Salvia miltiorrhiza extract improves menopausal symptoms in naturally aged mice

Objective: To investigate the efficacy and underlying mechanisms of standardized Salvia miltiorrhiza extract (SMEX) in alleviating menopausal symptoms using MCF-7 cells and an ovary-intact menopause mouse model resulting from hypothalamic-pituitary-ovarian axis aging. Methods: Estrogen receptor (ER)-related molecular responses were first assessed in MCF-7 cells treated with SMEX. In vivo efficacy was then evaluated in 52-week-old female mice orally administered SMEX (50 or 100 mg/kg/day) or 17β-estradiol (E 2 ) for 12 weeks. ER expression and downstream AKT/ERK signaling pathways in uterine tissues were determined. In addition, histological analysis of reproductive organs, assessment of serum lipid and hormone levels, neurotransmitter measurements, and behavioral tests were performed. Results: SMEX upregulated ERα and ERβ expression and suppressed pS2 mRNA in MCF-7 cells, indicating selective ER modulation. In SMEX-treated mice, uterine ER expression and activation of the AKT and ERK pathways were significantly increased, leading to partial restoration of epithelial thickness and stratification in the oviduct and vagina. SMEX also significantly reduced serum low-density lipoprotein cholesterol levels and reversed menopausal alterations in the follicle-stimulating hormone/ luteinizing hormone ratio. Additionally, it elevated serotonin and norepinephrine levels in the pituitary, thereby alleviating depressionlike behavior. Conclusions: SMEX modulates ER signaling and improves neurohormonal balance, effectively alleviating menopausal symptoms in both in vitro and in vivo models. This highlights its potential as a safe, natural alternative to hormone replacement therapy and as a promising functional ingredient in therapeutic natural products.