In men with hypogonadism who have undergone radical prostatectomy for low-grade prostate cancer, testosterone replacement therapy (TRT) helps improve sexual and physical function, according to the SPIRIT study.
After 12 weeks of treatment, the primary outcome of sexual activity significantly increased for TRT-treated men than for those who received placebo in analyses adjusted for phosphodiesterase-5 inhibitor use and age (between-group difference, 0.91 daily events, 95 percent confidence interval [CI], 0.56–1.26; p<0.001). [JAMA Intern Med 2026;doi:10.1001/jamainternmed.2026.1343]
Men in the TRT arm also had a significantly greater improvement in sexual desire (between-group difference, 2.96 units, 95 percent CI, 1.46–4.45) and prostate cancer quality-of-life sexual domain score (between-group difference, 5.35, 95 percent CI, 1.63–9.07), as well as a markedly greater decrease in negative affect score (between-group difference, −1.39, 95 percent CI, −2.53 to −0.25) compared with those in the placebo arm.
“Sexual activity is a composite marker of sexual function, and an important marker of quality of life in middle-aged and older adults,” the investigators said.
“Sexual activity decreases with age, but a majority of older men continue to be sexually active. In an observational study, the average sexual activity was 7.2 events per month in men aged 30–39 years and nearly half in men aged 80 years. An increase of 0.91 daily sexual events appears favourable in the context of these data on sexual activity in older men,” they added. [JAMA Netw Open 2020;3:e203833; J Sex Res 2018;55:146-151; J Gerontol B Psychol Sci Soc Sci 2011;66:502-512]
As for physical function, TRT conferred a significant increase in whole-body (treatment effect, 2.56 kg), appendicular (treatment effect, 1.50 kg), and trunk lean mass (treatment effect, 1.06 kg) compared with placebo. These changes in the TRT arm were accompanied by substantial improvements in VO2 peak (treatment effect, 0.16 L/min) and loaded stair climbing power (treatment effect, 33.0 W).
“The lean mass gains were associated with significant improvements in physical performance, supporting their clinical meaningfulness,” the investigators pointed out.
SPIRIT included ≥40-year-old men with organ-confined, low-grade prostate cancer (Gleason score of 6 or 7), undetectable prostate-specific antigen (PSA) for at least 2 years after radical prostatectomy, a mean of 2 testosterone levels <275 ng/dL, and low libido, erectile dysfunction, or fatigue.
A total of 136 men (mean age 68.6 years, 86 percent White, mean BMI 29.5 kg/m2, 38 percent had Gleason score of 6) underwent randomization to treatment with either testosterone cypionate at 100 mg (n=68) or placebo (n=68) for 12 weeks, with follow-up conducted for another 12 weeks.
The Psychosexual Diary Questionnaire question 4 score, DeRogatis Inventory of Sexual Function-Sexual Desire, 26-item Expanded Prostate Cancer Index Composite, and Positive and Negative Affect Schedule were used to assess sexual function and affect outcomes.
As for safety, none of the men in either treatment arm experienced biochemical recurrence (PSA ≥ 0.2 ng/mL) during the 12-week intervention or the 12-week follow-up. Serum PSA levels remained undetectable in all but three men.
“This group of men with low-grade, organ-confined prostate cancer represents 50 percent to 60 percent of men diagnosed with prostate cancer today,” the investigators noted.
Between 40 percent and 50 percent of this population undergo radical prostatectomy, which leads to bothersome sexual and physical symptoms and the development of hypogonadism for a substantial proportion of men, they added. [N Engl J Med 2008;358:1250-1261; Asian J Urol 2025;doi:10.1016/j.ajur.2025.06.001]
“Therefore, the SPIRIT findings of TRT’s efficacy in improving overall sexual activity and sexual desire, well-being, body composition, aerobic performance, and physical function, and short-term safety … would be valuable to this group of patients with prostate cancer and their treating clinicians for informing their treatment decision,” the investigators said.
They acknowledged that the trial was neither long enough nor large enough to evaluate clinical recurrence or long-term safety and emphasized that the findings do not apply to men with high-grade prostate cancer or those treated with androgen deprivation therapy or radiation therapy.