Protective Effect of Marjoram Against Letrozole-Induced Ovarian Damage in Rats with Polycystic Ovarian Syndrome Entails Activation of Nrf2 and Suppression of NF-κB

<b>Objectives</b>: This study aimed to evaluate marjoram's ameliorative effects in a letrozole-induced PCOS rat model and to explore its mechanism of action, focusing on Nrf2 activation and NF-κB suppression in ovarian tissue. <b>Methods</b>: In this study, PCOS was induced by the oral administration of letrozole (1 mg/kg/day) for 21 days. Rats were then divided into six groups: control (0.5% CMC), letrozole, letrozole + metformin (2 mg/100 g), and letrozole + MRJ extract (20, 40, or 60 mg/kg). All groups received oral treatment for 21 days. Biochemical analysis was performed using serum and plasma; while ovarian tissue homogenate was used for antioxidant enzymes and inflammatory and apoptosis biomarkers. <b>Results</b>: The letrozole-treated animals exhibited significant increases in final body weights, as well as ovary length and weight. In terms of biochemical parameters, there were significant increases in fasting blood glucose and insulin, HOMA-IR, and serum levels of cholesterol, triglycerides (TGs), and LDL-c and a decrease in HDL levels. Concerning the hormonal profile, testosterone and LH levels were significantly elevated while a notable decrease in FSH and estradiol levels was observed. Similarly, letrozole-treated rats showed significantly elevated levels of MDA and many other inflammatory mediators such as IL-6, TNF-α, and ICAM-1. A significant increase in the markers of intrinsic cell apoptosis, such as Bax and caspase-3, and the reduced levels of Bcl-2 and antioxidant mediators, including GSH, SOD, and HO-1, as well as mRNA and nuclear expression of Nrf2, compared to control rats, have been reported. The ovaries of the rats with PCOS treated with metformin and MRJ (60 mg/kg) showed the most significant improvements. Similarly, TEM also demonstrated a dose-dependent ameliorating effect. <b>Conclusions</b>: The current study highlights marjoram's protective effect against letrozole-induced ovarian damage in rats with polycystic ovarian syndrome, suggesting its potential as a complementary and therapeutic agent for managing PCOS.