Abstract：
OBJECTIVE: Is there any difference in ovarian response and embryo ploidy following progesterone-primed ovarian stimulation (PPOS) using micronized progesterone or GnRH antagonist protocol?
CONCLUSIONS: 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.
BACKGROUND: 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.
METHODS: 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.
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).
RESULTS: 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.
CONCLUSIONS: 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.
CONCLUSIONS: 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.
BACKGROUND: 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.
BACKGROUND: The study was registered at Clinical Trials Gov. (NCT04108039).
CONCLUSIONS: 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.
BACKGROUND: 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.
METHODS: 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.
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).
RESULTS: 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.
CONCLUSIONS: 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.
CONCLUSIONS: 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.
BACKGROUND: 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.
BACKGROUND: The study was registered at Clinical Trials Gov. (NCT04108039).
摘要：
目的：使用微粉化孕酮或GnRH拮抗剂方案的孕酮引发的卵巢刺激（PPOS）后，卵巢反应和胚胎倍性是否有差异？
结论：使用微粉化孕酮作为PPOS的垂体下调导致更多的卵母细胞回收和与GnRH拮抗剂方案相当的整倍体胚泡数量。
背景：尽管大多数人认为GnRH拮抗剂是在IVF/ICSI的卵巢刺激（OS）期间控制LH激增的黄金标准方案，PPOS协议越来越多地用于冻结所有协议。尽管如此，尽管PPOS协议取得了有希望的结果，一项早期随机试验报道,与GnRH拮抗剂方案相比,使用醋酸甲羟孕酮下调后,卵母细胞受者的活产可能较低.当前前瞻性研究的范围是调查具有微粉化孕酮的PPOS是否导致与GnRH拮抗剂方案相当的整倍体胚泡产量。
方法：在这项前瞻性研究中，在2019年9月至2022年1月期间,44名女性在6个月内接受了GnRH拮抗剂方案或口服微粉化孕酮的PPOS方案,连续接受了两次OS方案.
方法：总的来说，44名女性接受了两个OS周期，两个周期中rFSH的固定剂量相同（225或300IU）。在第一个周期中，使用灵活的GnRH拮抗剂方案进行下调（每天0.25mg，只要一个14毫米的卵泡），经过1个月的冲洗期，从刺激第1天起，用200mg口服微粉化孕酮控制LH激增。两个周期完成后，所有产生的胚泡都进行了非整倍体筛查的遗传分析（非整倍体的植入前遗传学测试，PGT-A）。
结果：方案之间的比较未发现操作系统持续时间之间的差异。触发当天的激素谱显示，除FSH外，所有测试激素的方案之间存在统计学上的显着差异：血清E2水平显着升高，与拮抗剂周期相比，PPOS周期中更高的LH水平和更高的孕酮水平，分别。与GnRH拮抗剂方案相比，PPOS方案导致显著更高的卵母细胞数量(12.7±8.09对10.3±5.84;平均值[DBM]-2.4[95%CI-4.1至-0.73]之间的差异)，中期II（9.1±6.12对7.3±4.15；DBM-1.8[95%CI-3.1至-0.43]），和2个原核（7.1±4.99对5.7±3.35；DBM-1.5[95%CI-2.6.1至-0.32]），分别。然而，在PPOS和GnRH拮抗剂方案之间，囊胚的平均数量（2.9±2.11对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对2.9±2.15；DBM-0.07[95％CI-0.70至0.56]）没有观察到差异，分别。关于每个活检胚胎的整倍体率，在PPOS和拮抗剂组中发现29%[95%CI21.8-38.1%]和35%[95%CI26.6-43.9%],分别。最后,主要结局没有观察到差异，PPOS与GnRh拮抗剂的比较，整倍体胚胎的平均数量为0.86±0.90和1.00±1.12。
结论：这项研究能够检测整倍体胚胎的平均数量的差异，而不是妊娠结局。此外,根据协议，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,其间有1个月的洗脱期.
结论：在冻结全部方案的情况下，临床医生可以安全地考虑口服微粉化孕酮来控制LH激增，患者可以从口服给药的药物优势中受益。以更低的成本获取更多数量的卵母细胞，胚胎倍性率没有任何妥协。
背景：这项研究得到了Theramex的无限制资助。N.P.P.已获得默克·塞罗诺的研究资助，Organon,Ferring制药,罗氏,Theramex,IBSA,GedeonRichter,和BesinsHealthcare；来自默克·塞罗诺的讲座酬劳，Organon,Ferring制药，贝辛斯国际,罗氏诊断,IBSA,Theramex,和GedeonRichter；MerckSerono的咨询费，Organon,BesinsHealthcare,IBSA。M.d.M.V.,F.M.,I.R.宣布没有利益冲突。
背景：该研究已在临床试验部门注册。（NCT04108039）。
结论：使用微粉化孕酮作为PPOS的垂体下调导致更多的卵母细胞回收和与GnRH拮抗剂方案相当的整倍体胚泡数量。
背景：尽管大多数人认为GnRH拮抗剂是在IVF/ICSI的卵巢刺激（OS）期间控制LH激增的黄金标准方案，PPOS协议越来越多地用于冻结所有协议。尽管如此，尽管PPOS协议取得了有希望的结果，一项早期随机试验报道,与GnRH拮抗剂方案相比,使用醋酸甲羟孕酮下调后,卵母细胞受者的活产可能较低.当前前瞻性研究的范围是调查具有微粉化孕酮的PPOS是否导致与GnRH拮抗剂方案相当的整倍体胚泡产量。
方法：在这项前瞻性研究中，在2019年9月至2022年1月期间,44名女性在6个月内接受了GnRH拮抗剂方案或口服微粉化孕酮的PPOS方案,连续接受了两次OS方案.
方法：总的来说，44名女性接受了两个OS周期，两个周期中rFSH的固定剂量相同（225或300IU）。在第一个周期中，使用灵活的GnRH拮抗剂方案进行下调（每天0.25mg，只要一个14毫米的卵泡），经过1个月的冲洗期，从刺激第1天起，用200mg口服微粉化孕酮控制LH激增。两个周期完成后，所有产生的胚泡都进行了非整倍体筛查的遗传分析（非整倍体的植入前遗传学测试，PGT-A）。
结果：方案之间的比较未发现操作系统持续时间之间的差异。触发当天的激素谱显示，除FSH外，所有测试激素的方案之间存在统计学上的显着差异：血清E2水平显着升高，与拮抗剂周期相比，PPOS周期中更高的LH水平和更高的孕酮水平，分别。与GnRH拮抗剂方案相比，PPOS方案导致显著更高的卵母细胞数量(12.7±8.09对10.3±5.84;平均值[DBM]-2.4[95%CI-4.1至-0.73]之间的差异)，中期II（9.1±6.12对7.3±4.15；DBM-1.8[95%CI-3.1至-0.43]），和2个原核（7.1±4.99对5.7±3.35；DBM-1.5[95%CI-2.6.1至-0.32]），分别。然而，在PPOS和GnRH拮抗剂方案之间，囊胚的平均数量（2.9±2.11对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对2.9±2.15；DBM-0.07[95％CI-0.70至0.56]）没有观察到差异，分别。关于每个活检胚胎的整倍体率，在PPOS和拮抗剂组中发现29%[95%CI21.8-38.1%]和35%[95%CI26.6-43.9%],分别。最后,主要结局没有观察到差异，PPOS与GnRh拮抗剂的比较，整倍体胚胎的平均数量为0.86±0.90和1.00±1.12。
结论：这项研究能够检测整倍体胚胎的平均数量的差异，而不是妊娠结局。此外,根据协议，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,其间有1个月的洗脱期.
结论：在冻结全部方案的情况下，临床医生可以安全地考虑口服微粉化孕酮来控制LH激增，患者可以从口服给药的药物优势中受益。以更低的成本获取更多数量的卵母细胞，胚胎倍性率没有任何妥协。
背景：这项研究得到了Theramex的无限制资助。N.P.P.已获得默克·塞罗诺的研究资助，Organon,Ferring制药,罗氏,Theramex,IBSA,GedeonRichter,和BesinsHealthcare；来自默克·塞罗诺的讲座酬劳，Organon,Ferring制药，贝辛斯国际,罗氏诊断,IBSA,Theramex,和GedeonRichter；MerckSerono的咨询费，Organon,BesinsHealthcare,IBSA。M.d.M.V.,F.M.,I.R.宣布没有利益冲突。
背景：该研究已在临床试验部门注册。（NCT04108039）。
