Khaoula Ben Messaoud, Nina Zaks, Frederick Licciardi, Cecilia Høst Ramlau-Hansen, Linda G Kahn, Magdalena Janecka
STUDY QUESTION Is there an association between infertility diagnosis and long-term adult-onset psychiatric conditions in women? SUMMARY ANSWER Infertility diagnosis in women is linked to higher risks of mood disorders, anxiety- and stress-related disorders, and behavioral syndromes with physical components, but not schizophrenia or other psychotic disorders, particularly notable from 9 years after the first infertility diagnosis. WHAT IS KNOWN ALREADY Infertility, especially in women, is associated with major mental health challenges around the time of diagnosis. However, the long-term connection with a wide range of psychiatric disorders is largely unknown. STUDY DESIGN, SIZE, DURATION This study employed a matched-pair design within the UK Biobank (UKB) cohort, including 3893 females with a diagnosis of infertility and 15 603 matched female controls, totaling 19 496 participants. PARTICIPANTS/MATERIALS, SETTING, METHODS Female UKB participants with a diagnosis of infertility were matched to females without the diagnosis in a 1:4 ratio based on year of birth, index of deprivation of their residency area, and primary care data linkage status. The diagnosis of female infertility was identified by the first occurrence of a primary or secondary diagnosis in either primary care or hospital records. Additional analyses explored interactions between infertility diagnosis and both miscarriage and childbearing status on psychiatric conditions. MAIN RESULTS AND THE ROLE OF CHANCE Diagnosis of infertility was associated with higher risks of mood disorders, anxiety- and stress-related disorders, and behavioral syndromes with physical components, but not with schizophrenia or other psychotic disorders. The most notable increases in the risk of psychiatric diagnoses were observed 9 years after the first infertility diagnosis. No significant interactions were found between infertility diagnosis and either miscarriage or childbearing status on psychiatric conditions. Sensitivity analysis confirmed the robustness of these associations across different data sources for infertility diagnosis and psychiatric condition ascertainment. LIMITATIONS, REASONS FOR CAUTION The study’s limitations include the racial homogeneity and the overall healthier status of the UKB cohort compared to the general UK population and the potential underestimation of associations due to misclassification of subfecund women. WIDER IMPLICATIONS OF THE FINDINGS These results emphasize the need for integrated mental health support in infertility care and long-term monitoring of infertility patients for psychiatric risks. STUDY FUNDING/COMPETING INTEREST(S) None. No competing interests were declared. TRIAL REGISTRATION NUMBER n/a.
{"title":"Female infertility diagnosis and adult-onset psychiatric conditions: a matched cohort study","authors":"Khaoula Ben Messaoud, Nina Zaks, Frederick Licciardi, Cecilia Høst Ramlau-Hansen, Linda G Kahn, Magdalena Janecka","doi":"10.1093/humrep/deaf202","DOIUrl":"https://doi.org/10.1093/humrep/deaf202","url":null,"abstract":"STUDY QUESTION Is there an association between infertility diagnosis and long-term adult-onset psychiatric conditions in women? SUMMARY ANSWER Infertility diagnosis in women is linked to higher risks of mood disorders, anxiety- and stress-related disorders, and behavioral syndromes with physical components, but not schizophrenia or other psychotic disorders, particularly notable from 9 years after the first infertility diagnosis. WHAT IS KNOWN ALREADY Infertility, especially in women, is associated with major mental health challenges around the time of diagnosis. However, the long-term connection with a wide range of psychiatric disorders is largely unknown. STUDY DESIGN, SIZE, DURATION This study employed a matched-pair design within the UK Biobank (UKB) cohort, including 3893 females with a diagnosis of infertility and 15 603 matched female controls, totaling 19 496 participants. PARTICIPANTS/MATERIALS, SETTING, METHODS Female UKB participants with a diagnosis of infertility were matched to females without the diagnosis in a 1:4 ratio based on year of birth, index of deprivation of their residency area, and primary care data linkage status. The diagnosis of female infertility was identified by the first occurrence of a primary or secondary diagnosis in either primary care or hospital records. Additional analyses explored interactions between infertility diagnosis and both miscarriage and childbearing status on psychiatric conditions. MAIN RESULTS AND THE ROLE OF CHANCE Diagnosis of infertility was associated with higher risks of mood disorders, anxiety- and stress-related disorders, and behavioral syndromes with physical components, but not with schizophrenia or other psychotic disorders. The most notable increases in the risk of psychiatric diagnoses were observed 9 years after the first infertility diagnosis. No significant interactions were found between infertility diagnosis and either miscarriage or childbearing status on psychiatric conditions. Sensitivity analysis confirmed the robustness of these associations across different data sources for infertility diagnosis and psychiatric condition ascertainment. LIMITATIONS, REASONS FOR CAUTION The study’s limitations include the racial homogeneity and the overall healthier status of the UKB cohort compared to the general UK population and the potential underestimation of associations due to misclassification of subfecund women. WIDER IMPLICATIONS OF THE FINDINGS These results emphasize the need for integrated mental health support in infertility care and long-term monitoring of infertility patients for psychiatric risks. STUDY FUNDING/COMPETING INTEREST(S) None. No competing interests were declared. TRIAL REGISTRATION NUMBER n/a.","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"34 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535854","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}
Carla Ritagliati, Faye Devine, Jochen Buck, Lonny R Levin
STUDY QUESTION How does soluble adenylyl cyclase (sAC)-generated cyclic AMP (cAMP) control hyperactivated motility in human sperm? SUMMARY ANSWER sAC-generated cAMP rapidly initiates and is required to maintain hyperactivated motility in human sperm. WHAT IS KNOWN ALREADY Mouse and human sperm devoid of sAC activity (either genetically or pharmacologically) are immotile and do not undergo capacitation; thus, the HCO3−-dependent stimulation of sAC and consequent increase in cAMP is responsible for activating basal motility and initiating capacitation in multiple mammalian species. Among the changes sperm undergo during capacitation is acquisition of hyperactivated motility, which is presumed to be essential for male fertility. STUDY DESIGN, SIZE, DURATION In this study, the kinetics of cAMP generation and motility were assessed in sperm from healthy semen donors with no known fertility issues subjected to capacitating media components (HCO3− and albumin). Controls included cAMP agonists and adenylyl cyclase inhibitors. PARTICIPANTS/MATERIALS, SETTING, METHODS The motility of sperm purified from donors’ semen samples was analyzed by a Computer-Assisted Sperm Analysis (CASA) system, and the intracellular cAMP was quantified using a cAMP ELISA. MAIN RESULTS AND THE ROLE OF CHANCE HCO3− stimulates sAC-dependent cAMP production and the transition to hyperactivated motility at the earliest times measured. Sperm hyperactivated motility seems to be a reversible process, as maintaining hyperactivated motility requires sustained sAC activation. LIMITATIONS, REASONS FOR CAUTION The CASA system, used to measure hyperactivated motility, employs snapshot technology; sperm trajectories are observed for only short segments of time. This is an ex vivo study of sperm motility parameters in aqueous solutions. The conditions used were established for successful IVF, and the capacitation-induced hyperactivated motility studied here is proven essential for IVF and positively correlated with in vivo fertilization competence. However, in vivo, ejaculated sperm must navigate through the female reproductive tract, which is lined by viscous mucus, to reach the site of fertilization. Future studies should examine motility behaviors in solutions whose viscosity more accurately reflects the mucus-lined environment of the female reproductive tract. WIDER IMPLICATIONS OF THE FINDINGS There are two novel findings presented here; that hyperactivation of human sperm occurs early during capacitation and that hyperactivated motility is reversible. These findings raise the possibility that the rapid, sAC-dependent hyperactivated motility allows human sperm to escape the harsh vaginal environment. Its roles modulating sperm motility define sAC as an optimal target for both male and female contraception. Additionally, sAC inhibitors with different off-rates are shown here to be useful tools enabling us to study the kinetics of sAC activation in a physiological context. STUDY FUNDING/COM
研究问题：可溶性腺苷酸环化酶（sAC）产生的环AMP （cAMP）如何控制人类精子的过度激活运动性？sac产生的cAMP迅速启动并需要维持人类精子的高激活运动性。已知情况：小鼠和人类精子缺乏sAC活性（无论是基因上的还是药理学上的）是不动的，不会发生能化；因此，在多种哺乳动物中，依赖于HCO3−的sAC刺激和随之而来的cAMP增加是激活基础运动和启动能化的原因。精子在获能过程中经历的变化包括获得过度激活的运动性，这被认为是男性生育能力所必需的。研究设计、大小、持续时间在这项研究中，对来自健康精子供体的精子cAMP生成动力学和运动性进行了评估，这些精子来自没有已知生育问题的精子，并受到能化介质成分（HCO3 -和白蛋白）的影响。对照组包括cAMP激动剂和腺苷酸环化酶抑制剂。使用计算机辅助精子分析（CASA）系统分析从供者精液样本中纯化的精子的活力，并使用cAMP酶联免疫吸附测定细胞内cAMP。主要结果和机会HCO3−的作用刺激sac依赖性cAMP的产生，并在最早测量的时间过渡到过度激活的运动。精子过度激活的运动似乎是一个可逆的过程，因为维持过度激活的运动需要持续的sAC激活。用于测量过度激活运动性的CASA系统采用快照技术；精子的轨迹只能在很短的时间内观察到。这是精子在水溶液中运动参数的离体研究。体外受精成功所使用的条件已经建立，本研究中所研究的能化诱导的超激活运动对体外受精至关重要，并与体内受精能力呈正相关。然而，在体内，射精的精子必须通过布满粘稠粘液的女性生殖道，才能到达受精地点。未来的研究应该检查溶液中的运动行为，其粘度更准确地反映了女性生殖道的粘液环境。研究结果的更广泛含义这里提出了两个新的发现；人类精子的过度激活发生在获能期的早期，并且过度激活的运动是可逆的。这些发现提出了一种可能性，即快速的、依赖于sac的过度激活运动使人类精子能够逃离恶劣的阴道环境。其调节精子活力的作用使sAC成为男性和女性避孕的最佳目标。此外，具有不同脱除率的sAC抑制剂在这里被证明是有用的工具，使我们能够在生理背景下研究sAC激活动力学。研究资金/竞争利益(S)本研究由男性避孕倡议（给J.B.和L.R.L.）和国家卫生研究院通过HD113015和HD111549（给J.B.和L.R.L.）资助。C.R.被授予男性避孕倡议奖学金。L.R.L.和J.B.是一组体内有效的sAC抑制剂（专利PCT/US2022/02652）的共同发明人，也是Sacyl Pharmaceuticals Inc.的共同创始人、共同所有人和董事会成员，该公司授权sAC抑制剂开发为按需男性避孕药。C.R.一直是Sacyl Pharmaceuticals Inc.的有偿顾问。试验注册号n / a
{"title":"Sustained soluble adenylyl cyclase (sAC)-generated cAMP is necessary and sufficient for hyperactivated motility in human sperm","authors":"Carla Ritagliati, Faye Devine, Jochen Buck, Lonny R Levin","doi":"10.1093/humrep/deaf225","DOIUrl":"https://doi.org/10.1093/humrep/deaf225","url":null,"abstract":"STUDY QUESTION How does soluble adenylyl cyclase (sAC)-generated cyclic AMP (cAMP) control hyperactivated motility in human sperm? SUMMARY ANSWER sAC-generated cAMP rapidly initiates and is required to maintain hyperactivated motility in human sperm. WHAT IS KNOWN ALREADY Mouse and human sperm devoid of sAC activity (either genetically or pharmacologically) are immotile and do not undergo capacitation; thus, the HCO3−-dependent stimulation of sAC and consequent increase in cAMP is responsible for activating basal motility and initiating capacitation in multiple mammalian species. Among the changes sperm undergo during capacitation is acquisition of hyperactivated motility, which is presumed to be essential for male fertility. STUDY DESIGN, SIZE, DURATION In this study, the kinetics of cAMP generation and motility were assessed in sperm from healthy semen donors with no known fertility issues subjected to capacitating media components (HCO3− and albumin). Controls included cAMP agonists and adenylyl cyclase inhibitors. PARTICIPANTS/MATERIALS, SETTING, METHODS The motility of sperm purified from donors’ semen samples was analyzed by a Computer-Assisted Sperm Analysis (CASA) system, and the intracellular cAMP was quantified using a cAMP ELISA. MAIN RESULTS AND THE ROLE OF CHANCE HCO3− stimulates sAC-dependent cAMP production and the transition to hyperactivated motility at the earliest times measured. Sperm hyperactivated motility seems to be a reversible process, as maintaining hyperactivated motility requires sustained sAC activation. LIMITATIONS, REASONS FOR CAUTION The CASA system, used to measure hyperactivated motility, employs snapshot technology; sperm trajectories are observed for only short segments of time. This is an ex vivo study of sperm motility parameters in aqueous solutions. The conditions used were established for successful IVF, and the capacitation-induced hyperactivated motility studied here is proven essential for IVF and positively correlated with in vivo fertilization competence. However, in vivo, ejaculated sperm must navigate through the female reproductive tract, which is lined by viscous mucus, to reach the site of fertilization. Future studies should examine motility behaviors in solutions whose viscosity more accurately reflects the mucus-lined environment of the female reproductive tract. WIDER IMPLICATIONS OF THE FINDINGS There are two novel findings presented here; that hyperactivation of human sperm occurs early during capacitation and that hyperactivated motility is reversible. These findings raise the possibility that the rapid, sAC-dependent hyperactivated motility allows human sperm to escape the harsh vaginal environment. Its roles modulating sperm motility define sAC as an optimal target for both male and female contraception. Additionally, sAC inhibitors with different off-rates are shown here to be useful tools enabling us to study the kinetics of sAC activation in a physiological context. STUDY FUNDING/COM","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"7 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535853","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}
Recent advances in the development of stem-cell-based embryo models and endometrial assembloids have fuelled understanding of their respective biology. However, a faithful combined approach is required to truly advance our understanding of implantation processes. This mini-review considers the most recent developments in producing reliable in vitro models of the human endometrium and human embryo, and the next steps required to combine their respective potential. While the fundamental biology of implantation is the primary driver of in vitro model development, the combined effort of embryo and endometrial models to generate new models of implantation provides the opportunity to manipulate either compartment to further understand the aetiologies of reproductive dysfunction. Through combining both systems, their efforts are symbiotic, each extending the relevance and utility of their counterpart to generate a whole greater than the sum of its parts.
{"title":"New models of implantation: towards a whole better than the sum of parts","authors":"T M Rawlings, S A Guttridge, E S Lucas","doi":"10.1093/humrep/deaf223","DOIUrl":"https://doi.org/10.1093/humrep/deaf223","url":null,"abstract":"Recent advances in the development of stem-cell-based embryo models and endometrial assembloids have fuelled understanding of their respective biology. However, a faithful combined approach is required to truly advance our understanding of implantation processes. This mini-review considers the most recent developments in producing reliable in vitro models of the human endometrium and human embryo, and the next steps required to combine their respective potential. While the fundamental biology of implantation is the primary driver of in vitro model development, the combined effort of embryo and endometrial models to generate new models of implantation provides the opportunity to manipulate either compartment to further understand the aetiologies of reproductive dysfunction. Through combining both systems, their efforts are symbiotic, each extending the relevance and utility of their counterpart to generate a whole greater than the sum of its parts.","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"28 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535852","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}
Increasing evidence supports the role of male infertility as a harbinger of broader health issues, given that infertile men often exhibit higher rates of chronic conditions later in life. Infertile men have double the risk of developing testicular and breast cancer and an increased risk of high-grade prostate cancer, are more likely to develop ischemic heart disease, hypertension, heart disease, and hyperlipidemia, and have higher cardiovascular mortality compared to fertile men. The risk of developing Type 2 diabetes seems to increase with the severity of the spermatogenic dysfunction, and metabolic abnormalities such as insulin resistance, increased visceral adiposity, and systemic inflammation are often reported in men with male factor infertility. The relative risk of developing autoimmune diseases such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus, and thyroiditis is significantly higher in infertile compared to fertile men, although the absolute risk is low. Male infertility also confers a 26% increased risk of early mortality, and the risk is even increased for men with azoospermia. On the other hand, a linear relationship between all semen parameters and life expectancy was found in a recent study. To explain the relationship between male infertility and increased risk of morbidity and mortality, hormonal, lifestyle/behavior, and genetic factors have been previously called into question. In the present mini review, the immune system alteration and the epigenetic hypotheses are exposed in more detail. The proposed evidence suggest that health screening for related conditions should be offered as part of the routine male infertility workup, to facilitate earlier detection and preventative care, and to position reproductive evaluations as a pivotal moment for long-term health intervention.
{"title":"Are infertile men at a higher risk of morbidity and early mortality?","authors":"Ettore Caroppo, Michael L Eisenberg","doi":"10.1093/humrep/deaf201","DOIUrl":"https://doi.org/10.1093/humrep/deaf201","url":null,"abstract":"Increasing evidence supports the role of male infertility as a harbinger of broader health issues, given that infertile men often exhibit higher rates of chronic conditions later in life. Infertile men have double the risk of developing testicular and breast cancer and an increased risk of high-grade prostate cancer, are more likely to develop ischemic heart disease, hypertension, heart disease, and hyperlipidemia, and have higher cardiovascular mortality compared to fertile men. The risk of developing Type 2 diabetes seems to increase with the severity of the spermatogenic dysfunction, and metabolic abnormalities such as insulin resistance, increased visceral adiposity, and systemic inflammation are often reported in men with male factor infertility. The relative risk of developing autoimmune diseases such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus, and thyroiditis is significantly higher in infertile compared to fertile men, although the absolute risk is low. Male infertility also confers a 26% increased risk of early mortality, and the risk is even increased for men with azoospermia. On the other hand, a linear relationship between all semen parameters and life expectancy was found in a recent study. To explain the relationship between male infertility and increased risk of morbidity and mortality, hormonal, lifestyle/behavior, and genetic factors have been previously called into question. In the present mini review, the immune system alteration and the epigenetic hypotheses are exposed in more detail. The proposed evidence suggest that health screening for related conditions should be offered as part of the routine male infertility workup, to facilitate earlier detection and preventative care, and to position reproductive evaluations as a pivotal moment for long-term health intervention.","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"174 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145515918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Foundation models in IVF: from speculation to implementation with FEMI.","authors":"Zeev Shoham","doi":"10.1093/humrep/deaf226","DOIUrl":"https://doi.org/10.1093/humrep/deaf226","url":null,"abstract":"","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"19 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491478","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}
Understanding human early embryo development from fertilization to gastrulation is essential to improve medically assisted reproduction. Faced with technical and ethical limitations, research into peri-implantation stages has been transformed by the recent onset of single-cell omics technologies. These approaches encompassing transcriptomics, epigenomics, and proteomics now enable unprecedented resolution of cellular heterogeneity, lineage specification, and spatial organization during early development. Here, we review the major discoveries permitted by single-cell omics methods, presented chronologically to reflect the progression of embryonic development. We address, among others, the delineation of blastomere contributions, mechanisms of embryonic genome activation, and the sequential specification of the trophectoderm, epiblast, and hypoblast lineages. We also explore how single-cell omics clarifies the effects of aneuploidy, uncovers mural-polar trophectoderm maturation, revises X chromosome regulation, and enables identification of rare post-implantation populations like primordial germ cells and amnion.
{"title":"The contribution of single-cell omics technologies to improve knowledge on human early embryo development.","authors":"Océane Girard,Eva Moinard,Laurent David,Thomas Fréour","doi":"10.1093/humrep/deaf206","DOIUrl":"https://doi.org/10.1093/humrep/deaf206","url":null,"abstract":"Understanding human early embryo development from fertilization to gastrulation is essential to improve medically assisted reproduction. Faced with technical and ethical limitations, research into peri-implantation stages has been transformed by the recent onset of single-cell omics technologies. These approaches encompassing transcriptomics, epigenomics, and proteomics now enable unprecedented resolution of cellular heterogeneity, lineage specification, and spatial organization during early development. Here, we review the major discoveries permitted by single-cell omics methods, presented chronologically to reflect the progression of embryonic development. We address, among others, the delineation of blastomere contributions, mechanisms of embryonic genome activation, and the sequential specification of the trophectoderm, epiblast, and hypoblast lineages. We also explore how single-cell omics clarifies the effects of aneuploidy, uncovers mural-polar trophectoderm maturation, revises X chromosome regulation, and enables identification of rare post-implantation populations like primordial germ cells and amnion.","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"68 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Reply: Foundation models in IVF: from speculation to implementation with FEMI.","authors":"Hugo L Hammer,Vajira Thambawita,Michael A Riegler","doi":"10.1093/humrep/deaf227","DOIUrl":"https://doi.org/10.1093/humrep/deaf227","url":null,"abstract":"","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"22 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491479","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 the clinical pregnancy rates and cell lineage-related markers of equal-grade Day 5 (D5) and Day 6 (D6) embryos the same?SUMMARY ANSWERHigh-grade D5 (HG D5) blastocysts have a higher live birth rate than high-grade D6 (HG D6) blastocysts, which could be associated with differences in intrinsic OCT4 expression.WHAT IS KNOWN ALREADYIn IVF cycles, D5 blastocysts are generally considered to be of higher quality and are preferred for embryo transfer over D6 blastocysts. However, the differences between delayed D6 embryos and D5 embryos remain poorly understood. This study aimed to perform an immunofluorescence (IF)-based analysis to evaluate cell content-related differences between same-grade D5 and D6 blastocysts and to assess how these differences may be associated with the clinical pregnancy outcomes following frozen-thawed embryo transfer cycles.STUDY DESIGN, SIZE, DURATIONThis retrospective study included 774 frozen-thawed single blastocyst transfer (SBT) cycles at the Taipei Fertility Center from March 2020 to February 2023. All D5 (D5-SBT) and D6 (D6-SBT) frozen-thawed cycles (n = 774) were classified as high grade (≥BB, n = 694) or low grade (<BB, n = 80).PARTICIPANTS/MATERIALS, SETTING, METHODSFor the cell content analyses, IF staining with the pluripotent marker OCT4 was used to determine the cell numbers in the inner cell mass (ICM), and the trophectoderm (TE) marker GATA3 was used to evaluate the TE region. Same-grade frozen-thawed D5 blastocysts (n = 20), D6 blastocysts (n = 20), and D5 blastocysts cultured to D6 (ExD6, n = 17) were used to assess differences in the cell number in the TE and ICM by evaluating OCT4 and GATA3 expression. The total number of cells was visualized using DAPI staining. OCT4 and GATA3 transcripts were analysed with quantitative reverse transcription polymerase chain reaction (qRT-PCR).MAIN RESULTS AND THE ROLE OF CHANCEFor the clinical results, in the single euploid embryo transfer cycle, the overall biochemical pregnancy rate (HCG+, 71.8% vs 52.3%, P < 0.0001), clinical pregnancy rate (SAC+, +66.7% vs 47.7%, P = 0.0001) and live birth rate (59.5% vs 37.9%, P < 0.0001) were significantly higher in the D5-SBT group than in the D6-SBT group. Among HG embryos, the D5-SBT group consistently demonstrated better clinical outcomes. A generalized linear mixed model revealed that the odds ratios were significantly elevated only for D5 embryos but not for other confounders, highlighting the importance of developmental timing. On the other hand, the staining results showed no significant differences in the numbers of TE, ICM, or total cells between the same-grade D5 and D6 blastocysts. However, a notable decrease in OCT4-positive cells was observed in D6 embryos, suggesting a reduction in embryo quality (D5 vs D6: 64 ± 4% vs 49 ± 5% per embryo). ExD6 blastocysts had a significantly increased number of TE cells compared to D6 blastocysts, reflecting greater expansion of the TE population. Gene expression an
{"title":"Increased OCT4 expression in Day 5 blastocysts may explain the increased clinical outcomes of D5 versus D6 blastocyst transfers.","authors":"Jui-Hua Lee,Wei-Fang Chang,Shang-Yu Tzeng,Yi-Xuan Lee,Shun-Jen Tan,Ruey-Sheng Wang,Jason Yen-Ping Ho,Shyr-Yeu Lin,Yuh-Ming Hwu,Chii-Ruey Tzeng","doi":"10.1093/humrep/deaf211","DOIUrl":"https://doi.org/10.1093/humrep/deaf211","url":null,"abstract":"STUDY QUESTIONAre the clinical pregnancy rates and cell lineage-related markers of equal-grade Day 5 (D5) and Day 6 (D6) embryos the same?SUMMARY ANSWERHigh-grade D5 (HG D5) blastocysts have a higher live birth rate than high-grade D6 (HG D6) blastocysts, which could be associated with differences in intrinsic OCT4 expression.WHAT IS KNOWN ALREADYIn IVF cycles, D5 blastocysts are generally considered to be of higher quality and are preferred for embryo transfer over D6 blastocysts. However, the differences between delayed D6 embryos and D5 embryos remain poorly understood. This study aimed to perform an immunofluorescence (IF)-based analysis to evaluate cell content-related differences between same-grade D5 and D6 blastocysts and to assess how these differences may be associated with the clinical pregnancy outcomes following frozen-thawed embryo transfer cycles.STUDY DESIGN, SIZE, DURATIONThis retrospective study included 774 frozen-thawed single blastocyst transfer (SBT) cycles at the Taipei Fertility Center from March 2020 to February 2023. All D5 (D5-SBT) and D6 (D6-SBT) frozen-thawed cycles (n = 774) were classified as high grade (≥BB, n = 694) or low grade (<BB, n = 80).PARTICIPANTS/MATERIALS, SETTING, METHODSFor the cell content analyses, IF staining with the pluripotent marker OCT4 was used to determine the cell numbers in the inner cell mass (ICM), and the trophectoderm (TE) marker GATA3 was used to evaluate the TE region. Same-grade frozen-thawed D5 blastocysts (n = 20), D6 blastocysts (n = 20), and D5 blastocysts cultured to D6 (ExD6, n = 17) were used to assess differences in the cell number in the TE and ICM by evaluating OCT4 and GATA3 expression. The total number of cells was visualized using DAPI staining. OCT4 and GATA3 transcripts were analysed with quantitative reverse transcription polymerase chain reaction (qRT-PCR).MAIN RESULTS AND THE ROLE OF CHANCEFor the clinical results, in the single euploid embryo transfer cycle, the overall biochemical pregnancy rate (HCG+, 71.8% vs 52.3%, P < 0.0001), clinical pregnancy rate (SAC+, +66.7% vs 47.7%, P = 0.0001) and live birth rate (59.5% vs 37.9%, P < 0.0001) were significantly higher in the D5-SBT group than in the D6-SBT group. Among HG embryos, the D5-SBT group consistently demonstrated better clinical outcomes. A generalized linear mixed model revealed that the odds ratios were significantly elevated only for D5 embryos but not for other confounders, highlighting the importance of developmental timing. On the other hand, the staining results showed no significant differences in the numbers of TE, ICM, or total cells between the same-grade D5 and D6 blastocysts. However, a notable decrease in OCT4-positive cells was observed in D6 embryos, suggesting a reduction in embryo quality (D5 vs D6: 64 ± 4% vs 49 ± 5% per embryo). ExD6 blastocysts had a significantly increased number of TE cells compared to D6 blastocysts, reflecting greater expansion of the TE population. Gene expression an","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"27 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491480","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 QUESTIONIs there an association between neighborhood deprivation and frozen embryo transfer outcomes?SUMMARY ANSWERAfter adjusting for important reproductive characteristics most closely associated with embryo transfer outcomes, residual significant differences in live birth were present with a progressive decline in the probability of live birth as measures of socioeconomic disadvantage increased.WHAT IS KNOWN ALREADYResidence in a socioeconomically disadvantaged neighborhood is associated with adverse reproductive health outcomes, including decreased fecundability, preeclampsia, gestational diabetes, preterm birth, and low birthweight.STUDY DESIGN, SIZE, DURATIONRetrospective cohort study including 8155 patients undergoing first, single, euploid, frozen embryo transfer between 2017 and 2022 at a single university-affiliated fertility center. The primary outcome was live birth. Secondary outcomes included any pregnancy loss, mode of delivery, birthweight, and gestational age at delivery. After accounting for all inclusion criteria, only 2.5% of the total cases were excluded due to missing information on BMI, insurance status, or type of transfer protocol.PARTICIPANTS/MATERIALS, SETTING, METHODSA total of 8155 patients met inclusion criteria. The primary exposure of this study was the state decile Area of Deprivation Index (ADI) score, or the composite score that measures overall socioeconomic disadvantage at the Census block level. ADI scores were then divided into four groups: low or least disadvantaged (score 1-2, n = 3138, 38.5%), low-middle (score 3-5, n = 3145, 38.5%), middle-high (score 6-8, n = 1573, 19.3%), and high or most disadvantaged (score 9-10, n = 299, 3.7%).MAIN RESULTS AND THE ROLE OF CHANCEIndividuals living in areas with higher neighborhood deprivation (more disadvantaged) had a higher BMI and were more likely to be uninsured than those in areas of lower deprivation (less disadvantaged). Overall, 60.9% (n = 4963) of patients had a live birth with significantly lower rates in those living in neighborhoods with higher levels of socioeconomic disadvantage compared to those in neighborhoods with lower levels of socioeconomic disadvantage (P = 0.002). Compared to couples living in areas with the lowest deprivation index scores census blocks, the probability of live birth was significantly decreased for couples living in areas with low-middle, middle-high, and high scores in multivariable regression analyses after adjustment for maternal age, BMI, duration of time from initial consult to decision for IVF, primary infertility diagnosis, office location, insurance status, FET protocol, endometrial thickness, max estradiol level, and embryo grade (aOR 0.90 (95% CI 0.81-0.99), P = 0.047; aOR 0.87 (95% CI 0.77-0.99), P = 0.047; aOR 0.70 (95% CI 0.54-0.90), P = 0.006; respectively). Additionally, there was a significant dose-response relationship between neighborhood deprivation and probability of live birth (P = 0.003). Compared to
研究问题：邻里剥夺与冷冻胚胎移植结果之间是否存在关联？在调整了与胚胎移植结果最密切相关的重要生殖特征后，随着社会经济劣势指标的增加，活产的概率逐渐下降，活产的剩余显著差异仍然存在。已知情况居住在社会经济条件较差的社区与不良生殖健康结果相关，包括生育能力下降、先兆子痫、妊娠糖尿病、早产和低出生体重。研究设计、规模、持续时间回顾性队列研究包括8155例患者，于2017年至2022年在一所大学附属生育中心接受首次、单、整倍体冷冻胚胎移植。主要结局是活产。次要结局包括流产、分娩方式、出生体重和分娩时的胎龄。在考虑了所有纳入标准后，由于缺乏BMI、保险状况或转移方案类型的信息，只有2.5%的病例被排除在外。参与者/材料、环境、方法共8155例患者符合纳入标准。本研究的主要暴露是国家十分位剥夺面积指数（ADI）得分，或在人口普查区域水平上衡量整体社会经济劣势的综合得分。ADI评分分为低或最不利组（1-2分，n = 3138, 38.5%）、中低组（3-5分，n = 3145, 38.5%）、中高组（6-8分，n = 1573, 19.3%）、高或最不利组（9-10分，n = 299, 3.7%）。主要结果和机遇的作用生活在社区贫困程度较高的地区（更弱势）的个体比生活在贫困程度较低地区（更弱势）的个体有更高的BMI，更有可能没有保险。总体而言，60.9% （n = 4963）的患者活产，生活在社会经济劣势水平较高的社区的患者的活产率明显低于生活在社会经济劣势水平较低的社区的患者（P = 0.002）。与生活在剥夺指数得分最低的地区的夫妇相比，在多变量回归分析中，生活在低、中、中高和高得分地区的夫妇在调整了母亲年龄、体重指数、从最初咨询到决定试管婴儿的持续时间、原发性不孕症诊断、办公地点、保险状况、FET方案、子宫内膜厚度、最大雌二醇水平、胚胎分级(aOR 0.90 (95% CI 0.81-0.99), P = 0.047；aOR 0.87 (95% CI 0.77-0.99), P = 0.047；aOR 0.70 (95% CI 0.54 ~ 0.90), P = 0.006；分别)。此外，邻里剥夺与活产概率之间存在显著的剂量-反应关系（P = 0.003）。与生活在低邻里剥夺地区的夫妇相比，在调整后的模型中，生活在ADI最高的人口普查区域的夫妇怀孕失败的概率明显更高（aOR 1.64 (95% CI 1.21-2.24), P = 0.002）。分娩方式、出生体重或分娩时的胎龄均无差异。本研究的局限性包括其回顾性设计、外部效度和不同的患者经历。此外，社会经济地位仍然是一个多方面和广泛的概念，其中包括往往难以衡量的因素。研究结果的广泛意义本研究强调了在调整了与体外受精结果最密切相关的重要生殖特征后，居住在基于区域的社会经济劣势日益恶化的社区的人群的活产概率存在显著差异。我们的数据强调，生殖健康提供者不仅应该专注于优化临床和实验室流程，以改善患者的结果，还应该扩大关注和努力，以了解影响整体生殖健康的更广泛的系统、经济和地理因素。研究经费/竞争利益资金未用于本项目的目的。作者声明他们没有利益冲突。试验注册号不适用。
{"title":"Association of neighborhood deprivation and live birth after 8155 first, single euploid frozen embryo transfers: the lived patient experience matters.","authors":"Stephanie Willson,Kassie Bollig","doi":"10.1093/humrep/deaf209","DOIUrl":"https://doi.org/10.1093/humrep/deaf209","url":null,"abstract":"STUDY QUESTIONIs there an association between neighborhood deprivation and frozen embryo transfer outcomes?SUMMARY ANSWERAfter adjusting for important reproductive characteristics most closely associated with embryo transfer outcomes, residual significant differences in live birth were present with a progressive decline in the probability of live birth as measures of socioeconomic disadvantage increased.WHAT IS KNOWN ALREADYResidence in a socioeconomically disadvantaged neighborhood is associated with adverse reproductive health outcomes, including decreased fecundability, preeclampsia, gestational diabetes, preterm birth, and low birthweight.STUDY DESIGN, SIZE, DURATIONRetrospective cohort study including 8155 patients undergoing first, single, euploid, frozen embryo transfer between 2017 and 2022 at a single university-affiliated fertility center. The primary outcome was live birth. Secondary outcomes included any pregnancy loss, mode of delivery, birthweight, and gestational age at delivery. After accounting for all inclusion criteria, only 2.5% of the total cases were excluded due to missing information on BMI, insurance status, or type of transfer protocol.PARTICIPANTS/MATERIALS, SETTING, METHODSA total of 8155 patients met inclusion criteria. The primary exposure of this study was the state decile Area of Deprivation Index (ADI) score, or the composite score that measures overall socioeconomic disadvantage at the Census block level. ADI scores were then divided into four groups: low or least disadvantaged (score 1-2, n = 3138, 38.5%), low-middle (score 3-5, n = 3145, 38.5%), middle-high (score 6-8, n = 1573, 19.3%), and high or most disadvantaged (score 9-10, n = 299, 3.7%).MAIN RESULTS AND THE ROLE OF CHANCEIndividuals living in areas with higher neighborhood deprivation (more disadvantaged) had a higher BMI and were more likely to be uninsured than those in areas of lower deprivation (less disadvantaged). Overall, 60.9% (n = 4963) of patients had a live birth with significantly lower rates in those living in neighborhoods with higher levels of socioeconomic disadvantage compared to those in neighborhoods with lower levels of socioeconomic disadvantage (P = 0.002). Compared to couples living in areas with the lowest deprivation index scores census blocks, the probability of live birth was significantly decreased for couples living in areas with low-middle, middle-high, and high scores in multivariable regression analyses after adjustment for maternal age, BMI, duration of time from initial consult to decision for IVF, primary infertility diagnosis, office location, insurance status, FET protocol, endometrial thickness, max estradiol level, and embryo grade (aOR 0.90 (95% CI 0.81-0.99), P = 0.047; aOR 0.87 (95% CI 0.77-0.99), P = 0.047; aOR 0.70 (95% CI 0.54-0.90), P = 0.006; respectively). Additionally, there was a significant dose-response relationship between neighborhood deprivation and probability of live birth (P = 0.003). Compared to","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"1 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477413","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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