Human Reproduction Update最新文献

{"title":"Modeling the extension of ovarian function after therapeutic targeting of the primordial follicle reserve","authors":"Joshua Johnson, John W Emerson, Annika Smith, Kayla Medina, Evelyn E Telfer, Richard A Anderson, Sean D Lawley","doi":"10.1093/humupd/dmaf009","DOIUrl":"https://doi.org/10.1093/humupd/dmaf009","url":null,"abstract":"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.","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"35 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910216","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}

{"title":"Moving toward totipotency: the molecular and cellular features of totipotent and naive pluripotent stem cells.","authors":"Lingyue Hua,Yuyang Peng,Liying Yan,Peng Yuan,Jie Qiao","doi":"10.1093/humupd/dmaf006","DOIUrl":"https://doi.org/10.1093/humupd/dmaf006","url":null,"abstract":"BACKGROUNDDissecting the key molecular mechanism of embryonic development provides novel insights into embryogenesis and potential intervention strategies for clinical practices. However, the ability to study the molecular mechanisms of early embryo development in humans, such as zygotic genome activation and lineage segregation, is meaningfully constrained by methodological limitations and ethical concerns. Totipotent stem cells have an extended developmental potential to differentiate into embryonic and extraembryonic tissues, providing a suitable model for studying early embryo development. Recently, a series of ground-breaking results on stem cells have identified totipotent-like cells or induced pluripotent stem cells into totipotent-like cells.OBJECTIVE AND RATIONALEThis review followed the PRISMA guidelines, surveys the current works of literature on totipotent, naive, and formative pluripotent stem cells, introduces the molecular and biological characteristics of those stem cells, and gives advice for future research.SEARCH METHODSThe search method employed the terms 'totipotent' OR 'naive pluripotent stem cell' OR 'formative pluripotent stem cell' for unfiltered search on PubMed, Web of Science, and Cochrane Library. Papers included were those with information on totipotent stem cells, naive pluripotent stem cells, or formative pluripotent stem cells until June 2024 and were published in the English language. Articles that have no relevance to stem cells, or totipotent, naive pluripotent, or formative pluripotent cells were excluded.OUTCOMESThere were 152 records included in this review. These publications were divided into four groups according to the species of the cells included in the studies: 67 human stem cell studies, 70 mouse stem cell studies, 9 porcine stem cell studies, and 6 cynomolgus stem cell studies. Naive pluripotent stem cell models have been established in other species such as porcine and cynomolgus. Human and mouse totipotent stem cells, e.g. human 8-cell-like cells, human totipotent blastomere-like cells, and mouse 2-cell-like cells, have been successfully established and exhibit high developmental potency for both embryonic and extraembryonic contributions. However, the observed discrepancies between these cells and real embryos in terms of epigenetics and transcription suggest that further research is warranted. Our results systematically reviewed the established methods, molecular characteristics, and developmental potency of different naive, formative pluripotent, and totipotent stem cells. Furthermore, we provide a parallel comparison between animal and human models, and offer recommendations for future applications to advance early embryo research and assisted reproduction technologies.WIDER IMPLICATIONSTotipotent cell models provide a valuable resource to understand the underlying mechanisms of embryo development and forge new paths toward future treatment of infertility and regenerative medicine. However, cu","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"19 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889328","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}

{"title":"Remembering Professor John Collins.","authors":"","doi":"10.1093/humupd/dmaf008","DOIUrl":"https://doi.org/10.1093/humupd/dmaf008","url":null,"abstract":"","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744452","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}

{"title":"RNA modifications in female reproductive physiology and disease: emerging roles and clinical implications.","authors":"Yu Xiang, Hsun-Ming Chang, Peter C K Leung, Long Bai, Yimin Zhu","doi":"10.1093/humupd/dmaf005","DOIUrl":"https://doi.org/10.1093/humupd/dmaf005","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective and rationale: </strong>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.</p><p><strong>Search methods: </strong>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.</p><p><strong>Outcomes: </strong>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","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733287","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}

{"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":"https://doi.org/10.1093/humupd/dmaf007","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective and rationale: </strong>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.</p><p><strong>Search methods: </strong>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.</p><p><strong>Outcomes: </strong>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.</p><p><strong>Wider implications: </strong>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.</p><p><strong>Registration number: </strong>N/A.</p>","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and reproductive strategies to prevent mitochondrial diseases.","authors":"Noemi Castelluccio, Katharina Spath, Danyang Li, Irenaeus F M De Coo, Lyndsey Butterworth, Dagan Wells, Heidi Mertes, Joanna Poulton, Björn Heindryckx","doi":"10.1093/humupd/dmaf004","DOIUrl":"https://doi.org/10.1093/humupd/dmaf004","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631088","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}

{"title":"Molecular insights into sperm head shaping and its role in human male fertility","authors":"Jiaxin He, Xinle Lin, Chen Tan, Yong Li, Lilan Su, Ge Lin, Yue-Qiu Tan, Chaofeng Tu","doi":"10.1093/humupd/dmaf003","DOIUrl":"https://doi.org/10.1093/humupd/dmaf003","url":null,"abstract":"BACKGROUND Sperm head shaping, controlled by the acrosome-acroplaxome-manchette complex, represents a significant morphological change during spermiogenesis and involves numerous proteins expressed in a spatially and temporally specific manner. Defects in sperm head shaping frequently lead to teratozoospermia concomitant with oligozoospermia and asthenozoospermia, but the pathogenic mechanism underlying sperm head shaping, and its role in male infertility, remain poorly understood. OBJECTIVE AND RATIONALE This review aims to summarize the mechanism underlying sperm head shaping, reveal the relationship between gene defects associated with sperm head shaping and male infertility in humans and mice, and explore potential clinical improvements in ICSI treatment. SEARCH METHODS We searched the PubMed database for articles published in English using the keyword ‘sperm head shaping’ in combination with the following terms: ‘acrosome formation’, ‘proacrosomal vesicles (PAVs)’, ‘manchette’, ‘perinuclear theca (PT)’, ‘chromatin condensation’, ‘linker of nucleoskeleton and cytoskeleton (LINC) complex’, ‘histone-to-protamine (HTP) transition’, ‘male infertility’, ‘ICSI’, and ‘artificial oocyte activation (AOA)’. The selected publications until 1 August 2024 were critically summarized, integrated, and thoroughly discussed, and the irrelevant literature were excluded. OUTCOMES A total of 6823 records were retrieved. After careful screening, integrating relevant literature, and excluding articles unrelated to the topic of this review, 240 articles were ultimately included in the analysis. Firstly, we reviewed the important molecular events and structures integral to sperm head shaping, including PAV formation to fusion, acrosome attachment to the nucleus, structure and function of the manchette, PT, chromatin condensation, and HTP transition. Then, we set forth human male infertility associated with sperm head shaping and identified genes related to sperm head shaping resulting in teratozoospermia concomitant with oligozoospermia and asthenozoospermia. Finally, we summarized the outcomes of ICSI in cases of male infertility resulting from mutations in the genes associated with sperm head shaping, as well as the ICSI outcomes through AOA for infertile men with impaired sperm head. WIDER IMPLICATIONS Understanding the molecular mechanisms of sperm head shaping and its relationship with human male infertility holds profound clinical implications, which may contribute to risk prediction, genetic diagnosis, and the potential treatment of human male infertility.","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"12 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546155","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}

{"title":"A systematic review and meta-analysis of double trophectoderm biopsy and/or cryopreservation in PGT: balancing the need for a diagnosis against the risk of harm.","authors":"Letizia Li Piani, Pasquale Petrone, Mariafrancesca Brutto, Anick De Vos, Annelore Van Der Kelen, Alberto Vaiarelli, Laura Rienzi, Alessandro Conforti, Danilo Cimadomo, Willem Verpoest","doi":"10.1093/humupd/dmae031","DOIUrl":"10.1093/humupd/dmae031","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;To prevent the transfer of embryos affected by monogenic conditions and/or chromosomal defects, preimplantation genetic testing (PGT) requires trophectoderm biopsy and cryopreservation. In 2-6% of biopsies, the diagnosis may be inconclusive due to DNA amplification failure or low-quality results. In these cases, a round of re-warming, re-biopsy, and re-cryopreservation is required to obtain a genetic diagnosis. In other cases, when the IVF centre starts providing PGT and/or when the patients develop an indication because of multiple failures, miscarriages or the birth of an affected child after IVF, cryopreserved untested embryos may be warmed, biopsied, and then re-vitrified. However, it is still unclear whether multiple manipulations may reduce reproductive outcomes after PGT.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective and rationale: &lt;/strong&gt;This study aimed at conducting a systematic review to investigate the available evidence on the safety of double biopsy and/or double cryopreservation-warming and provide recommendations in this regard. We performed meta-analyses of the differences in the reproductive outcomes (live birth per embryo transfer [LBR per ET], clinical pregnancy rate per ET [CPR per ET], and miscarriage rate per clinical pregnancy [MR per CP]) in double cryopreservation and single biopsy (CBC) or double biopsy and double cryopreservation (BCBC) flows vs the control single biopsy and single cryopreservation (BC) flow. Cryo-survival rates before ET and gestational and perinatal outcomes were also reported.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Search methods: &lt;/strong&gt;PRISMA guidelines were followed to gather all available information from the literature (PubMed, Scopus, and Embase). We used Medical Subject Headings (MeSH) terms and a list of specific keywords relevant for the study question. We searched for original studies in humans, published in peer-reviewed journals in English up to April 2024. Four independent authors assessed the articles for inclusion. One included paper was retrieved from another source.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Outcomes: &lt;/strong&gt;A total of 4219 records were identified, and 10 studies were included in the meta-analysis. Certainty of evidence level ranged from low to moderate. Both the CBC and BCBC groups showed reduced reproductive outcomes compared to the control (BC). Specifically, live birth rates per embryo transfer were lower in the CBC group (OR: 0.56, 95% CI: 0.38-0.81, I2 = 58%; six studies) and the BCBC group (OR: 0.51, 95% CI: 0.34-0.77, I2 = 24%; six studies). CPR per ET were also lower in the CBC group (OR: 0.68, 95% CI: 0.51-0.92, I2 = 57%; seven studies) and the BCBC group (OR: 0.60, 95% CI: 0.46-0.78, I2 = 0%; seven studies). Additionally, MR per CPs were higher in both the CBC group (OR: 1.68, 95% CI: 1.02-2.77, I2 = 50%; seven studies) and the BCBC group (OR: 2.08, 95% CI: 1.13-3.83, I2 = 28%; seven studies). Cryo-survival as well as gestational and perinatal outcomes were within the expected norms in the st","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":"102-115"},"PeriodicalIF":14.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640315","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}

{"title":"Harnessing omics data for drug discovery and development in ovarian aging","authors":"Fengyu Zhang, Ming Zhu, Yi Chen, Guiquan Wang, Haiyan Yang, Xinmei Lu, Yan Li, Hsun-Ming Chang, Yang Wu, Yunlong Ma, Shuai Yuan, Wencheng Zhu, Xi Dong, Yue Zhao, Yang Yu, Jia Wang, Liangshan Mu","doi":"10.1093/humupd/dmaf002","DOIUrl":"https://doi.org/10.1093/humupd/dmaf002","url":null,"abstract":"BACKGROUND Ovarian aging occurs earlier than the aging of many other organs and has a lasting impact on women’s overall health and well-being. However, effective interventions to slow ovarian aging remain limited, primarily due to an incomplete understanding of the underlying molecular mechanisms and drug targets. Recent advances in omics data resources, combined with innovative computational tools, are offering deeper insight into the molecular complexities of ovarian aging, paving the way for new opportunities in drug discovery and development. OBJECTIVE AND RATIONALE This review aims to synthesize the expanding multi-omics data, spanning genome, transcriptome, proteome, metabolome, and microbiome, related to ovarian aging, from both tissue-level and single-cell perspectives. We will specially explore how the analysis of these emerging omics datasets can be leveraged to identify novel drug targets and guide therapeutic strategies for slowing and reversing ovarian aging. SEARCH METHODS We conducted a comprehensive literature search in the PubMed database using a range of relevant keywords: ovarian aging, age at natural menopause, premature ovarian insufficiency (POI), diminished ovarian reserve (DOR), genomics, transcriptomics, epigenomics, DNA methylation, RNA modification, histone modification, proteomics, metabolomics, lipidomics, microbiome, single-cell, genome-wide association studies (GWAS), whole-exome sequencing, phenome-wide association studies (PheWAS), Mendelian randomization (MR), epigenetic target, drug target, machine learning, artificial intelligence (AI), deep learning, and multi-omics. The search was restricted to English-language articles published up to September 2024. OUTCOMES Multi-omics studies have uncovered key mechanisms driving ovarian aging, including DNA damage and repair deficiencies, inflammatory and immune responses, mitochondrial dysfunction, and cell death. By integrating multi-omics data, researchers can identify critical regulatory factors and mechanisms across various biological levels, leading to the discovery of potential drug targets. Notable examples include genetic targets such as BRCA2 and TERT, epigenetic targets like Tet and FTO, metabolic targets such as sirtuins and CD38+, protein targets like BIN2 and PDGF-BB, and transcription factors such as FOXP1. WIDER IMPLICATIONS The advent of cutting-edge omics technologies, especially single-cell technologies and spatial transcriptomics, has provided valuable insights for guiding treatment decisions and has become a powerful tool in drug discovery aimed at mitigating or reversing ovarian aging. As technology advances, the integration of single-cell multi-omics data with AI models holds the potential to more accurately predict candidate drug targets. This convergence offers promising new avenues for personalized medicine and precision therapies, paving the way for tailored interventions in ovarian aging. REGISTRATION NUMBER Not applicable.","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"183 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462819","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}

{"title":"Defects in mRNA splicing and implications for infertility: a comprehensive review and in silico analysis.","authors":"Kuokuo Li, Yuge Chen, Yuying Sheng, Dongdong Tang, Yunxia Cao, Xiaojin He","doi":"10.1093/humupd/dmae037","DOIUrl":"https://doi.org/10.1093/humupd/dmae037","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective and rationale: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Search methods: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Outcomes: &lt;/strong&gt;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","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425790","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}