Synergistic Attenuation of Letrozole-Induced Granulosa Cell Dysfunction by Berberine and Resveratrol via Mitigation of Oxidative Stress, Inflammatory Pathways, and Steroidogenic Impairment

Research Article

Abstract

Polycystic ovary syndrome is a complex endocrine and metabolic disorder caused by hyperandrogenism, systemic low-grade inflammation, intraovarian oxidative stress, and impaired steroidogenesis. Granulosa cells serve as central targets of ovarian dysfunction, where suppressed aromatase activity and elevated reactive oxygen species disrupt follicular maturation. Evaluation of combined phytotherapy using berberine and resveratrol in a letrozole-induced human granulosa cell (KGN) model reveals profound cytoprotective and restorative mechanisms. Pharmacological inhibition of aromatase by letrozole (1 µM, 24 h) induces structural degeneration, reduces cell viability to 63.8%, elevates intracellular reactive oxygen species and lipid peroxidation, depletes superoxide dismutase and reduced glutathione, and promotes the hypersecretion of tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta. Concurrently, steroidogenesis shifts toward hyperandrogenism, marked by elevated testosterone and reduced estradiol levels. Monotherapy with either berberine or resveratrol significantly mitigates cellular damage; however, co-administration of both compounds demonstrates superior synergistic protection. Combined treatment restores cell viability to 92.5%, normalizes endogenous antioxidant defenses, suppresses pro-inflammatory cytokine secretion to baseline levels, and re-establishes the physiological estradiol-to-testosterone ratio. These findings demonstrate that dual targeting of metabolic and cellular defense pathways via berberine and resveratrol effectively reverses granulosa cell injury and steroidogenic dysfunction, establishing a strong theoretical foundation for combination botanical interventions in managing polycystic ovary syndrome pathology