Supraphysiological testosterone differentially regulates aortic atheroma and cardiac remodelling in the testicular feminised mouse

The cardiovascular actions of testosterone remain controversial, particularly regarding the safety of testosterone replacement therapy (TTh) in hypogonadal men. We investigated the effects of sustained supraphysiological testosterone exposure on aortic atherogenesis and cardiac remodelling in the testicular feminised (Tfm) mouse, a model of functional androgen receptor (AR) deficiency. Male Tfm mice and AR-intact XY littermate controls were fed a cholesterol-enriched diet for 28 weeks and received fortnightly intramuscular injections of saline or supraphysiological testosterone, alone or in combination with fulvestrant (oestrogen receptor antagonist) or anastrozole (aromatase inhibitor). Aortic lipid deposition was quantified by Oil Red O staining, while cardiac remodelling was assessed by heart weight, cardiomyocyte cross-sectional area and myocardial gene expression. Supraphysiological testosterone significantly reduced aortic fatty streak formation in Tfm mice compared with saline-treated controls (1.25 ± 0.36% vs. 2.85 ± 0.37%, p < 0.01), an effect preserved following fulvestrant or anastrozole treatment, consistent with mechanisms that do not require classical AR or oestrogen receptor signalling. No additional reduction in aortic lipid deposition was observed in AR-intact XY littermates. In contrast, supraphysiological testosterone increased heart weight, cardiomyocyte size and expression of hypertrophic markers exclusively in XY mice, with no evidence of cardiac remodelling in Tfm mice. Collectively, these findings demonstrate divergent tissue-specific cardiovascular actions of testosterone, whereby supraphysiological exposure promotes AR-dependent cardiac remodelling without conferring additional vascular benefit, supporting maintenance of physiological testosterone concentrations during TTh.