Low Testosterone May Signal Frailty in Elderly Men

Jill Stein

June 22, 2010

June 22, 2010 (San Diego, California) — Men 70 years and older who have low serum testosterone levels appear to be at increased risk for eventual frailty, according to data released here at ENDO 2010: The Endocrine Society 92nd Annual Meeting.

"While prior studies have reported cross-sectional associations between testosterone levels and frailty, this study is the first longitudinal analysis to demonstrate that free testosterone levels predict frailty," Zoe Hyde, MPH, PhD candidate, from the University of Western Australia in Perth, told Medscape Diabetes & Endocrinology. "Our findings suggest that testosterone could play a role in the pathogenesis of frailty and, in turn, provide a rationale for clinical studies to explore whether testosterone therapy could prevent or treat frailty."

She was quick to emphasize, however, that much more research is needed before testosterone can be "categorically blamed" for frailty and before testosterone supplementation can be recommended as a remedy. "Nonetheless, the data are intriguing," she said.

Ms. Hyde and her associates used the FRAIL scale to assess frailty in 3616 community-dwelling men between 70 and 88 years of age. The FRAIL scale evaluates functional status in older patients on 5 domains: fatigue, resistance (ability to climb a single flight of stairs), ambulation (ability to walk 1 block), illnesses (more than 5), and loss of weight (more than 5%). The scale was developed by the International Academy of Nutrition, Health, and Aging.

The investigators also measured testosterone levels in the study participants.

Frailty status was reevaluated in 1586 men 4 to 7 years after the initial assessments.

Unanswered Questions Prevent Any Definitive Conclusions

Although there is a broad body of research focusing on frailty, the topic is often fraught with myths and a lack of consensus among both researchers and the lay public, Ms. Hyde noted.

For example, contrary to popular belief, frailty is not an inevitable consequence of the aging process, even though frailty increases with age, she said.

Also, investigators do not agree on the precise definition of frailty. The condition is loosely defined as a decline in multiple organ systems that leads to functional impairments, a reduced ability to cope with stressors, and an increased risk for death and disability.

Ms. Hyde noted that frailty is "perhaps best conceptualized as a state of vulnerability, where modest stressors that the body is usually able to cope with are much more likely to lead to serious illness and hospitalization or perhaps even death."

The physiologic pathways that "set the stage" for frailty have not been clarified, she added. However, there is growing evidence to suggest that testosterone plays an important role by producing a loss of muscle and bone mass, which can increase the risk for frailty.

Earlier cross-sectional studies have explored the relation between testosterone and frailty. However, the results have been contradictory, which might be due to a lack of statistical power, she noted.

Longitudinal Design Strengthens Study Findings

At baseline, 548 men (15.2%) were considered frail, which meant that they had at least 3 deficits on the FRAIL scale. At follow-up, 364 men (23.0%) were deemed frail.

At baseline, each 1 standard deviation (SD) decrease in total or free testosterone level was associated with increased odds of frailty (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.11 - 1.38 for total testosterone and OR, 1.29; 95% CI, 1.15 -1.44 for free testosterone).

One SD of total testosterone was 5.6 nmol/L in this sample; 1 SD of free testosterone was 96.5 pmol/L. For every 97 pmol/L decrease in free testosterone, the odds of a man being frail increased by 29% at baseline and 22% at follow-up.

In contrast, lower luteinizing hormone (LH) levels were associated with reduced odds of frailty at baseline (OR, 0.88; 95% CI, 0.81 - 0.95). For every 5.3 IU/L decrease in LH, men were 12% less likely to be frail, Ms. Hyde reported.

After controlling for age, body mass index, smoking, diabetes, social support, and visual and hearing impairments, the Australian researcher told meeting attendees that only a lower free testosterone level at baseline predicted frailty at follow-up (OR, 1.22; 95% CI, 1.05 - 1.42).

"We need large-scale clinical trials to see if testosterone can prevent or treat frailty, and importantly, to assess the possible risks of therapy before we can recommend testosterone therapy in older men," Ms. Hyde said in an interview.

She added, however, that a healthy lifestyle is probably more important in achieving optimal testosterone levels. "My colleagues and I recently showed that a healthy lifestyle was associated with higher testosterone levels," she said. "Given that a healthy lifestyle will likely also reduce the risk of becoming frail, this is probably the best option for now. Men should keep physically active, not smoke, eat a nutritious diet, and keep their weight in a healthy range."

Ms. Hyde added that she is now conducting research to determine whether testosterone and related sex hormones can predict healthy aging in older men.

"This study adds to earlier work showing an association between low testosterone and measures of frailty in elderly men," James L. Rosenzweig, MD, an endocrinologist and associate professor of medicine at Boston University School of Medicine in Massachusetts, told Medscape Diabetes & Endocrinology.

He added that although he believes that prospective randomized studies should be conducted to examine whether testosterone replacement in elderly men is beneficial for thwarting frailty, there are safety concerns about supplemental testosterone in older men.

"The incidence of prostate cancer — which is often unrecognized — is dramatically increased in elderly men," he said. "Supplemental testosterone may, in fact, spur the growth of prostate cancer. So that would be one potential negative side effect of testosterone treatment."

He added, however, that it's well known that testosterone can increase muscle mass and bone density. "So it probably would be of interest to specifically look at how testosterone replacement affects these measures of frailty in an elderly population," he said.

The study was funded by the National Health and Medical Research Council of Australia and the MBF Foundation of Australia. Ms. Hyde and Dr. Rosenzweig have disclosed no relevant financial relationships.

ENDO 2010: The Endocrine Society 92nd Annual Meeting: Abstract OR17-3. Presented June 20, 2010.

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