目的:在拮抗剂方案中,黄体雌二醇(E2)预处理与未预处理相比,在接受抗体素α刺激的高龄女性中,获得的卵母细胞数量是否相似?
结论:在38-42岁的女性中,黄体E2编程拮抗剂周期与未预处理相比,获得的卵母细胞数量相似。
背景:用黄体E2预处理对拮抗剂周期进行编程是更好地组织IVF程序的有价值的工具,并且是安全的,对周期结局没有任何已知影响。然而,根据治疗群体的不同,观察到对回收卵母细胞数量的不同影响.在高龄女性中,可募集卵泡的数量倾向于减少,大小也更不均匀,但目前尚不清楚雌二醇预处理是否能通过其对FSH周期间升高的负反馈效应改变卵母细胞产量.
方法:这项非盲随机对照非劣效性试验于2016年至2022年之间进行,采用中央计算机化随机化和隐蔽分配。参与者是324名年龄在38-42岁接受IVF治疗的女性。主要终点是回收的卵母细胞总数。进行统计学分析,单侧α风险为2.5%和95%置信区间(CI),E2预处理的非劣效性由P值<0.025和两个卵母细胞内CI的δ边缘低于未预处理证明。次要终点是重组FSH的持续时间和总剂量,取消率,工作日卵母细胞拾取百分比(OPU),中期II卵母细胞和获得的胚胎总数,新鲜转移活产率,和累计活产率。
方法:这项多中心研究招募了有规律周期的女性,体重>50公斤,体重指数<32,IVF周期1-2。根据随机化,在第20-24天开始每天两次微粉化雌二醇2毫克,并持续到月经开始后的星期三,然后在星期五服用corifollitropinalfa,即在未经预处理的患者中刺激(S)1或来自自然周期的D1-3。在S6开始GnRH拮抗剂,在S8开始额外的FSH。
结果:随机分为E2预处理组(n=164)和非预处理组(n=160)(旨在治疗(ITT)人群)的患者的基本特征相似。共有291名患者开始治疗(按方案(PP)人群),E2预处理组147个,平均治疗前9.8天[2.6]和非预处理组144个[SD]。尽管年事已高,根据平均抗苗勒管激素(AMH)水平高于1.2ng/ml,两组的卵母细胞产量均在0至29之间,中位回收的卵母细胞数为6。我们证明了E2预处理的非劣效性,在PP群体中平均差异为-0.1卵母细胞95%CI[-1.5;1.3]P=0.004,在ITT群体中平均差异为-0.44卵母细胞[-1.84;0.97]P=0.014。E2预处理的患者在工作日取卵更常见(91.9对74.2%,P<0.001)。在到达OPU的患者中,刺激的持续时间在统计学上显着延长(11.7[1.7]对10.8[1.8]天,P<0.001),并且除Corifollitropinalfa外的额外FSH剂量在统计学上显着更高(1040[548]对778[504]IU,P<0.001)在E2预处理的患者中高于未预处理的患者。我们没有观察到任何显著差异的数量检索卵母细胞(8.4[6.1]对9.1[6.0]),与未预处理的患者相比,E2预处理的患者的中期2卵母细胞数量(7[5.5]对7.3[5.2])和获得的胚胎数量(5[4.6]对5.2[4.2]).新鲜转移后的活产率(16.2%对18.5%,分别),和每位患者的累计活产率(17.7%对22.9%,分别)两组相似。在PP人群中,31.6%的患者符合Poseidon分类第4组的标准(AMH<1.2ng/ml和/或窦卵泡计数<5)。在这个亚组的患者中,相反,我们观察到,与未预处理的患者相比,E2预处理的患者中回收的卵母细胞数量在统计学上更高(5.1[3.8]对3.4[2.7],分别,+1.7卵母细胞的平均差异[0.2;3.2]P=0.022),但在每位患者的累积活产率方面没有显着差异(15.7%对7.3%,分别)。
结论:我们的38岁以上受刺激的女性获得了广泛的卵母细胞,提示两组的卵巢老化阶段非常不同。E2预处理更有可能在卵巢衰老阶段增加卵母细胞产量,其特征是卵泡减少的队列不同步。另一个限制是AMH<1.2ng/ml患者的亚组分析中的样本量。最后,治疗前不使用安慰剂也可能导致偏倚.
结论:黄体E2预处理的计划拮抗剂周期似乎是高龄女性在工作日更好地安排卵母细胞回收的有用工具。然而,收集卵母细胞数量的潜在益处仍有待在更大的人群中证明,这些人群表现出在Posedon分类中卵巢储备能力下降的特征.
背景:(MSD)Organon的研究资助,法国。I.C.,S.D.,B.B.,X.M.,S.G.,和C.J.与这项研究没有利益冲突。I.C.D.宣布费用为默克KGaA的发言人,GedeonRichter,MSD(Organon,法国),套圈,Theramex,和IBSA以及默克KGaA顾问委员会的参与。I.C.D.还宣布咨询费,以及MerckKGaA的旅行和会议支持。N.M.宣布从MSD(Organon,法国);MSD的咨询费(Organon,法国),套圈,和默克KGaA;默克KGaA的酬金,通用电气,Genevrier(IBSAPharma),和Theramex;支持Theramex的旅行和会议,默克KGaG,和GedeonRichter;以及从GoodlifePharma支付给他们机构的设备。N.C.宣布IBSAPharma的拨款,默克KGaA,套圈,和GedeonRichter;IBSAPharma对旅行和会议的支持,默克KGaG,MSD(Organon,法国),GedeonRichter,和Theramex;以及默克KGaA顾问委员会的参与。A.G.L.宣布费用为默克KGaA的发言人,GedeonRichter,MSD(Organon,法国),套圈,Theramex,IBSA。
背景:ClinicalTrials.govNCT02884245。
■2016年8月29日。
■2016年11月4日。
OBJECTIVE: 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?
CONCLUSIONS: Programming antagonist cycles with luteal E2 gave similar number of retrieved oocytes compared to no-pretreatment in women aged 38-42 years.
BACKGROUND: 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.
METHODS: 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.
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.
RESULTS: 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).
CONCLUSIONS: 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.
CONCLUSIONS: 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.
BACKGROUND: 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.
BACKGROUND: ClinicalTrials.gov NCT02884245.
UNASSIGNED: 29 August 2016.
UNASSIGNED: 4 November 2016.