Martinez Francisca, Clua Elisabet, Roca Marta, Garcia Sandra, Polyzos Nikolaos P
Department of Obstetrics, Gynaecology and Reproductive Medicine, Dexeus Mujer, Dexeus University Hospital, Barcelona, Spain.
Hum Reprod. 2022 Nov 24;37(12):2777-2786. doi: 10.1093/humrep/deac222.
Is there any difference in the mean number of euploid embryos following luteal phase start (LS) and follicular phase start (FS) of ovarian stimulation?
The mean number of euploid blastocysts is equivalent independent of whether the inseminated oocytes are derived from FS or LS.
Starting ovarian stimulation at any time of the cycle ('random-start') is commonly used for emergency fertility preservation in cancer patients. A few retrospective studies have been published evaluating LS in women undergoing ovarian stimulation in the context of IVF, but there is a lack of robust data on the comparative efficacy of LS versus FS.Although 'random start' is commonly used in cancer survivors, few retrospective and uncontrolled studies have been published evaluating luteal phase stimulation in women undergoing ovarian stimulation in the context of IVF. Owing to this evident lack of robust data on the efficacy of LS, guidelines typically recommend the LS approach only for medical reasons and not in the context of IVF.
STUDY DESIGN, SIZE, DURATION: This is a prospective, equivalence study, with repeated stimulation cycles, conducted between May 2018 and December 2021. Overall, 44 oocyte donors underwent two identical consecutive ovarian stimulation cycles, one initiated in the FS and the other in the LS. The primary outcome of the study was to evaluate whether FS and LS in the same patient would result in equivalent numbers of euploid embryos following fertilization of oocytes with the same sperm sample.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 44 oocyte donors underwent two consecutive ovarian stimulation protocols with 150 μg corifollitropin alpha followed by 200 IU recombinant FSH (rFSH) in a fixed GnRH antagonist protocol. The only difference between the two cycles was the day of initiation of ovarian stimulation, which was in the early follicular phase (FS) in one cycle, and in the luteal phase (LS) in the other. Forty-four oocyte recipients participated in the study receiving a mean of six metaphase II (MII) oocytes from each stimulation cycle (FS and LS). All MIIs were inseminated with the corresponding recipient's partner sperm (which had been previously frozen) or donor sperm, in order to safeguard the use of the same sample for either the FS or LS. Following fertilization and blastocyst culture, all generated embryos underwent genetic analysis for aneuploidy screening (preimplantation genetic testing for aneuploidy).
FS resulted in a significantly shorter duration of ovarian stimulation (difference between means (DBM) -1.05 (95% CI -1.89; -0.20)) and a lower total additional dose of daily rFSH was needed (DBM -196.02 (95% CI -319.92; -72.12)) compared with LS. The donors' hormonal profile on the day of trigger was comparable between the two stimulation cycles, as well as the mean number of oocytes (23.70 ± 10.79 versus 23.70 ± 8.81) (DBM 0.00 (95% CI -3.03; 3.03)) and MII oocytes (20.27 ± 9.60 versus 20.73 ± 8.65) (DBM -0.45 (95% CI -2.82; 1.91)) between FS and LS cycles, respectively. Following fertilization, the overall blastocyst formation rate was 60.70% with a euploid rate of 57.1%. Comparisons between the two stimulation cycles did not reveal any significance differences in terms of fertilization rates (71.9% versus 71.4%), blastocyst formation rates (59.4% versus 62%) and embryo euploidy rates (56.9 versus 57.3%) for the comparison of FS versus LS, respectively. The mean number of euploid blastocysts was equivalent between the FS (1.59 ± 1.30) and the LS (1.61 ± 1.17), (DBM -0.02 (90%CI -0.48; 0.44)).
LIMITATIONS, REASONS FOR CAUTION: The study was performed in young, potentially fertile oocyte donors who are patients with high blastocyst euploidy rates. Although results may be extrapolated to young infertile women with good ovarian reserve, caution is needed prior to generalizing the results to infertile women of older age.
The current study provides evidence that initiation of ovarian stimulation in the luteal phase in young potentially fertile women may result in a comparable number of oocytes and comparable blastocyst euploidy rates compared with follicular phase stimulation. This may imply that in case of a freeze-all protocol in young patients with good ovarian reserve, clinicians may safely consider initiation of ovarian stimulation during the luteal phase.
STUDY FUNDING/COMPETING INTEREST(S): This research was supported by an unrestricted grant from MSD/Organon. N.P.P. has received Research grants and honoraria for lectures from: Merck Serono, MSD/Organon, Ferring Pharmaceuticals, Besins Intenational, Roche Diagnostics, IBSA, Theramex, Gedeon Richter. F.M., E.C., M.R. and S.G. declared no conflict of interests.
The study was registered at Clinical Trials Gov (NCT03555942).
在卵巢刺激的黄体期开始（LS）和卵泡期开始（FS）后，整倍体胚胎的平均数量是否存在差异？
无论受精的卵母细胞来自FS还是LS，整倍体囊胚的平均数量都是相等的。
在月经周期的任何时间开始卵巢刺激（“随机开始”）常用于癌症患者的紧急生育力保存。已经发表了一些回顾性研究，评估了体外受精（IVF）背景下接受卵巢刺激的女性的黄体期开始情况，但缺乏关于黄体期开始与卵泡期开始比较效果的有力数据。虽然“随机开始”在癌症幸存者中常用，但很少有回顾性和非对照研究发表，评估IVF背景下接受卵巢刺激的女性的黄体期刺激情况。由于明显缺乏关于黄体期开始效果的有力数据，指南通常仅出于医学原因推荐黄体期开始方法，而不是在IVF背景下。
研究设计、规模、持续时间：这是一项前瞻性等效性研究，采用重复刺激周期，于2018年5月至2021年12月进行。总体而言，44名卵母细胞捐赠者接受了两个相同的连续卵巢刺激周期，一个在卵泡期开始（FS），另一个在黄体期开始（LS）。该研究的主要结果是评估同一患者的FS和LS在使用相同精子样本使卵母细胞受精后是否会产生等量的整倍体胚胎。
参与者/材料、设置、方法：总体而言，44名卵母细胞捐赠者接受了两个连续的卵巢刺激方案，先使用150μg阿那曲唑，然后在固定的GnRH拮抗剂方案中使用200IU重组促卵泡素（rFSH）。两个周期之间的唯一区别是卵巢刺激开始的日期，一个周期在卵泡早期（FS），另一个在黄体期（LS）。44名卵母细胞接受者参与了该研究，每个刺激周期（FS和LS）平均接受6个中期II（MII）卵母细胞。所有MII卵母细胞均用相应接受者伴侣的精子（先前已冷冻）或供体精子进行受精，以确保在FS或LS中使用相同的样本。受精和囊胚培养后，所有产生的胚胎都进行了非整倍体筛查的基因分析（植入前基因检测非整倍体）。
与LS相比，FS导致卵巢刺激持续时间显著缩短（均值差异（DBM）-1.05（95%CI -1.89；-0.20）），并且每日rFSH的总额外剂量需求更低（DBM -196.02（95%CI -319.92；-72.12））。两个刺激周期之间，触发日的捐赠者激素谱以及卵母细胞平均数量（23.70±10.79对23.70±8.81）（DBM 0.00（95%CI -3.03；3.03））和MII卵母细胞数量（20.27±9.60对20.73±8.65）（DBM -0.45（95%CI -2.82；1.91））在FS和LS周期之间分别具有可比性。受精后总体囊胚形成率为60.70%，整倍体率为57.1%。FS与LS比较时，两个刺激周期在受精率（71.9%对71.4%）、囊胚形成率（59.4%对62%）和胚胎整倍体率（56.9对57.3%）方面未发现任何显著差异。FS（1.59±1.30）和LS（1.61±1.17）的整倍体囊胚平均数量相等，（DBM -他的02（90%CI -0.48；0.44））。
局限性、谨慎原因：该研究在年轻、潜在生育能力强且囊胚整倍体率高的卵母细胞捐赠者中进行。虽然结果可能外推至卵巢储备良好的年轻不孕女性，但在将结果推广至年龄较大的不孕女性之前需要谨慎。
当前研究提供的证据表明，年轻潜在生育能力强的女性在黄体期开始卵巢刺激可能与卵泡期刺激产生相当数量的卵母细胞和相当的囊胚整倍体率。这可能意味着在卵巢储备良好的年轻患者采用全冻方案的情况下，临床医生可以安全地考虑在黄体期开始卵巢刺激。
研究资金/利益冲突：本研究由默克雪兰诺/欧加农的无限制赠款支持。N.P.P. 从以下机构获得研究资助和讲座酬金：默克雪兰诺、默克雪兰诺/欧加农、辉凌制药、贝西尼斯国际、罗氏诊断、IBSA、赛美维、吉德昂·里奇特。F.M.、E.C.、M.R. 和 S.G. 声明无利益冲突。
该研究在Clinical Trials Gov（NCT03555942）注册。
