A body builder. Would more testosterone make him stronger? Credit: Wikimedia Commons

Testosterone is one of the most over-prescribed and poorly understood medications. It is prescribed to millions of men for myriad indications, many of them unproven. Athletes believe it will improve their muscle mass and strength. Older men look to it as an anti-aging remedy. Men with flagging libido hope it will restore their sex drive. Testosterone has developed a mythology of masculinity. This is very similar to the notions we had a generation ago about estrogen being a fountain of femininity before anyone actually studied it.

Part of the difficulty in deciphering the actions of testosterone has been that testosterone is naturally metabolized in men’s bodies to estrogen. The concentration of testosterone in our blood is ten thousand times greater than that of estrogen, but estrogen clearly has important effects in men which are independent of the effects of testosterone. Sorting out which hormone does what has been challenging.

This week the New England Journal of Medicine (NEJM) published a very cleverly designed study that helps untangle the roles of testosterone and estrogen in middle-aged men.

The study enrolled 400 healthy men between the ages of 20 and 50 who had normal testosterone levels. They all received monthly injections of Zoladex, a medication that shuts off testosterone production in the testes. They were then randomized to 5 different groups. One group applied placebo gel to their skin daily. The next four groups each applied increasing doses of testosterone gel daily, from one quarter the typical testosterone replacement dose to twice the typical dose. That means that these men had their native testosterone production halted, and were replaced with 5 different amounts of testosterone ranging from zero to twice the typical amount.

Half of the men in these five groups were also randomized to receive Arimidex, a medication that blocks conversion of testosterone to estrogen. So these half were deprived of estrogen, regardless of how much testosterone supplement they were receiving. The men receiving Arimidex experienced severe hot flashes from the absence of estrogen.

The men were followed for 16 weeks. They answered questionnaires about their physical function, health status, and sexual function. They did leg presses to measure leg strength. They had CT scans to measure body fat and lean body mass.

By the way, spare a kind thought for the intrepid men who volunteered for such a study. For the reward of only $1,000 and the knowledge that they have served science, they agreed to have their sex hormones altered for 16 weeks. That means the placebo group essentially underwent a temporary castration for the fee of $31.25 per week per testis.

The findings were definitive and surprising. Muscle size and strength were found to be (as expected) due only to testosterone. Estrogen played no role in muscle mass or strength. Interestingly testosterone levels had to get very low before muscle size and strength were affected, suggesting that testosterone supplementation for men with testosterone levels even near the lower limit of normal may not improve their strength. Very little testosterone is all the muscles need.

Body fat turns out to be entirely estrogen dependent, with body fat increasing as estrogen declines. So just as women gain body fat during menopause, men probably gain body fat as their estrogen levels decline with age.

Sexual function was clearly dependent on both testosterone and estrogen. It declined in men deprived of testosterone, but declined even more in men deprived of both hormones.

I know what you’re thinking. “My libido hasn’t been great recently. I should start taking some of my wife’s estrogen supplement.” That’s a terrible idea. The doses your wife takes would likely cause you to grow breasts. Your wife’s reaction to that would likely more than outweigh whatever increase in libido you may experience.

This study doesn’t give us any immediate help in treating patients, but it suggests that checking estrogen levels in men with symptoms of hormone deficiency may be reasonable. And it elucidates which hormones are responsible for which symptoms. The Testosterone Trial is an ongoing study in older men with low testosterone that will help demonstrate the health benefits and harms of testosterone replacement. The results are expected in about a year and will give us much more practical information about who may benefit from treatment.

In the meantime we should remember that masculinity isn’t a molecule. Youth isn’t a medicine. The difference between men and women can’t be prescribed. And even if everyone else is jumping on the latest unproven fad, we are wise to wait for the data. That takes real balls.

Learn more:

Middle-Aged Men, Too, Can Blame Estrogen for That Waistline (NY Times)
Male Sex Drive Depends on Both Estrogen and Testosterone (Bloomberg)
Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men (NEJM article)
Mechanisms of Action of Testosterone — Unraveling a Gordian Knot (NEJM editorial)