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Comparison of ovarian response to follitropin delta in Japanese and White IVF/ICSI patients

  • Author Footnotes
    # Joint first authors.
    Osamu Ishihara
    Footnotes
    # Joint first authors.
    Affiliations
    Department of Obstetrics and Gynaecology, Saitama Medical University, 38 Morohongo, Moroyama, Iruma-gun, Saitama 350-0495, Japan
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  • Author Footnotes
    # Joint first authors.
    Scott M Nelson
    Footnotes
    # Joint first authors.
    Affiliations
    School of Medicine, Glasgow Royal Infirmary, New Lister Building, University of Glasgow, 10 Alexandra Parade Royal Infirmary, Glasgow G31 2ER, UK; The Fertility Partnership, Oxford Business Park, Cowley, Oxford OX4 2HW, UK; NIHR Bristol Biomedical Research Centre, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
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  • Joan-Carles Arce
    Correspondence
    Corresponding author.
    Affiliations
    Ferring Pharmaceuticals, Reproductive Medicine and Maternal Health, Kay Fiskers Plads 11, Copenhagen 2300, Denmark
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  • Author Footnotes
    # Joint first authors.
Open AccessPublished:September 22, 2021DOI:https://doi.org/10.1016/j.rbmo.2021.09.014

      HIGHLIGHTS

      • Follitropin delta resulted in serum FSH levels that were not significantly different between Japanese and White patients.
      • The oocyte yield was not significantly different between Japanese and White patients.
      • At the same degree of ovarian response, serum oestradiol was significantly higher in Japanese patients.
      • At similar oestradiol levels, a significantly higher early OHSS rate was reported in Japanese patients.

      Abstract

      Research question

      Is ovarian response associated with individualized follitropin delta dosing regimen comparable across different ethnic populations?

      Design

      Post-hoc analysis of ovarian response in 800 IVF/intracytoplasmic sperm injection (ICSI) patients (170 Japanese women and 630 White women) undergoing stimulation with individualized follitropin delta dosing based on serum anti-Müllerian hormone concentration and body weight in two randomized controlled trials conducted in Japan (NCT03228680) and in Europe, North America and South America (NCT01956110).

      Results

      On average, Japanese women weighed 10 kg less, which affected the total follitropin delta dose, compared with White women (83.5 ± 28.9 versus 90.2 ± 25.2 µg). At the end of stimulation, serum FSH concentrations were not significantly different between Japanese and White women (median 14.3 versus 14.0 IU/l), whereas serum oestradiol concentrations were significantly higher in Japanese women (median 6517 versus 5298 pmol/l, P < 0.0001). Japanese and White women had a similar number of oocytes retrieved with no significant differences among all women who started stimulation (9.3 ± 5.4 versus 9.5 ± 5.7), potential low responders (7.2 ± 3.7 versus 7.6 ± 4.6) or potential high responders (10.8 ± 5.9 versus 11.0 ± 6.0). At each level of ovarian response, serum oestradiol concentrations were significantly higher in Japanese women (P = 0.024). The incidence of early ovarian hyperstimulation syndrome was significantly higher in Japanese women compared with White women; overall (10.0% versus 2.2%, P = 0.0124) and at similar serum oestradiol concentrations (P = 0.0137).

      Conclusions

      The individualized follitropin delta dosing provides similar serum FSH concentrations and similar oocyte yield in Japanese and White IVF/ICSI patients, but the oestradiol response is higher in Japanese women.

      Graphical abstract

      KEYWORDS

      Introduction

      Ovarian response to gonadotrophin treatment in assisted reproductive technology has been reported to differ across ethnicities, and it has been speculated that biological, genetic, environmental and dietary factors may play a role (
      • Sharara F.I.
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      Differences in in vitro fertilization (IVF) outcome between white and black women in an inner-city, university-based IVF program.
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      Asian ethnicity is associated with reduced pregnancy outcomes after assisted reproductive technology.
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      Asian ethnicity in anonymous oocyte donors is associated with increased estradiol levels but comparable recipient pregnancy rates compared with Caucasians.
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      Arabian Peninsula ethnicity is associated with lower ovarian reserve and ovarian response in women undergoing fresh ICSI cycles.
      ). A key factor like ovarian reserve has been shown to diverge between ethnic groups (
      • Bleil M.E.
      • Gregorich S.E.
      • Adler N.E.
      • Sternfeld B.
      • Rosen M.P.
      • Cedars M.I.
      Race/ethnic disparities in reproductive age: an examination of ovarian reserve estimates across four race/ethnic groups of healthy, regularly cycling women.
      ). Anti-Müllerian hormone (AMH) is the best predictor of ovarian reserve (
      • Arce J.-C.
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      • Fleming R.
      Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles: prediction of ovarian response and cumulative treatment outcome in good-prognosis patients.
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      • de Ziegler D.
      Can anti-Müllerian hormone concentrations be used to determine gonadotrophin dose and treatment protocol for ovarian stimulation?.
      ;
      • Nelson S.M.
      Biomarkers of ovarian response: current and future applications.
      ;
      • Toner J.P.
      • Seifer D.B.
      Why we may abandon basal follicle-stimulating hormone testing: a sea change in determining ovarian reserve using antimüllerian hormone.
      ;
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      • Fauser B.C.J.M.
      Anti-Müllerian hormone: ovarian reserve testing and its potential clinical implications.
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      • La Marca A.
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      • Visser J.A.
      • Wallace W.H.
      • Anderson R.A.
      The physiology and clinical utility of anti-Mullerian hormone in women.
      ;
      • La Marca A.
      • Sunkara S.K.
      Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice.
      ), and previous studies have suggested that both age and ethnicity have independent effects on serum AMH concentrations (
      • Seifer D.B
      • Golub E.T.
      • Lambert-Messerlian G.
      • Benning L.
      • Anastos K.
      • Watts D.H.
      • Cohen M.H.
      • Karim R.
      • Young M.A.
      • Minkoff H.
      • Greenblatt R.M.
      Variations in serum müllerian inhibiting substance between white, black, and Hispanic women.
      ;
      • Bleil M.E.
      • Gregorich S.E.
      • Adler N.E.
      • Sternfeld B.
      • Rosen M.P.
      • Cedars M.I.
      Race/ethnic disparities in reproductive age: an examination of ovarian reserve estimates across four race/ethnic groups of healthy, regularly cycling women.
      ;
      • Nelson S.M.
      • Aijun S.
      • Ling Q.
      • Tengda X.
      • Wei X.
      • Yan D.
      • Yanfang W.
      • Zenghui T.
      • Xinqi C.
      • Fraser A.
      • Clayton G.L.
      Ethnic discordance in serum anti-Müllerian hormone in healthy women: a population study from China and Europe.
      ;
      • Kotlyar A.M.
      • Seifer D.B.
      Ethnicity/race and age-specific variations of serum AMH in women-a review.
      ). Another patient characteristic that varies substantially across ethnic groups is body weight, which is relevant because the same dose of FSH will lead to lower serum FSH concentrations in heavy women compared with higher FSH exposure in leaner women (
      • Arce J.-C.
      • Klein B.M.
      • Erichsen L.
      Using AMH for determining a stratified gonadotropin dosing regimen for IVF/ICSI and optimizing outcomes.
      ;
      • 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.
      ). It is, therefore, apparent that factors such as ovarian reserve, body weight and drug exposure should be considered when comparing ovarian response across different ethnicities.
      The dosing algorithm for the novel recombinant FSH, follitropin delta, is individualized for each woman based on her serum AMH concentration and body weight. On the basis of human dose-response data (
      • Arce J.-C.
      • Nyboe Andersen A.
      • Fernández-Sánchez M.
      • Visnova H.
      • Bosch E.
      • García-Velasco J.A.
      • Barri P.
      • de Sutter P.
      • Klein B.M.
      • Fauser B.C.J.M.
      Ovarian response to recombinant human follicle-stimulating hormone: a randomized, antimüllerian hormone-stratified, dose-response trial in women undergoing in vitro fertilization/intracytoplasmic sperm injection.
      ;
      • Ishihara O.
      • Klein B.M.
      • Arce J.-C.
      Japanese Follitropin Delta Phase 2 Trial Group. Randomized, assessor-blind, antimüllerian hormone-stratified, dose-response trial in Japanese in vitro fertilization/intracytoplasmic sperm injection patients undergoing controlled ovarian stimulation with follitropin delta.
      ) and pharmacokinetic–pharmacodynamic modelling and simulation (
      • Arce J.-C.
      • Klein B.M.
      • Erichsen L.
      Using AMH for determining a stratified gonadotropin dosing regimen for IVF/ICSI and optimizing outcomes.
      ), the dosing regimen was found suitable for populations with different ethnicities. The dosing algorithm was subsequently validated in two large clinical trials conducted in Japanese women (
      • Ishihara O.
      • Arce J.-C.
      Japanese Follitropin Delta Phase 3 Trial (STORK) Group. Individualized follitropin delta dosing reduces OHSS risk in Japanese IVF/ICSI patients: a randomized controlled trial.
      ) and in predominantly White women (
      • Nyboe Andersen A.
      • Nelson S.M.
      • Fauser B.C.J.M.
      • García-Velasco J.A.
      • Klein B.M.
      • Arce J.-C.
      ESTHER-1 Study Group. Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial.
      ). No comparisons, however, have been conducted across ethnic groups after ovarian stimulation with the individualized dosing regimen. The present analysis investigates the comparability of FSH exposure and ovarian response, with focus on the oocyte yield across ethnicities when adjusting the gonadotrophin dose by patient characteristics.

      Materials and methods

       Trial designs

      This was a post-hoc analysis of ovarian response data from 800 IVF/intracytoplasmic sperm injection (ICSI) patients (170 Japanese women and 630 White women) included in two randomized, controlled, assessor-blind, multicentre phase 3 efficacy trials with follitropin delta (Rekovelle, Ferring Pharmaceuticals, Switzerland) conducted in Japan (clinicaltrials.gov registration number NCT03228680, registration date 25 July 2017) and outside Japan (Europe, North America and South America; NCT01956110, registration date 8 October 2013). The Japanese phase 3 efficacy trial was conducted in 347 IVF/ICSI patients across 17 investigational sites in Japan (
      • Ishihara O.
      • Arce J.-C.
      Japanese Follitropin Delta Phase 3 Trial (STORK) Group. Individualized follitropin delta dosing reduces OHSS risk in Japanese IVF/ICSI patients: a randomized controlled trial.
      ) and the non-Japanese phase 3 efficacy trial was conducted in 1326 IVF/ICSI patients of different ethnicity, including 95% White women, across 37 investigational sites in 11 countries (Belgium, Brazil, Canada, Czech Republic, Denmark, France, Italy, Poland, Russia, Spain and UK) (
      • Nyboe Andersen A.
      • Nelson S.M.
      • Fauser B.C.J.M.
      • García-Velasco J.A.
      • Klein B.M.
      • Arce J.-C.
      ESTHER-1 Study Group. Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial.
      ). Both trials were conducted in accordance with the International Council for Harmonisation Guidelines for Good Clinical Practice, the principles of the Declaration of Helsinki and applicable local regulatory requirements. The two trial protocols (identification numbers 000004 and 000273) were approved by the relevant Institutional Review Boards and Independent Ethics Committees before screening, and all patients provided written informed consent before trial commencement. Details of trial design, assessor blinding, comparator, population, treatment regimen, trial assessments and results are available in the primary scientific publications of the trials (
      • Nyboe Andersen A.
      • Nelson S.M.
      • Fauser B.C.J.M.
      • García-Velasco J.A.
      • Klein B.M.
      • Arce J.-C.
      ESTHER-1 Study Group. Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial.
      ;
      • Ishihara O.
      • Arce J.-C.
      Japanese Follitropin Delta Phase 3 Trial (STORK) Group. Individualized follitropin delta dosing reduces OHSS risk in Japanese IVF/ICSI patients: a randomized controlled trial.
      ).
      In general, the two trials had similar eligibility criteria. In brief, participating women were planning to undergo their first IVF/ICSI cycle, had been diagnosed with tubal infertility, unexplained infertility or endometriosis stage I/II, or had a partner diagnosed with male factor infertility. No eligibility criterion limited serum AMH concentration at screening. The Japanese trial included women aged 20–40 years, whereas the non-Japanese trial included women aged 18–40 years, reflecting the regional differences in clinical practice and access to fertility treatment.
      A total of 170 Japanese women and 630 White women underwent ovarian stimulation with follitropin delta (Rekovelle) (Ferring Pharmaceuticals, Saint-Prex, Switzerland). In both trials, women were treated with an individualized follitropin delta dose based on their serum AMH concentration at screening and body weight at randomization (AMH <15 pmol/l: 12 µg/day; AMH ≥15 pmol/l: 0.19–0.10 µg/kg/day; the maximum daily dose was 12 µg) in a fixed-dose regimen throughout stimulation. The minimum daily dose was 6 µg in the Japanese trial due to the generally lower body weight of the Japanese population, whereas the non-Japanese trial had no minimum dose limit. Stimulation was carried out in a gonadotrophin-releasing hormone (GnRH) antagonist cycle, with identical criteria for triggering of final follicular maturation and cycle cancellation. For women who underwent triggering of final follicular maturation with HCG, one blastocyst of the best quality available was transferred on day 5 after oocyte retrieval in the Japanese and non-Japanese trials, except for women aged 38 years or older with no good-quality blastocysts (grade 3BB or higher) who underwent double blastocyst transfer in the non-Japanese trial. For women with 25–35 follicles measuring a diameter of 12 mm or wider, GnRH agonist was used for triggering final follicular maturation. All cases of early ovarian hyperstimulation syndrome (OHSS) (defined as onset 9 days or fewer after triggering of final follicular maturation) were categorized as mild, moderate or severe OHSS according to Golan's classification system (
      • Golan A.
      • Ron-el R.
      • Herman A.
      • Soffer Y.
      • Weinraub Z.
      • Caspi E.
      Ovarian hyperstimulation syndrome: an update review.
      ). In both trials, all pregnancies in the fresh cycle were monitored by serum beta-HCG and ultrasound and were followed until live birth (defined as the birth of at least one live neonate).
      Blood samples were collected during the trials for assessment of AMH, FSH, LH, oestradiol and progesterone, and analysed by the same central laboratory at different geographic locations after cross-validation using the same assays in both trials. The serum concentration of AMH was measured at screening, whereas the remaining endocrine parameters were measured on stimulation day 1 before the start of stimulation and at the end of stimulation. The sensitivity and precision of the validated assays are presented in Supplementary Table 1.

       Statistical analysis

      Effects of individualized dosing with follitropin delta were compared between Japanese and White patients, adjusting for differences in age, screening AMH concentration and body weight between the two groups of patients. Duration of stimulation, total dose and daily dose were compared using analysis of covariance models with trial as a factor, and age, AMH concentration and body weight as covariates. Number of oocytes retrieved, number of fertilized oocytes and number of blastocysts were compared using negative binomial models with trial as a factor, and age, AMH concentration and body weight as covariates. The endocrine parameters were compared using multiplicative analysis of covariance models with trial as a factor and age, AMH concentration, body weight and serum concentration on stimulation day 1 as covariates. Incidence of poor ovarian response, excessive ovarian response, at least one blastocyst and early OHSS were compared using logistic regression models with trial as a factor and age, AMH concentration and body weight as covariates. The probability of an oocyte becoming a blastocyst and the fertilization rate were estimated and compared using mixed effect binomial models with trial as a fixed factor, age, AMH concentration and body weight as fixed covariates, and patient as random factor assuming normally distributed log-odds. Absolute differences, confidence intervals and P-values for negative binomial, logistic regression and binomial models were derived from model estimates using the delta method. The association between the number of oocytes retrieved and serum oestradiol concentrations at the end of stimulation was investigated by fitting linear models to data, allowing for different slopes and intercepts for Japanese and White patients, with age, AMH concentration, body weight, and serum oestradiol concentration on stimulation day 1 as covariates, and assuming a log-normally distributed residual variability. The graphical illustration applies the following categories of ovarian response: <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved. The association between serum oestradiol concentrations at the end of stimulation and early OHSS was investigated by plotting the early OHSS rates and 95% confidence intervals using subgroups of serum oestradiol concentrations (≤1000 pmol/l followed by intervals of 2000 pmol/l up to >15,000 pmol/l), by fitting local regression curves to individual data, and by adding the logarithm of the serum oestradiol concentration at the end of stimulation as a covariate to the model when analysing incidence of early OHSS.
      The analyses included all randomized and exposed women in the Japanese trial (n = 170) and all randomized and exposed White women in the non-Japanese trial (n = 630). SAS, version 9.4 (SAS Institute Inc., USA) was used for all statistical analyses.

      Results

       Baseline characteristics

      An overview of demographics and baseline characteristics of Japanese and White women is presented in Table 1. No major difference was found in mean age between Japanese and White women treated with individualized follitropin delta dosing (34.2 versus 33.3 years). Japanese women weighed on average 54.5 kg compared with the average body weight of 64.8 kg in White women. Similarly, the average body mass index (BMI) of Japanese women was 21.4 kg/m2, which was lower than that in White women, in whom the BMI was 23.6 kg/m2. Regarding the ovarian reserve, the median AMH concentration was similar between the two groups, and 59.4% of Japanese women and 54.4% of White women had a normal or high ovarian reserve, as reflected by a serum AMH concentration of ≥15 pmol/l. No notable differences were found in infertility history between the two groups, except for the White group that had more couples with severe male factor infertility and fewer couples with unexplained infertility.
      Table 1DEMOGRAPHICS AND BASELINE CHARACTERISTICS
      CharacteristicJapanese women (n = 170)White women (n = 630)
      Age
       All patients, years34.2 ± 3.533.3 ± 3.9
       <3588 (51.8)374 (59.4)
       35–3751 (30.0)154 (24.4)
       38–4031 (18.2)102 (16.2)
      Weight, kg54.5 ± 7.564.8 ± 10.8
      BMI, kg/m221.4 ± 2.723.6 ± 3.4
      Infertility history
       Duration of infertility, months34.3 ± 26.034.3 ± 22.9
       Primary infertility109 (64.1)451 (71.6)
      Reason of infertility
       Unexplained infertility81 (47.6)266 (42.2)
       Tubal infertility28 (16.5)81 (12.9)
       Male factor56 (32.9)260 (41.3)
       Endometriosis stage I/II4 (2.4)21 (3.3)
       Other1 (0.6)2 (0.3)
      Endocrine profile
      AMH, TSH and prolactin values are based on the screening samples, whereas the remaining endocrine parameters are based on the samples taken on stimulation day 1 before start of stimulation. AMH, anti-Müllerian hormone; BMI, body mass index; TSH, thyroid-stimulating hormone.
       AMH, pmol/l18.2 (11.0–28.2)16.1 (8.9–24.9)
       FSH, IU/l8.2 (7.0–9.6)7.5 (6.2–9.3)
       LH, IU/l3.7 (2.8–4.6)4.5 (3.5–5.9)
       Oestradiol, pmol/l165.0 (133.3–209.2)158.2 (128.6–199.0)
       Inhibin B, ng/l83.0 (65.0–105.0)94.0 (68.0–126.0)
       Progesterone, nmol/l0.8 (0.8–2.0)1.7 (0.8–2.3)
       TSH, µIU/l1.6 (1.1–2.1)1.5 (1.1–2.0)
       Prolactin, µg/l10.1 (7.5–12.8)10.2 (7.2–13.7)
      Values are mean ± SD, median (25th to 75th percentiles) or n (%), unless otherwise stated.
      a AMH, TSH and prolactin values are based on the screening samples, whereas the remaining endocrine parameters are based on the samples taken on stimulation day 1 before start of stimulation.AMH, anti-Müllerian hormone; BMI, body mass index; TSH, thyroid-stimulating hormone.

       Ovarian response

      The main ovarian response data associated with follitropin delta treatment in Japanese and White women are presented in Table 2. The average duration of stimulation with follitropin delta was 8.9 days in both groups. The lower body weight in Japanese women compared with White women led to slightly lower follitropin delta doses, as demonstrated by an average daily dose of 9.4 µg in Japanese women and 10.2 µg in White women, and an average total dose of 83.5 µg and 90.2 µg, respectively; however, none of these differences were statistically significant. Serum FSH concentrations at the end of stimulation were not significantly different, with a median serum FSH concentration of 14.3 IU/l in Japanese women and 14.0 IU/l in White women. No significant difference was found in the serum progesterone concentrations at the end of stimulation between the two groups, whereas significantly higher (both P < 0.0001) serum concentrations of LH and oestradiol were observed in Japanese women compared with White women.
      Table 2OVARIAN RESPONSE OUTCOMES WITH INDIVIDUALIZED FOLLITROPIN DELTA DOSING IN JAPANESE AND WHITE WOMEN
      Outcome variableJapanese women (n = 170)White women (n = 630)Estimated difference (ratio for endocrine variables)95% CIP-value
      Daily dose, µg/day9.4 ± 2.510.2 ± 2.20.00−0.22 to 0.220.9962
      Duration of stimulation, days8.9 ± 1.98.9 ± 2.00.16−0.19 to 0.510.3694
      Total dose, µg83.5 ± 28.990.2 ± 25.22.30−1.53 to 6.130.2390
      FSH, IU/l
      Serum concentrations are observed values at the end of stimulation, whereas the comparison between treatment groups also takes into account the serum concentration on stimulation day 1.
      14.3 (11.6–19.7)14.0 (11.0–17.7)1.000.96 to 1.040.9712
      LH, IU/l
      Serum concentrations are observed values at the end of stimulation, whereas the comparison between treatment groups also takes into account the serum concentration on stimulation day 1.
      1.6 (1.0–2.5)1.4 (0.8–2.5)1.481.26 to 1.73<0.0001
      Oestradiol, pmol/l
      Serum concentrations are observed values at the end of stimulation, whereas the comparison between treatment groups also takes into account the serum concentration on stimulation day 1.
      6517 (4465–9033)5298 (3520–7716)1.291.15 to 1.45<0.0001
      Progesterone, nmol/l
      Serum concentrations are observed values at the end of stimulation, whereas the comparison between treatment groups also takes into account the serum concentration on stimulation day 1.
      2.5 (1.9–3.5)2.5 (1.8–3.6)0.950.85 to 1.060.3673
      Oocytes retrieved9.3 ± 5.49.5 ± 5.70.18−0.86 to 1.210.7378
      Women with AMH <15 pmol/l (at risk of hyporesponse)
       Oocytes retrieved7.2 ± 3.77.6 ± 4.6−0.43−1.44 to 0.590.4080
       Poor responders (<4 oocytes)8 (11.6)46 (16.1)−3.0−10.1 to 4.10.4063
      Women with AMH ≥15 pmol/l (at risk of hyperresponse)
       Oocytes retrieved10.8 ± 5.911.0 ± 6.00.14−1.37 to 1.640.8583
       Excessive responders (≥20 oocytes)8 (8.0)31 (9.1)1.6−5.8 to 9.00.6732
      Fertilized oocytes5.2 ± 3.85.2 ± 3.80.04−0.65 to 0.730.8994
      Fertilization rate, %54.5 ± 26.156.4 ± 24.7−1.0−5.5 to 3.40.6545
      Blastocysts, day 53.0 ± 2.83.1 ± 2.8−0.01−0.51 to 0.480.9536
      Women with at least one blastocyst, %141 (82.9)527 (83.7)0.71−5.85 to 7.280.8311
      Blastocyst rate, %32.5 ± 23.033.4 ± 22.6−0.8−4.8 to 3.30.7142
      Early OHSS (any grade)
      Onset 9 days or fewer after triggering of final follicular maturation. AMH, anti-Müllerian hormone; OHSS, ovarian hyperstimulation syndrome.
      17 (10.0)14 (2.2)6.31.4 to 11.20.0124
      Values are mean ± SD, median (25th to 75th percentiles) or n (%), unless otherwise stated. Data are for all patients, unless otherwise stated. Please see the statistical analysis section for further details.
      a Serum concentrations are observed values at the end of stimulation, whereas the comparison between treatment groups also takes into account the serum concentration on stimulation day 1.
      b Onset 9 days or fewer after triggering of final follicular maturation.AMH, anti-Müllerian hormone; OHSS, ovarian hyperstimulation syndrome.
      In most patients, HCG was used to trigger final follicular maturation whereas 1.2% of Japanese women and 1.6% of White women underwent triggering with GnRH agonist due to risk of OHSS. Treatment with the individualized follitropin delta dosing regimen resulted in an average of 9.3 oocytes retrieved for Japanese women and 9.5 oocytes retrieved for White women, among all who started stimulation (estimated difference 0.18, 95% CI −0.86 to 1.21) (Table 2 and Figure 1). Among women with low ovarian reserve (based on a serum AMH concentration <15 pmol/l), the mean number of oocytes retrieved with follitropin delta was 7.2 in the Japanese group and 7.6 in the White group (estimated difference −0.43, 95% CI −1.44 to 0.59), and the proportion of patients with fewer than four oocytes was not significantly different between the two groups (11.6% of Japanese women and 16.1% of White women). Among women with either normal or high ovarian reserve (based on a serum AMH concentration ≥15 pmol/l), the average oocyte yield with follitropin delta was also comparable between the two groups (10.8 oocytes in Japanese women and 11.0 oocytes in White women) (estimated difference 0.14, 95% CI −1.37 to 1.64). In this subpopulation, 8.0% of Japanese women and 9.1% of White women had 20 or more oocytes, with no significant difference between the two groups.
      Figure 1
      Figure 1Oocytes retrieved with individualized follitropin delta dosing in Japanese and White women. The mean number of oocytes retrieved are presented overall and by anti-Müllerian hormone (AMH) concentration (<15 pmol/l and ≥15 pmol/l) in the groups. Values are mean ± SE.
      As shown in Figure 2a, at each category of ovarian response (<4, 4–7, 8–14, 15–19 and ≥20 oocytes retrieved), the serum oestradiol concentrations at the end of stimulation were significantly higher in Japanese women compared with White women. No difference was found in the slope of the lines between the two groups, but the intercept was significantly higher for Japanese women (estimated difference 1134 pmol/l; P = 0.0024). After adjusting for baseline serum concentration and other covariates, the estimated serum oestradiol concentration was 29% higher (95% CI 1.15 to 1.45) in Japanese women compared with White women (Table 2).
      Figure 2
      Figure 2The associations between serum oestradiol concentrations at the end of stimulation and number of oocytes retrieved, as well as early ovarian hyperstimulation syndrome (OHSS) rates with individualized follitropin delta dosing in Japanese and White women. (A) Symbols and error bars indicate geometric means and 95% confidence intervals for subgroups of women with <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved. Lines indicate estimated linear associations estimated from individual data. The slope of the lines did not differ between Japanese and White women, but the intercept was statistically significantly higher for Japanese women (P = 0.0024); (B) symbols and error bars indicate early OHSS rates and 95% confidence intervals using subgroups of serum oestradiol concentrations (≤1000 pmol/l followed by intervals of 2000 pmol/l up to >15,000 pmol/l). Curves are local regression curves fitted to individual data. At similar oestradiol concentrations, the incidence of early OHSS was significantly higher in Japanese women than in White women (P = 0.0137).
      The incidence of early OHSS of any grade was significantly higher in Japanese women than in White women after stimulation with follitropin delta (10.0% versus 2.2%, P = 0.0124) (Table 2). This observation was also made independent of serum oestradiol concentrations at the end of stimulation (Figure 2b). At similar oestradiol concentrations, the incidence of early OHSS was significantly higher in Japanese women compared with White women (P = 0.0137).

       Embryo development and outcome

      The average number of fertilized oocytes after stimulation with follitropin delta was 5.2 in both groups and the average number of blastocysts on day 5 after oocyte retrieval was 3.0 in Japanese women and 3.1 in White women (Table 2 and Supplementary Figure 1). The fertilization and blastocyst rates were not significantly different between Japanese and White women (Table 2). Furthermore, no significant difference was found in the proportion of women with at least one blastocyst between the two groups, with 82.9% in the Japanese group and 83.7% in the White group. Among all women who started stimulation, the live birth rate after the fresh cycle was 23.5% in Japanese women and 30.3% in White women, and the live birth rate per fresh cycle with transfer was 29.6% and 35.6%, respectively; however, none of these differences were statistically significant.

      Discussion

      This investigation found that Japanese and White IVF/ICSI patients responded with comparable oocyte yields when exposed to similar serum FSH concentrations after ovarian stimulation with recombinant FSH. The serum oestradiol concentrations, however, were significantly higher in Japanese patients across all categories of ovarian response. Furthermore, at any given oestradiol concentration or oocyte yield, Japanese women had a significantly higher incidence of OHSS than their White counterparts. These findings may have substantial clinical implications as it would suggest that the monitoring of only follicular development in Japanese patients may not be sufficient to understand the full ovarian response to gonadotrophins, and the addition of oestradiol monitoring may help to optimize ovarian stimulation.
      Ethnic differences in ovarian response after stimulation with gonadotrophins, including endocrine parameters and oocyte yield, have been reported (
      • Sharara F.I.
      • McClamrock H.D.
      Differences in in vitro fertilization (IVF) outcome between white and black women in an inner-city, university-based IVF program.
      ;
      • Purcell K.
      • Schembri M.
      • Frazier L.M.
      • Rall M.J.
      • Shen S.
      • Croughan M.
      • Grainger D.A.
      • Fujimoto V.Y.
      Asian ethnicity is associated with reduced pregnancy outcomes after assisted reproductive technology.
      ;
      • Huddleston H.G.
      • Rosen M.P.
      • Lamb J.D.
      • Modan A.
      • Cedars M.I.
      • Fujimoto V.Y.
      Asian ethnicity in anonymous oocyte donors is associated with increased estradiol levels but comparable recipient pregnancy rates compared with Caucasians.
      ;
      • Tabbalat A.M.
      • Pereira N.
      • Klauck D.
      • Melhem C.
      • Elias R.T.
      • Rosenwaks Z.
      Arabian Peninsula ethnicity is associated with lower ovarian reserve and ovarian response in women undergoing fresh ICSI cycles.
      ). Potential differences in factors such as body weight and, therefore, FSH exposure, distribution of FSH receptor polymorphisms, AMH concentrations at similar age, analytical methods for hormonal parameters, gonadotrophin doses, stimulation protocols or clinical criteria for oocyte retrieval, could have affected the interpretation of previous reports. Some of these confounding factors have been addressed in this investigation, as Japanese and White IVF/ICSI patients had been stratified according to similar AMH categories, underwent a similar stimulation protocol with identical criteria for oocyte triggering and cycle cancellation, and all endocrine parameters were analysed using identical methods. Critically important is that similar FSH concentrations were achieved across both ethnic populations as dosing of follitropin delta is individualized according to body weight and, therefore, taking into consideration the different volume of distribution between the populations. The present study included a broad range of White IVF/ICSI patients distributed across several different countries and regions, whereas previous comparisons of ethnicity have mostly been limited to a single country. Nevertheless, the heterogeneity among the study population from different countries and regions can be viewed as a potential limitation of the present investigation.
      Besides the similar oocyte yield, the most interesting finding from our study was that Japanese women presented with end-of-stimulation serum oestradiol concentrations that were 29% higher than White women. This is in line with a previous study also reporting a higher oestradiol response in Asian IVF/ICSI patients compared with White IVF/ICSI patients after gonadotrophin stimulation (
      • Purcell K.
      • Schembri M.
      • Frazier L.M.
      • Rall M.J.
      • Shen S.
      • Croughan M.
      • Grainger D.A.
      • Fujimoto V.Y.
      Asian ethnicity is associated with reduced pregnancy outcomes after assisted reproductive technology.
      ). Similarly, 25% higher oestradiol concentrations have been observed in Asian oocyte donors after adjustment for BMI (
      • Huddleston H.G.
      • Rosen M.P.
      • Gibson M.
      • Cedars M.I.
      • Fujimoto V.Y.
      Ethnic variation in estradiol metabolism in reproductive age Asian and white women treated with transdermal estradiol.
      ). The difference in serum oestradiol concentrations between the two populations in the present study was not considered to be attributed to an analytical issue. The same hormone assays were used by the same central laboratory, although at different geographic locations in Japan and outside Japan. The use of quality controls in accordance with the assay descriptions and cross-validation between laboratories should allow for a direct comparison of measurements. Potentially, genetic differences could contribute to the different serum oestradiol responses to exogenous FSH stimulation (
      • Sudo S.
      • Kudo M.
      • Wada S.-I.
      • Sato O.
      • Hsueh A.J.W.
      • Fujimoto S.
      Genetic and functional analyses of polymorphisms in the human FSH receptor gene.
      ;
      • Miyoshi Y.
      • Noguchi S.
      Polymorphisms of estrogen synthesizing and metabolizing genes and breast cancer risk in Japanese women.
      ;
      • Tang H.
      • Yan Y.
      • Wang T.
      • Zhang T.
      • Shi W.
      • Fan R.
      • Yao Y.
      • Zhai S.
      Effect of follicle-stimulating hormone receptor Asn680Ser polymorphism on the outcomes of controlled ovarian hyperstimulation: an updated meta-analysis of 16 cohort studies.
      ). It has been reported that Japanese and White women have different FSH receptor polymorphisms. Japanese women have a higher proportion of the FSH receptor variant Thr307-Asn680, which is linked to higher serum oestradiol concentrations than the FSH receptor variant Ala307-Ser680; a variant that is more frequently occurring in White women (
      • Sudo S.
      • Kudo M.
      • Wada S.-I.
      • Sato O.
      • Hsueh A.J.W.
      • Fujimoto S.
      Genetic and functional analyses of polymorphisms in the human FSH receptor gene.
      ). Also, higher oestradiol concentrations have been linked to the polymorphisms of the oestrogen synthesizing gene CYP19 (aromatase) and these polymorphisms also differ between Japanese and White women (
      • Miyoshi Y.
      • Noguchi S.
      Polymorphisms of estrogen synthesizing and metabolizing genes and breast cancer risk in Japanese women.
      ).
      Another hypothesis is that a higher LH tonus during the follicular phase of ovarian stimulation may contribute to the elevation of oestradiol, although the actual differences observed in serum LH concentrations between Japanese and White women in our study were considered minimal for influencing serum oestradiol concentrations in a meaningful manner. Nevertheless, population-specific genetic factors concerning the LH gene have been reported (
      • Lamminen T.
      • Huhtaniemi I.
      A common genetic variant of luteinizing hormone; relation to normal and aberrant pituitary-gonadal function.
      ;
      • Themmen A.P.N.
      An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms.
      ).
      It is of clinical relevance that higher oestradiol concentrations could influence a safety end point, such as OHSS as well as efficacy outcomes. Rates of OHSS of up to 22% have been reported for other gonadotrophins in Japanese IVF patients participating in clinical trials (
      • Fujiwara T.
      A multi-center, randomized, open-label, parallel group study of a natural micronized progesterone vaginal tablet as a luteal support agent in Japanese women undergoing assisted reproductive technology.
      ;
      • Ishihara O.
      • Klein B.M.
      • Arce J.-C.
      Japanese Follitropin Delta Phase 2 Trial Group. Randomized, assessor-blind, antimüllerian hormone-stratified, dose-response trial in Japanese in vitro fertilization/intracytoplasmic sperm injection patients undergoing controlled ovarian stimulation with follitropin delta.
      ;
      • Ishihara O.
      • Arce J.-C.
      Japanese Follitropin Delta Phase 3 Trial (STORK) Group. Individualized follitropin delta dosing reduces OHSS risk in Japanese IVF/ICSI patients: a randomized controlled trial.
      ), which seems somewhat higher than the incidences reported in trials conducted outside Japan. Whether biological or methodological differences, e.g. interpretation of OHSS definitions, or differences in patient-reporting aspects or clinical practice in OHSS monitoring procedures, contribute to the higher OHSS rates reported in Japanese women is not known. Approaches to reduce the incidence of OHSS have been implemented with the development of individualized dosing of gonadotrophins based on biomarkers of ovarian response (
      • Nelson S.M.
      Biomarkers of ovarian response: current and future applications.
      ;
      • Arce J.-C.
      • Klein B.M.
      • Erichsen L.
      Using AMH for determining a stratified gonadotropin dosing regimen for IVF/ICSI and optimizing outcomes.
      ), by using GnRH agonist for triggering, freeze all cycles, or both (
      • Nelson S.M.
      Prevention and management of ovarian hyperstimulation syndrome.
      ). An approximate 50% decrease in early OHSS risk has been reported in Japanese and White populations when using the individualized algorithm-based fixed dosing with follitropin delta in comparison to recombinant FSH at the lowest approved dose of 150 IU (
      • Nyboe Andersen A.
      • Nelson S.M.
      • Fauser B.C.J.M.
      • García-Velasco J.A.
      • Klein B.M.
      • Arce J.-C.
      ESTHER-1 Study Group. Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial.
      ;
      • Ishihara O.
      • Arce J.-C.
      Japanese Follitropin Delta Phase 3 Trial (STORK) Group. Individualized follitropin delta dosing reduces OHSS risk in Japanese IVF/ICSI patients: a randomized controlled trial.
      ), attributed to the less excessive oocyte yield and lower oestradiol response. Nevertheless, it is noticeable that the incidence of OHSS observed with individualized dosing of follitropin delta in Japanese women is still significantly higher than that reported in White women. Traditionally, high serum oestradiol concentrations have been used as an indicator for the risk of developing OHSS, but the number of follicles has been found to be a better predictor than oestradiol concentrations in predominantly White women (
      • Papanikolaou E.G.
      • Pozzobon C.
      • Kolibianakis E.M.
      • Camus M.
      • Tournaye H.
      • Fatemi H.M.
      • Van Steirteghem A.
      • Devroey P.
      Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin-releasing hormone antagonist in vitro fertilization cycles.
      ;
      • Griesinger G.
      • Verweij P.J.M.
      • Gates D.
      • Devroey P.
      • Gordon K.
      • Stegmann B.J.
      • Tarlatzis B.C.
      Prediction of ovarian hyperstimulation syndrome in patients treated with corifollitropin alfa or rFSH in a GnRH antagonist protocol.
      ). As Japanese women seem to have similar numbers of oocytes retrieved as White women but higher OHSS rates, it should be considered if serum oestradiol concentrations contribute to explain the differences in OHSS rates. The addition of oestradiol measurements to ultrasound monitoring has been reported to not increase the probability of pregnancy or decrease the probability of OHSS, but the consequential recommendation is based on studies mainly conducted in White women and applying the long GnRH agonist protocol (). The findings of the present study provide a rationale to consider expanding the monitoring of ovarian response in Japanese patients beyond follicular development alone, and include serum oestradiol concentration measurements, to potentially minimize the OHSS risk.
      The number of oocytes, fertilized oocytes and blastocysts, as well as the proportion of women undergoing embryo transfer, were similar between Japanese and White women. Although the differences in live birth rates between the two populations did not reach statistical significance, the live birth rates per started cycle and per cycle with transfer were around 5% lower in Japanese women than in White women, and some differences in study population characteristics such as age and BMI, as well as a slight variation in transfer policy, could explain part of it. Interestingly, some researchers have speculated that the endocrine milieu created by gonadotrophin stimulation may be different in Asian women affecting efficacy outcomes (
      • Purcell K.
      • Schembri M.
      • Frazier L.M.
      • Rall M.J.
      • Shen S.
      • Croughan M.
      • Grainger D.A.
      • Fujimoto V.Y.
      Asian ethnicity is associated with reduced pregnancy outcomes after assisted reproductive technology.
      ;
      • Langen E.S.
      • Shahine L.K.
      • Lamb J.D.
      • Lathi R.B.
      • Milki A.A.
      • Fujimoto V.Y.
      • Westphal L.M.
      Asian ethnicity and poor outcomes after in vitro fertilization blastocyst transfer.
      ). Supraphysiologic elevations of oestradiol and other hormone responses during ovarian stimulation may have a negative effect on implantation in fresh cycles (
      • Simón C.
      • Garcia Velasco J.J.
      • Valbuena D.
      • Peinado J.A.
      • Moreno C.
      • Remohí J.
      • Pellicer A.
      Increasing uterine receptivity by decreasing estradiol levels during the preimplantation period in high responders with the use of a follicle-stimulating hormone step-down regimen.
      ;
      • Bourgain C.
      • Devroey P.
      The endometrium in stimulated cycles for IVF.
      ;
      • Kolibianakis E.M.
      • Albano C.
      • Kahn J.
      • Camus M.
      • Tournaye H.
      • Van Steirteghem A.C.
      • Devroey P.
      Exposure to high levels of luteinizing hormone and estradiol in the early follicular phase of gonadotropin-releasing hormone antagonist cycles is associated with a reduced chance of pregnancy.
      ). The oestradiol concentrations have also been shown to affect the window of endometrial receptivity (
      • Ma W.-G.
      • Song H.
      • Das S.K.
      • Paria B.C.
      • Dey S.K.
      Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation.
      ) and to be a predictor of pregnancy outcome (
      • Vaughan D.A.
      • Harrity C.
      • Sills E.S.
      • Mocanu E.V.
      Serum estradiol:oocyte ratio as a predictor of reproductive outcome: an analysis of data from >9000 IVF cycles in the Republic of Ireland.
      ;
      • Lyttle Schumacher B.M.
      • Mersereau J.E.
      • Steiner A.Z.
      Cycle day, estrogen level, and lead follicle size: analysis of 27,790 in vitro fertilization cycles to determine optimal start criteria for gonadotropin-releasing hormone antagonist.
      ). It remains to be investigated if these higher serum oestradiol concentrations in Japanese patients modify endometrial receptivity or its window, affecting implantation and success rates in fresh transfer cycles.
      In conclusion, the individualized follitropin delta dosing provides similar serum FSH concentrations and similar oocyte yield in Japanese and White IVF/ICSI patients. Interestingly, the present study confirms that oestradiol response to stimulation with recombinant FSH is significantly higher in Japanese patients than in White patients. Monitoring of serum oestradiol response may be considered for optimizing ovarian stimulation in Japanese women.

      Acknowledgements

      The authors acknowledge the patients, investigators and staff at participating sites in the two trials. The authors also thank Lisbeth Helmgaard and Maria Gullberg (Global Medical Writing, Ferring Pharmaceuticals, Denmark) for assistance in writing the manuscript, Bjarke M. Klein (Global Biometrics, Ferring Pharmaceuticals, Denmark) for statistical analysis support, Ankur Chakraborty (Global Biometrics, Ferring Pharmaceuticals, Denmark) for statistical programming and other members in the clinical team at Ferring Pharmaceuticals. Both trials were funded by Ferring Pharmaceuticals.

      Appendix. Supplementary materials

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      Biography

      Joan-Carles Arce, MD, PhD, graduated from the Autonomous University of Barcelona, Spain, and the Free University of Brussels, Belgium, and completed a postdoctoral fellowship at the University of Connecticut Health Center, USA. He is the Senior Vice President of Reproductive Medicine and Maternal Health, Ferring Pharmaceuticals, overseeing drug development programmes.
      Key message
      Individualized follitropin delta dosing results in similar serum FSH concentrations and oocyte yield across ethnic groups, but in significantly higher serum oestradiol concentrations in Japanese women compared with White women. Monitoring of serum oestradiol response may be considered for optimizing ovarian stimulation in Japanese women.