Frailty is increasingly acknowledged as a significant geriatric condition. Please describe how frailty manifests within the clinical setting and how it relates to hypogonadism and testosterone therapy. Please review the latest findings regarding the relationship between frailty and hypogonadism and the implications to clinical practice and future research.



Response by John E. Morley, MB, BCh
Findings from a recent survey of community-dwelling men (n=320; age range, 64-74 y) participating in the Hertfordshire Cohort Study indicate that approximately 4% of older men are frail.¹ Though various definitions of frailty have been proposed,^2,3 the original by Fried et al requires 3 or more of the following: unintentional weight loss (eg, 10 pounds in a year), self-reported exhaustion, low physical activity, slow walking speed, and weakness as measured by grip strength.⁴

The signs and symptoms of frailty reflect reduced functional reserve and the consequent diminished resilience to psychological or physical stressors, which may accelerate physical and cognitive decline, disability, and death.^5,6 Causes of frailty are multifactorial and include sarcopenia, weight loss, impaired executive function, and specific comorbid conditions, such as anemia and diabetes.^7,8 Declines in circulating hormones, including testosterone, have been associated with comorbid conditions and hemoglobin levels that may portend frailty,⁹ and longitudinal and cross-sectional studies have linked low testosterone levels with poor mobility, balance impairment, and higher risk of falls.^10,11

The relationship between low bioavailable testosterone (bioT) levels and frailty has been shown to be independent. The Osteoporotic Fractures in Men (MrOS) study of community-dwelling men aged 65 years or older (n=1469) investigated both cross-sectional and longitudinal associations of sex hormones (estradiol, bioavailable estradiol, testosterone, bioT, and sex hormone-binding globulin) with frailty status.¹² According to the cross-sectional analysis, after adjusting for age, body size, health status, and medical conditions, men in the lowest quartile of bioT were at 1.39-fold increased risk of worse frailty status compared with men in the highest quartile. The longitudinal analysis, adjusted for age, revealed that men in the lowest quartile of bioT had a 1.51-fold higher risk of worse frailty status at follow-up 4.1 y later (n=1245).

Recent studies in Australia and Taiwan confirmed that low free testosterone is associated with frailty,^13,14 but a third new investigation did not.¹⁵

Many individual testosterone trials have shown that the administration of exogenous testosterone enhances muscle mass and strength, bone density, and body composition.^16-19 Furthermore, studies in older men at greater risk of frailty have demonstrated testosterone therapy improves upper limb strength, physical performance, grip strength, and lean body mass.^20,21 Page et al’s study of older men (age, ≥65 y; n=50) with low serum testosterone (<350 ng/dL) demonstrated that testosterone therapy for 3 years improves physical performance, grip strength, body composition, and lean body mass.¹⁷

A study recently published by Journal of the American Geriatrics Society showed that older frail men treated with low-dose testosterone therapy exhibit favorable changes in body composition (ie, increased lean mass and decreased fat mass) and modest changes in axial bone mineral density.²² Using higher doses of testosterone, a study in England found that testosterone for 6 months in frail elderly men improves physical function, lean body mass, and isometric knee-extension peak torque.¹⁶ (This study is discussed in more detail by M. M. Miner in the response below.) Similar findings have been reported by Basaria et al,²³ and a Caminiti et al study in frail patients with chronic heart failure reported improved function with the administration of testosterone therapy.²⁴

It needs to be pointed out that, in frail individuals, peripheral edema occurs for many reasons other than heart failure but is often mistaken for heart failure. As testosterone administration causes water retention, edema may increase. In all studies of patients with heart disease, resulting edema has been easily treated with low-dose diuretics. In patients with frailty or heart disease, 4 patients receiving testosterone therapy died, whereas 9 patients receiving placebo died (J. E. Morley, unpublished data). A meta-analysis in healthy older patients receiving testosterone in controlled trials found no corresponding increase in cardiovascular disease.²⁵

These studies reinforce the need to carefully consider the appropriate use of testosterone administration in older frail men with hypogonadism.⁹ Though testosterone therapy has not been clearly demonstrated to reverse frailty, current data seem sufficient to support testosterone treatment for older frail men with hypogonadism. Large-scale, longitudinal, placebo-controlled trials are necessary to evaluate testosterone administration for safety (using, particularly, cardiovascular endpoints) and efficacy, as measured by objective endpoints, such as improved quality of life, strength, and bone mineral density.

Response by Martin M. Miner, MD
Age-related hypogonadism is associated with reduced muscle mass and lower-extremity strength, limited physical function, and poor mobility.

Recognizing that testosterone therapy has been shown to increase muscle mass and strength in healthy older men, Basaria et al sought to evaluate the safety and efficacy of testosterone therapy in older men with mobility limitations, a marker of frailty and a common geriatric condition that predicts disability, poor quality of life, and death.²³ The randomized, placebo-controlled Testosterone in Older Men With Mobility Limitations (TOM) trial was designed to determine the effects of testosterone therapy on lower extremity strength and physical function in older men with limited mobility and low serum total or free testosterone. Men aged 65 years or older with total testosterone levels between 100 and 350 ng/dL or free testosterone levels <50 pg/mL were enrolled for 6 months. The primary efficacy endpoint was change from baseline in maximal voluntary muscle strength in a leg-press exercise. Secondary endpoints included chest-press strength, 50-m walking speed, and stair-climbing speed and power. Findings showed that the group receiving testosterone therapy had significantly greater improvements in leg-press and chest-press strength and in stair-climbing while carrying a load.

Cardiovascular adverse events were not a planned primary or secondary outcome, and thus a structured evaluation of cardiovascular adverse events was not performed.²³ However, based on an incidence of cardiovascular adverse events higher in the testosterone group than in the placebo group, a National Institute on Aging data and safety monitoring board determined it necessary to discontinue study enrollment and testosterone therapy administration. The authors noted that important factors may have contributed to the higher rate of cardiovascular adverse events in the treatment arm. Frail elderly men with limitations in mobility are more likely to have clinical and subclinical cardiovascular disease than those without limitations in mobility. Furthermore, certain aspects of the study (small size, older and sicker population, early termination of the study, likelihood of chance contributing to observed outcomes) should limit extrapolating from these findings. Further research is needed to clarify the safety issues raised by this trial.

Findings from Srinivas-Shankar et al’s recent randomized, double-blind, placebo-controlled study of testosterone therapy administered to intermediate-frail and frail elderly men reinforce the potential benefit of testosterone therapy in this population.¹⁶ Men with low to borderline-low testosterone treated for 6 months demonstrated lower-limb muscle-strength loss prevention and improved quality of life, body composition, and physical function, as measured by isometric knee-extension peak torque, increased lean body mass and decreased fat mass, and somatic and sexual symptom scores. No serious cardiovascular adverse events were noted.

When considering the findings within the clinical setting, these studies reinforce the need to carefully weigh the benefits and appropriateness of testosterone therapy when managing hypogonadism in older frail patients with multiple latent comorbidities and the need to vigilantly and cautiously monitor these patients. Patients treated with testosterone therapy should be monitored regularly with physical examination and serum evaluation (complete blood count and prostate-specific antigen) at baseline, 3 months, and 6 and 12 months, and then yearly. Testosterone levels should be evaluated to ensure treatment is efficacious and supraphysiologic levels have not been attained. It is necessary to ensure that appropriate secondary preventive measures are taken (administering lipid- and glucose-lowering therapy, antihypertensive agents, and antithrombotic agents) to reduce the risk of cardiovascular adverse events, particularly within an older frail population.

References

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2. Abellan van Kan G, Rolland YM, Morley JE, Vellas B. Frailty: toward a clinical definition. J Am Med Dir Assoc. 2008;9(2):71-72.
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17. Page ST, Amory JK, Bowman FD, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab. 2005;90(3):1502-1510.
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24. Caminiti G, Volterrani M, Iellamo F, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure: a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol. 2009;54(10):919-927.

25. Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. 2005;60(11):1451-1457.

 

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