Cardiovascular and Metabolic Consequences of Testosterone Supplements in Young and Old Male Spontaneously Hypertensive Rats: Implications for Testosterone Supplements in Men

BACKGROUND: The safety of testosterone supplements in men remains unclear. In the present study, we tested the hypothesis that in young and old male spontaneously hypertensive rats (SHR), long‐term testosterone supplements increase blood pressure and that the mechanism is mediated in part by activation of the renin‐angiotensin system. METHODS AND RESULTS: In untreated males, serum testosterone exhibited a sustained decrease after 5 months of age, reaching a nadir by 18 to 22 months of age. The reductions in serum testosterone were accompanied by an increase in body weight until very old age (18 months). Testosterone supplements were given for 6 weeks to young (12 weeks‐YMSHR) and old (21–22 months‐OMSHR) male SHR that increased serum testosterone by 2‐fold in young males and by 4‐fold in old males. Testosterone supplements decreased body weight, fat mass, lean mass, and plasma leptin, and increased plasma estradiol in YMSHR but had no effect in OMSHR. Mean arterial pressure (MAP) was significantly higher in OMSHR than in YMSHR and testosterone supplements decreased MAP in OMSHR, but significantly increased MAP in YMSHR. Enalapril, the angiotensin‐converting enzyme inhibitor, reduced MAP in both control and testosterone‐supplemented YMSHR, but had a greater effect on MAP in testosterone‐treated rats, suggesting the mechanism responsible for the increase in MAP in YMSHR is mediated at least in part by activation of the renin‐angiotensin system. CONCLUSIONS: Taken together with previous studies, these data suggest that testosterone supplements may have differential effects on men depending on age, cardiovascular and metabolic status, and dose and whether given long‐term or short‐term.