BACKGROUND Modern lifestyle has led to an increase in the age at conception. Advanced age is one of the critical risk factors for female-related infertility. It is well known that maternal age positively correlates with the deterioration of oocyte quality and chromosomal abnormalities in oocytes and embryos. The effect of age on endometrial function may be an equally important factor influencing implantation rate, pregnancy rate, and overall female fertility. However, there are only a few published studies on this topic, suggesting that this area has been under-explored. Improving our knowledge of endometrial aging from the biological (cellular, molecular, histological) and clinical perspectives would broaden our understanding of the risks of age-related female infertility. OBJECTIVE AND RATIONALE The objective of this narrative review is to critically evaluate the existing literature on endometrial aging with a focus on synthesizing the evidence for the impact of endometrial aging on conception and pregnancy success. This would provide insights into existing gaps in the clinical application of research findings and promote the development of treatment options in this field. SEARCH METHODS The review was prepared using PubMed (Medline) until February 2023 with the keywords such as ‘endometrial aging’, ‘receptivity’, ‘decidualization’, ‘hormone’, ‘senescence’, ‘cellular’, ‘molecular’, ‘methylation’, ‘biological age’, ‘epigenetic’, ‘oocyte recipient’, ‘oocyte donation’, ‘embryo transfer’, and ‘pregnancy rate’. Articles in a language other than English were excluded. OUTCOMES In the aging endometrium, alterations occur at the molecular, cellular, and histological levels suggesting that aging has a negative effect on endometrial biology and may impair endometrial receptivity. Additionally, advanced age influences cellular senescence, which plays an important role during the initial phase of implantation and is a major obstacle in the development of suitable senolytic agents for endometrial aging. Aging is also accountable for chronic conditions associated with inflammaging, which eventually can lead to increased pro-inflammation and tissue fibrosis. Furthermore, advanced age influences epigenetic regulation in the endometrium, thus altering the relation between its epigenetic and chronological age. The studies in oocyte donation cycles to determine the effect of age on endometrial receptivity with respect to the rates of implantation, clinical pregnancy, miscarriage, and live birth have revealed contradictory inferences indicating the need for future research on the mechanisms and corresponding causal effects of women’s age on endometrial receptivity. WIDER IMPLICATIONS Increasing age can be accountable for female infertility and IVF failures. Based on the complied observations and synthesized conclusions in this review, advanced age has been shown to have a negative impact on endometrial functioning. This information can provide recommendations for future research focusing on molecular mechanisms of age-related cellular senescence, cellular composition, and transcriptomic changes in relation to endometrial aging. Additionally, further prospective research is needed to explore newly emerging therapeutic options, such as the senolytic agents that can target endometrial aging without affecting decidualization. Moreover, clinical trial protocols, focusing on oocyte donation cycles, would be beneficial in understanding the direct clinical implications of endometrial aging on pregnancy outcomes.

中文翻译：

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高龄女性子宫内膜容受性：不孕症的一个被低估的因素


背景 现代生活方式导致受孕年龄的增加。高龄是女性相关不孕症的关键危险因素之一。众所周知，母体年龄与卵母细胞质量恶化以及卵母细胞和胚胎的染色体异常呈正相关。年龄对子宫内膜功能的影响可能是影响着床率、妊娠率和女性整体生育能力的同等重要因素。然而，关于这个主题的已发表研究很少，这表明该领域尚未得到充分探索。从生物学（细胞、分子、组织学）和临床角度提高我们对子宫内膜衰老的了解，将拓宽我们对与年龄相关的女性不孕症风险的理解。客观和基本原理 本叙述性综述的目的是批判性地评估关于子宫内膜衰老的现有文献，重点是综合子宫内膜衰老对受孕和妊娠成功影响的证据。这将提供对研究结果临床应用现有差距的见解，并促进该领域治疗方案的开发。检索方法 截至 2023 年 2 月，该评价是使用 PubMed （Medline） 编写的，关键词包括 “子宫内膜衰老”、“容受性”、“蜕膜化”、“激素”、“衰老”、“细胞”、“分子”、“甲基化”、“生物年龄”、“表观遗传”、“卵母细胞受体”、“卵母细胞捐赠”、“胚胎移植”和“妊娠率”。英语以外的文章被排除在外。 结果 在衰老的子宫内膜中，分子、细胞和组织学水平发生改变，表明衰老对子宫内膜生物学有负面影响，并可能损害子宫内膜容受性。此外，高龄会影响细胞衰老，这在植入的初始阶段起着重要作用，是开发合适的子宫内膜衰老 senolytic 剂的主要障碍。衰老也是与炎症相关的慢性病的原因，这最终会导致促炎和组织纤维化的增加。此外，高龄会影响子宫内膜的表观遗传调控，从而改变其表观遗传年龄与实际年龄之间的关系。对卵母细胞捐献周期的研究确定了年龄对子宫内膜容受性的影响，包括着床率、临床妊娠率、流产率和活产率，揭示了相互矛盾的推论，表明未来需要研究女性年龄对子宫内膜容受性的机制和相应的因果影响。更广泛的影响 年龄的增长可能是女性不孕症和 IVF 失败的原因。根据本综述中的综合观察和综合结论，高龄已被证明对子宫内膜功能有负面影响。这些信息可以为未来的研究提供建议，重点是与年龄相关的细胞衰老、细胞组成和与子宫内膜衰老相关的转录组学变化的分子机制。此外，需要进一步的前瞻性研究来探索新兴的治疗方案，例如可以在不影响蜕膜化的情况下靶向子宫内膜衰老的 senolytic 药物。 此外，侧重于卵母细胞捐献周期的临床试验方案将有助于了解子宫内膜衰老对妊娠结局的直接临床影响。