K Gunther,D Liu,M Cortesi,E Powell,E Nesbitt-Hawes,J A Abbott,C E Ford
STUDY QUESTIONCan patient-derived organoid models be reliably established from diverse surgical phenotypes of endometriosis, and how do clinical factors such as hormonal treatment affect their growth success and morphology?SUMMARY ANSWEREndometriosis organoids can be established across all major surgical phenotypes with variable efficiency, and hormonal treatment at the time of biospecimen collection significantly reduces organoid establishment success.WHAT IS KNOWN ALREADYOrganoid cultures have been developed from eutopic endometrium and select endometriosis tissue biospecimens previously, but their feasibility as pre-clinical models of endometriosis across diverse tissue types and clinical presentations remains unclear.STUDY DESIGN, SIZE, DURATIONTwenty-eight endometriosis tissue biospecimens were obtained from 23 patients undergoing surgery, with organoid cultures assessed through successive stages of establishment, passage, and cryopreservation.PARTICIPANTS/MATERIALS, SETTING, METHODSEndometriosis biospecimens, including deep infiltrating endometriosis (DIE), ovarian endometrioma (OMA), and superficial peritoneal (SUP) biospecimens, were processed into organoid cultures using a validated low-Wnt culture system. Organoid viability, morphology, hormone receptor expression, and cellular composition were evaluated by microscopy, immunohistochemistry, and quantitative morphometric analysis.MAIN RESULTS AND THE ROLE OF CHANCEOverall, 22/28 (78.6%) biospecimens established 3-dimensional structures, with 15/28 (53.6%) remaining viable after cryopreservation. Establishment success differed by phenotype (OMA 71.4%, DIE 63.6%, SUP 30%). Progesterone receptor expression was retained in SUP and DIE-derived organoids (7/7, 100%), while OMA-derived organoids showed substantial reductions (4/5 cases). Biospecimens from patients receiving hormonal treatment were smaller (P = 0.038) and had reduced organoid establishment success (3/13, 23.1% vs 12/15, 80.0%, P = 0.003). Organoids exhibited distinct morphological patterns correlating with disease phenotype.LIMITATIONS, REASONS FOR CAUTIONUniform culture conditions may limit growth of certain subtypes, and the in vitro organoid models may not fully represent in vivo tissue complexity. Sample sizes were modest, and pooling tissues from the same patient could mask intra-patient heterogeneity.WIDER IMPLICATIONS OF THE FINDINGSThese organoid models offer a promising platform for studying subtype-specific endometriosis biology, including hormone resistance mechanisms, and could inform personalized therapeutic development. The impact of hormonal treatment on organoid viability underscores the need to consider clinical context in pre-clinical models of endometriosis.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the National Endometriosis Clinical and Scientific Trials (NECST) Network, funded by the Australian Government Department of Health and Aged Care (Grant 4-I66SNMA), and by a research grant from E
研究问题：从子宫内膜异位症的不同手术表型中，能否可靠地建立患者来源的类器官模型？激素治疗等临床因素如何影响其生长成功和形态？子宫内膜异位症类器官可以在所有主要的手术表型中以不同的效率建立，生物标本收集时的激素治疗显着降低了类器官的建立成功率。类器官培养物已经从异位子宫内膜和选择性子宫内膜异位症组织生物标本中发展出来，但它们作为不同组织类型和临床表现的子宫内膜异位症临床前模型的可行性尚不清楚。研究设计、大小、持续时间从23例接受手术的患者中获得28个子宫内膜异位症组织生物标本，通过建立、传代和冷冻保存的连续阶段评估类器官培养。参与者/材料、环境、方法使用经过验证的低wnt培养系统将子宫内膜异位症生物标本，包括深度浸润性子宫内膜异位症（DIE）、卵巢子宫内膜异位症（OMA）和浅表腹膜（SUP）生物标本处理成类器官培养。通过显微镜、免疫组织化学和定量形态计量学分析评估类器官活力、形态、激素受体表达和细胞组成。总体而言，22/28（78.6%）的生物标本建立了三维结构，15/28（53.6%）的生物标本在低温保存后仍能存活。建立成功率因表型而异（OMA 71.4%, DIE 63.6%, SUP 30%）。在SUP和dye衍生类器官中，孕酮受体的表达保持不变（7/ 7,100%），而oma衍生类器官的表达明显减少（4/5）。接受激素治疗的患者的生物标本较小（P = 0.038），类器官建立成功率降低（3/13,23.1% vs 12/15, 80.0%, P = 0.003）。类器官表现出与疾病表型相关的独特形态模式。限制，注意原因：统一的培养条件可能限制某些亚型的生长，体外类器官模型可能不能完全代表体内组织的复杂性。样本量适中，汇集来自同一患者的组织可以掩盖患者内部的异质性。这些类器官模型为研究亚型特异性子宫内膜异位症生物学提供了一个有希望的平台，包括激素抵抗机制，并可以为个性化治疗开发提供信息。激素治疗对类器官活力的影响强调了在子宫内膜异位症的临床前模型中考虑临床背景的必要性。研究经费/竞争利益(S)本研究由澳大利亚政府卫生和老年护理部（Grant 4-I66SNMA）资助的国家子宫内膜异位症临床和科学试验（NECST）网络支持，由澳大利亚子宫内膜异位症向c.e.f., d.l.和j.a.a.k.g.提供研究经费，由澳大利亚政府研究培训计划奖学金和NECST网络充值奖学金支持，这并不影响本研究的进行或结果。资助者在研究设计、数据收集和分析、发表决定或手稿准备方面没有任何作用。J.A.A.获得了Hologic、Gedeon Richter和BD的咨询费，Hologic、Bayer、Organon和Gedeon Richter的个人付款，Gedeon Richter的差旅支持，并参加了Hologic和Gideon Richter的数据安全监测咨询委员会。他是澳大利亚子宫内膜异位症指导委员会的前任主席，也是微创妇科杂志的联合主编。所有其他作者声明没有竞争利益。试验注册号/ a。
{"title":"Patient-derived epithelial cell organoids mimic the phenotypic complexity of endometriosis subtypes.","authors":"K Gunther,D Liu,M Cortesi,E Powell,E Nesbitt-Hawes,J A Abbott,C E Ford","doi":"10.1093/humrep/deaf230","DOIUrl":"https://doi.org/10.1093/humrep/deaf230","url":null,"abstract":"STUDY QUESTIONCan patient-derived organoid models be reliably established from diverse surgical phenotypes of endometriosis, and how do clinical factors such as hormonal treatment affect their growth success and morphology?SUMMARY ANSWEREndometriosis organoids can be established across all major surgical phenotypes with variable efficiency, and hormonal treatment at the time of biospecimen collection significantly reduces organoid establishment success.WHAT IS KNOWN ALREADYOrganoid cultures have been developed from eutopic endometrium and select endometriosis tissue biospecimens previously, but their feasibility as pre-clinical models of endometriosis across diverse tissue types and clinical presentations remains unclear.STUDY DESIGN, SIZE, DURATIONTwenty-eight endometriosis tissue biospecimens were obtained from 23 patients undergoing surgery, with organoid cultures assessed through successive stages of establishment, passage, and cryopreservation.PARTICIPANTS/MATERIALS, SETTING, METHODSEndometriosis biospecimens, including deep infiltrating endometriosis (DIE), ovarian endometrioma (OMA), and superficial peritoneal (SUP) biospecimens, were processed into organoid cultures using a validated low-Wnt culture system. Organoid viability, morphology, hormone receptor expression, and cellular composition were evaluated by microscopy, immunohistochemistry, and quantitative morphometric analysis.MAIN RESULTS AND THE ROLE OF CHANCEOverall, 22/28 (78.6%) biospecimens established 3-dimensional structures, with 15/28 (53.6%) remaining viable after cryopreservation. Establishment success differed by phenotype (OMA 71.4%, DIE 63.6%, SUP 30%). Progesterone receptor expression was retained in SUP and DIE-derived organoids (7/7, 100%), while OMA-derived organoids showed substantial reductions (4/5 cases). Biospecimens from patients receiving hormonal treatment were smaller (P = 0.038) and had reduced organoid establishment success (3/13, 23.1% vs 12/15, 80.0%, P = 0.003). Organoids exhibited distinct morphological patterns correlating with disease phenotype.LIMITATIONS, REASONS FOR CAUTIONUniform culture conditions may limit growth of certain subtypes, and the in vitro organoid models may not fully represent in vivo tissue complexity. Sample sizes were modest, and pooling tissues from the same patient could mask intra-patient heterogeneity.WIDER IMPLICATIONS OF THE FINDINGSThese organoid models offer a promising platform for studying subtype-specific endometriosis biology, including hormone resistance mechanisms, and could inform personalized therapeutic development. The impact of hormonal treatment on organoid viability underscores the need to consider clinical context in pre-clinical models of endometriosis.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the National Endometriosis Clinical and Scientific Trials (NECST) Network, funded by the Australian Government Department of Health and Aged Care (Grant 4-I66SNMA), and by a research grant from E","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"197 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609932","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}
V Vernimmen,M De Rycke,C Moutou,J Dreesen,M J Blok,R van Minkelen,J Lauer-Zillhardt,P Verdyck,K Keymolen,C van Uum,I Homminga,L Brandts,C T R M Stumpel,E Coonen,M Heijligers,W van Zelst-Stams,M Zamani Esteki,A van den Wijngaard,C E M de Die-Smulders,A D C Paulussen
STUDY QUESTIONHow do the genetic complexities of neurofibromatosis type 1 (NF1) impact reproductive counseling, preimplantation genetic testing (PGT) design, and PGT treatment?SUMMARY ANSWERWe established association between both incidence and tissue mosaicism with multiple exon deletions and specific single-nucleotide variants (SNVs) in neurofibromin 1 (NF1), a clinical actionable finding that we structured as a flowchart outlining challenges in and an approach for reproductive counseling, PGT design, and PGT treatment for NF1.WHAT IS KNOWN ALREADYNF1 has a prevalence of 1 in 2500-3000 and is one of the most frequently requested autosomal dominant indications for PGT. NF1 is a large gene with a high mutation rate, resulting in a 50% de novo occurrence, many different reported variants scattered across the gene and relatively frequent mosaicism.STUDY DESIGN, SIZE, DURATIONWe conducted a retrospective, observational cohort study on PGT molecular design for NF1 in three large PGT centers (n = 281 couples), starting from the first assay for NF1 developed in 2004 until 2022.PARTICIPANTS/MATERIALS, SETTING, METHODSA PGT assay was developed for 281 couples with 218 different variants in NF1. Newly described variants (n = 76) were scored using the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) classification system and submitted prior to publication in the Leiden Open Variation Database (LOVD). The employed techniques were PCR-based PGT using short tandem repeat markers (n = 230), SNP-array-based PGT (n = 39), and next-generation sequencing (NGS)-based PGT (n = 12). Minisequencing (SNAPshot) or double amplification refractory mutation system (D-ARMS) was used to incorporate SNVs. Small deletions and insertions were incorporated using fragment length analysis. All PGT assays were designed and validated according to local protocols and ESHRE guidelines.MAIN RESULTS AND THE ROLE OF CHANCEMosaicism was present in 8% of the sporadic cases (n = 13/168), of which about half were unknown prior to PGT (n = 6/13). Mosaicism was significantly higher in patients with multiple exon deletions (n = 4/6) as compared to patients with SNVs (n = 9/162) (P < 0.001, Fisher's exact test). Additionally, two recurrent SNVs were significantly associated with mosaicism (P <0.0167, Fisher's exact test). Importantly, three unrelated families with different NF1 variants in close relatives were identified.LIMITATIONS, REASONS FOR CAUTIONDue to its retrospective design, not all details on the genetic test results and clinical phenotype could be retrieved for some cases (n = 6). The extent to which our findings are applicable to centers worldwide depends on their local procedures and legislation.WIDER IMPLICATIONS OF THE FINDINGSOur findings substantially impact reproductive counseling for couples with NF1, enabling informed reproductive decision-making. For couples affected with NF1 proceeding with PGT, our findings alert co
{"title":"Preimplantation genetic testing for neurofibromatosis type 1: molecular genetic aspects and impact on reproductive counseling.","authors":"V Vernimmen,M De Rycke,C Moutou,J Dreesen,M J Blok,R van Minkelen,J Lauer-Zillhardt,P Verdyck,K Keymolen,C van Uum,I Homminga,L Brandts,C T R M Stumpel,E Coonen,M Heijligers,W van Zelst-Stams,M Zamani Esteki,A van den Wijngaard,C E M de Die-Smulders,A D C Paulussen","doi":"10.1093/humrep/deaf224","DOIUrl":"https://doi.org/10.1093/humrep/deaf224","url":null,"abstract":"STUDY QUESTIONHow do the genetic complexities of neurofibromatosis type 1 (NF1) impact reproductive counseling, preimplantation genetic testing (PGT) design, and PGT treatment?SUMMARY ANSWERWe established association between both incidence and tissue mosaicism with multiple exon deletions and specific single-nucleotide variants (SNVs) in neurofibromin 1 (NF1), a clinical actionable finding that we structured as a flowchart outlining challenges in and an approach for reproductive counseling, PGT design, and PGT treatment for NF1.WHAT IS KNOWN ALREADYNF1 has a prevalence of 1 in 2500-3000 and is one of the most frequently requested autosomal dominant indications for PGT. NF1 is a large gene with a high mutation rate, resulting in a 50% de novo occurrence, many different reported variants scattered across the gene and relatively frequent mosaicism.STUDY DESIGN, SIZE, DURATIONWe conducted a retrospective, observational cohort study on PGT molecular design for NF1 in three large PGT centers (n = 281 couples), starting from the first assay for NF1 developed in 2004 until 2022.PARTICIPANTS/MATERIALS, SETTING, METHODSA PGT assay was developed for 281 couples with 218 different variants in NF1. Newly described variants (n = 76) were scored using the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) classification system and submitted prior to publication in the Leiden Open Variation Database (LOVD). The employed techniques were PCR-based PGT using short tandem repeat markers (n = 230), SNP-array-based PGT (n = 39), and next-generation sequencing (NGS)-based PGT (n = 12). Minisequencing (SNAPshot) or double amplification refractory mutation system (D-ARMS) was used to incorporate SNVs. Small deletions and insertions were incorporated using fragment length analysis. All PGT assays were designed and validated according to local protocols and ESHRE guidelines.MAIN RESULTS AND THE ROLE OF CHANCEMosaicism was present in 8% of the sporadic cases (n = 13/168), of which about half were unknown prior to PGT (n = 6/13). Mosaicism was significantly higher in patients with multiple exon deletions (n = 4/6) as compared to patients with SNVs (n = 9/162) (P < 0.001, Fisher's exact test). Additionally, two recurrent SNVs were significantly associated with mosaicism (P <0.0167, Fisher's exact test). Importantly, three unrelated families with different NF1 variants in close relatives were identified.LIMITATIONS, REASONS FOR CAUTIONDue to its retrospective design, not all details on the genetic test results and clinical phenotype could be retrieved for some cases (n = 6). The extent to which our findings are applicable to centers worldwide depends on their local procedures and legislation.WIDER IMPLICATIONS OF THE FINDINGSOur findings substantially impact reproductive counseling for couples with NF1, enabling informed reproductive decision-making. For couples affected with NF1 proceeding with PGT, our findings alert co","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"2 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599766","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}
Jack Marozzi, Mark Hanly, Christos Venetis, Moira K O’Bryan, Robert McLachlan, Georgina M Chambers
STUDY QUESTION Is male infertility independently associated with an increased risk of incident hypertension, ischemic and non-ischemic heart disease, diabetes, and/or cerebrovascular disease? SUMMARY ANSWER Fathers diagnosed with male infertility have a modestly increased risk of heart disease, diabetes, and hypertension compared with fertile fathers, after controlling for measured confounders; however, some important confounders remain inadequately measured. WHAT IS KNOWN ALREADY Cohort studies suggest that infertile men have an increased risk of incident cardiometabolic diseases, including diabetes, hypertension, heart disease, and cerebrovascular disease, although findings are mixed. The reasons for this association are unclear, but cardiometabolic conditions and male infertility share a wide range of shared etiological factors including age, chronic conditions such as obesity and obstructive sleep apnea, cancers and their treatments, environmental exposures such as pollution and pesticides, lifestyle factors such as smoking and cardiorespiratory fitness, autoimmune conditions such as lupus and Hashimoto’s thyroiditis, as well as congenital conditions such as cystic fibrosis and muscular dystrophy. STUDY DESIGN, SIZE, DURATION Our population-based cohort study included 445 909 men whose partner conceived a child between January 2009 and September 2016 in New South Wales (NSW), Australia. We excluded men with a diagnosis of infertility prior to 2009, men who were under the age of 14 at the time of the child’s conception, and men diagnosed with cardiometabolic conditions in the 6.5 years prior to their index date. The index date was the later of the date of the child’s conception or the date of the vasectomy for fertile men or the date of diagnosis of infertility for infertile men, i.e. the time when the exposure status was determined. From the index date, we followed participants for 5 years up until the latest available date of September 2021. PARTICIPANTS/MATERIALS, SETTINGS, METHODS The study was conducted in NSW, Australia. We determined infertility status by a diagnosis of male infertility in the Australian and New Zealand Assisted Reproduction Database, hospital records, or a record of fertility-related procedures. We assessed the following outcomes: incident hypertension, ischemic and non-ischemic heart disease, all heart disease, diabetes, and cerebrovascular disease. We calculated age-standardized prevalence rates at baseline. We mapped potential confounding pathways using directed acyclic graphs and controlled for measured confounders using inverse probability of treatment weighting and g-computation. We estimated adjusted marginal risk ratios (aRR) and adjusted marginal risk differences (aRD) using robust Poisson regression. MAIN RESULTS AND THE ROLE OF CHANCE The number of events and 5-year crude incidence rate for the outcomes were: hypertension (events: 17 433, fertile: 41.09 per 1000 population, infertile: 70.03 per 1000 populati
研究问题：男性不育是否与高血压、缺血性和非缺血性心脏病、糖尿病和/或脑血管疾病发生风险增加独立相关？在控制了测量的混杂因素后，诊断为男性不育症的父亲与有生育能力的父亲相比，患心脏病、糖尿病和高血压的风险略有增加；然而，一些重要的混杂因素仍然没有得到充分的衡量。队列研究表明，不育男性发生心脏代谢疾病的风险增加，包括糖尿病、高血压、心脏病和脑血管疾病，尽管研究结果喜忧参半。这种关联的原因尚不清楚，但心脏代谢状况和男性不育有很多共同的病因，包括年龄、慢性疾病（如肥胖和阻塞性睡眠呼吸暂停）、癌症及其治疗、环境暴露（如污染和杀虫剂）、生活方式因素（如吸烟和心肺健康）、自身免疫性疾病（如狼疮和桥本甲状腺炎）。以及先天性疾病，如囊性纤维化和肌肉萎缩症。研究设计、规模、持续时间我们以人群为基础的队列研究包括澳大利亚新南威尔士州（NSW）的445909名男性，其伴侣在2009年1月至2016年9月期间怀孕。我们排除了在2009年之前被诊断为不孕症的男性，在孩子受孕时年龄在14岁以下的男性，以及在索引日期之前6.5年内被诊断患有心脏代谢疾病的男性。索引日期为孩子受孕日期或育龄男性输精管结扎日期或不育男性诊断不孕症日期中的较晚日期，即确定暴露状态的时间。从指数日期开始，我们跟踪了参与者5年，直到最晚的日期2021年9月。参与者/材料、环境、方法本研究在澳大利亚新南威尔士州进行。我们通过澳大利亚和新西兰辅助生殖数据库中的男性不育诊断、医院记录或与生育相关的手术记录来确定不育状态。我们评估了以下结果：高血压事件、缺血性和非缺血性心脏病、所有心脏病、糖尿病和脑血管疾病。我们计算了基线年龄标准化患病率。我们使用有向无环图绘制潜在的混杂路径，并使用处理权重的逆概率和g计算来控制测量的混杂因素。我们使用稳健泊松回归估计调整边际风险比（aRR）和调整边际风险差异（aRD）。结果的事件数和5年粗发病率为：高血压（事件：17433件，可育：41.09 / 1000人，不育：70.03 / 1000人），所有心脏病（事件：15549件，可育：36.44 / 1000人，不育：59.88 / 1000人），缺血性心脏病（事件：12628件，可育：29.24 / 1000人，不育：47.1 / 1000人），非缺血性心脏病(事件：5183件，可育：11.69 / 1000人口，不育：20.24 / 1000人口)、脑血管疾病（发病率：512，可育性：1.14 / 1000人口，不育性：1.78 / 1000人口）和糖尿病（发病率：7064，可育性：16.05 / 1000人口，不育性：27.59 / 1000人口）。与有生育能力的男性相比，诊断为不育症的男性发生高血压的风险增加：aRR = 1.20 (95% CI 1.11-1.31, P < 0.001), aRD = 1.1% (95% CI: 0.6%-1.6%, P < 0.001)；所有心脏病aRR = 1.20 (95% CI: 1.09-1.31, P < 0.001), aRD =0.9% (95% CI: 0.4%-1.4%, P < 0.001)；非缺血性心脏病aRR = 1.26 (95% CI: 1.08-1.48, P = 0.004), aRD = 0.4% (95% CI: 0.1%-0.7%, P = 0.009)；缺血性心脏病aRR = 1.13 (95% CI: 1.02 ~ 1.25, P = 0.020), aRD = 0.4% (95% CI: 0.1% ~ 0.7%, P = 0.028)；糖尿病aRR = 1.28 (95% CI 1.12-1.46, P < 0.001)，糖尿病aRR = 0.6% （0.2%-0.9%, P = 0.001）。两组脑血管病发生率无显著差异，aRR = 1.0 (95% CI 0.56 ~ 1.80, P = 0.996), aRD = 0.0% （95% CI:−0.1% ~ 0.1%,P = 0.996）。这些结果在敏感性分析中保持一致，包括扩大不孕症的暴露定义，10年随访期，改变随访中死亡人群的结果，以及使用替代指标日期。该队列包括有孩子的男性，因此不寻求或无法生育孩子的男性以及难以获得生殖保健的男性可能不包括在内。这可能会产生选择效应，使估计偏向于零。 由于数据限制，我们无法充分控制几个混杂因素，包括吸烟、饮食、心肺健康和饮酒等重要的生活方式因素，这可能使估计偏离零值。未测量和测量不充分的混杂因素的组合可能削弱观测到的估计，这似乎是合理的。研究结果的更广泛意义这些发现表明，男性不育症可能是心脏代谢风险轻微升高的早期指标，特别是与高血压、糖尿病和各种形式的心脏病有关。我们的研究是该主题中规模最大的，对混杂因素进行了广泛的控制。我们的发现与已发表的研究结果一致，表明被诊断为不育症的男性患糖尿病、高血压和心脏病的风险略高。从公共卫生的角度来看，生育治疗可能是早期发现和干预的机会，有助于预防被诊断为不育症的男性发生心脏代谢疾病，特别是考虑到男性通常与卫生系统的接触率较低。研究资金/竞争利益(S) J.M.博士候选人由医学研究未来基金（MRFF）新兴优先事项和消费者驱动研究计划：EPCD000007, 2020支持。M.K.O ' b。和通用公司都宣布收到了同一笔MRFF拨款给他们机构的款项。gmc报告说，他从澳大利亚MRFF基金中获得了资助，该基金支付给新南威尔士大学以支持这项工作，J.M.报告说，他也从MRFF基金中获得了博士学位的资助。C.V.宣布在《人类生殖》编辑委员会担任无薪职位，并在新南威尔士大学（UNSW）工作至2023年1月。新南威尔士大学所属的全国围产期流行病学和统计单位（NPESU）负责管理澳大利亚和新西兰辅助生殖数据库（ANZARD）。本研究使用来自ANZARD的数据。通用还宣布新南威尔士大学提供带薪就业。其余的作者没有什么要申报的。试验注册号n / a
{"title":"Male infertility and risk of cardiometabolic conditions: a population-based cohort study","authors":"Jack Marozzi, Mark Hanly, Christos Venetis, Moira K O’Bryan, Robert McLachlan, Georgina M Chambers","doi":"10.1093/humrep/deaf218","DOIUrl":"https://doi.org/10.1093/humrep/deaf218","url":null,"abstract":"STUDY QUESTION Is male infertility independently associated with an increased risk of incident hypertension, ischemic and non-ischemic heart disease, diabetes, and/or cerebrovascular disease? SUMMARY ANSWER Fathers diagnosed with male infertility have a modestly increased risk of heart disease, diabetes, and hypertension compared with fertile fathers, after controlling for measured confounders; however, some important confounders remain inadequately measured. WHAT IS KNOWN ALREADY Cohort studies suggest that infertile men have an increased risk of incident cardiometabolic diseases, including diabetes, hypertension, heart disease, and cerebrovascular disease, although findings are mixed. The reasons for this association are unclear, but cardiometabolic conditions and male infertility share a wide range of shared etiological factors including age, chronic conditions such as obesity and obstructive sleep apnea, cancers and their treatments, environmental exposures such as pollution and pesticides, lifestyle factors such as smoking and cardiorespiratory fitness, autoimmune conditions such as lupus and Hashimoto’s thyroiditis, as well as congenital conditions such as cystic fibrosis and muscular dystrophy. STUDY DESIGN, SIZE, DURATION Our population-based cohort study included 445 909 men whose partner conceived a child between January 2009 and September 2016 in New South Wales (NSW), Australia. We excluded men with a diagnosis of infertility prior to 2009, men who were under the age of 14 at the time of the child’s conception, and men diagnosed with cardiometabolic conditions in the 6.5 years prior to their index date. The index date was the later of the date of the child’s conception or the date of the vasectomy for fertile men or the date of diagnosis of infertility for infertile men, i.e. the time when the exposure status was determined. From the index date, we followed participants for 5 years up until the latest available date of September 2021. PARTICIPANTS/MATERIALS, SETTINGS, METHODS The study was conducted in NSW, Australia. We determined infertility status by a diagnosis of male infertility in the Australian and New Zealand Assisted Reproduction Database, hospital records, or a record of fertility-related procedures. We assessed the following outcomes: incident hypertension, ischemic and non-ischemic heart disease, all heart disease, diabetes, and cerebrovascular disease. We calculated age-standardized prevalence rates at baseline. We mapped potential confounding pathways using directed acyclic graphs and controlled for measured confounders using inverse probability of treatment weighting and g-computation. We estimated adjusted marginal risk ratios (aRR) and adjusted marginal risk differences (aRD) using robust Poisson regression. MAIN RESULTS AND THE ROLE OF CHANCE The number of events and 5-year crude incidence rate for the outcomes were: hypertension (events: 17 433, fertile: 41.09 per 1000 population, infertile: 70.03 per 1000 populati","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"55 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145593342","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}
R K Dhillon-Smith, M Khairy, T Bamford, V Sephton, A Richardson, A H Balen, A Coomarasamy
STUDY QUESTION What is the effect of progesterone administered via vaginal oil capsules versus pessaries, on clinical outcomes, when used for luteal phase support (LPS) in ART? SUMMARY ANSWER Our study findings indicate a higher live birth rate with vaginal oil capsules compared with pessaries, in both fresh and frozen cycles. In the frozen cycles, a lower miscarriage rate was observed with vaginal oil capsules compared with pessaries. WHAT IS KNOWN ALREADY Sufficient LPS, with exogenous progesterone, is essential during ART to improve implantation and pregnancy rates. Micronized vaginal progesterone (MVP) is the most commonly used form of luteal support worldwide. There are no head-to-head comparisons of vaginal oil capsules versus pessaries, with a focus on clinical efficacy, for LPS. STUDY DESIGN, SIZE, DURATION Retrospective cohort study of patients who completed ART cycles with either only vaginal oil capsules 600–800 mg/day or only pessaries 800 mg/day for LPS. Primary outcomes were live birth and miscarriage. Data for fresh IVF/ICSI cycles and frozen embryo transfer cycles with hormone replacement therapy (HRT-FET) were analysed separately. Multivariable regression analyses were performed with adjustment for female age, BMI, ethnicity, ovarian reserve, duration and cause of subfertility, stimulation protocol, number of previous cycles, number of oocytes, number of embryos transferred, previous live births, and previous miscarriages. PARTICIPANTS/MATERIALS, SETTING, METHODS Our study population consisted of women undergoing treatment across 14 Care Fertility clinics in the UK, from January 2017 to December 2022. We included women with stimulated IVF/ICSI cycles with fresh embryo transfer and autologous HRT-FET cycles. A total of 42 291 cycles were analysed; vaginal oil capsules were exclusively used in 25 738 cycles and pessaries exclusively in 16 553 cycles. MAIN RESULTS AND THE ROLE OF CHANCE In the IVF/ICSI group, the live birth rate was higher in those taking vaginal oil capsules compared with pessaries: 34.3% vs 27.8%; adjusted risk ratio (aRR) 1.11 (95% CI 1.04–1.19; P < 0.001). In the HRT-FET group, the live birth rate was also higher in those taking vaginal oil capsules compared to pessaries: 36.7% vs 32.9% (aRR 1.09; 95% CI 1.04–1.14; P < 0.001). The miscarriage rate was lower in those taking vaginal oil capsules compared to pessaries for both IVF/ICSI (13.4% vs 14.5%, P < 0.05) and HRT-FET cycles (17.2% vs 19.7%, P < 0.001) in the crude analysis. The adjusted analysis for miscarriage found a statistically significant difference only for HRT-FET cycles (aRR 0.87; 95% CI 0.82–0.93). LIMITATIONS, REASONS FOR CAUTION This is a retrospective cohort study. Whilst we have extensively adjusted for confounding, there can still be residual confounding. WIDER IMPLICATIONS OF THE FINDINGS An appropriately powered randomized controlled trial directly comparing the two drugs, focusing on clinical efficacy, is require
研究问题：在抗逆转录病毒治疗中用于黄体期支持（LPS）时，通过阴道油胶囊与子宫托给药的黄体酮对临床结果的影响是什么？我们的研究结果表明，在新鲜和冷冻周期中，阴道油胶囊比子宫托有更高的活产率。在冷冻周期中，阴道油胶囊与子宫托相比，流产率较低。在抗逆转录病毒治疗中，足够的脂多糖和外源性孕酮对于提高着床率和妊娠率至关重要。微粉阴道孕酮（MVP）是世界范围内最常用的黄体支持形式。没有直接比较阴道油胶囊和子宫托，重点是临床疗效，对LPS。研究设计、规模、持续时间回顾性队列研究，对完成ART周期的患者进行回顾性队列研究，这些患者要么只服用600-800毫克/天的阴道油胶囊，要么只服用800毫克/天的脂多糖子宫托。主要结局为活产和流产。分别分析新鲜IVF/ICSI周期和冷冻胚胎移植周期与激素替代疗法（HRT-FET）的数据。对女性年龄、体重指数、种族、卵巢储备、不孕持续时间和原因、刺激方案、既往周期数量、卵母细胞数量、移植胚胎数量、既往活产和既往流产进行调整后进行多变量回归分析。参与者/材料、环境、方法我们的研究人群包括2017年1月至2022年12月在英国14家生育护理诊所接受治疗的女性。我们纳入了接受刺激IVF/ICSI周期、新鲜胚胎移植和自体HRT-FET周期的女性。共分析了42 291个周期；阴道油胶囊专用于25738个周期，子宫托专用于16553个周期。在IVF/ICSI组中，阴道油胶囊组的活产率高于子宫托组：34.3%比27.8%；校正风险比（aRR） 1.11 （95% CI 1.04-1.19; P < 0.001）。在HRT-FET组中，与子宫托相比，服用阴道油胶囊的活产率也更高：36.7%对32.9% （aRR 1.09; 95% CI 1.04-1.14; P < 0.001）。在粗分析中，与子宫托相比，在IVF/ICSI （13.4% vs 14.5%, P < 0.05）和HRT-FET周期（17.2% vs 19.7%, P < 0.001）中，服用阴道油胶囊的流产率较低。对流产的校正分析发现，只有HRT-FET周期有统计学意义（aRR 0.87; 95% CI 0.82-0.93）。这是一项回顾性队列研究。虽然我们已经对混淆进行了广泛的调整，但仍然可能存在残留的混淆。研究结果的更广泛意义需要一项适当的随机对照试验，直接比较两种药物，关注临床疗效，以确定一种药物是否优于另一种药物。研究经费/竞争利益(S)本研究由国家卫生与保健研究所（NIHR）伯明翰生物医学研究中心（BRC）提供。R.K.D.S.收到了Ferring Pharmaceuticals和Besins Healthcare UK的讲座和演讲酬金。R.K.D.S.获得了IBSA Pharma和Theramex UK的旅费支持，并参加了Ferring Pharmaceuticals和IBSA Pharma的教育会议顾问委员会。A.C.曾任职于Ferring Pharmaceuticals、Theramax UK、Besins Healthcare UK和Organon Pharma UK的科学顾问委员会。M.K.得到了英国贝辛医疗保健公司和默克公司的旅行支持。A.H.B.是咨询委员会成员，并获得NovoNordisk Pharmaceuticals的演讲费，是Care Fertility UK和Care Fertility Leeds的股东。T.B.收到了默克公司和Gedeon Richter公司的讲座和演讲酬金。T.B.获得了IBSA Pharma、Vitrolife和Theramex的旅费支持，并获得了IBSA Pharma和imagine Life Sciences以顾问身份参加会议的报酬。A.R.收到了Gedeon Richter的演讲和演讲酬金。A.R.获得了Gedeon Richter的旅费支持，并获得了参加Ferring Pharmaceuticals教育会议顾问委员会的报酬。V.S.获得了IBSA制药公司的差旅支持，并支付了参加教育会议和担任Theramex顾问的费用。试验注册号n/a
{"title":"A comparison of progesterone via vaginal oil capsules versus pessaries for luteal phase support in assisted reproduction treatment: a multicentre cohort study of 42 291 cycles","authors":"R K Dhillon-Smith, M Khairy, T Bamford, V Sephton, A Richardson, A H Balen, A Coomarasamy","doi":"10.1093/humrep/deaf219","DOIUrl":"https://doi.org/10.1093/humrep/deaf219","url":null,"abstract":"STUDY QUESTION What is the effect of progesterone administered via vaginal oil capsules versus pessaries, on clinical outcomes, when used for luteal phase support (LPS) in ART? SUMMARY ANSWER Our study findings indicate a higher live birth rate with vaginal oil capsules compared with pessaries, in both fresh and frozen cycles. In the frozen cycles, a lower miscarriage rate was observed with vaginal oil capsules compared with pessaries. WHAT IS KNOWN ALREADY Sufficient LPS, with exogenous progesterone, is essential during ART to improve implantation and pregnancy rates. Micronized vaginal progesterone (MVP) is the most commonly used form of luteal support worldwide. There are no head-to-head comparisons of vaginal oil capsules versus pessaries, with a focus on clinical efficacy, for LPS. STUDY DESIGN, SIZE, DURATION Retrospective cohort study of patients who completed ART cycles with either only vaginal oil capsules 600–800 mg/day or only pessaries 800 mg/day for LPS. Primary outcomes were live birth and miscarriage. Data for fresh IVF/ICSI cycles and frozen embryo transfer cycles with hormone replacement therapy (HRT-FET) were analysed separately. Multivariable regression analyses were performed with adjustment for female age, BMI, ethnicity, ovarian reserve, duration and cause of subfertility, stimulation protocol, number of previous cycles, number of oocytes, number of embryos transferred, previous live births, and previous miscarriages. PARTICIPANTS/MATERIALS, SETTING, METHODS Our study population consisted of women undergoing treatment across 14 Care Fertility clinics in the UK, from January 2017 to December 2022. We included women with stimulated IVF/ICSI cycles with fresh embryo transfer and autologous HRT-FET cycles. A total of 42 291 cycles were analysed; vaginal oil capsules were exclusively used in 25 738 cycles and pessaries exclusively in 16 553 cycles. MAIN RESULTS AND THE ROLE OF CHANCE In the IVF/ICSI group, the live birth rate was higher in those taking vaginal oil capsules compared with pessaries: 34.3% vs 27.8%; adjusted risk ratio (aRR) 1.11 (95% CI 1.04–1.19; P &lt; 0.001). In the HRT-FET group, the live birth rate was also higher in those taking vaginal oil capsules compared to pessaries: 36.7% vs 32.9% (aRR 1.09; 95% CI 1.04–1.14; P &lt; 0.001). The miscarriage rate was lower in those taking vaginal oil capsules compared to pessaries for both IVF/ICSI (13.4% vs 14.5%, P &lt; 0.05) and HRT-FET cycles (17.2% vs 19.7%, P &lt; 0.001) in the crude analysis. The adjusted analysis for miscarriage found a statistically significant difference only for HRT-FET cycles (aRR 0.87; 95% CI 0.82–0.93). LIMITATIONS, REASONS FOR CAUTION This is a retrospective cohort study. Whilst we have extensively adjusted for confounding, there can still be residual confounding. WIDER IMPLICATIONS OF THE FINDINGS An appropriately powered randomized controlled trial directly comparing the two drugs, focusing on clinical efficacy, is require","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"14 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567205","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}
Antonella Ravaggi, Cosetta Bergamaschi, Jacopo Conforti, Giuseppe Ciravolo, Laura Zanotti, Aline S C Fabricio, Massimo Gion, Elia Cappelletto, Antonette E Leon, Diego Oreste Rossetti, Cesare Romagnolo, Stefano Calza, Eliana Bignotti, Franco Odicino
STUDY QUESTION Can a serum miRNA signature serve as a potential diagnostic biomarker for endometriosis (END)? SUMMARY ANSWER A miRNA-based diagnostic model demonstrated an accuracy of 65.8% in distinguishing END patients from control subjects (CTR), demonstrating good sensitivity but limited specificity. WHAT IS KNOWN ALREADY Existing research has examined the potential utility of circulating miRNAs as biomarkers for END diagnosis, revealing their differential expression between women with END and CTR. Nevertheless, the findings remain conflicting, and at present, neither a single miRNA nor a panel of them has yet been established as a reliable diagnostic test in clinical practice for the management of END. STUDY DESIGN, SIZE, DURATION We previously reported different miRNA expression patterns in serum samples from 67 END patients and 60 CTR by high-throughput RT-qPCR. In this multicenter study, a total of 364 patients with pathology-confirmed diagnosis of END or a benign non-END gynecological condition were retrospectively selected from a biobank or prospectively enrolled. The aims of the present study were to analyze, in the entire cohort of patients, a set of 23 potential diagnostic miRNAs via RT-qPCR and to create models capable of diagnosing END through cross-validated machine learning algorithms. PARTICIPANTS/MATERIALS, SETTING, METHODS Total RNA was extracted from serum samples collected before surgical treatment and miRNAs were evaluated by RT-qPCR. Diagnostic models were developed using both the Random Forest and Logistic Regression algorithms. The performance assessment of the various models was derived from internal validation, using repeated cross-validation. MAIN RESULTS AND THE ROLE OF CHANCE The most effective diagnostic model was constructed with 11 miRNAs: miR-140-3p, miR-181a-5p, miR-192-5p, miR-22-3p, miR-29a-3p, miR-30b-5p, miR-338-3p, miR-340-5p, miR-342-3p, miR-486-5p, and miR-652-3p. The diagnostic efficacy of the model was defined by an AUC of 70.4%, a sensitivity of 75.6%, a specificity of 53.5%, and an accuracy of 65.8%. The model that used six miRNAs (miR-192-5p, miR-30b-5p, miR-335-5p, miR-338-3p, miR-486-5p, miR-652-3p) was the best at identifying deep infiltrating endometriosis compared to the control group, with an AUC of 80.4% and an accuracy of 75.9%. A lower accuracy was achieved by the model differentiating ovarian endometrioma (OMA) from CTR (AUC = 65.8%; accuracy = 62.4%). LARGE SCALE DATA miRNA expression profiles have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession numbers GSE279435. LIMITATIONS, REASONS FOR CAUTION Despite the internal cross-validation, the models still need to be tested on larger cohorts of prospectively enrolled patients across several centers to enhance their accuracy and robustness. This testing will also facilitate monitoring the model in a real-world setting, potentially integrating the miRNA-based model with other diagnostic tools, suc
{"title":"Serum miRNA-based diagnostic models for endometriosis: from discovery to validation","authors":"Antonella Ravaggi, Cosetta Bergamaschi, Jacopo Conforti, Giuseppe Ciravolo, Laura Zanotti, Aline S C Fabricio, Massimo Gion, Elia Cappelletto, Antonette E Leon, Diego Oreste Rossetti, Cesare Romagnolo, Stefano Calza, Eliana Bignotti, Franco Odicino","doi":"10.1093/humrep/deaf221","DOIUrl":"https://doi.org/10.1093/humrep/deaf221","url":null,"abstract":"STUDY QUESTION Can a serum miRNA signature serve as a potential diagnostic biomarker for endometriosis (END)? SUMMARY ANSWER A miRNA-based diagnostic model demonstrated an accuracy of 65.8% in distinguishing END patients from control subjects (CTR), demonstrating good sensitivity but limited specificity. WHAT IS KNOWN ALREADY Existing research has examined the potential utility of circulating miRNAs as biomarkers for END diagnosis, revealing their differential expression between women with END and CTR. Nevertheless, the findings remain conflicting, and at present, neither a single miRNA nor a panel of them has yet been established as a reliable diagnostic test in clinical practice for the management of END. STUDY DESIGN, SIZE, DURATION We previously reported different miRNA expression patterns in serum samples from 67 END patients and 60 CTR by high-throughput RT-qPCR. In this multicenter study, a total of 364 patients with pathology-confirmed diagnosis of END or a benign non-END gynecological condition were retrospectively selected from a biobank or prospectively enrolled. The aims of the present study were to analyze, in the entire cohort of patients, a set of 23 potential diagnostic miRNAs via RT-qPCR and to create models capable of diagnosing END through cross-validated machine learning algorithms. PARTICIPANTS/MATERIALS, SETTING, METHODS Total RNA was extracted from serum samples collected before surgical treatment and miRNAs were evaluated by RT-qPCR. Diagnostic models were developed using both the Random Forest and Logistic Regression algorithms. The performance assessment of the various models was derived from internal validation, using repeated cross-validation. MAIN RESULTS AND THE ROLE OF CHANCE The most effective diagnostic model was constructed with 11 miRNAs: miR-140-3p, miR-181a-5p, miR-192-5p, miR-22-3p, miR-29a-3p, miR-30b-5p, miR-338-3p, miR-340-5p, miR-342-3p, miR-486-5p, and miR-652-3p. The diagnostic efficacy of the model was defined by an AUC of 70.4%, a sensitivity of 75.6%, a specificity of 53.5%, and an accuracy of 65.8%. The model that used six miRNAs (miR-192-5p, miR-30b-5p, miR-335-5p, miR-338-3p, miR-486-5p, miR-652-3p) was the best at identifying deep infiltrating endometriosis compared to the control group, with an AUC of 80.4% and an accuracy of 75.9%. A lower accuracy was achieved by the model differentiating ovarian endometrioma (OMA) from CTR (AUC = 65.8%; accuracy = 62.4%). LARGE SCALE DATA miRNA expression profiles have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession numbers GSE279435. LIMITATIONS, REASONS FOR CAUTION Despite the internal cross-validation, the models still need to be tested on larger cohorts of prospectively enrolled patients across several centers to enhance their accuracy and robustness. This testing will also facilitate monitoring the model in a real-world setting, potentially integrating the miRNA-based model with other diagnostic tools, suc","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"19 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567204","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}
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}
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