A Blázquez, I Miguel-Escalada, L Portas-Gómez, J J Guillén-Quílez, D Mataró, M Popovic, A Rodríguez-Aranda
STUDY QUESTION Does extending vaginal progesterone administration from 5–6 days improve pregnancy outcomes in Day 6 (D6) frozen embryo transfers (FETs) in oocyte donation cycles? SUMMARY ANSWER Prolonging the time of vaginal progesterone supplementation does not improve pregnancy outcomes after D6 FETs in oocyte recipients. WHAT IS KNOWN ALREADY Progesterone is critical for endometrial preparation prior to embryo transfer, but the optimal duration of administration remains unclear. D6 blastocysts are associated with poorer clinical outcomes compared to Day 5 (D5) blastocysts, potentially due to either intrinsic limitations in implantation capacity or a shifted window of implantation (WOI). Extending progesterone administration has been hypothesized to optimize the WOI for D6 blastocysts. STUDY DESIGN, SIZE, DURATION This retrospective cohort study included 485 FETs performed in 420 oocyte donation recipients, conducted from January 2020 to December 2023 in a single IVF center. Participants were divided into two groups based on the duration of progesterone supplementation: 5 days (P + 5, n = 282) and 6 days (P + 6, n = 203). PARTICIPANTS/MATERIALS, SETTING, METHODS The study involved oocyte recipients undergoing single D6 blastocyst transfer following endometrial preparation with vaginal progesterone (800 mg/day). Outcomes were analyzed using univariate and multivariate tests, including logistic regression adjusted for estrogen type and endometrial thickness. MAIN RESULTS AND THE ROLE OF CHANCE Mean recipient age (±SD) was 43.5 (±4.24) years, mean BMI was 25.1, and mean endometrial thickness was 9.6 mm on the day of transfer. Good-quality blastocysts accounted for 35% of all transfers. Clinical outcomes, including biochemical (26.24% vs 26.60%, P = 1.00), clinical (21.99% vs 20.69%, P = 0.83), and ongoing pregnancy (14.54% vs 13.30%, P = 0.79), as well as live birth (14.18% vs 10.66%, P = 0.27) and miscarriage rates (7.45% vs 7.39%, P = 1.00), were all similar between 5 and 6 days of progesterone supplementation, respectively. Adjusted analyses confirmed these findings. LIMITATIONS, REASONS FOR CAUTION The retrospective design warrants careful interpretation. Results are specific to vaginal progesterone in oocyte donation cycles and may not apply to other populations or progesterone delivery methods. Additionally, the D6 embryos analyzed were those that did not reach blastocyst by Day 5 (delayed, poor-prognosis, and typically transferred last), which likely biases outcomes toward lower live birth rates. WIDER IMPLICATIONS OF THE FINDINGS Compromised outcomes following D6 FETs compared to those of D5 blastocysts, likely reflect the intrinsic limitations of slow-developing embryos rather than a misaligned WOI. As prolonged progesterone exposure did not improve outcomes, the WOI may be broader than previously assumed, particularly in oocyte donation programs, where superior embryo quality may mitigate synchronization drawbacks. STUDY FUNDING/COMPETIN
研究问题：在卵母细胞捐赠周期中，在第6天（D6）冷冻胚胎移植（fet）中延长5-6天阴道黄体酮给药是否能改善妊娠结局？延长阴道补充黄体酮的时间并不能改善卵母细胞受体D6 fet后的妊娠结局。黄体酮对胚胎移植前的子宫内膜准备至关重要，但最佳给药时间尚不清楚。与第5天（D5）囊胚相比，第6天囊胚的临床结果较差，可能是由于植入能力的内在限制或植入窗口（WOI）的转移。延长黄体酮的使用时间可以优化D6囊胚的WOI。研究设计、规模、持续时间本回顾性队列研究包括在2020年1月至2023年12月在一个IVF中心对420名卵母细胞捐赠受者进行485例fet。参与者根据补充黄体酮的持续时间分为两组：5天（P + 5, n = 282）和6天（P + 6, n = 203）。受试者/材料、环境、方法本研究涉及在阴道孕酮（800 mg/天）子宫内膜制备后接受单D6囊胚移植的卵母细胞受体。结果分析采用单因素和多因素检验，包括调整雌激素类型和子宫内膜厚度的logistic回归。移植当日受者平均年龄（±SD）为43.5（±4.24）岁，平均BMI为25.1，平均子宫内膜厚度为9.6 mm。优质囊胚占所有移植的35%。补充黄体酮5 ~ 6 d的临床结局，包括生化指标（26.24% vs 26.60%, P = 1.00）、临床指标（21.99% vs 20.69%, P = 0.83）、孕期指标（14.54% vs 13.30%, P = 0.79）、活产率（14.18% vs 10.66%, P = 0.27）和流产率（7.45% vs 7.39%, P = 1.00）均相似。调整后的分析证实了这些发现。局限性，谨慎的理由回顾性设计需要仔细解释。结果是特异性的阴道孕酮在卵母细胞捐赠周期，可能不适用于其他人群或孕酮输送方法。此外，分析的D6胚胎是那些在第5天没有发育成囊胚的胚胎（延迟，预后差，通常最后转移），这可能会导致低活产率的结果。与D5囊胚相比，D6 fet的结果受到损害，可能反映了发育缓慢的胚胎的内在局限性，而不是WOI错位。由于长时间的孕酮暴露并没有改善结果，WOI可能比以前假设的更广泛，特别是在卵母细胞捐赠计划中，优越的胚胎质量可能减轻同步缺陷。研究经费/竞争利益(S)本研究由Eugin诊所内部资助，没有外部赞助。作者声明没有利益冲突。试验注册号na
{"title":"Prolonged vaginal progesterone supplementation does not improve outcomes for Day 6 frozen blastocyst transfers in oocyte donation cycles","authors":"A Blázquez, I Miguel-Escalada, L Portas-Gómez, J J Guillén-Quílez, D Mataró, M Popovic, A Rodríguez-Aranda","doi":"10.1093/humrep/deaf205","DOIUrl":"https://doi.org/10.1093/humrep/deaf205","url":null,"abstract":"STUDY QUESTION Does extending vaginal progesterone administration from 5–6 days improve pregnancy outcomes in Day 6 (D6) frozen embryo transfers (FETs) in oocyte donation cycles? SUMMARY ANSWER Prolonging the time of vaginal progesterone supplementation does not improve pregnancy outcomes after D6 FETs in oocyte recipients. WHAT IS KNOWN ALREADY Progesterone is critical for endometrial preparation prior to embryo transfer, but the optimal duration of administration remains unclear. D6 blastocysts are associated with poorer clinical outcomes compared to Day 5 (D5) blastocysts, potentially due to either intrinsic limitations in implantation capacity or a shifted window of implantation (WOI). Extending progesterone administration has been hypothesized to optimize the WOI for D6 blastocysts. STUDY DESIGN, SIZE, DURATION This retrospective cohort study included 485 FETs performed in 420 oocyte donation recipients, conducted from January 2020 to December 2023 in a single IVF center. Participants were divided into two groups based on the duration of progesterone supplementation: 5 days (P + 5, n = 282) and 6 days (P + 6, n = 203). PARTICIPANTS/MATERIALS, SETTING, METHODS The study involved oocyte recipients undergoing single D6 blastocyst transfer following endometrial preparation with vaginal progesterone (800 mg/day). Outcomes were analyzed using univariate and multivariate tests, including logistic regression adjusted for estrogen type and endometrial thickness. MAIN RESULTS AND THE ROLE OF CHANCE Mean recipient age (±SD) was 43.5 (±4.24) years, mean BMI was 25.1, and mean endometrial thickness was 9.6 mm on the day of transfer. Good-quality blastocysts accounted for 35% of all transfers. Clinical outcomes, including biochemical (26.24% vs 26.60%, P = 1.00), clinical (21.99% vs 20.69%, P = 0.83), and ongoing pregnancy (14.54% vs 13.30%, P = 0.79), as well as live birth (14.18% vs 10.66%, P = 0.27) and miscarriage rates (7.45% vs 7.39%, P = 1.00), were all similar between 5 and 6 days of progesterone supplementation, respectively. Adjusted analyses confirmed these findings. LIMITATIONS, REASONS FOR CAUTION The retrospective design warrants careful interpretation. Results are specific to vaginal progesterone in oocyte donation cycles and may not apply to other populations or progesterone delivery methods. Additionally, the D6 embryos analyzed were those that did not reach blastocyst by Day 5 (delayed, poor-prognosis, and typically transferred last), which likely biases outcomes toward lower live birth rates. WIDER IMPLICATIONS OF THE FINDINGS Compromised outcomes following D6 FETs compared to those of D5 blastocysts, likely reflect the intrinsic limitations of slow-developing embryos rather than a misaligned WOI. As prolonged progesterone exposure did not improve outcomes, the WOI may be broader than previously assumed, particularly in oocyte donation programs, where superior embryo quality may mitigate synchronization drawbacks. STUDY FUNDING/COMPETIN","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"21 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472896","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}
Giovanni Coticchio, Valentina Casciani, Laura Rienzi, Danilo Cimadomo, Chiara Cosseddu, Marilena Taggi, Sergio Ledda, Daniela Bebbere
The cell cortex, a cytoskeletal network with regulatory signalling pathways, is localized beneath the cell membrane: it is especially prominent in mammalian oocytes. As in other cells, the cortex ensures appropriate shape and robustness of oocytes. It is also involved in other key and more specific functions. The cortex is part of the interface between the germinal and somatic cell compartments; as such, it participates in the delicate bi-directional interaction by which oocytes regulate cumulus cell function and in return, oocytes receive nutrients and regulative factors from cumulus cells. During oocyte maturation, fertilization, and early development, the cortex undergoes major structural and functional modifications. Such changes are needed to support crucial processes, including meiotic spindle localization, polar body extrusion, chromosome segregation, and pronuclear formation. Cortex dysregulation may be also implicated in blastomere fragmentation during early embryo development. Mechanical properties of the cortex are associated with oocyte quality and developmental competence; with appropriate technology, such properties could be harnessed to develop new approaches to non-invasive oocyte assessment in human IVF.
{"title":"The emerging role of the oocyte cortical domain in maturation, fertilization, and development","authors":"Giovanni Coticchio, Valentina Casciani, Laura Rienzi, Danilo Cimadomo, Chiara Cosseddu, Marilena Taggi, Sergio Ledda, Daniela Bebbere","doi":"10.1093/humrep/deaf208","DOIUrl":"https://doi.org/10.1093/humrep/deaf208","url":null,"abstract":"The cell cortex, a cytoskeletal network with regulatory signalling pathways, is localized beneath the cell membrane: it is especially prominent in mammalian oocytes. As in other cells, the cortex ensures appropriate shape and robustness of oocytes. It is also involved in other key and more specific functions. The cortex is part of the interface between the germinal and somatic cell compartments; as such, it participates in the delicate bi-directional interaction by which oocytes regulate cumulus cell function and in return, oocytes receive nutrients and regulative factors from cumulus cells. During oocyte maturation, fertilization, and early development, the cortex undergoes major structural and functional modifications. Such changes are needed to support crucial processes, including meiotic spindle localization, polar body extrusion, chromosome segregation, and pronuclear formation. Cortex dysregulation may be also implicated in blastomere fragmentation during early embryo development. Mechanical properties of the cortex are associated with oocyte quality and developmental competence; with appropriate technology, such properties could be harnessed to develop new approaches to non-invasive oocyte assessment in human IVF.","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"133 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
STUDY QUESTION How does first-line chemotherapy alter follicular survival and the ovarian microenvironment? SUMMARY ANSWER First-line chemotherapy exposure prior to ovarian tissue cryopreservation (OTC) induces follicular DNA damage and apoptosis, and causes microenvironmental alterations including immune dysfunction, increased hypoxia and apoptosis, impaired cell cycle and DNA repair capacity, and disruption of the extracellular matrix (ECM). WHAT IS KNOWN ALREADY Although the mechanisms underlying chemotherapy-induced damage to germ cells are being increasingly deciphered, its impact on the ovarian microenvironment remains largely unexplored. The ovarian stroma is equally exposed to chemotherapy, and since its cells and components are in active communication with follicles, any microenvironmental changes induced by chemotherapy might affect follicles as well. STUDY DESIGN, SIZE, DURATION Cryopreserved ovarian cortex samples from 10 cancer patients (aged 24–30 years) who donated tissue for research purposes were analyzed. Of the 10 patients, 5 had received first-regimen chemotherapy and 5 age-matched controls had not undergone chemotherapy prior to OTC. Chemotherapy-induced ovarian injury was evaluated by comparing stromal and follicular alterations between chemotherapy-exposed and control patients. PARTICIPANTS/MATERIALS, SETTING, METHODS Cryopreserved ovarian cortex were processed directly after thawing. Proteins and biological processes dysregulated in response to chemotherapy were identified by mass spectrometry, and the data obtained were validated by western blotting and immunohistochemistry. Stromal and follicular alterations were further examined by (immuno)histochemistry, focusing on apoptosis (TUNEL), DNA damage (γH2Ax), oxidative stress (8-OHdG), proliferation (Ki67), fibrosis (picrosirius red), and analysis of follicle number, developmental stage and morphology. MAIN RESULTS AND THE ROLE OF CHANCE A total of 5209 proteins were detected in both chemotherapy-exposed and control ovaries, of which 237 proteins (4.5%) showed differential expression. Biological pathways related to immune response, hypoxia and apoptosis were upregulated after chemotherapy exposure, while those involved in cell cycle and DNA repair were downregulated. Markers of the ECM network were also dysregulated. Western blotting and immunostaining confirmed the significant upregulation of complement C3 (innate immunity; P = 0.032), SELENBP1 (hypoxia; P = 0.030) and KRT18 (apoptosis; P = 0.015) as well as a non-significant increase in SERPIN A3 level (ECM; P = 0.077) following chemotherapy-exposure, while NCBP2 (DNA repair) was reduced, though not significantly (P = 0.067). Targeted analyses demonstrated that despite increased stromal cell density following chemotherapy treatment (1.84 ± 0.15 × 106 cells/mm3 vs. 1.62 ± 0.13 × 106 cells/mm3; P = 0.036), no fibrosis was observed. Stromal apoptosis and oxidative stress levels were comparable in both groups (P = 0.464 and P
研究问题：一线化疗如何改变卵泡生存和卵巢微环境？卵巢组织冷冻保存（OTC）前一线化疗暴露可诱导卵泡DNA损伤和凋亡，并引起微环境改变，包括免疫功能障碍、缺氧和凋亡增加、细胞周期和DNA修复能力受损以及细胞外基质（ECM）破坏。虽然化疗引起的生殖细胞损伤的机制正在被越来越多地破译，但其对卵巢微环境的影响在很大程度上仍未被探索。卵巢基质同样暴露于化疗中，由于其细胞和成分与卵泡处于积极的交流中，化疗引起的任何微环境变化也可能影响卵泡。研究设计、大小、持续时间对10例捐献组织用于研究的癌症患者（年龄24-30岁）冷冻保存的卵巢皮质样本进行分析。在10名患者中，5名接受了第一方案化疗，5名年龄匹配的对照组在OTC之前未接受化疗。通过比较化疗暴露患者和对照患者间质和卵泡的改变来评估化疗诱导的卵巢损伤。受试者/材料、环境、方法冷冻保存卵巢皮质解冻后直接处理。通过质谱法鉴定对化疗反应失调的蛋白质和生物过程，并通过免疫印迹和免疫组织化学验证所获得的数据。通过（免疫）组织化学进一步检测基质和滤泡的改变，重点关注细胞凋亡（TUNEL）、DNA损伤（γH2Ax）、氧化应激（8-OHdG）、增殖（Ki67）、纤维化（微sirius red），以及卵泡数量、发育阶段和形态的分析。化疗暴露组和对照组共检测到5209个蛋白，其中237个（4.5%）表达差异。化疗暴露后，与免疫反应、缺氧和凋亡相关的生物学通路上调，而与细胞周期和DNA修复相关的生物学通路下调。ECM网络的标记物也出现了失调。Western blotting和免疫染色证实，化疗暴露后补体C3（先天免疫，P = 0.032）、SELENBP1（缺氧，P = 0.030）和KRT18（凋亡，P = 0.015）显著上调，SERPIN A3水平（ECM, P = 0.077）无显著升高，NCBP2 （DNA修复）水平降低，但不显著（P = 0.067）。靶向分析显示，尽管化疗后基质细胞密度增加（1.84±0.15 × 106细胞/mm3 vs. 1.62±0.13 × 106细胞/mm3； P = 0.036），但未观察到纤维化。两组间质凋亡和氧化应激水平具有可比性（P = 0.464和P = 0.247）。相比之下，第一方案化疗持续影响生殖细胞，增加卵泡凋亡（P = 0.013）， DNA损伤（P = 0.033）和可能的形态缺陷（P = 0.061），而不会耗尽卵巢储备。局限性，谨慎的原因：以前接受化疗的患者在OTC之前的不同时间接受了不同的低促性腺毒素化疗方案，这使得分离单个药物的作用或区分短期和长期失调的生物过程具有挑战性。此外，分析是在一个小队列中进行的，结果应谨慎解释。这些发现提供了化疗显著改变卵巢生殖细胞和基质的证据，强调需要进一步研究其潜在的分子机制及其对卵巢功能和生育能力的影响。他们还提出了可能导致这些化疗相关卵巢损伤的靶蛋白，用于未来的研究。研究经费/竞争利益(S)本研究由比利时国家科学研究基金会（fnrs）资助（拨款1.B.218.24F授予J.G.）。支助是由博杜安国王基金会和若莫特-德穆兰基金会管理的苏珊娜·杜尚、塞尔日·卢梭和让·格姆拉德博士基金提供的。CMMI得到了欧洲区域发展基金和瓦隆地区的支持。J.G.和i.d分别作为博士后研究员和高级研究员得到FNRS的支持。作者无利益冲突需要申报。试验注册号n / a
{"title":"Proteomic profiling reveals the molecular signatures of chemotherapy-induced human ovarian damage","authors":"Johanne Grosbois, Xavier Bisteau, Virginie Imbault, Louise Conrard, Margherita Condorelli, Necati Findikli, Pascale Lybaert, Isabelle Demeestere","doi":"10.1093/humrep/deaf203","DOIUrl":"https://doi.org/10.1093/humrep/deaf203","url":null,"abstract":"STUDY QUESTION How does first-line chemotherapy alter follicular survival and the ovarian microenvironment? SUMMARY ANSWER First-line chemotherapy exposure prior to ovarian tissue cryopreservation (OTC) induces follicular DNA damage and apoptosis, and causes microenvironmental alterations including immune dysfunction, increased hypoxia and apoptosis, impaired cell cycle and DNA repair capacity, and disruption of the extracellular matrix (ECM). WHAT IS KNOWN ALREADY Although the mechanisms underlying chemotherapy-induced damage to germ cells are being increasingly deciphered, its impact on the ovarian microenvironment remains largely unexplored. The ovarian stroma is equally exposed to chemotherapy, and since its cells and components are in active communication with follicles, any microenvironmental changes induced by chemotherapy might affect follicles as well. STUDY DESIGN, SIZE, DURATION Cryopreserved ovarian cortex samples from 10 cancer patients (aged 24–30 years) who donated tissue for research purposes were analyzed. Of the 10 patients, 5 had received first-regimen chemotherapy and 5 age-matched controls had not undergone chemotherapy prior to OTC. Chemotherapy-induced ovarian injury was evaluated by comparing stromal and follicular alterations between chemotherapy-exposed and control patients. PARTICIPANTS/MATERIALS, SETTING, METHODS Cryopreserved ovarian cortex were processed directly after thawing. Proteins and biological processes dysregulated in response to chemotherapy were identified by mass spectrometry, and the data obtained were validated by western blotting and immunohistochemistry. Stromal and follicular alterations were further examined by (immuno)histochemistry, focusing on apoptosis (TUNEL), DNA damage (γH2Ax), oxidative stress (8-OHdG), proliferation (Ki67), fibrosis (picrosirius red), and analysis of follicle number, developmental stage and morphology. MAIN RESULTS AND THE ROLE OF CHANCE A total of 5209 proteins were detected in both chemotherapy-exposed and control ovaries, of which 237 proteins (4.5%) showed differential expression. Biological pathways related to immune response, hypoxia and apoptosis were upregulated after chemotherapy exposure, while those involved in cell cycle and DNA repair were downregulated. Markers of the ECM network were also dysregulated. Western blotting and immunostaining confirmed the significant upregulation of complement C3 (innate immunity; P = 0.032), SELENBP1 (hypoxia; P = 0.030) and KRT18 (apoptosis; P = 0.015) as well as a non-significant increase in SERPIN A3 level (ECM; P = 0.077) following chemotherapy-exposure, while NCBP2 (DNA repair) was reduced, though not significantly (P = 0.067). Targeted analyses demonstrated that despite increased stromal cell density following chemotherapy treatment (1.84 ± 0.15 × 106 cells/mm3 vs. 1.62 ± 0.13 × 106 cells/mm3; P = 0.036), no fibrosis was observed. Stromal apoptosis and oxidative stress levels were comparable in both groups (P = 0.464 and P","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"169 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472888","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}
Linda D Applegarth, Nancy L Kaufman, Charlene Thomas, Gabriela Beroukhim, Shelun Tsai, Mitasha Joseph-Sohan
STUDY QUESTION What are the satisfaction levels, as defined by emotional comfort or contentment, of adult individuals conceived via donor-assisted reproduction concerning the method, timing, and circumstances surrounding the disclosure/discovery of their conception? SUMMARY ANSWER Inadvertent discovery and older age at the time of disclosure of donor-conceived status are associated with lower rates of satisfaction among donor-conceived individuals. WHAT IS KNOWN ALREADY The proliferation of commercial DNA testing has resulted in many donor-conceived people learning inadvertently of their donor origins. As a result, donor-conceived people, healthcare professionals, and parents seek information and research about best disclosure practices and outcomes. STUDY DESIGN, SIZE, DURATION A survey-based cross-sectional cohort study from 2022 to 2023 was conducted involving 530 participants, of whom 422 completed the survey. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 546 people ages 18 years and over opened the survey, with 530 people qualifying to complete the survey as donor-conceived persons (DCPs). Four hundred and twenty-two DCPs (79.6%) completed the survey. Descriptive statistics were applied, and data distributions were analyzed for a selection of appropriate statistical tests; parametric tests such as Student’s t-test or ANOVA, and non-parametric tests such as Mann U Whitney or Kruskal-Wallis Rank Sum test were utilized as applicable, for comparing continuous data between groups. Multivariable logistic regression analyses were used to examine satisfaction levels, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE After accounting for age at discovery, sex, the origin of disclosure, and education, individuals with early intentional disclosure were more than three times as likely to experience disclosure satisfaction as those with late unintentional disclosure/inadvertent discovery (P-value = 0.005) LIMITATIONS, REASONS FOR CAUTION Lack of ethnic diversity among survey respondents, and limited control over reposting of the survey to other sites, potentially contributing to sampling bias. WIDER IMPLICATIONS OF THE FINDINGS Preliminary but substantial evidence that early, intentional disclosure to DCPs results in greater satisfaction and acceptance. This data will ultimately assist all stakeholders, including reproductive health professionals and parents in family-building counseling and decision-making. STUDY FUNDING/COMPETING INTEREST(s) None. TRIAL REGISTRATION NUMBER N/A.
研究问题：通过供体辅助生殖受孕的成年人对其受孕的方法、时间和披露/发现的环境的满意程度（以情感安慰或满足感来定义）是多少？无意发现和披露供体怀孕状态时的年龄较大与供体怀孕个体的满意度较低有关。商业DNA检测的激增导致许多捐赠者怀孕的人无意中了解到他们的捐赠者来源。因此，捐赠者怀孕的人、医疗保健专业人员和父母寻求有关最佳披露实践和结果的信息和研究。研究设计、规模、持续时间一项基于调查的横断面队列研究于2022年至2023年进行，涉及530名参与者，其中422人完成了调查。参与者/材料、环境、方法共有546名18岁及以上的人参与了调查，其中530人有资格作为供体受孕者（dcp）完成调查。422名dcp（79.6%）完成了调查。采用描述性统计，并对数据分布进行分析，以选择适当的统计检验；参数检验，如学生t检验或方差分析，以及非参数检验，如Mann U Whitney或Kruskal-Wallis秩和检验，适用时用于组间连续数据的比较。使用多变量逻辑回归分析来检查满意度水平，调整潜在的混杂因素。在考虑了发现的年龄、性别、披露的来源和教育程度后，早期有意披露的个体对披露的满意度是晚期无意披露/无意发现的个体的三倍多（p值= 0.005）。可能导致抽样偏差。初步但实质性的证据表明，早期、有意地向dcp披露会带来更大的满意度和接受度。这些数据最终将协助所有利益攸关方，包括生殖健康专业人员和父母进行家庭建设咨询和决策。研究经费/竞争利益无。试验注册号n / a。
{"title":"Secrets and lies and donor conceptions: what donor-conceived individuals feel about their disclosure/discovery experience","authors":"Linda D Applegarth, Nancy L Kaufman, Charlene Thomas, Gabriela Beroukhim, Shelun Tsai, Mitasha Joseph-Sohan","doi":"10.1093/humrep/deaf215","DOIUrl":"https://doi.org/10.1093/humrep/deaf215","url":null,"abstract":"STUDY QUESTION What are the satisfaction levels, as defined by emotional comfort or contentment, of adult individuals conceived via donor-assisted reproduction concerning the method, timing, and circumstances surrounding the disclosure/discovery of their conception? SUMMARY ANSWER Inadvertent discovery and older age at the time of disclosure of donor-conceived status are associated with lower rates of satisfaction among donor-conceived individuals. WHAT IS KNOWN ALREADY The proliferation of commercial DNA testing has resulted in many donor-conceived people learning inadvertently of their donor origins. As a result, donor-conceived people, healthcare professionals, and parents seek information and research about best disclosure practices and outcomes. STUDY DESIGN, SIZE, DURATION A survey-based cross-sectional cohort study from 2022 to 2023 was conducted involving 530 participants, of whom 422 completed the survey. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 546 people ages 18 years and over opened the survey, with 530 people qualifying to complete the survey as donor-conceived persons (DCPs). Four hundred and twenty-two DCPs (79.6%) completed the survey. Descriptive statistics were applied, and data distributions were analyzed for a selection of appropriate statistical tests; parametric tests such as Student’s t-test or ANOVA, and non-parametric tests such as Mann U Whitney or Kruskal-Wallis Rank Sum test were utilized as applicable, for comparing continuous data between groups. Multivariable logistic regression analyses were used to examine satisfaction levels, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE After accounting for age at discovery, sex, the origin of disclosure, and education, individuals with early intentional disclosure were more than three times as likely to experience disclosure satisfaction as those with late unintentional disclosure/inadvertent discovery (P-value = 0.005) LIMITATIONS, REASONS FOR CAUTION Lack of ethnic diversity among survey respondents, and limited control over reposting of the survey to other sites, potentially contributing to sampling bias. WIDER IMPLICATIONS OF THE FINDINGS Preliminary but substantial evidence that early, intentional disclosure to DCPs results in greater satisfaction and acceptance. This data will ultimately assist all stakeholders, including reproductive health professionals and parents in family-building counseling and decision-making. STUDY FUNDING/COMPETING INTEREST(s) None. TRIAL REGISTRATION NUMBER N/A.","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"1 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472890","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}
João C Ribeiro, Raquel L Bernardino, Paula Jorge, Margarida Geraldo, Emília Vieira, Rosário Santos, Alberto Barros, Aminata Touré, Tarsila G Castro, Artur Cavaco-Paulo, Marco G Alves, Pedro F Oliveira
Study Question Does the interaction between CFTR and AQP7 in human spermatozoa play a role in the molecular mechanisms underlying sperm motility? Summary Answer CFTR inhibition reduces sperm motility and AQP7-mediated glycerol permeability in human spermatozoa, and CFTR and AQP7 co-localize in the equatorial segment of the sperm head, with in silico modeling suggesting a potential interaction between these proteins. What Is Known Already CFTR modulates the permeability of aquaglyceroporins in multiple tissues, and their interaction is mediated by the scaffolding protein NHERF1. AQP7-mediated glycerol permeability correlates with sperm motility. Study Design, Size, Duration Semen samples were collected from normozoospermic men (normal motility; n = 33) and men with asthenozoospermia (reduced motility; n = 15) at a fertility clinic between September 2020 and January 2021. Participants/Materials, Setting, Methods Isolated sperm from men with normozoospermia were used to study the effect of CFTR on sperm motility (N = 10) and glycerol permeability (N = 23). Sperm from 14 asthenozoospermic samples and 13 normozoospermic samples were used to compare the effect of CFTR on AQP7-mediated glycerol permeability, after screening for the absence of common CFTR gene variants. Sperm membrane permeability to glycerol was measured using stopped-flow light scattering, and the effect of CFTR conductance was modulated using a specific inhibitor (CFTRinh172). The interaction between CFTR and AQP7 was investigated using co-immunofluorescence, proximity ligation assay, and in silico approaches like ColabFold and GROMACS. Gaussian distribution of the data was measured by the Shapiro–Wilk normality test. Data showing non-normal distribution was treated with the Kruskal–Wallis test, whereas normal distribution data were treated with an ordinary one-way ANOVA. Comparisons between normozoospermic and asthenozoospermic groups were performed using an unpaired two-tailed Mann–Whitney U test. A P-value less than 0.05 was considered significantly different. Main Results and the Role of Chance CFTR inhibition negatively affected sperm motility (0.53 ± 0.11-fold variation to control, P < 0.05) and AQP7-mediated glycerol permeability (0.459-fold [0.314; 0.537] variation to control, P < 0.01). Despite this, the effect of CFTR dysfunction on AQP7-mediated glycerol permeability of sperm from normo- versus asthenozoospermic samples did not reach statistical significance (P = 0.068) due to low statistical power, but a tendency was apparent. A larger sample size is needed to confirm this trend. CFTR and AQP7 (the main glycerol diffuser in human sperm) co-localize and are in proximity in the midpiece and in the equatorial section of the sperm head in human sperm. In silico analysis supports the interaction of CFTR with AQP7 intermediated by NHERF1, indicating a mechanism of physical modulation of AQP7 permeability by CFTR. Limitations, Reasons for Caution Only cystic fibrosi
人类精子中CFTR和AQP7的相互作用是否在精子运动的分子机制中发挥作用？在人类精子中，CFTR抑制会降低精子活力和AQP7介导的甘油渗透性，并且CFTR和AQP7在精子头部的赤道段共定位，计算机模拟表明这些蛋白之间可能存在相互作用。CFTR调节多种组织中水甘油孔蛋白的通透性，它们的相互作用是由支架蛋白NHERF1介导的。aqp7介导的甘油渗透性与精子活力相关。研究设计、大小、持续时间2020年9月至2021年1月在生育诊所从正常精子男性（运动能力正常，n = 33）和弱精子男性（运动能力降低，n = 15）中收集精液样本。研究对象/材料、环境、方法采用正常精子症男性的精子，研究CFTR对精子活力（N = 10）和甘油渗透性（N = 23）的影响。通过筛选缺失常见CFTR基因变异的14个弱精子和13个正常精子样本，比较CFTR对aqp7介导的甘油通透性的影响。采用停流光散射法测量精子膜对甘油的通透性，并使用特异性抑制剂（CFTRinh172）调节CFTR电导的影响。CFTR和AQP7之间的相互作用通过共免疫荧光、近距离结扎试验以及ColabFold和GROMACS等计算机方法进行了研究。数据的高斯分布采用Shapiro-Wilk正态性检验。显示非正态分布的数据用Kruskal-Wallis检验处理，而正态分布的数据用普通的单因素方差分析处理。正常精子组和弱精子组之间的比较采用非配对双尾Mann-Whitney U检验。p值小于0.05为差异显著。Chance CFTR抑制对精子活力（与对照组相比差异为0.53±0.11倍，P < 0.05）和aqp7介导的甘油通透性（与对照组相比差异为0.459倍[0.314;0.537],P < 0.01）产生负性影响。尽管如此，由于统计能力较低，CFTR功能障碍对正常精子和弱活精子aqp7介导的精子甘油通透性的影响没有达到统计学意义（P = 0.068），但趋势很明显。需要更大的样本量来证实这一趋势。CFTR和AQP7（人类精子中主要的甘油扩散器）在人类精子头部的中部和赤道部分共定位并接近。In silico分析支持CFTR与NHERF1介导的AQP7相互作用，提示CFTR物理调节AQP7通透性的机制。本研究仅筛选了囊性纤维化相关的CFTR变异；假设良性变异的存在可能会轻微降低CFTR功能，这可能会影响结果。通过假定其与渗透性休克后精子体积随时间的变化成比例，间接测量了甘油的渗透性。需要更大的样本量来确认没有达到统计显著性的趋势。此外，在非营养物缓冲液中进行药理学分析，以确定通道的直接作用；这种情况不同于生理介质，代表了本研究的特定局限性。我们的研究结果表明，CFTR和AQP7之间的功能和物理相互作用的新机制可能是一些弱精子症和特发性男性不育病例的基础；这些结果也增加了我们对控制精子运动的分子机制的认识。研究资金/竞争利益(S)本研究由funda para a Ciência ea tecologia （FCT）资助UMIB (UIDB/00215/2020，和UIDP/00215/2020)， itr -人口健康综合和转化研究实验室（LA/P/0064/2020）和研究生jo o C. Ribeiro （UI/BD/150749/2020）。这项工作由联邦政府通过COMPETE/QREN、FSE/POPH和POCI-COMPETE 2020 （poci -01-0145- federal -007491）基金共同资助。本项目由国家科学就业刺激计划（编号：CEEC-INST/00026/2018）资助。本工作还得到了FCT/MCTES通过国家基金对LAQV-REQUIMTE （LA/P/ 0008/202-DOI 10.54499/LA/P/0008/2020, UIDP/50006/2020 - doi 10.54499/UIDP/50006/2020，和UIDB/50006/2020 - doi 10.54499/UIDB/50006/2020）和iBiMed （UIDB/04501/2020 - doi 10.54499/UIDB/04501/2020和UIDP/04501/2020 - doi 10.54499/UIDP/04501/2020）的支持和帮助。没有需要申报的利益冲突。试验注册号。
{"title":"A novel CFTR-AQP7 protein complex regulates glycerol transport and motility of human sperm","authors":"João C Ribeiro, Raquel L Bernardino, Paula Jorge, Margarida Geraldo, Emília Vieira, Rosário Santos, Alberto Barros, Aminata Touré, Tarsila G Castro, Artur Cavaco-Paulo, Marco G Alves, Pedro F Oliveira","doi":"10.1093/humrep/deaf210","DOIUrl":"https://doi.org/10.1093/humrep/deaf210","url":null,"abstract":"Study Question Does the interaction between CFTR and AQP7 in human spermatozoa play a role in the molecular mechanisms underlying sperm motility? Summary Answer CFTR inhibition reduces sperm motility and AQP7-mediated glycerol permeability in human spermatozoa, and CFTR and AQP7 co-localize in the equatorial segment of the sperm head, with in silico modeling suggesting a potential interaction between these proteins. What Is Known Already CFTR modulates the permeability of aquaglyceroporins in multiple tissues, and their interaction is mediated by the scaffolding protein NHERF1. AQP7-mediated glycerol permeability correlates with sperm motility. Study Design, Size, Duration Semen samples were collected from normozoospermic men (normal motility; n = 33) and men with asthenozoospermia (reduced motility; n = 15) at a fertility clinic between September 2020 and January 2021. Participants/Materials, Setting, Methods Isolated sperm from men with normozoospermia were used to study the effect of CFTR on sperm motility (N = 10) and glycerol permeability (N = 23). Sperm from 14 asthenozoospermic samples and 13 normozoospermic samples were used to compare the effect of CFTR on AQP7-mediated glycerol permeability, after screening for the absence of common CFTR gene variants. Sperm membrane permeability to glycerol was measured using stopped-flow light scattering, and the effect of CFTR conductance was modulated using a specific inhibitor (CFTRinh172). The interaction between CFTR and AQP7 was investigated using co-immunofluorescence, proximity ligation assay, and in silico approaches like ColabFold and GROMACS. Gaussian distribution of the data was measured by the Shapiro–Wilk normality test. Data showing non-normal distribution was treated with the Kruskal–Wallis test, whereas normal distribution data were treated with an ordinary one-way ANOVA. Comparisons between normozoospermic and asthenozoospermic groups were performed using an unpaired two-tailed Mann–Whitney U test. A P-value less than 0.05 was considered significantly different. Main Results and the Role of Chance CFTR inhibition negatively affected sperm motility (0.53 ± 0.11-fold variation to control, P &lt; 0.05) and AQP7-mediated glycerol permeability (0.459-fold [0.314; 0.537] variation to control, P &lt; 0.01). Despite this, the effect of CFTR dysfunction on AQP7-mediated glycerol permeability of sperm from normo- versus asthenozoospermic samples did not reach statistical significance (P = 0.068) due to low statistical power, but a tendency was apparent. A larger sample size is needed to confirm this trend. CFTR and AQP7 (the main glycerol diffuser in human sperm) co-localize and are in proximity in the midpiece and in the equatorial section of the sperm head in human sperm. In silico analysis supports the interaction of CFTR with AQP7 intermediated by NHERF1, indicating a mechanism of physical modulation of AQP7 permeability by CFTR. Limitations, Reasons for Caution Only cystic fibrosi","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"39 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472891","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}
Yulia Wilk Goldsher,Hadeel Al-Hadi,Brendan Mullen,Emery Potter,Emily MacLeod,Katherine Lajkosz,Gilad Karavani,Yonah Krakowsky,Ethan D Grober,Alexandra L Millman
STUDY QUESTIONHow does gender-affirming hormone therapy (GAHT) regimen impact testicular spermatogenesis in transgender and gender diverse (TGD) individuals?SUMMARY ANSWERCyproterone acetate (CPA) and progesterone significantly impair spermatogenesis, whereas spironolactone does not, compared to no use of anti-androgen.WHAT IS KNOWN ALREADYGAHT is known to suppress spermatogenesis in TGD individuals assigned male at birth, but the extent of impairment varies across hormone regimens. Prior studies suggest that anti-androgens and progestogens may exert distinct effects on testicular function, but direct comparisons between regimens are limited.STUDY DESIGN, SIZE, DURATIONThis was a retrospective single-center cohort study including 287 TGD patients who underwent gender-affirming orchiectomy between November 2017 and January 2024. A total of 573 testis specimens were histologically reviewed.PARTICIPANTS/MATERIALS, SETTING, METHODSAll included patients had received GAHT prior to surgery, with exposure categorized based on the type and duration of hormone therapy. The primary exposure variables were estrogen use (N = 287, 100%), anti-androgen type (CPA: N = 127, 44.3%; spironolactone: N = 110, 38.3%), and progesterone use (N = 73, 25.4%). Testicular histology was evaluated to determine spermatogenesis stage, and multivariable regression was performed to identify independent predictors of impaired sperm maturation.MAIN RESULTS AND THE ROLE OF CHANCEIn total, 287 patients were included in the study period, and 573 testis specimens were reviewed. Mean age at surgery was 33.9 years (SD = 11.7, range = 18.4-80.6), and duration of GAHT was 3.8 years (SD = 3.0, range = 1-28). Older age was associated with impairment in spermatogenesis, with a mean age of 41.4 (SD = 12.8, range = 23.0-66.5) for end-stage testis failure and a mean age of 33.4 (SD = 11.2, range = 20.2-80.6) for complete maturation (P = 0.002). Hormone therapy duration did not show a significant difference between groups (P = 0.22). GAHT included estrogen (n = 287, 100%), progesterone (n = 73, 25.4%), and an anti-androgen (n = 259, 90.2%). CPA (n = 127, 44.3%) and spironolactone (N = 110, 38.3%) were the most common anti-androgens used. Spermatogenesis was most significantly impaired with the use of CPA, with only 8.7% of patients having active spermatogenesis versus 53.3% of patients taking spironolactone (P < 0.001). Progesterone use had an independent negative effect on spermatogenesis (P = 0.005).LIMITATIONS, REASONS FOR CAUTIONThe retrospective design and absence of a control group of untreated individuals limit direct causal inferences. Variability in GAHT duration, adherence, and regimen composition may introduce confounding effects due to self-reporting. Additionally, histological assessment alone does not confirm functional fertility potential, and future studies should explore this aspect.WIDER IMPLICATIONS OF THE FINDINGSThese findings provide clinically relevant insights for fertilit
{"title":"Impact of gender-affirming hormone therapy on spermatogenesis: analysis of testicular histological specimens.","authors":"Yulia Wilk Goldsher,Hadeel Al-Hadi,Brendan Mullen,Emery Potter,Emily MacLeod,Katherine Lajkosz,Gilad Karavani,Yonah Krakowsky,Ethan D Grober,Alexandra L Millman","doi":"10.1093/humrep/deaf216","DOIUrl":"https://doi.org/10.1093/humrep/deaf216","url":null,"abstract":"STUDY QUESTIONHow does gender-affirming hormone therapy (GAHT) regimen impact testicular spermatogenesis in transgender and gender diverse (TGD) individuals?SUMMARY ANSWERCyproterone acetate (CPA) and progesterone significantly impair spermatogenesis, whereas spironolactone does not, compared to no use of anti-androgen.WHAT IS KNOWN ALREADYGAHT is known to suppress spermatogenesis in TGD individuals assigned male at birth, but the extent of impairment varies across hormone regimens. Prior studies suggest that anti-androgens and progestogens may exert distinct effects on testicular function, but direct comparisons between regimens are limited.STUDY DESIGN, SIZE, DURATIONThis was a retrospective single-center cohort study including 287 TGD patients who underwent gender-affirming orchiectomy between November 2017 and January 2024. A total of 573 testis specimens were histologically reviewed.PARTICIPANTS/MATERIALS, SETTING, METHODSAll included patients had received GAHT prior to surgery, with exposure categorized based on the type and duration of hormone therapy. The primary exposure variables were estrogen use (N = 287, 100%), anti-androgen type (CPA: N = 127, 44.3%; spironolactone: N = 110, 38.3%), and progesterone use (N = 73, 25.4%). Testicular histology was evaluated to determine spermatogenesis stage, and multivariable regression was performed to identify independent predictors of impaired sperm maturation.MAIN RESULTS AND THE ROLE OF CHANCEIn total, 287 patients were included in the study period, and 573 testis specimens were reviewed. Mean age at surgery was 33.9 years (SD = 11.7, range = 18.4-80.6), and duration of GAHT was 3.8 years (SD = 3.0, range = 1-28). Older age was associated with impairment in spermatogenesis, with a mean age of 41.4 (SD = 12.8, range = 23.0-66.5) for end-stage testis failure and a mean age of 33.4 (SD = 11.2, range = 20.2-80.6) for complete maturation (P = 0.002). Hormone therapy duration did not show a significant difference between groups (P = 0.22). GAHT included estrogen (n = 287, 100%), progesterone (n = 73, 25.4%), and an anti-androgen (n = 259, 90.2%). CPA (n = 127, 44.3%) and spironolactone (N = 110, 38.3%) were the most common anti-androgens used. Spermatogenesis was most significantly impaired with the use of CPA, with only 8.7% of patients having active spermatogenesis versus 53.3% of patients taking spironolactone (P < 0.001). Progesterone use had an independent negative effect on spermatogenesis (P = 0.005).LIMITATIONS, REASONS FOR CAUTIONThe retrospective design and absence of a control group of untreated individuals limit direct causal inferences. Variability in GAHT duration, adherence, and regimen composition may introduce confounding effects due to self-reporting. Additionally, histological assessment alone does not confirm functional fertility potential, and future studies should explore this aspect.WIDER IMPLICATIONS OF THE FINDINGSThese findings provide clinically relevant insights for fertilit","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"33 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477750","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}
Sara Pietroforte, Marion Martins, Montserrat Barragan, Elena Ibañez, Rita Vassena, Mina Popovic, Tim Sanchez, Denny Sakkas, Filippo Zambelli
STUDY QUESTION Is there a relationship between the mitochondrial activity and the meiotic progression of oocytes from germinal vesicle (GV) to metaphase II (MII) stages in young and advanced maternal age (AMA) women? SUMMARY ANSWER Poor mitochondrial metabolism impairs the meiotic progression of human GV oocytes, contributing to a lower oocyte maturation capacity of AMA oocytes. WHAT IS KNOWN ALREADY AMA oocytes are characterized by diminished quality, mostly due to the higher rates of chromosomal segregation errors occurring during meiosis I. Another hallmark of AMA oocytes is impaired mitochondrial metabolism. Studies in mice have suggested a link between metabolic dysfunction and meiotic failure, but this relationship has not been fully elucidated in humans. Metabolic dynamics can be visualized by indirect measurements through mitochondrial staining and quantified more directly using fluorescence lifetime imaging microscopy (FLIM). This live-imaging approach can generate metabolic timelapse profiles of oocytes throughout meiosis. In the present study, we explored mitochondrial distribution and functionality in human oocytes at the GV and MII stages, obtained from young and AMA women, to establish the role of mitochondrial metabolism in meiosis progression. STUDY DESIGN, SIZE, DURATION A total of 340 GV oocytes from young (≤34 years) and AMA (>37 years) women were included in the study. Denuded GVs were matured in vitro in G2-plus medium for 30 h. Maturation was determined by the presence of the extruded first polar body (PB1). The collected oocytes were processed for mitochondrial protein imaging (n = 80), or for live imaging (n = 171). Moreover, 89 oocytes were used for loss-of-function analysis by treating young GVs with 1 μM trifluoromethoxy-carbonylcyanide-phenylhydrazone (FCCP) for 30 min before in vitro maturation. PARTICIPANTS/MATERIALS, SETTING, METHODS The proteins dihydrolipoamide-S-acetyltransferase (D-LAT) and translocase-of-outer mitochondrial-membrane (TOMM20) were analyzed in young and AMA oocytes by immunofluorescence to assess mitochondrial activity and localization, respectively. Fluorescence mean intensities (arbitrary-unit, AU) were quantified with ImageJ and compared by t-test; maturation rates were compared by chi-squared test. FLIM comprehensive metabolism (NAD(P)H; FAD+) was taken at GV stage. Different FLIM parameters (fluorescence intensity, fraction bound, short/long lifetime) and the Redox ratio (NAD(P)H intensity/FAD+ intensity) were evaluated. MAIN RESULTS AND THE ROLE OF CHANCE The findings revealed that active mitochondria are specifically localized in the subcortical area, while mitochondria in general are distributed across the whole oocyte. This pattern was substantially maintained in AMA oocytes, which were in turn characterized by a lower mitochondrial activity (D-LAT intensity of 78 614 ± 58 534 AU in young, 12 517 ± 10 187 AU in AMA, P = 0.003), while a lower number of mitochondria was observed In
{"title":"Mitochondrial metabolism influences meiotic maturation in human oocytes of young and advanced maternal age women","authors":"Sara Pietroforte, Marion Martins, Montserrat Barragan, Elena Ibañez, Rita Vassena, Mina Popovic, Tim Sanchez, Denny Sakkas, Filippo Zambelli","doi":"10.1093/humrep/deaf207","DOIUrl":"https://doi.org/10.1093/humrep/deaf207","url":null,"abstract":"STUDY QUESTION Is there a relationship between the mitochondrial activity and the meiotic progression of oocytes from germinal vesicle (GV) to metaphase II (MII) stages in young and advanced maternal age (AMA) women? SUMMARY ANSWER Poor mitochondrial metabolism impairs the meiotic progression of human GV oocytes, contributing to a lower oocyte maturation capacity of AMA oocytes. WHAT IS KNOWN ALREADY AMA oocytes are characterized by diminished quality, mostly due to the higher rates of chromosomal segregation errors occurring during meiosis I. Another hallmark of AMA oocytes is impaired mitochondrial metabolism. Studies in mice have suggested a link between metabolic dysfunction and meiotic failure, but this relationship has not been fully elucidated in humans. Metabolic dynamics can be visualized by indirect measurements through mitochondrial staining and quantified more directly using fluorescence lifetime imaging microscopy (FLIM). This live-imaging approach can generate metabolic timelapse profiles of oocytes throughout meiosis. In the present study, we explored mitochondrial distribution and functionality in human oocytes at the GV and MII stages, obtained from young and AMA women, to establish the role of mitochondrial metabolism in meiosis progression. STUDY DESIGN, SIZE, DURATION A total of 340 GV oocytes from young (≤34 years) and AMA (&gt;37 years) women were included in the study. Denuded GVs were matured in vitro in G2-plus medium for 30 h. Maturation was determined by the presence of the extruded first polar body (PB1). The collected oocytes were processed for mitochondrial protein imaging (n = 80), or for live imaging (n = 171). Moreover, 89 oocytes were used for loss-of-function analysis by treating young GVs with 1 μM trifluoromethoxy-carbonylcyanide-phenylhydrazone (FCCP) for 30 min before in vitro maturation. PARTICIPANTS/MATERIALS, SETTING, METHODS The proteins dihydrolipoamide-S-acetyltransferase (D-LAT) and translocase-of-outer mitochondrial-membrane (TOMM20) were analyzed in young and AMA oocytes by immunofluorescence to assess mitochondrial activity and localization, respectively. Fluorescence mean intensities (arbitrary-unit, AU) were quantified with ImageJ and compared by t-test; maturation rates were compared by chi-squared test. FLIM comprehensive metabolism (NAD(P)H; FAD+) was taken at GV stage. Different FLIM parameters (fluorescence intensity, fraction bound, short/long lifetime) and the Redox ratio (NAD(P)H intensity/FAD+ intensity) were evaluated. MAIN RESULTS AND THE ROLE OF CHANCE The findings revealed that active mitochondria are specifically localized in the subcortical area, while mitochondria in general are distributed across the whole oocyte. This pattern was substantially maintained in AMA oocytes, which were in turn characterized by a lower mitochondrial activity (D-LAT intensity of 78 614 ± 58 534 AU in young, 12 517 ± 10 187 AU in AMA, P = 0.003), while a lower number of mitochondria was observed In ","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"13 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472892","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}
F Horta, A Vuyyuru, H Newman, G Ballerin, S Mercer, E Rolfe, M Haft-Tananian, M Pangestu, P Temple-Smith, B Vollenhoven, R B Gilchrist, S Catt
STUDY QUESTION Is it possible to assess label-free live cell metabolic imaging during early oocyte and embryo development? SUMMARY ANSWER Label-free metabolic imaging can be systematically used during early development, showing no differences between controls and illuminated oocytes and embryos in terms of early development, blastocyst formation, and embryo outgrowth. WHAT IS KNOWN ALREADY Non-invasive methods that are reliable to assess oocyte and embryo quality are a significant aim for ARTs. Changes in metabolic activity could lead to cell death or altered early development and low implantation potential. This could potentially be predicted by incorporating non-invasive measurements of metabolism. Metabolic imaging has been investigated through complex methodologies; however, scientific evidence for its utility during early oocyte and embryo development requires further investigation to assess potential translation in clinical settings. Measurements of metabolic activity could be a useful tool, as the autofluorescence of molecules such as nicotinamide adenine dinucleotide phosphate hydrogen (NAD(P)H) and flavin adenine dinucleotide (FAD) are a straightforward representation of mitochondrial function. STUDY DESIGN, SIZE, DURATION Female mice (n = 15) and super-ovulated female mice (n = 30) were used to produce oocytes and embryos, respectively. Oocytes and in-vivo produced embryos were divided into the control group, sham control group, and illuminated group. Illuminated samples were assessed for both NAD(P)H and FAD levels in oocytes and NAD(P)H levels during early embryo development every 3 h using arbitrary units of autofluorescence (AU). Produced blastocysts were assessed for total cell and inner-cell-mass (ICM) number (by immunostaining for Oct4) and embryo outgrowth assays. Furthermore, safety live birth studies were also conducted. PARTICIPANTS/MATERIALS, SETTING, METHODS F1 (C57BL6/CBA) mouse strain was used. NAD(P)H and FAD autofluorescence levels were measured during oocyte and embryo development using confocal microscopy (Olympus FV1200). A confocal Z-stacking function was used to record 15 focal planes, using a 20×/0.95 NA air objective of the entire oocytes and embryos and opening the confocal pinhole system completely. Images were then collected and analysed using FIJI software (version: 2.0.0-rc-69/1.52n; ImageJ). Developmental rates, blastocyst cell numbers, outgrowth rates (for 4 days post blastocyst formation), and live birth rates were assessed. MAIN RESULTS AND THE ROLE OF CHANCE Oocyte IVM and embryo culture experiments showed no significant differences in developmental rates between study groups (P > 0.05). Similarly, the total number of cells from blastocysts (control: 82.9 ± 5.6; sham: 76.5 ± 3.3; Illuminated: 77.1 ± 4.2; ± SEM) and ICM cells (control: 10.8 ± 1.3; sham: 9.4 ± 0.7; Illuminated: 11.9 ± 0.8; ± SEM) did not differ between groups (P > 0.05). Outgrowth assays of the study groups presented similar
{"title":"Investigating metabolic activity during oocyte and early embryo development through label-free metabolic imaging: a systematic approach for timelapse applications","authors":"F Horta, A Vuyyuru, H Newman, G Ballerin, S Mercer, E Rolfe, M Haft-Tananian, M Pangestu, P Temple-Smith, B Vollenhoven, R B Gilchrist, S Catt","doi":"10.1093/humrep/deaf196","DOIUrl":"https://doi.org/10.1093/humrep/deaf196","url":null,"abstract":"STUDY QUESTION Is it possible to assess label-free live cell metabolic imaging during early oocyte and embryo development? SUMMARY ANSWER Label-free metabolic imaging can be systematically used during early development, showing no differences between controls and illuminated oocytes and embryos in terms of early development, blastocyst formation, and embryo outgrowth. WHAT IS KNOWN ALREADY Non-invasive methods that are reliable to assess oocyte and embryo quality are a significant aim for ARTs. Changes in metabolic activity could lead to cell death or altered early development and low implantation potential. This could potentially be predicted by incorporating non-invasive measurements of metabolism. Metabolic imaging has been investigated through complex methodologies; however, scientific evidence for its utility during early oocyte and embryo development requires further investigation to assess potential translation in clinical settings. Measurements of metabolic activity could be a useful tool, as the autofluorescence of molecules such as nicotinamide adenine dinucleotide phosphate hydrogen (NAD(P)H) and flavin adenine dinucleotide (FAD) are a straightforward representation of mitochondrial function. STUDY DESIGN, SIZE, DURATION Female mice (n = 15) and super-ovulated female mice (n = 30) were used to produce oocytes and embryos, respectively. Oocytes and in-vivo produced embryos were divided into the control group, sham control group, and illuminated group. Illuminated samples were assessed for both NAD(P)H and FAD levels in oocytes and NAD(P)H levels during early embryo development every 3 h using arbitrary units of autofluorescence (AU). Produced blastocysts were assessed for total cell and inner-cell-mass (ICM) number (by immunostaining for Oct4) and embryo outgrowth assays. Furthermore, safety live birth studies were also conducted. PARTICIPANTS/MATERIALS, SETTING, METHODS F1 (C57BL6/CBA) mouse strain was used. NAD(P)H and FAD autofluorescence levels were measured during oocyte and embryo development using confocal microscopy (Olympus FV1200). A confocal Z-stacking function was used to record 15 focal planes, using a 20×/0.95 NA air objective of the entire oocytes and embryos and opening the confocal pinhole system completely. Images were then collected and analysed using FIJI software (version: 2.0.0-rc-69/1.52n; ImageJ). Developmental rates, blastocyst cell numbers, outgrowth rates (for 4 days post blastocyst formation), and live birth rates were assessed. MAIN RESULTS AND THE ROLE OF CHANCE Oocyte IVM and embryo culture experiments showed no significant differences in developmental rates between study groups (P &gt; 0.05). Similarly, the total number of cells from blastocysts (control: 82.9 ± 5.6; sham: 76.5 ± 3.3; Illuminated: 77.1 ± 4.2; ± SEM) and ICM cells (control: 10.8 ± 1.3; sham: 9.4 ± 0.7; Illuminated: 11.9 ± 0.8; ± SEM) did not differ between groups (P &gt; 0.05). Outgrowth assays of the study groups presented similar","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"23 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472889","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}
Edgar Del Llano,Marlene Rasschaert,Christophe Arnoult,Philippe Robert,Pierre F Ray,Corinne Loeuillet
STUDY QUESTIONDoes the administration of an oil-based iodinated contrast medium (OSCM) in the mouse uterus have a positive effect on fertility similarly to what is observed in women following hysterosalpingography (HSG)?SUMMARY ANSWERFollowing IUI of a small number of sperm (mimicking oligozoospermia), fertilization and birth rates were improved in female mice who had previously received an intrauterine administration of an OSCM confirming a pro-fertility effect.WHAT IS KNOWN ALREADYHSG is a common diagnostic procedure used in infertile or subfertile women, primarily to assess the patency of fallopian tubes. It consists in injecting an iodinated contrast medium into the uterus to enable the imaging of the female reproductive tract by radiography. In the absence of obstruction, the contrast medium fills the uterus and transits through the fallopian tubes before overflowing in the peritoneal cavity. Several studies reported that in the few months following HSG, women injected with an OSCM (ethyl esters of iodinated fatty acids of poppy seed oil) had an enhanced pregnancy rate (either spontaneous or following IUI) compared to those administered with a water-based contrast medium. This suggests that OSCM administration in the female reproductive tract could improve fertility. However, the physiological mechanisms underlying this potential effect remain unknown.STUDY DESIGN, SIZE, DURATIONOSCM or PBS (phosphate buffered saline, control) were administered into the uteri of B6D2 female mice (5-9 weeks old, total n = 73). Two weeks later, intrauterine insemination was performed with mouse epididymis sperm from B6D2 male mice (8-16 weeks old). Females were euthanized and fertilized oocytes collected and incubated for 4 days up to the blastocyst stage (n = 52). Alternatively, females were left until delivery (n = 21).PARTICIPANTS/MATERIALS, SETTING, METHODSFemale nulliparous mice were administered either with PBS or OSCM directly into the uterus. After 2 weeks, females were inseminated with a controlled number of sperm. The resulting fertilized/unfertilized oocytes were collected and counted the following day to calculate the fertilization rates and then further incubated in vitro to follow the development to the blastocyst stage. In addition, females were mated with vasectomized males to allow implantation, subsequent pregnancy and birth.MAIN RESULTS AND THE ROLE OF CHANCEFirst, females were inseminated with a high number of sperm (5 × 10e5 spermatozoa). Comparable fertilization rates (67.0 ± 5.4% and 60.0 ± 8.0%, P > 0.05) were observed from oocytes originating from OSCM and PBS-administered mice, respectively. This showed that when inseminating with a high number of sperm, uterine OSCM administration had no deleterious effect but did not improve fertilization. We postulated that the potential beneficial effect of OSCM administration might be masked by the optimal reproductive system of young mice. It was therefore decided to test the effect of OSCM in s
{"title":"Administration of ethiodized poppy seed oil-based contrast agent into the uterus enhances fertilization rate in mice inseminated with low sperm numbers.","authors":"Edgar Del Llano,Marlene Rasschaert,Christophe Arnoult,Philippe Robert,Pierre F Ray,Corinne Loeuillet","doi":"10.1093/humrep/deaf204","DOIUrl":"https://doi.org/10.1093/humrep/deaf204","url":null,"abstract":"STUDY QUESTIONDoes the administration of an oil-based iodinated contrast medium (OSCM) in the mouse uterus have a positive effect on fertility similarly to what is observed in women following hysterosalpingography (HSG)?SUMMARY ANSWERFollowing IUI of a small number of sperm (mimicking oligozoospermia), fertilization and birth rates were improved in female mice who had previously received an intrauterine administration of an OSCM confirming a pro-fertility effect.WHAT IS KNOWN ALREADYHSG is a common diagnostic procedure used in infertile or subfertile women, primarily to assess the patency of fallopian tubes. It consists in injecting an iodinated contrast medium into the uterus to enable the imaging of the female reproductive tract by radiography. In the absence of obstruction, the contrast medium fills the uterus and transits through the fallopian tubes before overflowing in the peritoneal cavity. Several studies reported that in the few months following HSG, women injected with an OSCM (ethyl esters of iodinated fatty acids of poppy seed oil) had an enhanced pregnancy rate (either spontaneous or following IUI) compared to those administered with a water-based contrast medium. This suggests that OSCM administration in the female reproductive tract could improve fertility. However, the physiological mechanisms underlying this potential effect remain unknown.STUDY DESIGN, SIZE, DURATIONOSCM or PBS (phosphate buffered saline, control) were administered into the uteri of B6D2 female mice (5-9 weeks old, total n = 73). Two weeks later, intrauterine insemination was performed with mouse epididymis sperm from B6D2 male mice (8-16 weeks old). Females were euthanized and fertilized oocytes collected and incubated for 4 days up to the blastocyst stage (n = 52). Alternatively, females were left until delivery (n = 21).PARTICIPANTS/MATERIALS, SETTING, METHODSFemale nulliparous mice were administered either with PBS or OSCM directly into the uterus. After 2 weeks, females were inseminated with a controlled number of sperm. The resulting fertilized/unfertilized oocytes were collected and counted the following day to calculate the fertilization rates and then further incubated in vitro to follow the development to the blastocyst stage. In addition, females were mated with vasectomized males to allow implantation, subsequent pregnancy and birth.MAIN RESULTS AND THE ROLE OF CHANCEFirst, females were inseminated with a high number of sperm (5 × 10e5 spermatozoa). Comparable fertilization rates (67.0 ± 5.4% and 60.0 ± 8.0%, P > 0.05) were observed from oocytes originating from OSCM and PBS-administered mice, respectively. This showed that when inseminating with a high number of sperm, uterine OSCM administration had no deleterious effect but did not improve fertilization. We postulated that the potential beneficial effect of OSCM administration might be masked by the optimal reproductive system of young mice. It was therefore decided to test the effect of OSCM in s","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"128 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433744","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}
Lily I Wright,Ivan Wangsaputra,Terence Garner,Megan C Sharps,Roger Sturmey,Peter T Ruane,Adam Stevens
STUDY QUESTIONCan network modelling of single-cell transcriptomic data identify cellular developmental trajectories of fallopian tube (FT) epithelium and reveal functional and pathological divergence from the endometrium?SUMMARY ANSWERA bidirectional differentiation trajectory originating from a novel OVGP1+ progenitor population of FT epithelial cells was uncovered, and causal network modelling of whole-transcriptome activity in the FT and endometrium revealed functional divergence between their secretory epithelial cells, with implications for ectopic pregnancy candidate genes.WHAT IS KNOWN ALREADYThe FT forms the in vivo peri-conceptual environment, which has a significant impact on programming offspring health. The FT epithelium establishes this environment; however, the epithelial cell types are poorly characterized in health and disease.STUDY DESIGN, SIZE, DURATIONPublicly available, benign FT single-cell RNA sequencing (scRNA-seq) samples from 13 women across three previous studies were combined. Endometrial scRNA-seq samples from 13 women from one study were used to demonstrate transcriptomic differences between the epithelia of the two tissues. Network models of transcriptomic action were constructed with hypergraphs.PARTICIPANTS/MATERIALS, SETTING, METHODSA meta-analysis of FT scRNA-seq samples was performed to identify epithelial populations. Differential gene expression assessed differences between FT and endometrial epithelial scRNA-seq data. Functional differences between secretory cells in the tissues were characterized using hypergraph models. To identify associations with ectopic pregnancy, expression quantitative trait loci (eQTLs) from a recent GWAS were mapped onto the network models.MAIN RESULTS AND THE ROLE OF CHANCEEpithelial cells (n = 14 360) were clustered into eight secretory and ciliated epithelial populations in the meta-analysis of three scRNA-seq datasets. A novel OVGP1+ epithelial progenitor cell was also identified, and its bidirectional differentiation to mature secretory or mature ciliated populations was mapped by RNA velocity analysis. This progenitor exhibited a high velocity magnitude (12.47) and low confidence (0.69): a combination strongly indicative of multipotent progenitor status. Comparing FT epithelial cells with endometrial epithelial cells revealed 5.3-fold fewer shared genes between FT and endometrial glandular secretory cells than between FT and endometrial ciliated cells, suggesting functional divergence of secretory cells along the reproductive tract. Hypergraphs were used to identify highly coordinated regions of the transcriptome robustly associated with functional gene networks. In the FT secretory cells, these networks were enriched for lipid-related (false discovery rate (FDR) < 0.002) and immune-related (FDR < 0.00007) pathways. We mapped eQTLs from a GWAS meta-analysis of 7070 women with ectopic pregnancy over a range of significance (P = 1.68 × 10-21-5.8 × 10-4) to the hypergraphs of FT
{"title":"Identification of novel differentiation trajectories and gene network associations with ectopic pregnancy in fallopian tube epithelium.","authors":"Lily I Wright,Ivan Wangsaputra,Terence Garner,Megan C Sharps,Roger Sturmey,Peter T Ruane,Adam Stevens","doi":"10.1093/humrep/deaf200","DOIUrl":"https://doi.org/10.1093/humrep/deaf200","url":null,"abstract":"STUDY QUESTIONCan network modelling of single-cell transcriptomic data identify cellular developmental trajectories of fallopian tube (FT) epithelium and reveal functional and pathological divergence from the endometrium?SUMMARY ANSWERA bidirectional differentiation trajectory originating from a novel OVGP1+ progenitor population of FT epithelial cells was uncovered, and causal network modelling of whole-transcriptome activity in the FT and endometrium revealed functional divergence between their secretory epithelial cells, with implications for ectopic pregnancy candidate genes.WHAT IS KNOWN ALREADYThe FT forms the in vivo peri-conceptual environment, which has a significant impact on programming offspring health. The FT epithelium establishes this environment; however, the epithelial cell types are poorly characterized in health and disease.STUDY DESIGN, SIZE, DURATIONPublicly available, benign FT single-cell RNA sequencing (scRNA-seq) samples from 13 women across three previous studies were combined. Endometrial scRNA-seq samples from 13 women from one study were used to demonstrate transcriptomic differences between the epithelia of the two tissues. Network models of transcriptomic action were constructed with hypergraphs.PARTICIPANTS/MATERIALS, SETTING, METHODSA meta-analysis of FT scRNA-seq samples was performed to identify epithelial populations. Differential gene expression assessed differences between FT and endometrial epithelial scRNA-seq data. Functional differences between secretory cells in the tissues were characterized using hypergraph models. To identify associations with ectopic pregnancy, expression quantitative trait loci (eQTLs) from a recent GWAS were mapped onto the network models.MAIN RESULTS AND THE ROLE OF CHANCEEpithelial cells (n = 14 360) were clustered into eight secretory and ciliated epithelial populations in the meta-analysis of three scRNA-seq datasets. A novel OVGP1+ epithelial progenitor cell was also identified, and its bidirectional differentiation to mature secretory or mature ciliated populations was mapped by RNA velocity analysis. This progenitor exhibited a high velocity magnitude (12.47) and low confidence (0.69): a combination strongly indicative of multipotent progenitor status. Comparing FT epithelial cells with endometrial epithelial cells revealed 5.3-fold fewer shared genes between FT and endometrial glandular secretory cells than between FT and endometrial ciliated cells, suggesting functional divergence of secretory cells along the reproductive tract. Hypergraphs were used to identify highly coordinated regions of the transcriptome robustly associated with functional gene networks. In the FT secretory cells, these networks were enriched for lipid-related (false discovery rate (FDR) < 0.002) and immune-related (FDR < 0.00007) pathways. We mapped eQTLs from a GWAS meta-analysis of 7070 women with ectopic pregnancy over a range of significance (P = 1.68 × 10-21-5.8 × 10-4) to the hypergraphs of FT ","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"200 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433751","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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