Effects of Testosterone Therapy for 3 Years on Muscle Performance and Physical Function in Older Men

Effects of Testosterone Therapy for 3 Years on Muscle Performance and Physical Function in Older Men

Declining testosterone levels – which is commonly seen in men as they get older - are associated with reduced lean body mass, muscle strength, physical function and performance.1-3 Evidence for a causal-effect relationship between testosterone levels and lean body (muscle) mass comes from several studies which have shown that testosterone treatment consistently increases lean body mass (which is a proxy measure for muscle mass).1,4-7

Here we summarize the results of the long-term TEAAM (Testosterone’s Effects on Atherosclerosis Progression in Aging Men) study, which also investigated effects of testosterone treatment on muscle performance, physical function, and lean body mass.8

Key Points

  • The TEAAM study enrolled men aged 60 years or older with low-normal testosterone levels, 3.5 - 13.9 nmol/L (100 and 400 g/dL) or free testosterone level less than 174 pmol/L (50 pg/mL).
  • Testosterone treatment for 3 years increased lean body mass, muscle strength and power, despite absence of exercise.
  • Men in the placebo group showed a decline in lean body mass, muscle strength and power, suggesting that long-term testosterone treatment not only prevents the age-related loss in muscle function, but actually improves muscle function.
  • Treatment effects tended to wane over time in parallel with the dropping testosterone levels. This underscores the importance of long-term adherence to testosterone treatment in order to realize benefits.

What is known

Well-documented increases in muscle mass with testosterone treatment 1,4-7 has stimulated interest in investigating the anabolic applications of testosterone to improve physical function and reduce the burden of disability in older adults.9-16 However, the effects of testosterone treatment on muscle performance and physical function have been inconsistent in previous studies, which were limited by relatively short duration, small sample sizes, and differences in testosterone doses and achieved testosterone levels.1,4-7,17,18

In addition, the effects of testosterone on other important measures of muscle performance, such as muscle power and fatigability, have not been well researched. Muscle power - the rate at which a muscle generates force - is more strongly associated with measures of physical function than muscle strength, and declines faster than strength with aging.19,20 Muscle fatigability (endurance) is related to the ability to delay onset of muscle fatigue, especially when performing movements at high workloads.21,22 The importance of endurance (fatigue resistance) in older people has gained increasing recognition.23 Importantly, less fatigability (i.e. greater endurance) of the leg muscles has been shown to be associated with longer walking endurance and better balance in older adults.24 Diabetic people are especially prone to premature muscle fatigue.25 Besides the reduction in strength, muscle dysfunction in type 2 diabetes is characterized by higher fatigability (reduced endurance) that affects both upper and lower body muscles.25 This effect is independent of the presence of diabetic complications and may be a more sensitive marker of muscular dysfunction than muscle strength.25

What this study adds

The TEAAM study enrolled subjects who were community-dwelling men aged 60 years or older with low to low-normal testosterone levels, defined as testosterone levels between 3.5–13.9 nmol/L (100 and 400 ng/dL) or free testosterone level less than 174 pmol/L (50 pg/mL) obtained in a fasting morning sample. None of the subjects were participating in resistance exercise training before or during the 36 months of the study. These men are similar to a substantial fraction of middle-aged and older men receiving testosterone prescriptions.26,27

Intervention and Measurements

Subjects were randomly assigned to receive either 7.5 g of 1% testosterone gel (75 mg of testosterone) or placebo gel daily for 3 years. If the total testosterone level was lower than 500 ng/dL (17.3 nmol/L), the testosterone dose was increased to 10 g daily; if it was higher than 900 ng/dL (31.2 nmol/L) the dose was reduced to 5 g. Testosterone levels were measured at 6, 18, and 36 months. Lean body mass was measured by DEXA (dual energy x-ray absorptiometry).

The stair-climbing test was used as a measure of physical function, because of its higher ceiling and stronger association with leg strength than some other measures of physical function, such as gait speed.17 Performance in a loaded stair climb test, in which participants carried a load while ascending stairs, was also assessed.

Maximal strength was assessed using the 1-repetition maximum (1-RM) method for seated leg-press and chest-press. Power was measured using the same machines, which also provided measurement of force and velocity (and hence, power). Muscle fatigability was assessed by having subjects perform as many full range-of-motion repetitions as possible at a fixed cadence of 4 seconds per repetition with a load equal to 80% or 70% of the baseline 1-RM for the leg press and chest press, respectively.

Results

The testosterone treated men achieved total testosterone levels of 650 ng/dL, 600 ng/dL and 450 ng/dL after 6, 18 and 36 months. The corresponding free testosterone levels were 120 pg/mL, 115 pg/mL and 85 pg/mL.

After 3 years, testosterone treated men had gained 0.7 kg lean body mass while placebo treated men had lost lean body mass, amounting to a significant between-group difference of 0.9 kg. Testosterone treated men showed increased performance in stair-climbing power (both unloaded and loaded), as well as chest and leg strength and power, while placebo treated men had reductions in these performance parameters.

It was concluded that compared to placebo, testosterone treatment in older men for 3 years resulted in significantly greater improvements in stair-climbing power, muscle mass, and power.8 Clinical meaningfulness of these treatment effects and their impact on disability in older adults with functional limitations remains to be studied.

As reported previously in our editorial “Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men”, testosterone treatment in this study was found to be safe.

Commentary

This study is notable in that it shows that long-term testosterone treatment for 3 years increases lean body mass, muscle strength and power in 60 year old men who are representative of a large majority of middle-aged and older men receiving testosterone prescriptions.

Interestingly, these men just had low-normal testosterone levels and were not diagnosed with testosterone deficiency (which requires presence of both low testosterone levels and symptoms indicative of testosterone deficiency). And they were not engaging in resistance exercise training during the 3 year-long study. Despite absence of exercise and not being diagnosed with testosterone deficiency (or hypogonadism), testosterone treatment did increase lean body mass, muscle strength and power. It should also be highlighted that the treatment effects tended to wane over time in parallel with the dropping testosterone levels. This underscores the importance of long-term adherence to testosterone treatment in order to realize benefits.

Unique to this 3-year study of testosterone administration in older men is the assessment of muscle power and endurance. Because muscle power - which is lost with aging at a faster rate than strength - is more strongly associated with functional performance in activities such as stair climbing, walking, and rising from a chair 19, it is important to assess the effectiveness of anabolic therapies on muscle power. Testosterone treated men significantly increased both lower and upper extremity power more than men receiving placebo. The changes in leg-press and chest-press power were significantly associated with changes in stair-climbing power, which reinforces the role of muscle power in performance of functional activities.

Muscle fatigability, assessed by the number of repetitions to failure at 80% of baseline chest press and leg-press strength (1-RM) was not affected in this study. Because endurance is on a continuum with muscle strength 28, the small strength gains over the course of the study in the testosterone treated men may not have been adequate to impact endurance. Greater gains in strength and hence endurance would likely have been seen if resistance exercise was performed throughout the study in conjunction with testosterone treatment.

Future research is needed to investigate if testosterone treatment together with resistance exercise training provides greater benefits than either alone. This is an important issue, as numerous studies have shown that a greater muscle strength (assessed by either the hand grip test, leg press, leg extension or chest press) is associated with a significant reduction in mortality, in both the general population as well as in clinical populations.29

Poor handgrip strength has also been linked to premature death in the oldest old population according to the findings of the Leiden 85-plus study.30 Death risk was significantly increased among participants with lowest handgrip strength at age 85 years by 35%, and at age 89 years by 104%.30 Interestingly, in this study it was also found that handgrip strength has a greater impact on mortality than old age. Furthermore, participants with a greater decline in strength over four years had a significantly increased risk by 72%.30 This is especially relevant to the results in the TEAAM trial, as men in the placebo group had a decline in muscle mass, power, and physical function over time, while testosterone treated men showed increases in these parameters.8 This suggests that testosterone treatment plays a role in attenuating the age-related decline in muscle mass, power, and physical function. Support for this comes from the TOM (Testosterone in Older Men with Mobility Limitations) study, which showed that testosterone treatment not only resulted in important improvements in muscle strength and stair-climbing power 17, but also significantly attenuated the age-related decline in aerobic capacity.31 Like muscle strength, aerobic capacity (also known as cardiorespiratory fitness) is associated with a marked reduction in death rates in the general population 32, as well as in people with the metabolic syndrome and depression.33 Notably, regardless of strength, individuals with higher cardiorespiratory fitness have a longer life expectancy than low cardiorespiratory fitness peers.34 Over the past three decades, cardiorespiratory fitness has emerged as a strong, independent predictor of all-cause and disease-specific mortality. The evidence supporting the prognostic use of cardiorespiratory fitness is so powerful that the American Heart Association recently advocated for the routine assessment of cardiorespiratory fitness as a clinical vital sign.

Other 3 year-long studies have investigated the effects of testosterone treatment on body composition.35 An early study showed that testosterone treatment – which increased testosterone levels from 367 ng/dL (12.7 nmol/L) before treatment to 625 ng/dL (21.7 nmol/L) by the sixth month of treatment and remained at that level for the remaining 3 years - significantly decreased fat mass (-2.9 kg) and increased lean mass (1.9 kg), whereas no change was seen in the placebo-treated men.35 A later second study showed that testosterone treatment – which increased testosterone levels from 288 to 479 ng/dL (10.0 to 16.6 nmol/L) - significantly decreased fat mass (-5.5%) and increased lean mass (3.77 kg), whereas no change was seen in the placebo-treated men.6 Testosterone treated men had a significant improvement in handgrip strength and performance in a timed functional test when compared with baseline and placebo. As was also shown in the TEAAM study presented above, placebo treated men in the second study had deterioration in performance parameters. This supports the notion that without testosterone treatment, there is a decline in physical function over time in older men with low or low-normal testosterone levels who are not receiving testosterone treatment.

Objective measures of physical capacity – such as those tested in the TEAAM study presented here – predict premature death, and may therefore provide useful tools for identifying people at higher risk of death.36 Interestingly, a new terminology “muscle function deficit” has been proposed to describe sarcopenia (aging-related loss of muscle mass) and other age-related muscle dysfunctions.37 The diagnostic criteria for muscle function deficit are the same measures of muscle performance - strength, power, endurance (fatigability) – that were evaluated in the TEAAM study. Future studies are needed to investigate the role of testosterone in the prevention of both age-related loss of muscle mass, performance decline and the development of muscle function deficit.

References:

1. Bhasin S, Woodhouse L, Casaburi R, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab. 2005;90(2):678-688.
2. Krasnoff JB, Basaria S, Pencina MJ, et al. Free testosterone levels are associated with mobility limitation and physical performance in community-dwelling men: the Framingham Offspring Study. J Clin Endocrinol Metab. 2010;95(6):2790-2799.
3. Roy TA, Blackman MR, Harman SM, Tobin JD, Schrager M, Metter EJ. Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men. Am J Physiol Endocrinol Metab. 2002;283(2):E284-294.
4. Storer TW, Woodhouse L, Magliano L, et al. Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men. J Am Geriatr Soc. 2008;56(11):1991-1999.
5. Storer TW, Magliano L, Woodhouse L, et al. Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension. J Clin Endocrinol Metab. 2003;88(4):1478-1485.
6. 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.
7. Kenny AM, Kleppinger A, Annis K, et al. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. J Am Geriatr Soc. 2010;58(6):1134-1143.
8. Storer TW, Basaria S, Traustadottir T, et al. Effects of Testosterone Supplementation for 3 Years on Muscle Performance and Physical Function in Older Men. J Clin Endocrinol Metab. 2017;102(2):583-593.
9. Kamel HK, Maas D, Duthie EH, Jr. Role of hormones in the pathogenesis and management of sarcopenia. Drugs Aging. 2002;19(11):865-877.
10. Giannoulis MG, Martin FC, Nair KS, Umpleby AM, Sonksen P. Hormone replacement therapy and physical function in healthy older men. Time to talk hormones? Endocr Rev. 2012;33(3):314-377.
11. De Spiegeleer A, Petrovic M, Boeckxstaens P, Van Den Noortgate N. Treating sarcopenia in clinical practice: where are we now? Acta Clin Belg. 2016;71(4):197-205.
12. Boirie Y. Physiopathological mechanism of sarcopenia. The journal of nutrition, health & aging. 2009;13(8):717-723.
13. Onder G, Della Vedova C, Landi F. Validated treatments and therapeutics prospectives regarding pharmacological products for sarcopenia. The journal of nutrition, health & aging. 2009;13(8):746-756.
14. O'Connell MD, Wu FC. Androgen effects on skeletal muscle: implications for the development and management of frailty. Asian journal of andrology. 2014;16(2):203-212.
15. Basualto-Alarcon C, Varela D, Duran J, Maass R, Estrada M. Sarcopenia and Androgens: A Link between Pathology and Treatment. Frontiers in endocrinology. 2014;5:217.
16. Maggio M, Lauretani F, Ceda GP. Sex hormones and sarcopenia in older persons. Curr Opin Clin Nutr Metab Care. 2013;16(1):3-13.
17. Travison TG, Basaria S, Storer TW, et al. Clinical meaningfulness of the changes in muscle performance and physical function associated with testosterone administration in older men with mobility limitation. J Gerontol A Biol Sci Med Sci. 2011;66(10):1090-1099.
18. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010;95(2):639-650.
19. Reid KF, Fielding RA. Skeletal muscle power: a critical determinant of physical functioning in older adults. Exerc Sport Sci Rev. 2012;40(1):4-12.
20. Reid KF, Pasha E, Doros G, et al. Longitudinal decline of lower extremity muscle power in healthy and mobility-limited older adults: influence of muscle mass, strength, composition, neuromuscular activation and single fiber contractile properties. Eur J Appl Physiol. 2014;114(1):29-39.
21. Justice JN, Mani D, Pierpoint LA, Enoka RM. Fatigability of the dorsiflexors and associations among multiple domains of motor function in young and old adults. Exp Gerontol. 2014;55:92-101.
22. Coen PM, Jubrias SA, Distefano G, et al. Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults. J Gerontol A Biol Sci Med Sci. 2013;68(4):447-455.
23. Christie A, Snook EM, Kent-Braun JA. Systematic review and meta-analysis of skeletal muscle fatigue in old age. Med Sci Sports Exerc. 2011;43(4):568-577.
24. Senefeld J, Yoon T, Hunter SK. Age differences in dynamic fatigability and variability of arm and leg muscles: Associations with physical function. Exp Gerontol. 2017;87(Pt A):74-83.
25. Orlando G, Balducci S, Bazzucchi I, Pugliese G, Sacchetti M. Muscle fatigability in type 2 diabetes. Diabetes Metab Res Rev. 2017;33(1).
26. Jasuja GK, Bhasin S, Reisman JI, Berlowitz DR, Rose AJ. Ascertainment of Testosterone Prescribing Practices in the VA. Med Care. 2015;53(9):746-752.
27. Jasuja GK, Bhasin S, Reisman JI, et al. Who Gets Testosterone? Patient Characteristics Associated with Testosterone Prescribing in the Veteran Affairs System: a Cross-Sectional Study. J Gen Intern Med. 2017;32(3):304-311.
28. (NSCA) NSCA. Essentials of Strength Training and Conditioning. 4 ed: Human Kinetics; 2015.
29. Volaklis KA, Halle M, Meisinger C. Muscular strength as a strong predictor of mortality: A narrative review. European journal of internal medicine. 2015;26(5):303-310.
30. Ling CH, Taekema D, de Craen AJ, Gussekloo J, Westendorp RG, Maier AB. Handgrip strength and mortality in the oldest old population: the Leiden 85-plus study. CMAJ. 2010;182(5):429-435.
31. Storer TW, Bhasin S, Travison TG, et al. Testosterone Attenuates Age-Related Fall in Aerobic Function in Mobility Limited Older Men With Low Testosterone. J Clin Endocrinol Metab. 2016;101(6):2562-2569.
32. Lee DC, Artero EG, Sui X, Blair SN. Mortality trends in the general population: the importance of cardiorespiratory fitness. J Psychopharmacol. 2010;24(4 Suppl):27-35.
33. Rethorst CD, Leonard D, Barlow CE, Willis BL, Trivedi MH, DeFina LF. Effects of depression, metabolic syndrome, and cardiorespiratory fitness on mortality: results from the Cooper Center Longitudinal Study. Psychol Med. 2017:1-7.
34. Ruiz JR, Sui X, Lobelo F, et al. Association between muscular strength and mortality in men: prospective cohort study. BMJ. 2008;337:a439.
35. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab. 1999;84(8):2647-2653.
36. Cooper R, Kuh D, Hardy R, Mortality Review G, Falcon, Teams HAS. Objectively measured physical capability levels and mortality: systematic review and meta-analysis. BMJ. 2010;341:c4467.
37. Correa-de-Araujo R, Hadley E. Skeletal muscle function deficit: a new terminology to embrace the evolving concepts of sarcopenia and age-related muscle dysfunction. J Gerontol A Biol Sci Med Sci. 2014;69(5):591-594.

G.COM.GM.MH.06.2017.0449
Last updated: 2017
G.GM.MH.04.2015.0334