Quercetin prevents primordial follicle loss via suppression of PI3K/Akt/Foxo3a pathway activation in cyclophosphamide-treated mice

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Rapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide-induced damage

“…Studies have also indicated that the ‘burnout’ effect could induce a reduction in primordial follicles following the activation and growth initiation of primordial follicles, as determined by the changing pattern of follicle numbers and TUNEL-negative primordial follicles even at 4 h/12 h/24 h and 3/7 days post-CTX exposure [ 10 , 14 , 25 ]. Despite the lack of direct evidence, numerous researchers have admitted the rationality of both theories and proposed a mechanism by which oocytes abandon their follicular quiescence to initiate DNA damage signaling pathways resulting in oocyte apoptosis [ 10 , 25 , 26 , 27 ]. Consistent with previous studies [ 10 , 14 ], we did not observe primordial follicle apoptosis on day 7 after CTX exposure.…”

Effects of quercetin on ovarian function and regulation of the ovarian PI3K/Akt/FoxO3a signalling pathway and oxidative stress in a rat model of cyclophosphamide‐induced premature ovarian failure

“…29 Li et al found that quercetin can prevent the loss of primordial follicles in mice by inhibiting the activation of the PI3K/Akt/FOXO3a pathway. 30 However, whether quercetin can inhibit ovarian oxidative stress and improve the ovarian microenvironment through the PI3K/Akt/FoxO3a signalling pathway has not been reported.…”

“…Himani found that quercetin can reduce apoptosis by inhibiting Akt/PKB phosphorylation, reducing mitochondrial cystic release and downregulating Cu–Zn peroxidase dismutase to inhibit the ROS reaction 29 . Li et al found that quercetin can prevent the loss of primordial follicles in mice by inhibiting the activation of the PI3K/Akt/FOXO3a pathway 30 . However, whether quercetin can inhibit ovarian oxidative stress and improve the ovarian microenvironment through the PI3K/Akt/FoxO3a signalling pathway has not been reported.…”

Signaling pathway intervention in premature ovarian failure

“…Liu et al found that exosomes from stem cells can enhance the expression of PI3K/Akt pathway, increase the proliferation rate of granulosa cells, and improve ovarian function in a POF mouse model (31). Li et al (32) found that quercetin attenuated cyclophosphamide-induced follicle loss by preventing the phosphorylation of PI3K/Akt/Foxo3 pathway members and maintaining the anti-Müllerian hormone level through reduced apoptosis in growing follicles (32). These findings imply that the PI3K/PTEN/Akt/Foxo3 cascade in oocytes is essential for the activation of primordial follicles (10).…”