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Reproductive ability in survivors of childhood, adolescent, and young adult Hodgkin lymphoma: a review. 儿童，青少年和青年霍奇金淋巴瘤幸存者的生殖能力:综述。
IF 13.3 1区 医学 Q1 OBSTETRICS & GYNECOLOGY
Human Reproduction Update
Pub Date : 2023-07-05 DOI: 10.1093/humupd/dmad002
Katja C E Drechsel, Maxime C F Pilon, Francis Stoutjesdijk, Salena Meivis, Linda J Schoonmade, William Hamish B Wallace, Eline van Dulmen-den Broeder, Auke Beishuizen, Gertjan J L Kaspers, Simone L Broer, Margreet A Veening
<p><strong>Background: </strong>Owing to a growing number of young and adolescent Hodgkin lymphoma (HL) survivors, awareness of (long-term) adverse effects of anticancer treatment increases. The risk of impaired reproductive ability is of great concern given its impact on quality of life. There is currently no review available on fertility after childhood HL treatment.</p><p><strong>Objective and rationale: </strong>The aim of this narrative review was to summarize existing literature on different aspects of reproductive function in male and female childhood, adolescent, and young adult HL survivors.</p><p><strong>Search methods: </strong>PubMed and EMBASE were searched for articles evaluating fertility in both male and female HL survivors aged <25 years at diagnosis. In females, anti-Müllerian hormone (AMH), antral follicle count, premature ovarian insufficiency (POI), acute ovarian failure, menstrual cycle, FSH, and pregnancy/live births were evaluated. In males, semen-analysis, serum FSH, inhibin B, LH, testosterone, and reports on pregnancy/live births were included. There was profound heterogeneity among studies and a lack of control groups; therefore, no meta-analyses could be performed. Results were presented descriptively and the quality of studies was not assessed individually.</p><p><strong>Outcomes: </strong>After screening, 75 articles reporting on reproductive markers in childhood or adolescent HL survivors were included. Forty-one papers reported on 5057 female HL survivors. The incidence of POI was 6-34% (median 9%; seven studies). Signs of diminished ovarian reserve or impaired ovarian function were frequently seen (low AMH 55-59%; median 57%; two studies. elevated FSH 17-100%; median 53%; seven studies). Most survivors had regular menstrual cycles. Fifty-one studies assessed fertility in 1903 male HL survivors. Post-treatment azoospermia was highly prevalent (33-100%; median 75%; 29 studies). Long-term follow-up data were limited, but reports on recovery of semen up to 12 years post-treatment exist. FSH levels were often elevated with low inhibin B (elevated FSH 0-100%; median 51.5%; 26 studies. low inhibin B 19-50%; median 45%; three studies). LH and testosterone levels were less evidently affected (elevated LH 0-57%, median 17%; 21 studies and low testosterone 0-43%; median 6%; 15 studies). In both sexes, impaired reproductive ability was associated with a higher dose of cumulative chemotherapeutic agents and pelvic radiotherapy. The presence of abnormal markers before treatment indicated that the disease itself may also negatively affect reproductive function (Females: AMH<p10 9%; one study and Males: azoospermia 0-50%; median 10%; six studies). Reports on chance to achieve pregnancy during survivorship are reassuring, although studies had their limitations and the results are difficult to evaluate. In the end, a diminished ovarian reserve does not exclude the chance of a live birth, and males with aberrant markers may still b
背景:由于越来越多的年轻和青少年霍奇金淋巴瘤(HL)幸存者，人们对抗癌治疗(长期)不良反应的认识也在增加。鉴于生殖能力受损的危险对生活质量的影响，令人极为关切。目前尚无关于儿童HL治疗后生育能力的综述。目的和理由:本综述的目的是总结现有的关于男性和女性儿童、青少年和青年HL幸存者生殖功能不同方面的文献。检索方法:检索PubMed和EMBASE中评估老年男性和女性HL幸存者生育能力的文章。结果:筛选后，纳入了75篇报告儿童或青少年HL幸存者生殖标志物的文章。41篇论文报道了5057名女性HL幸存者。POI的发生率为6-34%(中位数为9%;七个研究)。卵巢储备能力下降或卵巢功能受损的迹象是常见的(低AMH 55-59%;中值57%;两项研究。FSH升高17-100%;中值53%;七个研究)。大多数幸存者月经周期正常。51项研究评估了1903名男性HL幸存者的生育能力。治疗后无精子症发生率高(33-100%;中值75%;29研究)。长期随访数据有限，但存在治疗后12年精液恢复的报告。FSH水平常因抑制素B低而升高(FSH升高0-100%;中值51.5%;26的研究。抑制素B低19-50%;中值45%;三个研究)。LH和睾酮水平受影响不太明显(LH升高0-57%，中位数17%;21项研究和低睾酮0-43%;中值6%;15研究)。在两性中，生殖能力受损与较高剂量的累积化疗药物和盆腔放疗有关。治疗前异常标志物的存在表明疾病本身也可能对生殖功能产生负面影响(女性:amh更广泛的意义:本综述证实了HL治疗对性腺功能的负面影响，因此年轻HL幸存者应被告知他们未来的生殖生活，并应考虑保留生育能力。目前证据水平不足，需要对HL和(目前的)治疗方案对生殖功能的影响进行更多的试验。在这篇综述中，我们提出了可评估的生殖标记和(重复)测量的时间。
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引用次数: 2
Angiogenesis in abnormal uterine bleeding: a narrative review. 异常子宫出血中的血管生成：叙述性综述。
IF 14.8 1区 医学 Q1 OBSTETRICS & GYNECOLOGY
Human Reproduction Update
Pub Date : 2023-07-05 DOI: 10.1093/humupd/dmad004
Mei-An Middelkoop, Emma E Don, Wouter J K Hehenkamp, Nicole J Polman, Arjan W Griffioen, Judith A F Huirne
<p><strong>Background: </strong>Abnormal uterine bleeding (AUB) has a significant socioeconomic impact since it considerably impacts quality of life. Therapeutic options are frequently based on trial and error and do not target disease aetiology. Pathophysiological insight in this disease is required for the development of novel treatment options. If no underlying cause is found for the AUB (e.g. fibroids, adenomyosis, polyps), endometrial-AUB (AUB-E) is usually caused by a primary endometrium disorder. When AUB is induced by prescribed (exogenous) hormones, it is classified as iatrogenic-AUB (AUB-I). Considering vascular modulation and function, AUB-E and AUB-I both could potentially result from abnormal vascularization in the endometrium due to alterations in the process of angiogenesis and vascular maturation.</p><p><strong>Objective and rationale: </strong>We aim to investigate the fundamental role of angiogenesis and vascular maturation in patients with AUB and hypothesize that aberrant endometrial angiogenesis has an important role in the aetiology of both AUB-E and AUB-I, possibly through different mechanisms.</p><p><strong>Search methods: </strong>A systematic literature search was performed until September 2021 in the Cochrane Library Databases, Embase, PubMed, and Web of Science, with search terms such as angiogenesis and abnormal uterine bleeding. Included studies reported on angiogenesis in the endometrium of premenopausal women with AUB-E or AUB-I. Case reports, letters, reviews, editorial articles, and studies on AUB with causes classified by the International Federation of Gynecology and Obstetrics as myometrial, oncological, or infectious, were excluded. Study quality was assessed by risk of bias, using the Cochrane tool and the Newcastle-Ottawa Scale.</p><p><strong>Outcomes: </strong>Thirty-five out of 2158 articles were included. In patients with AUB-E, vascular endothelial growth factor A and its receptors (1 and 2), as well as the angiopoietin-1:angiopoietin-2 ratio and Tie-1, were significantly increased. Several studies reported on the differential expression of other pro- and antiangiogenic factors in patients with AUB-E, suggesting aberrant vascular maturation and impaired vessel integrity. Overall, endometrial microvessel density (MVD) was comparable in patients with AUB-E and controls. Interestingly, patients with AUB-I showed a higher MVD and higher expression of proangiogenic factors when compared to controls, in particular after short-term hormone exposure. This effect was gradually lost after longer-term exposure, while alterations in vessel maturation were observed after both short- and long-term exposures.</p><p><strong>Wider implications: </strong>AUB-E and AUB-I are most likely associated with aberrant endometrial angiogenesis and impaired vessel maturation. This review supports existing evidence that increased proangiogenic and decreased antiangiogenic factors cause impaired vessel maturation, resulting in more
背景：异常子宫出血（AUB）对社会经济产生了重大影响，因为它严重影响了人们的生活质量。治疗方案往往以反复试验为基础，并不针对疾病病因。要开发新的治疗方案，就必须深入了解这种疾病的病理生理学。如果找不到 AUB 的潜在病因（如子宫肌瘤、腺肌症、息肉），子宫内膜-AUB（AUB-E）通常是由原发性子宫内膜病变引起的。如果 AUB 是由处方（外源性）激素诱发的，则归类为先天性 AUB（AUB-I）。考虑到血管的调节和功能，AUB-E 和 AUB-I 都可能是由于血管生成和血管成熟过程中的改变导致子宫内膜血管异常所致：我们旨在研究血管生成和血管成熟在AUB患者中的基本作用，并假设异常的子宫内膜血管生成在AUB-E和AUB-I的病因学中具有重要作用，可能通过不同的机制：截至 2021 年 9 月，我们在 Cochrane Library Databases、Embase、PubMed 和 Web of Science 中进行了系统的文献检索，检索词包括血管生成和异常子宫出血。纳入的研究报告了患有 AUB-E 或 AUB-I 的绝经前妇女子宫内膜的血管生成情况。病例报告、信件、综述、社论文章，以及国际妇产科联盟归类为子宫肌瘤、肿瘤或感染性病因的 AUB 研究均被排除在外。研究质量采用科克伦工具和纽卡斯尔-渥太华量表（Newcastle-Ottawa Scale）根据偏倚风险进行评估：2158篇文章中有35篇被纳入。在 AUB-E 患者中，血管内皮生长因子 A 及其受体（1 和 2）以及血管生成素-1:血管生成素-2 比率和 Tie-1 均显著增加。一些研究报告称，AUB-E 患者体内其他促血管生成因子和抗血管生成因子的表达存在差异，这表明血管成熟异常和血管完整性受损。总体而言，AUB-E 患者的子宫内膜微血管密度（MVD）与对照组相当。有趣的是，与对照组相比，AUB-I 患者的微血管密度更高，促血管生成因子的表达也更高，尤其是在短期激素暴露后。这种效应在长期暴露后逐渐消失，而在短期和长期暴露后都观察到了血管成熟的改变：更广泛的影响：AUB-E 和 AUB-I 很可能与子宫内膜血管生成异常和血管成熟受损有关。本综述支持现有的证据，即促血管生成因子的增加和抗血管生成因子的减少会导致血管成熟受损，从而使血管更脆弱、更易渗透。这与我们的假设不谋而合，这些机制似乎在 AUB-E 和 AUB-I 的病理生理学中发挥了重要作用。探索这些患者血管生成的变化，可以为 AUB 的治疗提供靶点。
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引用次数: 0
Total fertilization failure after ICSI: insights into pathophysiology, diagnosis, and management through artificial oocyte activation. ICSI后完全受精失败:通过人工卵母细胞激活的病理生理，诊断和管理的见解。
IF 13.3 1区 医学 Q1 OBSTETRICS & GYNECOLOGY
Human Reproduction Update
Pub Date : 2023-07-05 DOI: 10.1093/humupd/dmad007
Gerard Campos, Romualdo Sciorio, Sandro C Esteves
<p><strong>Background: </strong>Total fertilization failure (TFF) is the failure of all metaphase II oocytes to fertilize in ART cycles. The phenomenon represents a known cause of infertility, affecting 1-3% of ICSI cycles. Oocyte activation deficiency (OAD) is the leading cause of fertilization failure, attributed to sperm- or oocyte-related issues, although until recently little attention has been given to oocyte-related deficiencies. Different strategies for overcoming TFF have been proposed in clinical settings, mainly using artificial oocyte activation (AOA) by calcium ionophores. Typically, AOA has been blindly applied with no previous diagnosis testing and, therefore, not considering the origin of the deficiency. The scarcity of data available and the heterogeneous population subjected to AOA make it challenging to draw firm conclusions about the efficacy and safety of AOA treatments.</p><p><strong>Objective and rationale: </strong>TFF leads to an unexpected, premature termination of ART, which inflicts a substantial psychological and financial burden on patients. This review aims to provide a substantial update on: the pathophysiology of fertilization failure, focusing both on sperm- and oocyte-related factors; the relevance of diagnostic testing to determine the cause of OAD; and the effectiveness and safety of AOA treatments to overcome fertilization failure.</p><p><strong>Search methods: </strong>Relevant studies were identified in the English-language literature using PubMed search terms, including fertilization failure, AOA, phospholipase C zeta (PLCζ), PLCZ1 mutations, oocyte-related factors, wee1-like protein kinase 2 (WEE2) mutations, PAT1 homolog 2 (PATL2) mutations, tubulin beta-8 chain (TUBB8) mutations, and transducin-like enhancer protein 6 (TLE6) mutations. All relevant publications until November 2022 were critically evaluated and discussed.</p><p><strong>Outcomes: </strong>Fertilization failure after ART has been predominantly associated with PLCζ deficiencies in sperm. The reason relates to the well-established inability of defective PLCζ to trigger the characteristic pattern of intracellular Ca2+ oscillations responsible for activating specific molecular pathways in the oocyte that lead to meiosis resumption and completion. However, oocyte deficiencies have recently emerged to play critical roles in fertilization failure. Specifically, mutations have been identified in genes such as WEE2, PATL2, TUBB8, and TLE6. Such mutations translate into altered protein synthesis that results in defective transduction of the physiological Ca2+ signal needed for maturation-promoting factor (MPF) inactivation, which is indispensable for oocyte activation. The effectiveness of AOA treatments is closely related to identifying the causal factor of fertilization failure. Various diagnostic tests have been developed to determine the cause of OAD, including heterologous and homologous tests, particle image velocimetry, immunostaining, and ge
背景:全受精失败(Total fertilfailure, TFF)是指在ART周期中所有中期卵母细胞都不能受精。这种现象是一种已知的不育原因，影响了1-3%的ICSI周期。卵母细胞激活缺陷(OAD)是受精失败的主要原因，归因于精子或卵母细胞相关问题，尽管直到最近才引起卵母细胞相关缺陷的关注。克服TFF的不同策略已在临床提出，主要是利用钙离子载体人工卵母细胞活化(AOA)。通常，AOA被盲目应用，没有先前的诊断测试，因此没有考虑缺陷的起源。由于现有数据的缺乏和接受AOA治疗的人群的异质性，因此很难得出关于AOA治疗的有效性和安全性的确切结论。目的和理由:TFF导致抗逆转录病毒治疗的意外过早终止，给患者造成巨大的心理和经济负担。这篇综述的目的是提供一个实质性的更新:受精失败的病理生理，重点是精子和卵细胞相关因素;诊断检测确定OAD病因的相关性;AOA处理克服受精失败的有效性和安全性。检索方法:使用PubMed检索词在英文文献中检索相关研究，包括受精失败、AOA、磷脂酶Cζ (PLCζ)、PLCZ1突变、卵母细胞相关因子、wee1样蛋白激酶2 (WEE2)突变、PAT1同源物2 (PATL2)突变、微管蛋白β -8链(TUBB8)突变和转导样增强蛋白6 (TLE6)突变。对2022年11月之前的所有相关出版物进行了批判性评估和讨论。结果:抗逆转录病毒治疗后受精失败主要与精子中PLCζ缺乏有关。原因是有缺陷的PLCζ无法触发细胞内Ca2+振荡的特征模式，这些振荡负责激活卵母细胞中导致减数分裂恢复和完成的特定分子途径。然而，最近发现卵母细胞缺陷在受精失败中起着关键作用。具体来说，在WEE2、PATL2、TUBB8和TLE6等基因中发现了突变。这些突变转化为蛋白质合成的改变，导致成熟促进因子(MPF)失活所需的生理Ca2+信号转导缺陷，而MPF失活对于卵母细胞活化是必不可少的。AOA处理的有效性与确定受精失败的原因密切相关。已经开发了各种诊断测试来确定OAD的病因，包括异源和同源测试、颗粒图像测速、免疫染色和基因测试。在此基础上，已有研究表明，基于诱导钙振荡的传统AOA策略在克服plc - ζ-精子不足导致的受精失败方面非常有效。相比之下，卵母细胞相关缺陷可能成功地管理使用替代AOA启动子，诱导MPF失活和减数分裂恢复。这些试剂包括环己亚胺、N,N,N'，N'-四(2-吡啶基甲基)乙烷-1,2-二胺(TPEN)、罗斯维汀和WEE2互补RNA。此外，当OAD是由卵母细胞不成熟引起时，应用改良的卵巢刺激方案和触发器可以改善受精。更广泛的意义:AOA治疗是一种很有前途的治疗方法，可以克服由精子和卵母细胞相关因素引起的受精失败。诊断受精失败的原因对提高AOA治疗的有效性和安全性至关重要。尽管大多数数据没有显示AOA对着床前和着床后胚胎发育的不良影响，但相关文献很少，最近主要使用小鼠的研究表明，AOA可能会导致胚胎和后代的表观遗传改变。在获得更可靠的数据之前，尽管获得了令人鼓舞的结果，但AOA在临床应用时应谨慎，并且必须经过适当的患者咨询。目前，AOA应该被视为一种创新的治疗方法，而不是一种既定的治疗方法。
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引用次数: 0
Contribution of semen to early embryo development: fertilization and beyond. 精液对早期胚胎发育的贡献:受精及以后。
IF 13.3 1区 医学 Q1 OBSTETRICS & GYNECOLOGY
Human Reproduction Update
Pub Date : 2023-07-05 DOI: 10.1093/humupd/dmad006
Montserrat Vallet-Buisan, Rajwa Mecca, Celine Jones, Kevin Coward, Marc Yeste
<p><strong>Background: </strong>It has long been thought that the factors affecting embryo and foetal development were exclusively maternally derived; hence, if issues regarding fertility and embryo development were to arise, the blame has traditionally been placed solely on the mother. An escalating interest in how paternal factors influence embryo development, however, has begun to prove otherwise. Evidence suggests that both seminal plasma (SP) and sperm contribute multiple factors that shape embryogenesis. This review thus focuses on the role that semen has in driving early embryonic development, and describes how paternal factors, such as SP, sperm centriole, sperm proteins, sperm RNA, sperm DNA, and its integrity, together with epigenetics, may influence the female reproductive tract and post-fertilization events. The important contributions of paternal factors to embryo development highlight the imperative need for further research in this area, which is sure to bring forth breakthroughs leading to improvements in infertility diagnosis and ART as well as reducing the risk of miscarriage.</p><p><strong>Objective and rationale: </strong>This review provides a comprehensive overview of the role of human semen in development of the early embryo, with the aim of providing a better understanding of the influence of SP and sperm on early embryonic divisions, gene and protein expression, miscarriage, and congenital diseases.</p><p><strong>Search methods: </strong>PubMed searches were performed using the terms 'sperm structure', 'capacitation', 'acrosome reaction', 'fertilization', 'oocyte activation', 'PLCζ', 'PAWP', 'sperm-borne oocyte activation factor', 'oocyte activation deficiency', 'sperm centriole', 'sperm transport', 'sperm mitochondria', 'seminal plasma', 'sperm epigenetics', 'sperm histone modifications', 'sperm DNA methylation', 'sperm-derived transcripts', 'sperm-derived proteins', 'sperm DNA fragmentation', 'sperm mRNA', 'sperm miRNAs', 'sperm piRNAs', and 'sperm-derived aneuploidy'. The reviewed articles were restricted to those published in English between 1980 and 2022.</p><p><strong>Outcomes: </strong>The data suggest that male-derived factors contribute much more than just the male haploid genome to the early embryo. Evidence indicates that semen contributes multiple factors that help shape the fate of embryogenesis. These male-derived factors include contributions from SP, the paternal centriole, RNA and proteins, and DNA integrity. In addition, epigenetic changes have an impact on the female reproductive tract, fertilization, and early stages of embryo development. For example, recent proteomic and transcriptomic studies have identified several sperm-borne markers that play important roles in oocyte fertilization and embryogenesis.</p><p><strong>Wider implications: </strong>This review highlights that several male-derived factors are required to work in tandem with female counterparts to allow for correct fertilization and deve
背景:长期以来，人们一直认为影响胚胎和胎儿发育的因素完全来自母体;因此，如果出现有关生育能力和胚胎发育的问题，传统上只归咎于母亲。然而，对父亲因素如何影响胚胎发育的兴趣日益浓厚，已经开始证明事实并非如此。有证据表明，精浆和精子都是影响胚胎发生的多种因素。因此，本文将重点介绍精液在推动早期胚胎发育中的作用，并描述诸如SP、精子中心粒、精子蛋白、精子RNA、精子DNA及其完整性以及表观遗传学等父系因素如何影响女性生殖道和受精后事件。父系因素对胚胎发育的重要贡献凸显了这一领域进一步研究的必要性，这一领域的研究必将带来突破，从而提高不孕症诊断和抗逆转录病毒治疗的水平，降低流产的风险。目的与理由:本文综述了人类精液在早期胚胎发育中的作用，旨在更好地了解SP和精子对早期胚胎分裂、基因和蛋白质表达、流产和先天性疾病的影响。搜索方法:PubMed检索使用以下术语进行:“精子结构”、“获能”、“顶体反应”、“受精”、“卵母细胞激活”、“PLCζ”、“PAWP”、“精子携带的卵母细胞激活因子”、“卵母细胞激活缺陷”、“精子中心粒”、“精子运输”、“精子线粒体”、“精液”、“精子表观遗传学”、“精子组蛋白修饰”、“精子DNA甲基化”、“精子衍生转录本”、“精子衍生蛋白质”、“精子DNA片段化”、“精子mRNA”、“精子miRNAs”、“精子mRNA”和“精子miRNAs”。“精子pirna”和“精子衍生的非整倍体”。被审查的文章仅限于1980年至2022年间用英文发表的文章。结果:数据表明，男性来源的因素对早期胚胎的贡献远不止男性单倍体基因组。有证据表明，精液有多种因素影响胚胎发生的命运。这些雄性来源的因素包括SP、父本中心粒、RNA和蛋白质以及DNA完整性的贡献。此外，表观遗传变化对女性生殖道、受精和胚胎发育的早期阶段也有影响。例如，最近的蛋白质组学和转录组学研究已经确定了几个在卵母细胞受精和胚胎发生中起重要作用的精子遗传标记。更广泛的意义:这篇综述强调了几个男性衍生的因素需要与女性对应的因素协同工作，以允许正确的受精和早期胚胎的发育。更深入地了解从精子细胞传递到胚胎的父系因素的作用，可以从男科的角度阐明如何改善抗逆转录病毒治疗。进一步的研究可能有助于防止遗传和表观遗传异常的传递，从而减少男性因素不育的发生率。此外，了解父亲贡献的确切机制可能有助于生殖科学家和体外受精临床医生确定复发性早期流产或受精失败的新原因。
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引用次数: 5
Beyond apoptosis: evidence of other regulated cell death pathways in the ovary throughout development and life. 细胞凋亡之外：卵巢在整个发育和生命过程中存在其他受调控的细胞死亡途径的证据。
IF 13.3 1区 医学 Q1 OBSTETRICS & GYNECOLOGY
Human Reproduction Update
Pub Date : 2023-07-05 DOI: 10.1093/humupd/dmad005
Jessica M Stringer, Lauren R Alesi, Amy L Winship, Karla J Hutt
<p><strong>Background: </strong>Regulated cell death is a fundamental component of numerous physiological processes; spanning from organogenesis in utero, to normal cell turnover during adulthood, as well as the elimination of infected or damaged cells throughout life. Quality control through regulation of cell death pathways is particularly important in the germline, which is responsible for the generation of offspring. Women are born with their entire supply of germ cells, housed in functional units known as follicles. Follicles contain an oocyte, as well as specialized somatic granulosa cells essential for oocyte survival. Follicle loss-via regulated cell death-occurs throughout follicle development and life, and can be accelerated following exposure to various environmental and lifestyle factors. It is thought that the elimination of damaged follicles is necessary to ensure that only the best quality oocytes are available for reproduction.</p><p><strong>Objective and rationale: </strong>Understanding the precise factors involved in triggering and executing follicle death is crucial to uncovering how follicle endowment is initially determined, as well as how follicle number is maintained throughout puberty, reproductive life, and ovarian ageing in women. Apoptosis is established as essential for ovarian homeostasis at all stages of development and life. However, involvement of other cell death pathways in the ovary is less established. This review aims to summarize the most recent literature on cell death regulators in the ovary, with a particular focus on non-apoptotic pathways and their functions throughout the discrete stages of ovarian development and reproductive life.</p><p><strong>Search methods: </strong>Comprehensive literature searches were carried out using PubMed and Google Scholar for human, animal, and cellular studies published until August 2022 using the following search terms: oogenesis, follicle formation, follicle atresia, oocyte loss, oocyte apoptosis, regulated cell death in the ovary, non-apoptotic cell death in the ovary, premature ovarian insufficiency, primordial follicles, oocyte quality control, granulosa cell death, autophagy in the ovary, autophagy in oocytes, necroptosis in the ovary, necroptosis in oocytes, pyroptosis in the ovary, pyroptosis in oocytes, parthanatos in the ovary, and parthanatos in oocytes.</p><p><strong>Outcomes: </strong>Numerous regulated cell death pathways operate in mammalian cells, including apoptosis, autophagic cell death, necroptosis, and pyroptosis. However, our understanding of the distinct cell death mediators in each ovarian cell type and follicle class across the different stages of life remains the source of ongoing investigation. Here, we highlight recent evidence for the contribution of non-apoptotic pathways to ovarian development and function. In particular, we discuss the involvement of autophagy during follicle formation and the role of autophagic cell death, necroptosis, py
背景：受调控的细胞死亡是许多生理过程的基本组成部分；从子宫内的器官发生，到成年期的正常细胞转换，以及在一生中消除感染或受损的细胞。通过调节细胞死亡途径进行质量控制在负责后代产生的种系中尤为重要。女性出生时拥有全部生殖细胞，这些生殖细胞位于卵泡的功能单元中。卵泡包含一个卵母细胞，以及对卵母细胞生存至关重要的特殊体细胞颗粒细胞。通过调节细胞死亡导致的卵泡损失发生在整个卵泡发育和生活过程中，并且在暴露于各种环境和生活方式因素后会加速。人们认为，消除受损卵泡是必要的，以确保只有最优质的卵母细胞才能繁殖。目的和原理：了解触发和执行卵泡死亡的确切因素对于揭示卵泡禀赋是如何最初确定的，以及卵泡数量是如何在女性的青春期、生殖期和卵巢衰老中保持的至关重要。细胞凋亡被认为是卵巢在发育和生命的各个阶段稳态所必需的。然而，卵巢中其他细胞死亡途径的参与尚不明确。这篇综述旨在总结关于卵巢细胞死亡调节因子的最新文献，特别关注非凋亡途径及其在卵巢发育和生殖生活的各个阶段的功能。搜索方法：使用PubMed和Google Scholar对2022年8月之前发表的人类、动物和细胞研究进行了全面的文献搜索，搜索词如下：卵子发生、卵泡形成、卵泡闭锁、卵母细胞丢失、卵细胞凋亡、卵巢调节性细胞死亡、卵巢非凋亡细胞死亡、，原始卵泡、卵母细胞质量控制、颗粒细胞死亡、卵巢自噬、卵母体内自噬、卵巢坏死、卵母内坏死、卵巢焦下垂、卵母中焦下垂、卵巢parthanatos和卵母细胞parthanato。结果：哺乳动物细胞中存在许多受调控的细胞死亡途径，包括凋亡、自噬细胞死亡、坏死和焦下垂。然而，我们对生命不同阶段每种卵巢细胞类型和卵泡类别中不同细胞死亡介质的理解仍然是正在进行的研究的来源。在这里，我们强调了非凋亡途径对卵巢发育和功能的贡献的最新证据。特别是，我们讨论了自噬在卵泡形成过程中的参与，以及自噬细胞死亡、坏死、pyroptosis和parthanatos在卵泡闭锁过程中的作用，特别是在对生理应激源（如氧化应激）的反应中。更广泛的含义：提高对卵巢中每种受调控细胞死亡途径作用的认识对于理解卵巢发育以及在整个生命周期中维持卵巢功能至关重要。这些信息不仅有助于我们了解女性的内分泌健康、生殖健康和生育能力，而且有助于确定新的生育保护目标。
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引用次数: 4
The impact of primary ciliary dyskinesia on female and male fertility: a narrative review. 原发性纤毛运动障碍对女性和男性生育能力的影响:综述。
IF 13.3 1区 医学 Q1 OBSTETRICS & GYNECOLOGY
Human Reproduction Update
Pub Date : 2023-05-02 DOI: 10.1093/humupd/dmad003
Lydia Newman, Jagrati Chopra, Claire Dossett, Elizabeth Shepherd, Amelia Bercusson, Mary Carroll, Woolf Walker, Jane S Lucas, Ying Cheong

Background: Primary ciliary dyskinesia (PCD) is a genetic condition affecting the structure and function of sperm flagellum and motile cilia including those in the male and female reproductive tracts. Infertility is a commonly reported feature of PCD, but there is uncertainty as to how best to counsel patients on their fertility prognosis.

Objective and rationale: This review aimed to summarize the prevalence of subfertility, possible underlying mechanisms, and the success of ART in men and women with PCD. The efficacy of ART in this patient group is relatively unknown and, hence, the management of infertility in PCD patients remains a challenge. There are no previous published or registered systematic reviews of fertility outcomes in PCD.

Search methods: Systematic literature searches were performed in Medline, Embase, Cochrane Library, and PubMed electronic databases to identify publications between 1964 and 2022 reporting fertility outcomes in men and women with PCD. Publications were excluded if they reported only animal studies, where gender was not specified or where subjects had a medical co-morbidity also known to impact fertility. Quality of evidence was assessed by critical appraisal and application of an appraisal tool for cross-sectional studies. The primary outcomes were natural conception in men and women with PCD, and conception following ART in men and women with PCD.

Outcomes: A total of 1565 publications were identified, and 108 publications were included after screening by two independent researchers. The quality of available evidence was low. The exact prevalence of subfertility in PCD is unclear but appears to be higher in men (up to 83% affected) compared to women (up to 61% affected). Variation in the prevalence of subfertility was observed between geographic populations which may be explained by differences in underlying genotype and cilia function. Limited evidence suggests subfertility in affected individuals is likely caused by abnormal cilia motion in the fallopian tubes, endometrium and efferent ductules, and dysmotile sperm. Some men and women with PCD benefited from ART, which suggests its use should be considered in the management of subfertility in this patient group. Further epidemiological and controlled studies are needed to determine the predictors of fertility and optimal management in this patient group.

Wider implications: It is important that patients with PCD receive evidence-based counselling about the potential impact of their condition on their fertility prognosis and what management options may be available to them if affected. Understanding the pathophysiology and optimal management of subfertility in PCD will increase our understanding of the role of cilia and the impact of wider secondary ciliopathies on reproduction.

背景:原发性纤毛运动障碍(PCD)是一种影响精子鞭毛和活动纤毛结构和功能的遗传性疾病，包括男性和女性生殖道的纤毛。不孕症是PCD的常见特征，但如何最好地咨询患者的生育预后尚不确定。目的和理由:本综述旨在总结不孕不育的患病率，可能的潜在机制，以及抗逆转录病毒治疗在男性和女性PCD中的成功。ART在这一患者群体中的疗效尚不清楚，因此，PCD患者不孕的管理仍然是一个挑战。以前没有关于PCD生育结果的已发表或已注册的系统综述。检索方法:在Medline、Embase、Cochrane Library和PubMed电子数据库中进行系统文献检索，以确定1964年至2022年间报道PCD男性和女性生育结果的出版物。如果出版物仅报道动物研究，且未指定性别，或受试者患有已知也会影响生育的合并症，则将其排除在外。证据质量通过批判性评价和应用横向研究的评价工具来评估。主要结果为PCD患者的自然受孕，以及PCD患者接受ART治疗后的受孕。结果:共纳入1565篇文献，经两名独立研究者筛选后纳入108篇文献。现有证据的质量很低。PCD中生育能力低下的确切患病率尚不清楚，但似乎男性(高达83%)高于女性(高达61%)。观察到不同地理人群的低生育能力患病率的差异，这可能是由潜在基因型和纤毛功能的差异来解释的。有限的证据表明，受影响个体的生育能力低下可能是由输卵管、子宫内膜和传出小管中的纤毛运动异常以及精子运动障碍引起的。一些患有PCD的男性和女性受益于ART，这表明应考虑将其用于治疗该患者群体的生育能力低下。需要进一步的流行病学和对照研究来确定该患者群体的生育预测因素和最佳管理。更广泛的意义:重要的是，PCD患者接受基于证据的咨询，了解他们的病情对其生育预后的潜在影响，以及如果受到影响，他们可以获得哪些管理选择。了解PCD的病理生理学和生育能力低下的最佳管理将增加我们对纤毛的作用和更广泛的继发性纤毛病对生殖的影响的理解。
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引用次数: 5
What is the optimal GnRH antagonist protocol for ovarian stimulation during ART treatment? A systematic review and network meta-analysis. ART 治疗期间卵巢刺激的最佳 GnRH 拮抗剂方案是什么？系统综述和网络荟萃分析。
IF 14.8 1区 医学 Q1 OBSTETRICS & GYNECOLOGY
Human Reproduction Update
Pub Date : 2023-05-02 DOI: 10.1093/humupd/dmac040
C A Venetis, A Storr, S J Chua, B W Mol, S Longobardi, X Yin, T D'Hooghe
<p><strong>Background: </strong>Several GnRH antagonist protocols are currently used during COS in the context of ART treatments; however, questions remain regarding whether these protocols are comparable in terms of efficacy and safety.</p><p><strong>Objective and rationale: </strong>A systematic review followed by a pairwise and network meta-analyses were performed. The systematic review and pairwise meta-analysis of direct comparative data according to the PRISMA guidelines evaluated the effectiveness of different GnRH antagonist protocols (fixed Day 5/6 versus flexible, ganirelix versus cetrorelix, with or without hormonal pretreatment) on the probability of live birth and ongoing pregnancy after COS during ART treatment. A frequentist network meta-analysis combining direct and indirect comparisons (using the long GnRH agonist protocol as the comparator) was also performed to enhance the precision of the estimates.</p><p><strong>Search methods: </strong>The systematic literature search was performed using Embase (Ovid), MEDLINE (Ovid), Cochrane Central Register of Trials (CENTRAL), SCOPUS and Web of Science (WOS), from inception until 23 November 2021. The search terms comprised three different MeSH terms that should be present in the identified studies: GnRH antagonist; assisted reproduction treatment; randomized controlled trial (RCT). Only studies published in English were included.</p><p><strong>Outcomes: </strong>The search strategy resulted in 6738 individual publications, of which 102 were included in the systematic review (corresponding to 75 unique studies) and 73 were included in the meta-analysis. Most studies were of low quality. One study compared a flexible protocol with a fixed Day 5 protocol and the remaining RCTs with a fixed Day 6 protocol. There was a lack of data regarding live birth when comparing the flexible and fixed GnRH antagonist protocols or cetrorelix and ganirelix. No significant difference in live birth rate was observed between the different pretreatment regimens versus no pretreatment or between the different pretreatment protocols. A flexible GnRH antagonist protocol resulted in a significantly lower OPR compared with a fixed Day 5/6 protocol (relative risk (RR) 0.76, 95% CI 0.62 to 0.94, I2 = 0%; 6 RCTs; n = 907 participants; low certainty evidence). There were insufficient data for a comparison of cetrorelix and ganirelix for OPR. OCP pretreatment was associated with a lower OPR compared with no pretreatment intervention (RR 0.79, 95% CI 0.69 to 0.92; I2 = 0%; 5 RCTs, n = 1318 participants; low certainty evidence). Furthermore, in the network meta-analysis, a fixed protocol with OCP resulted in a significantly lower OPR than a fixed protocol with no pretreatment (RR 0.84, 95% CI 0.71 to 0.99; moderate quality evidence). The surface under the cumulative ranking (SUCRA) scores suggested that the fixed protocol with no pretreatment is the antagonist protocol most likely (84%) to result in the highest OPR. Ther
背景：目前在抗逆转录病毒疗法的 COS 期间使用了几种 GnRH 拮抗剂方案；但是，这些方案在疗效和安全性方面是否具有可比性仍存在疑问：进行了系统综述以及配对分析和网络荟萃分析。根据 PRISMA 指南对直接比较数据进行的系统综述和配对荟萃分析评估了不同 GnRH 拮抗剂方案（固定第 5/6 天与灵活第 5/6 天、加尼瑞克与西曲瑞克、有无激素预处理）对 ART 治疗期间 COS 后活产和持续妊娠概率的有效性。为了提高估计值的精确度，还进行了频数网络荟萃分析，将直接比较和间接比较结合起来（使用长GnRH激动剂方案作为比较对象）：使用Embase（Ovid）、MEDLINE（Ovid）、Cochrane中央试验登记（CENTRAL）、SCOPUS和Web of Science（WOS）进行了系统性文献检索，检索时间从开始到2021年11月23日。检索词包括三个不同的 MeSH 词，这些词应出现在已确定的研究中：GnRH拮抗剂；辅助生殖治疗；随机对照试验（RCT）。仅纳入以英文发表的研究：搜索策略共获得 6738 篇文献，其中 102 篇被纳入系统综述（相当于 75 项独特的研究），73 篇被纳入荟萃分析。大多数研究质量不高。一项研究比较了灵活方案和固定的第 5 天方案，其余的研究则比较了固定的第 6 天方案。在比较灵活和固定的 GnRH 拮抗剂方案或西曲瑞克和加尼瑞克时，缺乏有关活产的数据。不同预处理方案与无预处理方案或不同预处理方案之间的活产率没有明显差异。与固定的第5/6天方案相比，灵活的GnRH拮抗剂方案可显著降低OPR（相对风险（RR）0.76，95% CI 0.62至0.94，I2 = 0%；6项研究；n = 907名参与者；低确定性证据）。没有足够的数据对西曲瑞克和加尼瑞克治疗 OPR 进行比较。与无预处理干预相比，OCP 预处理与较低的 OPR 相关（RR 0.79，95% CI 0.69 至 0.92；I2 = 0%；5 项 RCT，n = 1318 名参与者；低确定性证据）。此外，在网络荟萃分析中，与无预处理的固定方案相比，使用 OCP 的固定方案可显著降低 OPR（RR 0.84，95% CI 0.71 至 0.99；中等质量证据）。累积排名（SUCRA）得分表明，无预处理的固定方案是最有可能（84%）导致最高 OPR 的拮抗剂方案。在卵巢过度刺激综合征和流产率等其他结果方面，固定/灵活或 OCP 预处理/无预处理干预之间存在差异的证据不足：现有证据大多质量不高、确定性不高，这些证据表明，在临床决策中不应将不同的拮抗剂方案视为等同方案。需要进行更多试验，以评估加尼瑞克与西曲瑞克的比较效果、不同预处理干预措施（如孕激素或雌二醇）的效果或灵活方案中启动拮抗剂的不同标准的效果。此外，还需要进行更多的研究，探讨对卵巢刺激反应高或低的妇女使用 GnRH 拮抗剂的最佳方案。
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引用次数: 0
Epigenetic clocks provide clues to the mystery of uterine ageing. 表观遗传时钟为解开子宫老化之谜提供了线索。
IF 13.3 1区 医学 Q1 OBSTETRICS & GYNECOLOGY
Human Reproduction Update
Pub Date : 2023-05-02 DOI: 10.1093/humupd/dmac042
Pavel I Deryabin, Aleksandra V Borodkina
<p><strong>Background: </strong>Rising maternal ages and age-related fertility decline are a global challenge for modern reproductive medicine. Clinicians and researchers pay specific attention to ovarian ageing and hormonal insufficiency in this regard. However, uterine ageing is often left out of the picture, with the majority of reproductive clinicians being close to unanimous on the absence of age-related functional decline in the uterine tissues. Therefore, most existing techniques to treat an age-related decline in implantation rates are based primarily on hormonal supplementation and oocyte donation. Solving the issue of uterine ageing might lead to an adjustment to these methods.</p><p><strong>Objective and rationale: </strong>A focus on uterine ageing and the possibility of slowing it emerged with the development of the information theory of ageing, which identifies genomic instability and erosion of the epigenetic landscape as important drivers of age-related decline in the functionality of most cells and tissues. Age-related smoothing of this landscape and a decline in tissue function can be assessed by measuring the ticking of epigenetic clocks. Within this review, we explore whether the uterus experiences age-related alterations using this elegant approach. We analyse existing data on epigenetic clocks in the endometrium, highlight approaches to improve the accuracy of the clocks in this cycling tissue, speculate on the endometrial pathologies whose progression might be predicted by the altered speed of epigenetic clocks and discuss the possibilities of slowing down the ticking of these clocks.</p><p><strong>Search methods: </strong>Data for this review were identified by searches of Medline, PubMed and Google Scholar. References from relevant articles using the search terms 'ageing', 'maternal age', 'female reproduction', 'uterus', 'endometrium', 'implantation', 'decidualization', 'epigenetic clock', 'biological age', 'DNA methylation', 'fertility' and 'infertility' were selected. A total of 95 articles published in English between 1985 and 2022 were included, six of which describe the use of the epigenetic clock to evaluate uterine/endometrium ageing.</p><p><strong>Outcomes: </strong>Application of the Horvath and DNAm PhenoAge epigenetic clocks demonstrated a poor correlation with chronological age in the endometrium. Several approaches were suggested to enhance the predictive power of epigenetic clocks for the endometrium. The first was to increase the number of samples in the training dataset, as for the Zang clock, or to use more sophisticated clock-building algorithms, as for the AltumAge clock. The second method is to adjust the clocks according to the dynamic nature of the endometrium. Using either approach revealed a strong correlation with chronological age in the endometrium, providing solid evidence for age-related functional decline in this tissue. Furthermore, age acceleration/deceleration, as estimated by epigenetic c
背景:产妇年龄上升和与年龄相关的生育率下降是现代生殖医学面临的全球性挑战。临床医生和研究人员在这方面特别关注卵巢老化和激素不足。然而，子宫衰老往往被排除在画面之外，大多数生殖临床医生几乎一致认为子宫组织中没有与年龄相关的功能衰退。因此，大多数现有的治疗年龄相关性着床率下降的技术主要是基于激素补充和卵母细胞捐赠。解决子宫老化问题可能会导致对这些方法的调整。目的和理由:随着衰老信息理论的发展，对子宫衰老及其减缓的可能性的关注出现了，该理论认为基因组不稳定和表观遗传景观的侵蚀是大多数细胞和组织功能与年龄相关的衰退的重要驱动因素。通过测量表观遗传时钟的滴答声，可以评估与年龄相关的这种景观的平滑和组织功能的下降。在这篇综述中，我们探讨子宫是否经历与年龄相关的改变使用这种优雅的方法。我们分析了子宫内膜表观遗传时钟的现有数据，强调了提高这种循环组织中时钟准确性的方法，推测了子宫内膜病理的进展可能通过表观遗传时钟的改变速度来预测，并讨论了减缓这些时钟滴答声的可能性。检索方法:本综述的数据通过Medline、PubMed和Google Scholar进行检索。从相关文章中选择了使用搜索词“衰老”、“母亲年龄”、“女性生殖”、“子宫”、“子宫内膜”、“植入”、“去个性化”、“表观遗传时钟”、“生物年龄”、“DNA甲基化”、“生育能力”和“不孕症”的参考文献。从1985年到2022年，共收录了95篇英文文章，其中6篇描述了使用表观遗传时钟来评估子宫/子宫内膜老化。结果:Horvath和DNAm表型表观遗传时钟的应用表明，子宫内膜与实足年龄的相关性较差。提出了几种方法来增强表观遗传时钟对子宫内膜的预测能力。第一种方法是增加训练数据集中的样本数量，就像Zang时钟一样，或者使用更复杂的时钟构建算法，就像AltumAge时钟一样。第二种方法是根据子宫内膜的动态特性来调整生物钟。使用任何一种方法都显示子宫内膜与实足年龄有很强的相关性，为该组织与年龄相关的功能衰退提供了确凿的证据。此外，通过表观遗传时钟估计的年龄加速/减速可能是一种很有前途的工具，可以预测或深入了解各种子宫内膜病理的起源，包括复发性植入失败、癌症和子宫内膜异位症。最后，有几种策略可以减缓甚至逆转表观遗传时钟，从而降低与年龄相关的子宫损伤的风险。更广泛的影响:应该考虑子宫因素，以及卵巢问题，以纠正女性生育能力随着年龄的下降。表观遗传时钟可以测试，以获得对各种子宫内膜疾病更深入的了解。
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引用次数: 5
Obstetric, neonatal, and child health outcomes following embryo biopsy for preimplantation genetic testing. 胚胎植入前基因检测活检后的产科、新生儿和儿童健康结果。
IF 13.3 1区 医学 Q1 OBSTETRICS & GYNECOLOGY
Human Reproduction Update
Pub Date : 2023-05-02 DOI: 10.1093/humupd/dmad001
Alessandra Alteri, Greta Chiara Cermisoni, Mirko Pozzoni, Gerarda Gaeta, Paolo Ivo Cavoretto, Paola Viganò

Background: Preimplantation genetic testing (PGT) of embryos developed in vitro requires a biopsy for obtaining cellular samples for the analysis. Signs of cell injury have been described in association with this procedure. Thus, the consequences of the biopsy on obstetric and neonatal outcomes have been the subject of some quantitative analyses, although the reliability of data pooling may be limited by important issues in the various reports.

Objective and rationale: The present review identifies evidence for whether pregnancies conceived after embryo biopsy are associated with a higher risk of adverse obstetric, neonatal, and long-term outcomes. Available evidence has been summarized considering manipulation at various stages of embryo development.

Search methods: We used the scoping review methodology. Searches of article databases were performed with keywords pertaining to the embryo biopsy technique and obstetric, neonatal, and postnatal outcomes. Studies in which embryos were biopsied at different stages (i.e. both at the cleavage and blastocyst stages) were excluded. We included data on fresh and frozen embryo transfers. The final sample of 31 documents was subjected to qualitative thematic analysis.

Outcomes: Sound evidence is lacking to fully address the issues on the potential obstetric, neonatal or long-term consequences of embryo biopsy. For polar body biopsy, the literature is too scant to draw any conclusion. Some data, although limited and controversial, suggest a possible association of embryo biopsy at the cleavage stage with an increased risk of low birthweight and small for gestational age neonates compared to babies derived from non-biopsied embryos. An increase in preterm deliveries and birth defects in cases of trophectoderm biopsy was suggested. For both biopsy methods (at the cleavage and blastocyst stages), an increased risk for hypertensive disorders of pregnancy was found. However, these findings may be explained by confounders such as other embryo manipulation procedures or by intrinsic patient or population characteristics.

Wider implications: Since there is inadequate evidence to assess obstetric, neonatal, and long-term health outcomes following embryo biopsy, an invasive PGT strategy should be developed with a cautious approach. A non-invasive approach, based on the analysis of embryo cell-free DNA, needs to be pursued to overcome the potential limitations of embryo biopsy.

背景:体外胚胎的植入前遗传学检测(PGT)需要进行活组织检查以获得细胞样本进行分析。细胞损伤的迹象已被描述与此过程有关。因此，活检对产科和新生儿结局的影响一直是一些定量分析的主题，尽管数据汇集的可靠性可能受到各种报告中重要问题的限制。目的和理由:本综述确定了胚胎活检后妊娠是否与较高的不良产科、新生儿和长期预后风险相关的证据。现有的证据已经总结考虑操作在胚胎发育的各个阶段。检索方法:我们使用范围审查方法。在文章数据库中搜索与胚胎活检技术和产科、新生儿和产后结局相关的关键词。在不同阶段(即在卵裂期和囊胚期)对胚胎进行活检的研究被排除在外。我们纳入了新鲜和冷冻胚胎移植的数据。最后的31份文件样本进行了定性专题分析。结果:缺乏可靠的证据来充分解决胚胎活检对产科、新生儿或长期后果的潜在问题。对于极体活检，文献太少，无法得出任何结论。一些数据，尽管有限且有争议，表明在卵裂期进行胚胎活检可能与低出生体重和小胎龄新生儿的风险增加有关。在营养外胚层活检的情况下，早产和出生缺陷的增加被认为。对于两种活检方法(在卵裂期和囊胚期)，发现妊娠高血压疾病的风险增加。然而，这些发现可能是由其他胚胎操作程序或患者或群体固有特征等混杂因素解释的。更广泛的影响:由于没有足够的证据来评估胚胎活检后的产科、新生儿和长期健康结果，因此侵入性PGT策略应该以谨慎的方式发展。需要寻求一种基于胚胎无细胞DNA分析的非侵入性方法，以克服胚胎活检的潜在局限性。
{"title":"Obstetric, neonatal, and child health outcomes following embryo biopsy for preimplantation genetic testing.","authors":"Alessandra Alteri,&nbsp;Greta Chiara Cermisoni,&nbsp;Mirko Pozzoni,&nbsp;Gerarda Gaeta,&nbsp;Paolo Ivo Cavoretto,&nbsp;Paola Viganò","doi":"10.1093/humupd/dmad001","DOIUrl":"https://doi.org/10.1093/humupd/dmad001","url":null,"abstract":"<p><strong>Background: </strong>Preimplantation genetic testing (PGT) of embryos developed in vitro requires a biopsy for obtaining cellular samples for the analysis. Signs of cell injury have been described in association with this procedure. Thus, the consequences of the biopsy on obstetric and neonatal outcomes have been the subject of some quantitative analyses, although the reliability of data pooling may be limited by important issues in the various reports.</p><p><strong>Objective and rationale: </strong>The present review identifies evidence for whether pregnancies conceived after embryo biopsy are associated with a higher risk of adverse obstetric, neonatal, and long-term outcomes. Available evidence has been summarized considering manipulation at various stages of embryo development.</p><p><strong>Search methods: </strong>We used the scoping review methodology. Searches of article databases were performed with keywords pertaining to the embryo biopsy technique and obstetric, neonatal, and postnatal outcomes. Studies in which embryos were biopsied at different stages (i.e. both at the cleavage and blastocyst stages) were excluded. We included data on fresh and frozen embryo transfers. The final sample of 31 documents was subjected to qualitative thematic analysis.</p><p><strong>Outcomes: </strong>Sound evidence is lacking to fully address the issues on the potential obstetric, neonatal or long-term consequences of embryo biopsy. For polar body biopsy, the literature is too scant to draw any conclusion. Some data, although limited and controversial, suggest a possible association of embryo biopsy at the cleavage stage with an increased risk of low birthweight and small for gestational age neonates compared to babies derived from non-biopsied embryos. An increase in preterm deliveries and birth defects in cases of trophectoderm biopsy was suggested. For both biopsy methods (at the cleavage and blastocyst stages), an increased risk for hypertensive disorders of pregnancy was found. However, these findings may be explained by confounders such as other embryo manipulation procedures or by intrinsic patient or population characteristics.</p><p><strong>Wider implications: </strong>Since there is inadequate evidence to assess obstetric, neonatal, and long-term health outcomes following embryo biopsy, an invasive PGT strategy should be developed with a cautious approach. A non-invasive approach, based on the analysis of embryo cell-free DNA, needs to be pursued to overcome the potential limitations of embryo biopsy.</p>","PeriodicalId":55045,"journal":{"name":"Human Reproduction Update","volume":"29 3","pages":"291-306"},"PeriodicalIF":13.3,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d1/10/dmad001.PMC10152168.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9401613","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: 8
Offspring physiology following the use of IVM, IVF and ICSI: a systematic review and meta-analysis of animal studies. 使用IVM, IVF和ICSI后的后代生理:动物研究的系统回顾和荟萃分析。
IF 13.3 1区 医学 Q1 OBSTETRICS & GYNECOLOGY
Human Reproduction Update
Pub Date : 2023-05-02 DOI: 10.1093/humupd/dmac043
Kiri H Beilby, Ezra Kneebone, Tessa J Roseboom, Indah M van Marrewijk, Jeremy G Thompson, Robert J Norman, Rebecca L Robker, Ben Willem J Mol, Rui Wang
<p><strong>Background: </strong>Since the birth of the first baby using IVF technology in 1978, over 10 million children have been conceived via ART. Although most aspects of ARTs were developed in animal models, the introduction of these technologies into clinical practice was performed without comprehensive assessment of their long-term safety. The monitoring of these technologies over time has revealed differences in the physiology of babies produced using ARTs, yet due to the pathology of those presenting for treatment, it is challenging to separate the cause of infertility from the effect of treatments offered. The use of systematic review and meta-analysis to investigate the impacts of the predominant ART interventions used clinically in human populations on animals produced in healthy fertile populations offers an alternative approach to understanding the long-term safety of reproductive technologies.</p><p><strong>Objective and rationale: </strong>This systematic review and meta-analysis aimed to examine the evidence available from animal studies on physiological outcomes in the offspring conceived after IVF, IVM or ICSI, compared to in vivo fertilization, and to provide an overview on the landscape of research in this area.</p><p><strong>Search methods: </strong>PubMed, Embase and Commonwealth Agricultural Bureaux (CAB) Abstracts were searched for relevant studies published until 27 August 2021. Search terms relating to assisted reproductive technology, postnatal outcomes and mammalian animal models were used. Studies that compared postnatal outcomes between in vitro-conceived (IVF, ICSI or IVM) and in vivo-conceived mammalian animal models were included. In vivo conception included mating, artificial insemination, or either of these followed by embryo transfer to a recipient animal with or without in vitro culture. Outcomes included birth weight, gestation length, cardiovascular, metabolic and behavioural characteristics and lifespan.</p><p><strong>Outcomes: </strong>A total of 61 studies in five different species (bovine, equine, murine, ovine and non-human primate) met the inclusion criteria. The bovine model was the most frequently used in IVM studies (32/40), while the murine model was mostly used in IVF (17/20) and ICSI (6/8) investigations. Despite considerable heterogeneity, these studies suggest that the use of IVF or maturation results in offspring with higher birthweights and a longer length of gestation, with most of this evidence coming from studies in cattle. These techniques may also impair glucose and lipid metabolism in male mice. The findings on cardiovascular outcomes and behaviour outcomes were inconsistent across studies.</p><p><strong>Wider implications: </strong>Conception via in vitro or in vivo means appears to have an influence on measurable outcomes of offspring physiology, manifesting differently across the species studied. Importantly, it can be noted that these measurable differences are noticeable in health
背景:自1978年第一个使用体外受精技术的婴儿出生以来，已有超过1000万儿童通过ART受孕。尽管art的大多数方面是在动物模型中开发的，但将这些技术引入临床实践时并未对其长期安全性进行全面评估。随着时间的推移，对这些技术的监测揭示了使用抗逆转录病毒疗法产生的婴儿在生理上的差异，但由于那些前来治疗的人的病理，将不育的原因与所提供治疗的效果分开是具有挑战性的。通过系统回顾和荟萃分析来调查临床人群中使用的主要抗逆转录病毒治疗干预措施对健康可育人群中生产的动物的影响，为了解生殖技术的长期安全性提供了另一种方法。目的和基本原理:本系统综述和荟萃分析旨在研究体外受精、体外受精或ICSI受孕后后代生理结果与体内受精相比的动物研究证据，并概述该领域的研究前景。检索方法:检索PubMed、Embase和Commonwealth Agricultural bureau (CAB)摘要，检索截至2021年8月27日发表的相关研究。使用了与辅助生殖技术、产后结果和哺乳动物模型相关的搜索词。比较体外受孕(IVF, ICSI或IVM)和体内受孕哺乳动物模型的产后结局的研究包括在内。体内受孕包括交配，人工授精，或其中任何一种，然后将胚胎移植到有或没有体外培养的受体动物。结果包括出生体重、妊娠期长短、心血管、代谢和行为特征以及寿命。结果:5种不同物种(牛、马、鼠、羊和非人灵长类动物)共61项研究符合纳入标准。牛模型是IVM研究中最常用的模型(32/40)，而小鼠模型主要用于IVF(17/20)和ICSI(6/8)研究。尽管存在相当大的异质性，但这些研究表明，使用体外受精或成熟会导致后代的出生体重更高，妊娠期更长，这些证据大多来自对牛的研究。这些技术也可能损害雄性小鼠的葡萄糖和脂质代谢。研究中关于心血管结局和行为结局的发现不一致。更广泛的影响:通过体外或体内方式受孕似乎对后代生理的可测量结果有影响，在研究的物种中表现不同。重要的是，可以注意到，这些可测量的差异在健康的、可生育的动物种群中是明显的。因此，无论诊断为不孕症的病理基础如何，普通的ART干预措施可能对通过这些技术受孕的人产生长期影响。然而，由于本综述中强调的方法、结果和测量结果的异质性，很难得出确定的结论。优化研究新生殖技术安全性的动物和人类研究，将为保护新干预措施进入临床环境提供见解。也可以考虑谨慎地在临床上使用抗逆转录病毒药物，以减少在长期安全性得到充分证明之前受孕的儿童出现不良后果的机会。
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引用次数: 5
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