Human Reproduction Update最新文献

{"title":"A comparison of spermatogenesis between flies and men-conserved processes of male gamete production.","authors":"Brendan J Houston, Lachlan M Cauchi, Jessica E M Dunleavy, Richard Burke, Gary R Hime, Moira K O'Bryan","doi":"10.1093/humupd/dmaf018","DOIUrl":"https://doi.org/10.1093/humupd/dmaf018","url":null,"abstract":"<p><strong>Background: </strong>Spermatogenesis is a dynamic process that involves the co-ordinated development of millions of cells, from stem cells to highly polarized sperm capable of motility and fertility. It is, therefore, not surprising that many thousand genes are required for male fertility. Mutant mouse models are routinely employed to test the function of these genes as well as to validate genetic variants that may be causing human male infertility. The use of mice and other animal models has led to significant knowledge gain regarding the genetic regulation of mammalian male fertility. However, due to the sheer number of genes and genetic variants to be tested these approaches are expensive and time-consuming. We and others have investigated the use of alternate model organisms to expedite validation approaches, including the utility of the fruit fly Drosophila melanogaster.</p><p><strong>Objective and rationale: </strong>This review explores the conserved mechanisms of sperm production between mammals and flies, with a focus on the human setting where possible.</p><p><strong>Search methods: </strong>Studies were identified via PubMed using searches including keywords related to the focus of this review, including human, mammalian, and fly or Drosophila spermatogenesis and male fertility. Follow-up searches including using search terms for specific structures and processes for comparison between species included, but were not limited to, male reproductive tract, spermatogenesis, spermatogonia and stem cell niche, meiosis, spermiogenesis and its sub-processes, and sperm/spermatozoa. No time frame or species restrictions were placed on searches.</p><p><strong>Outcomes: </strong>We identify key phases of spermatogenesis that are highly conserved between humans and flies, including the early germ cell divisions and the ratio of haploid germ cells generated for each spermatogonial stem cell, allowing their use as a model organism to explore such processes. Some processes are moderately well conserved between mammals and flies, including meiosis with the notable absence of 'crossing over' in flies. We also identify some processes that are poorly conserved, such as a divergence in sperm tail accessory structures, for which flies are not likely a suitable model organism to decipher human biology or for mammals broadly. Examples of where the fly has been or could be useful to study mammalian gene function in male fertility have also been described.</p><p><strong>Wider implications: </strong>Drosophila melanogaster is undoubtedly a useful model organism for studying a wide range of human diseases with genetic origins, including male infertility. Both humans and flies possess a pair of testes with the primary role of generating sperm. The formation of cysts in Drosophila testes allows germ cells to constantly proliferate and stay synchronized at the respective maturation phase, as is the case for humans. While both organisms use a method of sper","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":""},"PeriodicalIF":16.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144849686","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":"BMI in children aged 1-18 years conceived after ART with fresh and frozen embryo transfer: a systematic review and meta-analyses.","authors":"Louise Laub Asserhøj,Liv Rytter Kielstrup,Christine Louise Grønholdt,Anna Sophie Lebech Kjaer,Nathalie Bülow,Rikke Beck Jensen,Anja Pinborg","doi":"10.1093/humupd/dmaf017","DOIUrl":"https://doi.org/10.1093/humupd/dmaf017","url":null,"abstract":"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 ","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"95 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144824855","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":"Embryo metabolism as a novel non-invasive preimplantation test: nutrients turn over and metabolomic analysis of human spent embryo culture media (SECM)","authors":"AliReza Alizadeh Moghadam Masouleh, Poopak Eftekhari-Yazdi, Amin Ebrahimi Sadrabadi, Reza Jafarzadeh Esfehani, Monica Tobler, Sven Schuchardt, Luca Gianaroli, Andreas Schmutzler","doi":"10.1093/humupd/dmaf015","DOIUrl":"https://doi.org/10.1093/humupd/dmaf015","url":null,"abstract":"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","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"25 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677667","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":"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":"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}

{"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":"10.1093/humupd/dmaf005","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective and rationale: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Search methods: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Outcomes: &lt;/strong&gt;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":"333-360"},"PeriodicalIF":14.8,"publicationDate":"2025-07-01","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":"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":"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":"269-306"},"PeriodicalIF":14.8,"publicationDate":"2025-07-01","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":"Building a human pluripotent stem cell-based gonadal niche: improving in vitro systems with in vivo insights","authors":"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","doi":"10.1093/humupd/dmaf012","DOIUrl":"https://doi.org/10.1093/humupd/dmaf012","url":null,"abstract":"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","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"16 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513154","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":"Protein O-GlcNAcylation in reproductive biology and the impact of metabolic disease","authors":"Atalie L Scrivener, Melissa Westwood, Peter T Ruane, John D Aplin","doi":"10.1093/humupd/dmaf013","DOIUrl":"https://doi.org/10.1093/humupd/dmaf013","url":null,"abstract":"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 ","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"17 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500722","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":"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}

{"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}