Study question: What effects do DLGAP5 defects have on human early embryo development?
Summary answer: DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3, leading to female infertility characterized by recurrent early embryonic arrest (REEA).
What is known already: REEA is a significant contributor to failures in assisted reproductive technology. While genetic factors play a crucial role, known gene variants account for only a small proportion of affected individuals, leaving many underlying genetic factors yet to be elucidated. The relationship between spindle assembly and early embryonic development has emerged as a key research focus, however, our understanding of bipolar spindles in human oocytes and early embryos remains limited, highlighting the need for further investigation into the essential molecular players involved.
Study design, size, duration: A total of 488 female patients experiencing infertility characterized as REEA were recruited from a university-affiliated center from November 2021 to December 2023.
Participants/materials, setting, methods: Whole-exome sequencing was performed on the REEA cohort to identify candidate variants. HeLa cells were transiently transfected with wild-type and mutant plasmids to evaluate protein abundance and localization. Mutant mRNAs were expressed at the zygote stage to monitor subsequent embryonic development. Immunoprecipitation-mass spectrometry was employed to identify altered interacting molecules associated with the candidate variants. Additionally, a site-directed mutant mouse model was developed to investigate the pathogenic mechanisms in vivo, validated with patient oocytes and arrested embryos.
Main results and the role of chance: The study identified two nonsense variants, one frameshift variant, and one missense pathogenic variant in the DLGAP5 gene of three independent families from the cohort of 488 REEA patients through whole-exome sequencing. All affected individuals displayed a Mendelian recessive inheritance pattern. These variants significantly altered protein length, abundance, or localization, resulting in spindle abnormalities in HeLa cells and mouse zygotes. Furthermore, the microinjection of exogenous mutant DLGAP5 mRNA into mouse zygote and the construction of Dlgap5 site-directed mutant mice successfully replicated the patient phenotypes. Functional studies, both in vivo and in vitro, revealed that DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3.
Limitations, reasons for caution: This study was unable to observe the dynamic changes in spindle assembly in oocytes from patients with DLGAP5 variants due to ethical restrictions. Additionally, a larger patient cohort is needed, particularly multi-center and multi-ethnic studies, to further establish t
{"title":"Biallelic variants in DLGAP5 cause spindle assembly defects and human early embryonic arrest.","authors":"Huiling Hu, Xian Wan, Jiaqi Sun, Shen Zhang, Jing Guo, Yinli Zhang, Fei Meng, Shuoping Zhang, Yifan Gu, Fei Gong, Hongqing Liao, Ge Lin, Wei Zheng","doi":"10.1093/humrep/deaf158","DOIUrl":"10.1093/humrep/deaf158","url":null,"abstract":"<p><strong>Study question: </strong>What effects do DLGAP5 defects have on human early embryo development?</p><p><strong>Summary answer: </strong>DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3, leading to female infertility characterized by recurrent early embryonic arrest (REEA).</p><p><strong>What is known already: </strong>REEA is a significant contributor to failures in assisted reproductive technology. While genetic factors play a crucial role, known gene variants account for only a small proportion of affected individuals, leaving many underlying genetic factors yet to be elucidated. The relationship between spindle assembly and early embryonic development has emerged as a key research focus, however, our understanding of bipolar spindles in human oocytes and early embryos remains limited, highlighting the need for further investigation into the essential molecular players involved.</p><p><strong>Study design, size, duration: </strong>A total of 488 female patients experiencing infertility characterized as REEA were recruited from a university-affiliated center from November 2021 to December 2023.</p><p><strong>Participants/materials, setting, methods: </strong>Whole-exome sequencing was performed on the REEA cohort to identify candidate variants. HeLa cells were transiently transfected with wild-type and mutant plasmids to evaluate protein abundance and localization. Mutant mRNAs were expressed at the zygote stage to monitor subsequent embryonic development. Immunoprecipitation-mass spectrometry was employed to identify altered interacting molecules associated with the candidate variants. Additionally, a site-directed mutant mouse model was developed to investigate the pathogenic mechanisms in vivo, validated with patient oocytes and arrested embryos.</p><p><strong>Main results and the role of chance: </strong>The study identified two nonsense variants, one frameshift variant, and one missense pathogenic variant in the DLGAP5 gene of three independent families from the cohort of 488 REEA patients through whole-exome sequencing. All affected individuals displayed a Mendelian recessive inheritance pattern. These variants significantly altered protein length, abundance, or localization, resulting in spindle abnormalities in HeLa cells and mouse zygotes. Furthermore, the microinjection of exogenous mutant DLGAP5 mRNA into mouse zygote and the construction of Dlgap5 site-directed mutant mice successfully replicated the patient phenotypes. Functional studies, both in vivo and in vitro, revealed that DLGAP5 deficiency disrupts normal spindle assembly through its interaction with TACC3.</p><p><strong>Limitations, reasons for caution: </strong>This study was unable to observe the dynamic changes in spindle assembly in oocytes from patients with DLGAP5 variants due to ethical restrictions. Additionally, a larger patient cohort is needed, particularly multi-center and multi-ethnic studies, to further establish t","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"2008-2019"},"PeriodicalIF":6.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834947","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}
Thairo A Pereira,Niral Thaker,André C Rubez,Victor F N Lima,Helen L Bernie,Sandro C Esteves
Obesity is a global health concern with major implications for male reproductive function. It disrupts endocrine and metabolic homeostasis, impairs semen quality, and is associated with reduced pregnancy and live birth rates. Hormonal imbalances, inflammation, and lipid stress are key contributors to these impairments. This mini-review summarizes current evidence on the impact of therapeutic interventions, including lifestyle modification, bariatric surgery, and pharmacological approaches such as glucagon-like peptide-1 (GLP-1) receptor agonists, on male fertility outcomes. Lifestyle interventions, particularly moderate-intensity exercise and dietary improvements, are first-line therapies and should be routinely encouraged. Caloric restriction and Mediterranean-style diets rich in antioxidants have been associated with improved semen quality and hormonal balance. Bariatric surgery raises testosterone levels and may improve sperm quality and assisted reproduction outcomes in some men, but declines in sperm concentration and cases of postoperative azoospermia have also been reported. These findings underscore the importance of preoperative fertility counselling and consideration of sperm cryopreservation. GLP-1 receptor agonists promote weight loss and may improve sperm motility and hormonal markers; however, isolated cases of reversible impairment in sperm quality have been reported. Despite growing clinical use of these interventions, it remains unclear whether the observed benefits stem from weight loss itself or the specific treatment modalities. Longitudinal studies are needed to determine whether fertility improvements translate into higher conception rates. The reproductive safety of GLP-1 agonists in the preconception period also warrants further investigation. We recommend prioritizing pragmatic clinical trials with functional fertility endpoints, as well as mechanistic studies in well-characterized male obesity phenotypes and evaluation of offspring health. Ultimately, a shift is necessary from a narrow focus on weight loss to a broader emphasis on enhancing metabolic health. Personalized approaches tailored towards hormonal profiles, comorbidities, and fertility goals, supported by behavioural counselling and multidisciplinary care, are essential for advancing the treatment of obesity-related male infertility.
{"title":"Managing obesity-related male infertility: insights from weight loss intervention.","authors":"Thairo A Pereira,Niral Thaker,André C Rubez,Victor F N Lima,Helen L Bernie,Sandro C Esteves","doi":"10.1093/humrep/deaf180","DOIUrl":"https://doi.org/10.1093/humrep/deaf180","url":null,"abstract":"Obesity is a global health concern with major implications for male reproductive function. It disrupts endocrine and metabolic homeostasis, impairs semen quality, and is associated with reduced pregnancy and live birth rates. Hormonal imbalances, inflammation, and lipid stress are key contributors to these impairments. This mini-review summarizes current evidence on the impact of therapeutic interventions, including lifestyle modification, bariatric surgery, and pharmacological approaches such as glucagon-like peptide-1 (GLP-1) receptor agonists, on male fertility outcomes. Lifestyle interventions, particularly moderate-intensity exercise and dietary improvements, are first-line therapies and should be routinely encouraged. Caloric restriction and Mediterranean-style diets rich in antioxidants have been associated with improved semen quality and hormonal balance. Bariatric surgery raises testosterone levels and may improve sperm quality and assisted reproduction outcomes in some men, but declines in sperm concentration and cases of postoperative azoospermia have also been reported. These findings underscore the importance of preoperative fertility counselling and consideration of sperm cryopreservation. GLP-1 receptor agonists promote weight loss and may improve sperm motility and hormonal markers; however, isolated cases of reversible impairment in sperm quality have been reported. Despite growing clinical use of these interventions, it remains unclear whether the observed benefits stem from weight loss itself or the specific treatment modalities. Longitudinal studies are needed to determine whether fertility improvements translate into higher conception rates. The reproductive safety of GLP-1 agonists in the preconception period also warrants further investigation. We recommend prioritizing pragmatic clinical trials with functional fertility endpoints, as well as mechanistic studies in well-characterized male obesity phenotypes and evaluation of offspring health. Ultimately, a shift is necessary from a narrow focus on weight loss to a broader emphasis on enhancing metabolic health. Personalized approaches tailored towards hormonal profiles, comorbidities, and fertility goals, supported by behavioural counselling and multidisciplinary care, are essential for advancing the treatment of obesity-related male infertility.","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"53 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189380","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}
STUDY QUESTIONAre semen quality parameters randomly distributed across space, or do they exhibit spatial patterns that may reflect underlying environmental influences?SUMMARY ANSWERSemen quality parameters are not randomly distributed in Switzerland but exhibit distinct spatial clustering, with identifiable hotspots indicating areas of comparatively higher values and coldspots indicating areas of comparatively lower values.WHAT IS KNOWN ALREADYRegional differences in semen quality across Europe suggest environmental influences, but most studies are limited to urban areas with small samples and low geographic precision, leaving gaps in understanding precise geographical patterns at a national level.STUDY DESIGN, SIZE, DURATIONThis is a cross-sectional study, including 2677 men aged 18-22 from the general Swiss population who were recruited between 2005 and 2018 during military conscription.PARTICIPANTS/MATERIALS, SETTING, METHODSEach participant provided a semen sample and completed a questionnaire on health and lifestyle, including demographic details on their residence. Georeferenced data were used to compute the level of spatial dependence using the local Getis-Ord Gi* statistic with a 25 km spatial lag to identify clusters of high versus low semen parameter values across Switzerland. The parameters assessed included semen volume, sperm concentration, total sperm count, and sperm morphology. Participants belonging to the same Getis-Ord Gi* class for each semen parameter formed a persistent cluster. To assess differences in environmental exposure between high- and low-persistent clusters, land use data within a 500 m radius of each participant's place of residence were extracted from national registries for the periods of 1992-1997 and 2004-2009.MAIN RESULTS AND THE ROLE OF CHANCESemen quality parameters are not randomly distributed across Switzerland, with distinct local clusters of high values (hotspots) and low values (coldspots) identified. A persistent low-value cluster was observed in central western Switzerland. Analysis of national land use data revealed significant differences in agricultural land types between clusters: fodder and field crops accounted for 52.0% of the land use in the coldspot, compared to 28.3% in the hotspot and 30.1% in the non-significant cluster. Additionally, the mean proportion of built areas (housing and infrastructure) near participants' residences was significantly lower in the coldspot (32.6%) compared to the hotspots (53.3%).LIMITATIONS, REASONS FOR CAUTIONAlthough the study population is nationwide and broadly representative, the sample size used for individual-level spatial analyses limits statistical power.WIDER IMPLICATIONS OF THE FINDINGSTo our knowledge, this is the first study to apply spatial dependence methods to investigate semen quality parameters using individual-level data at a national scale. This approach can be extended to larger datasets to further explore the relationship between environme
{"title":"Exploring geographical differences in semen quality of young men using spatial dependence analysis.","authors":"Rita Rahban,Hugo-Alejandro Santa-Ramírez,Alfred Senn,Eric Stettler,Idris Guessous,Stéphane Joost,Serge Nef","doi":"10.1093/humrep/deaf182","DOIUrl":"https://doi.org/10.1093/humrep/deaf182","url":null,"abstract":"STUDY QUESTIONAre semen quality parameters randomly distributed across space, or do they exhibit spatial patterns that may reflect underlying environmental influences?SUMMARY ANSWERSemen quality parameters are not randomly distributed in Switzerland but exhibit distinct spatial clustering, with identifiable hotspots indicating areas of comparatively higher values and coldspots indicating areas of comparatively lower values.WHAT IS KNOWN ALREADYRegional differences in semen quality across Europe suggest environmental influences, but most studies are limited to urban areas with small samples and low geographic precision, leaving gaps in understanding precise geographical patterns at a national level.STUDY DESIGN, SIZE, DURATIONThis is a cross-sectional study, including 2677 men aged 18-22 from the general Swiss population who were recruited between 2005 and 2018 during military conscription.PARTICIPANTS/MATERIALS, SETTING, METHODSEach participant provided a semen sample and completed a questionnaire on health and lifestyle, including demographic details on their residence. Georeferenced data were used to compute the level of spatial dependence using the local Getis-Ord Gi* statistic with a 25 km spatial lag to identify clusters of high versus low semen parameter values across Switzerland. The parameters assessed included semen volume, sperm concentration, total sperm count, and sperm morphology. Participants belonging to the same Getis-Ord Gi* class for each semen parameter formed a persistent cluster. To assess differences in environmental exposure between high- and low-persistent clusters, land use data within a 500 m radius of each participant's place of residence were extracted from national registries for the periods of 1992-1997 and 2004-2009.MAIN RESULTS AND THE ROLE OF CHANCESemen quality parameters are not randomly distributed across Switzerland, with distinct local clusters of high values (hotspots) and low values (coldspots) identified. A persistent low-value cluster was observed in central western Switzerland. Analysis of national land use data revealed significant differences in agricultural land types between clusters: fodder and field crops accounted for 52.0% of the land use in the coldspot, compared to 28.3% in the hotspot and 30.1% in the non-significant cluster. Additionally, the mean proportion of built areas (housing and infrastructure) near participants' residences was significantly lower in the coldspot (32.6%) compared to the hotspots (53.3%).LIMITATIONS, REASONS FOR CAUTIONAlthough the study population is nationwide and broadly representative, the sample size used for individual-level spatial analyses limits statistical power.WIDER IMPLICATIONS OF THE FINDINGSTo our knowledge, this is the first study to apply spatial dependence methods to investigate semen quality parameters using individual-level data at a national scale. This approach can be extended to larger datasets to further explore the relationship between environme","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"95 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188797","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}
Liu Liu,Shao Huang,Feng Jiang,Guoqing Liang,Xiaobin Zhu,Hong Zhu,Weidong Tian
STUDY QUESTIONHow can integrating updated single-cell transcriptomics and protein-protein interactions (PPIs) with machine learning algorithms improve gene prioritization for spermatogenic failure and predict ICSI outcomes?SUMMARY ANSWERA machine learning framework integrating single-cell RNA sequencing (scRNA-seq) and PPI networks efficiently identified 320 candidate genes for spermatogenic failure and achieved high precision in predicting ICSI outcomes (precision-recall (PRC)-AUC=0.96, 95% CI: 0.89-1.00; receiver operating characteristic (ROC)-AUC = 0.82, 95% CI: 0.63-0.97).WHAT IS KNOWN ALREADYOver 100 genes are implicated in spermatogenic failure, yet patients with distinct genetic backgrounds exhibit highly variable ICSI outcomes. While machine learning-based gene prioritization offers potential for novel gene discovery, the existing methods rely on bulk RNA sequencing or lack multi-omics integration, limiting their ability to leverage single-cell resolution or predict clinical outcomes.STUDY DESIGN, SIZE, DURATIONThis study combined scRNA-seq data (capturing cell type- and developmental stage-specific expression) from healthy human tissues with PPI networks to train predictive models. Validation included 5-fold cross-validation, functional enrichment analyses, and clinical data from whole-exome sequencing (WES) and ICSI outcomes in 34 patients with spermatogenic failure subtypes (azoospermia, asthenozoospermia, teratozoospermia).PARTICIPANTS/MATERIALS, SETTING, METHODSPublic datasets (Human Protein Atlas, STRING, Gene Expression Omnibus) provided scRNA-seq and PPI data. Node2Vec-derived PPI network embeddings and cell type- and developmental stage-specific expression features were used to train random forest classifiers. Gene Ontology, Mammalian Phenotype Ontology enrichment analyses, and WES of patient blood samples validated candidate genes and ICSI outcomes.MAIN RESULTS AND THE ROLE OF CHANCEOur models demonstrated robust performance in spermatogenic failure gene prediction (PRC-AUC = 0.88, 95% CI: 0.83-0.93; ROC-AUC = 0.98, 95% CI: 0.96-0.99), subtype classification (e.g. teratozoospermia, PRC-AUC = 0.96, 95% CI: 0.91-0.99; ROC-AUC = 0.94, 95% CI: 0.87-0.98), and ICSI outcome prediction (PRC-AUC = 0.96, 95% CI: 0.89-1.00; ROC-AUC = 0.82, 95% CI: 0.63-0.97). WES of patient samples revealed an increased detection rate of likely causative variants among a subset of model-predicted genes, rising from 11.8% to 29.4%, with clinical outcomes aligning with model predictions.LIMITATIONS, REASONS FOR CAUTIONModel limitations include training on literature-curated or database-annotated gene labels, which may introduce misclassification or annotation bias. Additionally, the absence of experimental validation and the limited size and diversity of external cohorts necessitate further verification.WIDER IMPLICATIONS OF THE FINDINGSThis integrative machine learning framework provides a powerful tool for uncovering genetic contributors to male infertili
{"title":"Identifying candidate genes for spermatogenic failure and predicting ICSI outcomes using single-cell RNA sequencing and protein-protein interaction networks.","authors":"Liu Liu,Shao Huang,Feng Jiang,Guoqing Liang,Xiaobin Zhu,Hong Zhu,Weidong Tian","doi":"10.1093/humrep/deaf186","DOIUrl":"https://doi.org/10.1093/humrep/deaf186","url":null,"abstract":"STUDY QUESTIONHow can integrating updated single-cell transcriptomics and protein-protein interactions (PPIs) with machine learning algorithms improve gene prioritization for spermatogenic failure and predict ICSI outcomes?SUMMARY ANSWERA machine learning framework integrating single-cell RNA sequencing (scRNA-seq) and PPI networks efficiently identified 320 candidate genes for spermatogenic failure and achieved high precision in predicting ICSI outcomes (precision-recall (PRC)-AUC=0.96, 95% CI: 0.89-1.00; receiver operating characteristic (ROC)-AUC = 0.82, 95% CI: 0.63-0.97).WHAT IS KNOWN ALREADYOver 100 genes are implicated in spermatogenic failure, yet patients with distinct genetic backgrounds exhibit highly variable ICSI outcomes. While machine learning-based gene prioritization offers potential for novel gene discovery, the existing methods rely on bulk RNA sequencing or lack multi-omics integration, limiting their ability to leverage single-cell resolution or predict clinical outcomes.STUDY DESIGN, SIZE, DURATIONThis study combined scRNA-seq data (capturing cell type- and developmental stage-specific expression) from healthy human tissues with PPI networks to train predictive models. Validation included 5-fold cross-validation, functional enrichment analyses, and clinical data from whole-exome sequencing (WES) and ICSI outcomes in 34 patients with spermatogenic failure subtypes (azoospermia, asthenozoospermia, teratozoospermia).PARTICIPANTS/MATERIALS, SETTING, METHODSPublic datasets (Human Protein Atlas, STRING, Gene Expression Omnibus) provided scRNA-seq and PPI data. Node2Vec-derived PPI network embeddings and cell type- and developmental stage-specific expression features were used to train random forest classifiers. Gene Ontology, Mammalian Phenotype Ontology enrichment analyses, and WES of patient blood samples validated candidate genes and ICSI outcomes.MAIN RESULTS AND THE ROLE OF CHANCEOur models demonstrated robust performance in spermatogenic failure gene prediction (PRC-AUC = 0.88, 95% CI: 0.83-0.93; ROC-AUC = 0.98, 95% CI: 0.96-0.99), subtype classification (e.g. teratozoospermia, PRC-AUC = 0.96, 95% CI: 0.91-0.99; ROC-AUC = 0.94, 95% CI: 0.87-0.98), and ICSI outcome prediction (PRC-AUC = 0.96, 95% CI: 0.89-1.00; ROC-AUC = 0.82, 95% CI: 0.63-0.97). WES of patient samples revealed an increased detection rate of likely causative variants among a subset of model-predicted genes, rising from 11.8% to 29.4%, with clinical outcomes aligning with model predictions.LIMITATIONS, REASONS FOR CAUTIONModel limitations include training on literature-curated or database-annotated gene labels, which may introduce misclassification or annotation bias. Additionally, the absence of experimental validation and the limited size and diversity of external cohorts necessitate further verification.WIDER IMPLICATIONS OF THE FINDINGSThis integrative machine learning framework provides a powerful tool for uncovering genetic contributors to male infertili","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"5 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203774","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}
STUDY QUESTIONHow does allograft inflammatory factor-1 (AIF-1) affect endometrial receptivity in women with recurrent implantation failure (RIF)?SUMMARY ANSWERSignificant upregulation of AIF-1 in the endometrial stromal cells of women with RIF inhibits cell proliferation and decidualization via the p38 mitogen-activated protein kinase (MAPK) phosphorylation, thereby reducing endometrial receptivity.WHAT IS KNOWN ALREADYRIF is a challenging clinical issue, with AIF-1, a cytokine-inducible protein linked to allograft rejection, potentially contributing to its pathogenesis. However, the precise mechanisms remain elusive.STUDY DESIGN, SIZE, DURATIONThis study analyzed endometrial tissue samples from women diagnosed with RIF and a control group of fertile women from December 2018 to December 2023. Single-cell RNA sequencing (scRNA-seq) data from public datasets (GSE111976, GSE250130, GSE183837) were integrated to characterize AIF-1 expression patterns in endometrium. Isolated human endometrial stromal cells (HESCs) from the human endometrium and an endometrial stromal cell line were used for in vitro analysis, and an in vivo mouse model with AIF-1 overexpression in the uterus was employed to evaluate implantation outcomes.PARTICIPANTS/MATERIALS, SETTING, METHODSMid-secretory endometrial samples were collected from the 18 patients with RIF and 18 control patients; endometrial samples from another five different phases during the menstrual cycle were collected from 30 additional control patients. Quantitative PCR, western blot, immunohistochemical and immunofluorescence analyses, and RNA sequencing were conducted to determine the expression levels of AIF-1 and various markers. Cell proliferation, decidualization, and trophoblast outgrowth were measured. AIF-1 overexpression and gene silencing were achieved by plasmid injection and short hairpin RNA, respectively. For in vivo experiments, CD-1 mice with intrauterine injection of an AIF-1 plasmid were used. Phosphorylation of p38 was inhibited by PD169316.MAIN RESULTS AND THE ROLE OF CHANCEBased on scRNA-seq analysis and our own endometrial tissue detection, AIF-1 was significantly increased in HESCs in patients with RIF compared with their control group during the mid-secretory phase. AIF-1 overexpression resulted in reduced cell proliferation, inadequate cell decidualization, and diminished embryo outgrowth in in vitro experiments, and it reduced the number of embryo implantation sites in CD-1 mice; these effects were mitigated by PD169316, an inhibitor of p38 MAPK.LIMITATIONS, REASONS FOR CAUTIONAlthough the study establishes a link between increased AIF-1 expression in endometrial stromal cells and reduced endometrial receptivity, the role of AIF-1 in endometrial macrophages during embryo implantation remains unclear.WIDER IMPLICATIONS OF THE FINDINGSThe findings suggest that targeting the AIF-1 and p38 MAPK pathway could serve as a promising therapeutic strategy to improve endometrial receptivity in
{"title":"Increased AIF-1-mediated p38 MAPK phosphorylation in the mid-secretory endometrium impairs endometrial receptivity in women with recurrent implantation failure.","authors":"Mingjuan Zhou,Jingru Duan,Xiaowei Zhou,Hanfei Zhu,Dan Zhang,Bufang Xu,Aijun Zhang","doi":"10.1093/humrep/deaf174","DOIUrl":"https://doi.org/10.1093/humrep/deaf174","url":null,"abstract":"STUDY QUESTIONHow does allograft inflammatory factor-1 (AIF-1) affect endometrial receptivity in women with recurrent implantation failure (RIF)?SUMMARY ANSWERSignificant upregulation of AIF-1 in the endometrial stromal cells of women with RIF inhibits cell proliferation and decidualization via the p38 mitogen-activated protein kinase (MAPK) phosphorylation, thereby reducing endometrial receptivity.WHAT IS KNOWN ALREADYRIF is a challenging clinical issue, with AIF-1, a cytokine-inducible protein linked to allograft rejection, potentially contributing to its pathogenesis. However, the precise mechanisms remain elusive.STUDY DESIGN, SIZE, DURATIONThis study analyzed endometrial tissue samples from women diagnosed with RIF and a control group of fertile women from December 2018 to December 2023. Single-cell RNA sequencing (scRNA-seq) data from public datasets (GSE111976, GSE250130, GSE183837) were integrated to characterize AIF-1 expression patterns in endometrium. Isolated human endometrial stromal cells (HESCs) from the human endometrium and an endometrial stromal cell line were used for in vitro analysis, and an in vivo mouse model with AIF-1 overexpression in the uterus was employed to evaluate implantation outcomes.PARTICIPANTS/MATERIALS, SETTING, METHODSMid-secretory endometrial samples were collected from the 18 patients with RIF and 18 control patients; endometrial samples from another five different phases during the menstrual cycle were collected from 30 additional control patients. Quantitative PCR, western blot, immunohistochemical and immunofluorescence analyses, and RNA sequencing were conducted to determine the expression levels of AIF-1 and various markers. Cell proliferation, decidualization, and trophoblast outgrowth were measured. AIF-1 overexpression and gene silencing were achieved by plasmid injection and short hairpin RNA, respectively. For in vivo experiments, CD-1 mice with intrauterine injection of an AIF-1 plasmid were used. Phosphorylation of p38 was inhibited by PD169316.MAIN RESULTS AND THE ROLE OF CHANCEBased on scRNA-seq analysis and our own endometrial tissue detection, AIF-1 was significantly increased in HESCs in patients with RIF compared with their control group during the mid-secretory phase. AIF-1 overexpression resulted in reduced cell proliferation, inadequate cell decidualization, and diminished embryo outgrowth in in vitro experiments, and it reduced the number of embryo implantation sites in CD-1 mice; these effects were mitigated by PD169316, an inhibitor of p38 MAPK.LIMITATIONS, REASONS FOR CAUTIONAlthough the study establishes a link between increased AIF-1 expression in endometrial stromal cells and reduced endometrial receptivity, the role of AIF-1 in endometrial macrophages during embryo implantation remains unclear.WIDER IMPLICATIONS OF THE FINDINGSThe findings suggest that targeting the AIF-1 and p38 MAPK pathway could serve as a promising therapeutic strategy to improve endometrial receptivity in ","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"17 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140352","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}
STUDY QUESTIONWhat is the optimal number of frozen donor oocytes to thaw and fertilize to achieve one live birth while minimizing supernumerary embryos?SUMMARY ANSWERFor patients who want only one child, fertilizing 6-7 frozen donor oocytes would result in approximately one supernumerary embryo while maintaining the live birth rate.WHAT IS ALREADY KNOWNStudies on frozen donor oocyte outcomes focus on live birth rate, but little is known about the resulting number of supernumerary embryos.STUDY DESIGN, SIZE, DURATIONThis is a retrospective cohort study using data from the 2016-2020 Society for Assisted Reproductive Technology Clinic Outcomes Reporting System. A total of 11,554 frozen donor oocyte recipients undergoing their first cycle with frozen donor oocytes were included.PARTICIPANTS/MATERIALS, SETTING, METHODSThe 11,554 frozen donor oocyte recipients were stratified into quartiles based on the number of frozen donor oocytes thawed (<6, 6, 7, and >7). The primary outcome was the number of supernumerary blastocysts, defined as the number of blastocysts remaining after the first live birth, or at the final transfer cycle if the patient did not have a live birth.MAIN RESULTS AND THE ROLE OF CHANCEOn average, patients thawed 6.74 ± 1.96 oocytes, resulting in 4.77 ± 2.07 2PNs (2 pronuclei), 2.44 ± 1.59 usable embryos, and 1.02 ± 1.47 supernumerary blastocysts. The average number of cryopreserved supernumerary blastocysts increased as the number of frozen donor oocytes thawed increased (0.50 vs. 0.90 vs. 0.99 vs. 1.49 blastocysts in each quartile, respectively, P<0.01). However, live birth rates were only significantly lower when less than six frozen donor oocytes were thawed and fertilized (37.6% vs. 48.5% vs. 50.3% vs. 51.3%, P<0.01).LIMITATIONS, REASONS FOR CAUTIONThere are limitations to utilizing national databases, including missing data and the inability to extrapolate additional nuanced information not originally collected.WIDER IMPLICATIONS OF THE FINDINGSThe number of supernumerary blastocysts increases even with small increases in the number of frozen donor oocytes exposed to sperm. While thawing 6-7 frozen donor oocytes aligns with most practices, almost a quarter of patients thawed more than 7 frozen donor oocytes, which led to a significant increase in the number of supernumerary embryos to 1.49 without a significant increase in live birth rate.STUDY FUNDING/COMPETING INTEREST(S)Xiaoyue Ma, MSc is partially supported by the following grant: Clinical and Translational Science Center at Weill Cornell Medical College (1-UL1-TR002384-01). Steven Spandorfer is a former President of the Society for Assisted Reproductive Technology.TRIAL REGISTRATION NUMBERNot applicable.
研究问题：冷冻供体卵母细胞解冻和受精的最佳数量是多少，以实现一个活产，同时最大限度地减少多余胚胎？对于只想要一个孩子的患者，在保持活产率的情况下，使6-7个冷冻供体卵母细胞受精将导致大约一个多余胚胎。已知情况对冷冻供体卵母细胞结果的研究主要集中在活产率上，但对由此产生的多余胚胎数量知之甚少。研究设计、规模、持续时间这是一项回顾性队列研究，使用的数据来自2016-2020年辅助生殖技术协会临床结果报告系统。共有11554例冷冻供体卵母细胞受体接受了第一个周期的冷冻供体卵母细胞。参与者/材料、环境、方法根据冷冻供体卵母细胞的解冻数量，将11,554例冷冻供体卵母细胞受体分层(7)。主要结果是多余囊胚的数量，定义为第一次活产后剩余囊胚的数量，或者如果患者没有活产，则在最后的移植周期。患者平均解冻卵母细胞6.74±1.96个，产生2 pns（2原核）4.77±2.07个，可用胚胎2.44±1.59个，多余囊胚1.02±1.47个。随着供体卵母细胞解冻数量的增加，平均冷冻多余囊胚数量增加（每四分位数分别为0.50 vs 0.90 vs 0.99 vs 1.49， P<0.01）。而当供体卵母细胞解冻受精率小于6个时，活产率显著降低（37.6% vs 48.5% vs 50.3% vs 51.3%， P<0.01）。局限性，谨慎的原因利用国家数据库存在局限性，包括缺少数据和无法推断最初未收集的额外细微信息。研究结果的更广泛意义：即使与精子接触的冷冻供体卵母细胞数量略有增加，多余囊胚的数量也会增加。虽然解冻6-7个冷冻供体卵母细胞符合大多数做法，但近四分之一的患者解冻超过7个冷冻供体卵母细胞，导致多余胚胎数量显著增加至1.49个，但活产率没有显著增加。研究经费/竞争利益(S)Xiaoyue Ma，理学硕士由以下资助部分支持：威尔康奈尔医学院临床与转化科学中心（1-UL1-TR002384-01）。Steven Spandorfer是辅助生殖技术协会的前主席。试验注册号不适用。
{"title":"Optimizing the number of cryopreserved donor oocytes to fertilize with a focus on minimizing excess embryos.","authors":"S Tsai,X Ma,S Spring,S Spandorfer","doi":"10.1093/humrep/deaf187","DOIUrl":"https://doi.org/10.1093/humrep/deaf187","url":null,"abstract":"STUDY QUESTIONWhat is the optimal number of frozen donor oocytes to thaw and fertilize to achieve one live birth while minimizing supernumerary embryos?SUMMARY ANSWERFor patients who want only one child, fertilizing 6-7 frozen donor oocytes would result in approximately one supernumerary embryo while maintaining the live birth rate.WHAT IS ALREADY KNOWNStudies on frozen donor oocyte outcomes focus on live birth rate, but little is known about the resulting number of supernumerary embryos.STUDY DESIGN, SIZE, DURATIONThis is a retrospective cohort study using data from the 2016-2020 Society for Assisted Reproductive Technology Clinic Outcomes Reporting System. A total of 11,554 frozen donor oocyte recipients undergoing their first cycle with frozen donor oocytes were included.PARTICIPANTS/MATERIALS, SETTING, METHODSThe 11,554 frozen donor oocyte recipients were stratified into quartiles based on the number of frozen donor oocytes thawed (<6, 6, 7, and >7). The primary outcome was the number of supernumerary blastocysts, defined as the number of blastocysts remaining after the first live birth, or at the final transfer cycle if the patient did not have a live birth.MAIN RESULTS AND THE ROLE OF CHANCEOn average, patients thawed 6.74 ± 1.96 oocytes, resulting in 4.77 ± 2.07 2PNs (2 pronuclei), 2.44 ± 1.59 usable embryos, and 1.02 ± 1.47 supernumerary blastocysts. The average number of cryopreserved supernumerary blastocysts increased as the number of frozen donor oocytes thawed increased (0.50 vs. 0.90 vs. 0.99 vs. 1.49 blastocysts in each quartile, respectively, P<0.01). However, live birth rates were only significantly lower when less than six frozen donor oocytes were thawed and fertilized (37.6% vs. 48.5% vs. 50.3% vs. 51.3%, P<0.01).LIMITATIONS, REASONS FOR CAUTIONThere are limitations to utilizing national databases, including missing data and the inability to extrapolate additional nuanced information not originally collected.WIDER IMPLICATIONS OF THE FINDINGSThe number of supernumerary blastocysts increases even with small increases in the number of frozen donor oocytes exposed to sperm. While thawing 6-7 frozen donor oocytes aligns with most practices, almost a quarter of patients thawed more than 7 frozen donor oocytes, which led to a significant increase in the number of supernumerary embryos to 1.49 without a significant increase in live birth rate.STUDY FUNDING/COMPETING INTEREST(S)Xiaoyue Ma, MSc is partially supported by the following grant: Clinical and Translational Science Center at Weill Cornell Medical College (1-UL1-TR002384-01). Steven Spandorfer is a former President of the Society for Assisted Reproductive Technology.TRIAL REGISTRATION NUMBERNot applicable.","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"10 6 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140183","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}
STUDY QUESTIONWhat other zinc finger SWIM domain-containing protein 7 (SWS1/ZSWIM7) partners are involved in premature ovarian insufficiency (POI)?SUMMARY ANSWERThis study identifies novel pathogenic variants in zinc finger SWIM domain-containing protein 7 (SWS1/ZSWIM7) and its partner, SWSAP1, which impair interhomolog homologous recombination (IH-HR) and lead to isolated POI.WHAT IS KNOWN ALREADYKnockout mice models of the SWS1-complex (also known as the SWS1-SWSAP1-SPIDR complex or Shu complex) are infertile due to meiotic arrest. Variants of both SWS1/ZSWIM7 and SPIDR are described in POI, but so far, no SWSAP1 variants have been described in female infertility.STUDY DESIGN, SIZE, DURATIONScreening for SWS1-complex variants was performed using exome or genome sequencing data from women with POI as ongoing patient care. In silico modelling, IH-HR assays, and western-blot analysis were performed to test the impact of novel variants identified in genes of the SWS1-complex (SWSAP1 and SWS1/ZSWIM7) on homologous recombination, protein expression, and protein interactions.PARTICIPANTS/MATERIALS, SETTING, METHODSFive unrelated patients from France were enrolled based on their exome or genome sequencing result as part of ongoing patient care. All the patients were diagnosed with POI and met the European Society of Human Reproduction and Embryology (ESHRE) diagnostic criteria for POI. Functional validation was performed using mouse embryonic stem cells to study the impact of two novel variants found in two patients.MAIN RESULTS AND THE ROLE OF CHANCEWe report five different pathogenic or likely pathogenic variants in five patients. We report the previously described c.231_232del and c.176C>T variants in SWS1/ZSWIM7, as well as two novel variants, c.22del and c.151C>T. Additionally, we report a homozygous frameshift deletion in SWSAP1 (c.353del). All the patients display a similar phenotype of severe isolated POI, associated with primary or early secondary amenorrhea and signs of puberty delay. In silico modelling and IH-HR assays of both SWS1/ZSWIM7 c.176C>T and SWSAP1 c.353del indicated a partial decrease or absence of IH-HR activity in Sws1-/- or Swsap1-/- cells, respectively, and destabilization of the SWSAP1 truncation mutant.LIMITATIONS, REASONS FOR CAUTIONIdentification of other patients carrying SWSAP1 variants is needed to evaluate in-depth phenotype to genotype correlations. Future studies should evaluate the role of other genes in the SWS1-complex and explore the potential for therapeutic interventions targeting homologous recombination.WIDER IMPLICATIONS OF THE FINDINGSThese findings provide direct clinical and functional evidence that all three members of the SWS1-complex are implicated in female fertility and recapitulate the observed mouse phenotypes. IH-HR assays provide a relevant functional approach to validate novel variants in homologous recombination genes for POI patients, given the importance of IH-HR for meiotic progression.STUD
{"title":"SWS1-complex in premature ovarian insufficiency: SWSAP1 as a new POI gene.","authors":"Anna Lokchine,Fang Zhang,Laurence Cluzeau,Lorrie Le Page,Marc-Antoine Belaud-Rotureau,Marc Planes,Laura Mary,Annabelle Esvant,Erika Launay,Jaidah Fergus-Mackie,Bénédicte Nouyou,Laure Metayer-Amelot,Linda Akloul,Pierre Marijon,Wilfrid Carré,Ariane Cuny,Elisa Dybal,Solène Duros,Mathilde Domin-Bernhard,Sophie Christin-Maitre,Sylvie Odent,François Vialard,Elena J Tucker,Maria Jasin,Sylvie Jaillard","doi":"10.1093/humrep/deaf177","DOIUrl":"https://doi.org/10.1093/humrep/deaf177","url":null,"abstract":"STUDY QUESTIONWhat other zinc finger SWIM domain-containing protein 7 (SWS1/ZSWIM7) partners are involved in premature ovarian insufficiency (POI)?SUMMARY ANSWERThis study identifies novel pathogenic variants in zinc finger SWIM domain-containing protein 7 (SWS1/ZSWIM7) and its partner, SWSAP1, which impair interhomolog homologous recombination (IH-HR) and lead to isolated POI.WHAT IS KNOWN ALREADYKnockout mice models of the SWS1-complex (also known as the SWS1-SWSAP1-SPIDR complex or Shu complex) are infertile due to meiotic arrest. Variants of both SWS1/ZSWIM7 and SPIDR are described in POI, but so far, no SWSAP1 variants have been described in female infertility.STUDY DESIGN, SIZE, DURATIONScreening for SWS1-complex variants was performed using exome or genome sequencing data from women with POI as ongoing patient care. In silico modelling, IH-HR assays, and western-blot analysis were performed to test the impact of novel variants identified in genes of the SWS1-complex (SWSAP1 and SWS1/ZSWIM7) on homologous recombination, protein expression, and protein interactions.PARTICIPANTS/MATERIALS, SETTING, METHODSFive unrelated patients from France were enrolled based on their exome or genome sequencing result as part of ongoing patient care. All the patients were diagnosed with POI and met the European Society of Human Reproduction and Embryology (ESHRE) diagnostic criteria for POI. Functional validation was performed using mouse embryonic stem cells to study the impact of two novel variants found in two patients.MAIN RESULTS AND THE ROLE OF CHANCEWe report five different pathogenic or likely pathogenic variants in five patients. We report the previously described c.231_232del and c.176C>T variants in SWS1/ZSWIM7, as well as two novel variants, c.22del and c.151C>T. Additionally, we report a homozygous frameshift deletion in SWSAP1 (c.353del). All the patients display a similar phenotype of severe isolated POI, associated with primary or early secondary amenorrhea and signs of puberty delay. In silico modelling and IH-HR assays of both SWS1/ZSWIM7 c.176C>T and SWSAP1 c.353del indicated a partial decrease or absence of IH-HR activity in Sws1-/- or Swsap1-/- cells, respectively, and destabilization of the SWSAP1 truncation mutant.LIMITATIONS, REASONS FOR CAUTIONIdentification of other patients carrying SWSAP1 variants is needed to evaluate in-depth phenotype to genotype correlations. Future studies should evaluate the role of other genes in the SWS1-complex and explore the potential for therapeutic interventions targeting homologous recombination.WIDER IMPLICATIONS OF THE FINDINGSThese findings provide direct clinical and functional evidence that all three members of the SWS1-complex are implicated in female fertility and recapitulate the observed mouse phenotypes. IH-HR assays provide a relevant functional approach to validate novel variants in homologous recombination genes for POI patients, given the importance of IH-HR for meiotic progression.STUD","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"10 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127293","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}
STUDY QUESTIONDoes endometriosis and/or adenomyosis, diagnosed using the International Deep Endometriosis Analysis (IDEA) group and the Morphological Uterus Sonographic Assessment (MUSA) group revised definitions, impact cumulative live birth rates (CLBR) after three consecutive IVF or ICSI treatments?SUMMARY ANSWERWomen with endometriosis and/or adenomyosis, as diagnosed using transvaginal ultrasonography, had a 15% reduced chance of having a cumulative live birth after three consecutive IVF/ICSI treatments compared to women without these conditions.WHAT IS KNOWN ALREADYWomen with endometriosis or adenomyosis reportedly have lower live birth rates after their first IVF/ICSI treatment. However, most women undergo multiple cycles, and given their shared pathophysiology, the combined impact of both conditions over consecutive treatments remains unclear.STUDY DESIGN, SIZE, DURATIONThis was a prospective cohort study of 1035 women undergoing up to three consecutive IVF/ICSI treatments at a university hospital between January 2019 and April 2024. Swedish regulations entitle women to up to three subsidized treatment cycles, including fresh and/or frozen embryo transfers, until the birth of a living child is achieved.PARTICIPANTS/MATERIALS, SETTING, METHODSAll 1035 included women underwent a transvaginal ultrasound examination prior to starting their first treatment. Using the IDEA and revised MUSA definitions, respectively, in total 293 (28.3%) women had endometriosis and/or direct features of adenomyosis on ultrasonography. All 1035 women underwent the first treatment cycle. In total, 818 (79.0%) women [595 (80.2%) of women without endometriosis and/or adenomyosis and 223 (76.1%) of women with either of the diseases] underwent all treatments they were eligible for. A total of 217 (21.0%) women dropped out after the first or second treatment even if they had not achieved a live birth. In total, 1725 fresh treatment cycles were initiated, leading to 1283 fresh and 622 frozen embryo transfers. Live births were recorded. The adjusted relative risk (aRR) for cumulative live birth after three consecutive IVF/ICSI treatment cycles was calculated on an intention-to-treat (ITT) as well as per-protocol (PP) basis, using a modified Poisson regression analysis, adjusting for age as a potential confounder.MAIN RESULTS AND THE ROLE OF CHANCEThe CLBR over three consecutive IVF/ICSI treatment cycles was 666/818 (81.4%) in the total cohort. In an ITT and PP analyses, respectively, women with endometriosis and/or adenomyosis had a lower CLBR of 156/293 (53.2%) or 156/223 (70.0%) compared to women without, CLBR of 510/742 (68.7%) or 510/595 (85.7%), P < 0.001. The aRR for cumulative live birth for women with endometriosis and/or adenomyosis was aRR (ITT) 0.80 (95% CI, 0.71-0.90), P < 0.001, and aRR (PP) 0.85 (95% CI, 0.77-0.93), P < 0.001 compared to women without the diseases. After stratifying the results per treatment cycle, the LBR after the first treatment for wome
研究问题：使用国际深部子宫内膜异位症分析（IDEA）组和子宫形态超声评估（MUSA）组修订定义诊断的子宫内膜异位症和/或子宫腺肌症是否会影响连续三次IVF或ICSI治疗后的累积活产率（CLBR） ？经阴道超声检查诊断为子宫内膜异位症和/或子宫内膜异位症的妇女，在连续三次IVF/ICSI治疗后，与没有这些情况的妇女相比，累计活产的机会降低了15%。据报道，患有子宫内膜异位症或子宫腺肌症的女性在第一次体外受精/ICSI治疗后的活产率较低。然而，大多数女性经历多个周期，并且考虑到它们共同的病理生理，两种情况对连续治疗的综合影响尚不清楚。研究设计、规模、持续时间：这是一项前瞻性队列研究，纳入了1035名女性，她们在2019年1月至2024年4月期间在一所大学医院接受了多达三次连续IVF/ICSI治疗。瑞典的规定赋予妇女最多三个补贴治疗周期，包括新鲜和/或冷冻胚胎移植，直到实现一个活孩子的出生。参与者/材料、环境、方法所有1035名妇女在开始第一次治疗前接受阴道超声检查。分别使用IDEA和修订后的MUSA定义，共有293名（28.3%）女性在超声检查上有子宫内膜异位症和/或子宫腺肌症的直接特征。所有1035名妇女都接受了第一个治疗周期。总共有818名（79.0%）妇女[595名（80.2%）无子宫内膜异位症和/或子宫腺肌症的妇女和223名（76.1%）患有这两种疾病中的任何一种的妇女]接受了她们符合条件的所有治疗。总共有217名（21.0%）妇女在第一次或第二次治疗后退出，即使她们没有活产。总共启动了1725个新鲜处理周期，导致1283个新鲜胚胎移植和622个冷冻胚胎移植。记录活产。连续三个IVF/ICSI治疗周期后累计活产的调整相对风险（aRR）在意向治疗（ITT）和每个方案（PP）的基础上计算，使用改进的泊松回归分析，调整年龄作为潜在混杂因素。在整个队列中，连续三个IVF/ICSI治疗周期的CLBR为666/818（81.4%）。在ITT和PP分析中，患有子宫内膜异位症和/或子宫腺肌症的女性的CLBR分别为156/293（53.2%）或156/223(70.0%)，低于没有子宫内膜异位症的女性，CLBR分别为510/742（68.7%）或510/595 (85.7%),P < 0.001。子宫内膜异位症和/或子宫内膜异位症患者累积活产的aRR为aRR (ITT) 0.80 (95% CI, 0.71-0.90), P < 0.001, aRR (PP) 0.85 (95% CI, 0.77-0.93), P < 0.001。在对每个治疗周期的结果进行分层后，子宫内膜异位症和/或子宫内膜异位症妇女第一次治疗后的LBR为90/293 (30.7%)，aRR为0.69 (95% CI 0.57-0.84), P < 0.001，第二次治疗后的LBR为44/154 (28.6%)，aRR为0.72 (95% CI 0.54-0.96), P = 0.023，第三次治疗后的LBR为22/84 (26.2%)，aRR为0.83 (95% CI 0.54-1.28), P = 0.183。对于没有疾病的妇女，LBR在第一个周期为335/742(45.1%)，在第二个周期为132/319(41.4%)，在第三个周期为43/133（32.3%）。与冷冻胚胎移植相比，新鲜胚胎移植后的差异最大。局限性和注意的原因超声检查是在一家三级保健医院由一位具有子宫内膜异位症和bbb专长的检查人员进行的。根据修订后的MUSA定义，子宫腺肌症的直接特征是病理性的，而间接特征仅表明该疾病。有可能是一些在这项研究中被认为是健康的、只有间接特征的女性实际上患有这种疾病，因此被错误地分类了。研究结果的广泛意义尽管在三个IVF/ICSI周期中CLBR较低，子宫内膜异位症和/或子宫内膜异位症的妇女在连续治疗下仍有合理的机会实现活产。第一次治疗后的阴性结果不应成为拒绝进一步尝试的理由。未来的研究应该探索提高这一人群治疗成功率的策略，包括长期抑制方案的作用、外源性黄体酮剂量和个性化胚胎移植方法。研究经费/竞争利益(S)本研究由瑞典sk地区的区域研究基金支持。试验注册号/ a。
{"title":"Cumulative live birth rates under three consecutive IVF/ICSI treatment cycles are reduced in women with endometriosis and/or adenomyosis diagnosed by ultrasonography.","authors":"Sara Alson,Amelie Stenqvist,Povilas Sladkevicius","doi":"10.1093/humrep/deaf184","DOIUrl":"https://doi.org/10.1093/humrep/deaf184","url":null,"abstract":"STUDY QUESTIONDoes endometriosis and/or adenomyosis, diagnosed using the International Deep Endometriosis Analysis (IDEA) group and the Morphological Uterus Sonographic Assessment (MUSA) group revised definitions, impact cumulative live birth rates (CLBR) after three consecutive IVF or ICSI treatments?SUMMARY ANSWERWomen with endometriosis and/or adenomyosis, as diagnosed using transvaginal ultrasonography, had a 15% reduced chance of having a cumulative live birth after three consecutive IVF/ICSI treatments compared to women without these conditions.WHAT IS KNOWN ALREADYWomen with endometriosis or adenomyosis reportedly have lower live birth rates after their first IVF/ICSI treatment. However, most women undergo multiple cycles, and given their shared pathophysiology, the combined impact of both conditions over consecutive treatments remains unclear.STUDY DESIGN, SIZE, DURATIONThis was a prospective cohort study of 1035 women undergoing up to three consecutive IVF/ICSI treatments at a university hospital between January 2019 and April 2024. Swedish regulations entitle women to up to three subsidized treatment cycles, including fresh and/or frozen embryo transfers, until the birth of a living child is achieved.PARTICIPANTS/MATERIALS, SETTING, METHODSAll 1035 included women underwent a transvaginal ultrasound examination prior to starting their first treatment. Using the IDEA and revised MUSA definitions, respectively, in total 293 (28.3%) women had endometriosis and/or direct features of adenomyosis on ultrasonography. All 1035 women underwent the first treatment cycle. In total, 818 (79.0%) women [595 (80.2%) of women without endometriosis and/or adenomyosis and 223 (76.1%) of women with either of the diseases] underwent all treatments they were eligible for. A total of 217 (21.0%) women dropped out after the first or second treatment even if they had not achieved a live birth. In total, 1725 fresh treatment cycles were initiated, leading to 1283 fresh and 622 frozen embryo transfers. Live births were recorded. The adjusted relative risk (aRR) for cumulative live birth after three consecutive IVF/ICSI treatment cycles was calculated on an intention-to-treat (ITT) as well as per-protocol (PP) basis, using a modified Poisson regression analysis, adjusting for age as a potential confounder.MAIN RESULTS AND THE ROLE OF CHANCEThe CLBR over three consecutive IVF/ICSI treatment cycles was 666/818 (81.4%) in the total cohort. In an ITT and PP analyses, respectively, women with endometriosis and/or adenomyosis had a lower CLBR of 156/293 (53.2%) or 156/223 (70.0%) compared to women without, CLBR of 510/742 (68.7%) or 510/595 (85.7%), P < 0.001. The aRR for cumulative live birth for women with endometriosis and/or adenomyosis was aRR (ITT) 0.80 (95% CI, 0.71-0.90), P < 0.001, and aRR (PP) 0.85 (95% CI, 0.77-0.93), P < 0.001 compared to women without the diseases. After stratifying the results per treatment cycle, the LBR after the first treatment for wome","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"90 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089863","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}
Carmen Shu Man Ng,Paul Yu Wing Tong,Evelyn Wong,Heidi Hiu Yee Cheng,Jennifer Ka Yee Ko,Raymond Hang Wun Li,Ernest Hung Yu Ng
STUDY QUESTIONDoes the use of virtual reality (VR) reduce pain levels experienced by women during transvaginal oocyte retrieval using paracervical block and conscious sedation?SUMMARY ANSWERThe use of VR did not reduce pain levels during oocyte retrieval using paracervical block and conscious sedation.WHAT IS KNOWN ALREADYConscious sedation is commonly used for pain relief during oocyte retrieval, and the concurrent use of more than one method of sedation and analgesia resulted in better pain relief than a single modality. Many studies have shown promising results in reducing anxiety and pain with the use of VR during medical procedures.STUDY DESIGN, SIZE, DURATIONThis is a randomized controlled trial of 160 infertile women undergoing transvaginal oocyte retrieval using paracervical block and conscious sedation between December 2022 and October 2023.PARTICIPANTS/MATERIALS, SETTING, METHODSThe study was conducted in a university-affiliated assisted reproduction unit. Recruited women were randomly assigned into the VR group (n = 80) and the standard care group (n = 80). Pain levels upon vaginal puncture and oocyte retrieval were recorded using a 100-point visual analogue scale.MAIN RESULTS AND THE ROLE OF CHANCEBoth groups were comparable in terms of demographic parameters, ovarian stimulation responses, and the anxiety trait and state scores. There was no significant difference in maximal pain level at vaginal puncture (50.8 ± 23.6 vs. 54.8 ± 25.4; 95% CI -11.7, 3.7; P = 0.30) and oocyte retrieval (56.4 ± 24.6 vs. 60.3 ± 26.8; 95% CI -12.0, 4.2; P = 0.34) between the VR group and standard care group. The satisfaction score was similar in both groups.LIMITATIONS, REASONS FOR CAUTIONThe small sample size of the study was a limitation. Blinding participants and researchers were not feasible due to the nature of the study. The degree of immersion was also affected when viewing the VR headset from a prone perspective, and the experience was also limited by the standardization of VR scenario and audio. The pain score recorded by the visual analogue scale was a subjective measurement.WIDER IMPLICATIONS OF THE FINDINGSAlthough the use of VR was otherwise well tolerated without major side effect, its routine use for pain relief during oocyte retrieval cannot be supported.STUDY FUNDING/COMPETING INTEREST(S)The study was supported by an internal grant (Professor P.C. Ho Research and Development Fund in Reproductive Medicine). None of the authors has conflicts of interest to declare.TRIAL REGISTRATION NUMBERClinicalTrials.gov with identifier NCT05218382.TRIAL REGISTRATION DATE18 December 2021.DATE OF FIRST PATIENT’S ENROLMENT1 December 2022.
研究问题：使用虚拟现实（VR）是否可以减少女性在经阴道取卵过程中使用宫颈旁阻滞和有意识镇静的疼痛程度？结论：在宫颈旁阻滞和清醒镇静下，VR的使用并没有减少卵母细胞回收过程中的疼痛程度。已知情况：在取卵过程中，意识镇静通常用于缓解疼痛，同时使用多种镇静和镇痛方法比单一方式更能缓解疼痛。许多研究表明，在医疗过程中使用虚拟现实技术可以减少焦虑和疼痛。研究设计、规模、持续时间：这是一项随机对照试验，在2022年12月至2023年10月期间，160名不育症妇女采用宫颈旁阻滞和清醒镇静经阴道取卵。参与者/材料、环境、方法本研究在一所大学附属辅助生殖机构进行。招募的女性被随机分配到VR组（n = 80）和标准治疗组（n = 80）。阴道穿刺和卵母细胞回收时的疼痛水平用100点视觉模拟量表记录。主要结果和机会的作用两组在人口学参数、卵巢刺激反应、焦虑特征和状态评分方面具有可比性。阴道穿刺时的最大疼痛水平（50.8±23.6比54.8±25.4;95% CI -11.7, 3.7; P = 0.30）和卵母细胞回收时的最大疼痛水平（56.4±24.6比60.3±26.8;95% CI -12.0, 4.2; P = 0.34）在VR组和标准护理组之间无显著差异。两组的满意度得分相似。局限性，注意原因本研究样本量小是一个局限性。由于研究的性质，对参与者和研究人员进行盲法是不可行的。俯卧视角观看VR头显也会影响沉浸感，VR场景和音频的标准化也会限制体验。视觉模拟量表记录的疼痛评分是一种主观测量。研究结果的更广泛意义尽管VR的使用在其他方面耐受良好且无主要副作用，但不能支持其在卵母细胞提取期间用于缓解疼痛的常规使用。研究经费/竞争利益(S)本研究获内部拨款（何炳平教授生殖医学研究及发展基金）资助。所有作者均无利益冲突需要申报。试验注册编号clinicaltrials .gov，标识符NCT05218382。试验注册日期为2021年12月18日。第一位患者入组日期：2022年12月1日。
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