Top Line: There is pretty solid evidence that testosterone replacement to physiologic levels does not increase risk of developing de novo prostate cancer.
The Study: The next question becomes whether this is safe in men with prior history of more favorable prostate cancer. Enter the proof-of-concept SPIRIT trial where 136 hypogonadal men at least 2 years post-prostatectomy for favorable prostate cancer (grade group 1-2) with undetectable PSA (<0.04 ng/mL) were randomized to weekly IM testosterone versus placebo for 12 weeks. The primary endpoint was to assess for PSA increases to 0.2 ng/mL during or immediately after receipt of endogenous testosterone. PSA remained <0.2 ng/mL (read: at baseline, weeks 2, 4, 6, 8, 12, and 3 months after stopping medication) in all patients, though two receiving testosterone and one receiving placebo had transient detectable PSA measurements between 0.04-<0.2. Meanwhile, those receiving testosterone enjoyed predictable quality-of-life gains: sexual activity improved by nearly one additional daily event versus placebo with parallel boosts in libido and EPIC sexual function scores. Testosterone replacement also increased lean body mass (+2.6 kg), improved stair-climb power and VO2 peak, and trimmed fat mass.
The Study: The next question becomes whether this is safe in men with prior history of more favorable prostate cancer. Enter the proof-of-concept SPIRIT trial where 136 hypogonadal men at least 2 years post-prostatectomy for favorable prostate cancer (grade group 1-2) with undetectable PSA (<0.04 ng/mL) were randomized to weekly IM testosterone versus placebo for 12 weeks. The primary endpoint was to assess for PSA increases to 0.2 ng/mL during or immediately after receipt of endogenous testosterone. PSA remained <0.2 ng/mL (read: at baseline, weeks 2, 4, 6, 8, 12, and 3 months after stopping medication) in all patients, though two receiving testosterone and one receiving placebo had transient detectable PSA measurements between 0.04-<0.2. Meanwhile, those receiving testosterone enjoyed predictable quality-of-life gains: sexual activity improved by nearly one additional daily event versus placebo with parallel boosts in libido and EPIC sexual function scores. Testosterone replacement also increased lean body mass (+2.6 kg), improved stair-climb power and VO2 peak, and trimmed fat mass.
TBL: If we are comfortable with men remaining naturally eugonadal following prostatectomy for biochemically-controlled favorable prostate cancer, the same should apply to men who achieve physiologic levels of testosterone with exogenous help, though larger trials with longer follow-up are sure to come. | Bhasin, JAMA Intern Med 2026