Therapeutic effects of pomegranate hot-water extract via inhibition of apoptosis and oxidative stress in a DHEA-induced mouse model of PCOS

Background: Polycystic ovarian syndrome (PCOS), which affects approximately 10 % of women of reproductive age worldwide, is closely associated with metabolic disturbances such as obesity and insulin resistance. Despite its high prevalence, the pathophysiology of PCOS is still not fully understood, underscoring the need for appropriate animal models and effective therapeutic strategies. Methods: In this study, we established a PCOS mouse model through subcutaneous administration of dehydroepiandrosterone (DHEA) and investigated the therapeutic potential of a pomegranate (Punica granatum L.) hot water extract (Pg-hWE) (also called ESTROBAL®), administered orally. Results: Histological analysis of ovarian tissue sections of mice showed that Pg-hWE improved ovulation function and suppressed cell death of follicles by promoting maintenance and regeneration of corpus luteum and reducing the number of atretic follicles. Furthermore, Pg-hWE showed inhibitory effects on gene and protein levels of apoptosis factors such as BAX, cleaved caspase-3, and cleaved caspase-9 in ovarian and uterine tissues. In addition, in ovarian tissues, it promoted apoptosis such as BAX and inhibited the expression of inflammation-related genes such as IL-6, TNF-α, and IFN-γ, while increasing the expression of Bcl-2, an anti-apoptosis factor. Plus, Pg-hWE demonstrated the ability to modulate hormonal balance by regulating the expression of CYP11A1 and CYP17A1, key genes encoding enzymes involved in androgen biosynthesis. Supporting these findings, studies using CHO-K1 cells confirmed that Pg-hWE exerts both anti-apoptotic and antioxidant effects, thereby linking its roles in mitigating PCOS, suppressing cell death, and controlling oxidative stress. Conclusion: Collectively, these results indicate that Pg-hWE ameliorates PCOS-related pathology by reducing oxidative stress, suppressing apoptosis, and supporting hormonal balance, highlighting its promise as a natural therapeutic candidate.