Study tracks symptoms in men as testosterone levels decline
Low testosterone production can reduce strength, muscle size and lean mass. If the testosterone isn’t being converted to estrogen, men may see an increase in body fat. And a deficiency of either can spark a decline in sexual function, according to a new study of hundreds of volunteers.
The research, published in the New England Journal of Medicine, comes at a time when testosterone supplements are being widely advertised to men in the U.S., for example, in commercials urging them to be treated for “Low T.”
From 2001 to 2011, the number of U.S. men receiving such treatment more than tripled and replacement therapy has become a nearly-$2 billion business.
Unlike new drugs that are approved for a specific problem, testosterone is subject to “surging overuse from off-label prescribing for diverse unproven indications, including use in older men as an anti-aging or sexual tonic and in younger men for bodybuilding or doping,” even though the way it works is not well understood, David Handelsman of the University of Sydney writes in a Journal editorial.
“The bottom line is there are tens of millions who are aging and who are having their hormone levels changed,” lead study author Dr. Joel Finkelstein of Massachusetts General Hospital in Boston told Reuters Health. “We don’t know which men should be treated, whether it’s effective and whether it’s actually safe.”
The new study was an attempt to separate the effects of testosterone and estrogen - most of which is made by the body from testosterone - on men’s sexual function, strength, muscle size and lean and fat mass, and to discover how much testosterone is needed for health.
“This study allows us to begin to be more sensible about the diagnosis and treatment of low testosterone,” Dr. Bradley Anawalt, chairman of The Endocrine Society’s Hormone Health Network, told Reuters Health. He was not connected with the research.
“It shows that testosterone has different effects at different levels for different tissues,” he said.
A group of 400 healthy volunteers were injected with a drug to shut down natural production of both testosterone and estrogen, then for 16 weeks they were given varying doses of testosterone gel, placebo gel and anastrozole to prevent testosterone from being converted to estradiol, a form of estrogen.
Although the sensitivity of various androgen target tissues is known to vary, the diagnosis of androgen deficiency is typically based on a single laboratory criterion: a testosterone level at least 2 SD below the mean value in normal young men. In this study, we found that the dose of testosterone required to prevent adverse changes in a variety of measures varies considerably. When aromatization was intact, fat accumulation began with mild gonadal steroid deficiency (a testosterone level of approximately 300 to 350 ng per deciliter), whereas lean mass, thigh-muscle area, and muscle strength were preserved until gonadal steroid deficiency was more marked (a testosterone level ≤ 200 ng per deciliter). Sexual desire and erectile function, the two major domains of sexual function, showed distinct patterns of change as serum testosterone levels were reduced. The variation in tissue sensitivity to androgens could be due to polymorphisms affecting polyglutamine repeat length in the androgen-receptor gene, tissue-specific differences in androgen-receptor expression or local hormone metabolism, or, as shown in the present study, variation in the roles of androgens and estrogens in the regulation of target-tissue responses.
Observational studies have shown that lean mass and strength are reduced and fat mass is increased in men with low testosterone levels. Men with hypogonadism report less sexual activity, fewer sexual thoughts, and fewer spontaneous erections than men with normal testosterone levels. Moreover, testosterone replacement increases lean mass, decreases fat mass, and can improve sexual function in men with hypogonadism. These observations have led to the widespread belief that undesirable changes in body composition and sexual dysfunction in men with hypogonadism are due to androgen deficiency. However, because estradiol is a metabolite of testosterone, it is difficult to distinguish the effects of androgens from those of estrogens in observational studies, or even in randomized, controlled trials if aromatizable androgens are used without the administration of an aromatase inhibitor.
By administering a variety of testosterone doses with and without concomitant aromatase inhibition, we found that changes in lean mass, thigh-muscle area, and leg-press strength were attributable to changes in testosterone levels, whereas changes in fat measures were primarily related to changes in estradiol levels. Both androgens and estrogens contributed to the maintenance of normal libido and erectile function. Although these results may be surprising, they are consistent with studies showing that body fat is increased in humans and male mice with null mutations of the aromatase gene or the estrogen-receptor α gene and that sexual function is markedly impaired in mice and humans with these genetic defects.
Among the findings, sexual desire dropped progressively with lower testosterone levels.
Testosterone levels had to be extremely low, however, before erectile dysfunction appeared. But if estrogen production declined, that had an effect on sexual function regardless of how much testosterone the man was producing.
Testosterone levels also had to be very low before the researchers saw declines in leg strength, the size of the thigh muscle and lean body mass.
When estrogen production was blocked, there was an increase in body fat regardless of how much testosterone was in the blood. When it was not blocked, only a mild reduction in testosterone was enough to increase body fat.
But estrogen levels alone had no effect on leg strength, muscle size or the leanness of the body.
The researchers said that, for the moment, symptoms - and not just a man’s testosterone level - should determine whether he is a candidate for testosterone replacement therapy.
The pattern of results also shows that if testosterone therapy is given, it should be in a form that the body can convert into estrogen, they said.
The men in the study were ages 20 to 50 years old. The researchers hope to run the same test on older men to see if the results hold for them.
“The real big picture here is what happens with aging,” Finkelstein said. “This is a huge public health issue. At middle age, testosterone levels do decline modestly. At the same time, men have other changes that can be associated with testosterone. They lose muscle mass and gain fat, and lose sex drive and lose bone, etc. The question is whether the changes that occur with aging are causally related to the changes that occur in hormones.”
“Longer studies are required to partition the effects of testosterone on bone density and fractures, or on prostate growth and diseases,” Handelsman said in his editorial.
Similarly, he pointed out, an “equally demanding analysis” could shed light on testosterone’s influence over metabolism, cardiovascular heath, memory, mood and behavior, as well as the effects of age and obesity.
In this study, the men started out with testosterone levels that averaged more than 500 nanograms per deciliter of blood. Fat accumulation began when the level dropped to about 300 to 350 ng. Lean mass, muscle strength and thigh-muscle area started to drop at 200 ng.
“I think this will help clinicians make more rational decisions about whom to treat with testosterone,” said Finkelstein. “It also teaches clinicians that there is no one answer to what’s a low level. If the patient’s interested in sexual function, it’s one level. If they’re interested in bone loss, it’s another level. Unfortunately it’s not one size fits all.”
Anawalt, of the University of Washington in Seattle, said he is concerned that some people will use the new findings to push for more aggressive testosterone treatment. He said that would be irresponsible.
“In practice, a lot of clinicians who are prudent and cautious have said, ‘Maybe the patient’s symptoms are due to low testosterone.’ But generally, the results are pretty disappointing when you give it,” he said.
In his practice, “If they come in with a little extra weight and their testosterone levels are on the low end of normal, I tell them you have to diet, start exercising four to five times a week and usually your testosterone levels will start coming up,” said Anawalt. “That’s the right answer for a lot of these guys.”
SOURCE: New England Journal of Medicine, online September 11, 2013.
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Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men
Conclusions
The amount of testosterone required to maintain lean mass, fat mass, strength, and sexual function varied widely in men. Androgen deficiency accounted for decreases in lean mass, muscle size, and strength; estrogen deficiency primarily accounted for increases in body fat; and both contributed to the decline in sexual function. Our findings support changes in the approach to evaluation and management of hypogonadism in men. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number NCT00114114.)
Joel S. Finkelstein, M.D., Hang Lee, Ph.D., Sherri-Ann M. Burnett-Bowie, M.D., M.P.H., J. Carl Pallais, M.D., M.P.H., Elaine W. Yu, M.D., Lawrence F. Borges, M.D., Brent F. Jones, M.D., Christopher V. Barry, M.P.H., Kendra E. Wulczyn, B.A., Bijoy J. Thomas, M.D., and Benjamin Z. Leder, M.D.
N Engl J Med 2013; 369:1011-1022