STUDY QUESTION Is there any difference in ovarian response and embryo ploidy following progesterone-primed ovarian stimulation (PPOS) using micronized progesterone or GnRH antagonist protocol? SUMMARY ANSWER Pituitary downregulation with micronized progesterone as PPOS results in higher number of oocytes retrieved and a comparable number of euploid blastocysts to a GnRH antagonist protocol. WHAT IS KNOWN ALREADY Although the GnRH antagonist is considered by most the gold standard protocol for controlling the LH surge during ovarian stimulation (OS) for IVF/ICSI, PPOS protocols are being increasingly used in freeze-all protocols. Still, despite the promising results of PPOS protocols, an early randomized trial reported potentially lower live births in recipients of oocytes resulting following downregulation with medroxyprogesterone acetate as compared with a GnRH antagonist protocol. The scope of the current prospective study was to investigate whether PPOS with micronized progesterone results in an equivalent yield of euploid blastocysts to a GnRH antagonist protocol. STUDY DESIGN, SIZE, DURATION In this prospective study, performed between September 2019 to January 2022, 44 women underwent two consecutive OS protocols within a period of 6 months in a GnRH antagonist protocol or in a PPOS protocol with oral micronized progesterone. PARTICIPANTS/MATERIALS, SETTING, METHODS Overall, 44 women underwent two OS cycles with an identical fixed dose of rFSH (225 or 300 IU) in both cycles. Downregulation in the first cycles was performed with the use of a flexible GnRH antagonist protocol (0.25 mg per day as soon as one follicle of 14 mm) and consecutively, after a washout period of 1 month, control of LH surge was performed with 200 mg of oral micronized progesterone from stimulation Day 1. After the completion of both cycles, all generated blastocysts underwent genetic analysis for aneuploidy screening (preimplantation genetic testing for aneuplody, PGT-A). MAIN RESULTS AND THE ROLE OF CHANCE Comparisons between protocols did not reveal differences between the duration of OS. The hormonal profile on the day of trigger revealed statistically significant differences between protocols in all the tested hormones except for FSH: with significantly higher serum E2 levels, more elevated LH levels and higher progesterone levels in PPOS cycles as compared with antagonist cycles, respectively. Compared with the GnRH antagonist protocol, the PPOS protocol resulted in a significantly higher number of oocytes (12.7 ± 8.09 versus 10.3 ± 5.84; difference between means [DBM] –2.4 [95% CI –4.1 to –0.73]), metaphase II (9.1 ± 6.12 versus 7.3 ± 4.15; DBM –1.8 [95% CI –3.1 to –0.43]), and 2 pronuclei (7.1 ± 4.99 versus 5.7 ± 3.35; DBM –1.5 [95% CI –2.6.1 to –0.32]), respectively. Nevertheless, no differences were observed regarding the mean number of blastocysts between the PPOS and GnRH antagonist protocols (2.9 ± 2.11 versus 2.8 ± 2.12; DBM –0.07 [95% CI –0.67 to 0.53]) and the mean number of biopsied blastocysts (2.9 ± 2.16 versus 2.9 ± 2.15; DBM –0.07 [95% CI –0.70 to 0.56]), respectively. Concerning the euploidy rates per biopsied embryo, a 29% [95% CI 21.8–38.1%] and a 35% [95% CI 26.6–43.9%] were noticed in the PPOS and antagonist groups, respectively. Finally, no difference was observed for the primary outcome, with a mean number of euploid embryos of 0.86 ± 0.90 versus 1.00 ± 1.12 for the comparison of PPOS versus GnRh antagonist. LIMITATIONS, REASONS FOR CAUTION The study was powered to detect differences in the mean number of euploid embryos and not in terms of pregnancy outcomes. Additionally, per protocol, there was no randomization, the first cycle was always a GnRH antagonist cycle and the second a PPOS with 1 month of washout period in between. WIDER IMPLICATIONS OF THE FINDINGS In case of a freeze-all protocol, clinicians may safely consider oral micronized progesterone to control the LH surge and patients could benefit from the advantages of a medication of oral administration, with a potentially higher number of oocytes retrieved at a lower cost, without any compromise in embryo ploidy rates. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by an unrestricted grant from Theramex. N.P.P. has received Research grants from Merck Serono, Organon, Ferring Pharmaceutical, Roche, Theramex, IBSA, Gedeon Richter, and Besins Healthcare; honoraria for lectures from: Merck Serono, Organon, Ferring Pharmaceuticals, Besins International, Roche Diagnostics, IBSA, Theramex, and Gedeon Richter; consulting fees from Merck Serono, Organon, Besins Healthcare, and IBSA. M.d.M.V., F.M., and I.R. declared no conflicts of interest. TRIAL REGISTRATION NUMBER The study was registered at Clinical Trials Gov. (NCT04108039).

中文翻译：

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口服微粉化黄体酮引发卵巢刺激与 GnRH 拮抗剂方案后的卵巢反应和胚胎倍性。重复卵巢刺激周期的前瞻性研究

研究问题 使用微粉化孕酮或 GnRH 拮抗剂方案进行孕酮引发的卵巢刺激 (PPOS) 后，卵巢反应和胚胎倍性是否有任何差异？摘要答案 与 GnRH 拮抗剂方案相比，PPOS 时使用微粉化黄体酮下调垂体会导致获得更多的卵母细胞和相当数量的整倍体囊胚。已知信息 虽然 GnRH 拮抗剂被大多数人认为是 IVF/ICSI 卵巢刺激 (OS) 期间控制 LH 激增的金标准方案，但 PPOS 方案越来越多地用于全冷冻方案。尽管如此，尽管 PPOS 方案取得了有希望的结果，但一项早期随机试验报告称，与 GnRH 拮抗剂方案相比，醋酸甲羟孕酮下调后，卵母细胞受体的活产率可能较低。当前前瞻性研究的范围是调查 PPOS 与微粉化黄体酮是否能产生与 GnRH 拮抗剂方案相同的整倍体囊胚产量。研究设计、规模、持续时间 在这项于 2019 年 9 月至 2022 年 1 月期间进行的前瞻性研究中，44 名女性在 6 个月内接受了两次连续 OS 方案，分别是 GnRH 拮抗剂方案或口服微粉化黄体酮的 PPOS 方案。参与者/材料、环境、方法 总体而言，44 名女性接受了两个 OS 周期，两个周期中均使用相同的固定剂量的 rFSH（225 或 300 IU）。第一个周期中的下调是通过使用灵活的 GnRH 拮抗剂方案（每个卵泡 14 毫米时每天 0.25 毫克）进行的，随后在 1 个月的清除期后，用 200 毫克控制 LH 激增第 1 天刺激产生的口服微粉化黄体酮。两个周期完成后，所有生成的囊胚均接受非整倍体筛查的遗传分析（非整倍体植入前遗传检测，PGT-A）。主要结果和机会的作用 方案之间的比较没有揭示 OS 持续时间之间的差异。触发当天的激素分布显示除 FSH 之外的所有测试激素的方案之间存在统计学显着差异：与拮抗剂周期相比，PPOS 周期中的血清 E2 水平显着更高，LH 水平更高，黄体酮水平更高。与 GnRH 拮抗剂方案相比，PPOS 方案产生的卵母细胞数量显着增加（12.7 ± 8.09 与 10.3 ± 5.84；平均值之间的差异 [DBM] –2.4 [95% CI –4.1 至 –0.73]），中期 II ( 9.1 ± 6.12 对比 7.3 ± 4.15；DBM –1.8 [95% CI –3.1 至 –0.43]），和 2 个原核（7.1 ± 4.99 对比 5.7 ± 3.35；DBM –1.5 [95% CI –2.6.1 至 –0.32] ）， 分别。尽管如此，PPOS 和 GnRH 拮抗剂方案之间的平均囊胚数量没有观察到差异（2.9 ± 2.11 与 2.8 ± 2.12；DBM –0.07 [95% CI –0.67 至 0]。53]）和活检囊胚的平均数量（2.9 ± 2.16 与 2.9 ± 2.15；DBM –0.07 [95% CI –0.70 至 0.56]）。关于每个活检胚胎的整倍体率，PPOS 组和拮抗剂组分别为 29% [95% CI 21.8–38.1%] 和 35% [95% CI 26.6–43.9%]。最后，主要结果没有观察到差异，PPOS 与 GnRh 拮抗剂比较的平均整倍体胚胎数量为 0.86 ± 0.90，而平均数量为 1.00 ± 1.12。局限性和注意理由该研究旨在检测整倍体胚胎平均数量的差异，而不是妊娠结局的差异。此外，根据方案，没有随机化，第一个周期始终是 GnRH 拮抗剂周期，第二个周期是 PPOS，中间有 1 个月的清除期。研究结果的更广泛意义 如果采用全冷冻方案，临床医生可以安全地考虑口服微粉化黄体酮来控制 LH 激增，并且患者可以受益于口服药物的优势，并且在成本更低，且胚胎倍性率没有任何影响。研究经费/竞争利益 这项研究得到了 Theramex 的无限制资助的支持。 NPP 已获得来自 Merck Serono、Organon、Ferring Pharmaceutical、Roche、Theramex、IBSA、Gedeon Richter 和 Besins Healthcare 的研究资助；讲座酬金：Merck Serono、Organon、Ferring Pharmaceuticals、Besins International、Roche Diagnostics、IBSA、Theramex 和 Gedeon Richter； Merck Serono、Organon、Besins Healthcare 和 IBSA 的咨询费。 MdMV、FM 和 IR 声明不存在利益冲突。试验注册号 该研究已在临床试验政府 (NCT04108039) 注册。研究经费/竞争利益 这项研究得到了 Theramex 的无限制资助的支持。 NPP 已获得来自 Merck Serono、Organon、Ferring Pharmaceutical、Roche、Theramex、IBSA、Gedeon Richter 和 Besins Healthcare 的研究资助；讲座酬金：Merck Serono、Organon、Ferring Pharmaceuticals、Besins International、Roche Diagnostics、IBSA、Theramex 和 Gedeon Richter； Merck Serono、Organon、Besins Healthcare 和 IBSA 的咨询费。 MdMV、FM 和 IR 声明不存在利益冲突。试验注册号 该研究已在临床试验政府 (NCT04108039) 注册。研究经费/竞争利益 这项研究得到了 Theramex 的无限制资助的支持。 NPP 已获得来自 Merck Serono、Organon、Ferring Pharmaceutical、Roche、Theramex、IBSA、Gedeon Richter 和 Besins Healthcare 的研究资助；讲座酬金：Merck Serono、Organon、Ferring Pharmaceuticals、Besins International、Roche Diagnostics、IBSA、Theramex 和 Gedeon Richter； Merck Serono、Organon、Besins Healthcare 和 IBSA 的咨询费。 MdMV、FM 和 IR 声明不存在利益冲突。试验注册号 该研究已在临床试验政府 (NCT04108039) 注册。