Benefits and Risks of Testosterone Replacement Therapy in Men

A 72-year-old man presents for follow-up for hypertension and hyperlipidemia, for which he takes atorvastatin, metoprolol, and amlodipine. His body mass index is 28 kg/m², and he has no history of cardiovascular disease. He is sedentary and admits to eating too much junk food. He report daily fatigue with some subjective muscle weakness, decreased libido, and erectile dysfunction. He has read on the internet that testosterone is often low at his age and that replacing it could improve his symptoms.

Testosterone levels tend to diminish with age, declining by 2.8% each year after age 40 years. Approximately 20% of men in their 60s and 50% of men in their 80s have testosterone levels below 300 ng/dL (10.41 nmol/L), which is considered testosterone deficiency.^1,2 Older men are more likely to experience sexual dysfunction, muscle mass loss, fatigue, and low bone density, all linked to decreased testosterone.³ Although 50% of men older than 65 years report symptoms of sexual dysfunction, it is unclear how many of them have low testosterone levels and whether low testosterone is the sole cause of their symptoms.⁴

In one study, approximately 5% of men in their 70s experience sexual symptoms concomitant with low testosterone levels.⁵ Still, many men use exogenous testosterone to relieve symptoms and increase muscle mass. Between 2000 and 2013, testosterone supplement sales in the United States increased from $100 million to $2.7 billion, and sales are estimated to increase to $4.3 billion by 2030.^5,6

Testosterone measurement and replacement therapy are controversial. Most studies suggest that multiple morning testosterone measurements (before 10 am) are needed to accurately diagnose male hypogonadism because levels are diurnal, with known decline from morning into afternoon.⁷ One study found that two-thirds of physicians measure levels in the afternoon, and those artificially low levels account for approximately 70% of low levels recorded, resulting in a high false-positive rate.⁸

Most studies used a morning cut-off level of 300 ng/dL as a threshold for hypogonadism after multiple morning measurements, although norms differ with age.⁹ In addition, many formulations of testosterone replacement therapy are available (eg, pills, patches, gels, injections), none of which is clearly superior.³ A meta-analysis that found benefit from testosterone replacement therapy overall found no difference among different formulations.¹⁰ Most studies in this analysis used only one form of testosterone replacement therapy, typically a patch.

It is important to distinguish between studies that enrolled men receiving testosterone for sexual symptoms regardless of their testosterone level from those that enrolled only men with documented low morning testosterone levels. A recent Cochrane review of 43 randomized controlled trials including men with sexual dysfunction who took testosterone regardless of testosterone levels found no benefit. Most of the funded studies (19 of 21) were supported by pharmaceutical companies, and many excluded men with underlying medical and psychological illness. Study duration ranged from 6 weeks to 24 months.^11,12

The most consistent benefit of testosterone replacement therapy in men with low levels is improved sexual desire and function. A small trial in China showed significant improvement in erectile dysfunction with treatment vs placebo after 3 months; the International Index of Erectile Function-15 score (range 0–30) increased by 14.4 in the treatment group and decreased by 5.2 in the placebo group.¹³ The Testosterone Trials, a group of seven randomized trials that evaluated the effects of testosterone treatment in 790 older men with low testosterone over 1 year, showed statistically significant improvements in sexual function and desire among treated men, with higher levels of testosterone correlating with improved sexual function.¹⁴