Lingjin Xia, Jiami Huang, Qi Che, Jian Zhang, Zhaofeng Zhang, Yupei Shen, Difei Wang, Yushun Zhong, Suying Liu, Jing Du
<p><strong>Study question: </strong>Can novel genetic factors contributing to early embryonic arrest in infertile patients be identified, along with the underlying mechanisms of the pathogenic variant?</p><p><strong>Summary answer: </strong>We identified a heterozygous variant in the SPRY4 (sprouty RTK signaling antagonist 4) in infertile patients and conducted in vitro and in vivo studies to investigate the effects of the variant/deletion, highlighting its critical role in female reproductive health.</p><p><strong>What is known already: </strong>SPRY4 acts as a negative regulator of receptor tyrosine kinases (RTKs) and functions as a tumor suppressor. Its abnormal expression can lead to recurrent miscarriage by affecting trophoblast function. In mice, Spry4 knockout (KO) leads to craniofacial anomalies and growth defects. A human study links the SPRY4 variant to a male patient with isolated hypogonadotropic hypogonadism (IHH), hypothetically impacting gonadotropin-releasing hormone (GnRH) neurons, and causing reproductive dysfunctions. SPRY4 is thus potentially integral in regulating endocrine homeostasis and reproductive function. To date, no study has reported SPRY4 variants associated with female fertility, and a causal relationship has not been established with functional evidence.</p><p><strong>Study design, size, duration: </strong>Whole-exome sequencing (WES) was performed in 392 infertile women who suffered from primary infertility of unknown reason, and the heterozygous SPRY4 variant were identified in one independent family. The infertile patients presenting were recruited from July 2017 to November 2023.</p><p><strong>Participants/materials, setting, methods: </strong>Women diagnosed with primary infertility were recruited from the Reproduction Center of Zhongshan Hospital, Fudan University. Genomic DNA was extracted from peripheral blood for WES analysis. The SPRY4 variant were identified through WES, in silico analysis, and variant screening. All variants were confirmed by Sanger sequencing. The effects of the variants were investigated in human embryonic kidney (HEK) 293T (HEK293T) cells via western blotting, and in mouse oocytes and embryos through complementary RNA (cRNA) injection, RNA sequencing, fluorescence, absorbance, and RT-qPCR assays. Gene function was further examined in Spry4 KO mice via histology, western blotting, ELISA, and RT-qPCR assays.</p><p><strong>Main results and the role of chance: </strong>We identified a missense heterozygous pathogenic variant in SPRY4 (GRCh38, GenBank: NM_030964.5, c.157C>T p.(Arg53Trp), rs200531302) that reduces SPRY4 protein levels in HEK293T cells and disrupts the redox system and mitochondrial function in mouse oocyte, and perturbs developmental potential in mouse embryos. These phenotypes could be partially reversed by the exogenous addition of Nrf1 cRNA. Additionally, Spry4-/- mice exhibit ovarian oxidative stress and decreased ovarian function.</p><p><strong>Limitations, reasons f
{"title":"A heterozygous SPRY4 variant identified in female infertility characterized by reduced oocyte potential and early embryonic arrest.","authors":"Lingjin Xia, Jiami Huang, Qi Che, Jian Zhang, Zhaofeng Zhang, Yupei Shen, Difei Wang, Yushun Zhong, Suying Liu, Jing Du","doi":"10.1093/humrep/deae231","DOIUrl":"10.1093/humrep/deae231","url":null,"abstract":"<p><strong>Study question: </strong>Can novel genetic factors contributing to early embryonic arrest in infertile patients be identified, along with the underlying mechanisms of the pathogenic variant?</p><p><strong>Summary answer: </strong>We identified a heterozygous variant in the SPRY4 (sprouty RTK signaling antagonist 4) in infertile patients and conducted in vitro and in vivo studies to investigate the effects of the variant/deletion, highlighting its critical role in female reproductive health.</p><p><strong>What is known already: </strong>SPRY4 acts as a negative regulator of receptor tyrosine kinases (RTKs) and functions as a tumor suppressor. Its abnormal expression can lead to recurrent miscarriage by affecting trophoblast function. In mice, Spry4 knockout (KO) leads to craniofacial anomalies and growth defects. A human study links the SPRY4 variant to a male patient with isolated hypogonadotropic hypogonadism (IHH), hypothetically impacting gonadotropin-releasing hormone (GnRH) neurons, and causing reproductive dysfunctions. SPRY4 is thus potentially integral in regulating endocrine homeostasis and reproductive function. To date, no study has reported SPRY4 variants associated with female fertility, and a causal relationship has not been established with functional evidence.</p><p><strong>Study design, size, duration: </strong>Whole-exome sequencing (WES) was performed in 392 infertile women who suffered from primary infertility of unknown reason, and the heterozygous SPRY4 variant were identified in one independent family. The infertile patients presenting were recruited from July 2017 to November 2023.</p><p><strong>Participants/materials, setting, methods: </strong>Women diagnosed with primary infertility were recruited from the Reproduction Center of Zhongshan Hospital, Fudan University. Genomic DNA was extracted from peripheral blood for WES analysis. The SPRY4 variant were identified through WES, in silico analysis, and variant screening. All variants were confirmed by Sanger sequencing. The effects of the variants were investigated in human embryonic kidney (HEK) 293T (HEK293T) cells via western blotting, and in mouse oocytes and embryos through complementary RNA (cRNA) injection, RNA sequencing, fluorescence, absorbance, and RT-qPCR assays. Gene function was further examined in Spry4 KO mice via histology, western blotting, ELISA, and RT-qPCR assays.</p><p><strong>Main results and the role of chance: </strong>We identified a missense heterozygous pathogenic variant in SPRY4 (GRCh38, GenBank: NM_030964.5, c.157C>T p.(Arg53Trp), rs200531302) that reduces SPRY4 protein levels in HEK293T cells and disrupts the redox system and mitochondrial function in mouse oocyte, and perturbs developmental potential in mouse embryos. These phenotypes could be partially reversed by the exogenous addition of Nrf1 cRNA. Additionally, Spry4-/- mice exhibit ovarian oxidative stress and decreased ovarian function.</p><p><strong>Limitations, reasons f","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345716","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}
Guido Pennings, Wybo Dondorp, Mina Popovic, Susana Chuva de Sousa Lopes, Heidi Mertes
The current article provides an ethical reflection on the moral status of the human embryo, which is a crucial factor in determining permissible actions involving embryos and the extent of their protection. It advocates for the extension of the research period for embryos to 28-days post fertilization. It also states that integrated embryo-like structures (ELSs) should not currently be given the same moral status as natural embryos. However, if they pass the relevant tests, they should be subject to the same rules as natural embryos.
{"title":"Ethical considerations on the moral status of the embryo and embryo-like structures†.","authors":"Guido Pennings, Wybo Dondorp, Mina Popovic, Susana Chuva de Sousa Lopes, Heidi Mertes","doi":"10.1093/humrep/deae228","DOIUrl":"10.1093/humrep/deae228","url":null,"abstract":"<p><p>The current article provides an ethical reflection on the moral status of the human embryo, which is a crucial factor in determining permissible actions involving embryos and the extent of their protection. It advocates for the extension of the research period for embryos to 28-days post fertilization. It also states that integrated embryo-like structures (ELSs) should not currently be given the same moral status as natural embryos. However, if they pass the relevant tests, they should be subject to the same rules as natural embryos.</p>","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M Elena Ter Welle-Butalid, Josien G Derhaag, Bo E van Bree, Ingeborg J H Vriens, Mariëtte Goddijn, Eva M E Balkenende, Catharina C M Beerendonk, Anna M E Bos, Irene Homminga, Sofie H Benneheij, H C van Os, Jesper M J Smeenk, Marieke O Verhoeven, Casandra C A W van Bavel, Vivianne C G Tjan-Heijnen, Ron J T van Golde
<p><strong>Study question: </strong>What are the reproductive outcomes of patients who cryopreserved oocytes or embryos in the context of fertility preservation in the Netherlands?</p><p><strong>Summary answer: </strong>This study shows that after a 10-year follow-up period, the utilization rate to attempt pregnancy using cryopreserved oocytes or embryos was 25.5% and the cumulative live birth rate after embryo transfer was 34.6% per patient.</p><p><strong>What is known already: </strong>Fertility preservation by freezing oocytes or embryos is an established treatment for women with a risk of premature ovarian failure (caused by a benign or oncological disease) or physiological age-related fertility decline. Little is known about the success of cryopreservation, the utilization rate of oocytes or embryos, or the live birth rates.</p><p><strong>Study design, size, duration: </strong>A retrospective observational study was performed in the Netherlands. Data were collected between 2017 and 2019 from 1112 women who cryopreserved oocytes or embryos more than 2 years ago in the context of fertility preservation in 10 IVF centers in the Netherlands.</p><p><strong>Participants/materials, setting, methods: </strong>A total of 1112 women were included in this study. Medical files and patient databases were used to extract data. Women were categorized based on indication of fertility preservation: oncological, benign, or non-medical. To indicate statistical differences the t-test or Mann-Whitney U test was used. Kaplan-Meier analyses were used for time endpoints, and log-rank analyses were used to assess statistical differences. The study protocol was approved by the medical ethics committee.</p><p><strong>Main results and the role of chance: </strong>Fertility preservation cycles have been performed increasingly over the years in the Netherlands. In the first years, less than 10 cycles per year were performed, increasing to more than 300 cycles per year 10 years later. Initially, embryos were frozen in the context of fertility preservation. In later years, cryopreservation of oocytes became the standard approach. Cryopreservation of oocytes versus embryos resulted in comparable numbers of used embryos (median of 2) for transfer and comparable live birth rates (33.9% and 34.6%, respectively). The 5-year utilization rate was 12.3% and the 10-year utilization rate was 25.5%. The cumulative clinical pregnancy rate was 35.6% and the cumulative live birth rate was 34.6% per patient. Those who had fertility preservation due to benign diseases returned earlier to use their cryopreserved embryos or oocytes.</p><p><strong>Limitations, reasons for caution: </strong>The follow-up period after the fertility preservation procedure varied between patients in this study and not all frozen oocytes or embryos had been used at the end of this study. This might have led to underestimated outcomes reported in this study. Furthermore, intention to treat cannot be fully determin
研究问题：在荷兰，冷冻保存卵母细胞或胚胎的患者的生育结果如何？这项研究表明，经过 10 年的随访，使用冷冻保存的卵母细胞或胚胎尝试怀孕的利用率为 25.5%，胚胎移植后每位患者的累计活产率为 34.6%：通过冷冻卵母细胞或胚胎来保存生育能力是一种成熟的治疗方法，适用于有卵巢早衰风险（由良性疾病或肿瘤引起）或与年龄有关的生理性生育能力下降的妇女。人们对冷冻保存的成功率、卵母细胞或胚胎的利用率或活产率知之甚少：在荷兰进行了一项回顾性观察研究。数据收集于2017年至2019年期间，来自荷兰10家试管婴儿中心的1112名女性，她们在2年多前的生育力保存背景下冷冻了卵母细胞或胚胎：本研究共纳入了 1112 名女性。研究使用医疗档案和患者数据库提取数据。根据保留生育能力的指征对妇女进行分类：肿瘤、良性或非医学指征。统计差异采用 t 检验或 Mann-Whitney U 检验。时间终点采用卡普兰-梅耶分析法，统计差异采用对数秩分析法。研究方案已获医学伦理委员会批准：多年来，荷兰的生育力保存周期越来越多。最初，每年进行的周期不到 10 个，10 年后增加到每年 300 多个。最初，胚胎冷冻是在生育力保存的背景下进行的。后来，冷冻保存卵母细胞成为标准方法。冷冻保存卵母细胞和胚胎的结果是，用于移植的胚胎数量相当（中位数为 2 个），活产率相当（分别为 33.9% 和 34.6%）。5 年使用率为 12.3%，10 年使用率为 25.5%。每位患者的累计临床妊娠率为 35.6%，累计活产率为 34.6%。因良性疾病而进行生育力保存的患者较早返回使用其冷冻保存的胚胎或卵细胞：本研究中，不同患者接受生育力保存术后的随访时间各不相同，而且在本研究结束时，并非所有冷冻卵母细胞或胚胎都已使用。这可能导致本研究中报告的结果被低估。此外，由于本研究中未包括开始生育力保存程序但未成功（因反应低而取消）的妇女，因此无法完全确定治疗意向：本研究提供了各种生育力保存适应症后的生殖结果数据。这些知识可为专业人士和未来的患者提供参考，以改善在保留生育力的情况下有关卵巢刺激的咨询和知情决策：本研究未获得任何资助。作者不存在与本研究相关的利益冲突。V.T.H. 从阿斯利康（AstraZeneca）、吉利德（Gilead）、诺华（Novartis）、礼来（Eli Lily）、辉瑞（Pfizer）和第一三共（Daiichi Sankyo）那里获得了资助，用于本研究之外的研究。V.T.H.从 Eli Lily 公司获得了本次研究之外的咨询费。M.G.从加柏公司（Guerbet）和菲林公司（Ferring）获得了本研究之外的研究补助金。E.M.E.B.接受了荷兰生育力保护网络（The Dutch Network of Fertility Preservation）的资助，用于本研究之外的一项研究：不详。
{"title":"Outcomes of female fertility preservation with cryopreservation of oocytes or embryos in the Netherlands: a population-based study.","authors":"M Elena Ter Welle-Butalid, Josien G Derhaag, Bo E van Bree, Ingeborg J H Vriens, Mariëtte Goddijn, Eva M E Balkenende, Catharina C M Beerendonk, Anna M E Bos, Irene Homminga, Sofie H Benneheij, H C van Os, Jesper M J Smeenk, Marieke O Verhoeven, Casandra C A W van Bavel, Vivianne C G Tjan-Heijnen, Ron J T van Golde","doi":"10.1093/humrep/deae243","DOIUrl":"https://doi.org/10.1093/humrep/deae243","url":null,"abstract":"<p><strong>Study question: </strong>What are the reproductive outcomes of patients who cryopreserved oocytes or embryos in the context of fertility preservation in the Netherlands?</p><p><strong>Summary answer: </strong>This study shows that after a 10-year follow-up period, the utilization rate to attempt pregnancy using cryopreserved oocytes or embryos was 25.5% and the cumulative live birth rate after embryo transfer was 34.6% per patient.</p><p><strong>What is known already: </strong>Fertility preservation by freezing oocytes or embryos is an established treatment for women with a risk of premature ovarian failure (caused by a benign or oncological disease) or physiological age-related fertility decline. Little is known about the success of cryopreservation, the utilization rate of oocytes or embryos, or the live birth rates.</p><p><strong>Study design, size, duration: </strong>A retrospective observational study was performed in the Netherlands. Data were collected between 2017 and 2019 from 1112 women who cryopreserved oocytes or embryos more than 2 years ago in the context of fertility preservation in 10 IVF centers in the Netherlands.</p><p><strong>Participants/materials, setting, methods: </strong>A total of 1112 women were included in this study. Medical files and patient databases were used to extract data. Women were categorized based on indication of fertility preservation: oncological, benign, or non-medical. To indicate statistical differences the t-test or Mann-Whitney U test was used. Kaplan-Meier analyses were used for time endpoints, and log-rank analyses were used to assess statistical differences. The study protocol was approved by the medical ethics committee.</p><p><strong>Main results and the role of chance: </strong>Fertility preservation cycles have been performed increasingly over the years in the Netherlands. In the first years, less than 10 cycles per year were performed, increasing to more than 300 cycles per year 10 years later. Initially, embryos were frozen in the context of fertility preservation. In later years, cryopreservation of oocytes became the standard approach. Cryopreservation of oocytes versus embryos resulted in comparable numbers of used embryos (median of 2) for transfer and comparable live birth rates (33.9% and 34.6%, respectively). The 5-year utilization rate was 12.3% and the 10-year utilization rate was 25.5%. The cumulative clinical pregnancy rate was 35.6% and the cumulative live birth rate was 34.6% per patient. Those who had fertility preservation due to benign diseases returned earlier to use their cryopreserved embryos or oocytes.</p><p><strong>Limitations, reasons for caution: </strong>The follow-up period after the fertility preservation procedure varied between patients in this study and not all frozen oocytes or embryos had been used at the end of this study. This might have led to underestimated outcomes reported in this study. Furthermore, intention to treat cannot be fully determin","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545091","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}
Ruiqiong Zhou, Zhenghong Zhu, Mei Dong, Zhaoyi Wang, Li Huang, Songlu Wang, Xiqian Zhang, Fenghua Liu
<p><strong>Study question: </strong>Are serum vitamin D levels associated with the incidence of endometrial polyps (EPs) in infertile patients?</p><p><strong>Summary answer: </strong>Serum 25(OH)D levels were nonlinearly correlated with the incidence of EPs in infertile women.</p><p><strong>What is known already: </strong>EPs are a common condition that may affect the receptivity of the endometrium in women of reproductive age. Vitamin D regulates cell proliferation and differentiation, apoptosis, angiogenesis, anti-inflammation, and immunomodulation, in addition to its well-known functions in balancing calcium and phosphorus. Previous studies have shown that vitamin D concentrations are associated with reproductive outcomes, and that low vitamin D levels are associated with the incidence of colorectal polyps and nasal polyps. There is little evidence regarding the relationship between EPs and serum vitamin D levels.</p><p><strong>Study design, size, duration: </strong>We conducted a cross-sectional study using data from Guangdong Women and Children Hospital from January 2019 to October 2023, enrolling 3107 patients.</p><p><strong>Participants/materials, setting, methods: </strong>A total of 3107 infertile patients who underwent hysteroscopy were included in this study; 642 patients had endometrial polyps and 2465 had a normal uterine cavity. Hysteroscopy findings included risk of EPs, polyp size, percentage of multiple polyps, and incidence of chronic endometritis (CE). Serum vitamin D were assessed by measuring total 25(OH)D using chemiluminescence. According to international guideline recommendations for vitamin D deficiency, patients were divided into two groups: the <50 nmol/l group and the ≥50 nmol/l group. Univariable and multivariable logistic regression models, stratified analyses, and smooth curve fitting were used to examine the relationship between serum 25(OH)D levels and risk of EPs.</p><p><strong>Main results and the role of chance: </strong>Of all patients, 23.8% (740/3107) were vitamin D deficient (<50 nmol/l). The incidence of EPs was significantly higher in the 25(OH)D < 50 nmol/l group than in the ≥50 nmol/l group (24.9% vs 19.3%; P = 0.001). However, there were no differences in polyp size, proportion of multiple polyps, and presence of CE between the two groups. After controlling for confounders, 25(OH)D ≥ 50 nmol/l (compared with <50 nmol/l) was negatively associated with risk of EPs (adjusted OR, 0.733; 95% CI, 0.598-0.898). Other variables that had an impact on polyp incidence included BMI, type of infertility, CA125, and CD138-positive plasma cells. In addition, a linear regression model between age and serum 25(OH)D levels showed a positive linear association. Subgroup analyses were performed for different age groups, and the risk of EPs was significantly higher in the 25(OH)D < 50 nmol/l group than in the ≥50 nmol/l group, both in the younger subgroup (23.8% vs 19.1%) and in the older subgroup (28.0% vs 19.9%). The smo
研究问题：血清维生素D水平与不孕患者子宫内膜息肉（EPs）的发病率是否相关？血清25（OH）D水平与不孕妇女子宫内膜息肉的发病率呈非线性相关：EPs是一种可能影响育龄妇女子宫内膜接受能力的常见疾病。维生素 D 除了众所周知的平衡钙和磷的功能外，还能调节细胞增殖和分化、细胞凋亡、血管生成、抗炎和免疫调节。以往的研究表明，维生素 D 浓度与生殖结果有关，维生素 D 水平低与结肠直肠息肉和鼻息肉的发病率有关。有关 EPs 与血清维生素 D 水平之间关系的证据很少：我们利用广东省妇女儿童医院2019年1月至2023年10月的数据进行了一项横断面研究，共纳入3107名患者：本研究共纳入3107例接受宫腔镜检查的不孕患者，其中642例患者患有子宫内膜息肉，2465例患者宫腔正常。宫腔镜检查结果包括EPs风险、息肉大小、多发性息肉比例和慢性子宫内膜炎（CE）发病率。血清维生素 D 通过化学发光法测定总 25(OH)D 进行评估。根据维生素 D 缺乏的国际指南建议，将患者分为两组：主要结果组和偶然作用组：在所有患者中，23.8%（740/3107）的患者缺乏维生素 D（局限性、需谨慎的原因：在解释我们的研究结果时应谨慎，因为这是一项相关性研究，不能从我们的结果中推断因果关系。此外，由于有严格的纳入和排除标准，我们的结果可能无法推广到未选择的人群，包括绝经前妇女或其他种族的妇女：这项研究首次证明，维生素 D 缺乏是不孕患者发生 EPs 的一个独立风险因素。确定可改变的风险因素（如维生素 D 缺乏）有助于制定治疗息肉或防止息肉发展的新策略。需要进一步开展临床干预试验和实验室研究，以评估维生素D对EP发展的影响并阐明其机制：本研究由国家自然科学基金（82101718）和广东省自然科学基金（2022A1515010776）资助。本研究不涉及任何利益冲突。试验注册号：不适用。
{"title":"Nonlinear correlation between serum vitamin D levels and the incidence of endometrial polyps in infertile women.","authors":"Ruiqiong Zhou, Zhenghong Zhu, Mei Dong, Zhaoyi Wang, Li Huang, Songlu Wang, Xiqian Zhang, Fenghua Liu","doi":"10.1093/humrep/deae241","DOIUrl":"10.1093/humrep/deae241","url":null,"abstract":"<p><strong>Study question: </strong>Are serum vitamin D levels associated with the incidence of endometrial polyps (EPs) in infertile patients?</p><p><strong>Summary answer: </strong>Serum 25(OH)D levels were nonlinearly correlated with the incidence of EPs in infertile women.</p><p><strong>What is known already: </strong>EPs are a common condition that may affect the receptivity of the endometrium in women of reproductive age. Vitamin D regulates cell proliferation and differentiation, apoptosis, angiogenesis, anti-inflammation, and immunomodulation, in addition to its well-known functions in balancing calcium and phosphorus. Previous studies have shown that vitamin D concentrations are associated with reproductive outcomes, and that low vitamin D levels are associated with the incidence of colorectal polyps and nasal polyps. There is little evidence regarding the relationship between EPs and serum vitamin D levels.</p><p><strong>Study design, size, duration: </strong>We conducted a cross-sectional study using data from Guangdong Women and Children Hospital from January 2019 to October 2023, enrolling 3107 patients.</p><p><strong>Participants/materials, setting, methods: </strong>A total of 3107 infertile patients who underwent hysteroscopy were included in this study; 642 patients had endometrial polyps and 2465 had a normal uterine cavity. Hysteroscopy findings included risk of EPs, polyp size, percentage of multiple polyps, and incidence of chronic endometritis (CE). Serum vitamin D were assessed by measuring total 25(OH)D using chemiluminescence. According to international guideline recommendations for vitamin D deficiency, patients were divided into two groups: the <50 nmol/l group and the ≥50 nmol/l group. Univariable and multivariable logistic regression models, stratified analyses, and smooth curve fitting were used to examine the relationship between serum 25(OH)D levels and risk of EPs.</p><p><strong>Main results and the role of chance: </strong>Of all patients, 23.8% (740/3107) were vitamin D deficient (<50 nmol/l). The incidence of EPs was significantly higher in the 25(OH)D < 50 nmol/l group than in the ≥50 nmol/l group (24.9% vs 19.3%; P = 0.001). However, there were no differences in polyp size, proportion of multiple polyps, and presence of CE between the two groups. After controlling for confounders, 25(OH)D ≥ 50 nmol/l (compared with <50 nmol/l) was negatively associated with risk of EPs (adjusted OR, 0.733; 95% CI, 0.598-0.898). Other variables that had an impact on polyp incidence included BMI, type of infertility, CA125, and CD138-positive plasma cells. In addition, a linear regression model between age and serum 25(OH)D levels showed a positive linear association. Subgroup analyses were performed for different age groups, and the risk of EPs was significantly higher in the 25(OH)D < 50 nmol/l group than in the ≥50 nmol/l group, both in the younger subgroup (23.8% vs 19.1%) and in the older subgroup (28.0% vs 19.9%). The smo","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521767","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 What is the significance of visceral adipose tissue (VAT) in the pathogenesis of polycystic ovary syndrome (PCOS) and its impact on the regulation of metabolic disorders in women with PCOS? SUMMARY ANSWER We revealed a potentially causal relationship between increased genetically predicted VAT and PCOS-related traits, and found that VAT exhibited impaired glucose metabolism and mitochondrial oxidative phosphorylation (OXPHOS) in women with PCOS. WHAT IS KNOWN ALREADY PCOS is a common reproductive endocrine disorder accompanied by many metabolic abnormalities. Adipose tissue is a metabolically active endocrine organ that regulates multiple physiological processes, and VAT has a much stronger association with metabolism than subcutaneous adipose tissue does. STUDY DESIGN, SIZE, DURATION Mendelian randomization (MR) analysis was used to investigate the potential causal association between genetically predicted VAT and the risk of PCOS. Data for MR analysis were extracted from European population cohorts. VAT samples from sixteen PCOS patients and eight control women who underwent laparoscopic surgery were collected for proteomics and targeted metabolomics analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS PCOS was diagnosed according to the 2003 Rotterdam Criteria. The control subjects were women who underwent laparoscopic investigation for infertility or benign indications. Proteomics was performed by TMT labeling and liquid chromatography-tandem mass spectrometry analysis, and targeted metabolomics was performed by ultra-performance liquid chromatography-tandem mass spectrometry analysis. The key differentially expressed proteins (DEPs) were validated by immunoblotting. MAIN RESULTS AND THE ROLE OF CHANCE MR analysis revealed a potentially causal relationship between increased genetically predicted VAT and PCOS, as well as related traits, such as polycystic ovaries, total testosterone, bioavailable testosterone, and anti-Müllerian hormone, while a negative relationship was found with sex hormone-binding globulin. Enrichment pathway analysis of DEPs indicated the inhibition of glycolysis and activation of mitochondrial OXPHOS in the VAT of PCOS patients. MR analysis revealed that key DEPs involved in glycolysis and OXPHOS were significantly linked to PCOS and its related traits. Dot blot assay confirmed a significant decrease in glycolysis enzymes PKM2 and HK1, and an increase in mitochondrial Complex I and III subunits, NDUFS3 and UQCR10. Moreover, metabolomics analysis confirmed down-regulated metabolites of energy metabolic pathways, in particular glycolysis. Further analysis of PCOS and control subjects of normal weight revealed that dysregulation of glucose metabolism and OXPHOS in VAT of women with PCOS was independent of obesity. LARGE SCALE DATA The mass spectrometry proteomics data have been deposited to the iProX database (http://www.iprox.org) with the iProX accession: IPX0005774001. LIMITATIONS, REASONS FOR CAUTION There
{"title":"Mendelian randomization and multi-omics approach analyses reveal impaired glucose metabolism and oxidative phosphorylation in visceral adipose tissue of women with polycystic ovary syndrome","authors":"Yurong Zhang, Xintong Jiang, Xueling Song, Jiajia Zhang, Weian Mao, Wei Chen, Shuai Yuan, Yijie Chen, Liangshan Mu, Yue Zhao","doi":"10.1093/humrep/deae244","DOIUrl":"https://doi.org/10.1093/humrep/deae244","url":null,"abstract":"STUDY QUESTION What is the significance of visceral adipose tissue (VAT) in the pathogenesis of polycystic ovary syndrome (PCOS) and its impact on the regulation of metabolic disorders in women with PCOS? SUMMARY ANSWER We revealed a potentially causal relationship between increased genetically predicted VAT and PCOS-related traits, and found that VAT exhibited impaired glucose metabolism and mitochondrial oxidative phosphorylation (OXPHOS) in women with PCOS. WHAT IS KNOWN ALREADY PCOS is a common reproductive endocrine disorder accompanied by many metabolic abnormalities. Adipose tissue is a metabolically active endocrine organ that regulates multiple physiological processes, and VAT has a much stronger association with metabolism than subcutaneous adipose tissue does. STUDY DESIGN, SIZE, DURATION Mendelian randomization (MR) analysis was used to investigate the potential causal association between genetically predicted VAT and the risk of PCOS. Data for MR analysis were extracted from European population cohorts. VAT samples from sixteen PCOS patients and eight control women who underwent laparoscopic surgery were collected for proteomics and targeted metabolomics analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS PCOS was diagnosed according to the 2003 Rotterdam Criteria. The control subjects were women who underwent laparoscopic investigation for infertility or benign indications. Proteomics was performed by TMT labeling and liquid chromatography-tandem mass spectrometry analysis, and targeted metabolomics was performed by ultra-performance liquid chromatography-tandem mass spectrometry analysis. The key differentially expressed proteins (DEPs) were validated by immunoblotting. MAIN RESULTS AND THE ROLE OF CHANCE MR analysis revealed a potentially causal relationship between increased genetically predicted VAT and PCOS, as well as related traits, such as polycystic ovaries, total testosterone, bioavailable testosterone, and anti-Müllerian hormone, while a negative relationship was found with sex hormone-binding globulin. Enrichment pathway analysis of DEPs indicated the inhibition of glycolysis and activation of mitochondrial OXPHOS in the VAT of PCOS patients. MR analysis revealed that key DEPs involved in glycolysis and OXPHOS were significantly linked to PCOS and its related traits. Dot blot assay confirmed a significant decrease in glycolysis enzymes PKM2 and HK1, and an increase in mitochondrial Complex I and III subunits, NDUFS3 and UQCR10. Moreover, metabolomics analysis confirmed down-regulated metabolites of energy metabolic pathways, in particular glycolysis. Further analysis of PCOS and control subjects of normal weight revealed that dysregulation of glucose metabolism and OXPHOS in VAT of women with PCOS was independent of obesity. LARGE SCALE DATA The mass spectrometry proteomics data have been deposited to the iProX database (http://www.iprox.org) with the iProX accession: IPX0005774001. LIMITATIONS, REASONS FOR CAUTION There ","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490622","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}
Lise Andrea Arge, Yunsung Lee, Karoline Hansen Skåra, Mikko Myrskylä, Cecilia Høst Ramlau-Hansen, Siri Eldevik Håberg, Maria Christine Magnus
STUDY QUESTION Is there an association between male or female epigenetic age acceleration (EAA) or deceleration (EAD) and fecundability? SUMMARY ANSWER We do not find compelling evidence of an association between EAA or EAD and fecundability. WHAT IS KNOWN ALREADY Prior research has shown that female accelerated epigenetic aging is associated with unfavorable clinical fecundity outcomes and use of in vitro fertilization, and that epigenetic aging in sperm cells is associated with unfavorable sperm parameters. Studies of epigenetic aging and fecundability among individuals who conceive naturally are lacking. STUDY DESIGN, SIZE, DURATION This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa), a population-based pregnancy cohort which recruited pregnant couples between 1999 and 2008. We used data from 1657 couples (women and men) with planned naturally conceived pregnancies and available blood samples. PARTICIPANTS/MATERIALS, SETTING, METHODS Methylation levels were measured in DNA from blood samples taken recruitment (at ∼18 gestational weeks) from pregnant women and their partners using the Illumina Methylation EPIC Array. To obtain a measure of EAA/EAD, we performed a linear regression of each of seven different established epigenetic biomarkers (DNAmAge by Horvath, DNAmAge by Hannum et al., PhenoAge by Levine et al., DunedinPoAm by Belsky et al., DunedinPACE by Belsky et al., DNAmTL by Lu et al., and GrimAge by Lu et al.) against chronological age. We fitted proportional probability regression models to obtain fecundability ratios (FRs) for each standard deviation increase in epigenetic aging, and obtained crude and adjusted (for body mass index, smoking, and education level) estimates. Results were evaluated at a false discovery rate (FDR) of 5%. We evaluated all models for non-linear associations using categories of epigenetic age where appropriate. MAIN RESULTS AND THE ROLE OF CHANCE Although the DunedinPACE clock in males demonstrated slightly increasing fecundability with increasing EAA (adjusted FR 1.05 per one standard deviation increase in EAA, 95% CI 1.00–1.10), this was not robust when evaluated at an FDR of 5%. We found evidence of non-linearity between biological aging and fecundability in two models in females and three models in males, but non-linear associations were weak and conflicting. LIMITATIONS, REASONS FOR CAUTION As MoBa is a pregnancy cohort, our findings may not be generalizable to all couples attempting conception. Fecundability is a couple-level measure, and any impacts of epigenetic aging in each partner may be obscured by effects of the other partner. WIDER IMPLICATIONS OF THE FINDINGS Our findings contrast with those of prior studies, which have indicated an association between EAA and unfavorable clinical fertility outcomes in populations using fertility treatments, possibly due to less important effects of epigenetic aging among couples who conceive naturally. More research is needed on
研究问题 男性或女性表观遗传年龄加速（EAA）或减速（EAD）与受精能力之间是否存在关联？简答 我们没有发现令人信服的证据表明 EAA 或 EAD 与受精能力有关。既往研究表明，女性表观遗传加速衰老与不利的临床受孕结果和体外受精的使用有关，精子细胞的表观遗传衰老与不利的精子参数有关。目前还缺乏对自然受孕者的表观遗传老化和受精能力的研究。研究设计、规模和持续时间 本研究基于挪威母亲、父亲和儿童队列研究（MoBa），这是一项基于人口的怀孕队列研究，在1999年至2008年间招募了怀孕夫妇。我们使用了 1657 对计划自然怀孕的夫妇（女性和男性）的数据，并采集了他们的血液样本。使用 Illumina Methylation EPIC Array 测量了孕妇及其伴侣在妊娠 18 周时采集的血液样本中 DNA 的甲基化水平。为了获得 EAA/EAD 的测量值，我们将 7 种不同的既定表观遗传生物标志物（Horvath 的 DNAmAge、Hannum 等人的 DNAmAge、Levine 等人的 PhenoAge、Belsky 等人的 DunedinPoAm、Belsky 等人的 DunedinPACE、Lu 等人的 DNAmTL 和 Lu 等人的 GrimAge）中的每一种与实际年龄进行了线性回归。我们拟合了比例概率回归模型，以获得表观遗传老化每增加一个标准差的受精率比值（FRs），并获得粗略估计值和调整估计值（根据体重指数、吸烟和教育水平）。我们以 5%的错误发现率 (FDR) 对结果进行了评估。我们酌情使用表观遗传年龄分类对所有非线性关联模型进行了评估。主要结果和偶然性的作用 虽然 DunedinPACE 时钟显示男性的受精率随着 EAA 的增加而略有增加（EAA 每增加一个标准差，调整 FR 值为 1.05，95% CI 为 1.00-1.10），但在 FDR 为 5%的情况下进行评估时，这一结果并不稳健。我们在两个雌性模型和三个雄性模型中发现了生物衰老与受精率之间非线性关系的证据，但非线性关系较弱且相互矛盾。局限性、注意事项 由于 MoBa 是一个怀孕队列，我们的研究结果可能无法推广到所有试图受孕的夫妇。可育性是一种夫妇层面的衡量标准，每对夫妇表观遗传老化的任何影响都可能被另一对夫妇的影响所掩盖。我们的研究结果与之前的研究结果形成了鲜明的对比，之前的研究结果表明，在使用生育治疗的人群中，EAA 与不利的临床生育结果之间存在关联，这可能是由于在自然受孕的夫妇中，表观遗传老化的影响并不那么重要。我们需要对基于血液的 EAA 与男女临床生育参数之间的关系进行更多的研究。研究经费/合作利益 本研究得到了挪威研究委员会（Research Council of Norway）的支持，包括医学生研究计划资助项目（项目编号：271555/F20）、卓越中心资助项目（项目编号：262700）以及妇女健康计划资助项目（320656）。此外，该研究还获得了战略研究委员会（SRC）、FLUX联合会（决定号：345130和345131）、美国国家老龄化研究所（R01AG075208）、马克斯-普朗克协会（决定号：5714240218）、赫尔辛基大学社会科学学院简和阿托斯-埃尔科基金会（Jane and Aatos Erkko Foundation）以及赫尔辛基市、万塔市和埃斯波市对马克斯-普朗克-赫尔辛基大学中心的资助，以及欧洲研究理事会的共同资助；欧洲研究理事会（ERC Synergy、BIOSFER，资助号 101071773；地平线 2020 研究与创新计划，资助号 947684）。作者声明无利益冲突。试验注册号 n/a。
{"title":"Epigenetic aging and fecundability: the Norwegian Mother, Father and Child Cohort Study","authors":"Lise Andrea Arge, Yunsung Lee, Karoline Hansen Skåra, Mikko Myrskylä, Cecilia Høst Ramlau-Hansen, Siri Eldevik Håberg, Maria Christine Magnus","doi":"10.1093/humrep/deae242","DOIUrl":"https://doi.org/10.1093/humrep/deae242","url":null,"abstract":"STUDY QUESTION Is there an association between male or female epigenetic age acceleration (EAA) or deceleration (EAD) and fecundability? SUMMARY ANSWER We do not find compelling evidence of an association between EAA or EAD and fecundability. WHAT IS KNOWN ALREADY Prior research has shown that female accelerated epigenetic aging is associated with unfavorable clinical fecundity outcomes and use of in vitro fertilization, and that epigenetic aging in sperm cells is associated with unfavorable sperm parameters. Studies of epigenetic aging and fecundability among individuals who conceive naturally are lacking. STUDY DESIGN, SIZE, DURATION This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa), a population-based pregnancy cohort which recruited pregnant couples between 1999 and 2008. We used data from 1657 couples (women and men) with planned naturally conceived pregnancies and available blood samples. PARTICIPANTS/MATERIALS, SETTING, METHODS Methylation levels were measured in DNA from blood samples taken recruitment (at ∼18 gestational weeks) from pregnant women and their partners using the Illumina Methylation EPIC Array. To obtain a measure of EAA/EAD, we performed a linear regression of each of seven different established epigenetic biomarkers (DNAmAge by Horvath, DNAmAge by Hannum et al., PhenoAge by Levine et al., DunedinPoAm by Belsky et al., DunedinPACE by Belsky et al., DNAmTL by Lu et al., and GrimAge by Lu et al.) against chronological age. We fitted proportional probability regression models to obtain fecundability ratios (FRs) for each standard deviation increase in epigenetic aging, and obtained crude and adjusted (for body mass index, smoking, and education level) estimates. Results were evaluated at a false discovery rate (FDR) of 5%. We evaluated all models for non-linear associations using categories of epigenetic age where appropriate. MAIN RESULTS AND THE ROLE OF CHANCE Although the DunedinPACE clock in males demonstrated slightly increasing fecundability with increasing EAA (adjusted FR 1.05 per one standard deviation increase in EAA, 95% CI 1.00–1.10), this was not robust when evaluated at an FDR of 5%. We found evidence of non-linearity between biological aging and fecundability in two models in females and three models in males, but non-linear associations were weak and conflicting. LIMITATIONS, REASONS FOR CAUTION As MoBa is a pregnancy cohort, our findings may not be generalizable to all couples attempting conception. Fecundability is a couple-level measure, and any impacts of epigenetic aging in each partner may be obscured by effects of the other partner. WIDER IMPLICATIONS OF THE FINDINGS Our findings contrast with those of prior studies, which have indicated an association between EAA and unfavorable clinical fertility outcomes in populations using fertility treatments, possibly due to less important effects of epigenetic aging among couples who conceive naturally. More research is needed on ","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489367","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, Alessandro Bartolacci, Valentino Cimadomo, Samuele Trio, Federica Innocenti, Andrea Borini, Alberto Vaiarelli, Laura Rienzi, Aisling Ahlström, Danilo Cimadomo
<p><strong>Study question: </strong>Can more reliable time cut-offs of embryo developmental incompetence be generated by combining time-lapse technology (TLT), artificial intelligence, and preimplantation genetics screening for aneuploidy (PGT-A)?</p><p><strong>Summary answer: </strong>Embryo developmental incompetence can be better predicted by time cut-offs at multiple developmental stages and for different ranges of maternal age.</p><p><strong>What is known already: </strong>TLT is instrumental for the continual and undisturbed observation of embryo development. It has produced morphokinetic algorithms aimed at selecting embryos able to generate a viable pregnancy, however, such efforts have had limited success. Regardless, the potential of this technology for improving multiple aspects of the IVF process remains considerable. Specifically, TLT could be harnessed to discriminate developmentally incompetent embryos: i.e. those unable to develop to the blastocyst stage or affected by full-chromosome meiotic aneuploidies. If proven valuable, this application would prevent the non-productive use of such embryos, thereby improving laboratory and clinical efficiency and reducing patient stress and costs due to unnecessary embryo transfer and cryopreservation.</p><p><strong>Study design, size, duration: </strong>The training dataset involved embryos of PGT-A cycles cultured in Embryoscope with a single media (836 euploid and 1179 aneuploid blastocysts and 1874 arrested embryos; 2013-2020). Selection criteria were ejaculated sperm, own (not donated) fresh oocytes, trophectoderm biopsy and comprehensive-chromosome-testing to diagnose uniform aneuploidies. Out-of-sample (30% of training), internal (299 euploid and 490 aneuploid blastocysts and 680 arrested embryos; 2021-2022) and external (97 euploid, 110 aneuploid and 603 untested blastocysts and 514 arrested embryos, 2018 to early 2022) validations were conducted.</p><p><strong>Participants/materials, setting, methods: </strong>A training dataset (70%) was used to define thresholds. Several models were generated by fitting outcomes to each timing (tPNa-t8) and maternal age. ROC curves pinpointed in-sample classification values associated with 95%, 99% and 99.99% true-positive rate for predicting incompetence. These values were integrated with upper limits of maternal age ranges (<35, 35-37, 38-40, 41-42, and >42 years) in logit functions to identify time cut-offs, whose accuracy was tested on the validation datasets through confusion matrices.</p><p><strong>Main results and the role of chance: </strong>For developmental (in)competence, the best performing (i) tPNa cut-offs were 27.8 hpi (error-rate: 0/743), 32.6 hpi (error rate: 0/934), 26.8 hpi (error rate: 0/1178), 22.9 hpi (error-rate: 1/654, 0.1%) and 17.2 hpi (error rate: 4/423, 0.9%) in the <35, 35-37, 38-40, 41-42, and >42 years groups, respectively; (ii) tPNf cut-offs were 36.7 hpi (error rate: 0/738), 47.9 hpi (error rate: 0/921), 45.6 hpi (e
{"title":"Time will tell: time-lapse technology and artificial intelligence to set time cut-offs indicating embryo incompetence.","authors":"Giovanni Coticchio, Alessandro Bartolacci, Valentino Cimadomo, Samuele Trio, Federica Innocenti, Andrea Borini, Alberto Vaiarelli, Laura Rienzi, Aisling Ahlström, Danilo Cimadomo","doi":"10.1093/humrep/deae239","DOIUrl":"https://doi.org/10.1093/humrep/deae239","url":null,"abstract":"<p><strong>Study question: </strong>Can more reliable time cut-offs of embryo developmental incompetence be generated by combining time-lapse technology (TLT), artificial intelligence, and preimplantation genetics screening for aneuploidy (PGT-A)?</p><p><strong>Summary answer: </strong>Embryo developmental incompetence can be better predicted by time cut-offs at multiple developmental stages and for different ranges of maternal age.</p><p><strong>What is known already: </strong>TLT is instrumental for the continual and undisturbed observation of embryo development. It has produced morphokinetic algorithms aimed at selecting embryos able to generate a viable pregnancy, however, such efforts have had limited success. Regardless, the potential of this technology for improving multiple aspects of the IVF process remains considerable. Specifically, TLT could be harnessed to discriminate developmentally incompetent embryos: i.e. those unable to develop to the blastocyst stage or affected by full-chromosome meiotic aneuploidies. If proven valuable, this application would prevent the non-productive use of such embryos, thereby improving laboratory and clinical efficiency and reducing patient stress and costs due to unnecessary embryo transfer and cryopreservation.</p><p><strong>Study design, size, duration: </strong>The training dataset involved embryos of PGT-A cycles cultured in Embryoscope with a single media (836 euploid and 1179 aneuploid blastocysts and 1874 arrested embryos; 2013-2020). Selection criteria were ejaculated sperm, own (not donated) fresh oocytes, trophectoderm biopsy and comprehensive-chromosome-testing to diagnose uniform aneuploidies. Out-of-sample (30% of training), internal (299 euploid and 490 aneuploid blastocysts and 680 arrested embryos; 2021-2022) and external (97 euploid, 110 aneuploid and 603 untested blastocysts and 514 arrested embryos, 2018 to early 2022) validations were conducted.</p><p><strong>Participants/materials, setting, methods: </strong>A training dataset (70%) was used to define thresholds. Several models were generated by fitting outcomes to each timing (tPNa-t8) and maternal age. ROC curves pinpointed in-sample classification values associated with 95%, 99% and 99.99% true-positive rate for predicting incompetence. These values were integrated with upper limits of maternal age ranges (<35, 35-37, 38-40, 41-42, and >42 years) in logit functions to identify time cut-offs, whose accuracy was tested on the validation datasets through confusion matrices.</p><p><strong>Main results and the role of chance: </strong>For developmental (in)competence, the best performing (i) tPNa cut-offs were 27.8 hpi (error-rate: 0/743), 32.6 hpi (error rate: 0/934), 26.8 hpi (error rate: 0/1178), 22.9 hpi (error-rate: 1/654, 0.1%) and 17.2 hpi (error rate: 4/423, 0.9%) in the <35, 35-37, 38-40, 41-42, and >42 years groups, respectively; (ii) tPNf cut-offs were 36.7 hpi (error rate: 0/738), 47.9 hpi (error rate: 0/921), 45.6 hpi (e","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499366","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}
Hui Cheng, Fu Wei, Julieta S Del Valle, Tessa H R Stolk, Judith A Huirne, Joyce D Asseler, Gonneke S K Pilgram, Lucette A J Van Der Westerlaken, Norah M Van Mello, Susana M Chuva De Sousa Lopes
<p><strong>Study question: </strong>Can secondary follicles be obtained from cultured cryopreserved-thawed human ovarian cortical tissue?</p><p><strong>Summary answer: </strong>We obtained high-quality secondary follicles from cultured cryopreserved-thawed human ovarian cortical tissue from cis female donors (cOVA), but not from trans masculine donors (tOVA) in the same culture conditions.</p><p><strong>What is known already: </strong>The in vitro growth of oocytes present in unilaminar follicles into metaphase II stage (MII) oocytes has been previously achieved starting from freshly obtained ovarian cortical tissue from adult cis female donors. This involved a multi-step culture protocol and the first step included the transition from unilaminar follicles to multilayered secondary follicles. Given that the ovarian cortex (from both cis female and trans masculine donors) used for fertility preservation is cryopreserved, it is crucial to investigate the potential of unilaminar follicles from cryopreserved-thawed ovarian cortex to grow in culture.</p><p><strong>Study design, size, duration: </strong>Cryopreserved-thawed ovarian cortical tissue from adult trans masculine donors (n = 3) and adult cis female donors (n = 3) was used for in vitro culture following the first culture step described in two published culture protocols (7-8 days and 21 days) and compared to freshly isolated ovarian cortex from trans masculine donors (n = 3) and to ovarian cortex prior to culture.</p><p><strong>Participants/materials, setting, methods: </strong>Ovarian cortical tissue was obtained from adult trans masculine donors undergoing gender-affirming surgery while using testosterone, and from adult cis female donors undergoing oophorectomy for fertility preservation purposes before chemotherapy. The ovarian cortex was fixed either prior (day 0) or after the culture period. Follicular survival, growth, and morphology were assessed through histology and immunofluorescence.</p><p><strong>Main results and the role of chance: </strong>We quantified the different stages of follicular development (primordial, primary, secondary, and atretic) after culture and observed an increase in the percentage of secondary follicles as well as an increase in COLIV deposition in the stromal compartment regardless of the culture media used. The quality of the secondary follicles obtained from cOVA was comparable to those prior to culture. However, in the same culture conditions, the secondary follicles from tOVA (fresh and cryo) showed low-quality secondary follicles, containing oocytes with small diameter, granulosa cells that expressed abnormal levels of KRT19 and steroidogenic-marker STAR and lacked ACTA2+ theca cells, when compared to tOVA secondary follicles prior to culture.</p><p><strong>Limitations, reasons for caution: </strong>The number of different donors used was limited.</p><p><strong>Wider implications of the findings: </strong>Our study revealed that cryopreserved-thawed cO
{"title":"In vitro growth of secondary follicles from cryopreserved-thawed ovarian cortex.","authors":"Hui Cheng, Fu Wei, Julieta S Del Valle, Tessa H R Stolk, Judith A Huirne, Joyce D Asseler, Gonneke S K Pilgram, Lucette A J Van Der Westerlaken, Norah M Van Mello, Susana M Chuva De Sousa Lopes","doi":"10.1093/humrep/deae240","DOIUrl":"https://doi.org/10.1093/humrep/deae240","url":null,"abstract":"<p><strong>Study question: </strong>Can secondary follicles be obtained from cultured cryopreserved-thawed human ovarian cortical tissue?</p><p><strong>Summary answer: </strong>We obtained high-quality secondary follicles from cultured cryopreserved-thawed human ovarian cortical tissue from cis female donors (cOVA), but not from trans masculine donors (tOVA) in the same culture conditions.</p><p><strong>What is known already: </strong>The in vitro growth of oocytes present in unilaminar follicles into metaphase II stage (MII) oocytes has been previously achieved starting from freshly obtained ovarian cortical tissue from adult cis female donors. This involved a multi-step culture protocol and the first step included the transition from unilaminar follicles to multilayered secondary follicles. Given that the ovarian cortex (from both cis female and trans masculine donors) used for fertility preservation is cryopreserved, it is crucial to investigate the potential of unilaminar follicles from cryopreserved-thawed ovarian cortex to grow in culture.</p><p><strong>Study design, size, duration: </strong>Cryopreserved-thawed ovarian cortical tissue from adult trans masculine donors (n = 3) and adult cis female donors (n = 3) was used for in vitro culture following the first culture step described in two published culture protocols (7-8 days and 21 days) and compared to freshly isolated ovarian cortex from trans masculine donors (n = 3) and to ovarian cortex prior to culture.</p><p><strong>Participants/materials, setting, methods: </strong>Ovarian cortical tissue was obtained from adult trans masculine donors undergoing gender-affirming surgery while using testosterone, and from adult cis female donors undergoing oophorectomy for fertility preservation purposes before chemotherapy. The ovarian cortex was fixed either prior (day 0) or after the culture period. Follicular survival, growth, and morphology were assessed through histology and immunofluorescence.</p><p><strong>Main results and the role of chance: </strong>We quantified the different stages of follicular development (primordial, primary, secondary, and atretic) after culture and observed an increase in the percentage of secondary follicles as well as an increase in COLIV deposition in the stromal compartment regardless of the culture media used. The quality of the secondary follicles obtained from cOVA was comparable to those prior to culture. However, in the same culture conditions, the secondary follicles from tOVA (fresh and cryo) showed low-quality secondary follicles, containing oocytes with small diameter, granulosa cells that expressed abnormal levels of KRT19 and steroidogenic-marker STAR and lacked ACTA2+ theca cells, when compared to tOVA secondary follicles prior to culture.</p><p><strong>Limitations, reasons for caution: </strong>The number of different donors used was limited.</p><p><strong>Wider implications of the findings: </strong>Our study revealed that cryopreserved-thawed cO","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464096","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 In addition to chromosomal euploidy, can the transcriptome of blastocysts be used as a novel predictor of embryo implantation potential? SUMMARY ANSWER This retrospective analysis showed that based on differentially expressed genes (DEGs) between euploid blastocysts which resulted and did not result in a clinical pregnancy, machine learning models could help improve implantation rates by blastocyst optimization. WHAT IS KNOWN ALREADY Embryo implantation is a multifaceted process, with implantation loss and pregnancy failure related not only to blastocyst euploidy but also to the intricate dialog between blastocyst and endometrium. Although in vitro studies have revealed the characteristics of trophectoderm (TE) differentiation in implanted blastocysts and the function of TE placentation at the implantation site, the precise molecular mechanisms of embryo implantation and their clinical application remain to be fully elucidated. STUDY DESIGN, SIZE, DURATION This study involved 102 patients who underwent 111 cycles for preimplantation genetic testing for aneuploidies (PGT-A) between March 2022 and July 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS The study included 412 blastocysts biopsied at Day 5 [D5] or Day 6 [D6] for patients who underwent PGT-A. The biopsy lysates were split and subjected to DNA and RNA sequencing (DNA- and RNA-seq). One part was used for PGT-A to detect DNA copy number variations, whereas the other part was assessed simultaneously by RNA-seq to determine the transcriptome characteristics. To validate the reliability and accuracy of RNA-seq obtained from this strategy, we initially analyzed the transcriptome of blastocysts with chromosomal aneuploidies. Subsequently, we compared the transcriptomic features of blastocysts with different rates of formation (D5 vs D6) and investigated the network of interactions between key blastulation genes and the receptive endometrium. Then to evaluate the implantation potential of euploid blastocysts, we identified DEGs between euploid blastocysts that resulted in clinical pregnancy (defined as the presence of a gestational sac detected by ultrasound after 5 weeks) and those that did not. These DEGs were then employed to construct a predictive model for optimizing blastocyst selection. MAIN RESULTS AND THE ROLE OF CHANCE The successful detection rate of PGT-A was remarkably high at 99.8%. The RNA data may infer aneuploidy for both trisomy and monosomy. Between the euploid blastocysts that formed on D5 and D6, 187 DEGs were predominantly involved in cell differentiation for embryonic placenta development, the PPAR signaling pathway, and the Notch signaling pathway. These D5/D6 DEGs also exhibited a functional dialog with the receptive phase endometrium-specific genes through protein–protein interaction networks, indicating that the embryo undergoes further differentiation for post-implantation development. Furthermore, a modeling strategy using 280 DEGs between blastocysts le
{"title":"Multi-omics PGT: re-evaluation of euploid blastocysts for implantation potential based on RNA sequencing","authors":"Jiamin Jin, Jieliang Ma, Xiufen Wang, Fang Hong, YinLi Zhang, Feng Zhou, Cheng Wan, Yangyun Zou, Ji Yang, Sijia Lu, Xiaomei Tong","doi":"10.1093/humrep/deae237","DOIUrl":"https://doi.org/10.1093/humrep/deae237","url":null,"abstract":"STUDY QUESTION In addition to chromosomal euploidy, can the transcriptome of blastocysts be used as a novel predictor of embryo implantation potential? SUMMARY ANSWER This retrospective analysis showed that based on differentially expressed genes (DEGs) between euploid blastocysts which resulted and did not result in a clinical pregnancy, machine learning models could help improve implantation rates by blastocyst optimization. WHAT IS KNOWN ALREADY Embryo implantation is a multifaceted process, with implantation loss and pregnancy failure related not only to blastocyst euploidy but also to the intricate dialog between blastocyst and endometrium. Although in vitro studies have revealed the characteristics of trophectoderm (TE) differentiation in implanted blastocysts and the function of TE placentation at the implantation site, the precise molecular mechanisms of embryo implantation and their clinical application remain to be fully elucidated. STUDY DESIGN, SIZE, DURATION This study involved 102 patients who underwent 111 cycles for preimplantation genetic testing for aneuploidies (PGT-A) between March 2022 and July 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS The study included 412 blastocysts biopsied at Day 5 [D5] or Day 6 [D6] for patients who underwent PGT-A. The biopsy lysates were split and subjected to DNA and RNA sequencing (DNA- and RNA-seq). One part was used for PGT-A to detect DNA copy number variations, whereas the other part was assessed simultaneously by RNA-seq to determine the transcriptome characteristics. To validate the reliability and accuracy of RNA-seq obtained from this strategy, we initially analyzed the transcriptome of blastocysts with chromosomal aneuploidies. Subsequently, we compared the transcriptomic features of blastocysts with different rates of formation (D5 vs D6) and investigated the network of interactions between key blastulation genes and the receptive endometrium. Then to evaluate the implantation potential of euploid blastocysts, we identified DEGs between euploid blastocysts that resulted in clinical pregnancy (defined as the presence of a gestational sac detected by ultrasound after 5 weeks) and those that did not. These DEGs were then employed to construct a predictive model for optimizing blastocyst selection. MAIN RESULTS AND THE ROLE OF CHANCE The successful detection rate of PGT-A was remarkably high at 99.8%. The RNA data may infer aneuploidy for both trisomy and monosomy. Between the euploid blastocysts that formed on D5 and D6, 187 DEGs were predominantly involved in cell differentiation for embryonic placenta development, the PPAR signaling pathway, and the Notch signaling pathway. These D5/D6 DEGs also exhibited a functional dialog with the receptive phase endometrium-specific genes through protein–protein interaction networks, indicating that the embryo undergoes further differentiation for post-implantation development. Furthermore, a modeling strategy using 280 DEGs between blastocysts le","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444286","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}
Ran S Rotem,Marc G Weisskopf,Brian Bateman,Krista Huybrechts,Sonia Hernández-Diáz
STUDY QUESTIONWhat are the roles of maternal preconception diabetes and related periconceptional hyperglycemia on the risk of major congenital malformations (MCMs) in offspring?SUMMARY ANSWERMaternal periconceptional glycated hemoglobin (HbA1c) levels over 5.6% were associated with an increased risk of congenital heart defects (CHD) in the offspring, and maternal preconception diabetes was associated with an increased risk of CHD, including when HbA1c levels were within euglycemic ranges.WHAT IS KNOWN ALREADYMaternal preconception diabetes has been linked with MCMs in the offspring. However, evidence concerning associations with specific periconception serum measures of hyperglycemia, and susceptibility of different organ systems, is inconsistent. Moreover, limited evidence exists concerning the effectiveness of antidiabetic medications in mitigating diabetes-related teratogenic risks.STUDY DESIGN, SIZE, DURATIONA large Israeli birth cohort of 46 534 children born in 2001-2020.PARTICIPANTS/MATERIALS, SETTING, METHODSMaternal HbA1c test results were obtained from 90 days before conception to mid-pregnancy. Maternal diabetes, other cardiometabolic conditions, and MCMs in newborns were ascertained based on clinical diagnoses, medication dispensing records, and laboratory test results using previously validated algorithms. Associations were modeled using generalized additive logistic regression models with thin plate penalized splines.MAIN RESULTS AND THE ROLE OF CHANCEMaternal periconceptional HbA1c value was associated with CHD in newborns, with the risk starting to increase at HbA1c values exceeding 5.6%. The association between HbA1c and CHD was stronger among mothers with type 2 diabetes mellitus (T2DM) compared to the other diabetes groups. Maternal pre-existing T2DM was associated with CHD even after accounting for HbA1C levels and other cardiometabolic comorbidities (odds ratio (OR)=1.89, 95% CI 1.18, 3.03); and the OR was materially unchanged when only mothers with pre-existing T2DM who had high adherence to antidiabetic medications and normal HbA1c levels were considered.LIMITATIONS, REASONS FOR CAUTIONThe rarity of some specific malformation groups limited the ability to conduct more granular analyses. The use of HbA1c as a time-aggregated measure of glycemic control may miss transient glycemic dysregulation that could be clinically meaningful for teratogenic risks.WIDER IMPLICATIONS OF THE FINDINGSThe observed association between pre-existing diabetes and the risk of malformations within HbA1c levels suggests underlying causal pathways that are partly independent of maternal glucose control. Therefore, treatments for hyperglycemia might not completely mitigate the teratogenic risk associated with maternal preconception diabetes.STUDY FUNDING/COMPETING INTEREST(S)The work was supported by NIH grants K99ES035433, R01HD097778, and P30ES000002. None of the authors reports competing interests.TRIAL REGISTRATION NUMBERN/A.
{"title":"Maternal periconception hyperglycemia, preconception diabetes, and risk of major congenital malformations in offspring.","authors":"Ran S Rotem,Marc G Weisskopf,Brian Bateman,Krista Huybrechts,Sonia Hernández-Diáz","doi":"10.1093/humrep/deae233","DOIUrl":"https://doi.org/10.1093/humrep/deae233","url":null,"abstract":"STUDY QUESTIONWhat are the roles of maternal preconception diabetes and related periconceptional hyperglycemia on the risk of major congenital malformations (MCMs) in offspring?SUMMARY ANSWERMaternal periconceptional glycated hemoglobin (HbA1c) levels over 5.6% were associated with an increased risk of congenital heart defects (CHD) in the offspring, and maternal preconception diabetes was associated with an increased risk of CHD, including when HbA1c levels were within euglycemic ranges.WHAT IS KNOWN ALREADYMaternal preconception diabetes has been linked with MCMs in the offspring. However, evidence concerning associations with specific periconception serum measures of hyperglycemia, and susceptibility of different organ systems, is inconsistent. Moreover, limited evidence exists concerning the effectiveness of antidiabetic medications in mitigating diabetes-related teratogenic risks.STUDY DESIGN, SIZE, DURATIONA large Israeli birth cohort of 46 534 children born in 2001-2020.PARTICIPANTS/MATERIALS, SETTING, METHODSMaternal HbA1c test results were obtained from 90 days before conception to mid-pregnancy. Maternal diabetes, other cardiometabolic conditions, and MCMs in newborns were ascertained based on clinical diagnoses, medication dispensing records, and laboratory test results using previously validated algorithms. Associations were modeled using generalized additive logistic regression models with thin plate penalized splines.MAIN RESULTS AND THE ROLE OF CHANCEMaternal periconceptional HbA1c value was associated with CHD in newborns, with the risk starting to increase at HbA1c values exceeding 5.6%. The association between HbA1c and CHD was stronger among mothers with type 2 diabetes mellitus (T2DM) compared to the other diabetes groups. Maternal pre-existing T2DM was associated with CHD even after accounting for HbA1C levels and other cardiometabolic comorbidities (odds ratio (OR)=1.89, 95% CI 1.18, 3.03); and the OR was materially unchanged when only mothers with pre-existing T2DM who had high adherence to antidiabetic medications and normal HbA1c levels were considered.LIMITATIONS, REASONS FOR CAUTIONThe rarity of some specific malformation groups limited the ability to conduct more granular analyses. The use of HbA1c as a time-aggregated measure of glycemic control may miss transient glycemic dysregulation that could be clinically meaningful for teratogenic risks.WIDER IMPLICATIONS OF THE FINDINGSThe observed association between pre-existing diabetes and the risk of malformations within HbA1c levels suggests underlying causal pathways that are partly independent of maternal glucose control. Therefore, treatments for hyperglycemia might not completely mitigate the teratogenic risk associated with maternal preconception diabetes.STUDY FUNDING/COMPETING INTEREST(S)The work was supported by NIH grants K99ES035433, R01HD097778, and P30ES000002. None of the authors reports competing interests.TRIAL REGISTRATION NUMBERN/A.","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443700","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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