Metformin protects prepubertal mice ovarian reserve against cyclophosphamide via regulation of the PI3K/Akt/mTOR signaling pathway and Yap-1.
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BACKGROUND: Cyclophosphamide is a widely utilized chemotherapeutic agent for pediatric cancers, known to elicit adverse effects, including perturbation of the PI3K/Akt/mTOR and Hippo signaling pathways, thereby diminishing ovarian reserve and fertility potential in females. Consequently, this investigation delves into the mitigative effects of metformin on cyclophosphamide-induced ovarian impairment in prepubertal mice. METHODS: Twenty-four 14-day-old NMRI female mice were distributed into four groups: Control (Cont), Cyclophosphamide (Cyc), Metformin (Met), and Metformin plus Cyclophosphamide (Met-Cyc). The Met-Cyc group was given daily doses of 150 mg/kg metformin for 11 consecutive days and in parallel 3 intermittent doses of 65 mg/kg cyclophosphamide once every three days. The Met and Cyc groups were given identical doses of Met or Cyc alone. The control group received normal saline treatment. On the 12th day, mice were sacrificed for analysis. Stereological methods were employed to measure the overall volume of the ovaries, including the medulla, cortex, and follicles, along with measuring anti-Müllerian hormone (AMH) levels using an ELISA kit. Furthermore, qRT-PCR was utilized to quantify the expression levels of genes, including P53, Bax, Bcl-2, Rad-51, Pten, Mtor, and Yap-1. RESULTS: The findings demonstrate that metformin ameliorates cyclophosphamide-induced ovarian toxicity by increasing AMH levels and attenuating the excessive activation of primordial follicles, the ratio of growing to quiescent follicles, and follicular atresia. This protective effect is mediated by the downregulation of apoptosis-related genes, upregulation of the gene involved in a reparative pathway, and modulation of the PI3K/Akt/mTOR pathway evidenced by increased expression of Pten, Mtor and Hippo pathway by Yap-1 expression. CONCLUSIONS: Our results advocate for the potential of metformin as a viable therapeutic option for preserving ovarian function in cyclophosphamide-treated adolescent girls, given its favorable side effect profile and ability to improve cyclophosphamide-induced ovarian damage.