Hum. Reprod. Update [JOURNAL]
Sun
200 papers
Moving toward totipotency: the molecular and cellular features of totipotent and naive pluripotent stem cells.
Hua L, Peng Y, Yan L … +2 more , Yuan P, Qiao J
Hum Reprod Update · 2025 Jul · PMID 40299455 · Publisher ↗
BACKGROUND: Dissecting 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 molec...
BACKGROUND: Dissecting 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 RATIONALE: This 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 METHODS: The 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. OUTCOMES: There 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 IMPLICATIONS: Totipotent 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, current in vitro cell models exhibit epigenetic and transcriptional differences from in vivo embryos, and many cell models are unstable across passages, thus imperfectly recapitulating embryonic development. In this regard, standardizing and expanding current research on totipotent stem cell models are essential to enhance our capability to resemble and decipher embryogenesis.
Remembering Professor John Collins.
Human Reproduction Update Editorial Team
Hum Reprod Update · 2025 May · PMID 40155322 · Publisher ↗
Abstract loading — click title to view on PubMed.
RNA modifications in female reproductive physiology and disease: emerging roles and clinical implications.
Xiang Y, Chang HM, Leung PCK … +2 more , Bai L, Zhu Y
Hum Reprod Update · 2025 Jul · PMID 40152541 · Publisher ↗
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...
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. Dysregulation of RNA modifications may exacerbate infertility-related conditions, such as POI, PCOS, and endometriosis. Although clinical investigations are still in their early stages, RNA modifications show great promise as diagnostic biomarkers and therapeutic targets, with the potential to improve fertility and reproductive health outcomes. WIDER IMPLICATIONS: This review explores a relatively underexamined area of epitranscriptomic research in female reproduction, offering the potential to significantly advance our understanding of reproductive biology. It underscores the clinical relevance of RNA modifications in infertility-related disorders and identifies potential biomarkers, as well as RMP-targeted therapies, that could shape future clinical decision-making and personalized treatments. These insights are crucial for reproductive clinicians and embryologists, presenting new avenues for diagnosis and therapeutic interventions in reproductive medicine. REGISTRATION NUMBER: N/A.
Ethical considerations for advancing research using organoid models derived from the placenta.
Schäffers OJM, Gribnau J, van Rijn BB … +1 more , Bunnik EM
Hum Reprod Update · 2025 Jul · PMID 40096642 · Full text
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: t...
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.
Genetic and reproductive strategies to prevent mitochondrial diseases.
Castelluccio N, Spath K, Li D … +6 more , De Coo IFM, Butterworth L, Wells D, Mertes H, Poulton J, Heindryckx B
Hum Reprod Update · 2025 Jul · PMID 40085924 · Publisher ↗
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 hete...
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.
Molecular insights into sperm head shaping and its role in human male fertility.
He J, Lin X, Tan C … +5 more , Li Y, Su L, Lin G, Tan YQ, Tu C
Hum Reprod Update · 2025 Jul · PMID 40037590 · Publisher ↗
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 te...
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.
Harnessing omics data for drug discovery and development in ovarian aging.
Zhang F, Zhu M, Chen Y … +14 more , Wang G, Yang H, Lu X, Li Y, Chang HM, Wu Y, Ma Y, Yuan S, Zhu W, Dong X, Zhao Y, Yu Y, Wang J, Mu L
Hum Reprod Update · 2025 May · PMID 39977580 · Publisher ↗
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, prima...
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.
Defects in mRNA splicing and implications for infertility: a comprehensive review and in silico analysis.
Li K, Chen Y, Sheng Y … +3 more , Tang D, Cao Y, He X
Hum Reprod Update · 2025 May · PMID 39953708 · Publisher ↗
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...
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 prioritizing splicing variants and strategies for functional validation and review splicing therapy approaches for other diseases, providing a reference for abnormal reproduction treatment. WIDER IMPLICATIONS: Our comprehensive review of trans-acting factors and cis-acting elements in mRNA splicing will further promote a more thorough understanding of reproductive regulatory processes, leading to improved pathogenic variant identification and potential treatments for human infertility. REGISTRATION NUMBER: N/A.
Parental conditions, modifiable lifestyle factors, and first trimester growth and development: a systematic review.
Graafland N, Rousian M, de Zwart ML … +3 more , Steegers-Theunissen RPM, Steegers EAP, Posthumus AG
Hum Reprod Update · 2025 May · PMID 39953705 · Full text
INTRODUCTION: The embryonic period in human development is the foundation of lifelong and even transgenerational health. Although previously believed to be uniform, there is increasing evidence that embryonic growth is i...
INTRODUCTION: The embryonic period in human development is the foundation of lifelong and even transgenerational health. Although previously believed to be uniform, there is increasing evidence that embryonic growth is influenced by the conditions and modifiable lifestyle factors of parents in the periconception period. In ongoing pregnancies, a delay in growth in the first trimester has been associated with miscarriages, malformations, low birth weight, preterm birth, and small for gestational age at birth. This has stimulated research on factors associated with variations in human embryonic growth. However, there is still no consensus on which parental conditions and modifiable lifestyle factors affect first trimester growth and development and to what extent. OBJECTIVE AND RATIONALE: A systematic review was undertaken according to PRISMA guidelines to provide an overview of literature on the associations between parental conditions and lifestyle factors in the periconception period and first trimester growth and development, with an aim to identify existing evidence gaps. SEARCH METHODS: A systematic search of the literature concerning articles on embryonic growth and lifestyle factors published between 1900 and 2024 was performed in six electronic databases. Studies were eligible for inclusion if they reported on the association between periconception parental conditions and/or modifiable lifestyle factors and an in vivo measure of first trimester growth or development (i.e. crown-rump length, embryonic volume and/or Carnegie stage) between 6 + 0 and 13 + 6 weeks gestational age in singleton pregnancies. Parental conditions and modifiable lifestyle factors were defined as ex utero determinants divided into characteristics (age, ethnicity, BMI, blood pressure), lifestyle risk factors (caffeine intake, alcohol consumption, and smoking), nutrition (dietary patterns and food groups), vitamins (vitamin B9/B11, vitamin B12, vitamin D, and supplements), and the ambient environment (air pollution, noise exposure, and neighborhood deprivation). Risk of bias of the included studies was assessed using the Newcastle-Ottawa Scale. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach was used to assess the evidence level of the studies included in the review. OUTCOMES: A total of 4708 unique records were identified, of which 34 studies were included in the systematic review. The majority of studies investigating smoking and BMI suggested an inverse association with embryonic growth and development, while maternal age, folic acid supplement use, and folate levels were positively associated with embryonic growth and development. Studies on blood pressure, ethnicity, vitamin B12, vitamin D, alcohol consumption, caffeine consumption, and ambient environment were too limited to conclude an association with embryonic growth and development. Reported effect estimates were heterogeneous for all determinants. Based on the GRADE criteria, the quality of evidence for the results of this review was considered low or very low. WIDER IMPLICATIONS: Some periconceptional parental conditions and modifiable lifestyle factors are associated with first trimester growth and development and should be considered in clinical preconception care. To advance our understanding and establish strong, high-level evidence-based recommendations, future research should prioritize methodological quality and focus on lifestyle intervention studies. REGISTRATION NUMBER: PROSPERO (ID: CRD42021240618).
Fertility in transgender and gender diverse people: systematic review of the effects of gender-affirming hormones on reproductive organs and fertility.
De Roo C, Schneider F, Stolk THR … +3 more , van Vugt WLJ, Stoop D, van Mello NM
Hum Reprod Update · 2025 May · PMID 39854640 · Publisher ↗
BACKGROUND: Transgender and gender diverse (TGD) people seek gender-affirming care at any age to manage gender identities or expressions that differ from their birth gender. Gender-affirming hormone treatment (GAHT) and...
BACKGROUND: Transgender and gender diverse (TGD) people seek gender-affirming care at any age to manage gender identities or expressions that differ from their birth gender. Gender-affirming hormone treatment (GAHT) and gender-affirming surgery may alter reproductive function and/or anatomy, limiting future reproductive options to varying degrees, if individuals desire to either give birth or become a biological parent. OBJECTIVE AND RATIONALE: TGD people increasingly pursue help for their reproductive questions, including fertility, fertility preservation, active desire for children, and future options. Their specific needs certainly require more insight into the effects of GAHT on gonads, gametes, and fertility. This systematic review aims to provide an overview of the current knowledge on the impact of GAHT on gonads, gametes, fertility, fertility preservation techniques, and outcomes. SEARCH METHODS: This review was registered in the PROSPERO registry under number CRD42024516133. A literature search (in PubMed, Embase, and Web of Science) was performed with a medical information specialist until 15 November 2024. OUTCOMES: In all TGD people using GAHT, histological changes have been reported.Using testosterone GAHT, ovarian cortical and stromal changes were reported by various studies. In most studies, persistent activity in folliculogenesis can be concluded based on the descriptions of the follicle count, distribution, and oocyte retrieval yield. However, there may be a negative effect on the fertilization rate in the presence of testosterone. Reports of successful ovarian stimulation, fertilization, pregnancies, and live births have been published, describing cases with and without testosterone discontinuation.After using oestrogen GAHT, testes are reported to be more atrophic, including smaller seminiferous tubules with heavy hyalinization and fibrosis. Spermatogenic levels varied widely from complete spermatogenesis to meiotic arrest with spermatids, to spermatogonial arrest, Sertoli cells only, or even tubular shadows. Oestrogen and anti-androgen treatment causes higher proportions of sperm abnormalities (i.e. low total sperm count, low sperm concentration, poor sperm motility) or azoospermia. However, after cessation, this may be restored. WIDER IMPLICATIONS: Although knowledge of the effect of GAHT is growing, blind spots remain to be uncovered. Therefore, additional research in this specific population is needed, preferably comparing outcomes before and after the start of GAHT. This may help to reveal the pure impact of GAHT on reproductive functioning. Research suggestions also include investigations into the reversibility of the GAHT effect, especially for those who start transition at a young age. Looking carefully at the presented data on GAHT effects on gonads and gametes, the correct advice is to assess and reassess reproductive wishes and preferences repeatedly, and also to explore individual fertility preservation needs during gender-affirming treatment, given the expanding knowledge and therapy opportunities. Finally, concerns regarding long-term health outcomes and quality of life of children born by the use of gametes preserved after exposure to GAHT require prospective follow-up studies.
Development and validation of a gonadotropin dose selection model for optimized ovarian stimulation in IVF/ICSI: an individual participant data meta-analysis.
Schouten N, Wang R, Torrance H … +20 more , Van Tilborg T, Bastu E, Bergh C, D'Hooghe T, Friis Petersen J, Jayaprakasan K, Khalaf Y, Klinkert E, La Marca A, Vuong L, Lapensée L, Lensen S, Magnusson Å, Allegra A, Nyboe Andersen A, Oudshoorn S, Popovic-Todorovic B, Mol BW, Eijkemans M, Broekmans F
Hum Reprod Update · 2025 Mar · PMID 39707165 · Full text
BACKGROUND: The ovarian response to gonadotropin stimulation varies widely among women, and could impact the probability of live birth as well as treatment risks. Many studies have evaluated the impact of different gonad...
BACKGROUND: The ovarian response to gonadotropin stimulation varies widely among women, and could impact the probability of live birth as well as treatment risks. Many studies have evaluated the impact of different gonadotropin starting doses, mainly based on predictive variables like ovarian reserve tests (ORT) including anti-Müllerian hormone (AMH), antral follicle count (AFC), and basal follicle-stimulating hormone (bFSH). A Cochrane systematic review revealed that individualizing the gonadotropin starting dose does not affect efficacy in terms of ongoing pregnancy/live birth rates, but may reduce treatment risks such as the development of ovarian hyperstimulation syndrome (OHSS). An individual patient data meta-analysis (IPD-MA) offers a unique opportunity to develop and validate a universal prediction model to help choose the optimal gonadotropin starting dose to minimize treatment risks without affecting efficacy. OBJECTIVE AND RATIONALE: The objective of this IPD-MA is to develop and validate a gonadotropin dose-selection model to guide the choice of a gonadotropin starting dose in IVF/ICSI, with the purpose of minimizing treatment risks without compromising live birth rates. SEARCH METHODS: Electronic databases including MEDLINE, EMBASE, and CRSO were searched to identify eligible studies. The last search was performed on 13 July 2022. Randomized controlled trials (RCTs) were included if they compared different doses of gonadotropins in women undergoing IVF/ICSI, presented at least one type of ORT, and reported on live birth or ongoing pregnancy. Authors of eligible studies were contacted to share their individual participant data (IPD). IPD and information within publications were used to determine the risk of bias. Generalized linear mixed multilevel models were applied for predictor selection and model development. OUTCOMES: A total of 14 RCTs with data of 3455 participants were included. After extensive modeling, women aged 39 years and over were excluded, which resulted in the definitive inclusion of 2907 women. The optimal prediction model for live birth included six predictors: age, gonadotropin starting dose, body mass index, AFC, IVF/ICSI, and AMH. This model had an area under the curve (AUC) of 0.557 (95% confidence interval (CI) from 0.536 to 0.577). The clinically feasible live birth model included age, starting dose, and AMH and had an AUC of 0.554 (95% CI from 0.530 to 0.578). Two models were selected as the optimal model for combined treatment risk, as their performance was equal. One included age, starting dose, AMH, and bFSH; the other also included gonadotropin-releasing hormone (GnRH) analog. The AUCs for both models were 0.769 (95% CI from 0.729 to 0.809). The clinically feasible model for combined treatment risk included age, starting dose, AMH, and GnRH analog, and had an AUC of 0.748 (95% CI from 0.709 to 0.787). WIDER IMPLICATIONS: The aim of this study was to create a model including patient characteristics whereby gonadotropin starting dose was predictive of both live birth and treatment risks. The model performed poorly on predicting live birth by modifying the FSH starting dose. On the contrary, predicting treatment risks in terms of OHSS occurrence and management by modifying the gonadotropin starting dose was adequate. This dose-selection model, consisting of easily obtainable patient characteristics, aids in the choice of the optimal gonadotropin starting dose for each individual patient to lower treatment risks and potentially reduce treatment costs.
The epigenetic approach of varicocele: a focus on sperm DNA and m6A-RNA methylation.
Naderi N, Tavalaee M, Nasr-Esfahani MH
Hum Reprod Update · 2025 Mar · PMID 39673728 · Publisher ↗
BACKGROUND: Varicocele is an abnormal dilation and torsion of the pampiniform venous plexus in the scrotum due to venous reflux, primarily affecting the left side. It affects 15% of men and is a prevalent contributor to...
BACKGROUND: Varicocele is an abnormal dilation and torsion of the pampiniform venous plexus in the scrotum due to venous reflux, primarily affecting the left side. It affects 15% of men and is a prevalent contributor to male infertility. Varicocele is a complex disorder influenced by genetic, epigenetic, and environmental factors. Epigenetic modifications, which regulate genome activity independently of DNA or RNA sequences, may contribute to the development and severity of varicocele. These include DNA methylation, histone modifications, and RNA modifications like N6-methyladenosine (m6A). Irregularities in DNA and m6A-RNA methylation during spermatogenesis can cause gene expression abnormalities, DNA damage, and decreased fertility in varicocele patients. OBJECTIVE AND RATIONALE: The review aims to comprehensively understand the underlying mechanisms of varicocele, a condition that can significantly impact male fertility. By exploring the role of methylation modifications, specifically DNA and m6A-RNA methylation, the review aims to synthesize evidence from basic, preclinical, and clinical research to expand the existing knowledge on this subject. The ultimate goal is to identify potential avenues for developing targeted treatments that can effectively improve varicocele and ultimately increase sperm quality in affected individuals. SEARCH METHODS: A thorough investigation of the scientific literature was conducted through searches in PubMed, Google Scholar, and Science Direct databases until May 2024. All studies investigating the relationship between DNA and m6A-RNA methylation and male infertility, particularly varicocele were reviewed, and the most pertinent reports were included. Keywords such as varicocele, epigenetics, DNA methylation, m6A-RNA methylation, hypermethylation, hypomethylation, spermatozoa, semen parameters, spermatogenesis, and male infertility were used during the literature search, either individually or in combination. OUTCOMES: The sperm has a specialized morphology essential for successful fertilization, and its epigenome is unique, potentially playing a key role in embryogenesis. Sperm DNA and RNA methylation, major epigenetic marks, regulate the expression of testicular genes crucial for normal spermatogenesis. This review explores the role of DNA and m6A-RNA methylation, in responding to oxidative stress and how various nutrients influence their function in varicocele condition. Evidence suggests a potential link between varicocele and aberrant DNA/m6A-RNA methylation patterns, especially hypomethylation, but the body of evidence is still limited. Further studies are needed to understand how abnormal expression of DNA/m6A-RNA methylation regulators affects testicular gene expression. Thus, analyzing sperm DNA 5mC/5hmC levels and m6A-RNA methylation regulators may reveal spermatogenesis defects and predict reproductive outcomes. WIDER IMPLICATIONS: Nutri-epigenomics is an emerging field that could enhance the knowledge and management of diseases with unpredictable risks and consequences, even among individuals with similar lifestyles, by elucidating the influence of nutrition on DNA/m6A-RNA methylation through one-carbon metabolism. However, the importance of one-carbon metabolism to varicocele is not well-recognized. Health status and diet influence one-carbon metabolism and its associated DNA/m6A-RNA methylation modification. Future research should identify optimal methylation patterns that promote health and investigate modulating one-carbon metabolism to achieve this. Furthermore, additional studies are necessary to develop personalized dietary strategies through clinical and longitudinal research. However, a research gap exists on dietary interventions utilizing epigenetics as a therapeutic method for treating varicocele. REGISTRATION NUMBER: Not applicable.
The modeling of human implantation and early placentation: achievements and perspectives.
Dimova T, Alexandrova M, Vangelov I … +2 more , You Y, Mor G
Hum Reprod Update · 2025 Mar · PMID 39673726 · Full text
BACKGROUND: Successful implantation is a critical step for embryo survival. The major losses in natural and assisted human reproduction appeared to occur during the peri-implantation period. Because of ethical constraint...
BACKGROUND: Successful implantation is a critical step for embryo survival. The major losses in natural and assisted human reproduction appeared to occur during the peri-implantation period. Because of ethical constraints, the fascinating maternal-fetal crosstalk during human implantation is difficult to study and thus, the possibility for clinical intervention is still limited. OBJECTIVE AND RATIONALE: This review highlights some features of human implantation as a unique, ineffective and difficult-to-model process and summarizes the pros and cons of the most used in vivo, ex vivo and in vitro models. We point out the variety of cell line-derived models and how these data are corroborated by well-defined primary cells of the same nature. Important aspects related to the handling, standardization, validation, and modus operandi of the advanced 3D in vitro models are widely discussed. Special attention is paid to blastocyst-like models recapitulating the hybrid phenotype and HLA profile of extravillous trophoblasts, which are a unique yet poorly understood population with a major role in the successful implantation and immune mother-embryo recognition. Despite raising new ethical dilemmas, extended embryo cultures and synthetic embryo models are also in the scope of our review. SEARCH METHODS: We searched the electronic database PubMed from inception until March 2024 by using a multi-stage search strategy of MeSH terms and keywords. In addition, we conducted a forward and backward reference search of authors mentioned in selected articles. OUTCOMES: Primates and rodents are valuable in vivo models for human implantation research. However, the deep interstitial, glandular, and endovascular invasion accompanied by a range of human-specific factors responsible for the survival of the fetus determines the uniqueness of the human implantation and limits the cross-species extrapolation of the data. The ex vivo models are short-term cultures, not relevant to the period of implantation, and difficult to standardize. Moreover, the access to tissues from elective terminations of pregnancy raises ethical and legal concerns. Easy-to-culture cancer cell lines have many limitations such as being prone to spontaneous transformation and lacking decent tissue characteristics. The replacement of the original human explants, primary cells or cancer cell lines with cultures of immortalized cell lines with preserved stem cell characteristics appears to be superior for in vitro modeling of human implantation and early placentation. Remarkable advances in our understanding of the peri-implantation stages have also been made by advanced three dimensional (3D) models i.e. spheroids, organoids, and assembloids, as placental and endometrial surrogates. Much work remains to be done for the optimization and standardization of these integrated and complex models. The inclusion of immune components in these models would be an asset to delineate mechanisms of immune tolerance. Stem cell-based embryo-like models and surplus IVF embryos for research bring intriguing possibilities and are thought to be the trend for the next decade for in vitro modeling of human implantation and early embryogenesis. Along with this research, new ethical dilemmas such as the moral status of the human embryo and the potential exploitation of women consenting to donate their spare embryos have emerged. The careful appraisal and development of national legal and ethical frameworks are crucial for better regulation of studies using human embryos and embryoids to reach the potential benefits for human reproduction. WIDER IMPLICATIONS: We believe that our data provide a systematization of the available information on the modeling of human implantation and early placentation and will facilitate further research in this field. A strict classification of the advanced 3D models with their pros, cons, applicability, and availability would help improve the research quality to provide reliable outputs.
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.
Li Piani L, Petrone P, Brutto M … +7 more , De Vos A, Van Der Kelen A, Vaiarelli A, Rienzi L, Conforti A, Cimadomo D, Verpoest W
Hum Reprod Update · 2025 Mar · PMID 39546333 · Publisher ↗
BACKGROUND: 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, t...
BACKGROUND: 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. OBJECTIVE AND RATIONALE: 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. SEARCH METHODS: 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. OUTCOMES: 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 studies reporting them. WIDER IMPLICATIONS: Improved genetic technologies, standardization of laboratory protocols, operators' proficiency with biopsy and cryopreservation, and continuous monitoring of the performance are essential to minimize inconclusive diagnoses and the putative impact of additional embryo manipulations. Although poorer reproductive outcomes might result from double biopsy and/or double cryopreservations, these practices may still be worthwhile to avoid transferring affected/aneuploid blastocysts. Therefore, the risks must be weighed against the potential benefits for each specific couple. REGISTRATION NUMBER: PROSPERO (ID: CRD42024503678).
Functional hypothalamic amenorrhoea and polycystic ovarian morphology: a narrative review about an intriguing association.
Ott J, Robin G, Hager M … +1 more , Dewailly D
Hum Reprod Update · 2025 Jan · PMID 39378412 · Full text
BACKGROUND: Functional hypothalamic amenorrhoea (FHA) is responsible for 20-35% of all cases of secondary amenorrhoea and, thus, is the second most common cause of secondary amenorrhoea after polycystic ovary syndrome (P...
BACKGROUND: Functional hypothalamic amenorrhoea (FHA) is responsible for 20-35% of all cases of secondary amenorrhoea and, thus, is the second most common cause of secondary amenorrhoea after polycystic ovary syndrome (PCOS). A high number of patients with FHA reveal polycystic ovarian morphology (PCOM) on ultrasound. The combination of amenorrhoea and PCOM can lead to confusion. First, amenorrhoeic women with PCOM fulfil the revised Rotterdam criteria and, thus, can easily be misdiagnosed with PCOS. Moreover, it has been claimed that some women with FHA and concomitant PCOM differ from those without PCOM in terms of endocrine regulation and metabolic traits. OBJECTIVE AND RATIONALE: The main focus of this article was on studies about FHA, which differentiated between patients with or without PCOM. The aim was to estimate the prevalence of PCOM and to look if it has an impact on pathophysiologic, diagnostic and therapeutic issues as well as on long-term consequences. SEARCH METHODS: Peer review original and review articles were selected from PubMed searches for this review. Searches were performed using the search terms 'polycystic AND functional hypothalamic amenorrhoea'. The reference lists of publications found were searched for relevant additional studies. The inclusion criteria for publications were: English language, patients' age ≥ 18 years, year of publication >1980, original studies, validated diagnosis of FHA, and validated diagnosis of PCOM using transvaginal ultrasound. OUTCOMES: The prevalence of PCOM in women with FHA varied from 41.9% to 46.7%, which is higher than in healthy non-PCOS controls. Hypothetically, the high prevalence might be due to a mixture of silent PCOM, as in the general population, and pre-existing PCOS. Several differences in metabolic and hormonal parameters were found between FHA-PCOM and FHA-non-PCOM patients. While oestrogen deficiency is common to both groups of patients, FHA-PCOM patients have a higher BMI, higher levels of anti-Müllerian hormone (AMH) and testosterone, a higher increase in LH in the course of a GnRH test, and lower sex hormone binding globulin (SHBG) levels than FHA-non-PCOM patients. The differential diagnosis between FHA-PCOM and PCOS, especially PCOS phenotype D (PCOM and oligo-/anovulation without hyperandrogenism), can be challenging. Several parameters have been suggested, which are helpful though not absolutely reliable. They include the typical causes for FHA (excessive exercise, energy deficit, and/or psychological stress), the serum levels of LH, testosterone, and SHBG, as well as the progestin challenge test. Whether FHA-PCOM has a different risk profile for long-term consequences concerning patients' metabolic and cardiovascular situation as well as their bone mass, is unclear. Concerning therapeutic aspects, there are only few data about FHA-PCOM compared to FHA-non-PCOM. To treat anovulation, the use of pulsatile GnRH treatment seems to be equally effective in both groups. Similar to FHA-non-PCOM patients, pulsatile GnRH therapy would be more efficient than exogenous gonadotropins in FHA-PCOM patients. WIDER IMPLICATIONS: Women with FHA-PCOM present a special sub-population of FHA patients. The diagnostic pitfall of FHA-PCOM should be emphasized in clinical guidelines about FHA and PCOS. The fact that almost half of the women with FHA have an ovarian follicle excess (i.e. PCOM) in face of low gonadotropin serum levels suggests that the intra-ovarian regulation of folliculogenesis is subject to individual variations, for unknown reasons, either genetic or epigenetic. Further studies are needed to investigate this hypothesis. REGISTRATION NUMBER: Not applicable.
Infertility treatment and offspring blood pressure-a systematic review and meta-analysis.
Yeung EH, Trees IR, Clayton PK … +3 more , Polinski KJ, Livinski AA, Putnick DL
Hum Reprod Update · 2025 Jan · PMID 39375871 · Full text
BACKGROUND: Studies have inconsistently observed that children conceived by IVF or ICSI have higher blood pressure compared to children not conceived by these ARTs. OBJECTIVE AND RATIONALE: The aim was to perform a syste...
BACKGROUND: Studies have inconsistently observed that children conceived by IVF or ICSI have higher blood pressure compared to children not conceived by these ARTs. OBJECTIVE AND RATIONALE: The aim was to perform a systematic review and meta-analysis of blood pressure measures of offspring conceived by ART and those conceived naturally. Resolving the suspicion of ART as a risk factor of higher blood pressure, and therefore of heart disease, has public health and clinical implications. SEARCH METHODS: A biomedical librarian searched the Embase, PubMed, and Web of Science databases. Searches were limited to records published in English since 1978. Grey literature was searched. Inclusion criteria were humans born via infertility treatment (vs no treatment) who underwent a blood pressure assessment. Exclusion criteria were non-human participants, non-quantitative studies, absence of a control group, and specialty populations (e.g. cancer patients only). Two reviewers independently screened each record's title and abstract and full text using Covidence, extracted data using Excel, and assessed bias using the National Heart, Lung, and Blood Institute's Quality Assessment Tool for cohort studies. OUTCOMES: Of 5082 records identified, 79 were included in the systematic review and 36 were included in the meta-analysis of systolic blood pressure (SBP) and diastolic blood pressure (DBP) in ART and non-ART groups. Overall, 34 reports including 40 effect sizes from 25 unique cohorts, compared blood pressure between ART (N = 5229) and non-ART (N = 8509, reference) groups with no covariate adjustment. No standardized mean differences (SMD) in SBP (0.06 per SD of mmHg, 95% CI = -0.05, 0.18) or DBP (0.11, 95% CI = -0.04, 0.25) by treatment were found, but the heterogeneity was considerable (I2=76% for SBP and 87% for DBP). Adjusted analyses were presented in 12 reports, representing 28 effect sizes from 21 unique cohorts (N = 2242 treatment vs N = 37 590 non-treatment). Studies adjusted for varied covariates including maternal (e.g. age, education, body mass index, smoking, pregnancy complications), child (e.g. sex, age, physical activity, BMI, height), and birth characteristics (e.g. birth weight and gestational age). Adjusted results similarly showed no SMD for SBP (-0.03, 95% CI = -0.13, 0.08) or DBP (0.02, 95% CI = -0.12, 0.16), though heterogeneity remained high (I2 = 64% and 86%). Funnel plots indicated a slight publication bias, but the trim and fill approach suggested no missing studies. Removal of five studies which adjusted for birth outcomes (potentially over-adjusting for mediators) made no material difference. Type of treatment (e.g. IVF vs ICSI), period effects by birth year (≤2000 vs >2000), offspring age group (<8, 8-14, 15+), or study location (e.g. Europe) did not modify the results. WIDER IMPLICATIONS: In conclusion, conception by ART was not associated with offspring blood pressure in a meta-analysis, although considerable heterogeneity was observed. Given the increasing number of children born using ART, perpetuating a difference in blood pressure would mean unnecessary risk screening for many children/adults on a population level. At a clinical level, couples considering these reproductive technologies have some reassurance that there is no evidence of strong vascular 'programming' due to the techniques used. REGISTRATION NUMBER: PROSPERO No. CRD42022374232.
New insights into the ovulatory process in the human ovary.
Jo M, Brännström M, Akins JW … +1 more , Curry TE
Hum Reprod Update · 2025 Jan · PMID 39331957 · Full text
BACKGROUND: Successful ovulation is essential for natural conception and fertility. Defects in the ovulatory process are associated with various conditions of infertility or subfertility in women. However, our understand...
BACKGROUND: Successful ovulation is essential for natural conception and fertility. Defects in the ovulatory process are associated with various conditions of infertility or subfertility in women. However, our understanding of the intra-ovarian biochemical mechanisms underlying this process in women has lagged compared to our understanding of animal models. This has been largely due to the limited availability of human ovarian samples that can be used to examine changes across the ovulatory period and delineate the underlying cellular/molecular mechanisms in women. Despite this challenge, steady progress has been made to improve our knowledge of the ovulatory process in women by: (i) collecting granulosa cells across the IVF interval, (ii) creating a novel approach to collecting follicular cells and tissues across the periovulatory period from normally cycling women, and (iii) developing unique in vitro models to examine the LH surge or hCG administration-induced ovulatory changes in gene expression, the regulatory mechanisms underlying the ovulatory changes, and the specific functions of the ovulatory factors. OBJECTIVE AND RATIONALE: The objective of this review is to summarize findings generated using in vivo and in vitro models of human ovulation, with the goal of providing new insights into the mechanisms underlying the ovulatory process in women. SEARCH METHODS: This review is based on the authors' own studies and a search of the relevant literature on human ovulation to date using PubMed search terms such as 'human ovulation EGF-signaling', 'human ovulation steroidogenesis', 'human ovulation transcription factor', 'human ovulation prostaglandin', 'human ovulation proteinase', 'human ovulation angiogenesis' 'human ovulation chemokine', 'human ovulatory disorder', 'human granulosa cell culture'. Our approach includes comparing the data from the authors' studies with the existing microarray or RNA-seq datasets generated using ovarian cells obtained throughout the ovulatory period from humans, monkeys, and mice. OUTCOMES: Current findings from studies using in vivo and in vitro models demonstrate that the LH surge or hCG administration increases the expression of ovulatory mediators, including EGF-like factors, steroids, transcription factors, prostaglandins, proteolytic systems, and other autocrine and paracrine factors, similar to those observed in other animal models such as rodents, ruminants, and monkeys. However, the specific ovulatory factors induced, their expression pattern, and their regulatory mechanisms vary among different species. These species-specific differences stress the necessity of utilizing human samples to delineate the mechanisms underlying the ovulatory process in women. WIDER IMPLICATIONS: The data from human ovulation in vivo and in vitro models have begun to fill the gaps in our understanding of the ovulatory process in women. Further efforts are needed to discover novel ovulatory factors. One approach to address these gaps is to improve existing in vitro models to more closely mimic in vivo ovulatory conditions in humans. This is critically important as the knowledge obtained from these human studies can be translated directly to aid in the diagnosis of ovulation-associated pathological conditions, for the development of more effective treatment to help women with anovulatory infertility or, conversely, to better manage ovulation for contraceptive purposes. REGISTRATION NUMBER: N/A.
Evaluating the diagnostic accuracy of androgen measurement in polycystic ovary syndrome: a systematic review and diagnostic meta-analysis to inform evidence-based guidelines.
Bizuneh AD, Joham AE, Teede H … +7 more , Mousa A, Earnest A, Hawley JM, Smith L, Azziz R, Arlt W, Tay CT
Hum Reprod Update · 2025 Jan · PMID 39305127 · Full text
BACKGROUND: Biochemical hyperandrogenism is a hallmark and diagnostic feature of polycystic ovary syndrome (PCOS). However, the most accurate androgen measurement for assessing biochemical hyperandrogenism in PCOS diagno...
BACKGROUND: Biochemical hyperandrogenism is a hallmark and diagnostic feature of polycystic ovary syndrome (PCOS). However, the most accurate androgen measurement for assessing biochemical hyperandrogenism in PCOS diagnosis remains uncertain. OBJECTIVE AND RATIONALE: This systematic review aimed to assess different androgen measures [including total testosterone (TT), calculated free testosterone (cFT), free androgen index (FAI), androstenedione (A4), dehydroepiandrosterone sulfate (DHEAS), and dihydrotestosterone (DHT)] for accuracy in diagnosing biochemical hyperandrogenism in women with PCOS, to inform the 2023 International PCOS Evidence-based Guidelines. SEARCH METHODS: To update evidence from the 2018 International PCOS Guidelines, a systematic search from 3 July 2017 to 23 June 2023 was conducted across Medline (Ovid), CINAHL, all EBM, EMBASE, and PsycInfo for articles evaluating androgens in the diagnosis of biochemical hyperandrogenism. The revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to assess the risk of bias and applicability. A diagnostic test accuracy meta-analysis was performed using STATA 18 software. Summary sensitivity and specificity were calculated with 95% CIs using the bivariate model, while the hierarchical summary receiver operating characteristics (ROC) model was used to produce a summary ROC curve. OUTCOMES: Of 23 studies reviewed, 18 were included in the meta-analysis, with data from 2857 participants (1650 with PCOS and 1207 controls). For diagnosing biochemical hyperandrogenism in PCOS, the pooled sensitivity, specificity, and AUC with 95% CI were for TT: 0.74 (0.63-0.82), 0.86 (0.77-0.91), and 0.87 (0.84-0.90); cFT: 0.89 (0.69-0.96), 0.83 (0.79-0.86), and 0.85 (0.81-0.88); FAI: 0.78 (0.70-0.83), 0.85 (0.76-0.90), and 0.87 (0.84-0.90); A4: 0.75 (0.60-0.86), 0.71 (0.51-0.85), and 0.80 (0.76-0.83); and DHEAS: 0.75 (0.61-0.85), 0.67 (0.48-0.81), and 0.77 (0.73-0.81), respectively. In subgroup analyses, liquid chromatography with tandem mass spectrometry (LC-MS/MS) had superior sensitivity for measuring cFT, FAI, A4, and DHEAS, and superior specificity for measuring TT, cFT, and FAI, compared to the direct immunoassay method. WIDER IMPLICATIONS: Our results directly informed the 2023 International PCOS Guideline recommendations to use TT and FT as the first-line laboratory tests to assess biochemical hyperandrogenism in the diagnosis of PCOS. cFT should be assessed by equilibrium dialysis or ammonium sulfate precipitation, or calculated using FAI. If TT or cFT are not elevated, A4 and DHEAS could also be considered, noting their poorer specificity. Laboratories should utilize LC-MS/MS for androgen measurement given its high accuracy. Future studies should focus on establishing optimal normative cut-off values in large, unselected, and ethnically diverse cohorts of women. REGISTRATION NUMBER: The review protocol was prepublished in the 2023 PCOS Guideline Technical Report (https://www.monash.edu/__data/assets/pdf_file/0010/3379591/TechnicalReport-2023.pdf).
Impact of Bisphenol A and its alternatives on oocyte health: a scoping review.
Peters AE, Ford EA, Roman SD … +4 more , Bromfield EG, Nixon B, Pringle KG, Sutherland JM
Hum Reprod Update · 2024 Dec · PMID 39277428 · Full text
BACKGROUND: Bisphenol A (BPA) is an endocrine disrupting chemical released from plastic materials, including food packaging and dental sealants, persisting in the environment and ubiquitously contaminating ecosystems and...
BACKGROUND: Bisphenol A (BPA) is an endocrine disrupting chemical released from plastic materials, including food packaging and dental sealants, persisting in the environment and ubiquitously contaminating ecosystems and human populations. BPA can elicit an array of damaging health effects and, alarmingly, 'BPA-free' alternatives mirror these harmful effects. Bisphenol exposure can negatively impact female fertility, damaging both the ovary and oocytes therein. Such damage can diminish reproductive capacity, pregnancy success, and offspring health. Despite global government regulations in place to indicate 'safe' BPA exposure levels, these policies have not considered the effects of bisphenols on oocyte health. OBJECTIVE AND RATIONALE: This scoping review was conducted to evaluate evidence on the effects of BPA and BPA alternatives on standardized parameters of oocyte health. In doing so, this review addresses a critical gap in the literature providing a comprehensive, up-to-date synthesis of the effects of bisphenols on oocyte health. SEARCH METHODS: This scoping review was conducted in accordance with PRISMA guidelines. Four databases, Medline, Embase, Scopus, and Web of Science, were searched twice (23 February 2022 and 1 August 2023) to capture studies assessing mammalian oocyte health post-bisphenol exposure. Search terms regarding oocytes, ovarian follicles, and bisphenols were utilized to identify relevant studies. Manuscripts written in English and reporting the effect of any bisphenol on mammalian oocyte health from all years were included. Parameters for toxicological studies were evaluated, including the number of bisphenol concentrations/doses tested, dosing regimen, biological replicates and/or animal numbers, and statistical information (for human studies). Standardized parameters of oocyte health including follicle counts, oocyte yield, oocyte meiotic capacity, morphology of oocyte and cumulus cells, and oocyte meiotic spindle integrity were extracted across the studies. OUTCOMES: After screening 3147 studies, 107 studies of either humans or mammalian animal models or humans were included. Of the in vitro exposure studies, 96.3% (26/27) and 94.1% (16/17) found at least one adverse effect on oocyte health using BPA or BPA alternatives (including BHPF, BPAF, BPB, BPF, and BPS), respectively. These included increased meiotic cell cycle arrest, altered morphology, and abnormal meiotic spindle/chromosomal alignment. In vivo, 85.7% (30/35) of studies on BPA and 92.3% (12/13) on BPA alternatives documented adverse effects on follicle development, morphology, or spindle/chromosome alignment. Importantly, these effects were recorded using levels below those deemed 'safe' for human exposure. Over half (11/21) of all human observational studies showed associations between higher urinary BPA levels and reduced antral follicle counts or oocyte yield in IVF patients. Recommendations are presented based on the identified shortcomings of the current evidence, incorporating elements of FDA requirements for future research in the field. WIDER IMPLICATIONS: These data highlight the detrimental impacts of low-level BPA and BPA alternative exposure, contributing to poor oocyte quality and reduced fertility. These outcomes are valuable in promoting the revision of current policies and guidelines pertaining to BPA exposure internationally. This study serves as a valuable resource to scientists, providing key recommendations on study design, reporting elements, and endpoint measures to strengthen future studies. Ultimately, this review highlights oocyte health as a fundamentally important endpoint in reproductive toxicological studies, indicating an important direction for future research into endocrine disrupting chemicals to improve fertility outcomes.
Ramadan during pregnancy and offspring health outcomes over the life course: a systematic review and meta-analysis.
Pradella F, Witte P, van Ewijk R
Hum Reprod Update · 2024 Dec · PMID 39178355 · Publisher ↗
BACKGROUND: Intermittent fasting, such as during Ramadan, is prevalent among pregnant women. However, the association between Ramadan during pregnancy and offspring health along the life course has not been fully establi...
BACKGROUND: Intermittent fasting, such as during Ramadan, is prevalent among pregnant women. However, the association between Ramadan during pregnancy and offspring health along the life course has not been fully established. OBJECTIVE AND RATIONALE: Fetal programming research indicates that prenatal exposures, particularly during early pregnancy, can cause long-term structural and physiological changes that adversely affect offspring health. Our objective was to systematically identify and assess the evidence regarding Ramadan during pregnancy. SEARCH METHODS: A total of 31 studies were sourced from PubMed, EMBASE, Web of Science, and EconLit. Included studies evaluated outcomes in individuals with prenatal Ramadan exposure, compared to unexposed Muslim controls. Main outcomes were birth weight, gestational length, and sex ratio in newborns; height, mortality, and cognition in children; and disabilities, chronic diseases, and human capital accumulation in adults. Each study was evaluated for risk of bias. The overall quality of evidence was appraised using the GRADE system. Random-effects meta-analyses were conducted for outcomes analyzed in at least three primary studies. OUTCOMES: The initial search identified 2933 articles, 1208 duplicates were deleted. There were 31 publications fulfilled the eligibility criteria for the qualitative synthesis; 22 studies were included in meta-analyses. The overall quality of the evidence was low to moderate and differed by study design and outcome. Among newborns, prenatal Ramadan exposure was not associated with birth weight (mean difference (MD) -3 g (95% CI -18 to 11; I2 = 70%) or the likelihood of prematurity (percentage point difference (PPD) 0.19 (95% CI -0.11 to 0.49; I2 = 0%)). The probability that the newborn is male was reduced (PPD -0.14 (95% CI -0.28 to -0.00; I2 = 0%)). This potentially reflects sex-specific mortality rates resulting from adverse in utero circumstances. In childhood, the exposed performed slightly poorer on cognitive tests (MD -3.10% of a standard deviation (95% CI -4.61 to -1.58; I2 = 51%)). Height among the exposed was reduced, and this pattern was already visible at ages below 5 years (height-for-age z-score MD -0.03 (95% CI -0.06 to -0.00; I2 = 76%)). A qualitative literature synthesis revealed that childhood mortality rates were increased in low-income contexts. In adulthood, the prenatally exposed had an increased likelihood of hearing disabilities (odds ratio 1.26 (95% CI 1.09 to 1.45; I2 = 32%)), while sight was not affected. Other impaired outcomes included chronic diseases or their symptoms, and indicators of human capital accumulation such as home ownership (qualitative literature synthesis). The first trimester emerged as a sensitive period for long-term impacts. WIDER IMPLICATIONS: Despite the need for more high-quality studies to improve the certainty of the evidence, the synthesis of existing research demonstrates that Ramadan during pregnancy is associated with adverse offspring health effects in childhood and especially adulthood, despite an absence of observable effects at birth. Not all health effects may apply to all Muslim communities, which are diverse in backgrounds and behaviors. Notably, moderating factors like daytime activity levels and dietary habits outside fasting hours have hardly been considered. It is imperative for future research to address these aspects. REGISTRATION NUMBER: PROSPERO (CRD42022325770).
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe