Department of Assisted Reproduction, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Zhizaoju Road no. 639, Huangpu District, Shanghai, People's Republic of China.
Reprod Biol Endocrinol. 2021 Apr 23;19(1):63. doi: 10.1186/s12958-021-00743-y.
Chemotherapy improves the survival rates of patients with various cancers but often causes some adverse effects, including ovarian damage, characterised by a decrease in primordial follicle stockpiles. Recent studies have revealed that chemotherapy may stimulate the PI3K signalling pathway, thereby resulting in accelerated primordial follicle activation and a decreased ovarian reserve. Quercetin is an inhibitor of the PI3K pathway; however, its protective effects against chemotherapy-induced follicle loss in mice have not been established. In this study, the effects of quercetin in a mouse model of cyclophosphamide-induced ovarian dysfunction were investigated.
C57BL/6 female mice were used for the study. Paraffin sections of mouse ovaries (n = 30 mice) were stained with haematoxylin and eosin for differential follicle counts. Apoptosis (n = 5 mice per group) was evaluated by TUNEL assay. Immunohistochemical staining for ki67 and Foxo3a (n = 5 mice per group) was performed to evaluate the activation of primordial follicles. The role of the PI3K signalling pathway in the ovaries (n = 45 mice) was assessed by western blotting.
Quercetin attenuated the cyclophosphamide-induced reduction in dormant primordial follicles. Analysis of the PI3K/Akt/Foxo3a pathway showed that quercetin decreased the phosphorylation of proteins that stimulate follicle activation in cyclophosphamide-induced ovaries. Furthermore, quercetin prevented cyclophosphamide-induced apoptosis in early growing follicles and early antral follicles, maintained anti-Müllerian hormone levels secreted by these follicles, and preserved the quiescence of the primordial follicle pool, as determined by intranuclear Foxo3a staining.
Quercetin attenuates cyclophosphamide-induced follicle loss by preventing the phosphorylation of PI3K/Akt/Foxo3a pathway members and maintaining the anti-Müllerian hormone level through reduced apoptosis in growing follicles. Accordingly, quercetin is expected to improve fertility preservation and the prevention of endocrine-related side effects of chemotherapy.
化疗提高了各种癌症患者的生存率，但常导致一些不良反应，包括卵巢损伤，其特征是原始卵泡储备减少。最近的研究表明，化疗可能会刺激 PI3K 信号通路，从而导致原始卵泡的激活加速和卵巢储备减少。槲皮素是 PI3K 通路的抑制剂；然而，其在保护化疗诱导的小鼠卵泡丢失方面的作用尚未确定。在本研究中，研究了槲皮素在环磷酰胺诱导的卵巢功能障碍小鼠模型中的作用。
使用 C57BL/6 雌性小鼠进行研究。用苏木精和伊红染色对小鼠卵巢石蜡切片进行差异卵泡计数（n=30 只小鼠）。通过 TUNEL 测定评估凋亡（每组 5 只小鼠）。用 ki67 和 Foxo3a 的免疫组织化学染色（每组 5 只小鼠）评估原始卵泡的激活。通过 Western blot 评估卵巢中 PI3K 信号通路的作用（n=45 只小鼠）。
槲皮素减弱了环磷酰胺引起的休眠原始卵泡减少。PI3K/Akt/Foxo3a 通路分析表明，槲皮素降低了刺激环磷酰胺诱导的卵巢中卵泡激活的蛋白的磷酸化。此外，槲皮素可预防环磷酰胺诱导的早期生长卵泡和早期腔前卵泡凋亡，维持这些卵泡分泌的抗苗勒管激素水平，并通过核内 Foxo3a 染色保持原始卵泡库的静止。
槲皮素通过防止 PI3K/Akt/Foxo3a 通路成员的磷酸化以及通过减少生长卵泡中的凋亡来维持抗苗勒管激素水平，从而减轻环磷酰胺引起的卵泡丢失。因此，槲皮素有望改善生育力保存和预防化疗的内分泌相关副作用。
