Efficacy and Safety of Testosterone Treatment in Men: An Evidence Report

Study Questions:

What are the benefits and harms of testosterone treatment for men without underlying organic causes of hypogonadism?


The authors utilized 38 randomized controlled trials (RCTs) of ≥6 months’ duration that evaluated transdermal or intramuscular testosterone therapies versus placebo or no treatment and reported prespecified patient-centered outcomes. Also included were 20 long-term observational studies, US Food and Drug Administration review data, and product labels that reported harms information. Efficacy was evaluated by results from RCTs and safety using results from RCTs and observational studies. Symptoms of hypogonadism were not universally required at baseline.


RCT studies varied from 38 to 790, with 15 trials having ≥100 men. Studies enrolled mostly older men who varied in age and symptoms. For those with total testosterone eligibility, criteria varied from <300 ng/dl in 31 studies but >400 ng/dl in five studies. Testosterone therapy improved sexual functioning and quality of life (QOL) in men with low testosterone levels, although effect sizes were small (low- to moderate-certainty evidence). Testosterone therapy had little to no effect on physical functioning, depressive symptoms, energy and vitality, or cognition. Harms evidence reported in trials was judged to be insufficient or of low certainty for most harm outcomes. No trials were powered to assess cardiovascular events or prostate cancer, and trials often excluded men at increased risk for these conditions. Observational studies were limited by confounding by indication and contraindication.


In older men with low testosterone levels without well-established medical conditions known to cause hypogonadism, testosterone therapy may provide small improvements in sexual functioning and QOL, but little to no benefit for other common symptoms of aging. Long-term efficacy and safety are unknown.


I agree with the authors, who concluded that the review had serious limitations: Few trials exceeded a 1-year duration, minimum important outcome differences were often not established or reported, RCTs were not powered to assess important harms, few data were available in men aged 18-50 years, definitions of low testosterone varied, and study entry criteria varied.

In fact, none of the RCTs had adequate design to establish endpoints of efficacy and safety, particularly related to QOL, atherosclerotic cardiovascular disease, and cancer. While the percent of men using testosterone replacement is not known, in the 2012 National Health and Nutrition Examination Survey (NHANES) US population study, the prevalence of symptomatic androgen deficiency in men between 30 and 79 years of age is estimated to be 5.6%. Considering the importance of symptoms of QOL attributable to low testosterone in men >50 years of age and the association with cardiovascular risk factors, diabetes, and vascular disease, and the increase in all-cause mortality in men with erectile dysfunction, it is surprising there has not been an appropriately designed RCT of hormone replacement therapy anywhere in the world.

Clinical Topics: Prevention

Keywords: Cardiovascular Diseases, Cognition, Depression, Erectile Dysfunction, Eunuchism, Hormone Replacement Therapy, Hypogonadism, Middle Aged, Primary Prevention, Prostatic Neoplasms, Quality of Life, Testosterone, Treatment Outcome

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