Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Reproductive Medicine Center, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, No.136, Jingzhou Road, Xiangcheng District, Xiangyang, 441021, Hubei Province, People's Republic of China.
Reprod Sci. 2024 Jan;31(1):30-44. doi: 10.1007/s43032-023-01294-w. Epub 2023 Jul 24.
Cyclophosphamide (CPM), a part of most cancer treatment regimens, has demonstrated high gonadal toxicity in females. Initially, CPM is believed to damage the ovarian reserve by premature activation of primordial follicles, for the fact that facing CPM damage, primordial oocytes show the activation of PTEN/PI3K/AKT pathways, accompanied by accelerated activation of follicle developmental waves. Meanwhile, primordial follicles are dormant and not considered the target of CPM. However, many researchers have found DNA DSBs and apoptosis within primordial oocytes under CPM-induced ovarian damage instead of premature accelerated activation. A stricter surveillance system of DNA damage is also thought to be in primordial oocytes. So far, the apoptotic death mechanism is considered well-proved, but the premature activation theory is controversial and unacceptable. The connection between the upregulation of PTEN/PI3K/AKT pathways and DNA DSBs and apoptosis within primordial oocytes is also unclear. This review aims to highlight the flaw and/or support of the disputed premature activation theory and the apoptosis mechanism to identify the underlying mechanism of CPM's injury on ovarian reserve, which is crucial to facilitate the discovery and development of effective ovarian protectants. Ultimately, this review finds no good evidence for follicle activation and strong consistent evidence for apoptosis.
环磷酰胺（CPM）是大多数癌症治疗方案的一部分，已被证明对女性具有很高的生殖毒性。最初，CPM 通过过早激活原始卵泡来破坏卵巢储备，因为面对 CPM 损伤，原始卵母细胞表现出 PTEN/PI3K/AKT 途径的激活，伴随着卵泡发育波的加速激活。同时，原始卵泡处于休眠状态，不被认为是 CPM 的靶标。然而，许多研究人员在 CPM 诱导的卵巢损伤下的原始卵母细胞中发现了 DNA DSB 和细胞凋亡，而不是过早的加速激活。原始卵母细胞中也存在更严格的 DNA 损伤监测系统。到目前为止，细胞凋亡的死亡机制被认为已经得到很好的证明，但过早激活理论存在争议，难以被接受。PTEN/PI3K/AKT 途径的上调与原始卵母细胞内的 DNA DSB 和细胞凋亡之间的关系也不清楚。本综述旨在强调有争议的过早激活理论和细胞凋亡机制的缺陷和/或支持，以确定 CPM 对卵巢储备损伤的潜在机制，这对于促进有效的卵巢保护剂的发现和开发至关重要。最终，本综述没有找到卵泡激活的良好证据，而凋亡的证据则非常充分。
