BACKGROUND Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating detailed data show that different chemotherapy regimens can lead to disturbance of ovarian hormone levels, reduced or lost fertility, and an increased risk of early menopause. Previous studies have often focused on the direct effects of chemotherapeutic drugs on ovarian follicles, such as direct DNA damage-mediated apoptotic death and primordial follicle burnout. Emerging evidence has revealed an imbalance in the ovarian microenvironment during chemotherapy. The ovarian microenvironment provides nutritional support and transportation of signals that stimulate the growth and development of follicles, ovulation, and corpus luteum formation. The close interaction between the ovarian microenvironment and follicles can determine ovarian function. Therefore, designing novel and precise strategies to manipulate the ovarian microenvironment may be a new strategy to protect ovarian function during chemotherapy. OBJECTIVE AND RATIONALE This review details the changes that occur in the ovarian microenvironment during chemotherapy and emphasizes the importance of developing new therapeutics that protect ovarian function by targeting the ovarian microenvironment during chemotherapy. SEARCH METHODS A comprehensive review of the literature was performed by searching PubMed up to April 2024. Search terms included 'ovarian microenvironment' (ovarian extracellular matrix, ovarian stromal cells, ovarian interstitial, ovarian blood vessels, ovarian lymphatic vessels, ovarian macrophages, ovarian lymphocytes, ovarian immune cytokines, ovarian oxidative stress, ovarian reactive oxygen species, ovarian senescence cells, ovarian senescence-associated secretory phenotypes, ovarian oogonial stem cells, ovarian stem cells), terms related to ovarian function (reproductive health, fertility, infertility, fecundity, ovarian reserve, ovarian function, menopause, decreased ovarian reserve, premature ovarian insufficiency/failure), and terms related to chemotherapy (cyclophosphamide, lfosfamide, chlormethine, chlorambucil, busulfan, melphalan, procarbazine, cisplatin, doxorubicin, carboplatin, taxane, paclitaxel, docetaxel, 5-fluorouraci, vincristine, methotrexate, dactinomycin, bleomycin, mercaptopurine). OUTCOMES The ovarian microenvironment shows great changes during chemotherapy, inducing extracellular matrix deposition and stromal fibrosis, angiogenesis disorders, immune microenvironment disturbance, oxidative stress imbalances, ovarian stem cell exhaustion, and cell senescence, thereby lowering the quantity and quality of ovarian follicles. Several methods targeting the ovarian microenvironment have been adopted to prevent and treat CAOD, such as stem cell therapy and the use of free radical scavengers, senolytherapies, immunomodulators, and proangiogenic factors. WIDER IMPLICATIONS Ovarian function is determined by its 'seeds' (follicles) and 'soil' (ovarian microenvironment). The ovarian microenvironment has been reported to play a vital role in CAOD and targeting the ovarian microenvironment may present potential therapeutic approaches for CAOD. However, the relation between the ovarian microenvironment, its regulatory networks, and CAOD needs to be further studied. A better understanding of these issues could be helpful in explaining the pathogenesis of CAOD and creating innovative strategies for counteracting the effects exerted on ovarian function. Our aim is that this narrative review of CAOD will stimulate more research in this important field. REGISTRATION NUMBER Not applicable.

中文翻译：

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卵巢微环境：防止化疗相关卵巢损伤的挑战和机遇。


背景化疗相关的卵巢损伤 （CAOD） 是绝经前妇女抗癌治疗最令人恐惧的短期和长期副作用之一。积累的详细数据表明，不同的化疗方案会导致卵巢激素水平紊乱、生育能力降低或丧失，以及增加更年期提前的风险。以前的研究通常集中在化疗药物对卵巢卵泡的直接影响上，例如直接 DNA 损伤介导的凋亡死亡和原始卵泡倦怠。新出现的证据表明化疗期间卵巢微环境失衡。卵巢微环境提供营养支持和信号运输，刺激卵泡生长发育、排卵和黄体形成。卵巢微环境和卵泡之间的密切相互作用可以决定卵巢功能。因此，设计新颖而精确的策略来操纵卵巢微环境可能是化疗期间保护卵巢功能的新策略。客观和基本原理 本综述详细介绍了化疗期间卵巢微环境发生的变化，并强调了开发新疗法的重要性，这些疗法通过在化疗期间靶向卵巢微环境来保护卵巢功能。检索方法 通过检索 PubMed 对截至 2024 年 4 月的文献进行了全面回顾。 检索词包括“卵巢微环境”（卵巢细胞外基质、卵巢基质细胞、卵巢间质、卵巢血管、卵巢淋巴管、卵巢巨噬细胞、卵巢淋巴细胞、卵巢免疫细胞因子、卵巢氧化应激、卵巢活性氧、卵巢衰老细胞、卵巢衰老相关分泌表型、卵巢卵巢干细胞、卵巢干细胞）、与卵巢功能相关的术语（生殖健康、生育能力、 不孕症、生育能力、卵巢储备、卵巢功能、绝经、卵巢储备减少、卵巢早衰/衰竭）以及与化疗相关的术语（环磷酰胺、LFOSFAMIDE、氮芥、苯丁酸氮芥、白消安、美法仑、丙卡巴肼、顺铂、多柔比星、卡铂、紫杉烷、紫杉醇、多西他赛、5-氟尿酸、长春新碱、甲氨蝶呤、放线菌素、博来霉素、巯基嘌呤）。结果 卵巢微环境在化疗过程中表现出很大的变化，诱导细胞外基质沉积和基质纤维化、血管生成障碍、免疫微环境紊乱、氧化应激失衡、卵巢干细胞耗竭和细胞衰老，从而降低卵巢卵泡的数量和质量。已采用几种针对卵巢微环境的方法来预防和治疗 CAOD，例如干细胞疗法和使用自由基清除剂、senoly疗法、免疫调节剂和促血管生成因子。更广泛的影响 卵巢功能由其 “种子” （卵泡） 和 “土壤” （卵巢微环境） 决定。据报道，卵巢微环境在 CAOD 中起着至关重要的作用，靶向卵巢微环境可能为 CAOD 提供潜在的治疗方法。 然而，卵巢微环境、其调节网络和 CAOD 之间的关系需要进一步研究。更好地了解这些问题可能有助于解释 CAOD 的发病机制和创建创新策略来抵消对卵巢功能的影响。我们的目标是，这份对 CAOD 的叙述性回顾将激发这一重要领域的更多研究。注册号 不适用。