使用黄体雌二醇对高龄妇女进行编程拮抗剂周期预处理与不进行预处理的比较:非劣效随机对照试验。

IF 6 1区 医学 Q1 OBSTETRICS & GYNECOLOGY
Isabelle Cédrin-Durnerin, Isis Carton, Nathalie Massin, Nicolas Chevalier, Sophie Dubourdieu, Bettina Bstandig, Xénia Michelson, Seydou Goro, Camille Jung, Anne Guivarc'h-Lévêque
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However, variable effects were observed on the number of retrieved oocytes depending on the treated population. In advanced-age women, recruitable follicles tend to decrease in number and to be more heterogeneous in size but it remains unclear if estradiol pretreatment could change the oocyte yield through its negative feed-back effect on FSH intercycle rise.</p><p><strong>Study design, size, duration: </strong>This non-blinded randomized controlled non-inferiority trial was conducted between 2016 and 2022 with centrally computerized randomization and concealed allocation. Participants were 324 women aged 38-42 years undergoing IVF treatment. The primary endpoint was the total number of retrieved oocytes. Statistical analysis was performed with one-sided alpha risk of 2.5% and 95% confidence interval (CI) with the non-inferiority of E2 pretreatment proved by a P value <0.025 and a lower delta margin of the CI within two oocytes compared to no pretreatment. Secondary endpoints were duration and total dosage of recombinant FSH, cancellation rate, percentage of oocyte pick-up (OPU) on working days, total number of metaphase II oocytes and obtained embryos, fresh transfer live birth rate, and cumulative live birth rate.</p><p><strong>Participants/materials, setting, methods: </strong>This multicentric study enrolled women with regular cycles, weight >50 kg and body mass index <32, IVF cycle 1-2. According to randomization, micronized estradiol 2 mg twice a day was started on days 20-24 and continued until Wednesday beyond the onset of menses followed by administration of corifollitropin alfa on Friday, i.e. stimulation (S)1 or from D1-3 of a natural cycle in unpretreated patients. GnRH antagonist was started at S6 and additional FSH at S8.</p><p><strong>Main results and the role of chance: </strong>Basal characteristics were similar in patients randomized in E2 pretreated (n = 164) and non-pretreated (n = 160) groups (intended to treat (ITT) population). A total of 291 patients started treatment (per protocol (PP) population), 147 in E2 pretreated group with a mean number [SD] of pre-treatment days 9.8 [2.6] and 144 in the non-pretreated group. Despite advanced age, oocyte yields ranged from 0 to 29 in both groups with a median number of 6 retrieved oocytes in accordance with a mean anti-Müllerian hormone (AMH) level above 1.2 ng/ml. We demonstrated the non-inferiority of E2 pretreatment with a mean difference of -0.1 oocyte 95% CI [-1.5; 1.3] P = 0.004 in the PP population and a mean difference of -0.44 oocyte [-1.84; 0.97] P = 0.014 in the ITT population. Oocyte retrieval was more often on working days in E2 pretreated patients (91.9 versus 74.2%, P < 0.001). In patients reaching OPU, the duration of stimulation was statistically significantly longer (11.7 [1.7] versus 10.8 [1.8] days, P < 0.001) and the extra FSH dosage in addition to corifollitropin alfa was statistically significantly higher (1040 [548] versus 778 [504] IU, P < 0.001) in E2 pretreated than non-pretreated patients. We did not observe any significant differences in the number of retrieved oocytes (8.4 [6.1] versus 9.1 [6.0]), in the number of Metaphase 2 oocytes (7 [5.5] versus 7.3 [5.2]) nor in the number of obtained embryos (5 [4.6] versus 5.2 [4.2]) in E2 pretreated patients compared to non-pretreated patients. The live birth rate after fresh transfer (16.2% versus 18.5%, respectively), and the cumulative live birth rate per patient (17.7% versus 22.9%, respectively) were similar in both groups. Among the PP population, 31.6% of patients fulfilled the criteria for group 4 of Poseïdon classification (AMH <1.2 ng/ml and/or antral follicle count <5). In this sub-group of patients, we observed in contrast a statistically higher number of retrieved oocytes in E2 pretreated patients compared to non-pretreated (5.1 [3.8] versus 3.4 [2.7], respectively, the mean difference of +1.7 oocyte [0.2; 3.2] P = 0.022) but without significant difference in the cumulative live birth rate per patient (15.7% versus 7.3%, respectively).</p><p><strong>Limitations, reasons for caution: </strong>Our stimulated women older than 38 years obtained a wide range of collected oocytes suggesting very different stages of ovarian aging in both groups. E2 pretreatment is more likely to increase oocyte yield at the stage of ovarian aging characterized by asynchrony of a reduced follicular cohort. Another limitation is the sample size in sub-group analysis of patients with AMH <1.2 ng/ml. 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In patients reaching OPU, the duration of stimulation was statistically significantly longer (11.7 [1.7] versus 10.8 [1.8] days, P < 0.001) and the extra FSH dosage in addition to corifollitropin alfa was statistically significantly higher (1040 [548] versus 778 [504] IU, P < 0.001) in E2 pretreated than non-pretreated patients. We did not observe any significant differences in the number of retrieved oocytes (8.4 [6.1] versus 9.1 [6.0]), in the number of Metaphase 2 oocytes (7 [5.5] versus 7.3 [5.2]) nor in the number of obtained embryos (5 [4.6] versus 5.2 [4.2]) in E2 pretreated patients compared to non-pretreated patients. The live birth rate after fresh transfer (16.2% versus 18.5%, respectively), and the cumulative live birth rate per patient (17.7% versus 22.9%, respectively) were similar in both groups. Among the PP population, 31.6% of patients fulfilled the criteria for group 4 of Poseïdon classification (AMH <1.2 ng/ml and/or antral follicle count <5). 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引用次数: 0

摘要

研究问题黄体雌二醇(E2)预处理与不预处理相比,在拮抗剂方案中使用促花粉素α刺激的高龄妇女是否能获得相似数量的卵母细胞?在38-42岁的妇女中,使用黄体E2进行拮抗剂周期方案与不进行前处理相比,获得的卵母细胞数量相似:黄体 E2 预处理拮抗剂周期是更好地组织试管婴儿程序的重要工具,而且安全,对周期结果没有任何已知影响。然而,根据治疗人群的不同,拮抗剂对取回卵母细胞数量的影响也不尽相同。在高龄女性中,可募集卵泡的数量往往会减少,大小也更不均匀,但雌二醇预处理是否会通过其对FSH周期间上升的负反馈效应而改变卵母细胞产量,目前仍不清楚:这项非盲随机对照非劣效性试验于2016年至2022年期间进行,采用中央电脑随机化和隐蔽分配。参与者为324名接受试管婴儿治疗的38-42岁女性。主要终点是取回的卵母细胞总数。统计分析采用单侧α风险2.5%和95%置信区间(CI),以P值证明E2预处理的非劣效性:这项多中心研究招募了周期规律、体重大于 50 千克且体重指数正常的女性:随机分入 E2 预处理组(164 人)和非预处理组(160 人)(意向治疗(ITT)人群)的患者基础特征相似。共有 291 名患者开始治疗(按方案(PP)人群),其中 E2 预处理组 147 人,平均治疗前天数 [SD] 为 9.8 [2.6],非预处理组 144 人。尽管年龄偏大,但两组的卵母细胞产量从 0 到 29 个不等,中位数为 6 个,抗缪勒氏管激素(AMH)平均水平高于 1.2 ng/ml。我们证明了 E2 预处理的非劣效性,在 PP 组中,平均差异为-0.1 个卵母细胞 95% CI [-1.5; 1.3] P = 0.004;在 ITT 组中,平均差异为-0.44 个卵母细胞 [-1.84; 0.97] P = 0.014。E2 预处理患者更常在工作日取卵(91.9% 对 74.2%,P 限制,谨慎原因):年龄超过 38 岁的受刺激妇女获得的卵母细胞采集范围很广,这表明两组妇女的卵巢衰老阶段截然不同。在卵巢衰老阶段,E2 预处理更有可能增加卵母细胞产量,而卵巢衰老的特点是卵泡群减少的不同步。另一个限制因素是AMH患者亚组分析的样本量:对高龄女性来说,在黄体E2预处理的情况下安排拮抗剂周期似乎是一种有用的工具,可以更好地安排在工作日取卵。然而,采集卵母细胞数量的潜在益处仍有待在更大的人群中证实,这些人群显示出波塞冬分类中卵巢储备功能下降的特征:法国 Organon 公司 (MSD) 的研究基金。I.C.、S.D.、B.B.、X.M.、S.G.和 C.J. 与本研究无利益冲突。I.C.D. 申报了默克集团、Gedeon Richter、MSD (Organon, France)、Ferring、Theramex 和 IBSA 的演讲酬金,以及默克集团顾问委员会的参与酬金。I.C.D. 还申报了默克公司的咨询费、差旅费和会议支持。N.M. 申报了其所在机构从 MSD (Organon, France) 获得的资助;从 MSD (Organon, France)、Ferring 和 Merck KGaA 获得的咨询费;从 Merck KGaA、General Electrics、Genevrier (IBSA Pharma) 和 Theramex 获得的酬金;从 Theramex、Merck KGaG 和 Gedeon Richter 获得的差旅和会议支持;以及从 Goodlife Pharma 向其所在机构支付的设备费。N.C. 申报了 IBSA Pharma、Merck KGaG、Ferring 和 Gedeon Richter 的资助;IBSA Pharma、Merck KGaG、MSD (Organon, France)、Gedeon Richter 和 Theramex 的差旅和会议支持;以及 Merck KGaA 咨询委员会的参与。A.G.L.申报了默克集团、Gedeon Richter、MSD(法国 Organon)、Ferring、Theramex 和 IBSA 的演讲费:ClinicalTrials.gov NCT02884245.试验注册日期:2016年8月29日.首例患者入组日期:2016年11月4日:首例患者入组日期:2016 年 11 月 4 日。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pretreatment with luteal estradiol for programming antagonist cycles compared to no pretreatment in advanced age women stimulated with corifollitropin alfa: a non-inferiority randomized controlled trial.

Study question: Does luteal estradiol (E2) pretreatment give a similar number of retrieved oocytes compared to no-pretreatment in advanced-aged women stimulated with corifollitropin alfa in an antagonist protocol?

Summary answer: Programming antagonist cycles with luteal E2 gave similar number of retrieved oocytes compared to no-pretreatment in women aged 38-42 years.

What is known already: Programming antagonist cycles with luteal E2 pretreatment is a valuable tool to organize the IVF procedure better and is safe without any known impact on cycle outcome. However, variable effects were observed on the number of retrieved oocytes depending on the treated population. In advanced-age women, recruitable follicles tend to decrease in number and to be more heterogeneous in size but it remains unclear if estradiol pretreatment could change the oocyte yield through its negative feed-back effect on FSH intercycle rise.

Study design, size, duration: This non-blinded randomized controlled non-inferiority trial was conducted between 2016 and 2022 with centrally computerized randomization and concealed allocation. Participants were 324 women aged 38-42 years undergoing IVF treatment. The primary endpoint was the total number of retrieved oocytes. Statistical analysis was performed with one-sided alpha risk of 2.5% and 95% confidence interval (CI) with the non-inferiority of E2 pretreatment proved by a P value <0.025 and a lower delta margin of the CI within two oocytes compared to no pretreatment. Secondary endpoints were duration and total dosage of recombinant FSH, cancellation rate, percentage of oocyte pick-up (OPU) on working days, total number of metaphase II oocytes and obtained embryos, fresh transfer live birth rate, and cumulative live birth rate.

Participants/materials, setting, methods: This multicentric study enrolled women with regular cycles, weight >50 kg and body mass index <32, IVF cycle 1-2. According to randomization, micronized estradiol 2 mg twice a day was started on days 20-24 and continued until Wednesday beyond the onset of menses followed by administration of corifollitropin alfa on Friday, i.e. stimulation (S)1 or from D1-3 of a natural cycle in unpretreated patients. GnRH antagonist was started at S6 and additional FSH at S8.

Main results and the role of chance: Basal characteristics were similar in patients randomized in E2 pretreated (n = 164) and non-pretreated (n = 160) groups (intended to treat (ITT) population). A total of 291 patients started treatment (per protocol (PP) population), 147 in E2 pretreated group with a mean number [SD] of pre-treatment days 9.8 [2.6] and 144 in the non-pretreated group. Despite advanced age, oocyte yields ranged from 0 to 29 in both groups with a median number of 6 retrieved oocytes in accordance with a mean anti-Müllerian hormone (AMH) level above 1.2 ng/ml. We demonstrated the non-inferiority of E2 pretreatment with a mean difference of -0.1 oocyte 95% CI [-1.5; 1.3] P = 0.004 in the PP population and a mean difference of -0.44 oocyte [-1.84; 0.97] P = 0.014 in the ITT population. Oocyte retrieval was more often on working days in E2 pretreated patients (91.9 versus 74.2%, P < 0.001). In patients reaching OPU, the duration of stimulation was statistically significantly longer (11.7 [1.7] versus 10.8 [1.8] days, P < 0.001) and the extra FSH dosage in addition to corifollitropin alfa was statistically significantly higher (1040 [548] versus 778 [504] IU, P < 0.001) in E2 pretreated than non-pretreated patients. We did not observe any significant differences in the number of retrieved oocytes (8.4 [6.1] versus 9.1 [6.0]), in the number of Metaphase 2 oocytes (7 [5.5] versus 7.3 [5.2]) nor in the number of obtained embryos (5 [4.6] versus 5.2 [4.2]) in E2 pretreated patients compared to non-pretreated patients. The live birth rate after fresh transfer (16.2% versus 18.5%, respectively), and the cumulative live birth rate per patient (17.7% versus 22.9%, respectively) were similar in both groups. Among the PP population, 31.6% of patients fulfilled the criteria for group 4 of Poseïdon classification (AMH <1.2 ng/ml and/or antral follicle count <5). In this sub-group of patients, we observed in contrast a statistically higher number of retrieved oocytes in E2 pretreated patients compared to non-pretreated (5.1 [3.8] versus 3.4 [2.7], respectively, the mean difference of +1.7 oocyte [0.2; 3.2] P = 0.022) but without significant difference in the cumulative live birth rate per patient (15.7% versus 7.3%, respectively).

Limitations, reasons for caution: Our stimulated women older than 38 years obtained a wide range of collected oocytes suggesting very different stages of ovarian aging in both groups. E2 pretreatment is more likely to increase oocyte yield at the stage of ovarian aging characterized by asynchrony of a reduced follicular cohort. Another limitation is the sample size in sub-group analysis of patients with AMH <1.2 ng/ml. Finally, the absence of placebo for pretreatment could also introduce possible bias.

Wider implications of the findings: Programming antagonist cycles with luteal E2 pretreatment seems a useful tool in advanced age women to better schedule oocyte retrievals on working days. However, the potential benefit of the number of collected oocytes remains to be demonstrated in a larger population displaying the characteristics of decreased ovarian reserve encountered in Poseïdon classification.

Study funding/competing interest(s): Research grant from (MSD) Organon, France. I.C., S.D., B.B., X.M., S.G., and C.J. have no conflict of interest with this study. I.C.D. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA and participation on advisory board from Merck KGaA. I.C.D. also declares consulting fees, and travel and meeting support from Merck KGaA. N.M. declares grants paid to their institution from MSD (Organon, France); consulting fees from MSD (Organon, France), Ferring, and Merck KGaA; honoraria from Merck KGaA, General Electrics, Genevrier (IBSA Pharma), and Theramex; support for travel and meetings from Theramex, Merck KGaG, and Gedeon Richter; and equipment paid to their institution from Goodlife Pharma. N.C. declares grants from IBSA Pharma, Merck KGaA, Ferring, and Gedeon Richter; support for travel and meetings from IBSA Pharma, Merck KGaG, MSD (Organon, France), Gedeon Richter, and Theramex; and participation on advisory board from Merck KGaA. A.G.L. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA.

Trial registration number: ClinicalTrials.gov NCT02884245.

Trial registration date: 29 August 2016.

Date of first patient’s enrolment: 4 November 2016.

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来源期刊
Human reproduction
Human reproduction 医学-妇产科学
CiteScore
10.90
自引率
6.60%
发文量
1369
审稿时长
1 months
期刊介绍: Human Reproduction features full-length, peer-reviewed papers reporting original research, concise clinical case reports, as well as opinions and debates on topical issues. Papers published cover the clinical science and medical aspects of reproductive physiology, pathology and endocrinology; including andrology, gonad function, gametogenesis, fertilization, embryo development, implantation, early pregnancy, genetics, genetic diagnosis, oncology, infectious disease, surgery, contraception, infertility treatment, psychology, ethics and social issues.
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