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Older men whose natural testosterone levels were in the middle range tended to live longer than those with the highest and lowest levels, suggesting that having too much of the hormone in old age may be no better for survival than having too little, researchers said.

The study, which divided the elderly, community-dwelling participants into four groups based on their testosterone levels, found that having total T levels in the middle two quartiles at baseline predicted reduced incidence of death compared with having the highest and lowest levels, and the association could not be explained by other risk factors, , of the University of Western Australia in Perth, and colleagueswrote in the

Men who died had lower mean baseline T (12.8 versus 13.2 nmol/L, P=0.013), dihydrotestosterone (DHT) (1.4 versus 1.5 nmol/L, P=0.002), and estradiol (71.6 versus 74.0 pmol/L, P=0.022).

The study did not include men taking testosterone therapy, but it was published just weeks after a widely reported study appearing in JAMA found that such treatment may increase the risk for heart attacks, strokes, and death in older men.

"Most of the prior research has suggested that there is a linear progression for testosterone, with lower levels associated with worse clinical outcomes," said Cleveland Clinic staff cardiologist , who was not involved with the study. "This paper is unique because it suggests there may be a U-shaped curve with respect to testosterone levels in older men, with a sort of sweet spot in the middle where outcomes are the best."

Researchers used liquid chromatography-tandem mass spectrometry (LC-MS/MD) to assess not only total testosterone, but also DHT and estradiol in the 3,690 men between the ages of 70 and 89 living in Perth, Western Australia. All blood samples were taken early in the morning and all were collected between 2001 to 2004.

Follow-up was 6.7 years, during which time 974 men died (26.4%).

Among the study findings:

• The percentage of men with circulating total testosterone levels in the two middle quartiles (between 9.82 and 15.8 nmol/L [282 to 455 ng/dL]) who died was 23.3% to 25.1%, compared with 30.8% among men with lower T levels and 26.5% among men with higher levels.
• After allowance for other risk factors, T and DHT were associated with all-cause mortality.
• Higher DHT was associated with lower ischemic heart disease mortality (Q3:Q1, HR=0.58, P=0.002; Q4:Q1, HR=0.69, P=0.026).
• Estradiol was not associated with either all-cause or ischemic heart disease mortality.

"Our results challenge the concept that lower T is associated with increased mortality in a linear fashion," the researchers wrote. "Instead, an optimal range of circulating total T corresponding to a range of 9.8 to 15.8 nmol/L (282-455 ng/dL) exists for older men, which predicts survival independent of other risk factors."

The researchers added that additional studies are needed to better understand the impact of natural and therapeutic androgen exposure on overall health and survival as men age.

"Sex hormones are an important predictor of mortality in older men, but we haven't determined if treatments to change testosterone and DHT levels can alter these outcomes," Yeap noted in a written press statement. "Additional research into these findings, including randomized clinical trials, could help identify ways to leverage this information to improve health in older men."

Krasuski agreed, adding that these findings, along with those from the JAMA study, raise as many questions as they answer.

"Both these papers underscore the point that (the impact of natural and therapeutic testosterone) is something that we don't understand very well," he told 乌鸦传媒. "The JAMA paper found that when we treat older men with low testosterone levels they seem to have worse outcomes. This paper looked at natural (androgen) levels, which could be markers for all kinds of other things."

He said our current understanding of the role of testosterone treatment on men's health, cardiovascular risk, and mortality is as confusing as that of estrogen therapy on women's health was a decade ago following the abrupt ending of the Women's Health Study.

"If someone has a particular viewpoint on testosterone, I'm sure I could find a paper that would validate that viewpoint," he said.

He added that more study is needed to determine if there really is a "sweet spot" optimal testosterone level for older men that would be associated with better survival.