Polycystic ovary syndrome (PCOS) is a complex endocrine–metabolic disorder characterized by hyperandrogenism, ovulatory dysfunction, insulin resistance, and chronic inflammation resulting in reproductive and metabolic complications. Traditional metformin therapy improves insulin sensitivity, while newer dual incretin agonists, such as tirzepatide, may offer broader metabolic and ovarian protection. The objective of this study is to investigate whether tirzepatide could alter hormonal parameters, metabolism, inflammation, and histopathology of a testosterone propionate–induced PCOS rat model compared with metformin. Thirty prepubertal female Wistar rats were divided into five groups (n = 6). PCOS was induced by testosterone propionate (10 mg/kg/day, subcutaneous) for 30 days. Rats were then given tirzepatide (0.88 and 1.32 mg/kg/week, subcutaneous), metformin (300 mg/kg/day, oral), or vehicle for 14 days. Serum reproductive hormones, lipid profile, fasting glucose, insulin, and HOMA-IR were assessed. The mRNA expression of ovarian Tnf-α and Il-6 was determined by RT qPCR, western blot analysis of caspase 3 protein, and histopathological assessment of ovarian morphology. Testosterone propionate resulted in pronounced hyperandrogenism and an increased LH/FSH ratio, dyslipidemia, hyperglycemia and insulin resistance, and ovarian inflammation and apoptosis. Tirzepatide induced significant improvements in estradiol, testosterone, LH, FSH, and LH/FSH ratio. A greater reduction in body weight, cholesterol, triglycerides, fasting glucose, insulin, and HOMA-IR was achieved with the higher dose of tirzepatide, demonstrating a clear dose-dependent improvement. Ovarian TNF-α, IL-6, and caspase 3 protein levels were significantly decreased by tirzepatide treatment, with similar effectiveness as metformin. Histological analysis showed reduced cystic follicles, increased developing follicles, and the presence of corpora lutea, especially at higher doses of tirzepatide. Tirzepatide effectively compensates for metabolic, inflammatory, and reproductive abnormalities in experimental PCOS and demonstrates dose-dependent potent activity similar to that of metformin, supporting its potential as an alternative therapy.
