Albert Ana Belén, Corachán Ana, Juárez-Barber Elena, Cozzolino Mauro, Pellicer Antonio, Alecsandru Diana, Cervelló Irene, Ferrero Hortensia
IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Department of Reproductive Medicine, Valencia, Spain.
IVIRMA Global Research Alliance, IVIRMA-Rome, Rome, Italy.
Hum Reprod. 2025 Aug 1;40(8):1562-1569. doi: 10.1093/humrep/deaf100.
What is the association between insulin resistance (IR), metformin treatment, and the outcomes of IVF in IR infertile women without polycystic ovarian syndrome (non-PCOS)?
IR among non-PCOS infertile women was associated with worse IVF outcomes compared to insulin-sensitive (IS) infertile women, and metformin treatment prior to embryo transfer (ET) was associated with improved reproductive outcomes.
Endometrium insulin-mediated glucose uptake is essential in human embryo implantation, decidualization, and pregnancy. IR has been described as a risk factor for spontaneous abortion in women undergoing IVF. While this condition has been studied in the context of PCOS and its association with poorer reproductive outcomes, with Metformin proposed as a possible treatment, there is a lack of studies examining the role of IR in non-PCOS infertile women.
STUDY DESIGN, SIZE, DURATION: Observational, multicenter, retrospective cohort study with clinical data from private fertility centers in Spain collected between January 2015 to November 2023. From 1659 patients a total of 1033 women met all the inclusion criteria and had available data for analysis.
PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included non-PCOS infertile women between 18 and 45 years old, with a BMI ≤30 kg/m2, available oral glucose tolerance test (OGTT) results, and an indication for IVF and ET using donated oocytes. The study population was stratified based on OGTT results in IS women (n = 718) and in IR women (n = 315). Among IR patients, we identified 198 who were not exposed to metformin at their first ET and 117 who were Metformin-exposed prior to their first ET. IVF outcomes, including biochemical pregnancy, biochemical miscarriage, clinical pregnancy, clinical miscarriage, and live birth rates were evaluated as primary outcomes in IS and not exposed IR groups. The association between metformin exposure and IVF outcomes among IR patients was assessed as secondary outcomes.
The prevalence of IR in non-PCOS infertile women was 30.5%. Compared to the IS group, unexposed IR women had a higher risk of clinical miscarriage [26.3% vs 17.6%; adjusted relative risk (aRR)=1.439 (1.078-1.921); P = 0.013] and lower live birth rates [9.6% vs 24.5%; aRR=0.422 (0.269-0.663); P < 0.001]. Alternatively, IR patients exposed to Metformin had a higher risk of clinical pregnancy [53.9% vs 35.9%; aRR = 1.467 (1.137-1.892) P = 0.003], lower risk of clinical miscarriage [13.7% vs 26.3%; aRR = 0.481 (0.288-0.804), P = 0.005], and higher live birth rates [40.2% vs 9.6%; aRR = 4.069 (2.445-6.774), P < 0.001] than unexposed IR patients.
LIMITATIONS, REASONS FOR CAUTION: Due to its retrospective nature, the inherent limitations of this pilot study are the potential heterogeneity and confounding factors among the study groups.
The findings of this study provide valuable insights into the role of the endometrial environment on reproductive outcomes in the context of IR among non-PCOS infertile women. Nevertheless, future prospective studies with larger sample sizes are essential to corroborate these findings to broader populations.
STUDY FUNDING/COMPETING INTEREST(S): This project was supported by the Spanish Ministry of Universities through the Formacion de Profesorado Universitario Program (FPU21/01178) awarded to A.B.A, the Instituto de Salud Carlos III, cofounded by the European Social Fund (ESF) 'Investing in your future' through the Miguel Servet Program (CP20/00120) awarded to H.F. and (CP19/00149) awarded to I.C. and Sara Borrell Contract (CD23/00157) awarded to A.C. The authors have no conflicts of interest to disclose.
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在无多囊卵巢综合征（非PCOS）的胰岛素抵抗（IR）不孕女性中，胰岛素抵抗、二甲双胍治疗与体外受精（IVF）结局之间有何关联？
与胰岛素敏感（IS）的不孕女性相比，非PCOS不孕女性中的IR与较差的IVF结局相关，且胚胎移植（ET）前使用二甲双胍治疗与改善生殖结局相关。
子宫内膜胰岛素介导的葡萄糖摄取在人类胚胎着床、蜕膜化和妊娠中至关重要。IR已被描述为接受IVF的女性自然流产的一个风险因素。虽然在PCOS背景下对这种情况及其与较差生殖结局的关联进行了研究，并提出二甲双胍作为一种可能的治疗方法，但缺乏研究来检验IR在非PCOS不孕女性中的作用。
研究设计、规模、持续时间：观察性、多中心、回顾性队列研究，收集了2015年1月至2023年11月期间西班牙私立生育中心的临床数据。1659例患者中，共有1033名女性符合所有纳入标准并具有可供分析的数据。
参与者/材料、设置、方法：该研究纳入了年龄在18至45岁之间、BMI≤30kg/m²、有口服葡萄糖耐量试验（OGTT）结果且有使用捐赠卵母细胞进行IVF和ET指征的非PCOS不孕女性。研究人群根据OGTT结果分为IS女性（n = 718）和IR女性（n = 315）。在IR患者中，我们确定了198例在首次ET时未接触二甲双胍的患者和117例在首次ET前接触二甲双胍的患者。将IVF结局，包括生化妊娠、生化流产、临床妊娠、临床流产和活产率作为IS组和未接触二甲双胍的IR组的主要结局进行评估。评估IR患者中二甲双胍暴露与IVF结局之间的关联作为次要结局。
非PCOS不孕女性中IR的患病率为30.5%。与IS组相比，未接触二甲双胍的IR女性临床流产风险更高[26.3%对17.6%；调整后相对风险（aRR）=1.439（1.078 - 1.921）；P = 0.013]，活产率更低[9.6%对24.5%；aRR = 0.422（0.269 - 0.663）；P < 0.001]。相比之下，接触二甲双胍的IR患者临床妊娠风险更高[53.9%对35.9%；aRR = 1.467（1.137 - 1.892），P = 0.003]，临床流产风险更低[13.7%对26.3%；aRR = 0.481（0.288 - 0.804），P = 0.005]，活产率更高[40.2%对9.6%；aRR = 4.069（2.445 - 6.774），P < 0.001]，高于未接触二甲双胍的IR患者。
局限性、谨慎的原因：由于其回顾性性质，这项初步研究的固有局限性是研究组之间潜在的异质性和混杂因素。
本研究结果为非PCOS不孕女性IR背景下子宫内膜环境对生殖结局的作用提供了有价值的见解。然而，未来需要更大样本量的前瞻性研究来在更广泛人群中证实这些发现。
研究资金/利益冲突：本项目由西班牙大学部通过授予A.B.A的大学教师培训计划（FPU21/01178）、卡洛斯三世卫生研究所资助，该研究所由欧洲社会基金（ESF）“投资你的未来”共同资助，通过授予H.F.的米格尔·塞尔维特计划（CP20/00120）以及授予I.C.的（CP19/00149）和授予A.C.的萨拉·博雷尔合同（CD23/00157）。作者没有利益冲突需要披露。
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