Pub Date : 2025-09-01eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf053
Wenxue Xiong, Xijia Tang, Lu Han, Li Ling
{"title":"Reply: Paternal age and neonatal health: unraveling epigenetic pathways.","authors":"Wenxue Xiong, Xijia Tang, Lu Han, Li Ling","doi":"10.1093/hropen/hoaf053","DOIUrl":"10.1093/hropen/hoaf053","url":null,"abstract":"","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf053"},"PeriodicalIF":11.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145115122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-29eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf049
Antoni Riera-Escamilla, Mohamed M Arafa, Ginevra Farnetani, Miguel J Xavier, Manon S Oud, Ahmad A Majzoub, Liliana Ramos, Chiara Abrardo, Matilde Spinelli, Daniel Moreno-Mendoza, Giuseppe Defazio, Elisabet Ars, Marc Pybus, Josvany R Sánchez Curbelo, Haitham T Elbardisi, Shoaib Nawaz, Najeeb Syed, Eduard Ruiz-Castané, Godfried W van der Heijden, Khalid A Fakhro, Joris A Veltman, Csilla Krausz
<p><strong>Study question: </strong>What is the diagnostic yield and the pre-testicular sperm extraction (TESE) prognostic value of a non-obstructive azoospermia (NOA)-specific virtual gene panel?</p><p><strong>Summary answer: </strong>The diagnostic yield in our cohort was 6.1%, and by combining our data with published literature, we identified 11 genes compatible with testicular sperm production and 19 genes associated with no sperm retrieval in carriers of pathogenic (P) or likely pathogenic (LP) mutations.</p><p><strong>What is known already: </strong>Azoospermia, the most severe form of male infertility, affects ∼1% of the male population, with TESE being the primary treatment option. However, in NOA, TESE fails in nearly 50% of cases and existing clinical parameters are unable to predict TESE failure. Over the past decade, next-generation sequencing (NGS) has identified several candidate NOA genes, but their diagnostic utility and impact on TESE outcomes have not been fully explored.</p><p><strong>Study design size and duration: </strong>A literature search was addressed to identify well-established NOA genes for designing a specific virtual gene panel for NOA. Our retrospective study analysed the diagnostic yield of the NGS-based virtual gene panel, comprising 145 genes, in 571 men affected by idiopathic NOA with known TESE outcomes. Subsequently, a second literature search was performed to identify carriers of LP/P variants in the genes where we identified mutations, focusing on individuals with known TESE outcomes. This approach allowed us to integrate the published data with our findings and predict a genotype-phenotype correlation between the affected genes and TESE success.</p><p><strong>Participants/materials settings methods: </strong>571 NOA patients with known TESE outcomes were recruited in two European and one Middle East centres. Variants were obtained from a whole-exome sequencing dataset and crossed with the 145 genes of the virtual gene panel. After a filtering process, variants were manually assessed and classified according to ACMG guidelines by using two methods: (i) In order to compare our data with previously published studies, we applied ACMG-AMP guidelines along with ClinGen recommendations used by other similar studies. (ii) A new approach was used to optimize ACMG-AMP guidelines with all ClinGen recommendations and incorporated NOA-specific rules addressing phenotypic, locus, and allelic heterogeneity. LP and P variants were confirmed by Sanger sequencing.</p><p><strong>Main results and the role of chance: </strong>By using the new variant classification approach adapted for NOA, we identified LP/P variants in 6.1% of patients, with a higher yield (9.4%) in cases with negative TESE outcomes and maturation arrest (11.7%). By integrating our findings with the literature, we highlight 19 genes recurrently associated with negative TESE outcomes and 11 genes associated with positive sperm retrieval either in the testis o
{"title":"Genetic determinants of testicular sperm extraction outcomes: insights from a large multicentre study of men with non-obstructive azoospermia.","authors":"Antoni Riera-Escamilla, Mohamed M Arafa, Ginevra Farnetani, Miguel J Xavier, Manon S Oud, Ahmad A Majzoub, Liliana Ramos, Chiara Abrardo, Matilde Spinelli, Daniel Moreno-Mendoza, Giuseppe Defazio, Elisabet Ars, Marc Pybus, Josvany R Sánchez Curbelo, Haitham T Elbardisi, Shoaib Nawaz, Najeeb Syed, Eduard Ruiz-Castané, Godfried W van der Heijden, Khalid A Fakhro, Joris A Veltman, Csilla Krausz","doi":"10.1093/hropen/hoaf049","DOIUrl":"10.1093/hropen/hoaf049","url":null,"abstract":"<p><strong>Study question: </strong>What is the diagnostic yield and the pre-testicular sperm extraction (TESE) prognostic value of a non-obstructive azoospermia (NOA)-specific virtual gene panel?</p><p><strong>Summary answer: </strong>The diagnostic yield in our cohort was 6.1%, and by combining our data with published literature, we identified 11 genes compatible with testicular sperm production and 19 genes associated with no sperm retrieval in carriers of pathogenic (P) or likely pathogenic (LP) mutations.</p><p><strong>What is known already: </strong>Azoospermia, the most severe form of male infertility, affects ∼1% of the male population, with TESE being the primary treatment option. However, in NOA, TESE fails in nearly 50% of cases and existing clinical parameters are unable to predict TESE failure. Over the past decade, next-generation sequencing (NGS) has identified several candidate NOA genes, but their diagnostic utility and impact on TESE outcomes have not been fully explored.</p><p><strong>Study design size and duration: </strong>A literature search was addressed to identify well-established NOA genes for designing a specific virtual gene panel for NOA. Our retrospective study analysed the diagnostic yield of the NGS-based virtual gene panel, comprising 145 genes, in 571 men affected by idiopathic NOA with known TESE outcomes. Subsequently, a second literature search was performed to identify carriers of LP/P variants in the genes where we identified mutations, focusing on individuals with known TESE outcomes. This approach allowed us to integrate the published data with our findings and predict a genotype-phenotype correlation between the affected genes and TESE success.</p><p><strong>Participants/materials settings methods: </strong>571 NOA patients with known TESE outcomes were recruited in two European and one Middle East centres. Variants were obtained from a whole-exome sequencing dataset and crossed with the 145 genes of the virtual gene panel. After a filtering process, variants were manually assessed and classified according to ACMG guidelines by using two methods: (i) In order to compare our data with previously published studies, we applied ACMG-AMP guidelines along with ClinGen recommendations used by other similar studies. (ii) A new approach was used to optimize ACMG-AMP guidelines with all ClinGen recommendations and incorporated NOA-specific rules addressing phenotypic, locus, and allelic heterogeneity. LP and P variants were confirmed by Sanger sequencing.</p><p><strong>Main results and the role of chance: </strong>By using the new variant classification approach adapted for NOA, we identified LP/P variants in 6.1% of patients, with a higher yield (9.4%) in cases with negative TESE outcomes and maturation arrest (11.7%). By integrating our findings with the literature, we highlight 19 genes recurrently associated with negative TESE outcomes and 11 genes associated with positive sperm retrieval either in the testis o","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf049"},"PeriodicalIF":11.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-20eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf043
Samuel Madureira Silva, Frédéric Chalmel, Andrea Errico, Katerina Papageorgiou, Guillaume Richer, Edith Chan Sock Peng, Antoine D Rolland, Kelly Tilleman, Guy T'Sjoen, Ilaria Dando, Tamara Vanhaecke, Ellen Goossens, Yoni Baert
<p><strong>Study question: </strong>Can testicular tissue from trans women (trans tissue) be used to create human testicular organoids?</p><p><strong>Summary answer: </strong>Testosterone-producing and cytotypic human testicular organoids with bicompartmental architecture can be successfully generated from trans tissue.</p><p><strong>What is known already: </strong>Testicular organoids are a promising tool for studying testicular function and the effects of toxicants. Immature testicular cells are currently the most efficient at forming organoids that closely recapitulate seminiferous tubule-like architecture and functions. However, the scarcity of immature human testicular tissue limits its use in high-throughput applications. Conversely, trans tissue is abundantly available and characterized by an immature phenotype.</p><p><strong>Study design size duration: </strong>Trans tissue-derived organoids (trans organoids) were histologically and androgenically compared to reference organoids derived from immature (prepubertal and pubertal) and adult cisgender testicular tissues. Additionally, long-term testosterone production and gonadotrophic stimulation were assessed in trans organoids. To evaluate their cytotypic and transcriptomic resemblance to reference testicular tissue stages, trans organoids were compared at the gene expression level to prepubertal, pubertal, and adult cisgender tissues, along with their tissue of origin.</p><p><strong>Participants/materials setting methods: </strong>Testicular tissue samples from transgender women, as well as from prepubertal, pubertal, and adult cisgender donors, were used to generate testicular organoids and to compare organoid formation efficiency and testosterone production according to tissue origin. These samples also served as references for transcriptomic comparisons with organoids derived from transgender women's testicular tissue at Day 14 of culture. Testicular organoids were generated and cultured using 3D Petri Dish<sup>®</sup> platforms. Histochemistry and immunofluorescence staining were employed to characterize cellular composition and spatial organization. Testosterone production in culture media was assessed using electrochemiluminescence immunoassays. RNA was extracted and sequenced from organoids derived from transgender women, as well as from tissue samples of all donor groups. Deconvolution and differential gene expression analyses were performed to compare the organoids with testicular tissues across all groups.</p><p><strong>Main results and the role of chance: </strong>Trans organoids form compartmentalized, cytotypic <i>de novo</i> tissues similar to those from pubertal testicular tissue. Additionally, trans organoids exhibit significant testosterone production, sustain this function over extended culture periods, and respond to gonadotrophic stimulation. Deconvolved bulk RNAseq data indicate that cell population proportions within these organoids are close to those in prepubertal a
研究问题：变性女性的睾丸组织（trans tissue）可以用来制造人类睾丸类器官吗？总结回答：具有双室结构的睾酮分泌和细胞型人类睾丸类器官可以成功地从跨组织中产生。已知情况：睾丸类器官是研究睾丸功能和毒物影响的一个很有前途的工具。目前，未成熟的睾丸细胞在形成类器官方面是最有效的，这些类器官与精管一样的结构和功能非常相似。然而，未成熟人类睾丸组织的稀缺性限制了其在高通量应用中的使用。相反，反式组织大量可用，其特征是不成熟的表型。研究设计规模持续时间：与未成熟（青春期前和青春期）和成年顺性睾丸组织的参考类器官相比，反组织来源的类器官在组织学和雄激素学上进行了比较。此外，长期睾酮分泌和促性腺刺激在反类器官中被评估。为了评估它们的细胞型和转录组学与参考睾丸组织阶段的相似性，我们在基因表达水平上比较了反式类器官与青春期前、青春期和成年顺性组织及其起源组织的差异。参与者/材料设置方法：使用变性女性、青春期前、青春期和成年顺性供体的睾丸组织样本来生成睾丸类器官，并根据组织来源比较类器官的形成效率和睾丸激素的产生。这些样本也可以作为转录组学比较的参考，在培养的第14天与来自跨性别女性睾丸组织的类器官进行比较。使用3D Petri Dish®平台生成和培养睾丸类器官。组织化学和免疫荧光染色表征细胞组成和空间组织。使用电化学发光免疫分析法评估培养基中睾酮的产生。从变性女性的类器官以及所有供体组的组织样本中提取RNA并进行测序。进行反褶积和差异基因表达分析，将所有组的类器官与睾丸组织进行比较。主要结果和突变的作用：反式类器官形成区隔化的细胞型新生组织，类似于青春期睾丸组织。此外，反式类器官表现出显著的睾酮分泌，在较长的培养周期内维持这一功能，并对促性腺刺激有反应。去卷积的大量RNAseq数据表明，这些类器官中的细胞群体比例接近青春期前和青春期睾丸组织中的细胞群体比例。基因表达聚集在青春期前和跨组织旁的类器官。功能分析显示，反式类器官与青春期前、青春期和反式组织共享不同的细胞过程。激素治疗的持续时间、小管内抗勒氏激素（一种不成熟的标志物）的表达以及供体组织中小管周围肌样细胞的比例等因素被发现可以预测转化类器官的成功形成。大规模数据：由于参与者隐私问题，大量RNA-seq原始和预处理数据存储在布鲁塞尔自由大学（VUB）机构数据存储库（VUB/IVTD/1/000001）中，访问受限。请联系Yoni Baert教授（yoni.baert@vub.be）获取数据。注意事项的局限性：本研究没有以方便的方式获得变性女性供体的激素数据。反褶积数据只允许比较细胞比例，而不是绝对数字。研究结果的更广泛意义：这项研究强调了反类器官作为一种新的、道德上可持续的基于人类的男性生殖健康研究、生殖毒理学和内分泌干扰研究模型的潜力。虽然反式组织是一种有价值的未成熟组织替代品，但进一步的研究应集中在优化类器官结构、评估其在生殖毒性测试中的应用以及促进生殖细胞分化方面。研究经费/利益冲突：本研究得到了VUB研究委员会（OZR4004）到s.m.s.，科学研究基金会-弗兰德斯（G026223N）和科学基金Willy Gepts到y.b.，战略研究计划89从VUB到e.g.和Mireille Aerens主席到T.V.的财政支持。作者声明没有利益冲突。
{"title":"A new human <i>in vitro</i> model of cytotypic and testosterone-producing organoids derived from testicular tissue of transgender women.","authors":"Samuel Madureira Silva, Frédéric Chalmel, Andrea Errico, Katerina Papageorgiou, Guillaume Richer, Edith Chan Sock Peng, Antoine D Rolland, Kelly Tilleman, Guy T'Sjoen, Ilaria Dando, Tamara Vanhaecke, Ellen Goossens, Yoni Baert","doi":"10.1093/hropen/hoaf043","DOIUrl":"10.1093/hropen/hoaf043","url":null,"abstract":"<p><strong>Study question: </strong>Can testicular tissue from trans women (trans tissue) be used to create human testicular organoids?</p><p><strong>Summary answer: </strong>Testosterone-producing and cytotypic human testicular organoids with bicompartmental architecture can be successfully generated from trans tissue.</p><p><strong>What is known already: </strong>Testicular organoids are a promising tool for studying testicular function and the effects of toxicants. Immature testicular cells are currently the most efficient at forming organoids that closely recapitulate seminiferous tubule-like architecture and functions. However, the scarcity of immature human testicular tissue limits its use in high-throughput applications. Conversely, trans tissue is abundantly available and characterized by an immature phenotype.</p><p><strong>Study design size duration: </strong>Trans tissue-derived organoids (trans organoids) were histologically and androgenically compared to reference organoids derived from immature (prepubertal and pubertal) and adult cisgender testicular tissues. Additionally, long-term testosterone production and gonadotrophic stimulation were assessed in trans organoids. To evaluate their cytotypic and transcriptomic resemblance to reference testicular tissue stages, trans organoids were compared at the gene expression level to prepubertal, pubertal, and adult cisgender tissues, along with their tissue of origin.</p><p><strong>Participants/materials setting methods: </strong>Testicular tissue samples from transgender women, as well as from prepubertal, pubertal, and adult cisgender donors, were used to generate testicular organoids and to compare organoid formation efficiency and testosterone production according to tissue origin. These samples also served as references for transcriptomic comparisons with organoids derived from transgender women's testicular tissue at Day 14 of culture. Testicular organoids were generated and cultured using 3D Petri Dish<sup>®</sup> platforms. Histochemistry and immunofluorescence staining were employed to characterize cellular composition and spatial organization. Testosterone production in culture media was assessed using electrochemiluminescence immunoassays. RNA was extracted and sequenced from organoids derived from transgender women, as well as from tissue samples of all donor groups. Deconvolution and differential gene expression analyses were performed to compare the organoids with testicular tissues across all groups.</p><p><strong>Main results and the role of chance: </strong>Trans organoids form compartmentalized, cytotypic <i>de novo</i> tissues similar to those from pubertal testicular tissue. Additionally, trans organoids exhibit significant testosterone production, sustain this function over extended culture periods, and respond to gonadotrophic stimulation. Deconvolved bulk RNAseq data indicate that cell population proportions within these organoids are close to those in prepubertal a","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf043"},"PeriodicalIF":11.1,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-18eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf045
Ze Xing, Meng-Meng Xie, Hui-Han Wang, Qi Cui, Xiao-Bin Wang
<p><strong>Study question: </strong>Are blood plasma trimethylamine N-oxide (TMAO) and related metabolites linked to the odds of asthenozoospermia?</p><p><strong>Summary answer: </strong>Increased blood plasma TMAO levels were positively associated with the odds of asthenozoospermia, while elevated levels of choline and L-carnitine were related to reduced asthenozoospermia odds, implying that TMAO and its related metabolites might play an important role in the development of asthenozoospermia.</p><p><strong>What is known already: </strong>Sperm motility and concentration are profoundly impaired by excessive reactive oxygen species (ROS). A positive correlation has been established between ROS levels and TMAO, which is regarded as a key regulatory factor for initiating mitochondrial ROS production. However, the precise interplay between TMAO and its metabolites and sperm quality remains inconclusive and insufficient.</p><p><strong>Study design size duration: </strong>This case-control study was conducted from June 2020 to December 2020. A total of 314 pairs of asthenozoospermia cases and normozoospermia controls, matched based on age, BMI, and smoking status, were included.</p><p><strong>Participants/materials setting methods: </strong>Blood plasma levels of TMAO and five related metabolites, such as choline, betaine, L-carnitine, methionine, and dimethylglycine, were measured using a liquid chromatography system coupled with tandem mass spectrometry. Multivariable conditional logistic regression models were used to estimate the odds ratios (ORs) and corresponding 95% CIs.</p><p><strong>Main results and the role of chance: </strong>Compared with the lowest quartile, a significant association was observed between blood plasma TMAO level (OR = 1.80, 95% CI = 1.16-2.81) and the odds of asthenozoospermia for the highest quartile. In contrast, choline (OR = 0.59, 95% CI = 0.37-0.92) and L-carnitine (OR = 0.58, 95% CI = 0.37-0.90) levels were significant inversely associated with the odds of asthenozoospermia. Additionally, for each per SD change, significant dose-response relationships were noted with increased odds of asthenozoospermia linked to elevated TMAO (OR = 1.31, 95% CI = 1.12-1.55), as well as L-carnitine (OR = 0.79, 95% CI = 0.67-0.93) and total methyl donors exposure (OR = 0.82, 95% CI = 0.70-0.96) levels.</p><p><strong>Limitations reasons for caution: </strong>We cannot infer causality from this study due to the case-control study. Since the current study was conducted on a population of Chinese men, the extrapolated results may not accurately reflect other regions or populations. As blood plasma TMAO and its metabolites were measured at a single time point and may not accurately represent long-term concentrations, the enduring effects on sperm quality may not be fully captured. Another limitation of the current study lies in its relatively modest sample size, which may have been insufficient to reach statistical power in subgroup analyses
研究问题：血浆三甲胺n -氧化物（TMAO）和相关代谢物与弱精子症的几率有关吗？摘要回答：血浆TMAO水平升高与弱精子症发生率呈正相关，而胆碱和左旋肉碱水平升高与弱精子症发生率降低相关，提示TMAO及其相关代谢物可能在弱精子症的发生中起重要作用。已知情况：过多的活性氧（ROS）会严重损害精子的活力和浓度。活性氧水平与氧化三甲胺之间存在正相关关系，氧化三甲胺被认为是启动线粒体活性氧生成的关键调节因子。然而，TMAO及其代谢物与精子质量之间的确切相互作用仍然是不确定和不充分的。研究设计规模持续时间：本病例对照研究于2020年6月至2020年12月进行。共有314对弱精子症患者和正常精子症对照组，根据年龄、BMI和吸烟状况进行匹配。参与者/材料设置方法：采用液相色谱联用串联质谱法测量血浆中TMAO和五种相关代谢物（如胆碱、甜菜碱、左旋肉碱、蛋氨酸和二甲基甘氨酸）的水平。采用多变量条件logistic回归模型估计优势比（ORs）和相应的95% ci。主要结果及偶然性的作用：与最低四分位数相比，最高四分位数的血浆TMAO水平（OR = 1.80, 95% CI = 1.16-2.81）与弱精子症的几率显著相关。相比之下，胆碱（OR = 0.59, 95% CI = 0.37-0.92）和左旋肉碱（OR = 0.58, 95% CI = 0.37-0.90）水平与弱精子症的发生率呈显著负相关。此外，对于每一个SD变化，显著的剂量-反应关系被注意到，与TMAO升高（OR = 1.31, 95% CI = 1.12-1.55）以及左旋肉碱（OR = 0.79, 95% CI = 0.67-0.93）和总甲基供体暴露（OR = 0.82, 95% CI = 0.70-0.96）水平相关的弱精子症的几率增加。注意的局限性：由于是病例对照研究，我们不能从本研究中推断出因果关系。由于目前的研究是在中国男性人群中进行的，推断的结果可能无法准确反映其他地区或人群。由于血浆TMAO及其代谢物是在单个时间点测量的，可能不能准确地代表长期浓度，因此可能无法完全捕获对精子质量的持久影响。当前研究的另一个局限性在于其相对适度的样本量，这可能不足以在亚组分析中达到统计效力。研究结果的更广泛含义：该研究表明，血浆TMAO水平升高与弱精子症的几率增加有关，而胆碱和左旋肉碱浓度升高可降低弱精子症的几率。我们的研究结果为TMAO及其代谢物可能作为弱精子症的潜在生物标志物提供了新的证据。研究资金/竞争利益：本研究未收到任何资金。所有作者无利益冲突需要声明。试验注册号：无。
{"title":"Blood plasma trimethylamine N-oxide and related metabolites and asthenozoospermia odds: a hospital-based matched case-control study in China.","authors":"Ze Xing, Meng-Meng Xie, Hui-Han Wang, Qi Cui, Xiao-Bin Wang","doi":"10.1093/hropen/hoaf045","DOIUrl":"10.1093/hropen/hoaf045","url":null,"abstract":"<p><strong>Study question: </strong>Are blood plasma trimethylamine N-oxide (TMAO) and related metabolites linked to the odds of asthenozoospermia?</p><p><strong>Summary answer: </strong>Increased blood plasma TMAO levels were positively associated with the odds of asthenozoospermia, while elevated levels of choline and L-carnitine were related to reduced asthenozoospermia odds, implying that TMAO and its related metabolites might play an important role in the development of asthenozoospermia.</p><p><strong>What is known already: </strong>Sperm motility and concentration are profoundly impaired by excessive reactive oxygen species (ROS). A positive correlation has been established between ROS levels and TMAO, which is regarded as a key regulatory factor for initiating mitochondrial ROS production. However, the precise interplay between TMAO and its metabolites and sperm quality remains inconclusive and insufficient.</p><p><strong>Study design size duration: </strong>This case-control study was conducted from June 2020 to December 2020. A total of 314 pairs of asthenozoospermia cases and normozoospermia controls, matched based on age, BMI, and smoking status, were included.</p><p><strong>Participants/materials setting methods: </strong>Blood plasma levels of TMAO and five related metabolites, such as choline, betaine, L-carnitine, methionine, and dimethylglycine, were measured using a liquid chromatography system coupled with tandem mass spectrometry. Multivariable conditional logistic regression models were used to estimate the odds ratios (ORs) and corresponding 95% CIs.</p><p><strong>Main results and the role of chance: </strong>Compared with the lowest quartile, a significant association was observed between blood plasma TMAO level (OR = 1.80, 95% CI = 1.16-2.81) and the odds of asthenozoospermia for the highest quartile. In contrast, choline (OR = 0.59, 95% CI = 0.37-0.92) and L-carnitine (OR = 0.58, 95% CI = 0.37-0.90) levels were significant inversely associated with the odds of asthenozoospermia. Additionally, for each per SD change, significant dose-response relationships were noted with increased odds of asthenozoospermia linked to elevated TMAO (OR = 1.31, 95% CI = 1.12-1.55), as well as L-carnitine (OR = 0.79, 95% CI = 0.67-0.93) and total methyl donors exposure (OR = 0.82, 95% CI = 0.70-0.96) levels.</p><p><strong>Limitations reasons for caution: </strong>We cannot infer causality from this study due to the case-control study. Since the current study was conducted on a population of Chinese men, the extrapolated results may not accurately reflect other regions or populations. As blood plasma TMAO and its metabolites were measured at a single time point and may not accurately represent long-term concentrations, the enduring effects on sperm quality may not be fully captured. Another limitation of the current study lies in its relatively modest sample size, which may have been insufficient to reach statistical power in subgroup analyses","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf045"},"PeriodicalIF":11.1,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><strong>Study question: </strong>Do social determinants of health (SDoH) influence the age at menopause among women?</p><p><strong>Summary answer: </strong>In our study, adverse SDoH, particularly family low income-to-poverty ratio (PIR), low education level, and the marital status of being widowed, are associated with earlier age at menopause.</p><p><strong>What is known already: </strong>Some prior studies have considered certain SDoH variables (such as educational attainment and marital status) as potential factors influencing age at menopause, but systematic evidence clearly defining the relationship between multidimensional SDoH and menopausal age remains lacking.</p><p><strong>Study design size duration: </strong>This cross-sectional analysis included 6083 naturally menopausal women from 10 cycles (1999-2018) of the United States National Health and Nutrition Examination Survey (NHANES) and excluded cases of surgical menopause.</p><p><strong>Participants/materials setting methods: </strong>The participants were derived from a nationally representative sample of the NHANES 1999-2018 in the USA. Eight SDoH variables were assessed: employment, PIR, food security, education, healthcare access, health insurance, housing stability, and marital status. Age at menopause was determined by self-reported last menstrual period among women with natural menopause. This study constructed weighted multivariate linear regression models and weighted quantile sum (WQS) analyses and calculated regression coefficients (β) and their 95% CIs. Subgroup analyses and sensitivity analyses were used to verify the robustness of our findings.</p><p><strong>Main results and the role of chance: </strong>After adjusting for relevant confounding factors, adverse PIR, education level, and marital status (such as being widowed) were significantly associated with earlier age at menopause. Specifically, compared to women with a PIR ≥500%, women with a PIR between 100% and 300% or PIR ≤100% had an earlier age at menopause by 0.877 years (95% CI: -1.526, -0.229, <i>P</i> = 0.008) and 1.296 years (95% CI: -2.105, -0.487, <i>P</i> = 0.002), respectively. Additionally, compared to women with an educational level of college or above, women with a high school education or less than a high school education had earlier age at menopause by 1.262 years (High school: 95% CI = -1.914, -0.609, <i>P</i> < 0.001) and 1.403 years (Less than high school: 95% CI = -2.062, -0.743, <i>P</i> < 0.001), respectively. Compared to women who were married or living with a partner, widowed women had earlier age at menopause by 1.363 years (95% CI = -1.887, -0.839, <i>P</i> < 0.001). Analysis using a WQS regression model based on decile categorization demonstrated that each 1-unit increase in the composite exposure index of adverse SDoH factors was associated with 3.302 years earlier age at menopause in women (95% CI = -4.129, -2.476, <i>P</i> < 0.001). The PIR contributed most substantially to the inver
研究问题：健康的社会决定因素（SDoH）是否影响女性绝经年龄？摘要回答：在我们的研究中，不良的性激素水平，特别是家庭低收入与贫困比（PIR）、低教育水平和丧偶的婚姻状况与绝经年龄提前有关。已知情况：一些先前的研究认为某些SDoH变量（如受教育程度和婚姻状况）是影响绝经年龄的潜在因素，但仍然缺乏明确定义多维SDoH与绝经年龄之间关系的系统证据。研究设计规模持续时间：该横断面分析包括来自美国国家健康与营养调查（NHANES） 10个周期（1999-2018）的6083名自然绝经妇女，并排除手术绝经病例。参与者/材料设置方法：参与者来自美国NHANES 1999-2018的全国代表性样本。评估了8个SDoH变量：就业、PIR、食品安全、教育、医疗保健获取、健康保险、住房稳定性和婚姻状况。绝经年龄由自然绝经妇女自我报告的最后一次月经确定。本研究构建多元加权线性回归模型和加权分位数和（WQS）分析，计算回归系数（β）及其95% ci。采用亚组分析和敏感性分析来验证我们研究结果的稳健性。主要结果及偶然性的作用：在调整相关混杂因素后，不良PIR、受教育程度、婚姻状况（如丧偶）与绝经年龄提前显著相关。具体而言，与PIR≥500%的女性相比，PIR在100%至300%之间或PIR≤100%的女性绝经年龄分别提前0.877年（95% CI: -1.526, -0.229, P = 0.008）和1.296年（95% CI: -2.105, -0.487, P = 0.002）。此外，与大学及以上学历的女性相比，高中学历或高中以下学历的女性绝经年龄提前1.262年（高中学历：95% CI = -1.914, -0.609, P P P P P）。谨慎的局限性原因：横断面设计限制了因果推理。尽管进行了敏感性分析，但未测量的混杂因素（如胎次、以前使用的激素、化学物质暴露）和回忆偏差可能仍然存在。研究结果的更广泛含义：这些发现证实了针对经济稳定、住房安全、就业支持和医疗保健获取的综合多维干预措施的实施，这可能比单一维度的政策调整产生更大的效益。此外，物质剥夺因素对生殖衰老的影响可能比之前认为的要大得多。研究经费/利益竞争：国家重点研发计划项目（2023YFC2705700）、武汉大学人民医院跨学科创新人才基金项目（JCRCYG-2022-009）、国家自然科学基金项目（72474005）资助。所有作者声明没有利益竞争。试验注册号：无。
{"title":"Association of social determinants of health and age at menopause: NHANES 1999-2018 observational study.","authors":"Yu Guan, Qian Liu, Zhimin Deng, Sirui Liu, Jia Liang, Yujie Zou, Tailang Yin, Dongdong Tang, Jue Liu, Yan Zhang","doi":"10.1093/hropen/hoaf050","DOIUrl":"10.1093/hropen/hoaf050","url":null,"abstract":"<p><strong>Study question: </strong>Do social determinants of health (SDoH) influence the age at menopause among women?</p><p><strong>Summary answer: </strong>In our study, adverse SDoH, particularly family low income-to-poverty ratio (PIR), low education level, and the marital status of being widowed, are associated with earlier age at menopause.</p><p><strong>What is known already: </strong>Some prior studies have considered certain SDoH variables (such as educational attainment and marital status) as potential factors influencing age at menopause, but systematic evidence clearly defining the relationship between multidimensional SDoH and menopausal age remains lacking.</p><p><strong>Study design size duration: </strong>This cross-sectional analysis included 6083 naturally menopausal women from 10 cycles (1999-2018) of the United States National Health and Nutrition Examination Survey (NHANES) and excluded cases of surgical menopause.</p><p><strong>Participants/materials setting methods: </strong>The participants were derived from a nationally representative sample of the NHANES 1999-2018 in the USA. Eight SDoH variables were assessed: employment, PIR, food security, education, healthcare access, health insurance, housing stability, and marital status. Age at menopause was determined by self-reported last menstrual period among women with natural menopause. This study constructed weighted multivariate linear regression models and weighted quantile sum (WQS) analyses and calculated regression coefficients (β) and their 95% CIs. Subgroup analyses and sensitivity analyses were used to verify the robustness of our findings.</p><p><strong>Main results and the role of chance: </strong>After adjusting for relevant confounding factors, adverse PIR, education level, and marital status (such as being widowed) were significantly associated with earlier age at menopause. Specifically, compared to women with a PIR ≥500%, women with a PIR between 100% and 300% or PIR ≤100% had an earlier age at menopause by 0.877 years (95% CI: -1.526, -0.229, <i>P</i> = 0.008) and 1.296 years (95% CI: -2.105, -0.487, <i>P</i> = 0.002), respectively. Additionally, compared to women with an educational level of college or above, women with a high school education or less than a high school education had earlier age at menopause by 1.262 years (High school: 95% CI = -1.914, -0.609, <i>P</i> < 0.001) and 1.403 years (Less than high school: 95% CI = -2.062, -0.743, <i>P</i> < 0.001), respectively. Compared to women who were married or living with a partner, widowed women had earlier age at menopause by 1.363 years (95% CI = -1.887, -0.839, <i>P</i> < 0.001). Analysis using a WQS regression model based on decile categorization demonstrated that each 1-unit increase in the composite exposure index of adverse SDoH factors was associated with 3.302 years earlier age at menopause in women (95% CI = -4.129, -2.476, <i>P</i> < 0.001). The PIR contributed most substantially to the inver","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf050"},"PeriodicalIF":11.1,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><strong>Study question: </strong>What is the effect of hCG on the epigenetic profile and the expression of other molecular factors in endometrial stromal cells (ESCs)?</p><p><strong>Summary answer: </strong>Our findings suggest that hCG treatment alters the molecular environment of decidualized ESCs, potentially influencing implantation and immune regulation through epigenetic modifications and changes in the levels of secreted proteins and micro-ribonucleic acids (miRNAs).</p><p><strong>What is known already: </strong>Embryo implantation depends not only on the quality of the embryo but also on the receptivity of the endometrium, the specialized lining of the uterus that undergoes dynamic changes to support pregnancy. Effective communication between the maternal and fetal compartments, facilitated by molecular signals and cellular interactions, is essential for successful implantation.</p><p><strong>Study design size duration: </strong>Cross-sectional study of patient-derived ESCs comparing untreated cells with cells treated with hCG and/or decidualization induction. The number of samples depends on the method and varies from 2 to 8. Results were analyzed after 6-, 24-, 48-, and 72-h time-points.</p><p><strong>Participants/materials setting methods: </strong>ESCs were isolated from patients undergoing assisted reproductive technologies. In the study, we analyzed changes in the epigenetic profile and other molecular factors of ESCs during decidualization and in <i>in vitro</i> response to the embryo-secreted factor, hCG. ESCs were induced for decidualization for 3 days (medroxyprogesterone acetate+cAMP), or treated with hCG for 24 h, or given combined treatment: 2 days of decidualization followed by 24 h of hCG. Furthermore, we compared decidualized ESCs with decidualized ESCs that were also treated with hCG. We examined various cellular properties, including morphology, metabolic activity, and cell viability of ESCs after induction of decidualization and hCG treatment. Additionally, we assessed changes in the expression of genes associated with decidualization, inflammatory response, apoptosis regulation, and epigenetic factors using RT-qPCR. The levels of histone modifications and the factors regulating these modifications were explored by performing western blot assays. Additionally, we performed a chromatin immunoprecipitation assay to extract gene regions enriched with the epigenetic modification H3K27Ac. Finally, we analyzed the protein and miRNA level changes in ESC extracellular vesicles (ESC-EVs) after the indicated treatments, using mass spectrometry and small RNA sequencing.</p><p><strong>Main results and the role of chance: </strong>Our study found that hCG treatment increased prolactin gene (<i>PRL)</i> expression (<i>P</i> < 0.05), while the expression of <i>IL6</i> and <i>BAK1</i> was inhibited in ESCs (<i>P</i> < 0.05). We also revealed that hCG affects epigenetic regulation, leading to changes in the expression of <i>EED</i>,
{"title":"Evaluating endometrial response to human chorionic gonadotropin: alterations in epigenetic regulation and extracellular vesicle cargo of endometrial stromal cells.","authors":"Deimantė Žukauskaitė, Erika Girniūtė, Rūta Navakauskienė","doi":"10.1093/hropen/hoaf051","DOIUrl":"10.1093/hropen/hoaf051","url":null,"abstract":"<p><strong>Study question: </strong>What is the effect of hCG on the epigenetic profile and the expression of other molecular factors in endometrial stromal cells (ESCs)?</p><p><strong>Summary answer: </strong>Our findings suggest that hCG treatment alters the molecular environment of decidualized ESCs, potentially influencing implantation and immune regulation through epigenetic modifications and changes in the levels of secreted proteins and micro-ribonucleic acids (miRNAs).</p><p><strong>What is known already: </strong>Embryo implantation depends not only on the quality of the embryo but also on the receptivity of the endometrium, the specialized lining of the uterus that undergoes dynamic changes to support pregnancy. Effective communication between the maternal and fetal compartments, facilitated by molecular signals and cellular interactions, is essential for successful implantation.</p><p><strong>Study design size duration: </strong>Cross-sectional study of patient-derived ESCs comparing untreated cells with cells treated with hCG and/or decidualization induction. The number of samples depends on the method and varies from 2 to 8. Results were analyzed after 6-, 24-, 48-, and 72-h time-points.</p><p><strong>Participants/materials setting methods: </strong>ESCs were isolated from patients undergoing assisted reproductive technologies. In the study, we analyzed changes in the epigenetic profile and other molecular factors of ESCs during decidualization and in <i>in vitro</i> response to the embryo-secreted factor, hCG. ESCs were induced for decidualization for 3 days (medroxyprogesterone acetate+cAMP), or treated with hCG for 24 h, or given combined treatment: 2 days of decidualization followed by 24 h of hCG. Furthermore, we compared decidualized ESCs with decidualized ESCs that were also treated with hCG. We examined various cellular properties, including morphology, metabolic activity, and cell viability of ESCs after induction of decidualization and hCG treatment. Additionally, we assessed changes in the expression of genes associated with decidualization, inflammatory response, apoptosis regulation, and epigenetic factors using RT-qPCR. The levels of histone modifications and the factors regulating these modifications were explored by performing western blot assays. Additionally, we performed a chromatin immunoprecipitation assay to extract gene regions enriched with the epigenetic modification H3K27Ac. Finally, we analyzed the protein and miRNA level changes in ESC extracellular vesicles (ESC-EVs) after the indicated treatments, using mass spectrometry and small RNA sequencing.</p><p><strong>Main results and the role of chance: </strong>Our study found that hCG treatment increased prolactin gene (<i>PRL)</i> expression (<i>P</i> < 0.05), while the expression of <i>IL6</i> and <i>BAK1</i> was inhibited in ESCs (<i>P</i> < 0.05). We also revealed that hCG affects epigenetic regulation, leading to changes in the expression of <i>EED</i>, ","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf051"},"PeriodicalIF":11.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-23eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf046
Elinor Sebire, Norah Spears, Rod T Mitchell, Agnes Stefansdottir
<p><strong>Study question: </strong>Does cancer treatment during pregnancy affect gonadal development in the exposed foetus?</p><p><strong>Summary answer: </strong>Our systematic review revealed that exposure <i>in utero</i> to many cancer therapies does negatively impact gonadal development.</p><p><strong>What is known already: </strong>It is well known that many cancer therapies can have a detrimental impact on the fertility of children and young people who have been treated for cancer. However, it is not yet known how much these agents impact the gonadal development and subsequent fertility of an <i>in utero-</i>exposed foetus.</p><p><strong>Study design size duration: </strong>We conducted a systematic review, following PRISMA guidelines, to investigate the evidence for associations between <i>in utero</i> cancer therapy exposure and gonadal development in human tissues and animal models. A systematic search was conducted across PubMed, Web of Science, and Google Scholar for titles or abstracts containing terms relating to chemotherapy or hormonal therapy agents, <i>in utero</i> exposure, and reproductive outcomes. We searched all available published articles up to July 2024.</p><p><strong>Participants/materials setting methods: </strong>Two independent reviewers performed title and abstract, then full-text screening, using inclusion/exclusion criteria decided <i>a priori</i>. We included clinical and laboratory studies on human foetal gonads and animal studies, <i>in vivo</i> and <i>in vitro</i>, where gonadal exposure occurred during the window that corresponded with human prenatal gonadal development. Data from the included studies were independently extracted and analysed by chemotherapy and hormonal drug class, focusing on reproductive outcome measures and results. Bias and quality assessments were performed with SciRAP <i>in vivo</i> or <i>in vitro</i> tool version 2.3.</p><p><strong>Main results and the role of chance: </strong>3360 titles and abstracts were screened for inclusion, following the removal of duplicates, with 57 undergoing full text review and 26 eligible studies identified for inclusion (human = 4, animal-model = 22). The collated results show clear evidence of significant germ cell loss and disruption to other gonadal cell types in male and female animal-model gonadal tissues exposed both <i>in vivo</i> and <i>in vitro</i> to various chemotherapy and hormone therapies, and human male foetal tissue exposed to chemotherapy <i>in vitro</i>.</p><p><strong>Limitations reasons for caution: </strong>The evidence provided was limited by the small number of studies available reporting on reproductive outcomes following <i>in utero</i> exposure to cancer therapies, a lack of comparable outcome measures, and the use of single-drug exposures compared to the more clinically relevant multi-drug combinations.</p><p><strong>Wider implications of the findings: </strong>This review provides evidence for the vulnerability of foetal gonads
研究问题：怀孕期间的癌症治疗是否会影响暴露胎儿的性腺发育？总结回答：我们的系统综述显示，子宫内暴露于许多癌症治疗确实对性腺发育产生负面影响。已知情况：众所周知，许多癌症疗法会对接受过癌症治疗的儿童和年轻人的生育能力产生不利影响。然而，目前尚不清楚这些药物对子宫内暴露胎儿的性腺发育和随后的生育能力有多大影响。研究设计规模持续时间：我们根据PRISMA指南进行了一项系统综述，以调查子宫内癌症治疗暴露与人类组织和动物模型性腺发育之间的关联证据。我们在PubMed、Web of Science和谷歌Scholar上进行了系统的搜索，寻找包含化疗或激素治疗药物、子宫内暴露和生殖结果相关术语的标题或摘要。我们检索了截至2024年7月的所有可用的已发表文章。参与者/材料设置方法：由两名独立审稿人进行标题和摘要筛选，然后进行全文筛选，采用先验确定的纳入/排除标准。我们纳入了人类胎儿性腺的临床和实验室研究以及体内和体外的动物研究，其中性腺暴露发生在与人类产前性腺发育相对应的窗口期间。纳入研究的数据被独立提取并按化疗和激素药物类别进行分析，重点关注生殖结果的测量和结果。使用SciRAP在体内或体外2.3版工具进行偏倚和质量评估。主要结果和偶然性的作用：在删除重复内容后，筛选了3360个标题和摘要，其中57个进行了全文审查，26个符合条件的研究被确定为纳入（人类= 4，动物模型= 22）。整理的结果明确表明，在体内和体外暴露于各种化疗和激素治疗的雄性和雌性动物模型性腺组织中，以及在体外暴露于化疗的人类男性胎儿组织中，生殖细胞的显著损失和其他性腺细胞类型的破坏。局限性：所提供的证据受到以下因素的限制：报告子宫内接受癌症治疗后生殖结果的现有研究数量较少，缺乏可比较的结果测量方法，以及与临床更相关的多药联合治疗相比使用单药暴露。研究结果的更广泛意义：本综述为胎儿性腺对癌症治疗药物的脆弱性以及子宫内暴露对性腺发育和生殖健康的潜在破坏性影响提供了证据。我们希望这些发现有助于提高人们对长期随访研究的必要性的认识，以探索在子宫内暴露于癌症制剂的人的生育能力是否受到影响，并确定他们是否需要生育保护策略。研究经费/竞争利益：本研究未收到专项经费。R.T.M.由英国研究与创新（UKRI）未来领袖奖学金（资助编号：MR/Y011783/1）支持。作者声明他们没有利益冲突。注册号：研究协议- prospero （RD42021272882和CRD42021271892）。
{"title":"The impact of <i>in utero</i> exposure to cancer treatments on foetal reproductive development and future fertility: a systematic review.","authors":"Elinor Sebire, Norah Spears, Rod T Mitchell, Agnes Stefansdottir","doi":"10.1093/hropen/hoaf046","DOIUrl":"10.1093/hropen/hoaf046","url":null,"abstract":"<p><strong>Study question: </strong>Does cancer treatment during pregnancy affect gonadal development in the exposed foetus?</p><p><strong>Summary answer: </strong>Our systematic review revealed that exposure <i>in utero</i> to many cancer therapies does negatively impact gonadal development.</p><p><strong>What is known already: </strong>It is well known that many cancer therapies can have a detrimental impact on the fertility of children and young people who have been treated for cancer. However, it is not yet known how much these agents impact the gonadal development and subsequent fertility of an <i>in utero-</i>exposed foetus.</p><p><strong>Study design size duration: </strong>We conducted a systematic review, following PRISMA guidelines, to investigate the evidence for associations between <i>in utero</i> cancer therapy exposure and gonadal development in human tissues and animal models. A systematic search was conducted across PubMed, Web of Science, and Google Scholar for titles or abstracts containing terms relating to chemotherapy or hormonal therapy agents, <i>in utero</i> exposure, and reproductive outcomes. We searched all available published articles up to July 2024.</p><p><strong>Participants/materials setting methods: </strong>Two independent reviewers performed title and abstract, then full-text screening, using inclusion/exclusion criteria decided <i>a priori</i>. We included clinical and laboratory studies on human foetal gonads and animal studies, <i>in vivo</i> and <i>in vitro</i>, where gonadal exposure occurred during the window that corresponded with human prenatal gonadal development. Data from the included studies were independently extracted and analysed by chemotherapy and hormonal drug class, focusing on reproductive outcome measures and results. Bias and quality assessments were performed with SciRAP <i>in vivo</i> or <i>in vitro</i> tool version 2.3.</p><p><strong>Main results and the role of chance: </strong>3360 titles and abstracts were screened for inclusion, following the removal of duplicates, with 57 undergoing full text review and 26 eligible studies identified for inclusion (human = 4, animal-model = 22). The collated results show clear evidence of significant germ cell loss and disruption to other gonadal cell types in male and female animal-model gonadal tissues exposed both <i>in vivo</i> and <i>in vitro</i> to various chemotherapy and hormone therapies, and human male foetal tissue exposed to chemotherapy <i>in vitro</i>.</p><p><strong>Limitations reasons for caution: </strong>The evidence provided was limited by the small number of studies available reporting on reproductive outcomes following <i>in utero</i> exposure to cancer therapies, a lack of comparable outcome measures, and the use of single-drug exposures compared to the more clinically relevant multi-drug combinations.</p><p><strong>Wider implications of the findings: </strong>This review provides evidence for the vulnerability of foetal gonads","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf046"},"PeriodicalIF":11.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-16eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf047
Jie Zhang, Shuwen Qiu, Hongyuan Gao, Xiaoyan Mao, Yi Guo, Ling Wu
<p><strong>Study question: </strong>Is there an association between the dominant follicle size on the day of the hCG ovulation trigger and reproductive, obstetric, and perinatal outcomes in modified natural cycle-frozen embryo transfer (NC-FET) cycles in which intensive luteal phase support (LPS) was utilized?</p><p><strong>Summary answer: </strong>The dominant follicle size on the day of triggering, ranging from above 10 to 18 mm or larger, was not associated with negative live birth or perinatal outcomes in modified NC-FETs when an intensive LPS was provided.</p><p><strong>What is known already: </strong>There is growing evidence concerning the optimal timing for triggering final oocyte maturation during IVF ovarian stimulation cycles to obtain mature oocytes. However, a consensus on the ideal follicle size for administering hCG in modified NC-FETs has yet to be established. Interestingly, it has been suggested that the presence of a mature oocyte may not be necessary for FET.</p><p><strong>Study design size duration: </strong>A retrospective cohort study was conducted at a university-affiliated reproductive medicine center. The study included women with regular menstrual cycles who underwent autologous modified NC-FETs between 2013 and 2023 for potential analysis.</p><p><strong>Participants/materials setting methods: </strong>Patients were categorized into eight groups based on the size of the dominant follicle at the time of hCG administration: <12, 12-12.9, 13-13.9, 14-14.9, 15-15.9, 16-16.9, 17-17.9, and ≥18 mm. The primary outcome measured was the live birth rate (LBR), while secondary outcomes included the rates of positive pregnancy tests, implantation, clinical pregnancy, and pregnancy loss, as well as perinatal and obstetric complications. A generalized estimating equation logistic regression model was employed to account for the clustered nature of the data and to adjust for potential confounding factors. The group with a follicle size ≥18 mm was designated as the reference group in the logistic regression analyses. An intensive LPS, consisting of 400 mg dydrogesterone plus 400 mg vaginal progesterone, was adopted.</p><p><strong>Main results and the role of chance: </strong>A total of 14 431 cycles that met the inclusion criteria were analyzed. The LBRs were similar across the eight groups. Furthermore, there were no significant differences in LBRs when the reference group was compared to the other follicle-size categories in the unadjusted models. Even after adjusting for several key confounders, the LBRs remained comparable between the study cohorts and the reference controls. Additionally, other reproductive parameters, such as rates of positive pregnancy tests, implantation, clinical pregnancy, and pregnancy loss, showed similar results between the control group and all other groups in both the unadjusted and confounder-adjusted analyses. Finally, pregnancies derived from the other follicle-size groups did not show increased risks
{"title":"Pregnancy and perinatal outcomes after modified natural cycle-frozen embryo transfers according to size of the dominant follicle on the hCG trigger day.","authors":"Jie Zhang, Shuwen Qiu, Hongyuan Gao, Xiaoyan Mao, Yi Guo, Ling Wu","doi":"10.1093/hropen/hoaf047","DOIUrl":"10.1093/hropen/hoaf047","url":null,"abstract":"<p><strong>Study question: </strong>Is there an association between the dominant follicle size on the day of the hCG ovulation trigger and reproductive, obstetric, and perinatal outcomes in modified natural cycle-frozen embryo transfer (NC-FET) cycles in which intensive luteal phase support (LPS) was utilized?</p><p><strong>Summary answer: </strong>The dominant follicle size on the day of triggering, ranging from above 10 to 18 mm or larger, was not associated with negative live birth or perinatal outcomes in modified NC-FETs when an intensive LPS was provided.</p><p><strong>What is known already: </strong>There is growing evidence concerning the optimal timing for triggering final oocyte maturation during IVF ovarian stimulation cycles to obtain mature oocytes. However, a consensus on the ideal follicle size for administering hCG in modified NC-FETs has yet to be established. Interestingly, it has been suggested that the presence of a mature oocyte may not be necessary for FET.</p><p><strong>Study design size duration: </strong>A retrospective cohort study was conducted at a university-affiliated reproductive medicine center. The study included women with regular menstrual cycles who underwent autologous modified NC-FETs between 2013 and 2023 for potential analysis.</p><p><strong>Participants/materials setting methods: </strong>Patients were categorized into eight groups based on the size of the dominant follicle at the time of hCG administration: <12, 12-12.9, 13-13.9, 14-14.9, 15-15.9, 16-16.9, 17-17.9, and ≥18 mm. The primary outcome measured was the live birth rate (LBR), while secondary outcomes included the rates of positive pregnancy tests, implantation, clinical pregnancy, and pregnancy loss, as well as perinatal and obstetric complications. A generalized estimating equation logistic regression model was employed to account for the clustered nature of the data and to adjust for potential confounding factors. The group with a follicle size ≥18 mm was designated as the reference group in the logistic regression analyses. An intensive LPS, consisting of 400 mg dydrogesterone plus 400 mg vaginal progesterone, was adopted.</p><p><strong>Main results and the role of chance: </strong>A total of 14 431 cycles that met the inclusion criteria were analyzed. The LBRs were similar across the eight groups. Furthermore, there were no significant differences in LBRs when the reference group was compared to the other follicle-size categories in the unadjusted models. Even after adjusting for several key confounders, the LBRs remained comparable between the study cohorts and the reference controls. Additionally, other reproductive parameters, such as rates of positive pregnancy tests, implantation, clinical pregnancy, and pregnancy loss, showed similar results between the control group and all other groups in both the unadjusted and confounder-adjusted analyses. Finally, pregnancies derived from the other follicle-size groups did not show increased risks","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf047"},"PeriodicalIF":11.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12343029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144838767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-15eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf048
Ane Bayona Cebada, Lía Nattero-Chávez, Esther De la Calle De la Villa, Alejandra Quintero Tobar, Sara de Lope Quiñones, Beatriz Dorado Avendaño, Tom Fiers, Jean-Marc Kaufman, Manuel Luque-Ramírez, Héctor F Escobar-Morreale
<p><strong>Study question: </strong>How frequent are androgen excess disorders, including polycystic ovary syndrome (PCOS), among women with Type 1 diabetes mellitus (T1D)?</p><p><strong>Summary answer: </strong>One in every four women with T1D suffer from undiagnosed androgen disorders, with the classic phenotype of PCOS being the most frequent.</p><p><strong>What is known already: </strong>Systemic iatrogenic hyperinsulinism is unavoidable in patients with T1D because insulin is administered subcutaneously instead of being secreted directly into the portal circulation. Since insulin acts as a co-gonadotrophin at the ovary, iatrogenic hyperinsulinism might trigger androgen secretion in predisposed women. Most studies conducted to date have reported increased prevalences of androgen excess disorders in premenopausal women with T1D, yet these studies were hampered by methodological limitations that preclude reaching a definite conclusion on the issue.</p><p><strong>Study design size and duration: </strong>From January 2020 to March 2024, we conducted a cross-sectional study including women with T1D.</p><p><strong>Participants setting methods: </strong>We recruited 149 consecutive premenopausal women with T1D who attended the diabetes clinics of an Academic Hospital at Madrid, Spain. We compared them with 295 typical patients with PCOS who did not have T1D. We used state-of-the-art mass spectrometry techniques to measure serum androgens and equilibrium dialysis to measure free testosterone and followed the latest guidelines to phenotype patients.</p><p><strong>Main results and the role of chance: </strong>Hyperandrogenic disorders (considering PCOS, idiopathic hyperandrogenism, and idiopathic hirsutism as a whole) were present in 39 (of 149) women with T1D (26%, 95% CI: 20-34%), including 30 women who fulfilled the PCOS diagnostic criteria, indicating a prevalence of 20% (95% CI: 15-27%). The most common PCOS phenotype was the classic combination of hyperandrogenism and ovulatory dysfunction. Women with T1D and PCOS were younger (mean age 25 ± 7 vs 31 ± 9 years-old, <i>P </i>= 0.003) and their onset of T1D was more frequently premenarcheal (73% vs 46%, <i>P </i>= 0.008) compared to those without PCOS. Compared to 295 typical patients with PCOS without T1D, the 30 women with T1D and PCOS showed milder hyperandrogenic signs and lower free testosterone concentrations [13 (9, 25) vs 21 (15, 29) pM, <i>P </i>< 0.001] regardless of the glucose tolerance of the former.</p><p><strong>Limitations reasons for caution: </strong>We acknowledge the possibility of selection bias: having excluded T1D women already diagnosed with PCOS, we may have underestimated actual prevalence rates. Also, the cross-sectional design of the study precluded us from obtaining any causality insights about the associations found here.</p><p><strong>Wider implications of the findings: </strong>One in every four women with T1D suffer androgen excess disorders, with the classic combina
研究问题：1型糖尿病（T1D）女性中雄激素过量紊乱（包括多囊卵巢综合征（PCOS））的发生率有多高？摘要回答：四分之一的T1D女性患有未确诊的雄激素紊乱，典型的多囊卵巢综合征是最常见的。已知情况：全身性医源性高胰岛素血症在T1D患者中是不可避免的，因为胰岛素是皮下注射，而不是直接分泌到门静脉循环中。由于胰岛素在卵巢中起促性腺激素的作用，医源性高胰岛素血症可能会引发易感女性的雄激素分泌。迄今为止进行的大多数研究都报告了绝经前T1D妇女雄激素过量紊乱的患病率增加，但这些研究受到方法学限制的阻碍，无法就该问题得出明确的结论。研究设计的规模和持续时间：从2020年1月到2024年3月，我们对患有T1D的女性进行了一项横断面研究。参与者设置方法：我们招募了149名连续在西班牙马德里一家学术医院糖尿病诊所就诊的绝经前T1D妇女。我们将他们与295名没有T1D的PCOS患者进行比较。我们使用最先进的质谱技术来测量血清雄激素和平衡透析来测量游离睾酮，并遵循最新的表型患者指南。主要结果和偶然性的作用：149名T1D女性中有39名（26%,95% CI: 20-34%）存在高雄激素疾病（考虑到多囊卵巢综合征、特发性高雄激素症和特发性多毛症），其中30名女性符合多囊卵巢综合征诊断标准，患病率为20% （95% CI: 15-27%）。最常见的PCOS表型是典型的高雄激素和排卵功能障碍的组合。患有T1D和PCOS的女性更年轻（平均年龄25±7岁vs 31±9岁，P = 0.003），与没有PCOS的女性相比，她们的T1D发病更频繁于月经前（73% vs 46%, P = 0.008）。与295名无T1D的PCOS患者相比，30名合并T1D和PCOS的女性表现出较轻的高雄激素症状和较低的游离睾酮浓度[13（9,25）比21 (15,29)pM, P]，谨慎的局限性原因：我们承认可能存在选择偏差：排除了已经诊断为PCOS的T1D女性，我们可能低估了实际患病率。此外，该研究的横断面设计使我们无法获得任何关于此处发现的关联的因果关系见解。研究结果的更广泛意义：四分之一的T1D女性患有雄激素过量紊乱，典型的雄激素过多和排卵功能障碍的组合是PCOS最常见的表型。月经初潮前发病的T1D女性特别容易发生雄激素过量紊乱，因此在年轻时采取预防措施可能会受益。对这些常见疾病进行常规筛查似乎是合理的，以避免雄激素过量和慢性排卵功能障碍对T1D妇女一般健康和生殖健康的负面影响。研究经费/竞争利益：这项工作由Salud Carlos III研究所的pi18 /01122和PI21/00116资助，并由欧盟共同资助。A.B.C.是Salud Carlos III研究所Río Hortega资助（CM19/00138）的接受者。CIBERDEM和IRYCIS也属于Salud Carlos III研究所。资金来源没有参与研究设计、数据收集、分析和解释，也没有参与论文的发表决定。作者没有需要披露的竞争利益。试验注册号：无。
{"title":"Androgen excess disorders remain undiagnosed in one of every four premenopausal women with Type 1 diabetes.","authors":"Ane Bayona Cebada, Lía Nattero-Chávez, Esther De la Calle De la Villa, Alejandra Quintero Tobar, Sara de Lope Quiñones, Beatriz Dorado Avendaño, Tom Fiers, Jean-Marc Kaufman, Manuel Luque-Ramírez, Héctor F Escobar-Morreale","doi":"10.1093/hropen/hoaf048","DOIUrl":"10.1093/hropen/hoaf048","url":null,"abstract":"<p><strong>Study question: </strong>How frequent are androgen excess disorders, including polycystic ovary syndrome (PCOS), among women with Type 1 diabetes mellitus (T1D)?</p><p><strong>Summary answer: </strong>One in every four women with T1D suffer from undiagnosed androgen disorders, with the classic phenotype of PCOS being the most frequent.</p><p><strong>What is known already: </strong>Systemic iatrogenic hyperinsulinism is unavoidable in patients with T1D because insulin is administered subcutaneously instead of being secreted directly into the portal circulation. Since insulin acts as a co-gonadotrophin at the ovary, iatrogenic hyperinsulinism might trigger androgen secretion in predisposed women. Most studies conducted to date have reported increased prevalences of androgen excess disorders in premenopausal women with T1D, yet these studies were hampered by methodological limitations that preclude reaching a definite conclusion on the issue.</p><p><strong>Study design size and duration: </strong>From January 2020 to March 2024, we conducted a cross-sectional study including women with T1D.</p><p><strong>Participants setting methods: </strong>We recruited 149 consecutive premenopausal women with T1D who attended the diabetes clinics of an Academic Hospital at Madrid, Spain. We compared them with 295 typical patients with PCOS who did not have T1D. We used state-of-the-art mass spectrometry techniques to measure serum androgens and equilibrium dialysis to measure free testosterone and followed the latest guidelines to phenotype patients.</p><p><strong>Main results and the role of chance: </strong>Hyperandrogenic disorders (considering PCOS, idiopathic hyperandrogenism, and idiopathic hirsutism as a whole) were present in 39 (of 149) women with T1D (26%, 95% CI: 20-34%), including 30 women who fulfilled the PCOS diagnostic criteria, indicating a prevalence of 20% (95% CI: 15-27%). The most common PCOS phenotype was the classic combination of hyperandrogenism and ovulatory dysfunction. Women with T1D and PCOS were younger (mean age 25 ± 7 vs 31 ± 9 years-old, <i>P </i>= 0.003) and their onset of T1D was more frequently premenarcheal (73% vs 46%, <i>P </i>= 0.008) compared to those without PCOS. Compared to 295 typical patients with PCOS without T1D, the 30 women with T1D and PCOS showed milder hyperandrogenic signs and lower free testosterone concentrations [13 (9, 25) vs 21 (15, 29) pM, <i>P </i>< 0.001] regardless of the glucose tolerance of the former.</p><p><strong>Limitations reasons for caution: </strong>We acknowledge the possibility of selection bias: having excluded T1D women already diagnosed with PCOS, we may have underestimated actual prevalence rates. Also, the cross-sectional design of the study precluded us from obtaining any causality insights about the associations found here.</p><p><strong>Wider implications of the findings: </strong>One in every four women with T1D suffer androgen excess disorders, with the classic combina","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf048"},"PeriodicalIF":11.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12311277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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