目的:来曲唑(LZ)与促性腺激素联合治疗在IVF中影响卵泡募集,卵母细胞数量和质量,胚胎质量,或活产率(LBR)?
结论:在卵泡募集中未发现LZ的影响,卵母细胞数量,胚胎质量,或LBR。
背景:IVF的多卵泡刺激产生超生理雌二醇水平。LZ是一种芳香酶抑制剂,可降低血清雌二醇,从而减少卵泡和黄体期的负反馈并增加内源性促性腺激素,在IVF治疗期间有效地使内分泌环境正常化。
方法:次要结果来自随机,一项双盲安慰剂对照试验(RCT)调查了FSH刺激IVF期间每日一次5mgLZ或安慰剂。RCT于2016年8月至2018年11月在丹麦大学医院的四家生育诊所进行,冻融胚胎移植(FET)的妊娠结局登记至2023年5月。
方法:59名预期卵巢储备正常的女性(抗苗勒管激素8-32nmol/l)被随机分为LZ(n=80)或安慰剂(n=79)。总共吸出1268个卵母细胞,发育成386个胚胎,并对形态和形态动力学进行了评估。在新鲜周期中转移了一百二十九个胚胎,在随后的FET周期中转移了158个胚胎。LZ对累积临床妊娠率(CPR)的影响,LBR,新鲜周期中的子宫内膜厚度,报告了FSH总消费量。
结果:LZ组和安慰剂组的卵母细胞可用胚胎比例相似,分别为0.31和0.36(平均差异(MD)-0.05,95%CI(-0.12;0.03),P=0.65)。取卵时抽吸卵泡的大小和数量相似,每名患者有11.8个与10.3个卵泡(MD1.5,95%CI(-0.5;3.1),P=0.50),以及8.0和7.9个卵母细胞的回收卵母细胞数量(MD0.1,95%CI(-1.4;1.6),P=0.39)在LZ和安慰剂组中,分别。在触发日从13至16毫米卵泡中取出卵母细胞的机会高出66%(95%CI(24%;108%),安慰剂组的P=0.002)比LZ组,而在触发日从≥17毫米卵泡中取出卵母细胞的机会高出50%(95%CI(2%;98%),LZ组的P=0.04)高于安慰剂组。与IVF或ICSI受精无关,每个回收的卵母细胞或每个中期II卵母细胞(MII)的两个前核受精卵母细胞的比例(2PN率)相似,为0.48vs0.57(MD-0.09,95%CI(-0.24;0.04),P=0.51),和0.62vs0.64(MD-0.02,95%CI(-0.13;0.07),P=0.78)在LZ和安慰剂组中,分别。然而,ICSI组的MII率显着降低,LZ与安慰剂组的MII率分别为0.75和0.88(MD-0.14,95%CI(-0.22;-0.06),P=0.03)。每位患者第5天的囊胚相似,为1.5vs2.0,P=0.52,以及每位患者第5天的玻璃化囊胚0.8vs1.2in(MD-0.4,95%CI(-1.0;0.2),P=0.52),每位患者第6天的玻璃化囊胚0.6vs0.6(MD0,95%CI(-0.3;0.3),P=1.00)在LZ与安慰剂组,分别。所有可用胚胎的形态学评估显示\'良好\'中的分布相似,\'公平\',和\'可怜\',在LZ与安慰剂组,比值比(OR)为0.895%CI(0.5;1.3),发育更好的类胚胎的P=0.68。386个胚胎中有二百九十五个在胚胎镜中培养。形态动力学注释显示,第3天具有高KIDscore™D3的几率高1.2倍(CI(0.8;1.9),LZ组与安慰剂组的P=0.68)。每次转移的CPR与31%和39%相当(风险差异为8%,95%CI(-25%;11%),P=0.65)在LZ和安慰剂组中,分别,以及针对转移日调整的每次转移的CPR,触发时的雌二醇和孕酮水平,黄体中期孕酮水平,检索到的卵母细胞数(调整后的OR)为0.8(95%CI(0.4;1.6),P=0.72)。每次转移发现可比较的LBR为28%对37%(MD-9%,95%CI(-26%;9%),P=0.60)和每位随机女性24%vs30%(MD为-6%,CI(-22%;8%),LZ组和安慰剂组的P=0.60),分别。此外,自上次卵母细胞抽吸以来4.8年,在新鲜或随后的FET循环中,总共有386个胚胎中的287个被转移,披露累积CPR,与38%和34%相似(MD95%CI(8%;16%),LZ与安慰剂组的P=0.70)。
结论:实验方案允许卵裂期和胚泡移植及玻璃化。使得有必要对它们的质量进行分类并汇集结果。这项研究能够检测荷尔蒙变化,但不能检测胚胎或妊娠结局。
结论:胚胎的相似利用率和质量支持将LZ联合治疗用于IVF,并具有特定的适应症作为生育力保存,以前患有癌症的患者,或可怜的反应者。LZ对来自不同卵泡大小和LBR的成熟卵母细胞的影响应在荟萃分析或更大的RCT中评估。
背景:获得了来自欧盟国际组织的资助,Sjaelland大学医院,丹麦,Ferring制药,还有GedeonRicther.罗氏诊断公司为分析做出了贡献。A.P.收到了Ferring的资助,默克·塞罗诺,还有GedeonRichter,来自Preglem的咨询费,诺和诺德,套圈,GedeonRichter,Cryos,&MerckA/S,GedeonRichter的演讲者费用,套圈,默克A/S,Theramex,&Organon,以及GedeonRichter的旅行支持.其余作者声明他们在研究或出版物中没有竞争利益。
背景:NCT02939898和NCT02946684。
Does letrozole (LZ) co-treatment during ovarian stimulation with gonadotropins for in IVF impact follicle recruitment, oocyte number and quality, embryo quality, or live birth rate (LBR)?
No impact of LZ was found in follicle recruitment, number of oocytes, quality of embryos, or LBR.
Multi-follicle stimulation for IVF produces supra-physiological oestradiol levels. LZ is an aromatase inhibitor that lowers serum oestradiol thus reducing negative feedback and increasing the endogenous gonadotropins in both the follicular and the luteal phases, effectively normalizing the endocrine milieu during IVF treatment.
Secondary outcomes from a randomized, double-blind placebo-controlled
trial (RCT) investigating once-daily 5 mg LZ or placebo during stimulation for IVF with FSH. The RCT was conducted at four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018 and pregnancy outcomes of frozen-thawed embryo transfers (FET) registered until May 2023.
One hundred fifty-nine women with expected normal ovarian reserve (anti-Müllerian hormone 8-32 nmol/l) were randomized to either co-treatment with LZ (n = 80) or placebo (n = 79). In total 1268 oocytes were aspirated developing into 386 embryos, and morphology and morphokinetics were assessed. One hundred twenty-nine embryos were transferred in the fresh cycle and 158 embryos in a subsequent FET cycle. The effect of LZ on cumulative clinical pregnancy rate (CPR), LBR, endometrial thickness in the fresh cycle, and total FSH consumption was reported.
The proportion of usable embryos of retrieved oocytes was similar in the LZ group and the placebo group with 0.31 vs 0.36 (mean difference (MD) -0.05, 95% CI (-0.12; 0.03), P = 0.65). The size and number of aspirated follicles at oocyte retrieval were similar with 11.8 vs 10.3 follicles per patient (MD 1.5, 95% CI (-0.5; 3.1), P = 0.50), as well as the number of retrieved oocytes with 8.0 vs 7.9 oocytes (MD 0.1, 95% CI (-1.4; 1.6), P = 0.39) in the LZ and placebo groups, respectively. The chance of retrieving an oocyte from the 13 to 16 mm follicles at trigger day was 66% higher (95% CI (24%; 108%), P = 0.002) in the placebo group than in the LZ group, whilst the chance of retrieving an oocyte from the ≥17 mm follicles at trigger day was 50% higher (95% CI (2%; 98%), P = 0.04) in the LZ group than in the placebo group. The proportion of fertilized oocytes with two-pronuclei per retrieved oocytes or per metaphase II oocytes (MII) (the 2PN rates) were similar regardless of fertilization with IVF or ICSI with 0.48 vs 0.57 (MD -0.09, 95% CI (-0.24; 0.04), P = 0.51), and 0.62 vs 0.64 (MD -0.02, 95% CI (-0.13; 0.07), P = 0.78) in the LZ and placebo groups, respectively. However, the MII rate in the ICSI group was significantly lower with 0.75 vs 0.88 in the LZ vs the placebo group (MD -0.14, 95% CI (-0.22; -0.06), P = 0.03). Blastocysts on Day 5 per patient were similar with 1.5 vs 2.0, P = 0.52, as well as vitrified blastocysts per patient Day 5 with 0.8 vs 1.2 in (MD -0.4, 95% CI (-1.0; 0.2), P = 0.52) and vitrified blastocysts per patient Day 6 with 0.6 vs 0.6 (MD 0, 95% CI (-0.3; 0.3), P = 1.00) in the LZ vs placebo group, respectively. Morphologic evaluation of all usable embryos showed a similar distribution in \'Good\', \'Fair\', and \'Poor\', in the LZ vs placebo group, with an odds ratio (OR) of 0.8 95% CI (0.5; 1.3), P = 0.68 of developing a better class embryo. Two hundred and ninety-five of the 386 embryos were cultured in an embryoscope. Morphokinetic annotations showed that the odds of having a high KIDscore™ D3 Day 3 were 1.2 times higher (CI (0.8; 1.9), P = 0.68) in the LZ group vs the placebo group. The CPR per transfer was comparable with 31% vs 39% (risk-difference of 8%, 95% CI (-25%; 11%), P = 0.65) in the LZ and placebo group, respectively, as well as CPR per transfer adjusted for day of transfer, oestradiol and progesterone levels at trigger, progesterone levels mid-luteal, and number of oocytes retrieved (adjusted OR) of 0.8 (95% CI (0.4; 1.6), P = 0.72). Comparable LBR were found per transfer 28% vs 37% (MD -9%, 95% CI (-26%; 9%), P = 0.60) and per randomized women 24% vs 30% (MD of -6%, CI (-22%; 8%), P = 0.60) in the LZ group and placebo group, respectively. Furthermore, 4.8 years since the last oocyte aspiration, a total of 287 of 386 embryos have been transferred in the fresh or a subsequently FET cycle, disclosing the cumulative CPR, which is similar with 38% vs 34% (MD 95% CI (8%; 16%), P = 0.70) in the LZ vs placebo group.
Both cleavage stage and blastocyst transfer and vitrification were permitted in the protocol, making it necessary to categorize their quality and pool the results. The
study was powered to detect hormonal variation but not embryo or pregnancy outcomes.
The similar utilization rate and quality of the embryos support the use of LZ co-treatment for IVF with specific indication as fertility preservation, patients with previous cancer, or poor responders. The effect of LZ on mature oocytes from different follicle sizes and LBRs should be evaluated in a meta-analysis or a larger RCT.
Funding was received from EU Interreg for ReproUnion, Sjaelland University Hospital, Denmark, Ferring Pharmaceuticals, and Gedeon Ricther. Roche Diagnostics contributed with assays. A.P. has received grants from Ferring, Merck Serono, and Gedeon Richter, consulting fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, & Merck A/S, speakers fees from Gedeon Richter, Ferring, Merck A/S, Theramex, & Organon, and travel support from Gedeon Richter. The remaining authors declare that they have no competing interests in the research or publication.
NCT02939898 and NCT02946684.