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The pathophysiological role of estrogens in the initial stages of pregnancy: molecular mechanisms and clinical implications for pregnancy outcome from the periconceptional period to end of the first trimester. 雌激素在妊娠初期的病理生理作用:从围孕期到妊娠早期结束的妊娠结局的分子机制和临床意义。
IF 14.8 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2023-11-02 DOI: 10.1093/humupd/dmad016
F Parisi, C Fenizia, A Introini, A Zavatta, C Scaccabarozzi, M Biasin, V Savasi
<p><strong>Background: </strong>Estrogens regulate disparate female physiological processes, thus ensuring reproduction. Altered estrogen levels and signaling have been associated with increased risks of pregnancy failure and complications, including hypertensive disorders and low birthweight babies. However, the role of estrogens in the periconceptional period and early pregnancy is still understudied.</p><p><strong>Objective and rationale: </strong>This review aims to summarize the current evidence on the role of maternal estrogens during the periconceptional period and the first trimester of pregnancies conceived naturally and following ART. Detailed molecular mechanisms and related clinical impacts are extensively described.</p><p><strong>Search methods: </strong>Data for this narrative review were independently identified by seven researchers on Pubmed and Embase databases. The following keywords were selected: 'estrogens' OR 'estrogen level(s)' OR 'serum estradiol' OR 'estradiol/estrogen concentration', AND 'early pregnancy' OR 'first trimester of pregnancy' OR 'preconceptional period' OR 'ART' OR 'In Vitro Fertilization (IVF)' OR 'Embryo Transfer' OR 'Frozen Embryo Transfer' OR 'oocyte donation' OR 'egg donation' OR 'miscarriage' OR 'pregnancy outcome' OR 'endometrium'.</p><p><strong>Outcomes: </strong>During the periconceptional period (defined here as the critical time window starting 1 month before conception), estrogens play a crucial role in endometrial receptivity, through the activation of paracrine/autocrine signaling. A derailed estrogenic milieu within this period seems to be detrimental both in natural and ART-conceived pregnancies. Low estrogen levels are associated with non-conception cycles in natural pregnancies. On the other hand, excessive supraphysiologic estrogen concentrations at time of the LH peak correlate with lower live birth rates and higher risks of pregnancy complications. In early pregnancy, estrogen plays a massive role in placentation mainly by modulating angiogenic factor expression-and in the development of an immune-tolerant uterine micro-environment by remodeling the function of uterine natural killer and T-helper cells. Lower estrogen levels are thought to trigger abnormal placentation in naturally conceived pregnancies, whereas an estrogen excess seems to worsen pregnancy development and outcomes.</p><p><strong>Wider implications: </strong>Most current evidence available endorses a relation between periconceptional and first trimester estrogen levels and pregnancy outcomes, further depicting an optimal concentration range to optimize pregnancy success. However, how estrogens co-operate with other factors in order to maintain a fine balance between local tolerance towards the developing fetus and immune responses to pathogens remains elusive. Further studies are highly warranted, also aiming to identify the determinants of estrogen response and biomarkers for personalized estrogen administration regimens
背景:雌激素调节不同的女性生理过程,从而确保生殖。雌激素水平和信号传导的改变与妊娠失败和并发症的风险增加有关,包括高血压疾病和低出生体重婴儿。然而,雌激素在围产期和早孕期的作用仍然研究不足。目的和原理:这篇综述旨在总结目前关于母体雌激素在自然受孕和ART后妊娠的围产期和前三个月的作用的证据。详细的分子机制和相关的临床影响被广泛描述。搜索方法:这篇叙述性综述的数据由七名研究人员在Pubmed和Embase数据库中独立确定。选择以下关键词:“雌激素”或“雌激素水平”或“血清雌二醇”或“雌二醇/雌激素浓度”,AND“早孕”或“妊娠早期”或“受孕期”或“ART”或“体外受精(IVF)”或“胚胎移植”或“冷冻胚胎移植”、“卵子捐赠”或“流产”或“怀孕结果”或“子宫内膜” 受孕前一个月),雌激素通过激活旁分泌/自分泌信号在子宫内膜容受性中发挥着至关重要的作用。在这段时间内,雌激素环境的紊乱似乎对自然妊娠和ART妊娠都是有害的。雌激素水平低与自然妊娠的非受孕周期有关。另一方面,LH峰值时超生理雌激素浓度过高与较低的活产率和较高的妊娠并发症风险相关。在妊娠早期,雌激素主要通过调节血管生成因子的表达在胎盘形成中发挥重要作用,并通过重塑子宫自然杀伤细胞和辅助T细胞的功能在免疫耐受性子宫微环境的形成中发挥巨大作用。在自然受孕的妊娠中,雌激素水平较低被认为会引发异常胎盘形成,而雌激素过量似乎会恶化妊娠发育和结局。更广泛的含义:目前大多数可用的证据都支持孕周和孕早期雌激素水平与妊娠结局之间的关系,进一步描述了优化妊娠成功率的最佳浓度范围。然而,雌激素如何与其他因素合作,以在对发育中的胎儿的局部耐受性和对病原体的免疫反应之间保持良好的平衡,仍然难以捉摸。进一步的研究是非常有必要的,也旨在确定雌激素反应的决定因素和ART中个性化雌激素给药方案的生物标志物。
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引用次数: 0
Endometrial scratching in women undergoing IVF/ICSI: an individual participant data meta-analysis. 接受IVF/ICSI的女性子宫内膜刮伤:个体参与者数据荟萃分析。
IF 14.8 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2023-11-02 DOI: 10.1093/humupd/dmad014
Nienke E van Hoogenhuijze, Gemma Lahoz Casarramona, Sarah Lensen, Cindy Farquhar, Mohan S Kamath, Aleyamma T Kunjummen, Nick Raine-Fenning, Sine Berntsen, Anja Pinborg, Shari Mackens, Zeynep Ozturk Inal, Ernest H Y Ng, Jennifer S M Mak, Sachin A Narvekar, Wellington P Martins, Mia Steengaard Olesen, Helen L Torrance, Ben W Mol, Marinus J C Eijkemans, Rui Wang, Frank J M Broekmans
<p><strong>Background: </strong>In IVF/ICSI treatment, the process of embryo implantation is the success rate-limiting step. Endometrial scratching has been suggested to improve this process, but it is unclear if this procedure increases the chance of implantation and live birth (LB) and, if so, for whom, and how the scratch should be performed.</p><p><strong>Objective and rationale: </strong>This individual participant data meta-analysis (IPD-MA) aims to answer the question of whether endometrial scratching in women undergoing IVF/ICSI influences the chance of a LB, and whether this effect is different in specific subgroups of women. After its incidental discovery in 2000, endometrial scratching has been suggested to improve embryo implantation. Numerous randomized controlled trials (RCTs) have been conducted, showing contradicting results. Conventional meta-analyses were limited by high within- and between-study heterogeneity, small study samples, and a high risk of bias for many of the trials. Also, the data integrity of several trials have been questioned. Thus, despite numerous RCTs and a multitude of conventional meta-analyses, no conclusion on the clinical effectiveness of endometrial scratching could be drawn. An IPD-MA approach is able to overcome many of these problems because it allows for increased uniformity of outcome definitions, can filter out studies with data integrity concerns, enables a more precise estimation of the true treatment effect thanks to adjustment for participant characteristics and not having to make the assumptions necessary in conventional meta-analyses, and because it allows for subgroup analysis.</p><p><strong>Search methods: </strong>A systematic literature search identified RCTs on endometrial scratching in women undergoing IVF/ICSI. Authors of eligible studies were invited to share original data for this IPD-MA. Studies were assessed for risk of bias (RoB) and integrity checks were performed. The primary outcome was LB, with a one-stage intention to treat (ITT) as the primary analysis. Secondary analyses included as treated (AT), and the subset of women that underwent an embryo transfer (AT+ET). Treatment-covariate interaction for specific participant characteristics was analyzed in AT+ET.</p><p><strong>Outcomes: </strong>Out of 37 published and 15 unpublished RCTs (7690 participants), 15 RCTs (14 published, one unpublished) shared data. After data integrity checks, we included 13 RCTs (12 published, one unpublished) representing 4112 participants. RoB was evaluated as 'low' for 10/13 RCTs. The one-stage ITT analysis for scratch versus no scratch/sham showed an improvement of LB rates (odds ratio (OR) 1.29 [95% CI 1.02-1.64]). AT, AT+ET, and low-RoB-sensitivity analyses yielded similar results (OR 1.22 [95% CI 0.96-1.54]; OR 1.25 [95% CI 0.99-1.57]; OR 1.26 [95% CI 1.03-1.55], respectively). Treatment-covariate interaction analysis showed no evidence of interaction with age, number of previous failed embryo
背景:在IVF/ICSI治疗中,胚胎植入过程是限制成功率的步骤。有人建议子宫内膜刮伤可以改善这一过程,但目前尚不清楚这种手术是否会增加植入和活产(LB)的机会,如果会,应该为谁以及如何进行刮伤。目的和理由:这项个体参与者数据荟萃分析(IPD-MA)旨在回答接受IVF/ICSI的女性子宫内膜抓挠是否会影响LB的机会,以及这种影响在特定的女性亚组中是否不同的问题。在2000年偶然发现后,子宫内膜刮伤被认为可以改善胚胎植入。已经进行了大量的随机对照试验,结果相互矛盾。传统的荟萃分析受到研究内部和研究之间高度异质性、研究样本小以及许多试验的高偏倚风险的限制。此外,一些试验的数据完整性也受到质疑。因此,尽管进行了大量的随机对照试验和常规荟萃分析,但无法得出子宫内膜刮伤临床有效性的结论。IPD-MA方法能够克服其中的许多问题,因为它允许增加结果定义的一致性,可以过滤出有数据完整性问题的研究,由于对参与者特征的调整,能够更精确地估计真实的治疗效果,并且不必在传统的荟萃分析中做出必要的假设,并且因为它允许亚组分析。检索方法:系统文献检索确定了接受IVF/ICSI的女性子宫内膜刮伤的随机对照试验。邀请符合条件的研究的作者分享本IPD-MA的原始数据。对偏倚风险(RoB)进行了评估,并进行了完整性检查。主要结果为LB,以一阶段意向治疗(ITT)作为主要分析。二次分析包括治疗时(AT)和接受胚胎移植的妇女子集(AT+ET)。在AT+ET中分析了特定参与者特征的治疗协变量相互作用。结果:在37项已发表和15项未发表的随机对照试验中(7690名参与者),15项随机对照试验(14项已发表,1项未发表)共享数据。在数据完整性检查后,我们纳入了13项随机对照试验(12项已发表,1项未发表),代表4112名参与者。10/13随机对照试验的RoB评价为“低”。抓伤与不抓伤/假手术的一阶段ITT分析显示LB发生率有所改善(比值比(OR)1.29[95%CI 1.02-1.64])。AT、AT+ET和低RoB敏感性分析得出了相似的结果(分别为OR 1.22[95%CI 0.96-1.54];OR 1.25[95%CI 0.99-1.57];OR 1.26[95%CI 1.03-1.55])。治疗协变量相互作用分析显示,没有证据表明与年龄、既往胚胎移植失败次数、治疗类型或不孕原因存在相互作用。更广泛的含义:这是第一个基于4000多名参与者的IPD的荟萃分析,它表明子宫内膜刮伤可能会提高接受IVF/ICSI的女性的LB率。年龄、既往胚胎移植失败次数、治疗类型和不孕原因的亚组分析无法确定子宫内膜刮伤表现较好或较差的亚组。子宫内膜刮伤的时机可能对其有效性起到一定作用。应谨慎考虑在临床实践中使用子宫内膜刮伤,这意味着应就证据水平和不确定性向患者提供适当的咨询。
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引用次数: 0
Assessing the influence of preconception diet on female fertility: a systematic scoping review of observational studies. 评估孕前饮食对女性生育能力的影响:观察性研究的系统范围综述。
IF 14.8 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2023-11-02 DOI: 10.1093/humupd/dmad018
Simon Alesi, Nahal Habibi, Thais Rasia Silva, Nicole Cheung, Sophia Torkel, Chau Thien Tay, Alejandra Quinteros, Hugo Winter, Helena Teede, Aya Mousa, Jessica A Grieger, Lisa J Moran

Background: Preconception diet is a proposed modifiable risk factor for infertility. However, there is no official guidance for women in the preconception period as to which dietary approaches may improve fertility.

Objective and rationale: A comprehensive synthesis of the relevant evidence is key to determine the potentially effective dietary patterns and components as well as evidence gaps, and to provide information for nutritional recommendations for couples planning a pregnancy.

Search methods: In this systematic scoping review, four electronic databases (Medline and EMBASE via Ovid processing, CAB Direct, and CINAHL via EBSCO) were searched for observational studies (prospective and retrospective cohort, cross-sectional, and case-control studies) from inception to 27 September 2021. Eligible studies included women of reproductive age during the preconception period, and evaluated exposures related to preconception diet and outcomes related to fertility. Results were synthesized using a descriptive approach.

Outcomes: A total of 36 studies were eligible for inclusion (31 prospective, 3 cross-sectional, and 2 case-control studies) and were published between 2007 and 2022. Of the assessed dietary exposures, increased adherence to the Mediterranean diet displayed the strongest and most consistent association with improved clinical pregnancy rates. Reducing trans fatty acids (TFAs), saturated fatty acids, and discretionary food intake (fast food and sugar-sweetened beverages) were associated with improvements in live birth, clinical pregnancy rates, and related ART outcomes. The dietary components of seafood, dairy, and soy demonstrated inconsistent findings across the few included studies.

Wider implications: Due to heterogeneity and the limited available literature on most exposures, there is insufficient evidence to support any specific dietary approach for improving fertility. However, following some of the dietary approaches outlined in this review (anti-inflammatory diets, reducing TFA, and discretionary food intake) are consistent with broad healthy eating guidelines, have little to no associated risk, and offer a plausible set of possible benefits. This warrants further exploration in randomized controlled trials.

背景:孕前饮食是一种可改变的不孕风险因素。然而,对于哪些饮食方法可以提高生育能力,没有针对处于先入为主阶段的妇女的官方指导。目标和理由:全面综合相关证据是确定潜在有效的饮食模式和成分以及证据差距的关键,也是为计划怀孕的夫妇提供营养建议的关键。搜索方法:在这项系统范围界定综述中,从开始到2021年9月27日,对四个电子数据库(通过Ovid处理的Medline和EMBASE、CAB Direct和通过EBSCO的CINAHL)进行了观察性研究(前瞻性和回顾性队列、横断面和病例对照研究)的搜索。符合条件的研究包括怀孕期的育龄妇女,并评估了与怀孕饮食相关的暴露和与生育相关的结果。结果采用描述性方法进行综合。结果:共有36项研究符合入选条件(31项前瞻性研究、3项横断面研究和2项病例对照研究),于2007年至2022年间发表。在评估的饮食暴露中,对地中海饮食的依从性增加与临床妊娠率的提高表现出最强烈、最一致的相关性。减少反式脂肪酸(TFAs)、饱和脂肪酸和可自由支配的食物摄入(快餐和含糖饮料)与活产、临床妊娠率和相关ART结果的改善有关。在少数纳入的研究中,海鲜、乳制品和大豆的饮食成分显示出不一致的结果。更广泛的影响:由于异质性和关于大多数暴露的可用文献有限,没有足够的证据支持任何提高生育率的特定饮食方法。然而,遵循本综述中概述的一些饮食方法(抗炎饮食、减少TFA和可自由支配的食物摄入)符合广泛的健康饮食指南,几乎没有相关风险,并提供了一系列可能的好处。这值得在随机对照试验中进一步探索。
{"title":"Assessing the influence of preconception diet on female fertility: a systematic scoping review of observational studies.","authors":"Simon Alesi, Nahal Habibi, Thais Rasia Silva, Nicole Cheung, Sophia Torkel, Chau Thien Tay, Alejandra Quinteros, Hugo Winter, Helena Teede, Aya Mousa, Jessica A Grieger, Lisa J Moran","doi":"10.1093/humupd/dmad018","DOIUrl":"10.1093/humupd/dmad018","url":null,"abstract":"<p><strong>Background: </strong>Preconception diet is a proposed modifiable risk factor for infertility. However, there is no official guidance for women in the preconception period as to which dietary approaches may improve fertility.</p><p><strong>Objective and rationale: </strong>A comprehensive synthesis of the relevant evidence is key to determine the potentially effective dietary patterns and components as well as evidence gaps, and to provide information for nutritional recommendations for couples planning a pregnancy.</p><p><strong>Search methods: </strong>In this systematic scoping review, four electronic databases (Medline and EMBASE via Ovid processing, CAB Direct, and CINAHL via EBSCO) were searched for observational studies (prospective and retrospective cohort, cross-sectional, and case-control studies) from inception to 27 September 2021. Eligible studies included women of reproductive age during the preconception period, and evaluated exposures related to preconception diet and outcomes related to fertility. Results were synthesized using a descriptive approach.</p><p><strong>Outcomes: </strong>A total of 36 studies were eligible for inclusion (31 prospective, 3 cross-sectional, and 2 case-control studies) and were published between 2007 and 2022. Of the assessed dietary exposures, increased adherence to the Mediterranean diet displayed the strongest and most consistent association with improved clinical pregnancy rates. Reducing trans fatty acids (TFAs), saturated fatty acids, and discretionary food intake (fast food and sugar-sweetened beverages) were associated with improvements in live birth, clinical pregnancy rates, and related ART outcomes. The dietary components of seafood, dairy, and soy demonstrated inconsistent findings across the few included studies.</p><p><strong>Wider implications: </strong>Due to heterogeneity and the limited available literature on most exposures, there is insufficient evidence to support any specific dietary approach for improving fertility. However, following some of the dietary approaches outlined in this review (anti-inflammatory diets, reducing TFA, and discretionary food intake) are consistent with broad healthy eating guidelines, have little to no associated risk, and offer a plausible set of possible benefits. This warrants further exploration in randomized controlled trials.</p>","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":" ","pages":"811-828"},"PeriodicalIF":14.8,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10663051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9834686","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}
引用次数: 0
Dissecting mammalian reproduction with spatial transcriptomics. 用空间转录组学解剖哺乳动物生殖。
IF 14.8 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2023-11-02 DOI: 10.1093/humupd/dmad017
Xin Zhang, Qiqi Cao, Shreya Rajachandran, Edward J Grow, Melanie Evans, Haiqi Chen
<p><strong>Background: </strong>Mammalian reproduction requires the fusion of two specialized cells: an oocyte and a sperm. In addition to producing gametes, the reproductive system also provides the environment for the appropriate development of the embryo. Deciphering the reproductive system requires understanding the functions of each cell type and cell-cell interactions. Recent single-cell omics technologies have provided insights into the gene regulatory network in discrete cellular populations of both the male and female reproductive systems. However, these approaches cannot examine how the cellular states of the gametes or embryos are regulated through their interactions with neighboring somatic cells in the native tissue environment owing to tissue disassociations. Emerging spatial omics technologies address this challenge by preserving the spatial context of the cells to be profiled. These technologies hold the potential to revolutionize our understanding of mammalian reproduction.</p><p><strong>Objective and rationale: </strong>We aim to review the state-of-the-art spatial transcriptomics (ST) technologies with a focus on highlighting the novel biological insights that they have helped to reveal about the mammalian reproductive systems in the context of gametogenesis, embryogenesis, and reproductive pathologies. We also aim to discuss the current challenges of applying ST technologies in reproductive research and provide a sneak peek at what the field of spatial omics can offer for the reproduction community in the years to come.</p><p><strong>Search methods: </strong>The PubMed database was used in the search for peer-reviewed research articles and reviews using combinations of the following terms: 'spatial omics', 'fertility', 'reproduction', 'gametogenesis', 'embryogenesis', 'reproductive cancer', 'spatial transcriptomics', 'spermatogenesis', 'ovary', 'uterus', 'cervix', 'testis', and other keywords related to the subject area. All relevant publications until April 2023 were critically evaluated and discussed.</p><p><strong>Outcomes: </strong>First, an overview of the ST technologies that have been applied to studying the reproductive systems was provided. The basic design principles and the advantages and limitations of these technologies were discussed and tabulated to serve as a guide for researchers to choose the best-suited technologies for their own research. Second, novel biological insights into mammalian reproduction, especially human reproduction revealed by ST analyses, were comprehensively reviewed. Three major themes were discussed. The first theme focuses on genes with non-random spatial expression patterns with specialized functions in multiple reproductive systems; The second theme centers around functionally interacting cell types which are often found to be spatially clustered in the reproductive tissues; and the thrid theme discusses pathological states in reproductive systems which are often associated with unique
背景:哺乳动物的生殖需要两种特殊细胞的融合:卵母细胞和精子。除了产生配子外,生殖系统还为胚胎的适当发育提供了环境。解读生殖系统需要了解每种细胞类型的功能和细胞间的相互作用。最近的单细胞组学技术为男性和女性生殖系统的离散细胞群体中的基因调控网络提供了见解。然而,这些方法无法检测配子或胚胎的细胞状态是如何通过与天然组织环境中相邻体细胞的相互作用来调节的,这是由于组织分离。新兴的空间组学技术通过保留待分析细胞的空间背景来应对这一挑战。这些技术有可能彻底改变我们对哺乳动物繁殖的理解。目的和原理:我们旨在回顾最先进的空间转录组学(ST)技术,重点强调它们在配子发生、胚胎发生和生殖病理学的背景下帮助揭示的关于哺乳动物生殖系统的新生物学见解。我们还旨在讨论将ST技术应用于生殖研究的当前挑战,并窥探空间组学领域在未来几年可以为生殖界提供什么。搜索方法:使用PubMed数据库搜索同行评议的研究文章和评论,使用以下术语的组合:“空间组学”、“生育能力”、“生殖”、“配子发生”、“胚胎发生”、《癌症生殖》、“空间转录组学”,“精子发生”,“卵巢”、“子宫”、“宫颈”、“睾丸”和其他与主题领域相关的关键词。对截至2023年4月的所有相关出版物进行了严格评估和讨论。结果:首先,概述了已应用于生殖系统研究的ST技术。讨论并列出了这些技术的基本设计原则以及优点和局限性,以指导研究人员选择最适合自己研究的技术。其次,对ST分析揭示的哺乳动物繁殖,特别是人类繁殖的新生物学见解进行了全面综述。讨论了三个主要主题。第一个主题关注在多个生殖系统中具有特殊功能的具有非随机空间表达模式的基因;第二个主题围绕功能相互作用的细胞类型展开,这些细胞类型通常在生殖组织中空间聚集;第三个主题讨论了生殖系统中的病理状态,这些状态通常与独特的细胞微环境有关。最后,强调了当前应用ST技术研究哺乳动物繁殖的实验和计算挑战,并提供了应对这些挑战的潜在解决方案。讨论了空间组学技术的未来发展方向,以及它们将如何造福于人类生殖领域,包括细胞和组织动力学的捕获、多模式分子图谱和基因扰动的空间表征。更广泛的含义:与单细胞技术一样,空间组学技术在为哺乳动物繁殖提供重要而新颖的见解方面具有巨大的潜力。我们的综述总结了ST技术提供的这些新的生物学见解,同时揭示了未来的发展。我们的综述为生殖生物学家和临床医生提供了ST技术的最新进展。它还可以促进在基础和临床生殖研究中采用尖端的空间技术。
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引用次数: 0
PCOS during the menopausal transition and after menopause: a systematic review and meta-analysis. 绝经过渡期和绝经后多囊卵巢综合征:系统回顾和荟萃分析。
IF 14.8 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2023-11-02 DOI: 10.1093/humupd/dmad015
Mercedes Millán-de-Meer, Manuel Luque-Ramírez, Lía Nattero-Chávez, Héctor F Escobar-Morreale
<p><strong>Background: </strong>Current knowledge about the consequences of PCOS during the late reproductive years and after menopause is limited.</p><p><strong>Objective and rationale: </strong>We performed a systematic review and meta-analysis of data on the pathophysiology, clinical manifestations, diagnosis, prognosis, and treatment of women ≥45 years of age-peri- or postmenopausal-with PCOS.</p><p><strong>Search methods: </strong>Studies published up to 15 April 2023, identified by Entrez-PubMed, EMBASE, and Scopus online facilities, were considered. We included cross-sectional or prospective studies that reported data from peri- or postmenopausal patients with PCOS and control women with a mean age ≥45 years. Three independent researchers performed data extraction. Meta-analyses of quantitative data used random-effects models because of the heterogeneity derived from differences in study design and criteria used to define PCOS, among other confounding factors. Sensitivity analyses restricted the meta-analyses to population-based studies, to studies including only patients diagnosed using the most widely accepted definitions of PCOS, only menopausal women or only women not submitted to ovarian surgery, and studies in which patients and controls presented with similar indexes of weight excess. Quality of evidence was assessed using the GRADE system.</p><p><strong>Outcomes: </strong>The initial search identified 1400 articles, and another six were included from the reference lists of included articles; 476 duplicates were deleted. We excluded 868 articles for different reasons, leaving 37 valid studies for the qualitative synthesis, of which 28 studies-published in 41 articles-were considered for the quantitative synthesis and meta-analyses. Another nine studies were included only in the qualitative analyses. Compared with controls, peri- and postmenopausal patients with PCOS presented increased circulating total testosterone (standardized mean difference, SMD 0.78 (0.35, 1.22)), free androgen index (SMD 1.29 (0.89, 1.68)), and androstenedione (SMD 0.58 (0.23, 0.94)), whereas their sex hormone-binding globulin was reduced (SMD -0.60 (-0.76, -0.44)). Women with PCOS showed increased BMI (SMD 0.57 (0.32, 0.75)), waist circumference (SMD 0.64 (0.42, 0.86)), and waist-to-hip ratio (SMD 0.38 (0.14, 0.61)) together with increased homeostasis model assessment of insulin resistance (SMD 0.56 (0.27, 0.84)), fasting insulin (SMD 0.61 (0.38, 0.83)), fasting glucose (SMD 0.48 (0.29, 0.68)), and odds ratios (OR, 95% CI) for diabetes (OR 3.01 (1.91, 4.73)) compared to controls. Women with PCOS versus controls showed decreased HDL concentrations (SMD -0.32 (-0.46, -0.19)) and increased triglycerides (SMD 0.31 (0.16, 0.46)), even though total cholesterol and LDL concentrations, as well as the OR for dyslipidaemia, were similar to those of controls. The OR for having hypertension was increased in women with PCOS compared with controls (OR 1.79 (1.36, 2.36)).
背景:目前对多囊卵巢综合征在生育后期和绝经后的后果的了解有限。目的和原理:我们对≥45岁女性的病理生理学、临床表现、诊断、预后和治疗数据进行了系统回顾和荟萃分析 年龄为围绝经期或绝经后多囊卵巢综合征患者。检索方法:截至2023年4月15日发表的研究,由Entrez PubMed、EMBASE和Scopus在线机构鉴定,被考虑在内。我们纳入了横断面或前瞻性研究,这些研究报告了围绝经期或绝经后多囊卵巢综合征患者和平均年龄≥45岁的对照女性的数据 年。三名独立研究人员进行了数据提取。定量数据的荟萃分析使用了随机效应模型,因为研究设计和用于定义多囊卵巢综合征的标准的差异以及其他混杂因素导致了异质性。敏感性分析将荟萃分析局限于基于人群的研究,仅包括使用最广泛接受的多囊卵巢综合征定义诊断的患者,仅包括更年期妇女或未接受卵巢手术的妇女,以及患者和对照组出现类似超重指标的研究。使用GRADE系统评估证据质量。结果:最初的搜索确定了1400篇文章,另外6篇从收录文章的参考文献列表中被收录;删除476个重复项。由于不同原因,我们排除了868篇文章,剩下37项有效的研究用于定性合成,其中41篇文章中发表的28项研究用于定量合成和荟萃分析。另有9项研究仅包含在定性分析中。与对照组相比,围绝经期和绝经后多囊卵巢综合征患者的循环总睾酮(标准化平均差,SMD 0.78(0.35,1.22))、游离雄激素指数(SMD 1.29(0.89,1.68))和雄烯二酮(SMD 0.58(0.23,0.94))增加,而其性激素结合球蛋白降低(SMD-0.60(-0.76,-0.44))。患有多囊卵巢综合征的女性表现出BMI(SMD 0.57(0.32,0.75))、腰围(SMD 0.64(0.42,0.86))和腰臀比(SMD 0.38(0.14,0.61))增加,同时胰岛素抵抗(SMD 0.5 6(0.27,0.84))、空腹胰岛素(SMD 0.6 1(0.38,0.83))的稳态模型评估增加,与对照组相比,空腹血糖(SMD 0.48(0.29,0.68))和糖尿病的比值比(OR,95%CI)(OR 3.01(1.91,4.73))。尽管总胆固醇和低密度脂蛋白浓度以及血脂异常的OR与对照组相似,但患有多囊卵巢综合征的女性与对照组相比,HDL浓度降低(SMD-0.32(-0.46,-0.19)),甘油三酯升高(SMD 0.31(0.16,0.46))。与对照组相比,PCOS女性患高血压的OR升高(OR 1.79(1.36,2.36))。尽管心肌梗死(OR 2.51(1.08,5.81))和中风(OR 1.75(1.03,2.99))在PCOS女性中比对照组更普遍,在患者和对照组中相似。当将荟萃分析限制在多囊卵巢综合征女性和对照组平均BMI相似的研究中时,唯一具有统计学意义的差异是前者的高密度脂蛋白胆固醇浓度降低,而在绝经后多囊卵巢综合症女性和对照者BMI相似的两项研究中,患者的血清雄激素浓度增加,这表明无论肥胖与否,高雄激素血症在绝经后仍会持续。更广泛的影响:多囊卵巢综合征患者在生殖晚期和绝经后,雄激素过度似乎持续存在。大多数心脏代谢合并症是由超重和多囊卵巢综合征频繁共存引起的,这突出了在这一人群中针对肥胖的重要性。然而,纳入的研究之间存在显著的异质性,而且这里收集的证据质量总体较低,因此无法就这个问题得出明确的结论。因此,为了对这些妇女进行适当的管理,肯定需要从有力的前瞻性研究中得出指导方针。
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引用次数: 0
Obstetric and neonatal outcomes after natural versus artificial cycle frozen embryo transfer and the role of luteal phase support: a systematic review and meta-analysis. 自然与人工周期冷冻胚胎移植后的产科和新生儿结局以及黄体期支持的作用:一项系统回顾和荟萃分析
IF 13.3 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2023-09-05 DOI: 10.1093/humupd/dmad011
T R Zaat, E B Kostova, P Korsen, M G Showell, F Mol, M van Wely
<p><strong>Background: </strong>The number of frozen embryo transfers (FET) has increased dramatically over the past decade. Based on current evidence, there is no difference in pregnancy rates when natural cycle FET (NC-FET) is compared to artificial cycle FET (AC-FET) in subfertile women. However, NC-FET seems to be associated with lower risk of adverse obstetric and neonatal outcomes compared with AC-FET cycles. Currently, there is no consensus about whether NC-FET needs to be combined with luteal phase support (LPS) or not. The question of how to prepare the endometrium for FET has now gained even more importance and taken the dimension of safety into account as it should not simply be reduced to the basic question of effectiveness.</p><p><strong>Objective and rationale: </strong>The objective of this project was to determine whether NC-FET, with or without LPS, decreases the risk of adverse obstetric and neonatal outcomes compared with AC-FET.</p><p><strong>Search methods: </strong>A systematic review and meta-analysis was carried out. A literature search was performed using the following databases: CINAHL, EMBASE, and MEDLINE from inception to 10 October 2022. Observational studies, including cohort studies, and registries comparing obstetric and neonatal outcomes between singleton pregnancies after NC-FET and those after AC-FET were sought. Risk of bias was assessed using the ROBINS-I tool. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. We calculated pooled odds ratios (ORs), pooled risk differences (RDs), pooled adjusted ORs, and prevalence estimates with 95% CI using a random effect model, while heterogeneity was assessed by the I2.</p><p><strong>Outcomes: </strong>The conducted search identified 2436 studies, 890 duplicates were removed and 1546 studies were screened. Thirty studies (NC-FET n = 56 445; AC-FET n = 57 231) were included, 19 of which used LPS in NC-FET. Birthweight was lower following NC-FET versus AC-FET (mean difference 26.35 g; 95% CI 11.61-41.08, I2 = 63%). Furthermore NC-FET compared to AC-FET resulted in a lower risk of large for gestational age (OR 0.88, 95% 0.83-0.94, I2 = 54%), macrosomia (OR 0.81; 95% CI 0.71-0.93, I2 = 68%), low birthweight (OR 0.81, 95% CI 0.77-0.85, I2 = 41%), early pregnancy loss (OR 0.73; 95% CI 0.61-0.86, I2 = 70%), preterm birth (OR 0.80; 95% CI 0.75-0.85, I2 = 20%), very preterm birth (OR 0.66, 95% CI 0.53-0.84, I2 = 0%), hypertensive disorders of pregnancy (OR 0.60, 95% CI 0.50-0.65, I2 = 61%), pre-eclampsia (OR 0.50; 95% CI 0.42-0.60, I2 = 44%), placenta previa (OR 0.84, 95% CI 0.73-0.97, I2 = 0%), and postpartum hemorrhage (OR 0.43; 95% CI 0.38-0.48, I2 = 53%). Stratified analyses on LPS use in NC-FET suggested that, compared to AC-FET, NC-FET with LPS decreased preterm birth risk, while NC-FET without LPS did not (OR 0.75, 95% CI 0.70-0.81). LPS use did not modify the other outcomes. Heterogeneity varied from
背景:在过去的十年中,冷冻胚胎移植(FET)的数量急剧增加。根据目前的证据,在低生育能力妇女中,自然周期FET (NC-FET)与人工周期FET (AC-FET)相比,妊娠率没有差异。然而,与AC-FET周期相比,NC-FET似乎与较低的不良产科和新生儿结局风险相关。目前,对于NC-FET是否需要与黄体期支持(LPS)联合使用,尚未达成共识。如何为FET准备子宫内膜的问题现在变得更加重要,并考虑到安全方面,因为它不应简单地简化为有效性的基本问题。目的和理由:该项目的目的是确定与AC-FET相比,NC-FET在加或不加LPS的情况下是否降低了产科和新生儿不良结局的风险。检索方法:进行系统综述和荟萃分析。使用以下数据库进行文献检索:CINAHL、EMBASE和MEDLINE,检索时间为成立至2022年10月10日。观察性研究,包括队列研究,以及比较NC-FET和AC-FET后单胎妊娠的产科和新生儿结局的登记。使用ROBINS-I工具评估偏倚风险。采用建议分级评估、发展和评价方法评价证据质量。我们使用随机效应模型计算合并优势比(or)、合并风险差异(RDs)、合并调整后的or和95% CI的患病率估计值,同时通过I2评估异质性。结果:进行的检索确定了2436项研究,删除了890项重复,筛选了1546项研究。30项研究(NC-FET n = 56 445;共纳入AC-FET (n = 57 231),其中19例采用LPS处理NC-FET。与AC-FET相比,NC-FET的出生体重更低(平均差26.35 g;95% ci 11.61-41.08, i2 = 63%)。此外,与AC-FET相比,NC-FET导致大胎龄(OR 0.88, 95% 0.83-0.94, I2 = 54%)、巨大儿(OR 0.81;95% CI 0.71-0.93, I2 = 68%),低出生体重(OR 0.81, 95% CI 0.77-0.85, I2 = 41%),早孕丢失(OR 0.73;95% CI 0.61-0.86, I2 = 70%),早产(OR 0.80;95% CI 0.75-0.85, I2 = 20%),重度早产(OR 0.66, 95% CI 0.53-0.84, I2 = 0%),妊娠期高血压疾病(OR 0.60, 95% CI 0.50-0.65, I2 = 61%),先兆子痫(OR 0.50;95% CI 0.42-0.60, I2 = 44%)、前置胎盘(OR 0.84, 95% CI 0.73-0.97, I2 = 0%)和产后出血(OR 0.43;95% ci 0.38-0.48, i2 = 53%)。对LPS在NC-FET中使用的分层分析表明,与AC-FET相比,LPS的NC-FET降低了早产风险,而不使用LPS的NC-FET则没有(OR 0.75, 95% CI 0.70-0.81)。LPS的使用没有改变其他结果。异质性从低到高,证据质量从极低到中等。更广泛的影响:本研究证实,与AC-FET相比,NC-FET降低了不良产科和新生儿结局的风险。我们估计,对于每一种不良后果,使用NC-FET可预防每1000名妇女4至22例。因此,NC-FET应该是排卵周期接受FET的女性的首选治疗方法。基于非常低质量的证据,与AC-FET相比,在NC-FET中使用LPS可降低早产风险。然而,由于存在许多不确定性,主要是关于脂多糖使用的有效性的争论,因此需要对脂多糖的有效性和安全性进行进一步的研究,目前还不能对脂多糖的使用提出建议。
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引用次数: 5
Insights from Mendelian randomization and genetic correlation analyses into the relationship between endometriosis and its comorbidities. 对子宫内膜异位症及其合并症之间关系的孟德尔随机化和遗传相关性分析的见解。
IF 13.3 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2023-09-05 DOI: 10.1093/humupd/dmad009
Isabelle M McGrath, Grant W Montgomery, Sally Mortlock
<p><strong>Background: </strong>Endometriosis remains a poorly understood disease, despite its high prevalence and debilitating symptoms. The overlap in symptoms and the increased risk of multiple other traits in women with endometriosis is becoming increasingly apparent through epidemiological data. Genetic studies offer a method of investigating these comorbid relationships through the assessment of causal relationships with Mendelian randomization (MR), as well as identification of shared genetic variants and genes involved across traits. This has the capacity to identify risk factors for endometriosis as well as provide insight into the aetiology of disease.</p><p><strong>Objective and rationale: </strong>We aim to review the current literature assessing the relationship between endometriosis and other traits using genomic data, primarily through the methods of MR and genetic correlation. We critically examine the limitations of these studies in accordance with the assumptions of the utilized methods.</p><p><strong>Search methods: </strong>The PubMed database was used to search for peer-reviewed original research articles using the terms 'Mendelian randomization endometriosis' and '"genetic correlation" endometriosis'. Additionally, a Google Scholar search using the terms '"endometriosis" "mendelian randomization" "genetic correlation"' was performed. All relevant publications (n = 21) published up until 7 October 2022 were included in this review. Upon compilation of all traits with published MR and/or genetic correlation with endometriosis, additional epidemiological and genetic information on their comorbidity with endometriosis was sourced by searching for the trait in conjunction with 'endometriosis' on Google Scholar.</p><p><strong>Outcomes: </strong>The association between endometriosis and multiple pain, gynaecological, cancer, inflammatory, gastrointestinal, psychological, and anthropometric traits has been assessed using MR analysis and genetic correlation analysis. Genetic correlation analyses provide evidence that genetic factors contributing to endometriosis are shared with multiple traits: migraine, uterine fibroids, subtypes of ovarian cancer, melanoma, asthma, gastro-oesophageal reflux disease, gastritis/duodenitis, and depression, suggesting the involvement of multiple biological mechanisms in endometriosis. The assessment of causality with MR has revealed several potential causes (e.g. depression) and outcomes (e.g. ovarian cancer and uterine fibroids) of a genetic predisposition to endometriosis; however, interpretation of these results requires consideration of potential violations of the MR assumptions.</p><p><strong>Wider implications: </strong>Genomic studies have demonstrated that there is a molecular basis for the co-occurrence of endometriosis with other traits. Dissection of this overlap has identified shared genes and pathways, which provide insight into the biology of endometriosis. Thoughtful MR studies are neces
背景:尽管子宫内膜异位症的发病率很高,症状也使人衰弱,但它仍然是一种鲜为人知的疾病。流行病学数据显示,子宫内膜异位症患者的症状重叠和多种其他特征的风险增加越来越明显。遗传学研究提供了一种通过孟德尔随机化(MR)评估因果关系,以及识别共享遗传变异和跨性状相关基因来调查这些共病关系的方法。这有能力识别子宫内膜异位症的风险因素,并提供对疾病病因的见解。目的和原理:我们的目的是回顾目前使用基因组数据评估子宫内膜异位症和其他性状之间关系的文献,主要通过MR和遗传相关性的方法。我们根据所用方法的假设,严格审查了这些研究的局限性。搜索方法:PubMed数据库用于搜索同行评审的原始研究文章,使用术语“孟德尔随机化子宫内膜异位症”和“遗传相关性”子宫内膜异位病。此外,谷歌学者使用“子宫内膜异位症”、“孟德尔随机化”、“遗传相关性”进行了搜索。所有相关出版物(n = 截至2022年10月7日发布的21)包含在本综述中。在汇编了与子宫内膜异位症的已发表MR和/或遗传相关性的所有特征后,通过在Google Scholar上搜索与“子宫内膜异位”相关的特征,获得了关于其与子宫内膜内膜异位症共病的额外流行病学和遗传信息。结果:子宫内膜异位与多种疼痛、妇科、癌症、炎症、,胃肠道、心理和人体测量特征已经使用MR分析和遗传相关性分析进行了评估。遗传相关性分析表明,导致子宫内膜异位症的遗传因素具有多种特征:偏头痛、子宫肌瘤、卵巢癌症亚型、黑色素瘤、哮喘、胃食管反流病、胃炎/十二指肠炎和抑郁症,这表明子宫内膜异位病涉及多种生物学机制。对MR因果关系的评估揭示了子宫内膜异位症遗传易感性的几个潜在原因(如抑郁症)和结果(如卵巢癌症和子宫肌瘤);然而,对这些结果的解释需要考虑潜在的违反MR假设的情况。更广泛的意义:基因组研究表明,子宫内膜异位症与其他特征共同发生是有分子基础的。对这种重叠的解剖已经确定了共享的基因和途径,这为子宫内膜异位症的生物学提供了见解。为了确定子宫内膜异位症合并症的因果关系,有必要进行深思熟虑的MR研究。考虑到7-11岁子宫内膜异位症的诊断延迟 多年来,确定危险因素对于帮助诊断和减轻疾病负担是必要的。识别子宫内膜异位症是一个危险因素的特征对于患者的整体治疗和咨询很重要。利用基因组数据来理清子宫内膜异位症与其他特征的重叠,为子宫内膜异位的病因提供了见解。
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引用次数: 2
Uterus transplantation: from research, through human trials and into the future. 子宫移植:从研究,到人体试验,再到未来。
IF 13.3 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2023-09-05 DOI: 10.1093/humupd/dmad012
Mats Brännström, Catherine Racowsky, Marie Carbonnel, Joseph Wu, Antonio Gargiulo, Eli Y Adashi, Jean Marc Ayoubi

Women suffering from absolute uterine factor infertility (AUFI) had no hope of childbearing until clinical feasibility of uterus transplantation (UTx) was documented in 2014 with the birth of a healthy baby. This landmark accomplishment followed extensive foundational work with a wide range of animal species including higher primates. In the present review, we provide a summary of the animal research and describe the results of cases and clinical trials on UTx. Surgical advances for graft removal from live donors and transplantation to recipients are improving, with a recent trend away from laparotomy to robotic approaches, although challenges persist regarding optimum immunosuppressive therapies and tests for graft rejection. Because UTx does not involve transplantation of the Fallopian tubes, IVF is required as part of the UTx process. We provide a unique focus on the intersection between these two processes, with consideration of when oocyte retrieval should be performed, whether, and for whom, preimplantation genetic testing for aneuploidy should be used, whether oocytes or embryos should be frozen and when the first embryo transfer should be performed post-UTx. We also address the utility of an international society UTx (ISUTx) registry for assessing overall UTx success rates, complications, and live births. The long-term health outcomes of all parties involved-the uterus donor (if live donor), the recipient, her partner and any children born from the transplanted graft-are also reviewed. Unlike traditional solid organ transplantation procedures, UTx is not lifesaving, but is life-giving, although as with traditional types of transplantation, costs, and ethical considerations are inevitable. We discuss the likelihood that costs will decrease as efficiency and efficacy improve, and that ethical complexities for and against acceptability of the procedure sharpen the distinctions between genetic, gestational, and social parenthood. As more programs wish to offer the procedure, we suggest a scheme for setting up a UTx program as well as future directions of this rapidly evolving field. In our 2010 review, we described the future of clinical UTx based on development of the procedure in animal models. This Grand Theme Review offers a closing loop to this previous review of more than a decade ago. The clinical feasibility of UTx has now been proved. Advancements include widening the criteria for acceptance of donors and recipients, improving surgery, shortening time to pregnancy, and improving post-UTx management. Together, these improvements catalyze the transition of UTx from experimental into mainstream clinical practice. The procedure will then represent a realistic and accessible alternative to gestational surrogacy for the treatment of AUFI and should become part of the armamentarium of reproductive specialists worldwide.

患有绝对子宫因素性不孕症(AUFI)的女性没有生育的希望,直到2014年子宫移植(UTx)的临床可行性被证明,并生下了一个健康的婴儿。这一具有里程碑意义的成就是在对包括高等灵长类动物在内的广泛动物物种进行了广泛的基础工作之后取得的。在本综述中,我们提供了动物研究的总结,并描述了UTx的病例和临床试验结果。尽管在最佳免疫抑制疗法和移植排斥试验方面仍然存在挑战,但活体供体移植和移植给受体的手术进展正在改善,最近的趋势是从剖腹手术到机器人手术。由于UTx不涉及输卵管移植,IVF是UTx过程的一部分。我们对这两个过程之间的交叉提供了独特的关注,考虑到何时应该进行卵母细胞提取,是否以及为谁应该使用非整倍体植入前基因检测,卵母细胞或胚胎是否应该冷冻,以及何时应该在utx后进行第一次胚胎移植。我们还讨论了国际社会UTx (ISUTx)登记在评估总体UTx成功率、并发症和活产方面的效用。所有相关方的长期健康结果——子宫供体(如果是活体供体)、接受者、她的伴侣和任何移植后出生的孩子——也会被回顾。与传统的实体器官移植程序不同,UTx不是挽救生命,而是赋予生命,尽管与传统类型的移植一样,成本和伦理考虑是不可避免的。我们讨论了成本随着效率和疗效的提高而降低的可能性,以及赞成和反对该程序可接受性的伦理复杂性,使遗传、妊娠和社会亲子关系之间的区别更加明显。随着越来越多的程序希望提供该程序,我们提出了建立UTx程序的方案以及这一快速发展领域的未来方向。在我们2010年的综述中,我们基于动物模型手术的发展描述了临床UTx的未来。这个大主题评论提供了一个闭合的循环,这是十多年前的评论。UTx的临床可行性现已得到证实。进展包括扩大接受供体和受者的标准、改进手术、缩短妊娠时间和改进utx术后管理。总之,这些改进促进了UTx从实验到主流临床实践的转变。该程序将代表一个现实的和可获得的替代妊娠代孕治疗AUFI,并应成为世界各地的生殖专家的装备的一部分。
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引用次数: 4
Advances in non-hormonal male contraception targeting sperm motility. 针对精子活力的非激素男性避孕研究进展。
IF 13.3 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2023-09-05 DOI: 10.1093/humupd/dmad008
Noemia A P Mariani, Joana V Silva, Margarida Fardilha, Erick J R Silva
<p><strong>Background: </strong>The high rates of unintended pregnancy and the ever-growing world population impose health, economic, social, and environmental threats to countries. Expanding contraceptive options, including male methods, are urgently needed to tackle these global challenges. Male contraception is limited to condoms and vasectomy, which are unsuitable for many couples. Thus, novel male contraceptive methods may reduce unintended pregnancies, meet the contraceptive needs of couples, and foster gender equality in carrying the contraceptive burden. In this regard, the spermatozoon emerges as a source of druggable targets for on-demand, non-hormonal male contraception based on disrupting sperm motility or fertilization.</p><p><strong>Objective and rationale: </strong>A better understanding of the molecules governing sperm motility can lead to innovative approaches toward safe and effective male contraceptives. This review discusses cutting-edge knowledge on sperm-specific targets for male contraception, focusing on those with crucial roles in sperm motility. We also highlight challenges and opportunities in male contraceptive drug development targeting spermatozoa.</p><p><strong>Search methods: </strong>We conducted a literature search in the PubMed database using the following keywords: 'spermatozoa', 'sperm motility', 'male contraception', and 'drug targets' in combination with other related terms to the field. Publications until January 2023 written in English were considered.</p><p><strong>Outcomes: </strong>Efforts for developing non-hormonal strategies for male contraception resulted in the identification of candidates specifically expressed or enriched in spermatozoa, including enzymes (PP1γ2, GAPDHS, and sAC), ion channels (CatSper and KSper), transmembrane transporters (sNHE, SLC26A8, and ATP1A4), and surface proteins (EPPIN). These targets are usually located in the sperm flagellum. Their indispensable roles in sperm motility and male fertility were confirmed by genetic or immunological approaches using animal models and gene mutations associated with male infertility due to sperm defects in humans. Their druggability was demonstrated by the identification of drug-like small organic ligands displaying spermiostatic activity in preclinical trials.</p><p><strong>Wider implications: </strong>A wide range of sperm-associated proteins has arisen as key regulators of sperm motility, providing compelling druggable candidates for male contraception. Nevertheless, no pharmacological agent has reached clinical developmental stages. One reason is the slow progress in translating the preclinical and drug discovery findings into a drug-like candidate adequate for clinical development. Thus, intense collaboration among academia, private sectors, governments, and regulatory agencies will be crucial to combine expertise for the development of male contraceptives targeting sperm function by (i) improving target structural characterization a
背景:高意外怀孕率和不断增长的世界人口给各国带来健康、经济、社会和环境威胁。迫切需要扩大避孕选择,包括男性避孕方法,以应对这些全球挑战。男性避孕仅限于避孕套和输精管结扎,这对许多夫妇来说是不适合的。因此,新型男性避孕方法可以减少意外怀孕,满足夫妇的避孕需求,促进性别平等承担避孕负担。在这方面,精子作为一种药物靶点的来源出现,以破坏精子活力或受精为基础的按需非激素男性避孕。目的和理由:更好地了解控制精子运动的分子可以为安全有效的男性避孕药带来创新的方法。本文综述了男性避孕中精子特异性靶点的前沿知识,重点讨论了那些在精子运动中起关键作用的靶点。我们还强调了针对精子的男性避孕药开发的挑战和机遇。检索方法:我们在PubMed数据库中使用以下关键词进行文献检索:“精子”、“精子活力”、“男性避孕”和“药物靶点”,并结合该领域的其他相关术语。在2023年1月之前以英文撰写的出版物也被考虑在内。结果:对男性避孕的非激素策略的研究发现了精子中特异性表达或丰富的候选物质,包括酶(pp1 γ - 2、GAPDHS和sAC)、离子通道(CatSper和KSper)、跨膜转运蛋白(sNHE、SLC26A8和ATP1A4)和表面蛋白(EPPIN)。这些靶标通常位于精子鞭毛中。它们在精子活力和男性生育能力中不可或缺的作用已通过遗传学或免疫学方法通过动物模型和与人类精子缺陷导致的男性不育相关的基因突变得到证实。通过在临床前试验中鉴定出具有抑精活性的药物样小有机配体,证明了它们的药物性。更广泛的影响:广泛的精子相关蛋白已经成为精子运动的关键调节因子,为男性避孕提供了令人信服的药物候选物。然而,目前还没有药物达到临床发展阶段。其中一个原因是将临床前和药物发现转化为适合临床开发的候选药物进展缓慢。因此,学术界、私营部门、政府和监管机构之间的密切合作对于结合针对精子功能的男性避孕药开发的专业知识至关重要,方法是:(i)改进目标结构特征和高选择性配体的设计,(ii)进行长期的临床前安全性、有效性和可逆性评估,以及(iii)为临床试验和监管评估建立严格的指导方针和终点。因此可以在人类身上进行试验。
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引用次数: 2
Opening the black box: why do euploid blastocysts fail to implant? A systematic review and meta-analysis. 打开黑盒子:为什么整倍体囊胚不能植入?系统回顾和荟萃分析。
IF 13.3 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2023-09-05 DOI: 10.1093/humupd/dmad010
Danilo Cimadomo, Laura Rienzi, Alessandro Conforti, Eric Forman, Stefano Canosa, Federica Innocenti, Maurizio Poli, Jenna Hynes, Laura Gemmell, Alberto Vaiarelli, Carlo Alviggi, Filippo Maria Ubaldi, Antonio Capalbo
<p><strong>Background: </strong>A normal chromosomal constitution defined through PGT-A assessing all chromosomes on trophectoderm (TE) biopsies represents the strongest predictor of embryo implantation. Yet, its positive predictive value is not higher than 50-60%. This gap of knowledge on the causes of euploid blastocysts' reproductive failure is known as 'the black box of implantation'.</p><p><strong>Objective and rationale: </strong>Several embryonic, maternal, paternal, clinical, and IVF laboratory features were scrutinized for their putative association with reproductive success or implantation failure of euploid blastocysts.</p><p><strong>Search methods: </strong>A systematic bibliographical search was conducted without temporal limits up to August 2021. The keywords were '(blastocyst OR day5 embryo OR day6 embryo OR day7 embryo) AND (euploid OR chromosomally normal OR preimplantation genetic testing) AND (implantation OR implantation failure OR miscarriage OR abortion OR live birth OR biochemical pregnancy OR recurrent implantation failure)'. Overall, 1608 items were identified and screened. We included all prospective or retrospective clinical studies and randomized-controlled-trials (RCTs) that assessed any feature associated with live-birth rates (LBR) and/or miscarriage rates (MR) among non-mosaic euploid blastocyst transfer after TE biopsy and PGT-A. In total, 41 reviews and 372 papers were selected, clustered according to a common focus, and thoroughly reviewed. The PRISMA guideline was followed, the PICO model was adopted, and ROBINS-I and ROB 2.0 scoring were used to assess putative bias. Bias across studies regarding the LBR was also assessed using visual inspection of funnel plots and the trim and fill method. Categorical data were combined with a pooled-OR. The random-effect model was used to conduct the meta-analysis. Between-study heterogeneity was addressed using I2. Whenever not suitable for the meta-analysis, the included studies were simply described for their results. The study protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number CRD42021275329).</p><p><strong>Outcomes: </strong>We included 372 original papers (335 retrospective studies, 30 prospective studies and 7 RCTs) and 41 reviews. However, most of the studies were retrospective, or characterized by small sample sizes, thus prone to bias, which reduces the quality of the evidence to low or very low. Reduced inner cell mass (7 studies, OR: 0.37, 95% CI: 0.27-0.52, I2 = 53%), or TE quality (9 studies, OR: 0.53, 95% CI: 0.43-0.67, I2 = 70%), overall blastocyst quality worse than Gardner's BB-grade (8 studies, OR: 0.40, 95% CI: 0.24-0.67, I2 = 83%), developmental delay (18 studies, OR: 0.56, 95% CI: 0.49-0.63, I2 = 47%), and (by qualitative analysis) some morphodynamic abnormalities pinpointed through time-lapse microscopy (abnormal cleavage patterns, spontaneous blastocyst collapse, longer time of morula formation I, time of blastulation
背景:通过在滋养外胚层(TE)活检中评估所有染色体的PGT-A定义的正常染色体结构是胚胎着床的最强预测因子。但其阳性预测值不高于50-60%。关于整倍体囊胚繁殖失败原因的这一知识缺口被称为“植入的黑盒子”。目的和理由:研究了胚胎、母体、父亲、临床和试管婴儿实验室的一些特征,以确定它们与整倍体囊胚生殖成功或着床失败的关系。检索方法:进行了系统的书目检索,没有时间限制,截止到2021年8月。关键词是“(囊胚或第5天胚胎或第6天胚胎或第7天胚胎)和(整倍体或染色体正常或着床前基因检测)和(着床或着床失败或流产或流产或活产或生化妊娠或反复着床失败)”。总共鉴定和筛选了1608个项目。我们纳入了所有前瞻性或回顾性临床研究和随机对照试验(rct),这些研究评估了TE活检和PGT-A后非嵌合整倍体囊胚移植中与活产率(LBR)和/或流产率(MR)相关的任何特征。共有41篇综述和372篇论文被选中,根据共同的焦点聚类,并进行了彻底的审查。遵循PRISMA指南,采用PICO模型,采用ROBINS-I和rob2.0评分法评估推定偏倚。关于LBR的研究偏差也通过漏斗图的目视检查和修剪填充法进行评估。分类数据与汇总或合并。采用随机效应模型进行meta分析。使用I2解决了研究间的异质性。凡是不适合纳入meta分析的研究,均对其结果进行简单描述。研究方案在http://www.crd.york.ac.uk/PROSPERO/注册(注册号CRD42021275329)。结果:我们纳入了372篇原始论文(335篇回顾性研究、30篇前瞻性研究和7篇随机对照试验)和41篇综述。然而,大多数研究是回顾性的,或者样本量小,因此容易产生偏倚,这使得证据的质量降低到低或非常低。减少内细胞质量(7项研究,OR: 0.37, 95% CI: 0.27-0.52, I2 = 53%),或TE质量(9项研究,OR: 0.53, 95% CI: 0.43-0.67, I2 = 70%),囊胚质量总体差于Gardner's bb级(8项研究,OR: 0.40, 95% CI: 0.24-0.67, I2 = 83%),发育迟缓(18项研究,OR: 0.56, 95% CI:0.49-0.63, I2 = 47%),并且(通过定性分析)通过延时显微镜发现的一些形态动力学异常(卵裂模式异常、囊胚自发塌陷、桑葚胚形成时间较长I、囊胚时间(tB)和囊胚持续时间)都与较差的生殖结局相关。即使在PGT-A的背景下,在≥38岁的女性中也报道了略低的LBR(7项研究,OR: 0.87, 95% CI: 0.75-1.00, I2 = 31%),而肥胖与较低的LBR(2项研究,OR: 0.66, 95% CI: 0.55-0.79, I2 = 0%)和较高的MR(2项研究,OR: 1.8, 95% CI: 1.08-2.99, I2 = 52%)相关。既往多次植入失败(RIF)的经历也与较低的LBR相关(3项研究,OR: 0.72, 95% CI: 0.55-0.93, I2 = 0%)。通过定性分析,在激素评估中,只有移植前的孕酮水平异常与PGT-A后的LBR和MR相关。在所采用的临床方案中,PGT-A后玻璃化加热胚胎移植比新鲜胚胎移植更有效(2项研究,OR: 1.56, 95% CI: 1.05-2.33, I2 = 23%)。最后,多次玻璃化-升温循环(2项研究,OR: 0.41, 95% CI: 0.22-0.77, I2 = 50%)或(通过定性分析)大量细胞活检可能会略微降低LBR,而同时开放透明带和TE活检比第3天孵化方案(3项研究,OR: 1.41, 95% CI: 1.18-1.69, I2 = 0%)的结果更好。更广泛的含义:胚胎选择的目的是缩短怀孕时间,同时尽量减少生殖风险。因此,了解哪些特征与整倍体囊胚的生殖能力相关,对于定义、实施和验证更安全、更有效的临床工作流程至关重要。今后的研究应侧重于:(i)系统地调查除新发染色体异常之外的生殖衰老机制,以及生活方式和营养如何可能加速或加剧其后果;(ii)改进对子宫和囊胚-子宫内膜对话的评估,两者本身都代表黑盒子;(iii)胚胎评估和体外受精方案的标准化/自动化;(iv)额外的侵入性或最好是非侵入性的胚胎选择工具。 只有填补了这些空白,我们才有可能最终破解“植入黑匣子”背后的谜题。
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引用次数: 3
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Human Reproduction Update
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