Sustained induction of PMOS-like phenotype in mice exposed to letrozole in drinking water

Polyendocrine metabolic ovarian syndrome (PMOS; formerly polycystic ovary syndrome) is the most common endocrinopathy affecting women of reproductive age, characterized by ovarian dysfunction and hyperandrogenism, with metabolic disturbances including insulin resistance and obesity also present for 50% of PMOS patients. Effective preclinical models are crucial for evaluating therapeutic interventions. However, current mouse models of hyperandrogenemia induced by aromatase inhibition typically rely on subcutaneous letrozole implants, which require surgical procedures and struggle to sustain PMOS-like phenotypes over an extended period necessary for thorough drug assessment. We hypothesized that an oral letrozole administration would provide extended maintenance of syndrome-like features. Female mice received letrozole either via subcutaneous implant (~1.67 mg/kg/day for 70 days) or orally in drinking water (~1 mg/kg/day for up to 130 days). Estrous cyclicity was monitored by vaginal cytology. Hormonal, metabolic, and histological assessments were performed. While a subcutaneous letrozole implant only sustained hyperandrogenic, metabolic and reproductive phenotypes for ~50 days, oral letrozole administration sustained complete anovulation for at least 100 days, maintaining a persistent diestrus stage. The oral letrozole treatment produced comprehensive PMOS-like features, including significantly elevated testosterone levels, increased luteinizing hormone concentration, pulse frequency and amplitude, enhanced hypothalamic androgen receptor expression, decreased hypothalamic progesterone receptor expression, cystic-like ovarian morphology, increased body weight, impaired insulin sensitivity, and elevated adiposity during the entire time of the treatment period (18 weeks), compared to the placebo treatment. Uterine weight was not decreased, suggesting normal circulating estrogen concentrations. These findings demonstrate that oral letrozole delivery offers a more accessible method of administration, resulting in a sustained induction of PMOS-like phenotypes. This approach effectively maintains both reproductive and metabolic features essential for comprehensive evaluation, thereby enhancing the model's utility for investigating therapeutic interventions in PMOS.