Pub Date : 2025-06-20eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf039
Peipei Pan, Chang Liu, Shiyi Lin, Haiqing Wang, Xia Chen, Haiyan Yang, Xuefeng Huang, Huan Zhang, Yili Teng
Study question: Is there an association between changes in endometrial thickness (EMT) following progesterone administration and pregnancy outcomes in frozen-thawed embryo transfers (FETs) at Day 3 (D3) and blastocyst stages?
Summary answer: Endometrial compaction is not associated with better pregnancy outcomes.
What is known already: Previous studies have shown conflicting results on the impact of EMT changes on FET outcomes.
Study design size duration: This study was a single-center retrospective cohort analysis of FETs from 1 January 2018 to 31 December 2022. A total of 9390 D3 FETs and 7063 blastocyst FETs were included during this period.
Participants/materials setting methods: D3 FETs and blastocyst FETs were divided into three groups: compaction group, non-change group, and expansion group. The impact of EMT changes after progesterone administration on HCG-positive, pregnancy, ongoing pregnancy, live birth, and pregnancy loss rates were analyzed for D3 and blastocyst FETs. EMT on the progesterone administration day (defined as EMT1) and on embryo transfer (ET)day (defined as EMT2) was measured exclusively by transvaginal ultrasound. Inverse probability weighting (IPW) and stratified logistic regressions were conducted to reduce the effects of confounding factors.
Main results and the role of chance: After IPW adjustment, in D3 FETs, women with compacted endometrium had the lowest HCG-positive rates (P = 0.012), clinical pregnancy rates (P < 0.001), ongoing pregnancy rates (P < 0.001), and live birth rates (LBRs) (P < 0.001) among the three groups. Among HCG-positive cases, the compaction group had the highest ectopic pregnancy rates (3.5% vs 2.6% vs 1.6%; P = 0.015) and the lowest LBRs (65.8% vs 68.3% vs 71.4%; P = 0.018). Univariate logistic regressions found that LBRs were weakly associated with compacted endometrium [odds ratio (OR) 0.831, 95% CI: 0.696-0.993]. Logistic regressions with IPW revealed that the compaction group was not associated with higher odds of pregnancy outcomes, including HCG positive, clinical pregnancy, ongoing pregnancy, ongoing pregnancy, and live births compared to the non-change group. In contrast, the expansion group was associated with higher odds of live birth per ETs (OR 1.166, 95% CI: 1.070-1.271; P = 0.001), and live birth per HCG-positive cases (OR 1.160, 95% CI: 1.028-1.309; P = 0.016). In blastocyst FETs, women with compacted endometrium had the lowest HCG-positive rates (P = 0.001) and clinical pregnancy rates (P = 0.031). Logistic regressions with IPW adjustment found that compaction group was associated with lower odds of HCG positive (OR 0.813, 95% CI: 0.668-0.989, P = 0.039) compared to the non-change group. Additionally, LBRs increased with the rising change ratios of EMT after progeste
研究问题：在第3天（D3）和囊胚期的冻融胚胎移植（fet）中，黄体酮给药后子宫内膜厚度（EMT）的变化与妊娠结局之间是否存在关联？总结回答：子宫内膜压实与更好的妊娠结局无关。已知情况：先前的研究显示，EMT变化对FET结果的影响结果相互矛盾。研究设计规模持续时间：本研究为2018年1月1日至2022年12月31日的单中心回顾性队列分析。在此期间共纳入9390个D3场效应管和7063个囊胚场效应管。受试者/材料设置方法：将D3型fet和囊胚型fet分为压实组、不变组和膨化组。分析孕酮给药后EMT变化对D3和囊胚fet的hcg阳性、妊娠、持续妊娠、活产率和流产率的影响。孕酮给药日（定义为EMT1）和胚胎移植（ET）日（定义为EMT2）的EMT仅通过阴道超声测量。采用逆概率加权（IPW）和分层逻辑回归来降低混杂因素的影响。主要结果及机会的作用：调整IPW后，D3 fet中，子宫内膜致密的妇女hcg阳性率最低（P = 0.012），临床妊娠率（P P P P = 0.015）， lbr最低(65.8% vs 68.3% vs 71.4%；p = 0.018)。单因素logistic回归发现，lbr与子宫内膜紧致性弱相关[比值比（OR） 0.831, 95% CI: 0.696-0.993]。与IPW的逻辑回归显示，与未改变组相比，压实组与妊娠结局（包括HCG阳性、临床妊娠、持续妊娠、持续妊娠和活产）的几率较高无关。相比之下，扩大组的每组ETs活产率较高(OR 1.166, 95% CI: 1.070-1.271；P = 0.001)，以及hcg阳性病例的活产率(OR 1.160, 95% CI: 1.028-1.309；p = 0.016)。在囊胚fet中，子宫内膜致密的妇女hcg阳性率最低（P = 0.001），临床妊娠率最低（P = 0.031）。经IPW调整后的Logistic回归发现，与未改变组相比，压实组HCG阳性的几率较低（OR 0.813, 95% CI: 0.668-0.989, P = 0.039）。此外，lbr随黄体酮给药后EMT变化率的升高而升高，但在一定范围内（D3组为30%，囊胚组为50%）。局限性：谨慎的原因：本研究仅包括对未经测试的胚胎进行fet的回顾性分析。研究结果的更广泛含义：D3 fet的子宫内膜扩张与lbr的改善呈正相关，但在囊胚fet中没有。这些发现表明，胚胎发育阶段特异性子宫内膜准备方案可能提高辅助生殖结果。研究经费/利益竞争：国家自然科学基金项目（82201856）、温州市科技局基础科研项目（Y20220006）、温州市生殖与遗传学重点实验室项目（2022HZSY0051）、浙江省医疗机构临床技术国际交流项目资助。作者无利益冲突需要申报。试验注册号：无。
{"title":"Endometrial compaction shows no association with improved pregnancy outcomes in hormonal replacement frozen-thawed embryo transfer: an analysis of over 16 000 cases.","authors":"Peipei Pan, Chang Liu, Shiyi Lin, Haiqing Wang, Xia Chen, Haiyan Yang, Xuefeng Huang, Huan Zhang, Yili Teng","doi":"10.1093/hropen/hoaf039","DOIUrl":"10.1093/hropen/hoaf039","url":null,"abstract":"<p><strong>Study question: </strong>Is there an association between changes in endometrial thickness (EMT) following progesterone administration and pregnancy outcomes in frozen-thawed embryo transfers (FETs) at Day 3 (D3) and blastocyst stages?</p><p><strong>Summary answer: </strong>Endometrial compaction is not associated with better pregnancy outcomes.</p><p><strong>What is known already: </strong>Previous studies have shown conflicting results on the impact of EMT changes on FET outcomes.</p><p><strong>Study design size duration: </strong>This study was a single-center retrospective cohort analysis of FETs from 1 January 2018 to 31 December 2022. A total of 9390 D3 FETs and 7063 blastocyst FETs were included during this period.</p><p><strong>Participants/materials setting methods: </strong>D3 FETs and blastocyst FETs were divided into three groups: compaction group, non-change group, and expansion group. The impact of EMT changes after progesterone administration on HCG-positive, pregnancy, ongoing pregnancy, live birth, and pregnancy loss rates were analyzed for D3 and blastocyst FETs. EMT on the progesterone administration day (defined as EMT1) and on embryo transfer (ET)day (defined as EMT2) was measured exclusively by transvaginal ultrasound. Inverse probability weighting (IPW) and stratified logistic regressions were conducted to reduce the effects of confounding factors.</p><p><strong>Main results and the role of chance: </strong>After IPW adjustment, in D3 FETs, women with compacted endometrium had the lowest HCG-positive rates (<i>P </i>= 0.012), clinical pregnancy rates (<i>P </i>< 0.001), ongoing pregnancy rates (<i>P </i>< 0.001), and live birth rates (LBRs) (<i>P </i>< 0.001) among the three groups. Among HCG-positive cases, the compaction group had the highest ectopic pregnancy rates (3.5% vs 2.6% vs 1.6%; <i>P </i>= 0.015) and the lowest LBRs (65.8% vs 68.3% vs 71.4%; <i>P </i>= 0.018). Univariate logistic regressions found that LBRs were weakly associated with compacted endometrium [odds ratio (OR) 0.831, 95% CI: 0.696-0.993]. Logistic regressions with IPW revealed that the compaction group was not associated with higher odds of pregnancy outcomes, including HCG positive, clinical pregnancy, ongoing pregnancy, ongoing pregnancy, and live births compared to the non-change group. In contrast, the expansion group was associated with higher odds of live birth per ETs (OR 1.166, 95% CI: 1.070-1.271; <i>P </i>= 0.001), and live birth per HCG-positive cases (OR 1.160, 95% CI: 1.028-1.309; <i>P </i>= 0.016). In blastocyst FETs, women with compacted endometrium had the lowest HCG-positive rates (<i>P </i>= 0.001) and clinical pregnancy rates (<i>P </i>= 0.031). Logistic regressions with IPW adjustment found that compaction group was associated with lower odds of HCG positive (OR 0.813, 95% CI: 0.668-0.989, <i>P </i>= 0.039) compared to the non-change group. Additionally, LBRs increased with the rising change ratios of EMT after progeste","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf039"},"PeriodicalIF":8.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-18eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf033
Jessica K Lu, Yin Jun Law, Ning Zhang, Evangelia T Katsika, Efstratios M Kolibianakis, Christos A Venetis
<p><strong>Study question: </strong>How is recurrent implantation failure (RIF) defined in published literature and what is the prognostic agreement of these definitions with recently introduced RIF criteria by ESHRE?</p><p><strong>Summary answer: </strong>RIF definitions used in current clinical studies are highly variable and only a low proportion of published studies on RIF meet the ESHRE RIF diagnostic threshold.</p><p><strong>What is known already: </strong>RIF is a key cause of ART failure and growing focus of ART research. However, RIF remains poorly and inconsistently defined in published literature, thereby making the interpretation and clinical applicability of RIF research difficult and highly problematic.</p><p><strong>Study design size duration: </strong>The electronic databases EMBASE (Ovid), PubMed, Cochrane Central Register Of Controlled Trials (CENTRAL), Scopus, and Web of Science were systematically searched up to 30 June 2024 using the search terms 'recurrent implantation failure' and 'repeated implantation failure' for original peer-reviewed journal articles that included RIF patients.</p><p><strong>Participants/materials setting methods: </strong>The following data were manually extracted from eligible full-text articles: study methodology and characteristics, ART characteristics, and the RIF definition used. Extracted RIF definitions were analysed according to predetermined specifiers. The prognostic profile of these RIF definitions was compared with the 2023 ESHRE-recommended threshold for RIF diagnosis.</p><p><strong>Main results and the role of chance: </strong>The literature search identified 9853 studies, of which 748 were eligible for inclusion. Of these 748 studies, 589 studies (78.7%) provided one RIF definition, 83 studies (11.1%) used two definitions, three studies (0.4%) provided three or more definitions while 73 studies (9.8%) did not provide a definition for RIF. Of the 838 RIF definitions retrieved, there were a total of 503 unique RIF definitions. The three most common specifiers used to define RIF were embryo morphological quality (n = 491, 58.6% of RIF definitions), number of transfer events (n = 439, 52.4%), and cumulative number of embryos transferred (n = 326, 38.9%). RIF was most frequently diagnosed as 'failure of ≥3 embryo transfer events' (n = 26) and 'failure of ≥3 stimulated cycles' (n = 22). The threshold for defining RIF based on the cumulative number of embryos transferred in total was significantly higher for cleavage-stage embryos compared to blastocysts (incidence rate ratio 2.15, <i>P</i> < 0.001). In most cases, the RIF definitions used did not meet the ESHRE-recommended RIF diagnostic threshold of >60% cumulative predicted chance of implantation.</p><p><strong>Limitations reasons for caution: </strong>This systematic review excluded abstracts and case-series. Several studies provided RIF definitions with limited detail or ambiguous terminology with potential for misclassification or misint
研究问题：在已发表的文献中如何定义复发性植入失败（RIF），这些定义与ESHRE最近引入的RIF标准的预后一致性如何？总结回答：目前临床研究中使用的RIF定义是高度可变的，只有一小部分已发表的RIF研究符合ESHRE RIF诊断阈值。已知情况：RIF是抗逆转录病毒治疗失败的主要原因，也是抗逆转录病毒治疗研究日益关注的焦点。然而，在已发表的文献中，RIF的定义仍然很差且不一致，从而使RIF研究的解释和临床适用性变得困难且存在很大问题。研究设计规模持续时间：系统地检索电子数据库EMBASE （Ovid）、PubMed、Cochrane Central Register Of Controlled Trials （Central）、Scopus和Web Of Science，检索词为“复发性植入失败”和“重复植入失败”，检索到2024年6月30日之前包括RIF患者的同行评审期刊文章。参与者/材料设置方法：从符合条件的全文文章中手动提取以下数据：研究方法和特征、ART特征和使用的RIF定义。提取的RIF定义根据预定的说明符进行分析。这些RIF定义的预后概况与2023年eshre推荐的RIF诊断阈值进行了比较。主要结果及偶然性的作用：文献检索共发现9853项研究，其中748项符合纳入条件。在这748项研究中，589项研究（78.7%）提供了一个RIF定义，83项研究（11.1%）使用了两个定义，3项研究（0.4%）提供了三个或更多定义，73项研究（9.8%）没有提供RIF的定义。在检索到的838个RIF定义中，总共有503个唯一的RIF定义。用于定义RIF的三个最常见的指标是胚胎形态质量（n = 491，占RIF定义的58.6%）、转移事件数（n = 439, 52.4%）和累计移植胚胎数（n = 326, 38.9%）。RIF最常被诊断为“≥3个胚胎移植事件失败”（n = 26）和“≥3个刺激周期失败”（n = 22）。卵裂期胚胎以累计移植胚胎总数定义RIF的阈值明显高于囊胚（发生率比为2.15，P为60%）。局限性：本系统综述排除了摘要和病例系列。一些研究提供的RIF定义细节有限或术语模糊，有可能被错误分类或误解。研究结果的更广泛含义：目前临床研究中使用的RIF定义之间仍然存在高度的可变性和差异。此外，满足ESHRE RIF诊断阈值的研究比例较低，这让人怀疑这些研究中的人群是否真正是RIF患者。因此，应谨慎解读已发表的研究结果。为了使RIF病因学和治疗干预的未来研究具有更广泛的临床适用性，必须仔细实施标准化的RIF定义。研究资金/竞争利益：本研究未寻求或获得特定的外部资金。所有作者均报告本研究无利益冲突。试验注册号：该试验在PROSPERO注册（CRD42022295349）。
{"title":"Variability and implications of recurrent implantation failure definitions used in the scientific literature: a systematic review.","authors":"Jessica K Lu, Yin Jun Law, Ning Zhang, Evangelia T Katsika, Efstratios M Kolibianakis, Christos A Venetis","doi":"10.1093/hropen/hoaf033","DOIUrl":"10.1093/hropen/hoaf033","url":null,"abstract":"<p><strong>Study question: </strong>How is recurrent implantation failure (RIF) defined in published literature and what is the prognostic agreement of these definitions with recently introduced RIF criteria by ESHRE?</p><p><strong>Summary answer: </strong>RIF definitions used in current clinical studies are highly variable and only a low proportion of published studies on RIF meet the ESHRE RIF diagnostic threshold.</p><p><strong>What is known already: </strong>RIF is a key cause of ART failure and growing focus of ART research. However, RIF remains poorly and inconsistently defined in published literature, thereby making the interpretation and clinical applicability of RIF research difficult and highly problematic.</p><p><strong>Study design size duration: </strong>The electronic databases EMBASE (Ovid), PubMed, Cochrane Central Register Of Controlled Trials (CENTRAL), Scopus, and Web of Science were systematically searched up to 30 June 2024 using the search terms 'recurrent implantation failure' and 'repeated implantation failure' for original peer-reviewed journal articles that included RIF patients.</p><p><strong>Participants/materials setting methods: </strong>The following data were manually extracted from eligible full-text articles: study methodology and characteristics, ART characteristics, and the RIF definition used. Extracted RIF definitions were analysed according to predetermined specifiers. The prognostic profile of these RIF definitions was compared with the 2023 ESHRE-recommended threshold for RIF diagnosis.</p><p><strong>Main results and the role of chance: </strong>The literature search identified 9853 studies, of which 748 were eligible for inclusion. Of these 748 studies, 589 studies (78.7%) provided one RIF definition, 83 studies (11.1%) used two definitions, three studies (0.4%) provided three or more definitions while 73 studies (9.8%) did not provide a definition for RIF. Of the 838 RIF definitions retrieved, there were a total of 503 unique RIF definitions. The three most common specifiers used to define RIF were embryo morphological quality (n = 491, 58.6% of RIF definitions), number of transfer events (n = 439, 52.4%), and cumulative number of embryos transferred (n = 326, 38.9%). RIF was most frequently diagnosed as 'failure of ≥3 embryo transfer events' (n = 26) and 'failure of ≥3 stimulated cycles' (n = 22). The threshold for defining RIF based on the cumulative number of embryos transferred in total was significantly higher for cleavage-stage embryos compared to blastocysts (incidence rate ratio 2.15, <i>P</i> < 0.001). In most cases, the RIF definitions used did not meet the ESHRE-recommended RIF diagnostic threshold of >60% cumulative predicted chance of implantation.</p><p><strong>Limitations reasons for caution: </strong>This systematic review excluded abstracts and case-series. Several studies provided RIF definitions with limited detail or ambiguous terminology with potential for misclassification or misint","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf033"},"PeriodicalIF":11.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-18eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf035
Baris Ata
{"title":"Why does the recurrent implantation failure literature need to be rewritten?","authors":"Baris Ata","doi":"10.1093/hropen/hoaf035","DOIUrl":"10.1093/hropen/hoaf035","url":null,"abstract":"","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf035"},"PeriodicalIF":11.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Study question: What are the effects of plasma trace metal element exposure on early embryological outcomes of IVF in couples?
Summary answer: Exposure to plasma trace metal elements before treatment is associated with early embryological outcomes of IVF in couples and both partners, with both harmful and beneficial effects on embryonic development.
What is known already: Trace metal element exposure is one of the strongest determinants of IVF outcomes, but existing studies have certain limitations, such as the limited range of trace metal elements considered, and most have focused only on maternal exposure, overlooking the contribution of paternal exposure. Few studies have explored the association between trace metal elements and early embryological outcomes of IVF from the couples' perspective.
Study design size duration: This couple-based prospective cohort study included a total of 1071 couples who underwent 1369 IVF treatment cycles between December 2020 and August 2023.
Participants/materials setting methods: Plasma concentrations of 21 trace metal elements were measured by an inductively coupled plasma mass spectrometer. Early IVF embryological outcomes included two-pronuclear (2PN) zygote numbers, best-quality embryo numbers, fertilization rates, and blastocyst numbers. Elastic net regression was employed to identify trace metal elements associated with early IVF embryological outcomes in both partners and couples. K-medoids clustering was used to identify the exposure patterns of trace metal elements in couples and both partners. Joint effects of trace metal mixtures were evaluated using quantile-based g-computation (QGC) and group-weighted quantile sum (groupWQS), while independent effects of individual trace metal element were assessed using the generalized linear mixed model.
Main results and the role of chance: In our study, the mean (SD) age was 32.60 (5.22) years for females and 33.79 (5.89) for males. The detection rates for all elements, except for beryllium (Be), exceeded 90%. High exposure to trace metal element mixtures in couples and male partners was associated with decreased numbers of best-quality embryos and blastocysts. Using QGC and groupWQS, we identified both harmful and beneficial metal mixtures that influence successful embryo development. Additionally, specific plasma trace metals such as iron (Fe), lithium (Li), strontium (Sr), and molybdenum (Mo) were positively associated with embryological outcomes, while metals like silver (Ag) and thallium (Tl) had adverse effects.
Limitations reasons for caution: We were limited by assessing plasma trace metal elements at a single time point, focusing only on fresh embryo transfer cycles, and being unable to control for unmeasured confounding factors (e.g. psychological factors and self-reported health conditions). Mor
{"title":"Association between trace metal element concentrations in human blood plasma and early MAR embryological outcomes: a couple-based prospective cohort study.","authors":"Yawen Cao, Shuangshuang Bao, Qianhui Yang, Yaning Sun, Yanlan Tang, Wei Ju, Junjun Liu, Wenbin Fang, Xuemei Wang, Caiyun Wu, Chaojie Li, Peng Zhu, Shanshan Shao, Fangbiao Tao, Guixia Pan","doi":"10.1093/hropen/hoaf034","DOIUrl":"10.1093/hropen/hoaf034","url":null,"abstract":"<p><strong>Study question: </strong>What are the effects of plasma trace metal element exposure on early embryological outcomes of IVF in couples?</p><p><strong>Summary answer: </strong>Exposure to plasma trace metal elements before treatment is associated with early embryological outcomes of IVF in couples and both partners, with both harmful and beneficial effects on embryonic development.</p><p><strong>What is known already: </strong>Trace metal element exposure is one of the strongest determinants of IVF outcomes, but existing studies have certain limitations, such as the limited range of trace metal elements considered, and most have focused only on maternal exposure, overlooking the contribution of paternal exposure. Few studies have explored the association between trace metal elements and early embryological outcomes of IVF from the couples' perspective.</p><p><strong>Study design size duration: </strong>This couple-based prospective cohort study included a total of 1071 couples who underwent 1369 IVF treatment cycles between December 2020 and August 2023.</p><p><strong>Participants/materials setting methods: </strong>Plasma concentrations of 21 trace metal elements were measured by an inductively coupled plasma mass spectrometer. Early IVF embryological outcomes included two-pronuclear (2PN) zygote numbers, best-quality embryo numbers, fertilization rates, and blastocyst numbers. Elastic net regression was employed to identify trace metal elements associated with early IVF embryological outcomes in both partners and couples. K-medoids clustering was used to identify the exposure patterns of trace metal elements in couples and both partners. Joint effects of trace metal mixtures were evaluated using quantile-based g-computation (QGC) and group-weighted quantile sum (groupWQS), while independent effects of individual trace metal element were assessed using the generalized linear mixed model.</p><p><strong>Main results and the role of chance: </strong>In our study, the mean (SD) age was 32.60 (5.22) years for females and 33.79 (5.89) for males. The detection rates for all elements, except for beryllium (Be), exceeded 90%. High exposure to trace metal element mixtures in couples and male partners was associated with decreased numbers of best-quality embryos and blastocysts. Using QGC and groupWQS, we identified both harmful and beneficial metal mixtures that influence successful embryo development. Additionally, specific plasma trace metals such as iron (Fe), lithium (Li), strontium (Sr), and molybdenum (Mo) were positively associated with embryological outcomes, while metals like silver (Ag) and thallium (Tl) had adverse effects.</p><p><strong>Limitations reasons for caution: </strong>We were limited by assessing plasma trace metal elements at a single time point, focusing only on fresh embryo transfer cycles, and being unable to control for unmeasured confounding factors (e.g. psychological factors and self-reported health conditions). Mor","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf034"},"PeriodicalIF":11.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12311266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-03eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf029
[This corrects the article DOI: 10.1093/hropen/hoae072.].
[这更正了文章DOI: 10.1093/hropen/hoae072。]
{"title":"Correction to: Birth defects reporting and the use of dydrogesterone: a disproportionality analysis from the World Health Organization pharmacovigilance database (VigiBase).","authors":"","doi":"10.1093/hropen/hoaf029","DOIUrl":"https://doi.org/10.1093/hropen/hoaf029","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1093/hropen/hoae072.].</p>","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 2","pages":"hoaf029"},"PeriodicalIF":8.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12132097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-26eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf030
Emre Pabuccu, Angela Aguilar, Roberto de Azevedo Antunes, Eran Gefen, Lee P Shulman
{"title":"Why does the latest pharmacovigilance data not reflect clinical experience with dydrogesterone?","authors":"Emre Pabuccu, Angela Aguilar, Roberto de Azevedo Antunes, Eran Gefen, Lee P Shulman","doi":"10.1093/hropen/hoaf030","DOIUrl":"10.1093/hropen/hoaf030","url":null,"abstract":"","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf030"},"PeriodicalIF":8.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12151318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-21eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf031
Laurent Chouchana, Alexandra Henry, Mathilde Bourdon, Chloé Maignien, Charles Chapron, Jean-Marc Treluyer, Jean Guibourdenche, Pietro Santulli
{"title":"Reply: Fetal safety of dydrogesterone: clarifying the role of pharmacovigilance.","authors":"Laurent Chouchana, Alexandra Henry, Mathilde Bourdon, Chloé Maignien, Charles Chapron, Jean-Marc Treluyer, Jean Guibourdenche, Pietro Santulli","doi":"10.1093/hropen/hoaf031","DOIUrl":"10.1093/hropen/hoaf031","url":null,"abstract":"","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf031"},"PeriodicalIF":8.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12151319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-15eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoaf028
Jichan Nie, Yunhua Yi, Xishi Liu, Sun-Wei Guo
<p><strong>Study question: </strong>Do all ectopic endometrial lesions (endometriosis and adenomyosis) universally have activated estrogen signaling?</p><p><strong>Summary answer: </strong>Estrogen signaling diminishes concordantly with increased fibrosis in ectopic endometrium, with deep endometriotic (DE) lesions exhibiting an estrogen biosynthesis capability and estrogen receptor β (ERβ) expression level comparable to that of control endometrium but having suppressed ERα.</p><p><strong>What is known already: </strong>Endometriosis and adenomyosis are both estrogen-dependent diseases driven by estrogen-mediated lesional development, progression, and symptom manifestation. Of note, ectopic endometrium is thought to have the ability to synthesize estradiol (E<sub>2</sub>) <i>in situ</i> from cholesterol due to upregulation of aromatase (CYP19A1), steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase type 2 (HSD3β2), and HSD17β1. In addition to increased estrogen biosynthesis, ERβ and G-protein coupled ER (GPER) are also overexpressed in ectopic endometrium. In particular, the prevailing view holds that prostaglandin E2 plays a vital role in facilitating estrogen biosynthesis and the upregulation of ERβ, positioning itself in the central nexus in a feed-forward loop linking hyperestrogenism and inflammation in all ectopic endometria.</p><p><strong>Study design size duration: </strong>After obtaining written informed consent, we collected lesional tissues from 19 patients with ovarian endometriosis (OE) and 20 patients each with adenomyosis (AD) and DE. As controls, normal endometrial tissue samples (CT) were procured from 20 cycling women free of endometriosis and adenomyosis, and age- and menstrual phase-matched with patients in the other groups. Additionally, primary ectopic or control endometrial stromal cells derived from eight subjects in each of the OE, AD, DE, and CT groups were cultured for experiments.</p><p><strong>Participants/materials setting methods: </strong>We performed immunohistochemistry and western blotting to assess the expression of proteins key to the estrogen biosynthesis (StAR, HSD3β2, aromatase, and HSD17β1) and estrogen receptors (ERα, ERβ, and GPER). Fibrosis was quantified via Masson trichrome staining. Real-time RT-PCR was performed to assess corresponding gene expression levels. The estrogen concentrations in cell cultures of primary stromal cells derived from different tissues were also measured by ELISA.</p><p><strong>Main results and the role of chance: </strong>Among all ectopic endometrial tissue samples, the extent of lesional fibrosis was the highest in the DE lesions, followed by the AD and then the OE lesions. The protein and gene expression levels of StAR, HSD3β2, aromatase, and HSD17β1, the four proteins critically involved in estrogen biosynthesis, were significantly higher than in the CT group in OE and AD lesions, but were lowest in DE lesions, which were comparable to that of c
{"title":"Progressively diminished estrogen signaling concordant with increased fibrosis in ectopic endometrium.","authors":"Jichan Nie, Yunhua Yi, Xishi Liu, Sun-Wei Guo","doi":"10.1093/hropen/hoaf028","DOIUrl":"10.1093/hropen/hoaf028","url":null,"abstract":"<p><strong>Study question: </strong>Do all ectopic endometrial lesions (endometriosis and adenomyosis) universally have activated estrogen signaling?</p><p><strong>Summary answer: </strong>Estrogen signaling diminishes concordantly with increased fibrosis in ectopic endometrium, with deep endometriotic (DE) lesions exhibiting an estrogen biosynthesis capability and estrogen receptor β (ERβ) expression level comparable to that of control endometrium but having suppressed ERα.</p><p><strong>What is known already: </strong>Endometriosis and adenomyosis are both estrogen-dependent diseases driven by estrogen-mediated lesional development, progression, and symptom manifestation. Of note, ectopic endometrium is thought to have the ability to synthesize estradiol (E<sub>2</sub>) <i>in situ</i> from cholesterol due to upregulation of aromatase (CYP19A1), steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase type 2 (HSD3β2), and HSD17β1. In addition to increased estrogen biosynthesis, ERβ and G-protein coupled ER (GPER) are also overexpressed in ectopic endometrium. In particular, the prevailing view holds that prostaglandin E2 plays a vital role in facilitating estrogen biosynthesis and the upregulation of ERβ, positioning itself in the central nexus in a feed-forward loop linking hyperestrogenism and inflammation in all ectopic endometria.</p><p><strong>Study design size duration: </strong>After obtaining written informed consent, we collected lesional tissues from 19 patients with ovarian endometriosis (OE) and 20 patients each with adenomyosis (AD) and DE. As controls, normal endometrial tissue samples (CT) were procured from 20 cycling women free of endometriosis and adenomyosis, and age- and menstrual phase-matched with patients in the other groups. Additionally, primary ectopic or control endometrial stromal cells derived from eight subjects in each of the OE, AD, DE, and CT groups were cultured for experiments.</p><p><strong>Participants/materials setting methods: </strong>We performed immunohistochemistry and western blotting to assess the expression of proteins key to the estrogen biosynthesis (StAR, HSD3β2, aromatase, and HSD17β1) and estrogen receptors (ERα, ERβ, and GPER). Fibrosis was quantified via Masson trichrome staining. Real-time RT-PCR was performed to assess corresponding gene expression levels. The estrogen concentrations in cell cultures of primary stromal cells derived from different tissues were also measured by ELISA.</p><p><strong>Main results and the role of chance: </strong>Among all ectopic endometrial tissue samples, the extent of lesional fibrosis was the highest in the DE lesions, followed by the AD and then the OE lesions. The protein and gene expression levels of StAR, HSD3β2, aromatase, and HSD17β1, the four proteins critically involved in estrogen biosynthesis, were significantly higher than in the CT group in OE and AD lesions, but were lowest in DE lesions, which were comparable to that of c","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf028"},"PeriodicalIF":8.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12165729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144303844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><strong>Study question: </strong>What are the molecular mechanisms underlying hypoxia-induced male reproductive impairment?</p><p><strong>Summary answer: </strong>Hypoxia compromises Septin2 (<i>Sept2</i>) transcription in spermatogonia, which impedes spermatogonial proliferation through protein phosphatase 2A (PP2A)-dependent AKT dephosphorylation.</p><p><strong>What is known already: </strong>Hypoxia is associated with impaired spermatogenesis and poor sperm parameters in men. Spermatogonia proliferation, a crucial early step in spermatogenesis, is essential for maintaining the spermatogenic cell population and ensuring sperm quality. However, the connection between hypoxia and spermatogonial proliferation remains poorly understood, and treatment options for hypoxia-related reproductive disorders are limited.</p><p><strong>Study design size duration: </strong>A cross-sectional study analyzed semen samples from 24 high-altitude (HA) residents, 6 pathological hypoxia (PH) patients, and 19 healthy controls to evaluate hypoxia-associated sperm parameter alterations. Complementary animal studies employing a hypobaric chamber-induced hypoxic mouse model (n = 5) confirmed reproductive impairments through assessment of birth rates, sperm quality, and testicular histopathology. Transcriptomic profiling of hypoxic versus normoxic mouse testes (n = 3/group) identified spermatogonial proliferation defects as a predominant pathological feature and pinpointed <i>Sept2</i> as a candidate mediator. Subsequent mechanistic investigations employed <i>in vitro</i> hypoxic culture of spermatogonial cell lines under hypoxic conditions coupled with pharmacological modulation of PP2A activity in mice (n = 3-5 per intervention group) to delineate the underlying molecular pathways.</p><p><strong>Participants/materials setting methods: </strong>Semen parameters were evaluated using computer-assisted sperm analysis (CASA; for sperm concentration, count, and motility), morphological staining (Pap staining for sperm deformity), and eosin-nigrosin staining (for sperm viability). In the hypoxic mouse model, fertility outcomes were assessed through fertility assessment (mating experiments), sperm parameters (CASA), testicular histology (H&E staining), and spermatogonia proliferation (immunohistochemistry and qPCR). In hypoxic spermatogonial cell models, cell proliferation was detected using CCK-8, EdU incorporation, flow cytometry, and western blotting. <i>Sept2</i> manipulation (knockdown/overexpression), followed by mechanistic analyses (dual-luciferase reporter assay, DNA pulldown/mass spectrometry, TMT-based quantitative proteomics, co-immunoprecipitation, etc.), was performed to investigate the mechanism underlying hypoxia-regulated spermatogonia proliferation. The SEPT2 inhibitor forchlorfenuron (FCF), the PP2A agonists celastrol, erlotinib, and FTY720, as well as PP2A inhibitor okadaic acid (OA) were used to investigate the role of the SEPT2-PP2A-AKT axis in male fer
{"title":"Hypoxia exposure impairs male fertility via inhibiting Septin2-mediated spermatogonial proliferation.","authors":"Zhibin Li, Shuying Li, Yufeng Xiao, Junfeng Guo, Jianchun Zhou, Yang Chen, Juan Yang, Chunli Gong, Bing He, Yuyun Wu, Nannan Gao, Huan Yang, Limin Gao, Hua Hu, Yunfang Zhang, Shiming Yang","doi":"10.1093/hropen/hoaf027","DOIUrl":"10.1093/hropen/hoaf027","url":null,"abstract":"<p><strong>Study question: </strong>What are the molecular mechanisms underlying hypoxia-induced male reproductive impairment?</p><p><strong>Summary answer: </strong>Hypoxia compromises Septin2 (<i>Sept2</i>) transcription in spermatogonia, which impedes spermatogonial proliferation through protein phosphatase 2A (PP2A)-dependent AKT dephosphorylation.</p><p><strong>What is known already: </strong>Hypoxia is associated with impaired spermatogenesis and poor sperm parameters in men. Spermatogonia proliferation, a crucial early step in spermatogenesis, is essential for maintaining the spermatogenic cell population and ensuring sperm quality. However, the connection between hypoxia and spermatogonial proliferation remains poorly understood, and treatment options for hypoxia-related reproductive disorders are limited.</p><p><strong>Study design size duration: </strong>A cross-sectional study analyzed semen samples from 24 high-altitude (HA) residents, 6 pathological hypoxia (PH) patients, and 19 healthy controls to evaluate hypoxia-associated sperm parameter alterations. Complementary animal studies employing a hypobaric chamber-induced hypoxic mouse model (n = 5) confirmed reproductive impairments through assessment of birth rates, sperm quality, and testicular histopathology. Transcriptomic profiling of hypoxic versus normoxic mouse testes (n = 3/group) identified spermatogonial proliferation defects as a predominant pathological feature and pinpointed <i>Sept2</i> as a candidate mediator. Subsequent mechanistic investigations employed <i>in vitro</i> hypoxic culture of spermatogonial cell lines under hypoxic conditions coupled with pharmacological modulation of PP2A activity in mice (n = 3-5 per intervention group) to delineate the underlying molecular pathways.</p><p><strong>Participants/materials setting methods: </strong>Semen parameters were evaluated using computer-assisted sperm analysis (CASA; for sperm concentration, count, and motility), morphological staining (Pap staining for sperm deformity), and eosin-nigrosin staining (for sperm viability). In the hypoxic mouse model, fertility outcomes were assessed through fertility assessment (mating experiments), sperm parameters (CASA), testicular histology (H&E staining), and spermatogonia proliferation (immunohistochemistry and qPCR). In hypoxic spermatogonial cell models, cell proliferation was detected using CCK-8, EdU incorporation, flow cytometry, and western blotting. <i>Sept2</i> manipulation (knockdown/overexpression), followed by mechanistic analyses (dual-luciferase reporter assay, DNA pulldown/mass spectrometry, TMT-based quantitative proteomics, co-immunoprecipitation, etc.), was performed to investigate the mechanism underlying hypoxia-regulated spermatogonia proliferation. The SEPT2 inhibitor forchlorfenuron (FCF), the PP2A agonists celastrol, erlotinib, and FTY720, as well as PP2A inhibitor okadaic acid (OA) were used to investigate the role of the SEPT2-PP2A-AKT axis in male fer","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 3","pages":"hoaf027"},"PeriodicalIF":8.3,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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