BACKGROUNDPreconception health (PCH) is a globally accepted strategy to reduce preventable adverse pregnancy outcomes and ultimately improve the health of the unborn child. Optimal PCH can be achieved through preconception care (PCC), which encompasses the behavioural, biomedical, and social interventions women and couples undertake and/or receive before conception. However, there is a lack of clarity on various aspects of PCH and PCC, such as what constitutes preconception risk factors, what the optimal interventions are, when the preconception period is, and who the overall target population is. Additionally, marginalised groups such as sexual and racial or ethnic minority individuals are routinely excluded from PCH research and PCC interventions. PCH and PCC are topical issues given changing societal norms worldwide, such as delayed childbirth, exponential rises in fertility treatments, and the growing trend of unplanned pregnancies. We hypothesised that the ambiguity surrounding the definition of PCH and PCC may limit their understanding and application to improve pregnancy and childhood outcomes.OBJECTIVE AND RATIONALEThis is a systematic review of existing definitions of PCH and PCC to understand the commonalities and disparities in definitions and critical components of PCH and PCC, to aid in the development of a comprehensive and globally standardised definition.SEARCH METHODSMEDLINE, PubMed, EMBASE, Cochrane Library, CINAHL, Google Scholar, PsychINFO, and Google were searched to identify published studies, guidelines, and public health websites containing definitions of PCH and PCC published between January 1993 and October 2024. No restrictions were placed on language. We searched academic databases, organisational reports, and policy documents to capture the full range of definitions across clinical, health, and policy contexts.OUTCOMESThe narrative synthesis of 176 publications showed heterogeneity in the definitions of PCH and PCC. The themes developed from the thematic analysis showed that PCC is preventative care which identifies and utilises interventions to manage individuals' preconception risk factors and aims to improve pregnancy outcomes by optimising the short- and long-term health of potential parents and their children. The analysis also showed that PCH is relevant across the entire reproductive lifespan. PCC was described as a continuum of care that occurs before conception and encompasses the health of all potential parents, not just women.WIDER IMPLICATIONSThis systematic review found there is a lack of universality in the definitions of PCH and PCC. Current definitions often narrowly focus on women planning pregnancy, which may exclude important demographics such as unintended pregnancies and fathers, and aligned health needs such as contraception in the preconception period. We propose that there is a need for a definition that captures various demographics and emphasises a life-course approach to reproductive health,
{"title":"What do we mean by preconception health and preconception care in research and policy? A systematic review.","authors":"Olivia Chingara,Annabelle Sümegi,Susan Logan,Siladitya Bhattacharya,Andrea Woolner","doi":"10.1093/humupd/dmag005","DOIUrl":"https://doi.org/10.1093/humupd/dmag005","url":null,"abstract":"BACKGROUNDPreconception health (PCH) is a globally accepted strategy to reduce preventable adverse pregnancy outcomes and ultimately improve the health of the unborn child. Optimal PCH can be achieved through preconception care (PCC), which encompasses the behavioural, biomedical, and social interventions women and couples undertake and/or receive before conception. However, there is a lack of clarity on various aspects of PCH and PCC, such as what constitutes preconception risk factors, what the optimal interventions are, when the preconception period is, and who the overall target population is. Additionally, marginalised groups such as sexual and racial or ethnic minority individuals are routinely excluded from PCH research and PCC interventions. PCH and PCC are topical issues given changing societal norms worldwide, such as delayed childbirth, exponential rises in fertility treatments, and the growing trend of unplanned pregnancies. We hypothesised that the ambiguity surrounding the definition of PCH and PCC may limit their understanding and application to improve pregnancy and childhood outcomes.OBJECTIVE AND RATIONALEThis is a systematic review of existing definitions of PCH and PCC to understand the commonalities and disparities in definitions and critical components of PCH and PCC, to aid in the development of a comprehensive and globally standardised definition.SEARCH METHODSMEDLINE, PubMed, EMBASE, Cochrane Library, CINAHL, Google Scholar, PsychINFO, and Google were searched to identify published studies, guidelines, and public health websites containing definitions of PCH and PCC published between January 1993 and October 2024. No restrictions were placed on language. We searched academic databases, organisational reports, and policy documents to capture the full range of definitions across clinical, health, and policy contexts.OUTCOMESThe narrative synthesis of 176 publications showed heterogeneity in the definitions of PCH and PCC. The themes developed from the thematic analysis showed that PCC is preventative care which identifies and utilises interventions to manage individuals' preconception risk factors and aims to improve pregnancy outcomes by optimising the short- and long-term health of potential parents and their children. The analysis also showed that PCH is relevant across the entire reproductive lifespan. PCC was described as a continuum of care that occurs before conception and encompasses the health of all potential parents, not just women.WIDER IMPLICATIONSThis systematic review found there is a lack of universality in the definitions of PCH and PCC. Current definitions often narrowly focus on women planning pregnancy, which may exclude important demographics such as unintended pregnancies and fathers, and aligned health needs such as contraception in the preconception period. We propose that there is a need for a definition that captures various demographics and emphasises a life-course approach to reproductive health,","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"100 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350720","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}
Hannah E Lyons, Cristina N Arriaran Scott, Sarah A Robertson, David J Sharkey
<p><strong>Background: </strong>Male fertility investigation is currently limited to semen analysis. However, the origins of abnormal sperm parameters are not well-understood, and normal sperm do not assure fertility in men. Improved pathophysiological and prognostic insight might be achieved utilising additional measures of male reproductive tract function. Cytokine and chemokine levels in seminal plasma (SP) may be relevant, but evidence on their clinical significance is unclear. The utility of measuring SP cytokines remains uncertain, and no consensus exists on which cytokines are most informative.</p><p><strong>Objective and rationale: </strong>To perform a systematic review and meta-analysis on the association between fertility status and concentration of seminal plasma cytokines in men. The sixth edition of the WHO laboratory manual for the examination and processing of human semen raises the prospect of evaluating cytokines in SP as part of an extended examination. We performed a systematic search and meta-analysis to assess whether the current literature is sufficient to identify cytokines present in human SP that exhibit a relationship with fertility status in men.</p><p><strong>Search methods: </strong>We searched PubMed, Web of Science, Scopus, and Embase from inception until April 2025, using keywords pertaining to seminal fluid and cytokines, restricted to humans and the English language. Original data with values reported as concentration of cytokines in SP of men clearly defined as infertile, compared to a discernible population of fertile/normozoospermic healthy control men, were included. A total of 5737 studies were identified, with 2737 duplicates removed. Title and abstract screening were performed for 3000 studies, then 291 studies underwent full-text screening, and 68 studies progressed to quality assessment using the NHLBI-NIH quality assessment tool and 52 studies underwent data extraction.</p><p><strong>Outcomes: </strong>We identified 52 research articles published from 1993 to 2025 that quantified at least one cytokine in the seminal plasma of 8153 men, after 19 studies of poor quality and/or containing serious flaws were excluded. Data on 30 cytokines in the SP of healthy control and infertile men were extracted and included in narrative synthesis. Compared to fertile controls, infertile men had elevated concentrations of IL6 (SMD 0.39, 95% CI; 0.14-0.64, I2 = 80.7%), TNFA (SMD 0.13, 95% CI; 0.00-0.25, I2 = 4.3%), and CXCL8 (SMD 0.24, 95% CI; 0.06-0.43, I2 = 0.0%) in seminal plasma. IL6 reported a high degree of heterogeneity between studies, whilst CXCL8 and TNFA reported low heterogeneity. No significant moderator effects due to study quality or composition of the control cohort were identified.</p><p><strong>Wider implications: </strong>With one in six couples experiencing infertility worldwide and a male factor identified as a primary or contributing cause in up to 50% of cases, there is a strong imperative to deve
{"title":"Seminal plasma cytokines in fertile versus infertile men: a systematic review and meta-analysis.","authors":"Hannah E Lyons, Cristina N Arriaran Scott, Sarah A Robertson, David J Sharkey","doi":"10.1093/humupd/dmag003","DOIUrl":"https://doi.org/10.1093/humupd/dmag003","url":null,"abstract":"<p><strong>Background: </strong>Male fertility investigation is currently limited to semen analysis. However, the origins of abnormal sperm parameters are not well-understood, and normal sperm do not assure fertility in men. Improved pathophysiological and prognostic insight might be achieved utilising additional measures of male reproductive tract function. Cytokine and chemokine levels in seminal plasma (SP) may be relevant, but evidence on their clinical significance is unclear. The utility of measuring SP cytokines remains uncertain, and no consensus exists on which cytokines are most informative.</p><p><strong>Objective and rationale: </strong>To perform a systematic review and meta-analysis on the association between fertility status and concentration of seminal plasma cytokines in men. The sixth edition of the WHO laboratory manual for the examination and processing of human semen raises the prospect of evaluating cytokines in SP as part of an extended examination. We performed a systematic search and meta-analysis to assess whether the current literature is sufficient to identify cytokines present in human SP that exhibit a relationship with fertility status in men.</p><p><strong>Search methods: </strong>We searched PubMed, Web of Science, Scopus, and Embase from inception until April 2025, using keywords pertaining to seminal fluid and cytokines, restricted to humans and the English language. Original data with values reported as concentration of cytokines in SP of men clearly defined as infertile, compared to a discernible population of fertile/normozoospermic healthy control men, were included. A total of 5737 studies were identified, with 2737 duplicates removed. Title and abstract screening were performed for 3000 studies, then 291 studies underwent full-text screening, and 68 studies progressed to quality assessment using the NHLBI-NIH quality assessment tool and 52 studies underwent data extraction.</p><p><strong>Outcomes: </strong>We identified 52 research articles published from 1993 to 2025 that quantified at least one cytokine in the seminal plasma of 8153 men, after 19 studies of poor quality and/or containing serious flaws were excluded. Data on 30 cytokines in the SP of healthy control and infertile men were extracted and included in narrative synthesis. Compared to fertile controls, infertile men had elevated concentrations of IL6 (SMD 0.39, 95% CI; 0.14-0.64, I2 = 80.7%), TNFA (SMD 0.13, 95% CI; 0.00-0.25, I2 = 4.3%), and CXCL8 (SMD 0.24, 95% CI; 0.06-0.43, I2 = 0.0%) in seminal plasma. IL6 reported a high degree of heterogeneity between studies, whilst CXCL8 and TNFA reported low heterogeneity. No significant moderator effects due to study quality or composition of the control cohort were identified.</p><p><strong>Wider implications: </strong>With one in six couples experiencing infertility worldwide and a male factor identified as a primary or contributing cause in up to 50% of cases, there is a strong imperative to deve","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":""},"PeriodicalIF":16.1,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147272964","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}
<p><strong>Background: </strong>Tryptophan metabolism within the placenta generates bioactive metabolites, including serotonin (5-hydroxytryptamine; 5-HT), melatonin, and kynurenine derivatives, that regulate immune tolerance, vascular function, oxidative balance, and fetal neurodevelopment. Increasing evidence indicates that placental handling of tryptophan is dynamically regulated across gestation and is highly sensitive to maternal environmental and metabolic cues.</p><p><strong>Objective and rationale: </strong>The aim of this review is to examine placental tryptophan metabolism across gestation, with a focus on the 5-HT, melatonin, and kynurenine pathways. We address how these pathways are regulated during normal pregnancy and how maternal factors, including inflammation, hypoxia, oxidative stress, and cardiometabolic dysfunction, influence placental tryptophan handling in pregnancy complications such as early pregnancy loss, preeclampsia, fetal growth restriction, and preterm birth.</p><p><strong>Search methods: </strong>PubMed was searched using predefined terms related to placental tryptophan metabolism, 5-HT, melatonin, kynurenine, fetal programming, neurodevelopment, and pregnancy complications. Only full-text, peer-reviewed articles published in English were included. Abstracts and conference proceedings were excluded due to their limited data reliability.</p><p><strong>Outcomes: </strong>Placental tryptophan metabolism shows clear gestational stage-dependent regulation, and early pregnancy emerges as a formative period when pathway activity and metabolite balance are first established. From early pregnancy, maternal-decidual kynurenine pathway activity and placental 5-HT synthesis intersect with immune tolerance, vascular adaptation, and neurodevelopmental signaling. Across gestation, maternal inflammation, hypoxia, oxidative stress, and cardiometabolic disturbance can redirect the tryptophan flux and shift the balance between 5-HT/melatonin and downstream kynurenine metabolites. Evidence across pregnancy complications links early pathway disruption to pregnancy loss and supports the view that early metabolic perturbations contribute to vulnerability for later placental dysfunction, including preeclampsia, fetal growth restriction, and preterm birth.</p><p><strong>Wider implications: </strong>Placental tryptophan metabolism changes across gestation, making early pregnancy a critical window when pathway balance and fetal exposure to neuroactive metabolites are first set. Maternal inflammation, metabolic status, nutrition, and drug exposures may alter this balance, with the placenta acting as the key interface that transmits maternal signals to the fetus and shapes neurodevelopmental trajectories. To define the clinical relevance of altered tryptophan catabolism, longitudinal human studies are needed to link placental phenotypes with pregnancy outcomes and postnatal neurodevelopment. These should be complemented by mechanistic models th
{"title":"The placental tryptophan pathway across gestation: implications for pregnancy outcomes.","authors":"Rona Karahoda, David Walker, Cilia Abad, Kasin Yadunandam Anandam, Padma Murthi, Frantisek Staud","doi":"10.1093/humupd/dmag001","DOIUrl":"https://doi.org/10.1093/humupd/dmag001","url":null,"abstract":"<p><strong>Background: </strong>Tryptophan metabolism within the placenta generates bioactive metabolites, including serotonin (5-hydroxytryptamine; 5-HT), melatonin, and kynurenine derivatives, that regulate immune tolerance, vascular function, oxidative balance, and fetal neurodevelopment. Increasing evidence indicates that placental handling of tryptophan is dynamically regulated across gestation and is highly sensitive to maternal environmental and metabolic cues.</p><p><strong>Objective and rationale: </strong>The aim of this review is to examine placental tryptophan metabolism across gestation, with a focus on the 5-HT, melatonin, and kynurenine pathways. We address how these pathways are regulated during normal pregnancy and how maternal factors, including inflammation, hypoxia, oxidative stress, and cardiometabolic dysfunction, influence placental tryptophan handling in pregnancy complications such as early pregnancy loss, preeclampsia, fetal growth restriction, and preterm birth.</p><p><strong>Search methods: </strong>PubMed was searched using predefined terms related to placental tryptophan metabolism, 5-HT, melatonin, kynurenine, fetal programming, neurodevelopment, and pregnancy complications. Only full-text, peer-reviewed articles published in English were included. Abstracts and conference proceedings were excluded due to their limited data reliability.</p><p><strong>Outcomes: </strong>Placental tryptophan metabolism shows clear gestational stage-dependent regulation, and early pregnancy emerges as a formative period when pathway activity and metabolite balance are first established. From early pregnancy, maternal-decidual kynurenine pathway activity and placental 5-HT synthesis intersect with immune tolerance, vascular adaptation, and neurodevelopmental signaling. Across gestation, maternal inflammation, hypoxia, oxidative stress, and cardiometabolic disturbance can redirect the tryptophan flux and shift the balance between 5-HT/melatonin and downstream kynurenine metabolites. Evidence across pregnancy complications links early pathway disruption to pregnancy loss and supports the view that early metabolic perturbations contribute to vulnerability for later placental dysfunction, including preeclampsia, fetal growth restriction, and preterm birth.</p><p><strong>Wider implications: </strong>Placental tryptophan metabolism changes across gestation, making early pregnancy a critical window when pathway balance and fetal exposure to neuroactive metabolites are first set. Maternal inflammation, metabolic status, nutrition, and drug exposures may alter this balance, with the placenta acting as the key interface that transmits maternal signals to the fetus and shapes neurodevelopmental trajectories. To define the clinical relevance of altered tryptophan catabolism, longitudinal human studies are needed to link placental phenotypes with pregnancy outcomes and postnatal neurodevelopment. These should be complemented by mechanistic models th","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":""},"PeriodicalIF":16.1,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146229882","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 Erden, Sezcan Mumusoglu, Esra Uyanik, Irem Yarali Ozbek, Sandro C Esteves, Peter Humaidan, Hakan Yarali
<p><strong>Background: </strong>The optimal endometrial preparation protocol for frozen embryo transfer (FET) remains a subject of ongoing investigation. HRT is the most commonly used approach, but natural cycle (NC) FET has regained attention due to potential improvements in maternal and perinatal outcomes. Despite growing observational evidence supporting NC FET, its adoption is limited by logistical challenges in cycle monitoring and scheduling. Recently, the natural proliferative phase (NPP) FET protocol has been introduced, combining the physiological benefits of a functional corpus luteum with greater scheduling flexibility.</p><p><strong>Objective and rationale: </strong>Previous systematic reviews have largely focused on luteal phase support (LPS) or have provided narrative summaries susceptible to selection bias. This systematic review aimed to evaluate the impact of different execution strategies on reproductive outcomes across true-NC and modified-NC and to compare NPP FET with other protocols.</p><p><strong>Search methods: </strong>A comprehensive search of MEDLINE, Embase, Global Health, and Cochrane Library was conducted from database inception to 10 November 2024. The search included keywords such as 'frozen embryo transfer', 'natural cycle', 'pregnancy', 'live birth', and 'delivery' with no language or filter restrictions. Reference lists of included studies were screened to identify additional relevant studies.</p><p><strong>Outcomes: </strong>A total of 70 studies were included: 8 randomized controlled trials (1 with low risk of bias and 7 with some concerns), 16 non-randomized interventional studies (with risk of bias being moderate for 4, serious for 6, and critical for another 6), and 46 observational studies (80.4% of which were good quality) assessing prognostic factors. In true-NC FET, prolonged follicular phases did not adversely affect outcomes. Ovulatory cycles were associated with significantly higher live birth rates (LBRs) than cycles with luteinized unruptured follicle (risk ratio (RR): 1.16, 95% CI: 1.04-1.29, I2 = 0%, three studies, 2907 cycles, very low-certainty evidence). Despite variability in ovulation timing methods, performing FET on serum LH surge +6 to +7 days yielded comparable reproductive outcomes. In modified-NC FET, two observational studies reported similar LBRs when triggering ovulation at follicle diameters between 13 and 22 mm, provided the endometrial thickness was >7 mm and serum progesterone was below 1.5 ng/ml. LPS with vaginal progesterone improved LBRs in true-NC compared to no LPS (RR: 1.43, 95% CI: 1.16-1.78, I2 = 0%, 923 cycles, two studies, moderate-certainty evidence), but showed no benefit in modified-NC FET (RR: 1.04, 95% CI: 0.82-1.32, I2 = 0%, 667 cycles, two studies, moderate-certainty evidence). In NPP FET, a meta-analysis showed higher LBRs compared to HRT FET (RR: 1.25, 95% CI: 1.13-1.38, I2 = 5.36%, 3397 cycles, three studies, very low-certainty evidence).</p><p><strong>Wider
{"title":"Revisiting natural cycle frozen embryo transfer: a systematic review and meta-analysis.","authors":"Murat Erden, Sezcan Mumusoglu, Esra Uyanik, Irem Yarali Ozbek, Sandro C Esteves, Peter Humaidan, Hakan Yarali","doi":"10.1093/humupd/dmag002","DOIUrl":"https://doi.org/10.1093/humupd/dmag002","url":null,"abstract":"<p><strong>Background: </strong>The optimal endometrial preparation protocol for frozen embryo transfer (FET) remains a subject of ongoing investigation. HRT is the most commonly used approach, but natural cycle (NC) FET has regained attention due to potential improvements in maternal and perinatal outcomes. Despite growing observational evidence supporting NC FET, its adoption is limited by logistical challenges in cycle monitoring and scheduling. Recently, the natural proliferative phase (NPP) FET protocol has been introduced, combining the physiological benefits of a functional corpus luteum with greater scheduling flexibility.</p><p><strong>Objective and rationale: </strong>Previous systematic reviews have largely focused on luteal phase support (LPS) or have provided narrative summaries susceptible to selection bias. This systematic review aimed to evaluate the impact of different execution strategies on reproductive outcomes across true-NC and modified-NC and to compare NPP FET with other protocols.</p><p><strong>Search methods: </strong>A comprehensive search of MEDLINE, Embase, Global Health, and Cochrane Library was conducted from database inception to 10 November 2024. The search included keywords such as 'frozen embryo transfer', 'natural cycle', 'pregnancy', 'live birth', and 'delivery' with no language or filter restrictions. Reference lists of included studies were screened to identify additional relevant studies.</p><p><strong>Outcomes: </strong>A total of 70 studies were included: 8 randomized controlled trials (1 with low risk of bias and 7 with some concerns), 16 non-randomized interventional studies (with risk of bias being moderate for 4, serious for 6, and critical for another 6), and 46 observational studies (80.4% of which were good quality) assessing prognostic factors. In true-NC FET, prolonged follicular phases did not adversely affect outcomes. Ovulatory cycles were associated with significantly higher live birth rates (LBRs) than cycles with luteinized unruptured follicle (risk ratio (RR): 1.16, 95% CI: 1.04-1.29, I2 = 0%, three studies, 2907 cycles, very low-certainty evidence). Despite variability in ovulation timing methods, performing FET on serum LH surge +6 to +7 days yielded comparable reproductive outcomes. In modified-NC FET, two observational studies reported similar LBRs when triggering ovulation at follicle diameters between 13 and 22 mm, provided the endometrial thickness was >7 mm and serum progesterone was below 1.5 ng/ml. LPS with vaginal progesterone improved LBRs in true-NC compared to no LPS (RR: 1.43, 95% CI: 1.16-1.78, I2 = 0%, 923 cycles, two studies, moderate-certainty evidence), but showed no benefit in modified-NC FET (RR: 1.04, 95% CI: 0.82-1.32, I2 = 0%, 667 cycles, two studies, moderate-certainty evidence). In NPP FET, a meta-analysis showed higher LBRs compared to HRT FET (RR: 1.25, 95% CI: 1.13-1.38, I2 = 5.36%, 3397 cycles, three studies, very low-certainty evidence).</p><p><strong>Wider ","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":""},"PeriodicalIF":16.1,"publicationDate":"2026-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146198246","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}
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}
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