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.