SAT-001 Supra-Physiological Testosterone Treatment Reduces Aortic Atheroma but Increases Markers of Cardiac Hypertrophy

Supra-physiological Testosterone Treatment Reduces Aortic Atheroma but Increases Markers of Cardiac Hypertrophy The impact of testosterone on the cardiovascular system is controversial and concerns have been raised in regard to the safety of testosterone replacement therapy (TTh) in hypogonadal men with cardiovascular disease. We have examined the effects of supra-physiological concentrations of testosterone upon aortic fatty streak formation in high-fat diet-fed testicular feminized (Tfm) mice, which exhibit non-functional androgen receptors (AR) and low circulating testosterone levels. Tfm mice were fed a high-cholesterol diet ad libitum for 28 weeks and received fortnightly intramuscular injections of either saline (Tfm, n=8, XY, n=8), 10uL of 250mg/mL testosterone alone (Tfm, n=8, XY, n=8), or in conjunction with either a 30uL intramuscular injection of 50mg/ml estrogen receptor-alpha antagonist fulvestrant (Tfm, n=8), or with 10mg/kg/day of aromatase inhibitor anastrazole in drinking water (Tfm, n=7). Cardiac tissue mRNA was analysed by qPCR for markers of hypertrophy (ANP, BNP, alpha-actin, MYH7, Gsk3-beta, SM22-alpha). A significant reduction in aortic fatty streak formation was observed in Tfm mice receiving supra-physiological testosterone compared to those receiving saline; 1.25+0.36% versus 2.85+0.37% respectively (p<0.01). No significant increase in aortic lipid deposition was observed in XY littermates administered supra-physiological testosterone compared to those receiving saline; 0.22+0.13% versus 0.32+0.12% respectively (p=ns). Aortic fatty streak formation in Tfm mice receiving supra-physiological testosterone in conjunction with fulvestrant or anastrazole was similar to that observed in Tfm mice receiving supra-physiological testosterone therapy alone; 0.71+0.18% and 1.09+0.81% respectively versus 1.25+0.36% (both p=ns) indicating non-genomic actions of testosterone. Hypertrophic markers and heart weights were elevated in XY littermates receiving supra-physiological testosterone but not in Tfm mice compared to placebo suggesting AR-dependent actions. This evidence suggests that supra-physiological levels of testosterone protect against diet induced aortic atheroma formation, at least in part, via non-genomic mechanisms but incur increased cardiovascular risk by potentially inducing cardiac hypertrophy via AR-dependent actions. Dose titration to physiological levels and careful monitoring of patients throughout treatment is key to eliciting the beneficial cardiovascular effects of TTh in hypogonadal men.