserve would have been misclassified to a greater dose of follitropin delta based on the Access AMH assay.LIMITATIONS REASONS FOR CAUTIONWe compared the values of the two principal automated assays, extrapolation of our findings to other automated AMH assays would require similar comprehensive examination.WIDER IMPLICATIONS OF THE FINDINGSAn international standard for the calibration of the automated AMH assays is warranted to facilitate efficient use of AMH as a companion diagnostic. The variable calibration of alternative automated AMH assays may adversely impact on the performance of the follitropin delta dosing algorithm.STUDY FUNDING/COMPETING INTEREST(S)No formal funding has been receiv...

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Follicular and endocrine dose responses according to anti‐Müllerian hormone levels in IVF patients treated with a novel human recombinant FSH (FE 999049)

Cited by 17 publications

References 27 publications

FSH Requirements for Follicle Growth During Controlled Ovarian Stimulation

FSH Requirements for Follicle Growth During Controlled Ovarian Stimulation

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

Non-equivalence of anti-Müllerian hormone automated assays—clinical implications for use as a companion diagnostic for individualised gonadotrophin dosing

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