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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\u2010like phenotypes over an extended period necessary for thorough drug assessment. We hypothesized that an oral letrozole administration would provide extended maintenance of syndrome\u2010like features. Female mice received letrozole either via subcutaneous implant (~1.67\u2009mg\/kg\/day for 70\u2009days) or orally in drinking water (~1\u2009mg\/kg\/day for up to 130\u2009days). 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\u2009days, oral letrozole administration sustained complete anovulation for at least 100\u2009days, maintaining a persistent diestrus stage. The oral letrozole treatment produced comprehensive PMOS\u2010like 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\u2010like ovarian morphology, increased body weight, impaired insulin sensitivity, and elevated adiposity during the entire time of the treatment period (18\u2009weeks), 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\u2010like 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.<\/jats:p>","DOI":"10.1111\/jne.70294","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T22:56:50Z","timestamp":1792450610000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sustained induction of\n                    <scp>PMOS<\/scp>\n                    \u2010like phenotype in mice exposed to letrozole in drinking water"],"prefix":"10.1111","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0844-977X","authenticated-orcid":false,"given":"Kennedy A.","family":"Stevenson","sequence":"first","affiliation":[{"name":"Centre for Neuroendocrinology, Department of Anatomy University of Otago School of Biomedical Sciences  Dunedin New 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