The role of mammalian target of rapamycin inhibitors in mitigating cyclophosphamide-induced ovarian damage in a murine model.

[OBJECTIVE] This study aimed to determine whether pre-treatment with everolimus or rapamycin could prevent ovarian follicle damage induced by cyclophosphamide (Cp).

[METHODS] A total of 120 female BDF-1 mice were randomly assigned into four groups receiving specific treatments. The control group received normal saline on days 1, 3, 5, and 13. The Cp group received saline on days 1, 3, and 5, followed by Cp administration on day 13. The everolimus+Cp group was given everolimus on days 1, 3, and 5, then Cp on day 13. Similarly, the rapamycin+Cp group received rapamycin on days 1, 3, and 5, followed by Cp on day 13. On day 20, all mice were euthanized, ovaries were harvested for histological analysis, and protein expression levels of B-cell lymphoma-extra large (BCL-xL), caspase 3, and mammalian target of rapamycin were evaluated by Western blot analysis.

[RESULTS] The number of primordial follicles was lower in the Cp group than in the control group. The everolimus group and the rapamycin group also showed reduced primordial follicle counts. No significant differences were observed in the proportions of G1 primordial or G1 secondary follicles among the groups. Compared to the control group, the Cp group and the everolimus group showed lower proportions of G1 primary follicles. However, the rapamycin group had a G1 primary follicle proportion similar to that of the control group. The Cp, everolimus, and rapamycin groups exhibited lower proportions of G1 antral follicles than the control group.

[CONCLUSION] Pre-treatment with rapamycin preserved the proportion of G1 primary follicles; however, neither everolimus nor rapamycin preserved the primordial follicle counts.