The Risks of Testosterone Therapy

What are the downsides of men taking supplemental testosterone? Medical practitioners are encouraged to inform men that it may make them less faithful. This is a theoretical concern based on the fact that higher testosterone levels are correlated with higher levels of sexual infidelity, as is larger testicle volume, as measured by a Prader orchidometer. Had to google image search that one. and what do you know? Anyway, care to hazard a guess as to lifetime prevalence of cheating? Evidently 49% of heterosexual men and 34% of homosexual men are unfaithful (along with 29% of heterosexual women and 4% of homosexual women).

What about “roid rage”? Testosterone is the anabolic steroid most commonly used by bodybuilders and carries a reputation of aggravating hostility. Soon after it was first synthesized in the 1930s, testosterone was administered by Nazi doctors to German soldiers to promote aggression on the battlefield, but levels of self-reported aggression among modern users appear to be small. Experimentally, though, a single dose does significantly increase “tit-for-tat” provoked aggression as well as increasing “social discounting,” in other words making men more selfish when placed in a generosity scenario.

The most ironic side effect to taking testosterone is developing low testosterone. The reason bodybuilders develop shrunken testicles is because taking exogenous (outside the body) testosterone instructs the feedback loop in the brain to downregulate endogenous (inside the body) production, leaving the body in an even greater state of deficiency should the testosterone therapy ever stop. This creates a vicious but profitable cycle of dependency. Average time to recover baseline testosterone production after stopping supplemental testosterone is 7 months, and sperm variables take over a year, and it can take multiple years for testicles to plump back up. (Testosterone use can cause 28ml testicles to shrink by 50% to 14 ml, that’s like going from a ping pong ball down to a large marble), but after stopping they can get back at least a third of the lost volume (to 19 ml) within about a year).

Men born with higher lifetime levels of testosterone tend to have lower risk of type 2 diabetes, and indeed, randomizing obese men to testosterone appeared to cut their risk of developing diabetes over the next two years from 21% down to 14%. Unfortunately 22% of the testosterone subjects developed a dangerously high hematocrit (compared to only 1% taking the placebo). Hematocrit is the proportion of our blood that’s made up of red blood cells (versus the surrounding liquid plasma). Testosterone stimulates our bone marrow to generate more red blood cells. This is good if you’re anemic (and indeed in the Testosterone Trials anemia was alleviated in the majority of anemic men in the testosterone group), but if you sludge up your blood with too many red cells it can put you at risk for heart attacks and strokes. That brings us to potentially the most serious side-effect.

In the Testosterone Trials, men randomized to testosterone accumulated significantly more plaque in their coronary arteries than the men who got the placebo. In fact the TOM trial, the Testosterone in Older Men trial, had to be cut short because the testosterone group was having ten times more cardiac events than the placebo group. The industry points to observational studies showing an association between low testosterone and more cardiovascular disease, suggesting testosterone could be protective, but this tendentious overinterpretation ignores the fact that low testosterone levels may just be acting as a barometer of ill health. Mendelian randomization studies looking at genetically determined testosterone levels and cardiovascular disease risk conclude there is no causal effect either way, but only placebo-controlled trials can tell usfor sure.

Only one out of eight reviews of the dozens of randomized double-blind placebo controlled trials concluded that testosterone significantly increased cardiovascular risk. Guess which one it was: could it have been the only one not written by testosterone manufacturer-funded researchers that took industry funding into account? Yes, and in trials not funded by drug companies, testosterone was found to double the odds of experiencing an adverse cardiovascular-related event. In response, the industry had the gall to suggest this perhaps “simply reflects an increase in sexual …activity, unmasking latent disease by precipitating exertional symptoms or events.” Regulators weren’t buying it. In 2014 Health Canada issued a testosterone black box warning of “a risk of serious and possibly life-threatening cardiovascular (heart and blood vessel) problems” and the following year the FDA followed suit, adding labeling about “possible increased risk of heart attacks and strokes in patients taking testosterone.” It was also made explicit that testosterone should only be used for classical hypogonadism and not given for aging-related purposes.  Since then, prescriptions for testosterone have sharply declined.

One leading anti-aging journal carried a commentary comparing testosterone replacement therapy to the emperor’s new clothes, noting the topic remains “astonishingly controversial.” What do you expect when there’s a billion-dollar industry at stake? An analysis of popular YouTube videos on the subject suggests mass misinformation persists. Yet a systematic review of more than 150 randomized controlled trials concluded “We identified no population of normal men for whom the benefits of testosterone use outweigh its risk.”

Surprisingly, testosterone therapy does not seem to worsen symptoms of prostate enlargement. What about prostate cancer? The role of testosterone in prostate cancer has been known since the 1940s when surgical castration was shown to cause a dramatic regression of tumors. To this day, testosterone suppression is universally accepted as the first-line treatment for symptomatic metastatic disease. Whether or not testosterone causes prostate cancer or merely accelerates it, the question is moot since autopsy studies show that as many as about one in three men in their 30s and two in three men by their 60s already have tiny prostate cancers growing inside them whether they know it or not. That’s why guidelines recommend rectal exams and PSA screening before starting testosterone.