Joshua J Fisher, Ashley Williams, Farhad Soheilmoghaddam, Georgia R Kafer
<p><strong>Background: </strong>Understanding the mechanisms that promote or hinder healthy placental development and functionality is fundamental to advancing the field of fetal and reproductive medicine. Syncytiotrophoblast (STB) are highly specialized trophoblast which develop and gain functional maturity during the first trimester of pregnancy. STB are critical to many placental functions and are often implicated in the etiology of placental pathologies. Recent advancements in cell biology have facilitated the development of innovative in vitro STB model systems. However, as the variety of available in vitro STB models grows, a critical assessment of the strengths, limitations, and appropriate applications of both established and emerging model systems is important for the field.</p><p><strong>Objective and rationale: </strong>With this review, we set out to compile and synthesize current knowledge on in vitro modeling of STB. Using this information, we sought to develop a balanced and thoughtful discussion regarding the use and suitability of various in vitro STB models. Our approach is grounded in a framework that considers placental development and physiology, with a specific focus on the capability of different models to recapitulate and thus enable the study of human STB differentiation, development, function, and dysfunction.</p><p><strong>Search method: </strong>This review assessed published literature sourced through the PubMed database. Search terms included 'human placenta models,' 'syncytiotrophoblast models,' 'syncytiotrophoblast development,' 'trophoblast stem cells,' 'trophoblast organoids,' and 'trophoblast cell models.' The literature search was limited to English-language publications available up to August 2025.</p><p><strong>Outcomes: </strong>We provide a narrative which explores the features, potential applications, and limitations of various STB models, including explant systems, immortalized trophoblast cell lines, stem cell-derived trophoblast, and a range of established and emerging 3D culture systems. Our evaluation focuses on the potential of each model to address specific research questions and highlights the challenges associated with modeling different stages of STB development and different unique aspects of STB functionality. Moreover, while remarkable progress in developing STB models has been made, no single system fully recapitulates the complex in vivo features of STB formation and function. Rather than being exhaustive, this review seeks to provide an evidence-based perspective on STB modeling in vitro which can encourage the careful consideration of the strengths and limitations of STB models.</p><p><strong>Wider implications: </strong>This review provides an overview of the in vitro STB models currently available and a commentary of the knowledge that these systems have contributed to our understanding of STB biology. While the field has made significant progress, ongoing refinement of existing models i
{"title":"Advantages, limitations, and innovative considerations for established and emerging models of human placental syncytiotrophoblast.","authors":"Joshua J Fisher, Ashley Williams, Farhad Soheilmoghaddam, Georgia R Kafer","doi":"10.1093/humupd/dmaf034","DOIUrl":"https://doi.org/10.1093/humupd/dmaf034","url":null,"abstract":"<p><strong>Background: </strong>Understanding the mechanisms that promote or hinder healthy placental development and functionality is fundamental to advancing the field of fetal and reproductive medicine. Syncytiotrophoblast (STB) are highly specialized trophoblast which develop and gain functional maturity during the first trimester of pregnancy. STB are critical to many placental functions and are often implicated in the etiology of placental pathologies. Recent advancements in cell biology have facilitated the development of innovative in vitro STB model systems. However, as the variety of available in vitro STB models grows, a critical assessment of the strengths, limitations, and appropriate applications of both established and emerging model systems is important for the field.</p><p><strong>Objective and rationale: </strong>With this review, we set out to compile and synthesize current knowledge on in vitro modeling of STB. Using this information, we sought to develop a balanced and thoughtful discussion regarding the use and suitability of various in vitro STB models. Our approach is grounded in a framework that considers placental development and physiology, with a specific focus on the capability of different models to recapitulate and thus enable the study of human STB differentiation, development, function, and dysfunction.</p><p><strong>Search method: </strong>This review assessed published literature sourced through the PubMed database. Search terms included 'human placenta models,' 'syncytiotrophoblast models,' 'syncytiotrophoblast development,' 'trophoblast stem cells,' 'trophoblast organoids,' and 'trophoblast cell models.' The literature search was limited to English-language publications available up to August 2025.</p><p><strong>Outcomes: </strong>We provide a narrative which explores the features, potential applications, and limitations of various STB models, including explant systems, immortalized trophoblast cell lines, stem cell-derived trophoblast, and a range of established and emerging 3D culture systems. Our evaluation focuses on the potential of each model to address specific research questions and highlights the challenges associated with modeling different stages of STB development and different unique aspects of STB functionality. Moreover, while remarkable progress in developing STB models has been made, no single system fully recapitulates the complex in vivo features of STB formation and function. Rather than being exhaustive, this review seeks to provide an evidence-based perspective on STB modeling in vitro which can encourage the careful consideration of the strengths and limitations of STB models.</p><p><strong>Wider implications: </strong>This review provides an overview of the in vitro STB models currently available and a commentary of the knowledge that these systems have contributed to our understanding of STB biology. While the field has made significant progress, ongoing refinement of existing models i","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":""},"PeriodicalIF":16.1,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146054884","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}
Adriana C H Neven,Maria Forslund,Sanjeeva Ranasinha,Parneet Sethi,Raja Ram Dhungana,Aya Mousa,Chau T Tay,Helena Teede,Jacqueline A Boyle
BACKGROUNDPolycystic ovary syndrome (PCOS) affects women globally, but its prevalence across World Health Organization (WHO) regions has not previously been reported.OBJECTIVE AND RATIONALEWe aimed to synthesize evidence on the prevalence of PCOS by diagnostic criteria and by WHO geographic regions to inform the International Evidence-Based PCOS Guideline.SEARCH METHODSA systematic search of OVID MEDLINE, All EBM, PsycInfo, EMBASE, and Cumulative Index to Nursing and Allied Health Literature was conducted from 1990 to November 2024. Studies assessing PCOS prevalence in an unselected population were included. Non-primary studies or those with unclear diagnostic criteria were excluded. The primary outcome was PCOS prevalence among adult women. The secondary outcome was PCOS prevalence among women of all ages. Random effects meta-analysis using the DerSimonian and Laird method was applied for estimating the overall effect size. Two reviewers independently assessed risk-of-bias (RoB) and evidence certainty.OUTCOMESThe search yielded 16 664 articles, of which 119 unique studies (in 137 articles) were eligible, and 92 (including 157 181 participants) were pooled in a meta-analysis. By diagnostic criteria, PCOS global prevalence among adult women only was 12.1% (95% CI: 9.8, 14.8; I2: 98.8%) using Rotterdam criteria, 7.9% (95% CI: 6.2, 9.9; I2: 96.2%) using the original National Institute of Health (NIH) criteria, 12.7% (95% CI: 8.2, 17.9; I2: 98.0%) using the Androgen Excess (AE)-PCOS criteria, and 7.8% (95% CI: 5.8, 10.0; I2: 99.4%) by self-report. By WHO regions, PCOS prevalence among adult women when using Rotterdam criteria was highest in the Eastern Mediterranean region (15.1%; 95% CI: 11.1, 19.7) and the South-East Asian region (14.3%; 95% CI: 5.8, 25.9), followed by the European region (11.7%; 95% CI: 5.1, 20.3), the region of the Americas (10.5%; 95% CI: 3.0, 21.7), and the Western Pacific region (9.1%; 95% CI: 6.2, 12.5), with no data from Africa. Subgroup analysis using Cochran's Q test indicated a statistically significant difference in prevalence by WHO region (P = 0.022). Subgroup analyses including adolescents yielded a lower prevalence globally, with a global prevalence of 11.4% (95% CI: 9.5, 13.5) by Rotterdam criteria, 7.1% (95% CI: 5.7, 8.7) by NIH criteria, 11.2% (95% CI: 7.4, 15.5) by AE-PCOS criteria, and 7.6% (95% CI: 5.8, 9.6) on self-report. Of the 119 studies, 30 had low, 49 had moderate, and 40 had high RoB. Certainty of evidence ranged from very low to low.WIDER IMPLICATIONSThis is the most comprehensive and contemporary review of PCOS prevalence and highlights past inconsistencies in diagnostic criteria and individual diagnostic features. Pooled PCOS prevalence was 12.1% by the Rotterdam criteria and was highest in the Eastern Mediterranean and the South-East Asian regions, with a potentially different health burden of PCOS across world regions. These findings directly inform International PCOS Guidelines, including updated
{"title":"Prevalence of polycystic ovary syndrome: a global and regional systematic review and meta-analysis.","authors":"Adriana C H Neven,Maria Forslund,Sanjeeva Ranasinha,Parneet Sethi,Raja Ram Dhungana,Aya Mousa,Chau T Tay,Helena Teede,Jacqueline A Boyle","doi":"10.1093/humupd/dmaf030","DOIUrl":"https://doi.org/10.1093/humupd/dmaf030","url":null,"abstract":"BACKGROUNDPolycystic ovary syndrome (PCOS) affects women globally, but its prevalence across World Health Organization (WHO) regions has not previously been reported.OBJECTIVE AND RATIONALEWe aimed to synthesize evidence on the prevalence of PCOS by diagnostic criteria and by WHO geographic regions to inform the International Evidence-Based PCOS Guideline.SEARCH METHODSA systematic search of OVID MEDLINE, All EBM, PsycInfo, EMBASE, and Cumulative Index to Nursing and Allied Health Literature was conducted from 1990 to November 2024. Studies assessing PCOS prevalence in an unselected population were included. Non-primary studies or those with unclear diagnostic criteria were excluded. The primary outcome was PCOS prevalence among adult women. The secondary outcome was PCOS prevalence among women of all ages. Random effects meta-analysis using the DerSimonian and Laird method was applied for estimating the overall effect size. Two reviewers independently assessed risk-of-bias (RoB) and evidence certainty.OUTCOMESThe search yielded 16 664 articles, of which 119 unique studies (in 137 articles) were eligible, and 92 (including 157 181 participants) were pooled in a meta-analysis. By diagnostic criteria, PCOS global prevalence among adult women only was 12.1% (95% CI: 9.8, 14.8; I2: 98.8%) using Rotterdam criteria, 7.9% (95% CI: 6.2, 9.9; I2: 96.2%) using the original National Institute of Health (NIH) criteria, 12.7% (95% CI: 8.2, 17.9; I2: 98.0%) using the Androgen Excess (AE)-PCOS criteria, and 7.8% (95% CI: 5.8, 10.0; I2: 99.4%) by self-report. By WHO regions, PCOS prevalence among adult women when using Rotterdam criteria was highest in the Eastern Mediterranean region (15.1%; 95% CI: 11.1, 19.7) and the South-East Asian region (14.3%; 95% CI: 5.8, 25.9), followed by the European region (11.7%; 95% CI: 5.1, 20.3), the region of the Americas (10.5%; 95% CI: 3.0, 21.7), and the Western Pacific region (9.1%; 95% CI: 6.2, 12.5), with no data from Africa. Subgroup analysis using Cochran's Q test indicated a statistically significant difference in prevalence by WHO region (P = 0.022). Subgroup analyses including adolescents yielded a lower prevalence globally, with a global prevalence of 11.4% (95% CI: 9.5, 13.5) by Rotterdam criteria, 7.1% (95% CI: 5.7, 8.7) by NIH criteria, 11.2% (95% CI: 7.4, 15.5) by AE-PCOS criteria, and 7.6% (95% CI: 5.8, 9.6) on self-report. Of the 119 studies, 30 had low, 49 had moderate, and 40 had high RoB. Certainty of evidence ranged from very low to low.WIDER IMPLICATIONSThis is the most comprehensive and contemporary review of PCOS prevalence and highlights past inconsistencies in diagnostic criteria and individual diagnostic features. Pooled PCOS prevalence was 12.1% by the Rotterdam criteria and was highest in the Eastern Mediterranean and the South-East Asian regions, with a potentially different health burden of PCOS across world regions. These findings directly inform International PCOS Guidelines, including updated ","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"31 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956087","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}
Dorian G Luijkx,Leila Ashtar,Nienke de Graeff,Edith Coonen,Stefan Giselbrecht,Guido M W R de Wert,Erik J Vrij,Rhiannon Grant,Ana M Pereira Daoud
BACKGROUNDStem cell-based embryo models (SCBEMs) are clusters of pluripotent stem cells that can mimic morphological and functional aspects of early human embryos to different degrees. When cultured from human cells, SCBEMs offer technically scalable and amenable tools that can help refine, reduce, and, in the future, perhaps replace the use of animals and human embryos in fundamental and clinical research. These advantages propelled the development of SCBEMs, and several distinct types have been generated over the past decade, including gastruloids, axioloids, blastoids, and post-implantation-like embryoids. For purposes of governance, advisory reports distinguish between SCBEMs based on their presumed capacity to continuously undergo organized human development-referred to here as developmental potential. However, since functionally testing this potential by transferring human SCBEMs to a uterus would be unethical and is recommended to be prohibited, scientists lack clear or consistent ways to assess it.OBJECTIVE AND RATIONALEThis narrative review aims to tackle the question of how to assess developmental potential in SCBEMs by clarifying the different ways in which it can be and is being conceptualized. We achieve this by synthesizing insights from governance, science, and ethics. First, we examine how developmental potential is described in contemporary governance frameworks, and which aspects are emphasized. Next, we discuss biological markers for developmental potential and show how their scientific basis (in embryos, let alone SCBEMs) remains poorly understood. Then, we explore how the aspects considered relevant for assessments of developmental potential in governance and science may pre-emptively hinge on underlying conceptual interpretations and lead to differing normative implications.SEARCH METHODSThis narrative review combines insights from both the academic and grey literature on the (ethics of) embryo models. Original and review articles were selected from PubMed and Biorxiv with the main focus on articles published since 2015. Search terms included: embryo quality, in vitro fertilization, Gardner system, blastoid, gastruloid, embryo research, potentiality argument, developmental potential, transcriptomics, epigenetics, embryo metabolism, and related terms. Additional sources were identified through snowballing. This work focuses predominantly on human SCBEMs, but references to animal models are made.OUTCOMESComparison of the descriptions currently recommended for governance suggests at least three criteria that are used to assess developmental potential in SCBEMs: composition, organization, and interaction. Scientifically, developmental potential is multifaceted and only partly characterized, making it necessary to measure a broader range of aspects, using human embryos as benchmarks when possible. Since the range and significance of these aspects can be shaped by underlying accounts of developmental potential, contemporary adviso
{"title":"Beyond integration: towards benchmarks for developmental potential in human stem cell-derived embryo models.","authors":"Dorian G Luijkx,Leila Ashtar,Nienke de Graeff,Edith Coonen,Stefan Giselbrecht,Guido M W R de Wert,Erik J Vrij,Rhiannon Grant,Ana M Pereira Daoud","doi":"10.1093/humupd/dmaf033","DOIUrl":"https://doi.org/10.1093/humupd/dmaf033","url":null,"abstract":"BACKGROUNDStem cell-based embryo models (SCBEMs) are clusters of pluripotent stem cells that can mimic morphological and functional aspects of early human embryos to different degrees. When cultured from human cells, SCBEMs offer technically scalable and amenable tools that can help refine, reduce, and, in the future, perhaps replace the use of animals and human embryos in fundamental and clinical research. These advantages propelled the development of SCBEMs, and several distinct types have been generated over the past decade, including gastruloids, axioloids, blastoids, and post-implantation-like embryoids. For purposes of governance, advisory reports distinguish between SCBEMs based on their presumed capacity to continuously undergo organized human development-referred to here as developmental potential. However, since functionally testing this potential by transferring human SCBEMs to a uterus would be unethical and is recommended to be prohibited, scientists lack clear or consistent ways to assess it.OBJECTIVE AND RATIONALEThis narrative review aims to tackle the question of how to assess developmental potential in SCBEMs by clarifying the different ways in which it can be and is being conceptualized. We achieve this by synthesizing insights from governance, science, and ethics. First, we examine how developmental potential is described in contemporary governance frameworks, and which aspects are emphasized. Next, we discuss biological markers for developmental potential and show how their scientific basis (in embryos, let alone SCBEMs) remains poorly understood. Then, we explore how the aspects considered relevant for assessments of developmental potential in governance and science may pre-emptively hinge on underlying conceptual interpretations and lead to differing normative implications.SEARCH METHODSThis narrative review combines insights from both the academic and grey literature on the (ethics of) embryo models. Original and review articles were selected from PubMed and Biorxiv with the main focus on articles published since 2015. Search terms included: embryo quality, in vitro fertilization, Gardner system, blastoid, gastruloid, embryo research, potentiality argument, developmental potential, transcriptomics, epigenetics, embryo metabolism, and related terms. Additional sources were identified through snowballing. This work focuses predominantly on human SCBEMs, but references to animal models are made.OUTCOMESComparison of the descriptions currently recommended for governance suggests at least three criteria that are used to assess developmental potential in SCBEMs: composition, organization, and interaction. Scientifically, developmental potential is multifaceted and only partly characterized, making it necessary to measure a broader range of aspects, using human embryos as benchmarks when possible. Since the range and significance of these aspects can be shaped by underlying accounts of developmental potential, contemporary adviso","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"26 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897513","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}
BACKGROUNDThe ovarian reserve is the quantity of non-growing primordial follicles (NGF) in paired ovaries. A low or high ovarian reserve at birth respectively may foreshadow early or late age at menopause. In textbooks, published papers, and internet modalities, a recurring theme is that for human females, on average, mid-gestation marks the peak supply of 7 million germ cells/NGF followed by large-scale depletion to about 1-2 million in paired ovaries at birth.OBJECTIVE AND RATIONALEWe test this narrative against the evidence for germ cell quantity and degeneration reported in peer-reviewed publications. Ovary sizes, volumes/shapes are particularly variable among same-age foetuses and at birth. Coupled with genomic mechanisms determining germ cell proliferation/differentiation/survival, substantial variations of germ cell numbers are recorded within and between individual studies. Across published papers, textbooks, and webpages, germ cell numbers in foetal-newborn ovaries range from thousands to 20 million. A massive 70-85% die-off among germ cells in foetal ovaries is reported during the second half of gestation. Although germ cell degeneration is a reality, we review also the evidence for the timing and extent of germ cell death in foetal/newborn human ovaries.SEARCH METHODSWe cite primary publications of human embryonic, foetal/newborn ovaries where data on germ cell numbers and death are reported, and similarly for studies of ovarian volume, shape, histology, and growth in foetal-early postnatal life. Searches to September 2025 used PubMed, Google Scholar, and DOIs/URLs from published papers, textbooks, and webpages, including keywords listed below. Textbook and webpage citations are a selection and not comprehensive, serving to illustrate the widespread narrative on human ovarian development.OUTCOMESGerm cell number estimates (oogonia, oocytes, NGF) in human embryonic, foetal, and newborn ovaries (n = 139) in seven studies from 1953 until 2011 used three different quantitation methods: (i) volumetric/model-based with correction factors, (ii) volumetric/modified stereology, and (iii) fractionator/optical dissector. In a 1963 study, germ cells in paired foetal ovaries at 20 weeks (n = 2) reported 6.8 million in total with 20% atretic, and at birth (n = 2), 2 million in total with 50% atretic, leading to the narrative that the mid-gestation human female foetus has 7 million germ cells/NGF that are subsequently depleted to 1-2 million by birth. Independent investigations of germ cell quantitation/degeneration do not confirm these findings for total numbers nor the substantial fractions reported as degenerating. In adult women, ovarian volume is strongly correlated with the numbers of NGF but an equivalent correlation between germ cell supply and ovarian volume during foetal life up to birth has not been investigated. We conclude that the narrative whereby human foetal ovaries develop millions of germ cells followed by most degenerating up to b
{"title":"The human ovarian reserve: the narrative and the science.","authors":"Jeffrey B Kerr,Raymond J Rodgers","doi":"10.1093/humupd/dmaf031","DOIUrl":"https://doi.org/10.1093/humupd/dmaf031","url":null,"abstract":"BACKGROUNDThe ovarian reserve is the quantity of non-growing primordial follicles (NGF) in paired ovaries. A low or high ovarian reserve at birth respectively may foreshadow early or late age at menopause. In textbooks, published papers, and internet modalities, a recurring theme is that for human females, on average, mid-gestation marks the peak supply of 7 million germ cells/NGF followed by large-scale depletion to about 1-2 million in paired ovaries at birth.OBJECTIVE AND RATIONALEWe test this narrative against the evidence for germ cell quantity and degeneration reported in peer-reviewed publications. Ovary sizes, volumes/shapes are particularly variable among same-age foetuses and at birth. Coupled with genomic mechanisms determining germ cell proliferation/differentiation/survival, substantial variations of germ cell numbers are recorded within and between individual studies. Across published papers, textbooks, and webpages, germ cell numbers in foetal-newborn ovaries range from thousands to 20 million. A massive 70-85% die-off among germ cells in foetal ovaries is reported during the second half of gestation. Although germ cell degeneration is a reality, we review also the evidence for the timing and extent of germ cell death in foetal/newborn human ovaries.SEARCH METHODSWe cite primary publications of human embryonic, foetal/newborn ovaries where data on germ cell numbers and death are reported, and similarly for studies of ovarian volume, shape, histology, and growth in foetal-early postnatal life. Searches to September 2025 used PubMed, Google Scholar, and DOIs/URLs from published papers, textbooks, and webpages, including keywords listed below. Textbook and webpage citations are a selection and not comprehensive, serving to illustrate the widespread narrative on human ovarian development.OUTCOMESGerm cell number estimates (oogonia, oocytes, NGF) in human embryonic, foetal, and newborn ovaries (n = 139) in seven studies from 1953 until 2011 used three different quantitation methods: (i) volumetric/model-based with correction factors, (ii) volumetric/modified stereology, and (iii) fractionator/optical dissector. In a 1963 study, germ cells in paired foetal ovaries at 20 weeks (n = 2) reported 6.8 million in total with 20% atretic, and at birth (n = 2), 2 million in total with 50% atretic, leading to the narrative that the mid-gestation human female foetus has 7 million germ cells/NGF that are subsequently depleted to 1-2 million by birth. Independent investigations of germ cell quantitation/degeneration do not confirm these findings for total numbers nor the substantial fractions reported as degenerating. In adult women, ovarian volume is strongly correlated with the numbers of NGF but an equivalent correlation between germ cell supply and ovarian volume during foetal life up to birth has not been investigated. We conclude that the narrative whereby human foetal ovaries develop millions of germ cells followed by most degenerating up to b","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"11 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145835985","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}
Alessandro M Volsa,Eva R Hoffmann,Pablo J Ross,Sebastian Canovas
BACKGROUNDMammalian embryo development involves a complex process governed by multiple layers of cellular and molecular regulation mechanisms. ART is widely used around the world to assist fertility in humans, with ∼12 million babies being born by ART in the last 40 years. These technologies are also used extensively for reproductive purposes in other mammalian species that have many analogies with human reproductive biology. Epitranscriptomic marks, including RNA modifications such as N6-methyladenosine (m6A) and N1-methyladenosine (m1A), modulate gene expression during gametogenesis and embryo development, and their dynamics are regulated by genes encoding m6A writers (METTL3, METTL14, and WTAP), readers (YTHDF2, YTHDC1-2, and PRRC2A), and erasers (ALKBH5 and FTO). However, the impact of ART on these epigenetic modifications remains poorly understood.OBJECTIVE AND RATIONALEThis narrative review explores the role of epitranscriptomic modifications in both naturally and ART-conceived embryos. It examines how RNA modifications regulate gametogenesis and early embryonic development and how ART-induced cellular stress might perturb these regulatory layers, potentially affecting gametogenesis, embryo competence, and offspring health. Understanding the interaction between ART and epitranscriptomic regulation is crucial for optimizing ART procedures and safeguarding offspring health.SEARCH METHODSThe PubMed and Scopus literature databases were utilized to search for peer-reviewed articles and reviews using terms such as 'epitranscriptomic', 'RNA modification', 'gametogenesis', 'embryo development', 'mammalian development', 'in vitro fertilization', 'ART', and 'assisted reproductive technologies' in combination or individually. All relevant publications until the current year have been critically evaluated and discussed.OUTCOMESEpitranscriptomic modifications, particularly m6A, have emerged as key regulators of RNA metabolism during gametogenesis and early embryo development. Evidence from both human and animal studies indicates that ART-related stressors, such as oxidative imbalance, hormonal stimulation, and cryopreservation, can disturb RNA methylation at the epitranscriptomic marks m1A and 5-methylcytosine by modulating the expression and activity of m6A writers, erasers, and readers, independently of global transcriptional changes. These alterations can affect embryo competence, placental function, lineage specification, and subsequent offspring development. Moreover, m6A-associated factors participate in stress adaptation and developmental signalling beyond their canonical methylation activity. Collectively, these findings underscore the remarkable sensitivity of the embryonic transcriptome to in vitro manipulation and highlight epitranscriptomic marks as both predictive biomarkers and mechanistic targets for improving the safety, efficacy, and long-term outcomes of assisted reproduction.WIDER IMPLICATIONSUnderstanding how ARTs influence the epitr
{"title":"Epitranscriptomic modifications in embryonic development: insights into natural and ART-induced mechanisms and implications.","authors":"Alessandro M Volsa,Eva R Hoffmann,Pablo J Ross,Sebastian Canovas","doi":"10.1093/humupd/dmaf032","DOIUrl":"https://doi.org/10.1093/humupd/dmaf032","url":null,"abstract":"BACKGROUNDMammalian embryo development involves a complex process governed by multiple layers of cellular and molecular regulation mechanisms. ART is widely used around the world to assist fertility in humans, with ∼12 million babies being born by ART in the last 40 years. These technologies are also used extensively for reproductive purposes in other mammalian species that have many analogies with human reproductive biology. Epitranscriptomic marks, including RNA modifications such as N6-methyladenosine (m6A) and N1-methyladenosine (m1A), modulate gene expression during gametogenesis and embryo development, and their dynamics are regulated by genes encoding m6A writers (METTL3, METTL14, and WTAP), readers (YTHDF2, YTHDC1-2, and PRRC2A), and erasers (ALKBH5 and FTO). However, the impact of ART on these epigenetic modifications remains poorly understood.OBJECTIVE AND RATIONALEThis narrative review explores the role of epitranscriptomic modifications in both naturally and ART-conceived embryos. It examines how RNA modifications regulate gametogenesis and early embryonic development and how ART-induced cellular stress might perturb these regulatory layers, potentially affecting gametogenesis, embryo competence, and offspring health. Understanding the interaction between ART and epitranscriptomic regulation is crucial for optimizing ART procedures and safeguarding offspring health.SEARCH METHODSThe PubMed and Scopus literature databases were utilized to search for peer-reviewed articles and reviews using terms such as 'epitranscriptomic', 'RNA modification', 'gametogenesis', 'embryo development', 'mammalian development', 'in vitro fertilization', 'ART', and 'assisted reproductive technologies' in combination or individually. All relevant publications until the current year have been critically evaluated and discussed.OUTCOMESEpitranscriptomic modifications, particularly m6A, have emerged as key regulators of RNA metabolism during gametogenesis and early embryo development. Evidence from both human and animal studies indicates that ART-related stressors, such as oxidative imbalance, hormonal stimulation, and cryopreservation, can disturb RNA methylation at the epitranscriptomic marks m1A and 5-methylcytosine by modulating the expression and activity of m6A writers, erasers, and readers, independently of global transcriptional changes. These alterations can affect embryo competence, placental function, lineage specification, and subsequent offspring development. Moreover, m6A-associated factors participate in stress adaptation and developmental signalling beyond their canonical methylation activity. Collectively, these findings underscore the remarkable sensitivity of the embryonic transcriptome to in vitro manipulation and highlight epitranscriptomic marks as both predictive biomarkers and mechanistic targets for improving the safety, efficacy, and long-term outcomes of assisted reproduction.WIDER IMPLICATIONSUnderstanding how ARTs influence the epitr","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"25 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145823893","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}
BACKGROUNDHuman-induced pluripotent stem cells (hiPSCs) offer immense potential in reproductive medicine, particularly for males who lack germ cells and cannot achieve biological parenthood through conventional ARTs. Early efforts to derive human germ cells from stem cells were hindered by low efficiency, subpar characterization, and the lack of standardized differentiation approaches. However, recent advancements have led to the development of defined protocols that mimic early embryonic development and allow the specification of transcriptomically and epigenetically validated human primordial germ cell-like cells (hPGCLCs). Current research focuses on maturing hPGCLCs in vitro, particularly within 3D culture systems that resemble their physiological microenvironment, with the aim of producing transplantable hiPSC-derived spermatogonial stem cells (SSCs) or differentiating them to sperm. At the same time, researchers are also testing whether hiPSCs generated from infertile patients can resume germline differentiation.OBJECTIVE AND RATIONALEThis narrative review aimed to summarize the key efforts and remaining challenges in differentiating male germ cells from human pluripotent stem cells (hPSCs), with a particular focus on defined and validated protocols for hPGCLC specification. In parallel, we addressed key safety and ethical considerations that must be accounted for the development of clinical applications. A deeper understanding of the approaching therapeutic use of hiPSCs in reproductive medicine is essential for developing novel regenerative fertility strategies.SEARCH METHODSPubMed, Scopus, and Web of Science were searched for studies attempting germ cell differentiation from hPSCs using relevant keywords ('stem cells', 'human pluripotent stem cells', 'human embryonic stem cells', 'human induced pluripotent stem cells', 'somatic cell reprogramming', 'infertility', 'germline', 'spermatogenesis', 'germ cells', and 'primordial germ cells'). No time period restriction was established. Studies with an exclusive focus on female germline differentiation were excluded. To maintain a human-focused perspective, only key animal studies are presented.OUTCOMESThe literature reveals a clear segregation among protocols for deriving germ cells from hPSCs, particularly between earlier studies lacking standardized differentiation conditions and characterization, and the most recent, defined protocols having transcriptomic and epigenetic validation against in vivo hPGCs. Moreover, during the last decade, the field has seen remarkable progress, with multiple efforts aimed at maturing hPGCLCs, closely recapitulating late male embryonic germline development. Additionally, hiPSCs derived from male patients at risk of infertility, particularly those without underlying genetic syndromes, generally retain the capacity for early germline commitment. While attempts at maturating patient germ cells beyond the hPGCLC state remain limited, the rapid pace of discovery a
背景：人类诱导的多能干细胞（hiPSCs）在生殖医学方面提供了巨大的潜力，特别是对于那些缺乏生殖细胞和不能通过传统的抗逆转录病毒疗法实现生物生育的男性。早期从干细胞中获得人类生殖细胞的努力受到效率低、特性不达标和缺乏标准化分化方法的阻碍。然而，最近的进展导致了模拟早期胚胎发育的定义方案的发展，并允许对转录组学和表观遗传学验证的人类原始生殖细胞样细胞（hpgclc）进行规范。目前的研究主要集中在体外成熟的hpgclc，特别是在类似其生理微环境的3D培养系统中，目的是产生可移植的hipsc衍生的精原干细胞（SSCs）或将其分化为精子。与此同时，研究人员也在测试不孕患者产生的hipsc能否恢复种系分化。目的和理由：本综述旨在总结从人类多能干细胞（hPSCs）中分化男性生殖细胞的关键努力和仍然存在的挑战，特别关注hPGCLC规范的定义和验证方案。同时，我们解决了临床应用开发必须考虑的关键安全和伦理问题。深入了解hipsc在生殖医学中的治疗用途对于开发新的再生生育策略至关重要。搜索方法使用相关关键词（“干细胞”、“人类多能干细胞”、“人类胚胎干细胞”、“人类诱导多能干细胞”、“体细胞重编程”、“不育”、“生殖系”、“精子发生”、“生殖细胞”和“原始生殖细胞”），对spubmed、Scopus和Web of Science进行搜索，以尝试从hPSCs中分化生殖细胞。没有时间限制。排除了专门关注女性生殖系分化的研究。为了保持以人类为中心的观点，只介绍了关键的动物研究。结果：文献揭示了从人乳头瘤干细胞中获得生殖细胞的方案之间存在明显的分离，特别是在缺乏标准化分化条件和表征的早期研究与最近定义的针对体内人乳头瘤干细胞的转录组学和表观遗传学验证的方案之间。此外，在过去的十年中，该领域取得了显著的进展，多项努力旨在成熟的hpgclc，密切再现晚期男性胚胎种系发育。此外，来自有不育风险的男性患者的hipsc，特别是那些没有潜在遗传综合征的患者，通常保留早期生殖细胞承育的能力。尽管将患者生殖细胞成熟到超越hPGCLC状态的尝试仍然有限，但近年来发现和改进的快速步伐表明，在不久的将来可能会取得进一步的突破，包括临床适用的生育恢复策略。从不孕症患者中产生hipsc并将其指定为hpgclc的能力支持了获得hipsc衍生的SSCs用于未来治疗的可行性。这些进步提出了重要的伦理、监管和社会问题，必须在研究人员、临床医生、政策制定者和公众之间积极讨论，以确保负责任和公平地获得这些技术。登记NUMBERN /。
{"title":"The road to restore male fertility using in vitro-derived germ cells.","authors":"Tiago Macedo,João Pedro Alves-Lopes","doi":"10.1093/humupd/dmaf029","DOIUrl":"https://doi.org/10.1093/humupd/dmaf029","url":null,"abstract":"BACKGROUNDHuman-induced pluripotent stem cells (hiPSCs) offer immense potential in reproductive medicine, particularly for males who lack germ cells and cannot achieve biological parenthood through conventional ARTs. Early efforts to derive human germ cells from stem cells were hindered by low efficiency, subpar characterization, and the lack of standardized differentiation approaches. However, recent advancements have led to the development of defined protocols that mimic early embryonic development and allow the specification of transcriptomically and epigenetically validated human primordial germ cell-like cells (hPGCLCs). Current research focuses on maturing hPGCLCs in vitro, particularly within 3D culture systems that resemble their physiological microenvironment, with the aim of producing transplantable hiPSC-derived spermatogonial stem cells (SSCs) or differentiating them to sperm. At the same time, researchers are also testing whether hiPSCs generated from infertile patients can resume germline differentiation.OBJECTIVE AND RATIONALEThis narrative review aimed to summarize the key efforts and remaining challenges in differentiating male germ cells from human pluripotent stem cells (hPSCs), with a particular focus on defined and validated protocols for hPGCLC specification. In parallel, we addressed key safety and ethical considerations that must be accounted for the development of clinical applications. A deeper understanding of the approaching therapeutic use of hiPSCs in reproductive medicine is essential for developing novel regenerative fertility strategies.SEARCH METHODSPubMed, Scopus, and Web of Science were searched for studies attempting germ cell differentiation from hPSCs using relevant keywords ('stem cells', 'human pluripotent stem cells', 'human embryonic stem cells', 'human induced pluripotent stem cells', 'somatic cell reprogramming', 'infertility', 'germline', 'spermatogenesis', 'germ cells', and 'primordial germ cells'). No time period restriction was established. Studies with an exclusive focus on female germline differentiation were excluded. To maintain a human-focused perspective, only key animal studies are presented.OUTCOMESThe literature reveals a clear segregation among protocols for deriving germ cells from hPSCs, particularly between earlier studies lacking standardized differentiation conditions and characterization, and the most recent, defined protocols having transcriptomic and epigenetic validation against in vivo hPGCs. Moreover, during the last decade, the field has seen remarkable progress, with multiple efforts aimed at maturing hPGCLCs, closely recapitulating late male embryonic germline development. Additionally, hiPSCs derived from male patients at risk of infertility, particularly those without underlying genetic syndromes, generally retain the capacity for early germline commitment. While attempts at maturating patient germ cells beyond the hPGCLC state remain limited, the rapid pace of discovery a","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785831","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}
Virginia Pensabene,Federica Agate,Andreia Santos Miranda,Helen Mary Picton
BACKGROUNDThis narrative review analyses the development of microfluidic technologies specifically applied to the IVF treatment, and their translation into clinical solution.OBJECTIVE AND RATIONALEStarting with an analysis of the latest scientific publications, the patent scenario and the current clinical trials were analysed aiming to identify the most developed applications, the challenges, and barriers for regulatory approval and clinical validation in different countries.SEARCH METHODSSearches were completed in English, by using a combination of these keywords (exceptions are included in the text in the different sections): Microfluidic, IVF, Assisted, clinical, fertility, human fertility, women fertility, reproduction, pregnancy, Assisted Reproductive Technology. These were used for previously published reviews and scientific journal papers using PubMed (National Center for Biotechnology Information at the U.S. National Library of Medicine), and Google Scholar, limited to the last decade (2013-2025); for completed or ongoing clinical trials using Clinicaltrials.gov; for existing patents and intellectual properties commercialization using lens.org, and crosschecked on espacenet.com from 2000 to 2025.OUTCOMESIt is approximately 20 years since the design of the first microfluidic systems for IVF. In the last 5 years, there have been over 130 publications proposing new microfluidic solutions, with pre-clinical validation data in animal models and humans. Our analysis highlighted three main areas of development that are discussed in terms of trends and advancements in oocyte and sperm processing and handling; proposed solutions to support in vitro embryo development; and microfluidic-based approaches and techniques for cryopreservation and female fertility preservation. In the last 20 years, progression of the microfluidic technology and improvement of manufacturing processes have led to an exponential rise of patents (1405) where microfluidics is applied to different steps of the assisted conception cycle. However, of these innovative techniques, only a limited number have progressed to clinical validation (19 trials commenced since 2009) and these have focused primarily on microfluidic sperm sorting and selection with multiple trials investigating its effectiveness in enhancing sperm quality and fertilization rates, and microfluidic embryo culture systems, where additional research is still needed to establish benefits over traditional culture environments. The key barriers to adoption include the need for long-term clinical outcome data, standardization of results across various patient populations, and regulatory challenges. We summarize the pathways needed to ensure compliance with quality standards and regulations in different countries. This analysis evaluates the different clinical trial requirements and challenges for participant recruitment, as well as study design complexity, and the definition of achievable endpoints and establishment
{"title":"Microfluidics for in vitro fertilization: from science to clinical validation.","authors":"Virginia Pensabene,Federica Agate,Andreia Santos Miranda,Helen Mary Picton","doi":"10.1093/humupd/dmaf028","DOIUrl":"https://doi.org/10.1093/humupd/dmaf028","url":null,"abstract":"BACKGROUNDThis narrative review analyses the development of microfluidic technologies specifically applied to the IVF treatment, and their translation into clinical solution.OBJECTIVE AND RATIONALEStarting with an analysis of the latest scientific publications, the patent scenario and the current clinical trials were analysed aiming to identify the most developed applications, the challenges, and barriers for regulatory approval and clinical validation in different countries.SEARCH METHODSSearches were completed in English, by using a combination of these keywords (exceptions are included in the text in the different sections): Microfluidic, IVF, Assisted, clinical, fertility, human fertility, women fertility, reproduction, pregnancy, Assisted Reproductive Technology. These were used for previously published reviews and scientific journal papers using PubMed (National Center for Biotechnology Information at the U.S. National Library of Medicine), and Google Scholar, limited to the last decade (2013-2025); for completed or ongoing clinical trials using Clinicaltrials.gov; for existing patents and intellectual properties commercialization using lens.org, and crosschecked on espacenet.com from 2000 to 2025.OUTCOMESIt is approximately 20 years since the design of the first microfluidic systems for IVF. In the last 5 years, there have been over 130 publications proposing new microfluidic solutions, with pre-clinical validation data in animal models and humans. Our analysis highlighted three main areas of development that are discussed in terms of trends and advancements in oocyte and sperm processing and handling; proposed solutions to support in vitro embryo development; and microfluidic-based approaches and techniques for cryopreservation and female fertility preservation. In the last 20 years, progression of the microfluidic technology and improvement of manufacturing processes have led to an exponential rise of patents (1405) where microfluidics is applied to different steps of the assisted conception cycle. However, of these innovative techniques, only a limited number have progressed to clinical validation (19 trials commenced since 2009) and these have focused primarily on microfluidic sperm sorting and selection with multiple trials investigating its effectiveness in enhancing sperm quality and fertilization rates, and microfluidic embryo culture systems, where additional research is still needed to establish benefits over traditional culture environments. The key barriers to adoption include the need for long-term clinical outcome data, standardization of results across various patient populations, and regulatory challenges. We summarize the pathways needed to ensure compliance with quality standards and regulations in different countries. This analysis evaluates the different clinical trial requirements and challenges for participant recruitment, as well as study design complexity, and the definition of achievable endpoints and establishment","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"138 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680617","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":"The value of narrative reviews: beyond data synthesis.","authors":"Madelon Van Wely","doi":"10.1093/humupd/dmaf027","DOIUrl":"https://doi.org/10.1093/humupd/dmaf027","url":null,"abstract":"","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"4 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583388","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}
Murat Sonmezer, Koray Gorkem Sacinti, Kutluk H Oktay
BACKGROUND There has been an unprecedented progress in the field of fertility preservation (FP) beginning in the late 1990s. Specifically, technological innovations, refinements in the protocols, and a deeper understanding of reproductive physiology have collectively contributed the increased success and utilization of FP methods. OBJECTIVE AND RATIONALE The objectives of this review are: (i) to identify the most recent and significant advances in FP, and (ii) based on evidence, to provide a comprehensive and up-to-date source of contemporary FP management approaches to guide clinicians in critical decision-making. In addition to cancer treatments, the indications for FP have expanded to include various systemic conditions such as haematological, metabolic, genetic, and immunological disorders, as well as gonadal surgery and a wish to delay childbearing. Due to the introduction of random start ovarian stimulation protocols and use of anti-oestrogen agents along with ovarian stimulation drugs, coupled with increased success with oocyte cryopreservation, improvements in ovarian tissue cryopreservation and refinements of transplantation techniques, women can now benefit from various FP options through an individualized approach. SEARCH METHODS We searched for peer-reviewed articles in PubMed, Embase, and Cochrane Library databases containing the key words: FP, ovarian ageing, chemotherapy, radiotherapy, embryo cryopreservation, oocyte cryopreservation, ovarian tissue cryopreservation, and in vitro follicle growth, in the English-language literature from inception to May 2025. OUTCOMES Cryopreservation of embryos have long been performed successfully in the field of ART. With the advent and widespread of use vitrification, the experimental tag was removed and oocyte cryopreservation was defined as a standard technique of FP. The applicability, success, and safety of random start ovarian stimulation protocols have been demonstrated in many studies including meta-analyses. Improvements in ovarian tissue cryopreservation outcomes have been reported with robotic surgery, use of neovascularizing extracellular matrix, and adjuvant pharmacotherapy. The use of GnRH analogues along with chemotherapy has been trialled as a way of avoiding the need for FP. Although the rate of premature ovarian insufficiency was reported to be lower in some patient populations treated this way, no improvements in live birth rates have been demonstrated. Among the emerging and future options are the use of ovarian tissue freezing and pharmacological approaches to delay menopause and reproductive ageing, non-suppressive gonadoprotective pharmacotherapy, in vitro gametogenesis and in vitro purging of cancer cells from ovarian tissue for cryopreservation. Animal studies have reported success with in vitro follicle growth, and progress is being made with human ovarian tissue. WIDER IMPLICATIONS The evolution of FP techniques has profound implications for clinical practice, not only
{"title":"Female fertility preservation: 25 years of progress, expanding indications and future prospects","authors":"Murat Sonmezer, Koray Gorkem Sacinti, Kutluk H Oktay","doi":"10.1093/humupd/dmaf026","DOIUrl":"https://doi.org/10.1093/humupd/dmaf026","url":null,"abstract":"BACKGROUND There has been an unprecedented progress in the field of fertility preservation (FP) beginning in the late 1990s. Specifically, technological innovations, refinements in the protocols, and a deeper understanding of reproductive physiology have collectively contributed the increased success and utilization of FP methods. OBJECTIVE AND RATIONALE The objectives of this review are: (i) to identify the most recent and significant advances in FP, and (ii) based on evidence, to provide a comprehensive and up-to-date source of contemporary FP management approaches to guide clinicians in critical decision-making. In addition to cancer treatments, the indications for FP have expanded to include various systemic conditions such as haematological, metabolic, genetic, and immunological disorders, as well as gonadal surgery and a wish to delay childbearing. Due to the introduction of random start ovarian stimulation protocols and use of anti-oestrogen agents along with ovarian stimulation drugs, coupled with increased success with oocyte cryopreservation, improvements in ovarian tissue cryopreservation and refinements of transplantation techniques, women can now benefit from various FP options through an individualized approach. SEARCH METHODS We searched for peer-reviewed articles in PubMed, Embase, and Cochrane Library databases containing the key words: FP, ovarian ageing, chemotherapy, radiotherapy, embryo cryopreservation, oocyte cryopreservation, ovarian tissue cryopreservation, and in vitro follicle growth, in the English-language literature from inception to May 2025. OUTCOMES Cryopreservation of embryos have long been performed successfully in the field of ART. With the advent and widespread of use vitrification, the experimental tag was removed and oocyte cryopreservation was defined as a standard technique of FP. The applicability, success, and safety of random start ovarian stimulation protocols have been demonstrated in many studies including meta-analyses. Improvements in ovarian tissue cryopreservation outcomes have been reported with robotic surgery, use of neovascularizing extracellular matrix, and adjuvant pharmacotherapy. The use of GnRH analogues along with chemotherapy has been trialled as a way of avoiding the need for FP. Although the rate of premature ovarian insufficiency was reported to be lower in some patient populations treated this way, no improvements in live birth rates have been demonstrated. Among the emerging and future options are the use of ovarian tissue freezing and pharmacological approaches to delay menopause and reproductive ageing, non-suppressive gonadoprotective pharmacotherapy, in vitro gametogenesis and in vitro purging of cancer cells from ovarian tissue for cryopreservation. Animal studies have reported success with in vitro follicle growth, and progress is being made with human ovarian tissue. WIDER IMPLICATIONS The evolution of FP techniques has profound implications for clinical practice, not only ","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"28 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472886","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}
Hadas Ganer Herman, Ido Feferkorn, Michael H Dahan, Shauna Reinblatt, Ezgi Demirtas, William Buckett
Background: There has been an increase in the average age of patients seeking fertility treatments over the past decades, with a significantly higher rate of advanced maternal age (AMA) patients undergoing IVF. It is unclear if different treatment strategies in IVF improve outcomes in AMA patients.
Objective and rationale: The aim of this systematic review was to assess the efficacy of different interventions employed in IVF in patients of AMA.
Search methods: A comprehensive search in Embase, Medline, and the Cochrane Library was performed. The search strategy included keywords related to IVF and AMA. We included all original peer-reviewed articles published in English, from January 1985 to September 2024, primarily designed to assess the efficacy of different interventions in IVF on clinical outcomes in AMA patients. Meta-analyses were performed for interventions for which sufficient randomized controlled trials existed.
Outcomes: A total of 151 studies were included in the review. AMA was not consistently defined in all studies reviewed, although common to all studies was an age above 35 years. For the majority of evidence, there appeared to be no clear advantage to any stimulation protocol in AMA patients. There also appeared to be no advantage to any specific FSH medication, while a meta-analysis performed for the addition of LH to follicular stimulating hormone in stimulation demonstrated similar clinical pregnancy and live birth rates. No good evidence was found to support the routine implementation of ICSI in AMA patients, while a meta-analysis performed for assisted hatching (AH) pointed to decreased live birth rates with its implementation. Low-quality evidence demonstrated an increase in live birth rates with multiple embryos transferred with an increase in multiple pregnancies delivered. Finally, a meta-analysis performed for preimplantation genetic testing for aneuploidy (PGT-A) pointed to similar live birth rates as for no testing.
Wider implications: This review failed to find an advantage to the routine implementation of treatment strategies such as specific stimulation protocols and gonadotropins, ICSI, and PGT-A, and a potential harmful effect for AH. Future high-quality randomized controlled trials are needed to affirm the majority of this review's conclusions.
{"title":"A meta-analysis and systematic review of advanced maternal age patients in IVF.","authors":"Hadas Ganer Herman, Ido Feferkorn, Michael H Dahan, Shauna Reinblatt, Ezgi Demirtas, William Buckett","doi":"10.1093/humupd/dmaf020","DOIUrl":"10.1093/humupd/dmaf020","url":null,"abstract":"<p><strong>Background: </strong>There has been an increase in the average age of patients seeking fertility treatments over the past decades, with a significantly higher rate of advanced maternal age (AMA) patients undergoing IVF. It is unclear if different treatment strategies in IVF improve outcomes in AMA patients.</p><p><strong>Objective and rationale: </strong>The aim of this systematic review was to assess the efficacy of different interventions employed in IVF in patients of AMA.</p><p><strong>Search methods: </strong>A comprehensive search in Embase, Medline, and the Cochrane Library was performed. The search strategy included keywords related to IVF and AMA. We included all original peer-reviewed articles published in English, from January 1985 to September 2024, primarily designed to assess the efficacy of different interventions in IVF on clinical outcomes in AMA patients. Meta-analyses were performed for interventions for which sufficient randomized controlled trials existed.</p><p><strong>Outcomes: </strong>A total of 151 studies were included in the review. AMA was not consistently defined in all studies reviewed, although common to all studies was an age above 35 years. For the majority of evidence, there appeared to be no clear advantage to any stimulation protocol in AMA patients. There also appeared to be no advantage to any specific FSH medication, while a meta-analysis performed for the addition of LH to follicular stimulating hormone in stimulation demonstrated similar clinical pregnancy and live birth rates. No good evidence was found to support the routine implementation of ICSI in AMA patients, while a meta-analysis performed for assisted hatching (AH) pointed to decreased live birth rates with its implementation. Low-quality evidence demonstrated an increase in live birth rates with multiple embryos transferred with an increase in multiple pregnancies delivered. Finally, a meta-analysis performed for preimplantation genetic testing for aneuploidy (PGT-A) pointed to similar live birth rates as for no testing.</p><p><strong>Wider implications: </strong>This review failed to find an advantage to the routine implementation of treatment strategies such as specific stimulation protocols and gonadotropins, ICSI, and PGT-A, and a potential harmful effect for AH. Future high-quality randomized controlled trials are needed to affirm the majority of this review's conclusions.</p><p><strong>Registration number: </strong>PROSPERO ID: CRD42022335889.</p>","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":"626-642"},"PeriodicalIF":16.1,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144849687","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}
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