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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.

journal of the american heart association

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