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Clinical outcomes of potential high responders after individualized FSH dosing based on anti-Müllerian hormone and body weight

Published:September 02, 2021DOI:https://doi.org/10.1016/j.rbmo.2021.08.024

      HIGHLIGHTS

      • Treatment of potential high responders with individualized follitropin delta dosing:
      • Normalises the average ovarian response
      • Reduces the incidence of preovulatory progesterone rises.
      • Reduces the ovarian hyperstimulation syndrome incidence
      • Reduces preventive interventions of ovarian hyperstimulation syndrome

      Abstract

      Research question

      How does the efficacy and safety of individualized follitropin delta dosing compare with conventional dosing for ovarian stimulation in potential high responders?

      Design

      Retrospective analysis of 153 potential high responders identified on the basis of baseline serum anti-Müllerian hormone (AMH) levels above 35 pmol/l, who were originally randomized to an individualized fixed dose of follitropin delta based on AMH and body weight (n = 78) or to a daily starting dose of 150 IU follitropin alfa (n = 75).

      Results

      At the end of stimulation, patients treated with individualized follitropin delta or conventional follitropin alfa had 12.1 ± 7.0 and 18.3 ± 7.0 (P < 0.001) follicles measuring 12 mm or wider, and 27.3% and 62.7% had serum progesterone levels higher than 3.18 nmol/l (P < 0.001), respectively. Overall number of oocytes in these two respective arms was 9.3 ± 6.7 and 17.9 ± 8.7 (P < 0.001), and the ongoing pregnancy rate per started cycle after fresh blastocyst transfer was 28.2% and 24.0%. The risk of ovarian hyperstimulation syndrome (OHSS) for all cases was three times higher in the conventional follitropin alfa arm at 16.0% versus 5.1% with individualized follitropin delta treatment (P = 0.025) and 26.7% versus 7.7% (P = 0.001) for early moderate or severe OHSS, preventive interventions for early OHSS, or both.

      Conclusions

      Treatment with individualized follitropin delta provides an improved efficacy–safety balance in women with high ovarian reserve, as it normalizes the ovarian response and decreases the risk of OHSS without compromising the chance of pregnancy.

      Graphical abstract

      KEYWORDS

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      References

        • Abbara A.
        • Patel A.
        • Hunjan T.
        • Clarke S.A.
        • Chia G.
        • Eng P.C.
        • Phylactou M.
        • Comninos A.N.
        • Lavery S.
        • Trew G.H.
        • Salim R.
        • Rai R.S.
        • Kelsey T.W.
        • Dhillo W.S.
        FSH requirements for follicle growth during controlled ovarian stimulation.
        Front. Endocrinol. 2019; 10: 1-11https://doi.org/10.3389/fendo.2019.00579
        • Adda-Herzog E.
        • Poulain M.
        • de Ziegler D.
        • Ayoubi J.M.
        • Fanchin R.
        Premature progesterone elevation in controlled ovarian stimulation: to make a long story short.
        Fertil. Steril. 2018; 109: 563-570https://doi.org/10.1016/j.fertnstert.2018.02.132
        • Arce J.-C.
        • Larsson P.
        • García-Velasco J.A.
        Establishing the follitropin delta dose that provides a comparable ovarian response to 150 IU/day follitropin alfa.
        Reprod. Biomed. Online. 2020; 41: 616-622https://doi.org/10.1016/j.rbmo.2020.07.006
        • Demirdjian G.
        • Bord S.
        • Lejeune C.
        • Masica R.
        • Rivière D.
        • Nicouleau L.
        • Denizot P.
        • Marquet P.Y
        Performance characteristics of the Access AMH assay for the quantitative determination of anti-Müllerian hormone (AMH) levels on the Access* family of automated immunoassay systems.
        Clin. Biochem. 2016; 49: 1267-1273https://doi.org/10.1016/j.clinbiochem.2016.08.005
        • Dewailly D.
        • Gronier H.
        • Poncelet E.
        • Robin G.
        • Leroy M.
        • Pigny P.
        • Duhamel A.
        • Catteau-Jonard S.
        Diagnosis of polycystic ovary syndrome (PCOS): revisiting the threshold values of follicle count on ultrasound and of the serum AMH level for the definition of polycystic ovaries.
        Hum. Reprod. 2011; 26: 3123-3129https://doi.org/10.1093/humrep/der297
        • Dietz de Loos A.
        • Hund M.
        • Buck K.
        • Meun C.
        • Sillman J.
        • Laven J.S.E.
        Establishing an anti-müllerian hormone (AMH) cut-off to determine polycystic ovarian morphology (PCOM) supporting diagnosis of polycystic ovarian syndrome (PCOS): the aphrodite study.
        Fertil. Steril. 2019; 112: e391https://doi.org/10.1016/j.fertnstert.2019.07.1116
        • Ferguson J.M.
        • Pépin D.
        • Duru C.
        • Matejtschuk P.
        • Donahoe P.K.
        • Burns C.J.
        Towards international standardization of immunoassays for Müllerian inhibiting substance/anti-Müllerian hormone.
        Reprod. Biomed. Online. 2018; 37: 631-640https://doi.org/10.1016/j.rbmo.2018.08.012
        • Fernández-Sánchez M.
        • Visnova H.
        • Yuzpe A.
        • Klein B.M.
        • Mannaerts B.
        • Arce J.-C.
        Individualization of the starting dose of follitropin delta reduces the overall OHSS risk and/or the need for additional preventive interventions: cumulative data over three stimulation cycles.
        Reprod. Biomed. Online. 2019; 38: 528-537https://doi.org/10.1016/j.rbmo.2018.12.032
        • Fleming R.
        • Fairbairn C.
        • Gaudoin M
        Objective multicentre performance of the automated assays for AMH and estimation of established critical concentrations.
        Hum. Fertil. 2018; 21: 269-274https://doi.org/10.1080/14647273.2017.1331298
        • Gardner D.K.
        • Schoolcraft W.
        In vitro culture of human blastocysts.
        in: Jansen R. Mortimer D. Towards reproductive certainty: infertility and genetics beyond 1999. Parthenon Press, Carnforth1999: 378-388 (1)
        • Gassner D.
        • Jung R
        First fully automated immunoassay for anti-Müllerian hormone.
        Clin. Chem. Lab. Med. 2014; 52: 1143-1152https://doi.org/10.1515/cclm-2014-0022
        • Golan A.
        • Ron-El R.
        • Herman A.
        • Soffer Y.
        • Weinraub Z.
        • Caspi E.
        Ovarian hyperstimulation syndrome: an update review.
        Obstet. Gynecol. Surv. 1989; 44: 430-440https://doi.org/10.1097/00006254-198906000-00004
        • Griesinger G.
        • Mannaerts B.
        • Andersen C.Y.
        • Witjes H.
        • Kolibianakis E.M.
        • Gordon K.
        Progesterone elevation does not compromise pregnancy rates in high responders: a pooled analysis of in vitro fertilization patients treated with recombinant follicle-stimulating hormone/gonadotropin-releasing hormone antagonist in six trials.
        Fertil. Steril. 2013; 100 (1622-1628.e3)https://doi.org/10.1016/j.fertnstert.2013.08.045
        • Johnstone E.B.
        • Rosen M.P.
        • Neril R.
        • Trevithick D.
        • Sternfeld B.
        • Murphy R.
        • Addauan-Andersen C.
        • McConnell D.
        • Reijo Pera R.
        • Cedars M.I.
        The polycystic ovary post-rotterdam: a common, age-dependent finding in ovulatory women without metabolic significance.
        J. Clin. Endocrinol. Metab. 2010; 95: 4965-4972https://doi.org/10.1210/jc.2010-0202
        • Lauritsen M.P.
        • Bentzen J.G.
        • Pinborg A.
        • Loft A.
        • Forman J.L.
        • Thuesen L.L.
        • Cohen A.
        • Hougaard D.M.
        • Nyboe Andersen A.
        The prevalence of polycystic ovary syndrome in a normal population according to the Rotterdam criteria versus revised criteria including anti-Müllerian hormone.
        Hum. Reprod. 2014; 29: 791-801https://doi.org/10.1093/humrep/det469
        • Laven J.S.E.
        • Mulders A.G.M.G.J.
        • Visser J.A.
        • Themmen A.P.
        • De Jong F.H.
        • Fauser B.C.J.M.
        Anti-Müllerian hormone serum concentrations in normoovulatory and anovulatory women of reproductive age.
        J. Clin. Endocrinol. Metab. 2004; 89: 318-323https://doi.org/10.1210/jc.2003-030932
        • Ledger W.L.
        • Fauser B.C.J.M.
        • Devroey P.
        • Zandvliet A.S.
        • Mannaerts B.M.J.L.
        Corifollitropin alfa doses based on body weight: clinical overview of drug exposure and ovarian response.
        Reprod. Biomed. Online. 2011; 23: 150-159https://doi.org/10.1016/j.rbmo.2011.04.002
        • Legro R.S.
        Obesity and PCOS: implications for diagnosis and treatment.
        Semin. Reprod. Med. 2012; 30: 496-506https://doi.org/10.1055/s-0032-1328878
        • Lie Fong S.
        • Laven J.S.E.
        • Duhamel A.
        • Dewailly D.
        Polycystic ovarian morphology and the diagnosis of polycystic ovary syndrome: redefining threshold levels for follicle count and serum anti-Müllerian hormone using cluster analysis.
        Hum. Reprod. 2017; 32: 1723-1731https://doi.org/10.1093/humrep/dex226
        • Nyboe Andersen A.
        • Nelson S.M.
        • Fauser B.C.J.M.
        • García-Velasco J.A.
        • Klein B.M.
        • Arce J.-C.
        Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial.
        Fertil. Steril. 2017; 107: 387-396https://doi.org/10.1016/j.fertnstert.2016.10.033
        • Pigny P.
        • Merlen E.
        • Robert Y.
        • Cortet-Rudelli C.
        • Decanter C.
        • Jonard S.
        • Dewailly D.
        Elevated serum level of anti-Mullerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest.
        J. Clin. Endocrinol. Metab. 2003; 88: 5957-5962https://doi.org/10.1210/jc.2003-030727
        • Rose T.H.
        • Röshammar D.
        • Erichsen L.
        • Grundemar L.
        • Ottesen J.T.
        Characterisation of population pharmacokinetics and endogenous follicle-stimulating hormone (FSH) levels after multiple dosing of a recombinant human FSH (FE 999049) in healthy women.
        Drugs R D. 2016; 16: 165-172https://doi.org/10.1007/s40268-016-0126-z
        • Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group
        Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.
        Fertil. Steril. 2004; 81: 19-25https://doi.org/10.1016/j.fertnstert.2003.10.004
        • Sahmay S.
        • Atakul N.
        • Oncul M.
        • Tuten A.
        • Aydogan B.
        • Seyisoglu H
        Serum anti-mullerian hormone levels in the main phenotypes of polycystic ovary syndrome.
        Eur. J. Obstet. Gynecol. Reprod. Biol. 2013; 170: 157-161https://doi.org/10.1016/j.ejogrb.2013.05.019
        • Teede H.J.
        • Misso M.L.
        • Costello M.F.
        • Dokras A.
        • Laven J.
        • Moran L.
        • Piltonen T.
        • Norman R.J.
        International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.
        Fertil. Steril. 2018; 110: 364-379https://doi.org/10.1016/j.fertnstert.2018.05.004
        • Van Zanden JJ
        • Wagenmakers-Huizinga L
        • Inia L
        • Kobold Muller
        Comparison of the automated Roche Elecsys Cobas Anti Mullerian Hormone (AMH) assay with the Beckman AMH Gen II ELISA.
        Ned Tijdschr Klin Chem Labgeneesk. 2016; 41: 214-215

      Biography

      Bernadette Mannaerts, PhD, graduated in medical biology from the University of Utrecht, the Netherlands, where she obtained her PhD in ‘Innovative drug development for infertility therapy’. She is Senior Medical Science Director at Reproductive Medicine and Women's Health at Ferring's Research in Copenhagen, Denmark, leading the global infertility drug development.
      Key message
      Potential high responders defined as women with serum anti-Müllerian hormone above 35 pmol/l undergoing ovarian stimulation with individualized follitropin delta dosing have a normalized ovarian response and, therefore, a considerably lower risk of ovarian hyperstimulation syndrome without a compromised chance of pregnancy after fresh blastocyst transfer.