Review: Efficacy and Safety of Testosterone for Older Adults With Functional Limitations

Close up of old man's hands holding wooden cane, seated

Given the aging of the population and longer life expectancy, prevention and treatment of age-related loss of muscle mass, strength, power and physical function has become a public health imperative.

Testosterone is a leading candidate for these purposes based on several suppositions: circulating testosterone levels decline with age and contribute to loss of skeletal muscle mass and performance; testosterone administration increases muscle mass, strength, and physical function in older adults and people with certain chronic diseases; and testosterone treatment of older men is safe.

Arijeet K. Gattu, MBBS, and Shalender Bhasin, MD, endocrinologists in the Division of Endocrinology, Diabetes and Hypertension at Brigham and Women’s Hospital, and colleagues critically appraise each of these hypotheses in Reviews in Endocrine and Metabolic Disorders.

Age‑related Decline in Testosterone and Its Effects

Multiple cross-sectional and longitudinal studies have established that serum total testosterone levels decline with advancing age. Because sex hormone–binding globulin levels increase with age, free testosterone levels decrease even more than total testosterone. Weight gain and certain chronic diseases accelerate the decline.

The age-related decline in testosterone primarily results from decreased rates of testicular testosterone production due to defects at all levels of the hypothalamic–pituitary–testicular axis.

In epidemiologic studies, low bioavailable or free testosterone levels have been tied to:

  • Low appendicular skeletal muscle mass
  • Reduced strength of upper- and lower-extremity muscles
  • Impairment in self-reported and objective measures of physical function
  • Increased risk of mobility limitation
  • Increased risk of the frailty syndrome and its progression
  • Increased risk of falls and bone fractures in older men

Trials of Testosterone in Older Men

Randomized trials in community-living, medically stable older men with low or low-normal testosterone levels have provided compelling evidence for testosterone replacement therapy. Compared with placebo, it’s associated with greater improvement in lean body mass, muscle strength, and measures of physical function strongly associated with muscle strength, such as stair climbing speed/power.

Testosterone treatment can also attenuate the age-related reduction in aerobic capacity. However, changes in some performance-based measures, such as walking speed and sit-to-stand time, have been modest and inconsistent across trials.

Efficacy of Testosterone for Adults With Chronic Diseases

Short-term testosterone therapy for HIV-infected men with low testosterone levels and weight loss is safe and can modestly increase body weight and lean body mass. Because of widely heterogeneous trial designs, there’s no strong evidence about how testosterone affects physical function or risk of disability in HIV-infected men or its long-term safety in this population.

Some evidence suggests testosterone supplementation can improve physical function, reduce exercise intolerance, and promote rehabilitation of adults with chronic obstructive pulmonary disease, but further studies are needed.

Likewise, the paucity of robust evidence about the efficacy of testosterone in improving physical function precludes a general recommendation about whether it can be used to treat functional limitations, sarcopenia, or frailty in all older adults.

Safety of Long‑term Testosterone Therapy

Whether testosterone replacement therapy increases the incidence of prostate cancer or cardiovascular events has been the source of much controversy and is still unclear. No trial has been long or large enough to address these issues definitively.

TRAVERSE, a large, randomized trial, is studying the effects of testosterone on the risk of major adverse cardiovascular events in men 45 to 80 years of age who have testosterone deficiency and an increased risk of cardiovascular events.

According to a 2013 narrative review, testosterone treatment does not worsen lower urinary tract symptoms in men who do not have severe symptoms at baseline.

Guidance for Prescribers

An expert panel of the Endocrine Society suggests considering short-term testosterone therapy for HIV-infected men with low testosterone levels and weight loss when other causes of weight loss have been excluded.

Clinicians may also consider offering testosterone on an individualized basis to older men with consistently low testosterone levels, anemia, and functional limitations after an explicit discussion of the uncertainty of long-term benefits and risks.

Leave a Reply