Thymoquinone Versus Metformin in Letrozole-Induced PCOS: Comparative Insights into Metabolic, Hormonal, and Ovarian Outcomes

<b>Objectives</b>: This study aimed to evaluate the effects of thymoquinone (TMQ) on metabolic, hormonal, and ovarian dysfunctions in a letrozole-induced polycystic ovary syndrome (PCOS) rat model and compare its efficacy with metformin, which is widely recognized as the first-line pharmacological treatment for PCOS. <b>Methods</b>: Thirty-two female Wistar Albino rats were randomly assigned into four groups: control (I), PCOS (II), PCOS + metformin (III), and PCOS + Thymoquinone (IV). PCOS was induced using 1 mg/kg/day letrozole for 21 days, followed by treatment with either metformin (500 mg/kg/day) or thymoquinone (50 mg/kg/day) for 30 days. Metabolic (glucose, insulin, HOMA-IR, lipid profile), hormonal (estrone, estradiol, testosterone, androstenedione), and histopathological parameters were assessed. <b>Results</b>: PCOS induction resulted in significant metabolic, hormonal, and ovarian dysfunctions. Final body weight was significantly higher in PCOS (309.0 ± 7.5 g) vs. control (275.3 ± 8.2 g, <i>p</i> < 0.001), but reduced by metformin (294.0 ± 7.4 g, <i>p</i> < 0.01) and thymoquinone (305.7 ± 7.5 g, <i>p</i> < 0.01). Glucose levels were significantly elevated in PCOS (341.8 ± 16.8 mg/dL) vs. control (260.0 ± 15.8 mg/dL, <i>p</i> < 0.01), while metformin (290.2 ± 19.7 mg/dL, <i>p</i> < 0.05) and thymoquinone (320.3 ± 13.7 mg/dL, <i>p</i> < 0.05) reduced glucose levels. Insulin and HOMA-IR were significantly increased in PCOS (<i>p</i> < 0.001), but reduced by both treatments (<i>p</i> < 0.01). Lipid profile improvements were observed, with significant reductions in TG and LDL-C and increases in HDL-C in both treatment groups (<i>p</i> < 0.05-0.01). PCOS induced hyperandrogenism, with increased testosterone and androstenedione (<i>p</i> < 0.05), and a decreased E2/E1 ratio (<i>p</i> < 0.001), which were significantly improved by metformin and thymoquinone (<i>p</i> < 0.01). Ovarian histopathology showed increased cystic and atretic follicles and reduced corpus luteum in PCOS (<i>p</i> < 0.05-0.01), which were significantly improved by both treatments. <b>Conclusions</b>: TMQ exerts metabolic, hormonal, and ovarian protective effects comparable to metformin, supporting its potential as a natural therapeutic alternative for PCOS management. Given that metformin is already established as a first-line pharmacological therapy, our findings suggest that TMQ may provide a promising complementary or alternative approach. Further clinical studies are warranted to evaluate its safety and efficacy in human PCOS patients.