SUN-143 A Preclinical Model of Testosterone Exposure in Female Mice Recapitulates the Human Phenotype

Abstract Disclosure: S. Roberts: None. A. Fontes: None. M. Magnuson: None. H. Kim: None. R. Singh: None. K. Victoria: None. R. Carroll: None. U. Kaiser: None. Background: Transgender and non-binary individuals are presenting at increasing rates for gender-affirming care. Some of these patients desire gender-affirming testosterone therapy, which is standard of care and associated with improved mental health and quality of life. Preclinical models have largely been underutilized in transgender health. We aimed to validate a mouse model of exogenous testosterone (T) therapy in postpubertal wild type (WT) females, recapitulating the treatment paradigm in humans, to characterize the effects on the neuroendocrine control of reproduction and on metabolism. Methods and Results: Thirty WT, gonad-intact, C57BL/6 female mice at age 8 weeks were treated with weekly SC injections of testosterone enanthate, either 0.9 mg/dose (High T) or 0.45 mg/dose (Low T), or sesame oil (Vehicle; V) for 6 weeks (n=10/treatment group). An additional control group of WT, gonad-intact male mice (n=10) receiving sesame oil injections (Male V) were also generated. Weekly peak serum T concentrations were higher in the Female High T group than in the Male V group (p<0.0001); Female Low T and Male V groups were similar (p=0.84); while Female V concentrations were much lower (p<0.0001). After two weeks of treatment, serum LH concentrations were significantly lower in Female High T and Low T compared to Female V mice (p<0.0001). Additionally, mean clitoral length was significantly higher in Female Low T and High T groups, compared to Female V mice (p<0.0001). Female Low T and High T groups entered persistent diestrus by two weeks of treatment for the remainder of the treatment period. Mean body weight and body length were associated significantly with time and treatment (p<0.0001). Female High T mice demonstrated the greatest mean percent change in body weight compared to baseline. In terms of metabolic effects, serum concentrations of the sexually dimorphic adipokines, adiponectin and leptin, declined significantly at six weeks of treatment compared to baseline in Female High T and Low T groups (p<0.0001). Serum resistin concentrations declined with treatment in Female High and Low T groups compared to baseline (p<0.001). Plasminogen activator inhibitor-1 concentrations increased with treatment in Female High T mice (p=0.01). Serum IL-6 and monocyte chemoattractant protein-1 did not differ among treatment groups. Conclusions: These findings indicate, through detailed reproductive phenotyping, that exogenous T exposure in postpubertal female mice recapitulates the human phenotype of increased body weight, lack of menstrual cyclicity and clitoromegaly. The sex steroid responsive adipokines, leptin and adiponectin, decreased to levels similar to male mice. This translational model can serve to help understand mechanisms of action of T on the neuroendocrine control of reproduction in humans, as well as the metabolic consequences of T therapy. Presentation: Sunday, July 13, 2025