Human reproduction open最新文献

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Lab-based semen parameters as predictors of long-term health in men-a systematic review. 基于实验室的精液参数作为男性长期健康的预测指标--系统综述。

IF 8.3 Q1 OBSTETRICS & GYNECOLOGY

Human reproduction open

Pub Date : 2024-11-08 eCollection Date: 2024-01-01 DOI: 10.1093/hropen/hoae066

Silvia Nedelcu, Srisailesh Vitthala, Abha Maheshwari

Study question: Can semen parameters predict long-term health outcomes in men?Summary answer: There is a lack of evidence to suggest a higher risk of comorbidities in men with poor semen concentration.What is known already: Male infertility has been long associated with a higher mortality risk and possibly higher chance of developing comorbidities but there has been less focus on semen analysis as a potential predictive factor.Study design size duration: We searched PubMed/MEDLINE, EMBASE, and EBM databases from inception to December 2023. MESH term strategy: heading 1 ('OR', semen analysis, sperm count, sperm parameter*, male infertility, azoospermia, aspermia, oligospermia, teratozoospermia, asthenozoospermia) 'AND' heading 2 ('OR', morbidity, mortality, diabetes, cancer, cardiovascular, death, hypertension, stroke, long-term health). We included all studies that analyzed the risk of mortality and/or future development of comorbidities in men with at least one semen analysis. Case series and reviews were excluded.Participants/materials setting methods: A narrative synthesis was done for all studies and meta-analysis where possible. Odds ratio (ORs) (95% CI, P-value) were calculated for all men with one suboptimal semen parameter and associated with the risk of a particular outcome. The risk of bias was assessed with QUADAS-2.Main results and the role of chance: Twenty-one studies were finally included. There was either a high or unclear risk of bias in all studies. The results only allowed for meta-analysis on categories of sperm concentration. We found a 2-fold increase in mortality risk in azoospermic men compared to oligospermic (OR 1.96, 95% CI: 1.29-2.96) and normozoospermic (OR 2.00, 95% CI: 1.23-3.25) groups, but not in oligospermic compared to normozoospermic (OR 1.04, 95% CI: 0.52-2.09). There was no difference in risk of cardiovascular disease in any of the sperm concentration groups (azoospermic-oligospermic OR 0.94, 95% CI: 0.74-1.20, azoospermic-normozoospermic OR 1.11, 95% CI: 0.71-1.75, and oligospermic-normozoospermic OR 1.12, 95% CI: 0.80-1.55). OR for diabetes in azoospermic men was higher only compared to oligospermic (OR 2.16, 95% CI: 1.55-3.01). The risk of all-site cancer was higher in azoospermic men compared to oligospermic (OR 2.16, 95% CI: 1.55-3.01) and normozoospermic (OR 2.18, 95% CI: 1.20-3.96). Only azoospermic men might be at higher risk of testicular cancer when compared to men with normal sperm concentration (OR 1.80, 95% CI: 1.12-2.89).Limitations reasons for caution: Although our pooled analysis shows an increased risk of mortality and all-site cancer risk in azoospermic men, the results show a lack of evidence to suggest a higher risk of comorbidities in men with poor semen concentration. Given the limited available data, the nature of the

研究问题精液参数能否预测男性的长期健康状况？目前尚无证据表明精液浓度低的男性患合并症的风险更高：男性不育长期以来一直与较高的死亡风险和可能较高的合并症发病几率相关，但精液分析作为潜在的预测因素却较少受到关注：我们检索了从开始到 2023 年 12 月的 PubMed/MEDLINE、EMBASE 和 EBM 数据库。MESH术语策略：标题1（'OR'，精液分析，精子数量，精子参数*，男性不育，无精子症，无精症，少精子症，畸形精子症，无精子症）'和'标题2（'OR'，发病率，死亡率，糖尿病，癌症，心血管，死亡，高血压，中风，长期健康）。我们纳入了所有分析男性死亡风险和/或未来合并症发展的研究，其中至少有一项精液分析。参与者/材料设置方法：对所有研究进行叙述性综合，并在可能的情况下进行荟萃分析。计算了所有精液参数不达标的男性与特定结果风险的比值比（ORs）（95% CI，P 值）。用 QUADAS-2 评估了偏倚风险：最终纳入了 21 项研究。所有研究的偏倚风险都很高或不明确。结果只允许对精子浓度类别进行荟萃分析。我们发现，与少精子男性（OR 1.96，95% CI：1.29-2.96）和正常无精子男性（OR 2.00，95% CI：1.23-3.25）相比，无精子男性的死亡风险增加了 2 倍，但与正常无精子男性相比，少精子男性的死亡风险没有增加（OR 1.04，95% CI：0.52-2.09）。任何精子浓度组的心血管疾病风险均无差异（无精子-少精子 OR 0.94，95% CI：0.74-1.20；无精子-无精子 OR 1.11，95% CI：0.71-1.75；少精子-无精子 OR 1.12，95% CI：0.80-1.55）。无精症男性患糖尿病的 OR 值仅高于少精症男性（OR 值为 2.16，95% CI：1.55-3.01）。与少精子男性（OR 2.16，95% CI：1.55-3.01）和正常无精子男性（OR 2.18，95% CI：1.20-3.96）相比，无精子男性罹患全部位癌症的风险更高。与精子浓度正常的男性相比，只有无精症男性患睾丸癌的风险可能更高（OR 1.80，95% CI：1.12-2.89）：尽管我们的汇总分析显示无精症男性的死亡风险和罹患全部位癌症的风险增加，但结果显示缺乏证据表明精液浓度低的男性罹患合并症的风险更高。鉴于可用数据有限、研究性质和偏倚风险较高，应谨慎解释这些结果：目前还没有足够的数据来证实精液分析作为男性长期健康状况不良预测指标的可用性，尤其是在普通人群中：本研究未获得任何资助。A.M.曾接受默克雪兰诺、Ferring、Gedeon Richter、Pharmasure和Cook Medical的资助参加医学会议；曾是Ferring顾问委员会的成员；曾应邀为默克雪兰诺顾问委员会做讲座。S.N. 曾获得 Ferring 和 Cook Medical 提供的参加医学会议的资助：PROSPERO 编号：CRD42024507563。

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引用次数: 0

Membrane-bound receptor for advanced glycation end products (RAGE) is a stable biomarker of low-quality sperm. 膜结合的高级糖化终产物受体（RAGE）是低质量精子的稳定生物标志物。

IF 8.3 Q1 OBSTETRICS & GYNECOLOGY

Human reproduction open

Pub Date : 2024-11-07 eCollection Date: 2024-01-01 DOI: 10.1093/hropen/hoae064

Jill Browning, Magda Ghanim, William Jagoe, Jennifer Cullinane, Louise E Glover, Mary Wingfield, Vincent P Kelly

Study question: Does receptor for advanced glycation end products (RAGE) on the surface membrane of the sperm cell function as a biomarker of low-quality sperm?

Summary answer: Membrane-bound RAGE at a cellular level directly correlates with low sperm motility, high cell permeability, decreased mitochondrial function, DNA fragmentation, and higher levels of apoptosis.

What is known already: RAGE has previously been measured by ELISA in low-quality sperm in diabetic men and has been shown to correlate with DNA fragmentation (terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay).

Study design size duration: Semen samples were recovered from 60 non-obese, non-diabetic and non-smoking subjects, washed with fresh media, and analysed directly or purified further by differential gradient centrifugation (DGC) or fractionated by direct swim-up before being analysed for sperm motility and molecular health parameters, including cell membrane permeability, cell death, mitochondrial membrane potential, DNA fragmentation, and RAGE protein expression.

Participants/materials setting methods: Sperm motility assessments were carried out by computer-assisted sperm analysis (CASA) on 1000 spermatozoa for washed samples and 300 spermatozoa for purified samples. Molecular sperm health parameters were evaluated using flow cytometry with the use of the following markers: DAPI for cell membrane permeability, Annexin V/DAPI for cell death (apoptosis and necrosis), MitoTracker^® Red CMXRos for mitochondrial membrane potential, TUNEL assay for DNA fragmentation and 8-hydroxy-2-deoxyguanosine for identification of oxidative damage to sperm DNA, and contrasted to membrane-bound RAGE expression levels, which were evaluated using an anti-RAGE monoclonal mouse antibody.

Main results and the role of chance: RAGE protein was shown to be present on the acrosomal and equatorial regions of sperm, with the levels of membrane bound receptor strongly correlating with poor sperm health across all parameters tested; motility (R ² = 0.5441, P < 0.0001) and mitochondrial membrane potential (R ² = 0.6181, P < 0.0001) being of particular note. The analysis was performed at a single cell level thereby removing confounding complications from soluble forms of the RAGE protein that can be found in seminal plasma. The expression of the RAGE protein was shown to be stable over time and its levels are therefore not subject to variation in sample handling or preparation time.

Large scale data: N/A.

Limitations reasons for caution: Inclusion criteria for this study were non-diabetic, non-obese and non-smoking participants to assess the distribution of RAGE expression in the general population, thereby excluding disease conditions that may inc

研究问题：精子细胞表面膜上的高级糖化终产物受体（RAGE）是否可作为低质量精子的生物标志物？在细胞水平上，膜结合的 RAGE 与精子活力低、细胞通透性高、线粒体功能下降、DNA 断裂和细胞凋亡水平升高直接相关：研究设计的规模和持续时间：从60名非肥胖、非糖尿病和非吸烟的受试者中采集精液样本，用新鲜培养基洗涤，直接分析或通过差分梯度离心法（DGC）进一步纯化，或通过直接泳升法分馏，然后分析精子活力和分子健康参数，包括细胞膜通透性、细胞死亡、线粒体膜电位、DNA碎片和RAGE蛋白表达：精子活力评估采用计算机辅助精子分析法（CASA）进行，水洗样本的精子数量为 1000 个，纯化样本的精子数量为 300 个。分子精子健康参数采用流式细胞术进行评估，并使用以下标记物：DAPI 检测细胞膜通透性，Annexin V/DAPI 检测细胞死亡（凋亡和坏死），MitoTracker® Red CMXRos 检测线粒体膜电位，TUNEL 检测 DNA 断裂，8-hydroxy-2-deoxyguanosine 检测精子 DNA 氧化损伤，并与膜结合 RAGE 表达水平进行对比，后者使用抗 RAGE 单克隆小鼠抗体进行评估：主要结果和偶然因素：RAGE 蛋白存在于精子的顶体和赤道区域，膜结合受体的水平与精子在所有测试参数中的健康状况密切相关；活力（R 2 = 0.5441，P R 2 = 0.6181，P 大比例数据：不适用：本研究的纳入标准是非糖尿病、非肥胖和非吸烟的参与者，以评估普通人群中 RAGE 表达的分布情况，从而排除可能增加精子中 RAGE 表达或导致精子质量低下的疾病。该研究并未涉及与男性不育症相关的其他患者亚群或疾病状态对 RAGE 表达的影响。流式细胞术精子分析法不适于研究精子数量少的男性：该研究结果表明，RAGE表达是精子细胞健康的分子标志物，可通过清除RAGE表达的精子改善辅助生殖，并通过将其作为男性不育症的生物标志物促进不明原因不育症的诊断：该研究由爱尔兰研究委员会根据爱尔兰政府计划（GOIPG/2015/3729）和爱尔兰企业创新合作伙伴计划（IP-2020-0952）资助。所有作者声明不存在利益冲突。

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引用次数: 0

Women may not benefit from repeated frozen embryo transfers: a retrospective analysis of the cumulative live birth rate of 43 972 women. 妇女可能无法从重复冷冻胚胎移植中获益：对 43 972 名妇女的累积活产率进行的回顾性分析。

IF 8.3 Q1 OBSTETRICS & GYNECOLOGY

Human reproduction open

Pub Date : 2024-10-28 eCollection Date: 2024-01-01 DOI: 10.1093/hropen/hoae063

Yuqi Zeng, Yali Liu, Yunhan Nie, Xi Shen, Tiantian Wang, Yanping Kuang, Li Wang

Study question: Which specific groups of women would not benefit from repeated frozen embryo transfers (FETs)?Summary answer: Women over 45 years of age should stop treatment after three FET attempts due to the absence of further benefits, while women aged 40-45 years and those with a diminished ovarian reserve and other causes of infertility have a lower chance of improving their cumulative live birth rate (CLBR) within five FET cycles and experience fewer advantages from repeated transfers.What is known already: In real-life scenarios of ART, women who fail to achieve a live birth often choose to undergo repeated FETs via the freeze-all strategy.Study design size duration: This retrospective study included 43 972 women who underwent 86 496 oocyte retrieval cycles and 82 022 FET cycles between January 2010 and March 2023 under the freeze-all strategy.Participants/materials setting methods: We categorized the population based on the female's age at the first oocyte pick-up (OPU) cycle (Groups 1-6: <30, 30-34, 35-39, 40-42, 43-44, and ≥45 years of age), number of retrieved oocytes at the first OPU cycle (Groups 1-5: 1-5, 6-10, 11-15, 16-20, and >20 oocytes), and causes of infertility (Groups 1-9: tubal factor, male factor, polycystic ovary syndrome, diminished ovarian reserve, endometriosis, other uterine factors, combined factors, unexplained infertility, and other infertility) to analyse their CLBRs within different FET cycles via Kaplan-Meier analysis (optimistic method) and the competing risk method (conservative method). We utilized multivariate Cox and Fine-Gray models to examine the associations between the CLBR and age, the number of retrieved oocytes, and nine causes of infertility.Main results and the role of chance: The CLBR decreased with increasing female age over five FET cycles (Groups 1-6: optimistic method: 96.4%, 94.2%, 86.0%, 50.2%, 23.1%, and 10.1%; conservative method: 87.1%, 82.0%, 67.8%, 33.9%, 13.8%, and 3.5%, respectively). Moreover, there was an increasing trend in the number of retrieved oocytes (Groups 1-5: optimistic method: 82.5%, 91.7%, 93.6%, 94.1%, and 96.2%; conservative method: 58.6%, 76.7%, 84.8%, 88.0%, and 92.5%, respectively). Furthermore, the CLBR varied across different causes of infertility (Groups 1-9: optimistic method: 91.7%, 93.1%, 96.6%, 79.2%, 89.9%, 76.1%, 90.0%, 92.9%, and 35.4%; conservative method: 77.3%, 79.4%, 88.9%, 46.7%, 72.7%, 62.1%, 74.4%, 78.8%, and 20.1%, respectively).Limitations reasons for caution: Calculating the actual CLBR for each person is difficult because some patients have remaining embryos that have not been transferred; additionally, the current statistical methodology uses both optimistic and conservative methods to calculate the CLBR, and in real life, the CLBR falls between the optimistic and conservative curve

研究问题：哪些特定妇女群体不会从重复冷冻胚胎移植（FET）中获益？45岁以上的妇女在尝试三次冷冻胚胎移植后，由于没有进一步的益处，应停止治疗；而40-45岁的妇女以及卵巢储备功能减退和其他原因导致不孕的妇女，在五个冷冻胚胎移植周期内提高累积活产率（CLBR）的几率较低，重复移植的益处也较少：在抗逆转录病毒疗法的实际应用中，未能实现活产的妇女通常会选择通过全部冷冻策略进行重复FET：这项回顾性研究纳入了 43 972 名女性，她们在 2010 年 1 月至 2023 年 3 月期间接受了 86 496 个卵母细胞取回周期和 82 022 个 FET 周期，均采用了冻存策略：我们根据女性首次取卵（OPU）周期时的年龄（1-6 组：20 个卵母细胞）和不孕原因（1-9 组：输卵管因素、男性因素、多囊肾）对人群进行了分类：输卵管因素、男性因素、多囊卵巢综合征、卵巢储备功能减退、子宫内膜异位症、其他子宫因素、综合因素、不明原因不孕症和其他不孕症），通过卡普兰-梅耶分析法（乐观法）和竞争风险法（保守法）分析她们在不同 FET 周期内的 CLBR。我们利用多变量 Cox 和 Fine-Gray 模型研究了 CLBR 与年龄、取卵数量和九种不孕原因之间的关系：在五个 FET 周期中，CLBR 随女性年龄的增加而下降（1-6 组：乐观法：分别为 96.4%、94.2%、86.0%、50.2%、23.1% 和 10.1%；保守法：分别为 87.1%、82.0%、67.8%、33.9%、13.8% 和 3.5%）。此外，取回的卵母细胞数量呈上升趋势（1-5 组：乐观法：82.5%、91.7%、93.6%、94.1% 和 96.2%；保守法：58.6%、76.7%、94.1% 和 96.2%）：分别为 58.6%、76.7%、84.8%、88.0% 和 92.5%）。此外，CLBR 在不同的不孕原因中也存在差异（1-9 组：乐观法：91.7%、93.1%、96.6%、79.2%、89.9%、76.1%、90.0%、92.9% 和 35.4%；保守法：77.3%、79.4%、79.4%、88.0% 和 92.5%）：需要注意的局限性：计算每个人的实际CLBR很困难，因为有些患者还有剩余的胚胎没有移植；此外，目前的统计方法使用乐观和保守两种方法来计算CLBR，而在现实生活中，CLBR介于乐观和保守曲线之间：我们的研究首次确定了未能从重复FET中获益的特定妇女亚群，以及在移植不成功后需要合理中止治疗的妇女亚群：本研究得到了国家自然科学基金的资助（基金号：82271732-Y.S.）：82271732 给 Y.K.，82071603 给 L.W.，82001502 给 Y.L.，82201888 给 X.S.）。作者声明他们在本研究中没有利益冲突：不适用。

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引用次数: 0

Sperm and leukocyte telomere length are related to sperm quality parameters in healthy men from the Led-Fertyl study. Led-Fertyl研究中健康男性的精子和白细胞端粒长度与精子质量参数有关。

IF 8.3 Q1 OBSTETRICS & GYNECOLOGY

Human reproduction open

Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI: 10.1093/hropen/hoae062

María Fernández de la Puente, Cristina Valle-Hita, Albert Salas-Huetos, María Ángeles Martínez, Elena Sánchez-Resino, Silvia Canudas, Daniel Torres-Oteros, Joana Relat, Nancy Babio, Jordi Salas-Salvadó

Study question: Could sperm and leukocyte telomere length (TL) be associated with sperm quality parameters and reproductive health in men from the general population?

Summary answer: A positive association between sperm and leukocyte TL with sperm concentration and total count has been demonstrated.

What is known already: Male factors account for almost half of cases of couple infertility, and shorter TLs have been observed in sperm from men with impaired sperm parameters. However, evidence in men from the general population is limited.

Study design size duration: A total of 200 volunteers of reproductive age were recruited between February 2021 and April 2023 to participate in the Lifestyle and Environmental Determinants of Seminogram and Other Male Fertility-Related Parameters (Led-Fertyl) cross-sectional study.

Participants/materials setting methods: TLs in sperm and leukocytes were measured using quantitative polymerase chain reaction (qPCR) in 168 and 194 participants, respectively. Sperm parameters, including concentration, total count, motility, vitality, and morphology, were analyzed using a computer-assisted sperm analysis (CASA) SCA^® system according to the World Health Organization (WHO) 2010 guidelines. Multivariable regression models were performed to assess the associations between sperm and leukocyte TL, either in tertiles or as continuous variables, and sperm quality parameters while adjusting for potential confounders.

Main results and the role of chance: Participants in tertiles 2 (T2) and 3 (T3) of sperm TL showed a higher sperm concentration (β: 1.09; 95% CI: 0.09-2.09 and β: 2.06; 95% CI: 1.04-3.09 for T2 and T3, respectively; P-trend < 0.001), compared to those in the reference tertile (T1). Participants in the highest tertile of sperm TL showed higher total sperm count (β: 3.83; 95% CI: 2.08-5.58 for T3 vs T1; P-trend < 0.001). Participants in the top tertile of leukocyte TL showed higher sperm concentration (β: 1.49; 95% CI: 0.44-2.54 for T3 vs T1; P-trend = 0.004), and total count (β: 3.49; 95% CI: 1.62-5.35 for T3 vs T1; P-trend < 0.001) compared with participants in T1. These results remained consistent when sperm and leukocyte TL were modelled as continuous variables.

Limitations reasons for caution: One limitation is the impossibility of establishing a cause-effect relationship due to the cross-sectional study design. Additionally, the sample size of the study cannot be considered large.

Wider implications of the findings: Sperm and leukocyte TLs are associated with sperm quality parameters in the general population. Additional determinations and further studies with larger sample sizes are needed to clarify the mechanisms underlying these associations and to investigate the further implications.

研究问题精子和白细胞端粒长度（TL）与普通人群中男性的精子质量参数和生殖健康是否相关？已证实精子和白细胞端粒长度与精子浓度和总计数呈正相关：男性因素几乎占夫妇不育症病例的一半，在精子参数受损的男性精子中观察到较短的TL。然而，来自普通人群的男性的证据却很有限：在 2021 年 2 月至 2023 年 4 月期间，共招募了 200 名育龄志愿者参与精液图和其他男性生育能力相关参数的生活方式和环境决定因素（Led-Fertyl）横断面研究：使用定量聚合酶链反应（qPCR）分别测量了 168 名和 194 名参与者精子和白细胞中的 TLs。根据世界卫生组织（WHO）2010 年指南，使用计算机辅助精子分析（CASA）SCA® 系统分析精子参数，包括浓度、总计数、活力、生命力和形态。在对潜在混杂因素进行调整后，采用多变量回归模型评估精子和白细胞TL（以三等分或连续变量表示）与精子质量参数之间的关系：主要结果和偶然性的作用：精子TL为2分层（T2）和3分层（T3）的参与者精子浓度较高（β：1.09; 95% CI: 0.09-2.09 和 β: 2.06; 95% CI: 1.04-3.09; P-trend P-trend P-trend = 0.004）和总计数（β：3.49; 95% CI: 1.62-5.35 for T3 vs T1; P-trend 局限性需谨慎的原因：局限性之一是横断面研究设计无法确定因果关系。此外，该研究的样本量也不能算大：研究结果的广泛意义：在普通人群中，精子和白细胞TL与精子质量参数有关。需要进行更多的测定和样本量更大的进一步研究，以明确这些关联的机制，并探讨进一步的影响：Led-Fertyl研究得到了西班牙政府生物医学研究官方资助机构卡洛斯三世健康研究所（ISCIII）通过健康研究基金（FIS）提供的支持，并由欧盟ERDF/ESF "创造欧洲的方式"/"投资你的未来"（PI21/01447）和塔拉戈纳省议会（2021/11-No.Exp. 8004330008-2021-0022642）共同资助。J.S.-S.是本研究的第一作者，他的部分研究经费由 ICREA 学术项目提供。M.F.d.l.P. 获得了 Rovira i Virgili 大学和塔拉戈纳省议会的博士前期资助（2020-PMF-PIPF-8）。C.V.-H.获得了加泰罗尼亚自治区政府（2022 FI_B100108）的博士前期资助。M.Á.M. 获得了 Sara Borrell 博士后奖学金（CD21/00045-Instituto de Salud Carlos III (ISCIII)）。所有作者声明不存在利益冲突：不适用。

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引用次数: 0

Reply: Emerging evidence of endometrial compaction in predicting ART outcomes. 回复：子宫内膜压实在预测抗逆转录病毒疗法结果方面的新证据。

IF 8.3 Q1 OBSTETRICS & GYNECOLOGY

Human reproduction open

Pub Date : 2024-10-11 eCollection Date: 2024-01-01 DOI: 10.1093/hropen/hoae061

Hannan Al-Lamee, Gayathri Delanerolle, Dharani K Hapangama, Nicola Tempest

引用次数: 0

Emerging evidence of endometrial compaction in predicting ART outcomes. 子宫内膜压实在预测抗逆转录病毒疗法结果方面的新证据。

IF 8.3 Q1 OBSTETRICS & GYNECOLOGY

Human reproduction open

Pub Date : 2024-10-10 eCollection Date: 2024-01-01 DOI: 10.1093/hropen/hoae060

Guangyao Lin, Stella Lim Jin Yie, Lianwei Xu

引用次数: 0

Steady morphokinetic progression is an independent predictor of live birth: a descriptive reference for euploid embryos. 稳定的形态发生是活产的独立预测指标：优生胚胎的描述性参考。

IF 8.3 Q1 OBSTETRICS & GYNECOLOGY

Human reproduction open

Pub Date : 2024-10-10 eCollection Date: 2024-01-01 DOI: 10.1093/hropen/hoae059

Aşina Bayram, Ibrahim Elkhatib, Erkan Kalafat, Andrea Abdala, Virginia Ferracuti, Laura Melado, Barbara Lawrenz, Human Fatemi, Daniela Nogueira

Study question: Can modelling the longitudinal morphokinetic pattern of euploid embryos during time-lapse monitoring (TLM) be helpful for selecting embryos with the highest live birth potential?

Summary answer: Longitudinal reference ranges of morphokinetic development of euploid embryos have been identified, and embryos with steadier progression during TLM are associated with higher chances of live birth.

What is known already: TLM imaging is increasingly adopted by fertility clinics as an attempt to improve the ability of selecting embryos with the highest potential for implantation. Many markers of embryonic morphokinetics have been incorporated into decision algorithms for embryo (de)selection. However, longitudinal changes during this temporal process, and the impact of such changes on embryonic competence remain unknown. Aiming to model the reference ranges of morphokinetic development of euploid embryos and using it as a single longitudinal trajectory might provide an additive value to the blastocyst morphological grade in identifying highly competent embryos.

Study design size duration: This observational, retrospective cohort study was performed in a single IVF clinic between October 2017 and June 2021 and included only autologous single euploid frozen embryo transfers (seFET).

Participants/materials setting methods: Reference ranges were developed from [hours post-insemination (hpi)] of the standard morphokinetic parameters of euploid embryos assessed as tPB2, tPNa, tPNf, t2-t9, tSC, tM, tSB, and tB. Variance in morphokinetic patterns was measured and reported as morphokinetic variance score (MVS). Nuclear errors (micronucleation, binucleation, and multinucleation) were annotated when present in at least one blastomere at the two- or four-cell stages. The blastocyst grade of expansion, trophectoderm (TE), and inner cell mass (ICM) were assessed immediately before biopsy using Gardner's criteria. Pre-implantation genetic diagnosis for aneuploidy (PGT-A) was performed by next-generation sequencing. All euploid embryos were singly transferred in a frozen transferred cycle and outcomes were assessed as live birth, pregnancy loss, or not pregnant. Association of MVS with live birth was investigated with regression analyses.

Main results and the role of chance: TLM data from 340 seFET blastocysts were included in the study, of which 189 (55.6%) resulted in a live birth. The median time for euploid embryos to reach blastulation was 109.9 hpi (95% CI: 98.8-121.0 hpi). The MVS was calculated from the variance in time taken for the embryo to reach all morphokinetic points and reflects the total morphokinetic variability it exhibits during its development. Embryos with more erratic kinetics, i.e. higher morphokinetic variance, had higher rates of pregnancy loss (P = 0.004) and no pregnancy (P < 0.001)

研究问题：在延时监测（TLM）过程中模拟优倍体胚胎的纵向形态运动模式是否有助于选择具有最高活产潜能的胚胎？已经确定了优倍体胚胎形态动力学发展的纵向参考范围，在延时监测期间胚胎形态动力学发展较为稳定的胚胎活产几率较高：TLM成像被越来越多的生育诊所采用，以提高选择最有可能植入的胚胎的能力。许多胚胎形态动力学标记已被纳入胚胎（去）选择的决策算法中。然而，这一时间过程中的纵向变化以及这些变化对胚胎能力的影响仍然未知。建立优倍体胚胎形态发育参考范围的模型，并将其作为单一纵向轨迹，可能会在识别高能力胚胎时为囊胚形态等级提供附加值：这项观察性、回顾性队列研究于2017年10月至2021年6月期间在一家IVF诊所进行，仅包括自体单倍性冷冻胚胎移植（seFET）.参与者/材料设置方法：根据[授精后数小时（hpi）]评估的优胚标准形态动力学参数（tPB2、tPNa、tPNf、t2-t9、tSC、tM、tSB 和 tB）制定参考范围。形态发生模式的差异以形态发生差异分（MVS）进行测量和报告。如果在两细胞或四细胞阶段至少有一个胚泡出现核错误（微核、双核和多核），则对其进行注释。在活检前立即使用加德纳标准评估囊胚的膨大等级、滋养层（TE）和内细胞团（ICM）。胚胎植入前的非整倍体基因诊断（PGT-A）是通过下一代测序进行的。所有非整倍体胚胎均在冷冻移植周期中进行单胎移植，结果评估为活产、妊娠失败或未怀孕。通过回归分析研究了 MVS 与活产的关系：研究纳入了 340 个 seFET 囊胚的 TLM 数据，其中 189 个囊胚（55.6%）最终活产。优倍体胚胎到达胚泡的中位时间为 109.9 hpi（95% CI：98.8-121.0 hpi）。MVS是根据胚胎达到所有形态动力点所需时间的差异计算得出的，反映了胚胎在发育过程中表现出的总形态动力变异性。胚胎动力学越不稳定，即形态动力学变异越大，则妊娠损失率（P = 0.004）和未妊娠率（P P = 0.002）以及 ICM 质量越高。具有相同 ICM 分级但形态运动变异模式不同的胚胎的活产率差异显著。ICM 分级为 A、B 和 C 的低 MVS 胚胎的活产率分别为 85%、76% 和 67%。然而，ICM 等级为 A、B 和 C 的高 MVS 胚胎的活产率分别为 65%、48% 和 21%（P P = 0.015），这一结果在重复交叉验证中仍然存在（0.64 ± 0.08 vs 0.60 ± 0.07，P 注意事项的局限性：由于排除了体外受精病例，目前该模型的实用性仅限于 ICSI 衍生胚胎。应进一步研究这些参考范围的实用性以及 MVS 与各种临床结果的关联：我们已开发出优倍体胚胎形态动力学发育的参考范围，以及测量发育囊胚总形态动力学变异性的标记物。对胚胎形态动力学进行纵向评估，而不是静态的时间点，可以更深入地了解哪些胚胎具有更高的活产潜能。所制定的参考范围和 MVS 与活产的关系与已知的形态学因素无关，可作为优先考虑胚胎移植的重要工具：本研究未获得任何外部资助。作者声明无利益冲突：不适用。

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引用次数: 0

Effects of ovarian stimulation on embryo euploidy: an analysis of 12 874 oocytes and 3106 blastocysts in cycles with preimplantation genetic testing for monogenic disorders. 卵巢刺激对胚胎非整倍体的影响：对 12 874 个卵母细胞和 3106 个囊胚进行的分析，这些卵母细胞和囊胚都进行了单基因遗传病植入前基因检测。

IF 8.3 Q1 OBSTETRICS & GYNECOLOGY

Human reproduction open

Pub Date : 2024-10-03 eCollection Date: 2024-01-01 DOI: 10.1093/hropen/hoae054

Congcong Ma, Xiaoyu Long, Liying Yan, Xiaohui Zhu, Lixue Chen, Rong Li, Ying Wang, Jie Qiao

Study question: Does ovarian stimulation and the ovarian response affect embryo euploidy?Summary answer: Ovarian stimulation and the ovarian response in women undergoing preimplantation genetic testing for monogenic disorders (PGT-M) cycles did not affect the rates of blastocyst euploidy.What is known already: Whether or not ovarian stimulation in IVF-embryo transfer has potential effects on embryo euploidy is controversial among studies for several reasons: (i) heterogeneity of the study populations, (ii) biopsies being performed at different stages of embryo development and (iii) evolution of the platforms utilized for ploidy assessment. Patients who undergo PGT-M cycles typically have no additional risks of aneuploidy, providing an ideal study population for exploring this issue.Study design size duration: A retrospective cohort study including embryos undergoing PGT-M was conducted at a single academically affiliated fertility clinic between June 2014 and July 2021.Participants/materials setting methods: A total of 617 women with 867 PGT-M cycles involving 12 874 retrieved oocytes and 3106 trophectoderm biopsies of blastocysts were included. The primary outcome of the study was median euploidy rate, which was calculated by dividing the number of euploid blastocysts by the total number of biopsied blastocysts for each cycle. Secondary outcomes included the median normal fertilization rate (two-pronuclear (2PN) embryos/metaphase II oocytes) and median blastulation rate (blastocyst numbers/2PN embryos).Main results and the role of chance: Comparable euploidy rates and fertilization rates were observed across all age groups, regardless of variations in ovarian stimulation protocols, gonadotropin dosages (both the starting and total dosages), stimulation durations, the inclusion of human menopausal gonadotrophin supplementation, or the number of oocytes retrieved (all P > 0.05). Blastulation rates declined with increasing starting doses of gonadotropins in women aged 31-34 years old (P = 0.005) but increased with increasing gonadotrophin starting doses in women aged 35-37 years old (P = 0.017). In women aged 31-34, 35-37, and 38-40 years old, blastulation rates were significantly reduced with increases in the number of oocytes retrieved (P = 0.001, <0.001, and 0.012, respectively).Limitations reasons for caution: Limitations include the study's retrospective nature and the relatively small number of patients of advanced age, especially patients older than 40 years old, leading to quite low statistical power. Second, as we considered euploidy rates as outcome measures, we did not analyze the effects of ovarian stimulation on uniform aneuploidy and mosaicism, respectively. Finally, we did not consider the effects of paternal characteristics on embryo euploidy s

研究问题：卵巢刺激和卵巢反应是否会影响胚胎整倍体？接受单基因遗传病胚胎植入前基因检测（PGT-M）周期的妇女的卵巢刺激和卵巢反应不会影响囊胚的非整倍体率：体外受精-胚胎移植中的卵巢刺激是否会对胚胎的非整倍体性产生潜在影响，在多项研究中都存在争议，原因有以下几点：(i) 研究对象的异质性；(ii) 在胚胎发育的不同阶段进行活检；(iii) 用于倍性评估的平台的演变。接受 PGT-M 周期的患者通常没有额外的非整倍体风险，因此是探讨这一问题的理想研究人群：2014年6月至2021年7月期间，在一家学术附属生殖诊所进行了一项回顾性队列研究，其中包括接受PGT-M的胚胎：共纳入了 617 名妇女的 867 个 PGT-M 周期，涉及 12 874 个取回的卵母细胞和 3106 个胚泡的滋养层活检。研究的主要结果是中位非整倍体率，计算方法是用每个周期的非整倍体囊胚数除以活检囊胚总数。次要结果包括正常受精率中位数（双核（2PN）胚胎/分裂期 II 卵母细胞）和囊胚形成率中位数（囊胚数/2PN 胚胎）：无论卵巢刺激方案、促性腺激素剂量（起始剂量和总剂量）、刺激持续时间、是否补充人类绝经期促性腺激素或取回的卵母细胞数量如何变化，在所有年龄组中均观察到相似的非整倍体率和受精率（所有 P > 0.05）。在 31-34 岁的女性中，随着促性腺激素起始剂量的增加，卵泡形成率下降（P = 0.005），但在 35-37 岁的女性中，随着促性腺激素起始剂量的增加，卵泡形成率上升（P = 0.017）。在 31-34 岁、35-37 岁和 38-40 岁的女性中，随着取卵数量的增加，胚泡形成率显著降低（P = 0.001）：研究的局限性包括：本研究为回顾性研究，高龄患者，尤其是 40 岁以上的高龄患者人数较少，导致统计学效应较低。其次，由于我们将非整倍体率作为结果测量指标，因此没有分别分析卵巢刺激对均匀非整倍体和嵌合体的影响。最后，由于囊胚非整倍体主要来源于母体减数分裂，因此我们没有考虑父方特征对胚胎非整倍体状态的影响。然而，精子因素可能会影响胚胎发育和囊胚形成率，因此也会影响分析的囊胚数量。排除严重畸形精子症患者，以及对接受 PGT-M 的妇女仅使用 ICSI 作为人工授精技术，有助于将父方因素的影响降至最低：研究结果的广泛意义：卵巢刺激和对刺激的反应并不影响接受 PGT-M 周期的妇女的囊胚非整倍体率。然而，在 31-40 岁的女性中，随着取回卵母细胞数量的增加，囊胚形成率显著下降：本研究得到了国家自然科学基金（批准号：81701407、82301826）、国家重点研发计划（2022YFC2702901、2022YFC2703004）、中国博士后科学基金（2022M710261）和中国博士后创新人才支持计划（BX20220020）的资助。无利益冲突。试验注册号：不适用。

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引用次数: 0

Speaking up for the safety of the children following frozen embryo transfer. 为冷冻胚胎移植后的儿童安全大声疾呼。

IF 8.3 Q1 OBSTETRICS & GYNECOLOGY

Human reproduction open

Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI: 10.1093/hropen/hoae058

Anja Pinborg, Christophe Blockeel, Giovanni Coticchio, Juan Garcia-Velasco, Pietro Santulli, Alison Campbell

引用次数: 0

High rate of detected variants in male PLCZ1 and ACTL7A genes causing failed fertilization after ICSI. 雄性 PLCZ1 和 ACTL7A 基因变异的高检出率导致卵胞浆内单精子显微注射受精失败。

IF 8.3 Q1 OBSTETRICS & GYNECOLOGY

Human reproduction open

Pub Date : 2024-09-28 eCollection Date: 2024-01-01 DOI: 10.1093/hropen/hoae057

Arantxa Cardona Barberán, Ramesh Reddy Guggilla, Cora Colenbier, Emma Van der Velden, Andrei Rybouchkin, Dominic Stoop, Luc Leybaert, Paul Coucke, Sofie Symoens, Annekatrien Boel, Frauke Vanden Meerschaut, Björn Heindryckx

Study question: What is the frequency of PLCZ1, ACTL7A, and ACTL9 variants in male patients showing fertilization failure after ICSI, and how effective is assisted oocyte activation (AOA) for them?

Summary answer: Male patients with fertilization failure after ICSI manifest variants in PLCZ1 (29.09%), ACTL7A (14.81%), and ACTL9 (3.70%), which can be efficiently overcome by AOA treatment with ionomycin.

What is known already: Genetic variants in PLCZ1, and more recently, in ACTL7A, and ACTL9 male genes, have been associated with total fertilization failure or low fertilization after ICSI. A larger patient cohort is required to understand the frequency at which these variants occur, and to assess their effect on the calcium ion (Ca²⁺) release during oocyte activation. AOA, using ionomycin, can restore fertilization and pregnancy rates in patients with PLCZ1 variants, but it remains unknown how efficient this is for patients with ACTL7A and ACTL9 variants.

Study design size duration: This prospective study involved two patient cohorts. In the first setting, group 1 (N = 28, 2006-2020) underwent only PLCZ1 genetic screening, while group 2 (N = 27, 2020-2023) underwent PLCZ1, ACTL7A, and ACTL9 genetic screening. Patients were only recruited when they had a mean fertilization rate of ≤33.33% in at least one ICSI cycle with at least four MII oocytes. Patients underwent a mouse oocyte activation test (MOAT) and at least one ICSI-AOA cycle using calcium chloride (CaCl₂) injection and double ionomycin exposure at our centre. All patients donated a saliva sample for genetic screening and a sperm sample for further diagnostic tests, including Ca²⁺ imaging.

Participants/materials setting methods: Genetic screening was performed via targeted next-generation sequencing. Identified variants were classified by applying the revised ACMG guidelines into a Bayesian framework and were confirmed by bidirectional Sanger sequencing. If variants of uncertain significance or likely pathogenic or pathogenic variants were found, patients underwent additional determination of the sperm Ca²⁺-releasing pattern in mouse (MOCA) and in IVM human (HOCA) oocytes. Additionally, ACTL7A immunofluorescence and acrosome ultrastructure analyses by transmission electron microscopy (TEM) were performed for patients with ACTL7A and/or ACTL9 variants.

Main results and the role of chance: Overall, the frequency rate of PLCZ1 variants was 29.09%. Moreover, 14.81% of patients carried ACTL7A variants and 3.70% carried ACTL9 variants. Seven different PLCZ1 variants were identified (p.Ile74Thr, p.Gln94*, p.Arg141His, p.His233Leu, p.Lys322*, p.Ile379Thr, and p.Ser500Leu), five o

研究问题：在ICSI受精失败的男性患者中，PLCZ1、ACTL7A和ACTL9变异的频率是多少？ICSI后受精失败的男性患者表现为PLCZ1（29.09%）、ACTL7A（14.81%）和ACTL9（3.70%）变异，使用离子霉素进行AOA治疗可有效克服这些变异：PLCZ1基因变异，以及最近的ACTL7A和ACTL9男性基因变异，都与ICSI受精失败或受精率低有关。要了解这些变异发生的频率，并评估它们对卵母细胞激活过程中钙离子（Ca2+）释放的影响，需要一个更大的患者群。使用离子霉素进行AOA可恢复PLCZ1变异患者的受精率和妊娠率，但ACTL7A和ACTL9变异患者的受精率和妊娠率如何仍是未知数：这项前瞻性研究涉及两组患者。在第一组中，第一组（N = 28，2006-2020 年）仅进行了 PLCZ1 基因筛查，而第二组（N = 27，2020-2023 年）则进行了 PLCZ1、ACTL7A 和 ACTL9 基因筛查。只有当患者在至少一个ICSI周期中至少有4个MII卵母细胞的平均受精率≤33.33%时，才会被招募。患者在本中心接受了小鼠卵母细胞激活试验（MOAT）和至少一次使用氯化钙（CaCl2）注射和双离子霉素暴露的 ICSI-AOA 周期。所有患者都捐献了用于基因筛查的唾液样本和用于进一步诊断测试（包括 Ca2+ 成像）的精子样本：基因筛查通过有针对性的新一代测序进行。根据贝叶斯框架中的 ACMG 指南修订版对识别出的变异进行分类，并通过双向 Sanger 测序进行确认。如果发现意义不确定的变异或可能致病或致病的变异，患者还需接受小鼠（MOCA）和IVM人类（HOCA）卵母细胞中精子Ca2+释放模式的额外测定。此外，还对ACTL7A和/或ACTL9变体患者进行了ACTL7A免疫荧光和顶体超微结构透射电子显微镜（TEM）分析：总体而言，PLCZ1变异体的频率为29.09%。此外，14.81%的患者携带ACTL7A变体，3.70%的患者携带ACTL9变体。研究发现了7种不同的PLCZ1变体（p.Ile74Thr、p.Gln94*、p.Arg141His、p.His233Leu、p.Lys322*、p.Ile379Thr和p.Ser500Leu），其中5种是新变体。有趣的是，PLCZ1变异p.Ser500Leu和p.His233Leu分别出现在14.55%和9.09%的病例中。在 ACTL7A 中发现了 5 个不同的变体（p.Tyr183His、p.Gly214Ser、p.Val340Met、p.Ser364Glnfs*9、p.Arg373Cys），其中 4 个是首次发现。此外，还发现了 ACTL9 的一种新型变异体（p.Arg271Pro）。MOCA和HOCA测试显示，除一名患者外，所有患者（包括PLCZ1杂合子变异体患者）在受精过程中都存在异常或无Ca2+释放。TEM分析显示，三名ACTL7A变异体患者的顶体超微结构异常，但与对照组相比，只有同源ACTL7A变异体患者的荧光强度降低。AOA 治疗大大提高了 19 名检测到变异的患者的受精率（从常规 ICSI 后的 11.24% 提高到 ICSI-AOA 后的 61.80%）、hCG 阳性率（从 10.64% 提高到 60.00%）和活产率（从 6.38% 提高到 37.14%），共产生了 13 名健康的新生儿。特别是，使用ACTL7A变异体患者的精子产生了四例活产和两例持续妊娠：基因筛查包括外显子和外侧内含子区域，这意味着深部内含子变异被遗漏。此外，影响受精过程的其他男性基因或可能的女性相关因素仍有待研究：PLCZ1、ACTL7A和ACTL9的基因筛查为ICSI后受精完全失败或受精率低提供了一种快速、经济、易行的诊断检测方法，无需进行MOAT或Ca2+分析等复杂的诊断检测。尽管如此，HOCA 仍是揭示不确定意义变异因果关系的最灵敏的功能检测方法。有趣的是，杂合子 PLCZ1 变异足以导致 ICSI 期间 Ca2+ 释放不足。最重要的是，使用 CaCl2 注射和双离子霉素暴露进行 AOA 治疗对这一患者群非常有效，包括 ACTL7A 变体患者，他们也表现出 Ca2+ 释放不足。研究经费/竞争利益：本研究得到佛兰德科学研究基金（FWO）（B.H.获得TBM项目基金T002223N）和特别研究基金（BOF）（B.H.获得起始基金BOF.STG.2021.0042.01）的支持。A.C.B.、R.R.G.、C.C.、E.V.D.V.、A.R.、D.S.、L.L.、P.C.、S.S.、A.B.和 F.V.M.没有任何需要披露的信息。B.H.报告获得了FWO和BOF的研究基金，并报告是比利时胚胎研究伦理委员会的董事会成员：不详。

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