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

An assessment of the results from the long-awaited TRAVERSE trial

Peter Attia

Read Time 15 minutes

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.

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  1. Thank you for this much sought-after topic. Could you advise on a sub-Q injection vs IM as far as effectiveness?

  2. I just want to thank Dr. Attia and his staff for the wealth of credible, detailed, scientific information that they provide to the public in a way that many lay people can understand and use to have intelligent conversations with their doctors. This kind of information is just not available anywhere else.

  3. The question being “Does TRT increase the risk of major cardiovascular events?”, maybe it is important to consider as well the patients that didn’t respond to the therapy… The percentage of these patients can be even higher in some studies and in the clinical practice. If TRT is increasing the levels or not of a patient, is it causing any cardiovascular AE during the clinical period of adjustments or individual investigation? If the TRT is not showing any significance to raise the testosterone level of a patient, it doesn’t mean the molecule is totally “invisible” for the organism.
    As always, every study seems to bring more questions than answers when we think of the biological systems… What about the mitocondrial health of each participant of the study?
    What is the role of estradiol in male hypogonadism? What about the (synthetic) molecule used in the study… how can we have a study done with the use of a bio identical testosterone?
    In 2014, I wrote an article about the Women’s Health Initiative study. Back then, so much prejudice and fear because of 1 study that used the synthetic progestin… It was when I realised few doctors really open and read studies – and even fewer know how to interpret studies results with “context”, a huge problem and one of the reasons science can act so slow. Thank you.

  4. As usual, great information and very helpful when talking with my primary care doctor, who is quite good, but generally unaware of this type of information.
    Thank you again!

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