Is testosterone replacement therapy both safe and effective in men with higher cardiovascular risk factors?

Though I’ve dedicated attention to the Women’s Health Initiative study (the largest hormone replacement study in women), until very recently, there wasn’t an equivalent study of testosterone replacement therapy (TRT) in men, despite testosterone’s importance in maintaining bone density, body composition, red blood cell production, and sexual function throughout adulthood. But with the recent publication of the TRAVERSE trial on TRT, there’s no better time to examine the benefits, concerns, and practical applications of testosterone therapy.

The Endocrine Society defines low testosterone (T) as any level of total serum testosterone below 300 ng/dL, although typically low T is only treated if symptomatic. As its name implies, total T levels refer to the concentration of all serum testosterone, but only 1-3% of testosterone is “free” or unbound. Approximately 45% of total T is bound to sex hormone-binding globulin (SHBG) and a little more than 50% is bound to the protein albumin. Testosterone is unavailable for bioactivity while it is bound to these proteins, but since testosterone binds only weakly to albumin, albumin-bound testosterone is readily released to exert its biological effects. Therefore, the amount of bioavailable T is generally calculated from the difference in total and SHBG-bound T.

Testosterone replacement therapy uses exogenous T to increase both total and free T levels and relieve the symptoms associated with low T, usually aiming to reach a therapeutic level of total T between 400 to 700 ng/dL. The benefits of TRT in hypogonadal men include changes in body composition, improved muscle mass and strength, increased bone mineral density, improved sexual desire and function, improved mood, energy, and quality of life.