BACKGROUND While oocyte IVM is practiced sporadically it has not achieved widespread clinical practice globally. However, recently there have been some seminal advances in our understanding of basic aspects of oocyte biology and ovulation from animal studies that have led to novel approaches to IVM. A significant recent advance in IVM technology is the use of biphasic IVM approaches. These involve the collection of immature oocytes from small antral follicles from minimally stimulated patients/animals (without hCG-priming) and an ∼24 h pre-culture of oocytes in an advanced culture system (‘pre-IVM’) prior to IVM, followed by routine IVF procedures. If safe and efficacious, this novel procedure may stand to make a significant impact on human ART practices. OBJECTIVE AND RATIONALE The objectives of this review are to examine the major scientific advances in ovarian biology with a unique focus on the development of pre-IVM methodologies, to provide an insight into biphasic IVM procedures, and to report on outcomes from animal and clinical human data, including safety data. The potential future impact of biphasic IVM on ART practice is discussed. SEARCH METHODS Peer review original and review articles were selected from PubMed and Web of Science searches for this narrative review. Searches were performed using the following keywords: oocyte IVM, pre-IVM, biphasic IVM, CAPA-IVM, hCG-triggered/primed IVM, natural cycle IVF/M, ex-vivo IVM, OTO-IVM, oocyte maturation, meiotic competence, oocyte developmental competence, oocyte capacitation, follicle size, cumulus cell (CC), granulosa cell, COC, gap-junction communication, trans-zonal process, cAMP and IVM, cGMP and IVM, CNP and IVM, EGF-like peptide and IVM, minimal stimulation ART, PCOS. OUTCOMES Minimizing gonadotrophin use means IVM oocytes will be collected from small antral (pre-dominant) follicles containing oocytes that are still developing. Standard IVM yields suboptimal clinical outcomes using such oocytes, whereas pre-IVM aims to continue the oocyte’s development ex vivo, prior to IVM. Pre-IVM achieves this by eliciting profound cellular changes in the oocyte’s CCs, which continue to meet the oocyte’s developmental needs during the pre-IVM phase. The literature contains 25 years of animal research on various pre-IVM and biphasic IVM procedures, which serves as a large knowledge base for new approaches to human IVM. A pre-IVM procedure based on c-type natriuretic peptide (named ‘capacitation-IVM’ (CAPA-IVM)) has undergone pre-clinical human safety and efficacy trials and its adoption into clinical practice resulted in healthy live birth rates not different from conventional IVF. WIDER IMPLICATIONS Over many decades, improvements in clinical IVM have been gradual and incremental but there has likely been a turning of the tide in the past few years, with landmark discoveries in animal oocyte biology finally making their way into clinical practice leading to improved outcomes for patients. Demonstration of favorable clinical results with CAPA-IVM, as the first clinically tested biphasic IVM system, has led to renewed interest in IVM as an alternative, low-intervention, low-cost, safe, patient-friendly ART approach, and especially for patients with PCOS. The same new approach is being used as part of fertility preservation in patients with cancer and holds promise for social oocyte freezing.

中文翻译：

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IVM 的新起点：使用 pre-IVM 使卵母细胞能够发育


背景 虽然卵母细胞 IVM 是零星的实践，但它尚未在全球范围内实现广泛的临床实践。然而，最近我们从动物研究中对卵母细胞生物学和排卵的基本方面的理解取得了一些开创性的进展，这导致了 IVM 的新方法。IVM 技术最近的一项重大进展是使用双相 IVM 方法。这些包括从最小刺激的患者/动物（无 hCG 启动）的小窦卵泡中收集未成熟的卵母细胞，并在 IVM 之前在高级培养系统（“IVM 前”）中对卵母细胞进行 ∼24 小时的预培养，然后进行常规 IVF 程序。如果安全有效，这种新颖的手术可能会对人类 ART 实践产生重大影响。客观和基本原理本综述的目的是检查卵巢生物学的主要科学进展，特别关注 IVM 前方法的开发，提供对双相 IVM 程序的见解，并报告动物和临床人体数据的结果，包括安全数据。讨论了双相 IVM 对 ART 实践的潜在未来影响。检索方法 同行评议、原始文献和综述文章选自 PubMed 和 Web of Science 检索中，用于本叙述性综述。使用以下关键词进行检索：卵母细胞 IVM、IV前、双相 IVM、CAPA-IVM、hCG 触发/引发的 IVM、自然周期 IVF/M、离体 IVM、OTO-IVM、卵母细胞成熟、减数分裂能力、卵母细胞发育能力、卵母细胞获能、卵泡大小、卵丘细胞 （CC）、颗粒细胞、COC、间隙连接通讯、跨带过程、cAMP 和 IVM、cGMP 和 IVM、CNP 和 IVM、EGF 样肽和 IVM， 最小刺激 ART，PCOS。 结果 尽量减少促性腺激素的使用意味着 IVM 卵母细胞将从含有仍在发育的卵母细胞的小窦（主要）卵泡中收集。标准 IVM 使用此类卵母细胞产生次优的临床结果，而 pre-IVM 旨在在 IVM 之前继续卵母细胞的体外发育。Pre-IVM 通过在卵母细胞的 CCs 中引发深刻的细胞变化来实现这一目标，这些变化在 IVM 前阶段继续满足卵母细胞的发育需求。该文献包含对各种 IVM 前和双相 IVM 程序的 25 年动物研究，为人类 IVM 的新方法提供了庞大的知识库。基于 c 型利钠肽的 IVM 前手术（名为“获能 IVM”（CAPA-IVM））已经进行了临床前人体安全性和有效性试验，并将其应用于临床实践，导致健康的活产率与传统 IVF 没有差异。更广泛的影响几十年来，临床 IVM 的改进是渐进的，但在过去几年中可能会出现转变，动物卵母细胞生物学的里程碑式发现最终进入临床实践，从而改善了患者的预后。CAPA-IVM 作为第一个经过临床测试的双相 IVM 系统，其良好的临床结果证明，这引起了人们对 IVM 作为一种替代、低干预、低成本、安全、患者友好的 ART 方法的新兴趣，尤其是对于 PCOS 患者。同样的新方法被用作癌症患者保留生育能力的一部分，并有望实现社会性卵母细胞冷冻。