Protective effect of N-acetylcysteine in doxorubicin-induced primary ovarian failure in female rats.

Objective: N-acetylcysteine (NAC), an aminothiol compound, eliminates free radicals and enhances glutathione (GSH) synthesis, thereby strengthening intracellular antioxidant defenses. Although its protective effects against ovarian injury have been reported, its efficacy in doxorubicin (DOX)-induced ovarian failure has not been demonstrated. This study aimed to investigate whether NAC exerts a protective role against DOX-induced ovarian toxicity in female rats.

Materials and methods: Twenty-one adult female rats were randomly assigned to three groups: Control, DOX (10 mg/kg, i.p., single dose), and DOX+NAC (150 mg/kg, i.p., for 5 days; DOX administered on day 3, one hour after NAC). Serum and tissue oxidative stress parameters, histopathological changes, proliferating cell nuclear antigen (PCNA) immunoreactivity, and TUNEL assay were evaluated.

Results: DOX significantly reduced serum anti-Müllerian hormone (AMH) (6.75 → 5.31 ng/mL; p<0.001) and GSH (422.64 → 280.98 mg/L; p<0.001), while increasing tumor necrosis factor alpha (TNF-α) (175.87 → 260.77 ng/L; p<0.001) and total oxidant status (TOS) (7.18 → 11.84 U/mL; p=0.002). NAC treatment reversed these alterations, namely: AMH (6.51 ng/mL; p=0.004), GSH (363.86 mg/L; p=0.018), TNF-α (184.55 ng/L; p<0.001), TOS (7.88 U/mL; p=0.003). In ovarian tissue, DOX reduced GSH (123.63 → 80.64 mg/L; p=0.001) and total antioxidant status (14.88 → 10.57 U/mL; p<0.001), while elevating TOS (7.14 → 12.64 U/mL; p<0.001) and caspase-3 (2.06 → 3.14 ng/mL; p<0.001). NAC significantly improved all these parameters (p≤0.005). Histologically, DOX caused edema, hemorrhage, infiltration, and a reduction in the percentage of healthy follicles, whereas NAC markedly ameliorated these alterations. Furthermore, NAC enhanced PCNA expression and reduced TUNEL-positive granulosa cells, supporting its anti-apoptotic effect.

Conclusion: NAC preserved ovarian reserve and follicular integrity by suppressing oxidative stress, inflammation, and apoptosis induced by DOX. These findings highlight NAC as a promising protective agent against chemotherapy-induced ovarian toxicity.