Pub Date : 2024-11-07eCollection Date: 2024-01-01DOI: 10.1093/hropen/hoae064
Jill Browning, Magda Ghanim, William Jagoe, Jennifer Cullinane, Louise E Glover, Mary Wingfield, Vincent P Kelly
<p><strong>Study question: </strong>Does receptor for advanced glycation end products (RAGE) on the surface membrane of the sperm cell function as a biomarker of low-quality sperm?</p><p><strong>Summary answer: </strong>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.</p><p><strong>What is known already: </strong>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).</p><p><strong>Study design size duration: </strong>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.</p><p><strong>Participants/materials setting methods: </strong>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<sup>®</sup> 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.</p><p><strong>Main results and the role of chance: </strong>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 (<i>R</i> <sup>2</sup> = 0.5441, <i>P</i> < 0.0001) and mitochondrial membrane potential (<i>R</i> <sup>2</sup> = 0.6181, <i>P</i> < 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.</p><p><strong>Large scale data: </strong>N/A.</p><p><strong>Limitations reasons for caution: </strong>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。
{"title":"Membrane-bound receptor for advanced glycation end products (RAGE) is a stable biomarker of low-quality sperm.","authors":"Jill Browning, Magda Ghanim, William Jagoe, Jennifer Cullinane, Louise E Glover, Mary Wingfield, Vincent P Kelly","doi":"10.1093/hropen/hoae064","DOIUrl":"10.1093/hropen/hoae064","url":null,"abstract":"<p><strong>Study question: </strong>Does receptor for advanced glycation end products (RAGE) on the surface membrane of the sperm cell function as a biomarker of low-quality sperm?</p><p><strong>Summary answer: </strong>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.</p><p><strong>What is known already: </strong>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).</p><p><strong>Study design size duration: </strong>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.</p><p><strong>Participants/materials setting methods: </strong>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<sup>®</sup> 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.</p><p><strong>Main results and the role of chance: </strong>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 (<i>R</i> <sup>2</sup> = 0.5441, <i>P</i> < 0.0001) and mitochondrial membrane potential (<i>R</i> <sup>2</sup> = 0.6181, <i>P</i> < 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.</p><p><strong>Large scale data: </strong>N/A.</p><p><strong>Limitations reasons for caution: </strong>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","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2024 4","pages":"hoae064"},"PeriodicalIF":8.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28eCollection Date: 2024-01-01DOI: 10.1093/hropen/hoae063
Yuqi Zeng, Yali Liu, Yunhan Nie, Xi Shen, Tiantian Wang, Yanping Kuang, Li Wang
<p><strong>Study question: </strong>Which specific groups of women would not benefit from repeated frozen embryo transfers (FETs)?</p><p><strong>Summary answer: </strong>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.</p><p><strong>What is known already: </strong>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.</p><p><strong>Study design size duration: </strong>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.</p><p><strong>Participants/materials setting methods: </strong>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.</p><p><strong>Main results and the role of chance: </strong>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).</p><p><strong>Limitations reasons for caution: </strong>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
{"title":"Women may not benefit from repeated frozen embryo transfers: a retrospective analysis of the cumulative live birth rate of 43 972 women.","authors":"Yuqi Zeng, Yali Liu, Yunhan Nie, Xi Shen, Tiantian Wang, Yanping Kuang, Li Wang","doi":"10.1093/hropen/hoae063","DOIUrl":"10.1093/hropen/hoae063","url":null,"abstract":"<p><strong>Study question: </strong>Which specific groups of women would not benefit from repeated frozen embryo transfers (FETs)?</p><p><strong>Summary answer: </strong>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.</p><p><strong>What is known already: </strong>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.</p><p><strong>Study design size duration: </strong>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.</p><p><strong>Participants/materials setting methods: </strong>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.</p><p><strong>Main results and the role of chance: </strong>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).</p><p><strong>Limitations reasons for caution: </strong>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","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2024 4","pages":"hoae063"},"PeriodicalIF":8.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11557905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-14eCollection Date: 2024-01-01DOI: 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
<p><strong>Study question: </strong>Could sperm and leukocyte telomere length (TL) be associated with sperm quality parameters and reproductive health in men from the general population?</p><p><strong>Summary answer: </strong>A positive association between sperm and leukocyte TL with sperm concentration and total count has been demonstrated.</p><p><strong>What is known already: </strong>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.</p><p><strong>Study design size duration: </strong>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.</p><p><strong>Participants/materials setting methods: </strong>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<sup>®</sup> 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.</p><p><strong>Main results and the role of chance: </strong>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; <i>P</i>-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; <i>P</i>-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; <i>P</i>-trend = 0.004), and total count (β: 3.49; 95% CI: 1.62-5.35 for T3 vs T1; <i>P</i>-trend < 0.001) compared with participants in T1. These results remained consistent when sperm and leukocyte TL were modelled as continuous variables.</p><p><strong>Limitations reasons for caution: </strong>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.</p><p><strong>Wider implications of the findings: </strong>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.</p><p
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。
{"title":"Sperm and leukocyte telomere length are related to sperm quality parameters in healthy men from the Led-Fertyl study.","authors":"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","doi":"10.1093/hropen/hoae062","DOIUrl":"https://doi.org/10.1093/hropen/hoae062","url":null,"abstract":"<p><strong>Study question: </strong>Could sperm and leukocyte telomere length (TL) be associated with sperm quality parameters and reproductive health in men from the general population?</p><p><strong>Summary answer: </strong>A positive association between sperm and leukocyte TL with sperm concentration and total count has been demonstrated.</p><p><strong>What is known already: </strong>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.</p><p><strong>Study design size duration: </strong>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.</p><p><strong>Participants/materials setting methods: </strong>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<sup>®</sup> 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.</p><p><strong>Main results and the role of chance: </strong>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; <i>P</i>-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; <i>P</i>-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; <i>P</i>-trend = 0.004), and total count (β: 3.49; 95% CI: 1.62-5.35 for T3 vs T1; <i>P</i>-trend < 0.001) compared with participants in T1. These results remained consistent when sperm and leukocyte TL were modelled as continuous variables.</p><p><strong>Limitations reasons for caution: </strong>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.</p><p><strong>Wider implications of the findings: </strong>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.</p><p","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2024 4","pages":"hoae062"},"PeriodicalIF":8.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-10eCollection Date: 2024-01-01DOI: 10.1093/hropen/hoae060
Guangyao Lin, Stella Lim Jin Yie, Lianwei Xu
{"title":"Emerging evidence of endometrial compaction in predicting ART outcomes.","authors":"Guangyao Lin, Stella Lim Jin Yie, Lianwei Xu","doi":"10.1093/hropen/hoae060","DOIUrl":"10.1093/hropen/hoae060","url":null,"abstract":"","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2024 4","pages":"hoae060"},"PeriodicalIF":8.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-10eCollection Date: 2024-01-01DOI: 10.1093/hropen/hoae059
Aşina Bayram, Ibrahim Elkhatib, Erkan Kalafat, Andrea Abdala, Virginia Ferracuti, Laura Melado, Barbara Lawrenz, Human Fatemi, Daniela Nogueira
<p><strong>Study question: </strong>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?</p><p><strong>Summary answer: </strong>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.</p><p><strong>What is known already: </strong>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.</p><p><strong>Study design size duration: </strong>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).</p><p><strong>Participants/materials setting methods: </strong>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.</p><p><strong>Main results and the role of chance: </strong>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 (<i>P</i> = 0.004) and no pregnancy (<i>P</i> < 0.001)
{"title":"Steady morphokinetic progression is an independent predictor of live birth: a descriptive reference for euploid embryos.","authors":"Aşina Bayram, Ibrahim Elkhatib, Erkan Kalafat, Andrea Abdala, Virginia Ferracuti, Laura Melado, Barbara Lawrenz, Human Fatemi, Daniela Nogueira","doi":"10.1093/hropen/hoae059","DOIUrl":"10.1093/hropen/hoae059","url":null,"abstract":"<p><strong>Study question: </strong>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?</p><p><strong>Summary answer: </strong>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.</p><p><strong>What is known already: </strong>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.</p><p><strong>Study design size duration: </strong>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).</p><p><strong>Participants/materials setting methods: </strong>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.</p><p><strong>Main results and the role of chance: </strong>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 (<i>P</i> = 0.004) and no pregnancy (<i>P</i> < 0.001)","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2024 4","pages":"hoae059"},"PeriodicalIF":8.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-03eCollection Date: 2024-01-01DOI: 10.1093/hropen/hoae054
Congcong Ma, Xiaoyu Long, Liying Yan, Xiaohui Zhu, Lixue Chen, Rong Li, Ying Wang, Jie Qiao
<p><strong>Study question: </strong>Does ovarian stimulation and the ovarian response affect embryo euploidy?</p><p><strong>Summary answer: </strong>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.</p><p><strong>What is known already: </strong>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.</p><p><strong>Study design size duration: </strong>A retrospective cohort study including embryos undergoing PGT-M was conducted at a single academically affiliated fertility clinic between June 2014 and July 2021.</p><p><strong>Participants/materials setting methods: </strong>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).</p><p><strong>Main results and the role of chance: </strong>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 <i>P</i> > 0.05). Blastulation rates declined with increasing starting doses of gonadotropins in women aged 31-34 years old (<i>P</i> = 0.005) but increased with increasing gonadotrophin starting doses in women aged 35-37 years old (<i>P</i> = 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 (<i>P</i> = 0.001, <0.001, and 0.012, respectively).</p><p><strong>Limitations reasons for caution: </strong>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
{"title":"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.","authors":"Congcong Ma, Xiaoyu Long, Liying Yan, Xiaohui Zhu, Lixue Chen, Rong Li, Ying Wang, Jie Qiao","doi":"10.1093/hropen/hoae054","DOIUrl":"https://doi.org/10.1093/hropen/hoae054","url":null,"abstract":"<p><strong>Study question: </strong>Does ovarian stimulation and the ovarian response affect embryo euploidy?</p><p><strong>Summary answer: </strong>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.</p><p><strong>What is known already: </strong>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.</p><p><strong>Study design size duration: </strong>A retrospective cohort study including embryos undergoing PGT-M was conducted at a single academically affiliated fertility clinic between June 2014 and July 2021.</p><p><strong>Participants/materials setting methods: </strong>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).</p><p><strong>Main results and the role of chance: </strong>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 <i>P</i> > 0.05). Blastulation rates declined with increasing starting doses of gonadotropins in women aged 31-34 years old (<i>P</i> = 0.005) but increased with increasing gonadotrophin starting doses in women aged 35-37 years old (<i>P</i> = 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 (<i>P</i> = 0.001, <0.001, and 0.012, respectively).</p><p><strong>Limitations reasons for caution: </strong>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","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2024 4","pages":"hoae054"},"PeriodicalIF":8.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30eCollection Date: 2024-01-01DOI: 10.1093/hropen/hoae058
Anja Pinborg, Christophe Blockeel, Giovanni Coticchio, Juan Garcia-Velasco, Pietro Santulli, Alison Campbell
{"title":"Speaking up for the safety of the children following frozen embryo transfer.","authors":"Anja Pinborg, Christophe Blockeel, Giovanni Coticchio, Juan Garcia-Velasco, Pietro Santulli, Alison Campbell","doi":"10.1093/hropen/hoae058","DOIUrl":"https://doi.org/10.1093/hropen/hoae058","url":null,"abstract":"","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2024 4","pages":"hoae058"},"PeriodicalIF":8.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-28eCollection Date: 2024-01-01DOI: 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
<p><strong>Study question: </strong>What is the frequency of <i>PLCZ1</i>, <i>ACTL7A</i>, and <i>ACTL9</i> variants in male patients showing fertilization failure after ICSI, and how effective is assisted oocyte activation (AOA) for them?</p><p><strong>Summary answer: </strong>Male patients with fertilization failure after ICSI manifest variants in <i>PLCZ1</i> (29.09%), <i>ACTL7A</i> (14.81%), and <i>ACTL9</i> (3.70%), which can be efficiently overcome by AOA treatment with ionomycin.</p><p><strong>What is known already: </strong>Genetic variants in <i>PLCZ1</i>, and more recently, in <i>ACTL7A</i>, and <i>ACTL9</i> 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 (Ca<sup>2+</sup>) release during oocyte activation. AOA, using ionomycin, can restore fertilization and pregnancy rates in patients with <i>PLCZ1</i> variants, but it remains unknown how efficient this is for patients with <i>ACTL7A</i> and <i>ACTL9</i> variants.</p><p><strong>Study design size duration: </strong>This prospective study involved two patient cohorts. In the first setting, group 1 (N = 28, 2006-2020) underwent only <i>PLCZ1</i> genetic screening, while group 2 (N = 27, 2020-2023) underwent <i>PLCZ1, ACTL7A</i>, and <i>ACTL9</i> 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 (CaCl<sub>2</sub>) 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 Ca<sup>2+</sup> imaging.</p><p><strong>Participants/materials setting methods: </strong>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 Ca<sup>2+</sup>-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 <i>ACTL7A</i> and/or <i>ACTL9</i> variants.</p><p><strong>Main results and the role of chance: </strong>Overall, the frequency rate of <i>PLCZ1</i> variants was 29.09%. Moreover, 14.81% of patients carried <i>ACTL7A</i> variants and 3.70% carried <i>ACTL9</i> variants. Seven different <i>PLCZ1</i> variants were identified (p.Ile74Thr, p.Gln94*, p.Arg141His, p.His233Leu, p.Lys322*, p.Ile379Thr, and p.Ser500Leu), five o
{"title":"High rate of detected variants in male <i>PLCZ1</i> and <i>ACTL7A</i> genes causing failed fertilization after ICSI.","authors":"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","doi":"10.1093/hropen/hoae057","DOIUrl":"https://doi.org/10.1093/hropen/hoae057","url":null,"abstract":"<p><strong>Study question: </strong>What is the frequency of <i>PLCZ1</i>, <i>ACTL7A</i>, and <i>ACTL9</i> variants in male patients showing fertilization failure after ICSI, and how effective is assisted oocyte activation (AOA) for them?</p><p><strong>Summary answer: </strong>Male patients with fertilization failure after ICSI manifest variants in <i>PLCZ1</i> (29.09%), <i>ACTL7A</i> (14.81%), and <i>ACTL9</i> (3.70%), which can be efficiently overcome by AOA treatment with ionomycin.</p><p><strong>What is known already: </strong>Genetic variants in <i>PLCZ1</i>, and more recently, in <i>ACTL7A</i>, and <i>ACTL9</i> 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 (Ca<sup>2+</sup>) release during oocyte activation. AOA, using ionomycin, can restore fertilization and pregnancy rates in patients with <i>PLCZ1</i> variants, but it remains unknown how efficient this is for patients with <i>ACTL7A</i> and <i>ACTL9</i> variants.</p><p><strong>Study design size duration: </strong>This prospective study involved two patient cohorts. In the first setting, group 1 (N = 28, 2006-2020) underwent only <i>PLCZ1</i> genetic screening, while group 2 (N = 27, 2020-2023) underwent <i>PLCZ1, ACTL7A</i>, and <i>ACTL9</i> 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 (CaCl<sub>2</sub>) 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 Ca<sup>2+</sup> imaging.</p><p><strong>Participants/materials setting methods: </strong>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 Ca<sup>2+</sup>-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 <i>ACTL7A</i> and/or <i>ACTL9</i> variants.</p><p><strong>Main results and the role of chance: </strong>Overall, the frequency rate of <i>PLCZ1</i> variants was 29.09%. Moreover, 14.81% of patients carried <i>ACTL7A</i> variants and 3.70% carried <i>ACTL9</i> variants. Seven different <i>PLCZ1</i> variants were identified (p.Ile74Thr, p.Gln94*, p.Arg141His, p.His233Leu, p.Lys322*, p.Ile379Thr, and p.Ser500Leu), five o","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2024 4","pages":"hoae057"},"PeriodicalIF":8.3,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18eCollection Date: 2024-01-01DOI: 10.1093/hropen/hoae056
Lisa De Witte, Machteld Baetens, Kelly Tilleman, Frauke Vanden Meerschaut, Sandra Janssens, Ariane Van Tongerloo, Virginie Szymczak, Dominic Stoop, Annelies Dheedene, Sofie Symoens, Björn Menten
<p><strong>Study question: </strong>To what extent can genotype analysis aid in the classification of (mosaic) aneuploid embryos diagnosed through copy number analysis of a trophectoderm (TE) biopsy?</p><p><strong>Summary answer: </strong>In a small portion of embryos, genotype analysis revealed signatures of meiotic or uniform aneuploidy in those diagnosed with intermediate copy number changes, and signatures of presumed mitotic or putative mosaic aneuploidy in those diagnosed with full copy number changes.</p><p><strong>What is known already: </strong>Comprehensive chromosome screening (CCS) for preimplantation genetic testing has provided valuable insights into the prevalence of (mosaic) chromosomal aneuploidy at the blastocyst stage. However, diagnosis of (mosaic) aneuploidy often relies solely on (intermediate) copy number analysis of a single TE biopsy. Integrating genotype information allows for independent assessment of the origin and degree of aneuploidy. Yet, studies aligning both datasets to predict (putative mosaic) aneuploidy in embryos remain scarce.</p><p><strong>Study design size duration: </strong>A single TE biopsy was collected from 1560 embryos derived from 221 couples tested for a monogenic disorder (n = 218) or microdeletion-/microduplication syndrome (n = 3). TE samples were subjected to both copy number and genotyping analysis.</p><p><strong>Participants/materials setting methods: </strong>Copy number and SNP genotyping analysis were conducted using GENType. Unbalanced chromosomal anomalies ≥10 Mb (or ≥20 Mb for copy number calls <50%) were classified by degree, based on low-range intermediate (LR, 30-50%), high-range intermediate (HR, 50-70%) or full (>70%) copy number changes. These categories were further subjected to genotyping analysis to ascertain the origin (and/or degree) of aneuploidy. For chromosomal gains, the meiotic division of origin (meiotic I/II versus non-meiotic or presumed mitotic) was established by studying the haplotypes. The level of monosomy (uniform versus putative mosaic) in the biopsy could be ascertained from the B-allele frequencies. For segmental aneuploidies, genotyping was restricted to deletions.</p><p><strong>Main results and the role of chance: </strong>Of 1479 analysed embryos, 24% (n = 356) exhibited a whole-chromosome aneuploidy, with 19% (n = 280) showing full copy number changes suggestive of uniform aneuploidy. Among 258 embryos further investigated by genotyping, 95% of trisomies with full copy number changes were identified to be of meiotic origin. For monosomies, a complete loss of heterozygosity (LOH) in the biopsy was observed in 97% of cases, yielding a 96% concordance rate at the embryo level (n = 248/258). Interestingly, 4% of embryos (n = 10/258) showed SNP signatures of non-meiotic gain or putative mosaic loss instead. Meanwhile, 5% of embryos (n = 76/1479) solely displayed HR (2.5%; n = 37) or LR (2.6%; n = 39) intermediate copy number changes, with an additional 2% showi
研究问题：基因型分析能在多大程度上帮助对通过滋养层外胚层（TE）活检拷贝数分析诊断出的（镶嵌）非整倍体胚胎进行分类？在一小部分胚胎中，基因型分析显示，被诊断为中等拷贝数变化的胚胎具有减数分裂或均匀非整倍体的特征，而被诊断为完全拷贝数变化的胚胎具有假定有丝分裂或假定镶嵌非整倍体的特征：用于胚胎植入前基因检测的染色体全面筛查（CCS）为了解胚泡阶段（马赛克）染色体非整倍体的发生率提供了宝贵的信息。然而，（马赛克）非整倍体的诊断通常仅依赖于对单个 TE 活检的（中间）拷贝数分析。整合基因型信息可对非整倍体的起源和程度进行独立评估。然而，将这两个数据集进行整合以预测胚胎（假定镶嵌）非整倍体的研究仍然很少：从 221 对夫妇的 1560 个胚胎中采集单个 TE 活检样本，这些夫妇均接受了单基因疾病（n = 218）或微缺失/微重复综合征（n = 3）检测。对 TE 样本进行了拷贝数和基因分型分析：使用 GENType 进行拷贝数和 SNP 基因分型分析。不平衡染色体异常≥10 Mb（或拷贝数调用70%≥20 Mb）拷贝数变化。对这些类别进一步进行基因分型分析，以确定非整倍体的来源（和/或程度）。对于染色体增益，通过研究单倍型确定起源的减数分裂（减数分裂 I/II 与非减数分裂或假定有丝分裂）。活组织检查中的单倍性（均匀或假定镶嵌）可通过 B 等位基因频率来确定。对于节段性非整倍体，基因分型仅限于缺失：在分析的 1479 个胚胎中，24%（n = 356）表现出全染色体非整倍体，19%（n = 280）表现出全拷贝数变化，提示为均匀非整倍体。在通过基因分型进一步研究的 258 个胚胎中，95% 的全拷贝数变化三体被确定为减数分裂源。至于单倍体，97%的病例在活检中观察到完全的杂合性缺失（LOH），胚胎水平的吻合率为 96%（n = 248/258）。有趣的是，有 4% 的胚胎（n = 10/258）显示出非减数分裂增益或假定镶嵌丢失的 SNP 特征。同时，5% 的胚胎（n = 76/1479）只显示 HR（2.5%；n = 37）或 LR（2.6%；n = 39）中间拷贝数变化，另有 2% 的胚胎同时显示中间和完全拷贝数变化。在可以进行基因分型的具有 HR 中间拷贝数变化的胚胎中（n = 25/37），92%（n = 23/25）的 SNP 特征与假定的镶嵌非整倍体一致。然而，有 8%（n = 2/25）的活检结果显示存在减数分裂三体（9%）或完全 LOH（7%）。在 LR 中间组中，33 个基因分型胚胎中有 1 个（3%）显示完全 LOH。此外，在 7% 的胚胎（n = 108/1479）（或 9%（n = 139）的胚胎中检测到节段性非整倍体，并伴有全染色体非整倍体）。这些错误通常（52%）以中间拷贝数值为特征，在检查时与基因分型数据密切吻合（94%-100%）：不适用：研究结果基于单个 TE 活检，且未通过胚胎解剖验证嵌合的真实程度。此外，三体综合征缺乏减数分裂起源的证据不应被视为有丝分裂错误的确凿证据。此外，由于缺乏辨别减数第二次分裂三体和非减数第一次分裂三体所需的重组事件，或无法获得父母双方的 DNA，基因分型诊断并非总能实现：研究结果的更广泛影响：仅将单个 TE 活检的（中间）拷贝数变化解释为胚胎（马赛克）非整倍体的证据仍不理想。将基因型信息与拷贝数状态结合起来，可以更全面地评估胚胎的遗传组成，包括单个 TE 活检的范围和范围。通过识别减数分裂畸变，特别是在假定的马赛克胚胎中，我们强调了基因分型分析作为去选择工具的潜在价值，最终努力减少不良临床结果：L.D.W.得到了佛兰德研究基金会（FWO；1S74621N）的资助。M.B.、K.T.、F.V.M.、S.J.、A.V.T.、V.S.、D.S.、A.D.和 S.S. 由根特大学医院资助。B.M. 由根特大学资助。作者无利益冲突。
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