Human Reproduction Update最新文献_第3页

BMI in children aged 1-18 years conceived after ART with fresh and frozen embryo transfer: a systematic review and meta-analyses. 采用新鲜和冷冻胚胎移植进行抗逆转录病毒治疗后怀孕的1-18岁儿童的BMI：一项系统综述和荟萃分析

IF 13.3 1区医学 Q1 OBSTETRICS & GYNECOLOGY

Human Reproduction Update

Pub Date : 2025-08-08 DOI: 10.1093/humupd/dmaf017

Louise Laub Asserhøj,Liv Rytter Kielstrup,Christine Louise Grønholdt,Anna Sophie Lebech Kjaer,Nathalie Bülow,Rikke Beck Jensen,Anja Pinborg

BACKGROUNDChildren conceived by ART exhibit varying birthweights based on the specific ART method employed. Those born after frozen embryo transfer (FET) are more prone to being born with a high birthweight and more children are born large-for-gestational age, while those born after fresh embryo transfer (fresh-ET) tend to have lower birthweights and are more often categorized as small-for-gestational age. Extensive research has established a link between both low and high birthweight and an increased risk of childhood obesity. One of the prevailing hypotheses suggests that ART may induce epigenetic modifications during fertilization, implantation, and early embryonic stages, influencing not only size at birth but also BMI and overall health of the offspring later in life.OBJECTIVE AND RATIONALEThis systematic review was undertaken to determine if available evidence in the literature supports the hypothesis that BMI is affected in children born after ART compared with naturally conceived children.SEARCH METHODSA literature search was performed until 20 March 2025, in PubMed (MEDLINE), EMBASE, and the Cochrane databases for original papers using medical subject headings, Emtree-terms, and free text words. The inclusion criteria were growth and anthropometrics (including BMI) in children born after ART aged 1-18 years. The review was done according to the PRISMA guidelines and data were extracted from the included studies whenever possible. The Robins-I tool was used to assess bias and GRADE was used to evaluate the certainty of the evidence in the included studies.OUTCOMESA total of 22 026 studies were found after removal of duplicates. Of these, 80 articles were selected for a full-length read-through. Additionally, 52 studies from the reference lists were identified and included for full-length read-through. Of these 132 studies, 32 met the inclusion criteria and were included in the qualitative analysis. Three meta-analyses were conducted. The first (A) compared BMI as SD scores (SDS) in children born after ART (n = 8902) with children born after natural conception (NC) (n = 61 818), and resulted in no difference in BMI (mean-difference 0.02, 95% CI: (-0.03; 0.06), I2 = 9%, moderate certainty). The second (B) investigated the difference in BMI (kg/m2) in children born after ART (n = 4297) and children born after NC (n = 37 233), and showed a slight decline in BMI of -0.16 kg/m2 (95% CI: (-0.26; -0.07), I2=87%, moderate certainty) in ART-conceived children versus NC children. The third meta-analysis (C) examined BMI (SDS) in children born after FET (n = 5146) compared with those born after fresh-ET (n = 15 709), and resulted in no difference in BMI (SDS) (mean-difference 0.08, 95% CI: (-0.02; 0.18), I2=84%) between FET and fresh-ET. Of the 32 studies included, 24 were classified as having low-quality evidence, while 8 were rated as very low quality, when combining the tools of Robins-I and GRADE.WIDER IMPLICATIONSThis systematic review provides

根据所采用的特定ART方法，通过ART孕育的儿童表现出不同的出生体重。冷冻胚胎移植（FET）后出生的孩子更容易出生时体重高，出生时胎龄大，而新鲜胚胎移植（fresh- et）后出生的孩子往往出生时体重较低，更常被归类为胎龄小。大量研究已经证实，出生体重高低与儿童肥胖风险增加之间存在联系。一种流行的假设认为ART可能在受精、着床和早期胚胎阶段诱导表观遗传修饰，不仅影响出生时的大小，还影响后代以后的体重指数和整体健康。目的和理由本系统综述旨在确定文献中现有证据是否支持ART后出生的儿童与自然受孕的儿童相比BMI受到影响的假设。检索方法在PubMed （MEDLINE）、EMBASE和Cochrane数据库中使用医学主题标题、emtree术语和自由文本词进行文献检索，直至2025年3月20日。纳入标准为1-18岁ART后出生儿童的生长和人体测量（包括BMI）。根据PRISMA指南进行审查，并尽可能从纳入的研究中提取数据。使用Robins-I工具评估偏倚，使用GRADE评估纳入研究证据的确定性。结果：剔除重复项后，共发现22 026项研究。其中，80篇文章被挑选出来进行全文通读。此外，从参考文献列表中确定了52项研究，并将其纳入全文通读。在这132项研究中，有32项符合纳入标准，被纳入定性分析。进行了三项荟萃分析。第一个(A)比较了ART后出生的儿童（n = 8902）和自然受孕后出生的儿童（n = 61 818）的BMI作为SD评分（SDS），结果发现BMI无差异(mean-difference 0.02, 95% CI: -0.03；0.06), I2 = 9%，中等确定性)。第二个(B)研究了ART后出生的儿童（n = 4297）和NC后出生的儿童（n = 37233）的BMI （kg/m2）的差异，结果显示BMI略有下降，为-0.16 kg/m2 (95% CI: -0.26；-0.07), I2=87%，中等确定性)。第三项荟萃分析(C)检查了FET后出生的儿童（n = 5146）与新鲜et后出生的儿童（n = 15 709）的BMI (SDS)，结果显示BMI （SDS）无差异(平均差异0.08,95% CI: -0.02；0.18), I2=84%)。在纳入的32项研究中，当结合Robins-I和GRADE工具时，24项研究被归类为低质量证据，而8项研究被评为极低质量证据。更广泛的意义本系统综述对现有文献进行了全面总结，研究了ART后出生的儿童与自然受孕的儿童的BMI。它通过使用年龄和性别标准化值为该领域增加了新颖可靠的信息。这项系统综述和荟萃分析的结果令人放心。为了进一步了解ART人群的健康状况，有必要对通过包括冷冻保存在内的各种ART方法受孕的儿童和成人的身体组成进行纵向研究。注册号prospero crd42021257788。

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引用次数: 0

Embryo metabolism as a novel non-invasive preimplantation test: nutrients turn over and metabolomic analysis of human spent embryo culture media (SECM) 胚胎代谢作为一种新的无创着床前试验：人废胚胎培养基（SECM）的营养翻转和代谢组学分析

IF 13.3 1区医学 Q1 OBSTETRICS & GYNECOLOGY

Human Reproduction Update

Pub Date : 2025-07-21 DOI: 10.1093/humupd/dmaf015

AliReza Alizadeh Moghadam Masouleh, Poopak Eftekhari-Yazdi, Amin Ebrahimi Sadrabadi, Reza Jafarzadeh Esfehani, Monica Tobler, Sven Schuchardt, Luca Gianaroli, Andreas Schmutzler

BACKGROUND Single embryo transfer is globally recommended during IVF treatments. Hence, there is a growing demand for better embryo selection. Additionally, to morphology and genetics, nutrient uptake/release and metabolome profiles in spent embryo culture media (SECM) are proposed as non-invasive biomarkers. Are they ready to be applied for clinical purposes? OBJECTIVE AND RATIONALE We reviewed methods of metabolism analysis for embryos, focusing on human SECM. SEARCH METHODS Until November 2024, the Cochrane Library, PubMed, and Google Scholar were surfed for peer-reviewed English-language studies in the human, with MeSH terms and keywords: ART, IVF, ICSI, aneuploidy, embryo transfer, embryo selection, culture media, metabolome, metabolomics, metabolic profile, artificial intelligence (AI), nutrients, carbohydrates, glucose, pyruvate, lactate, amino acids (AAs), fatty acids (FAs), and spent embryo culture medium (SECM). Also, the reference lists of all relevant articles were searched. OUTCOMES Forty-nine original publications (1989–2024) were found in which SECM samples were collected from 20 countries, focusing on preimplantation embryo metabolism single biomarker(s) of energy sources (glucose and pyruvate), AAs and free FAs (17 studies), or metabolomic analysis (32 studies). Focal points were blastocyst development, aneuploidy, embryo sex prediction, implantation, and pregnancy outcome. Eleven major companies, which supply embryo culture media, dominate the market. Nutrient composition of their culture media presents major challenges because they are not normally disclosed. In single-biomarker(s) studies, eight studies focus on glucose and pyruvate, eight on AAs, both alone and in combination with glucose or pyruvate, and their ratios. Since the absolute quantities of some AAs or glucose levels were reported in some studies, they all have the potential to become future biomarkers for clinical application. In metabolomics studies, almost all studies reported qualitative results, such as decrease/increase or the metabolite ratios. For absolute concentrations, the basal concentrations of the culture media must be considered. In sum, all differences in the experimental design, the platforms, and the results were analyzed. WIDER IMPLICATIONS Establishing a unified guideline for the reporting of metabolomics studies and a specific guideline outlining the minimum information required for SECM experiment publication will ensure that future studies provide all necessary and critical information. The metabolomics studies primarily focused on implantation and pregnancy, whereas we, as a first step, preferred multi-omics studies on absolute concentrations of metabolites of good vs poor quality and euploid vs aneuploid embryos. Following this step, these quantitative approaches might lead to more convincing successes. If small numbers of predictive biomarkers were identified, a simple, rapid, and cheap test could be developed for each medium, clinically p

背景：单胚胎移植是全球范围内推荐的IVF治疗方法。因此，对更好的胚胎选择的需求日益增长。此外，从形态学和遗传学的角度来看，废胚培养基（SECM）的营养摄取/释放和代谢组谱被认为是无创生物标志物。它们准备好应用于临床目的了吗？目的与原理综述了胚胎代谢分析方法，重点介绍了人类胚胎代谢分析方法。直到2024年11月，Cochrane Library、PubMed和谷歌Scholar检索了同行评议的人类英语研究，其MeSH术语和关键词为：ART、IVF、ICSI、非整倍体、胚胎移植、胚胎选择、培养基、代谢组学、代谢谱、人工智能（AI）、营养物质、碳水化合物、葡萄糖、丙酮酸、乳酸、氨基酸（AAs）、脂肪酸（FAs）和废胚胎培养基（SECM）。同时，检索所有相关文献的参考文献列表。结果：从20个国家收集了49篇原始出版物（1989-2024），其中收集了SECM样本，重点关注着落前胚胎代谢单一生物标志物的能量来源（葡萄糖和丙酮酸），AAs和游离FAs（17项研究）或代谢组学分析（32项研究）。重点是囊胚发育、非整倍性、胚胎性别预测、着床和妊娠结局。11家提供胚胎培养基的大公司主导着市场。他们的培养基的营养成分提出了重大挑战，因为它们通常不公开。在单一生物标志物研究中，8项研究关注葡萄糖和丙酮酸，8项研究关注单独或与葡萄糖或丙酮酸联合使用的AAs及其比例。由于一些研究报告了一些AAs的绝对数量或葡萄糖水平，它们都有可能成为未来临床应用的生物标志物。在代谢组学研究中，几乎所有的研究都报告了定性结果，例如代谢物比率的减少/增加。对于绝对浓度，必须考虑培养基的基础浓度。综上所述，分析了实验设计、平台和结果的所有差异。建立代谢组学研究报告的统一指南和概述SECM实验发表所需的最低信息的具体指南将确保未来的研究提供所有必要和关键的信息。代谢组学研究主要集中在着床和妊娠，而作为第一步，我们更倾向于多组学研究质量好与质量差以及整倍体与非整倍体胚胎的代谢物绝对浓度。遵循这一步骤，这些量化方法可能会导致更令人信服的成功。如果少量的预测性生物标志物被识别出来，就可以为每种培养基开发一种简单、快速、廉价的测试方法，并在生育中心进行临床试验。此外，还需要结合靶向代谢组学对基础培养基成分进行进一步研究。未来可能是由人工智能整合所有主要是非侵入性的信息、组学和其他。审查方案在OSF平台上注册：https://osf.io/mxtbg

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引用次数: 0

Ethical considerations for advancing research using organoid models derived from the placenta. 推进胎盘类器官模型研究的伦理考虑。

IF 14.8 1区医学 Q1 OBSTETRICS & GYNECOLOGY

Human Reproduction Update

Pub Date : 2025-07-01 DOI: 10.1093/humupd/dmaf007

Olivier J M Schäffers, Joost Gribnau, Bas B van Rijn, Eline M Bunnik

Background: The advent of organoid culture systems has revolutionized our ability to model and study complex tissues in vitro. The placenta is one of the last human organs to have a functional organoid model developed: trophoblast organoids. These 3-dimensional structures, derived from placental tissue, offer researchers a valuable tool for studying previously inaccessible processes that occur within the womb and play a significant role in determining the health of the offspring. While primarily used for research, trophoblast organoids hold promise for clinical applications, including prenatal diagnostics and therapeutic interventions, both of which may have commercial interest. However, to ensure that research with organoid models derived from the placenta is conducted responsibly, the relevant ethics of these models need to be addressed.

Objective and rationale: Ethical considerations related to organoid models derived from the placenta, such as trophoblast organoids are important but remain unexplored in literature. Therefore, the goal of this review is to explore the ethical considerations related to trophoblast organoids.

Search methods: Since there is no ethical research specifically addressing organoid models of the placenta to date, we have based our findings on discussions related to other organoid models and research involving fetal tissue, placenta, or umbilical cord blood. We employed a scoping review method to search PubMed, Embase, Medline (all), Bioethics Research Library, and Google Scholar for research articles, books, or other correspondence on ethical issues regarding these indicated topics, with no date limits.

Outcomes: Ethical considerations related to trophoblast organoids can be divided into three distinct categories. First, there is a need to assess the moral value of trophoblast organoids, including their potential relational and symbolic dimensions. Second, it is important to understand ethical issues associated with ownership and commercialization of trophoblast organoids. Last, there are considerations related to appropriate informed consent procedures. It is worth noting that these three categories are interconnected, with the second and third being largely dependent on the moral value attributed to trophoblast organoids. Future research should assess the perspectives of various stakeholders, including parents who may donate placental tissue for organoid research.

Wider implications: This review offers valuable insights into the ethical landscape surrounding the derivation of tissues or products from pregnancies, and their further application, highlighting areas that require attention and discussion within both the scientific community and the broader society.

Registration number: N/A.

背景：类器官培养系统的出现彻底改变了我们在体外模拟和研究复杂组织的能力。胎盘是最后一个有功能类器官模型的人体器官之一：滋养细胞类器官。这些来自胎盘组织的三维结构为研究人员提供了一种有价值的工具，可以研究子宫内发生的以前难以接近的过程，并在决定后代的健康方面发挥重要作用。虽然主要用于研究，但滋养细胞类器官有望用于临床应用，包括产前诊断和治疗干预，这两者都可能具有商业利益。然而，为了确保以负责任的方式进行胎盘类器官模型的研究，需要解决这些模型的相关伦理问题。目的和理由：与胎盘衍生的类器官模型（如滋养细胞类器官）相关的伦理考虑是重要的，但在文献中尚未探索。因此，本综述的目的是探讨与滋养细胞类器官相关的伦理问题。搜索方法：由于迄今为止还没有专门针对胎盘类器官模型的伦理研究，我们的研究结果基于与其他类器官模型和涉及胎儿组织、胎盘或脐带血的研究相关的讨论。我们采用范围审查方法检索PubMed、Embase、Medline（全部）、Bioethics Research Library和谷歌Scholar，检索与这些指定主题有关的研究文章、书籍或其他关于伦理问题的通信，没有日期限制。结果：与滋养细胞类器官相关的伦理考虑可分为三种不同的类别。首先，有必要评估滋养细胞类器官的道德价值，包括它们潜在的关系和象征维度。其次，重要的是要了解与滋养细胞类器官的所有权和商业化相关的伦理问题。最后，还有与适当的知情同意程序有关的考虑。值得注意的是，这三类是相互关联的，第二类和第三类在很大程度上取决于滋养细胞类器官的道德价值。未来的研究应该评估各种利益相关者的观点，包括可能为类器官研究捐赠胎盘组织的父母。更广泛的影响：本综述为围绕妊娠组织或产品的衍生及其进一步应用的伦理景观提供了有价值的见解，突出了科学界和更广泛的社会需要关注和讨论的领域。注册号：无。

{"title":"Ethical considerations for advancing research using organoid models derived from the placenta.","authors":"Olivier J M Schäffers, Joost Gribnau, Bas B van Rijn, Eline M Bunnik","doi":"10.1093/humupd/dmaf007","DOIUrl":"10.1093/humupd/dmaf007","url":null,"abstract":"Background: The advent of organoid culture systems has revolutionized our ability to model and study complex tissues in vitro. The placenta is one of the last human organs to have a functional organoid model developed: trophoblast organoids. These 3-dimensional structures, derived from placental tissue, offer researchers a valuable tool for studying previously inaccessible processes that occur within the womb and play a significant role in determining the health of the offspring. While primarily used for research, trophoblast organoids hold promise for clinical applications, including prenatal diagnostics and therapeutic interventions, both of which may have commercial interest. However, to ensure that research with organoid models derived from the placenta is conducted responsibly, the relevant ethics of these models need to be addressed.Objective and rationale: Ethical considerations related to organoid models derived from the placenta, such as trophoblast organoids are important but remain unexplored in literature. Therefore, the goal of this review is to explore the ethical considerations related to trophoblast organoids.Search methods: Since there is no ethical research specifically addressing organoid models of the placenta to date, we have based our findings on discussions related to other organoid models and research involving fetal tissue, placenta, or umbilical cord blood. We employed a scoping review method to search PubMed, Embase, Medline (all), Bioethics Research Library, and Google Scholar for research articles, books, or other correspondence on ethical issues regarding these indicated topics, with no date limits.Outcomes: Ethical considerations related to trophoblast organoids can be divided into three distinct categories. First, there is a need to assess the moral value of trophoblast organoids, including their potential relational and symbolic dimensions. Second, it is important to understand ethical issues associated with ownership and commercialization of trophoblast organoids. Last, there are considerations related to appropriate informed consent procedures. It is worth noting that these three categories are interconnected, with the second and third being largely dependent on the moral value attributed to trophoblast organoids. Future research should assess the perspectives of various stakeholders, including parents who may donate placental tissue for organoid research.Wider implications: This review offers valuable insights into the ethical landscape surrounding the derivation of tissues or products from pregnancies, and their further application, highlighting areas that require attention and discussion within both the scientific community and the broader society.Registration number: N/A.","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":"392-401"},"PeriodicalIF":14.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RNA modifications in female reproductive physiology and disease: emerging roles and clinical implications. 女性生殖生理和疾病中的 RNA 修饰：新出现的作用和临床意义。

IF 14.8 1区医学 Q1 OBSTETRICS & GYNECOLOGY

Human Reproduction Update

Pub Date : 2025-07-01 DOI: 10.1093/humupd/dmaf005

Yu Xiang, Hsun-Ming Chang, Peter C K Leung, Long Bai, Yimin Zhu

Background: RNA modifications, collectively known as the epitranscriptome, represent the third layer of gene regulation, influencing gene expression at transcriptional, post-transcriptional, and translational levels. RNA-modifying proteins (RMPs), including writers, erasers, and readers, are responsible for depositing, removing, and recognizing chemical modifications on RNA molecules. These modifications play a crucial role in linking molecular processes to cellular functions. Over the past few decades, a growing body of laboratory evidence, alongside advances in sequencing technologies, has uncovered connections between aberrant RNA modifications and reproductive disorders, highlighting their emerging roles in female fertility. Given the rapid expansion of epitranscriptomic research in female reproduction, a comprehensive review is needed to summarize the broader impacts of various RNA modifications, rather than focusing on individual RNA modifications alone.Objective and rationale: This review aims to elucidate the progress in understanding the role of RNA modifications in reproductive biology and how their dysregulations contribute to infertility-related conditions, such as polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), and endometriosis. Special focus will be given to RNA modifications in coding RNAs, particularly those linked to female fertility and supported by solid evidence. The ultimate objective is to explore how targeting the RNA-modification machinery can lead to the development of novel therapeutic interventions for restoring fertility.Search methods: We conducted a thorough review of peer-reviewed original research articles and reviews published over the past two decades using the PubMed search engine. Keywords included terms related to RNA modifications, such as 'N6-methyladenosine (m6A)', 'N4-acetylcytidine (ac4C)', and 'adenosine-to-inosine (A-I) editing', combined with terms related to female reproduction, such as 'ovary', 'oocyte', and 'embryo'. Additional relevant search phrases were also utilized to ensure comprehensive coverage of the topic.Outcomes: RNA modification has emerged as a transformative area in reproductive biology, with our understanding of the epitranscriptome growing rapidly due to significant advances in high-throughput sequencing technologies. Regulatory proteins play a crucial role in the correct deposition and functional implementation of RNA modifications. Knockout animal models have identified a broad, though still incomplete, list of RNA modifications involved in mammalian reproductive processes. These include prevalent modifications in mRNA, such as m6A, as well as A-I editing, and, to a lesser extent, 5-methylcytosine (m5C) and ac4C. These regulatory mechanisms impact various reproductive functions, including folliculogenesis, oocyte maturation, fertilization, and embryo development. D

背景：RNA修饰，统称为外转录组，代表了基因调控的第三层，在转录、转录后和翻译水平上影响基因表达。RNA修饰蛋白（rmp），包括写入器、擦除器和读取器，负责在RNA分子上沉积、去除和识别化学修饰。这些修饰在连接分子过程和细胞功能方面起着至关重要的作用。在过去的几十年里，随着测序技术的进步，越来越多的实验室证据揭示了异常RNA修饰和生殖障碍之间的联系，突出了它们在女性生育能力中的新作用。鉴于女性生殖的表观转录组学研究迅速扩大，需要全面回顾总结各种RNA修饰的广泛影响，而不是仅仅关注单个RNA修饰。目的与理由：本文旨在阐明RNA修饰在生殖生物学中的作用及其失调如何导致不孕相关疾病，如多囊卵巢综合征（PCOS）、卵巢早衰（POI）和子宫内膜异位症。将特别关注编码RNA中的RNA修饰，特别是那些与女性生育能力有关并有确凿证据支持的修饰。最终目的是探索靶向rna修饰机制如何导致恢复生育能力的新型治疗干预措施的发展。搜索方法：我们使用PubMed搜索引擎对过去二十年发表的同行评议的原创研究文章和评论进行了彻底的审查。关键词包括与RNA修饰相关的术语，如“n6 -甲基腺苷（m6A）”、“n4 -乙酰胞苷（ac4C）”和“腺苷-肌苷（A-I）编辑”，以及与女性生殖相关的术语，如“卵巢”、“卵母细胞”和“胚胎”。还使用了其他相关搜索短语，以确保全面覆盖该主题。结果：RNA修饰已成为生殖生物学的一个变革领域，由于高通量测序技术的重大进步，我们对表转录组的理解迅速增长。调节蛋白在RNA修饰的正确沉积和功能实现中起着至关重要的作用。敲除动物模型已经确定了一个广泛的，尽管仍然不完整的，涉及哺乳动物生殖过程的RNA修饰列表。这些包括mRNA中常见的修饰，如m6A，以及a - i编辑，以及较小程度上的5-甲基胞嘧啶（m5C）和ac4C。这些调节机制影响各种生殖功能，包括卵泡发生、卵母细胞成熟、受精和胚胎发育。RNA修饰的失调可能加剧不孕相关疾病，如POI、PCOS和子宫内膜异位症。尽管临床研究仍处于早期阶段，但RNA修饰作为诊断生物标志物和治疗靶点显示出巨大的前景，具有改善生育能力和生殖健康结果的潜力。更广泛的意义：这篇综述探讨了一个相对未被充分研究的女性生殖表观转录组学研究领域，提供了显著推进我们对生殖生物学的理解的潜力。它强调了RNA修饰在不孕相关疾病中的临床相关性，并确定了潜在的生物标志物，以及rmp靶向治疗，这可能会影响未来的临床决策和个性化治疗。这些见解对生殖临床医生和胚胎学家至关重要，为生殖医学的诊断和治疗干预提供了新的途径。注册号：无。

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引用次数: 0

Genetic and reproductive strategies to prevent mitochondrial diseases. 预防线粒体疾病的遗传和生殖策略。

IF 14.8 1区医学 Q1 OBSTETRICS & GYNECOLOGY

Human Reproduction Update

Pub Date : 2025-07-01 DOI: 10.1093/humupd/dmaf004

Noemi Castelluccio, Katharina Spath, Danyang Li, Irenaeus F M De Coo, Lyndsey Butterworth, Dagan Wells, Heidi Mertes, Joanna Poulton, Björn Heindryckx

Mitochondrial DNA (mtDNA) diseases pose unique challenges for genetic counselling and require tailored approaches to address recurrence risks and reproductive options. The intricate dynamics of mtDNA segregation and heteroplasmy shift significantly impact the chances of having affected children. In addition to natural pregnancy, oocyte donation, and adoption, IVF-based approaches can reduce the risk of disease transmission. Prenatal diagnosis (PND) and preimplantation genetic testing (PGT) remain the standard methods for women carrying pathogenic mtDNA mutations; nevertheless, they are not suitable for every patient. Germline nuclear transfer (NT) has emerged as a novel therapeutic strategy, while mitochondrial gene editing has increasingly become a promising research area in the field. However, challenges and safety concerns associated with all these techniques remain, highlighting the need for long-term follow-up studies, an improved understanding of disease mechanisms, and personalized approaches to diagnosis and treatment. Given the inherent risks of adverse maternal and child outcomes, careful consideration of the balance between potential benefits and drawbacks is also warranted. This review will provide critical insights, identify knowledge gaps, and underscore the importance of advancing mitochondrial disease research in reproductive health.

线粒体DNA （mtDNA）疾病对遗传咨询提出了独特的挑战，需要有针对性的方法来解决复发风险和生殖选择。mtDNA分离和异质性转移的复杂动态显著影响患病儿童的机会。除了自然妊娠、卵母细胞捐赠和收养外，基于体外受精的方法可以降低疾病传播的风险。产前诊断（PND）和胚胎植入前基因检测（PGT）仍然是携带致病性mtDNA突变妇女的标准方法；然而，它们并不适合每一个病人。种系核移植（NT）已成为一种新的治疗策略，而线粒体基因编辑也日益成为该领域的一个有前景的研究领域。然而，与所有这些技术相关的挑战和安全问题仍然存在，强调需要进行长期随访研究，提高对疾病机制的理解，以及个性化的诊断和治疗方法。鉴于孕产妇和儿童不良结局的固有风险，也有必要仔细考虑潜在利弊之间的平衡。这篇综述将提供关键的见解，确定知识空白，并强调推进线粒体疾病研究在生殖健康中的重要性。

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引用次数: 0

Building a human pluripotent stem cell-based gonadal niche: improving in vitro systems with in vivo insights 建立一个人类多能干细胞为基础的性腺生态位：改善体外系统与体内的见解

IF 13.3 1区医学 Q1 OBSTETRICS & GYNECOLOGY

Human Reproduction Update

Pub Date : 2025-06-28 DOI: 10.1093/humupd/dmaf012

Mathangi Lakshmipathi, Nina Dartée, Arina Puchkina, Madalena Vaz Santos, Ilse J de Bruin, Geert Hamer, Ans M M van Pelt, Susana M Chuva de Sousa Lopes, Callista L Mulder, Willy M Baarends

BACKGROUND The gonadal somatic niche is crucial for sex determination and gamete formation throughout the human life cycle. However, key steps in gonadal somatic lineage differentiation occur during embryonic and foetal development, making them difficult to study in humans. In vitro differentiation models are therefore needed to investigate gonadal development, support in vitro gametogenesis, and study infertility. A comprehensive overview of gonadal somatic niche differentiation, both in vivo and in vitro, is thus crucial. OBJECTIVE AND RATIONALE This review connects in vivo knowledge with in vitro differentiation systems for gonadal somatic niches, predominantly focusing on cell–cell signalling factors. It evaluates existing in vitro protocols for differentiating testicular and ovarian somatic niches, discusses them in the context of in vivo findings, and explores potential advancements in model systems. SEARCH METHODS A narrative review was conducted after a comprehensive search of the PubMed database through to February 2025; the review focused on search topics including: in vivo gonadal differentiation in humans and mice; in vitro differentiation of human embryonic stem cells or human-induced pluripotent stem cells into gonadal somatic cells (bipotential, Sertoli or granulosa cells); and evidence for the cell–cell signalling factors used in these protocols. OUTCOMES We investigated various strategies that aim to differentiate human pluripotent stem cells into gonadal somatic cell lineages. These include sequential growth factor differentiation recapitulating all known developmental progenitor stages, directed growth factor differentiation that omitted one or more developmental intermediates, and directed overexpression of key transcription factors. To induce differentiation, the growth factor-based protocols used various cell–cell signalling factors, with some derived from in vivo studies, while others lacked direct in vivo evidence. Despite significant advances in guiding pluripotent stem cells towards gonadal differentiation, challenges remain, such as the limited molecular and functional validation of the generated cell types. Consequently, complete human in vitro gametogenesis through co-culture techniques with pluripotent cell-derived germ cells has not yet been achieved, indicating that full functional maturation of the gonadal niche has not been attained with the current protocols. WIDER IMPLICATIONS Integrating knowledge on in vivo gonadal development with enhanced differentiation protocols offers the potential to reliably generate the gonadal somatic niche in vitro. This allows for more accurate modelling of the gonad, facilitating deeper insights into the normal and pathological processes involved in gonadal development and germ cell maturation. For example, it could help to identify mechanisms linked to infertility or differences of sex development. Importantly, as many of these models are based on human pluripotent stem cells, th

性腺体细胞生态位在整个人类生命周期中对性别决定和配子形成至关重要。然而，性腺体细胞谱系分化的关键步骤发生在胚胎和胎儿发育过程中，这使得它们难以在人类中进行研究。因此，需要体外分化模型来研究性腺发育，支持体外配子体发生和研究不孕症。因此，对体内和体外性腺体细胞生态位分化的全面概述是至关重要的。目的和原理本综述将体内知识与性腺体细胞生态位的体外分化系统联系起来，主要关注细胞-细胞信号因子。它评估了现有的用于区分睾丸和卵巢体细胞生态位的体外方案，在体内研究结果的背景下讨论了它们，并探索了模型系统的潜在进展。检索方法对PubMed数据库进行全面检索，检索时间截止到2025年2月；综述的检索主题包括：人与小鼠体内性腺分化；人胚胎干细胞或人诱导多能干细胞在体外分化为性腺体细胞（双潜能细胞、支持细胞或颗粒细胞）；以及这些协议中使用的细胞-细胞信号因子的证据。结果：我们研究了旨在将人类多能干细胞分化为性腺体细胞谱系的各种策略。这些包括序贯生长因子分化概括了所有已知的发育祖细胞阶段，定向生长因子分化省略了一个或多个发育中间体，以及定向过度表达关键转录因子。为了诱导分化，基于生长因子的方案使用了各种细胞-细胞信号因子，其中一些来自体内研究，而另一些则缺乏直接的体内证据。尽管在引导多能干细胞向性腺分化方面取得了重大进展，但仍然存在挑战，例如所生成的细胞类型的分子和功能验证有限。因此，通过与多能细胞来源的生殖细胞共培养技术完成的人类体外配子发生尚未实现，这表明目前的方案尚未实现性腺生态位的完全功能成熟。将体内性腺发育的知识与增强的分化方案相结合，提供了在体外可靠地产生性腺体细胞生态位的潜力。这允许更准确地模拟性腺，促进更深入地了解性腺发育和生殖细胞成熟的正常和病理过程。例如，它可以帮助确定与不孕或性发育差异有关的机制。重要的是，由于许多这些模型都是基于人类多能干细胞，因此它们具有个性化的潜力，使未来的患者特异性模型能够用于研究生殖疾病和开发量身定制的生育治疗。注册号码n/a。

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引用次数: 0

Protein O-GlcNAcylation in reproductive biology and the impact of metabolic disease 蛋白o - glcn酰化在生殖生物学和代谢性疾病中的影响

IF 13.3 1区医学 Q1 OBSTETRICS & GYNECOLOGY

Human Reproduction Update

Pub Date : 2025-06-27 DOI: 10.1093/humupd/dmaf013

Atalie L Scrivener, Melissa Westwood, Peter T Ruane, John D Aplin

BACKGROUND Protein O-GlcNAcylation is a reversible post-translational modification which regulates the function of thousands of proteins to control generic and cell type-specific actions. O-GlcNAc addition and removal downstream of the hexosamine biosynthetic pathway (HBP) is mediated by only two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Crucially, O-GlcNAcylation provides a regulatory layer to protein function that is responsive to metabolic status and thus metabolic disease impinges on this system. Animal and ex vivo models show that O-GlcNAcylation is important for peri-conceptual and pregnancy processes. OBJECTIVE AND RATIONALE Fundamental knowledge about O-GlcNAcylation of proteins involved in reproductive processes is lacking. Here, we give relevant, and mechanistically well understood, examples of how protein O-GlcNAcylation can affect cellular processes and examine available data on germ cells, embryonic development, endometrial receptivity, and placentation. OGT and OGA regulation are placed within the wider context of reproductive biology. We also highlight gaps in knowledge and suggest avenues for next-phase research. SEARCH METHODS PubMed and Google Scholar (2013–2024) were interrogated, including only publications in English. Search terms included: GlcNAc AND Oocyte, GlcNAc AND Sperm, GlcNAc AND Embryo, GlcNAc AND Cell Differentiation, GlcNAc AND Endometrium, GlcNAc AND Endometrial Receptivity, GlcNAc AND Placenta, GlcNAc AND diabetes, and GlcNAc AND obesity. OUTCOMES Some evidence for the global impact of O-GlcNAcylation in maturation of oocytes and sperm, pre-implantation development, implantation, and placentation has been gathered by pharmacological inhibition and/or targeted mutagenesis of OGT and OGA. Blocking or inactivating OGT gives an embryonic lethal phenotype in most species. Mouse embryos can tolerate inactivation of OGA, but the offspring are growth-restricted and die postnatally. In general, HBP utilization in pre-implantation differs between species. This is likely to be the case in post-implantation development too, but it is already clear from stem cell biology that O-GlcNAcylation is important in the differentiation of most embryonic cell lineages including neurones, osteoclasts, enterocytes, and adipocytes. The identification of the progesterone receptor as an OGT target suggests important and widespread involvement of O-GlcNAcylation in reproductive processes. In the adult endometrium, protein O-GlcNAcylation decreases during decidualization, however, there is some evidence to suggest that O-GlcNAcylation of specific proteins promotes receptivity to the implanting embryo. In placenta, key aspects of development (e.g. angiogenesis) and function (e.g. transport, hormone production) are influenced by O-GlcNAcylation. Hyperglycaemia-induced changes in protein O-GlcNAcylation have negative impacts throughout reproductive systems and while there is less information on the consequences of

蛋白质o - glcn酰化是一种可逆的翻译后修饰，它调节数千种蛋白质的功能，以控制一般和细胞类型特异性的行为。在己糖胺生物合成途径（HBP）下游，O-GlcNAc的添加和去除仅由两种酶介导：O-GlcNAc转移酶（OGT）和O-GlcNAcase （OGA）。至关重要的是，o - glcn酰化为蛋白质功能提供了一个调节层，该功能对代谢状态做出反应，因此代谢疾病会影响该系统。动物和离体模型表明，o - glcn酰化对围概念和妊娠过程很重要。目的与原理目前对参与生殖过程的o - glcn酰化蛋白缺乏基本的认识。在这里，我们给出了相关的、机制上很好理解的例子，说明蛋白质o - glcn酰化如何影响细胞过程，并检查了生殖细胞、胚胎发育、子宫内膜容受性和胎盘的现有数据。OGT和OGA调节被置于生殖生物学的更广泛的背景下。我们还强调了知识方面的差距，并提出了下一阶段研究的途径。检索方法检索PubMed和谷歌Scholar(2013-2024)，仅包括英文出版物。搜索词包括：GlcNAc与卵母细胞，GlcNAc与精子，GlcNAc与胚胎，GlcNAc与细胞分化，GlcNAc与子宫内膜，GlcNAc与子宫内膜容受性，GlcNAc与胎盘，GlcNAc与糖尿病，以及GlcNAc与肥胖。通过OGT和OGA的药物抑制和/或靶向诱变，已经收集了o - glcn酰化对卵母细胞和精子成熟、着床前发育、着床和胎盘的全球影响的一些证据。在大多数物种中，阻断或灭活OGT会导致胚胎致死表型。小鼠胚胎可以耐受OGA的失活，但其后代生长受限，并在出生后死亡。一般来说，不同物种在着床前对HBP的利用是不同的。这在胚胎植入后的发育过程中可能也是如此，但干细胞生物学已经清楚地表明，o - glcn酰化在大多数胚胎细胞系（包括神经元、破骨细胞、肠细胞和脂肪细胞）的分化中起着重要作用。孕酮受体作为OGT靶点的鉴定表明o - glcn酰化在生殖过程中重要而广泛的参与。在成人子宫内膜中，蛋白o - glcn酰化在去个体化过程中减少，然而，有证据表明特定蛋白的o - glcn酰化促进了着床胚胎的接受性。在胎盘中，发育（如血管生成）和功能（如运输、激素产生）的关键方面受到o - glcn酰化的影响。高血糖诱导的蛋白o - glcn酰化的改变对整个生殖系统都有负面影响，虽然关于脂质介导的这种翻译后修饰改变的后果的信息较少，但现有证据表明，肥胖个体中扭曲的蛋白o - glcn酰化导致生殖功能受损。本综述强调了蛋白o - glcn酰化作为生殖过程的调节因子，并确定了必须填补的巨大知识空白，以提高基本认识。针对o - glcn酰化调节网络，包括受体位点突变，在确定的生殖组织细胞群将推进知识。o - glcn酰化与代谢性疾病的界面需要解开，以确定干预措施如何减轻疾病影响生殖结果。注册号码。

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引用次数: 0

Spermatogonia: a unique stem cell orchestrating species-specific transition from pluripotency to sperm production. 精原细胞：一个独特的干细胞协调从多能性到精子产生的物种特异性转变。

IF 13.3 1区医学 Q1 OBSTETRICS & GYNECOLOGY

Human Reproduction Update

Pub Date : 2025-05-23 DOI: 10.1093/humupd/dmaf010

Fabian Schlag,Camille Dion,Lessly P Sepulveda-Rincon,Stefan Schlatt,Swati Sharma

BACKGROUNDMale germline stem cells are relevant for stem cell researchers but also for andrologists as they are crucial for testis function and initiation/maintenance of spermatogenesis. They are also considered a target for fertility preservation in the male; e.g. germ cell transplantation or testicular grafting rely on spermatogonial stem cells (SSCs) and may soon become clinical tools to recover fertility. In the current review, we report new insights into genesis of spermatogonia, germline plasticity, and models of spermatogonial expansion. These insights and an array of novel cellular and molecular tools have provided great technological advances and new knowledge and therefore the field of SSCs needs an up-to-date review.OBJECTIVEIn this review, we focus on the male germline starting with pluripotent precursors and ending with sperm. The recent discoveries on mechanisms and cellular events involved in the derivation of SSCs are highlighted. We summarize all information on clonal expansion of SSCs in several species. We revisit old models and formulate novel models for the initial phases of spermatogenesis considering species-specific differences. Specifically, the human situation will be presented, informing the reader on many primate-specific features (i.e. the existence of self-renewing progenitors, limited premeiotic mitotic steps, and small clonal sizes). This review is important as the current view on spermatogonia in the human testis needs an update taking in novel and unexpected findings derived from studies using new technologies, such as microfluidics, single-cell analysis, and xenografting. These findings also require re-interpretations of previously published results and models for spermatogonial function.SEARCH METHODSWe used PubMed and other relevant databases to reveal all available information. Search terms were flexibly combined. Baseline search terms were: spermatogonia/testis/stem cell/mitotic expansion/clone/primate/human/spermatogenesis/meiotic entry/germ cell niche/sperm production/spermatogenic efficiency.OUTCOMESSpermatogenesis in men relies on a stem cell system which is highly distinct from that of rodents. Derivation of spermatogonia from pluripotent precursors has been explored in approaches using embryonic stem cells and induced pluripotent stem cells leading to novel concepts which are highlighted. The testis is populated with five subpopulations of premeiotic germ cells with specific tasks and functions. We will specifically focus on these features in this review. Based on the internal or external stimuli received from the microenvironment through underlying signalling and regulatory networks, subpopulations may show diverse responses. The high plasticity and variable potency of spermatogonial populations may play an important and distinct role during normal or aberrant germline developments alike. SSC models are helpful tools to understand the rigorous checkpoints maintaining germline quality at pre-meiotic an

男性生殖系干细胞不仅对干细胞研究人员很重要，而且对男科医生也很重要，因为它们对睾丸功能和精子发生的开始/维持至关重要。它们也被认为是男性保持生育能力的目标；例如，生殖细胞移植或睾丸移植依赖于精原干细胞（SSCs），可能很快成为恢复生育能力的临床工具。在本综述中，我们报道了精原细胞的发生，种系可塑性和精原细胞扩张模型的新见解。这些见解和一系列新的细胞和分子工具提供了巨大的技术进步和新知识，因此SSCs领域需要最新的综述。目的综述从多能前体到精子的雄性生殖系研究进展。重点介绍了近年来有关ssc产生的机制和细胞事件的最新发现。我们总结了几种物种中ssc克隆扩增的所有信息。我们重新审视旧的模型，并制定新的模型，为精子发生的初始阶段考虑物种特异性差异。具体来说，将介绍人类的情况，向读者介绍许多灵长类动物特有的特征（即自我更新祖细胞的存在，有限的减数分裂前有丝分裂步骤和小克隆大小）。这篇综述是很重要的，因为目前对人类睾丸中的精原细胞的看法需要更新，因为使用新技术（如微流体、单细胞分析和异种移植）的研究获得了新的和意想不到的发现。这些发现还需要对先前发表的结果和精原功能模型进行重新解释。检索方法我们使用PubMed和其他相关数据库来显示所有可用的信息。搜索词被灵活地组合起来。基线检索词为：精原细胞/睾丸/干细胞/有丝分裂扩增/克隆/灵长类动物/人类/精子发生/减数分裂进入/生殖细胞生态位/精子产生/生精效率。结果：男性的精子发生依赖于一个与啮齿类动物截然不同的干细胞系统。从多能性前体衍生精原细胞的研究已经在使用胚胎干细胞和诱导多能性干细胞的方法中进行了探索，并提出了一些新的概念。睾丸中有5个具有特定任务和功能的早衰生殖细胞亚群。在本文中，我们将特别关注这些特性。基于来自微环境的内部或外部刺激，通过潜在的信号和调节网络，亚种群可能表现出不同的反应。精原群体的高可塑性和可变效力可能在正常或异常种系发育过程中发挥重要而独特的作用。SSC模型是理解在减数分裂前和减数分裂阶段维持种系质量的严格检查点的有用工具。通过计算各种物种的精原细胞比率得出的证据表明，在猕猴和人类等高等灵长类动物中，克隆扩增率较慢。相比之下，在啮齿类动物等小型动物中，克隆扩张的速度更快。讨论了种系发育中这些物种特异性差异的后果。本综述还讨论了未来临床应用和新疗法的进一步选择。我们对ssc及其体细胞生态位的修订理解为男性不育的原因提供了新的视角，不仅可以为治疗行动提供策略，还可以为生育能力保存和体外产生精子的策略提供策略。

{"title":"Spermatogonia: a unique stem cell orchestrating species-specific transition from pluripotency to sperm production.","authors":"Fabian Schlag,Camille Dion,Lessly P Sepulveda-Rincon,Stefan Schlatt,Swati Sharma","doi":"10.1093/humupd/dmaf010","DOIUrl":"https://doi.org/10.1093/humupd/dmaf010","url":null,"abstract":"BACKGROUNDMale germline stem cells are relevant for stem cell researchers but also for andrologists as they are crucial for testis function and initiation/maintenance of spermatogenesis. They are also considered a target for fertility preservation in the male; e.g. germ cell transplantation or testicular grafting rely on spermatogonial stem cells (SSCs) and may soon become clinical tools to recover fertility. In the current review, we report new insights into genesis of spermatogonia, germline plasticity, and models of spermatogonial expansion. These insights and an array of novel cellular and molecular tools have provided great technological advances and new knowledge and therefore the field of SSCs needs an up-to-date review.OBJECTIVEIn this review, we focus on the male germline starting with pluripotent precursors and ending with sperm. The recent discoveries on mechanisms and cellular events involved in the derivation of SSCs are highlighted. We summarize all information on clonal expansion of SSCs in several species. We revisit old models and formulate novel models for the initial phases of spermatogenesis considering species-specific differences. Specifically, the human situation will be presented, informing the reader on many primate-specific features (i.e. the existence of self-renewing progenitors, limited premeiotic mitotic steps, and small clonal sizes). This review is important as the current view on spermatogonia in the human testis needs an update taking in novel and unexpected findings derived from studies using new technologies, such as microfluidics, single-cell analysis, and xenografting. These findings also require re-interpretations of previously published results and models for spermatogonial function.SEARCH METHODSWe used PubMed and other relevant databases to reveal all available information. Search terms were flexibly combined. Baseline search terms were: spermatogonia/testis/stem cell/mitotic expansion/clone/primate/human/spermatogenesis/meiotic entry/germ cell niche/sperm production/spermatogenic efficiency.OUTCOMESSpermatogenesis in men relies on a stem cell system which is highly distinct from that of rodents. Derivation of spermatogonia from pluripotent precursors has been explored in approaches using embryonic stem cells and induced pluripotent stem cells leading to novel concepts which are highlighted. The testis is populated with five subpopulations of premeiotic germ cells with specific tasks and functions. We will specifically focus on these features in this review. Based on the internal or external stimuli received from the microenvironment through underlying signalling and regulatory networks, subpopulations may show diverse responses. The high plasticity and variable potency of spermatogonial populations may play an important and distinct role during normal or aberrant germline developments alike. SSC models are helpful tools to understand the rigorous checkpoints maintaining germline quality at pre-meiotic an","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"18 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modeling the extension of ovarian function after therapeutic targeting of the primordial follicle reserve 模拟原始卵泡储备治疗后卵巢功能的扩展

IF 13.3 1区医学 Q1 OBSTETRICS & GYNECOLOGY

Human Reproduction Update

Pub Date : 2025-05-05 DOI: 10.1093/humupd/dmaf009

Joshua Johnson, John W Emerson, Annika Smith, Kayla Medina, Evelyn E Telfer, Richard A Anderson, Sean D Lawley

BACKGROUND Women are increasingly choosing to delay childbirth, and those with low ovarian reserves indicative of primary ovarian insufficiency are at risk for sub- and infertility and also the early onset of menopause. Experimental strategies that promise to extend the duration of ovarian function in women are currently being developed. One strategy is to slow the rate of loss of existing primordial follicles (PFs), and a second is to increase, or ‘boost’, the number of autologous PFs in the human ovary. In both cases, the duration of ovarian function would be expected to be lengthened, and menopause would be delayed. This might be accompanied by an extended production of mature oocytes of sufficient quality to extend the fertile lifespan. OBJECTIVE AND RATIONALE In this work, we consider how slowing physiological ovarian aging might improve the health and well-being of patients, and summarize the current state-of-the-art of approaches being developed. We then use mathematical modeling to determine how interventions are likely to influence the duration of ovarian function quantitatively. Finally, we consider efficacy benchmarks that should be achieved so that individuals will benefit, and propose criteria that could be used to monitor ongoing efficacy in different patients as these strategies are being validated. SEARCH METHODS Current methods to estimate the size of the ovarian reserve and its relationship to the timing of the menopausal transition and menopause were compiled, and publications establishing methods designed to slow loss of the ovarian reserve or to deliver additional ovarian PFs to patients were identified. OUTCOMES We review our current understanding of the consequences of reproductive aging in women, and compare different approaches that may extend ovarian function in women at risk for POI. We also provide modeling of primordial reserve decay in the presence of therapies that slow PF loss or boost PF numbers. An interactive online tool is provided that estimates how different interventions would impact the duration of ovarian function across the natural population. Modeling output shows that treatments that slow PF loss would need to be applied as early as possible and for many years to achieve significant delay of menopause. In contrast, treatments that add additional PFs should occur as late as possible relative to the onset of menopause. Combined approaches slowing ovarian reserve loss while also boosting numbers of (new) PFs would likely offer some additional benefits in delaying menopause. WIDER IMPLICATIONS Extending ovarian function, and perhaps the fertile lifespan, is on the horizon for at least some patients. Modeling ovarian aging with and without such interventions complements and helps guide the clinical approaches that will achieve this goal. REGISTRATION NUMBER Not applicable.

越来越多的女性选择推迟生育，而那些卵巢储备不足表明原发性卵巢功能不全的女性有亚不育和不孕症的风险，也有提前绝经的风险。目前正在开发有望延长女性卵巢功能持续时间的实验策略。一种策略是减缓现有原始卵泡（PFs）的流失速度，另一种策略是增加或“增加”人类卵巢中自体卵泡的数量。在这两种情况下，卵巢功能的持续时间将被延长，更年期将被推迟。这可能伴随着足够质量的成熟卵母细胞的延长生产，以延长生育寿命。目的和原理在这项工作中，我们考虑如何减缓卵巢生理衰老可能改善患者的健康和福祉，并总结目前正在开发的最新方法。然后，我们使用数学模型来确定干预措施是如何定量影响卵巢功能持续时间的。最后，我们考虑了应该达到的疗效基准，以便个体受益，并提出了可用于监测不同患者持续疗效的标准，因为这些策略正在验证中。检索方法汇编了目前估计卵巢储备大小及其与绝经过渡和绝经时间的关系的方法，并确定了建立旨在减缓卵巢储备损失或向患者提供额外卵巢PFs的方法的出版物。我们回顾了目前对女性生殖衰老后果的理解，并比较了可能延长POI风险女性卵巢功能的不同方法。我们还提供了在减缓PF损失或增加PF数量的疗法存在下的原始储备衰减模型。提供了一个交互式在线工具，估计不同的干预措施将如何影响自然人群卵巢功能的持续时间。模型输出显示，减缓PF损失的治疗需要尽早应用，并持续多年，以实现更年期的显著延迟。相反，增加额外的PFs的治疗应该尽可能晚于绝经的开始。结合减缓卵巢储备损失的方法，同时增加（新的）PFs的数量，可能会在延迟更年期方面提供一些额外的好处。至少对一些患者来说，延长卵巢功能，甚至可能延长可生育的寿命即将到来。模拟卵巢衰老有或没有这样的干预补充和帮助指导临床方法，将实现这一目标。注册号不适用。

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引用次数: 0

Defects in mRNA splicing and implications for infertility: a comprehensive review and in silico analysis. mRNA剪接缺陷及其对不孕症的影响：一项全面的综述和计算机分析。

IF 14.8 1区医学 Q1 OBSTETRICS & GYNECOLOGY

Human Reproduction Update

Pub Date : 2025-05-01 DOI: 10.1093/humupd/dmae037

Kuokuo Li, Yuge Chen, Yuying Sheng, Dongdong Tang, Yunxia Cao, Xiaojin He

Background: mRNA splicing is a fundamental process in the reproductive system, playing a pivotal role in reproductive development and endocrine function, and ensuring the proper execution of meiosis, mitosis, and gamete function. Trans-acting factors and cis-acting elements are key players in mRNA splicing whose dysfunction can potentially lead to male and female infertility. Although hundreds of trans-acting factors have been implicated in mRNA splicing, the mechanisms by which these factors influence reproductive processes are fully understood for only a subset. Furthermore, the clinical impact of variations in cis-acting elements on human infertility has not been comprehensively characterized, leading to probable omissions of pathogenic variants in standard genetic analyses.Objective and rationale: This review aimed to summarize our current understanding of the factors involved in mRNA splicing regulation and their association with infertility disorders. We introduced methods for prioritizing and functionally validating splicing variants associated with human infertility. Additionally, we explored corresponding abnormal splicing therapies that could potentially provide insight into treating human infertility.Search methods: Systematic literature searches of human and model organisms were performed in the PubMed database between May 1977 and July 2024. To identify mRNA splicing-related genes and pathogenic variants in infertility, the search terms 'splice', 'splicing', 'variant', and 'mutation' were combined with azoospermia, oligozoospermia, asthenozoospermia, multiple morphological abnormalities of the sperm flagella, acephalic spermatozoa, disorders of sex development, early embryonic arrest, reproductive endocrine disorders, oocyte maturation arrest, premature ovarian failure, primary ovarian insufficiency, zona pellucida, fertilization defects, infertile, fertile, infertility, fertility, reproduction, and reproductive.Outcomes: Our search identified 5014 publications, of which 291 were included in the final analysis. This review provided a comprehensive overview of the biological mechanisms of mRNA splicing, with a focus on the roles of trans-acting factors and cis-acting elements. We highlighted the disruption of 52 trans-acting proteins involved in spliceosome assembly and catalytic activity and recognized splicing regulatory regions and epigenetic regulation associated with infertility. The 73 functionally validated splicing variants in the cis-acting elements of 54 genes have been reported in 20 types of human infertility; 27 of them were located outside the canonical splice sites and potentially overlooked in standard genetic analysis due to likely benign or of uncertain significance. The in silico prediction of splicing can prioritize potential splicing abnormalities that may be true pathogenic mechanisms. We also summarize the methods for pri

背景：mRNA剪接是生殖系统的一个基本过程，在生殖发育和内分泌功能中起关键作用，保证减数分裂、有丝分裂和配子功能的正常进行。反式作用因子和顺式作用因子是mRNA剪接的关键因素，其功能障碍可能导致男性和女性不育。尽管数百个反式作用因子与mRNA剪接有关，但这些因子影响生殖过程的机制仅对其中的一个子集有充分的了解。此外，顺式作用因子变异对人类不孕症的临床影响尚未得到全面表征，导致标准遗传分析中可能遗漏致病变异。目的和理由：本文旨在总结我们目前对mRNA剪接调节相关因素及其与不孕症的关系的了解。我们介绍了与人类不孕症相关的剪接变异的优先排序和功能验证方法。此外，我们还探索了相应的异常剪接疗法，可能为治疗人类不孕症提供潜在的见解。检索方法：1977年5月至2024年7月在PubMed数据库中系统检索人类和模式生物的文献。为了鉴定mRNA剪接相关基因和不孕症的致病变异，将“剪接”、“剪接”、“变异”和“突变”与无精子症、少精子症、弱精子症、精子鞭毛多种形态异常、头性精子、性发育障碍、早期胚胎停止、生殖内分泌障碍、卵母细胞成熟停止、卵巢早衰、原发性卵巢功能不全、透明带、受精缺陷、不育、可育、不育、生育、繁殖、生殖。结果：我们检索了5014篇文献，其中291篇被纳入最终分析。本文综述了mRNA剪接的生物学机制，重点介绍了反式作用因子和顺式作用元件的作用。我们强调了参与剪接体组装和催化活性的52个反式作用蛋白的破坏，以及与不孕症相关的剪接调控区域和表观遗传调控。在20种人类不孕症中，54种基因的顺式作用元件的73个功能验证剪接变异已被报道；其中27个位于典型剪接位点之外，由于可能是良性的或不确定的意义，可能在标准遗传分析中被忽视。剪接的计算机预测可以优先考虑潜在的剪接异常，这可能是真正的致病机制。我们还总结了剪接变异的优先排序方法和功能验证策略，并综述了其他疾病的剪接治疗方法，为异常生殖的治疗提供参考。更广泛的意义：我们对mRNA剪接中的反式作用因子和顺式作用因子的全面综述将进一步促进对生殖调控过程的更彻底的理解，从而改进致病变异的鉴定和人类不孕症的潜在治疗方法。注册号：无。

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引用次数: 0