Lepidium Sativum Extract Alleviates Reproductive and Developmental Toxicity in Polycystic Ovary Syndrome Induced by Letrozole and High-Fat Diet in Rats

Abstract Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by irregular menstrual cycles, hyperandrogenism, and polycystic ovarian morphology, leading to infertility and an increased risk of metabolic dysfunction. This study investigated the protective effects of Lepidium sativum seed extract (LSSE) on fertility and pregnancy outcomes in a rat model of PCOS induced by letrozole and a high-fat diet (HFD) (68% regular rat food pellets, 6% maize oil, 20% milk powder, and 6% ghee). PCOS was induced by oral administration of letrozole, an aromatase inhibitor, (1 mg/kg in 2% DMSO) along with an HFD for four weeks and the results were compared to the metformin antidiabetic agent. Sixty rats were divided into five groups ( n = 12): control, PCOS, PCOS + LSSE (250 mg/kg), PCOS + LSSE (500 mg/kg), and metformin (200 mg/kg). Half of the rats were euthanized after four weeks, while the remaining rats were housed with males (1 male: 2 females) for testing pregnancy outcomes. LSSE led to remarkable improvements in body weight, glucose, sex hormonal balance, liver and kidney functions, antioxidant and anti-inflammatory systems, mating and fertility indices, pregnancy outcomes, and fetal morphology. Histologically, LSSE treatment reduced ovarian cyst number and size, and enhanced the blood vessel, Graafian follicle, and endometrial morphologies. LSSE showed dose-dependent effects, with the high-dose demonstrating superior results in the biochemical parameters, while the low-dose showed the most promising pregnancy outcomes. LSSE exhibits potent protective effects against PCOS, surpassing metformin in several aspects. LSSE acts through multi-mechanistic action, including anti-inflammatory, antioxidant, metabolic, and hormone-balancing properties, along with its positive impact on fertility, suggesting that LSSE could be a promising natural alternative for PCOS management. Graphical Abstract