Review Article  Open Access


World J Mens Health. 2018 May;36(2):110-122. English.
Published online Mar 22, 2018.  https://doi.org/10.5534/wjmh.182001
Copyright © 2018 Korean Society for Sexual Medicine and Andrology
Testosterone Replacement, Muscle Strength, and Physical Function
You-Seon Nam,1 Gyeongsil Lee,2,* Jae Moon Yun,2 and Belong Cho1,2,3,4
1Department of Family Medicine, Seoul National University College of Medicine, Seoul, Korea.
2Department of Family Medicine, Seoul National University Hospital, Seoul, Korea.
3Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Korea.
4Institute on Aging, Seoul National University College of Medicine, Seoul, Korea.

Correspondence to: Belong Cho. Department of Family Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. Tel: +82-2-2072-2195, Fax: +82-2-766-3276, Email: belong@snu.ac.kr

*Current affiliation: Health Promotion Center, Chung-Ang University Hospital, Seoul, Korea

Received November 29, 2017; Revised December 19, 2017; Accepted December 26, 2017.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.




Abstract

Muscle strength and physical function decrease in older men, as do testosterone levels. Nonetheless, the effects of testosterone replacement therapy on muscle strength and physical function remain inconclusive and equivocal. We conducted a rapid systematic review, the results of which showed that testosterone replacement does not affect muscle strength (measured by hand grip strength and leg muscle strength), although it may increase physical function (measured by the 6-minute walk test, Physical Activity Scale for the Elderly score, and other physical performance tests). However, most of the studies were conducted in the United States or Europe and did not include participants from Asian or other ethnic backgrounds; therefore, further studies are needed to evaluate the effects of testosterone replacement in a broader population.

Keywords:
Aged; Muscle strength; Physical activity; Testosterone
INTRODUCTION

Decreased physical function is a representative sign of frailty in elderly people [1], which is usually accompanied by a decrease in testosterone levels in elderly men [2]. Lower testosterone levels are associated with decreased physical function and increased mortality [3], and frailty is associated with decreased quality of life [4]. However, there is no effective clinical treatment to restore physical function in the elderly. One of the mechanisms for the decreased physical function in the elderly is sarcopenia [5], and especially in elderly men, muscle mass is associated with testosterone levels [6].

Although many randomized controlled trials (RCTs) of testosterone replacement therapy (TRT) have been performed, these studies generally had small sample sizes and a variety of study designs, and the effects of TRT on improving physical function are equivocal [7, 8, 9]. While in one study [7] testosterone supplementation improved strength and was suggested to have a role in the treatment of frailty in hypogonadic males, another study [8] did not observe any increase in muscle strength, but only an increase in muscle mass.

Some systematic reviews (SRs) [10, 11, 12, 13] investigating the effects of TRT on the body have been published. However, one study [10] included middle-aged subjects and did not include recent studies. Although another study [13] performed a comprehensive SR including elderly men, the heterogeneity in the target groups and outcomes was large, and no significant conclusions were suggested. Accordingly, a quantitative analysis including recently published high-quality RCTs assessing physical function [2, 14] could yield additional clinical significance. Therefore, we conducted a rapid SRs, including elderly men receiving TRT, to assess the effects of TRT on muscle strength and physical function. We also performed quantitative analyses of the outcomes of some RCTs in order to determine their clinical significance. The search strategies and study selection criteria are explained at the end.

TESTOSTERONE REPLACEMENT THERAPY AND MUSCLE STRENGTH

Muscle strength is commonly measured with hand grip strength and the 1-repetition maximum (1-RM) for exercises performed as part of strength testing. Sixteen studies examined the effects of testosterone supplementation on muscle strength. Fourteen studies assessed muscle strength as a primary outcome and 2 as a secondary outcome. The other primary and secondary outcomes investigated in each of the studies are listed in Table 1 [2, 7, 8, 9, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27]. The most common measurements for muscle strength were hand grip strength and leg muscle strength (knee extension and flexion). Other measurements included single or double leg press, chest press, and triceps extension.


Table 1
Effects of testosterone on muscle strength and physical function
Click for larger imageClick for full tableDownload as Excel file

1. Hand grip

Ten studies included in the analysis measured muscle strength in terms of hand grip strength. Five of these studies were conducted in the United States, 2 in the United Kingdom, 1 in the Netherlands, 1 in Australia, and 1 in New Zealand. A total of 1002 participants were included in the analysis. The intervention period varied from 8 weeks to 1 year. All hand grip strength measurements were expressed in kilograms, except for one study [15], for which a pound-to-kilogram conversion was done for the purposes of our analysis. The overall results (Fig. 1) showed that TRT does not increase hand grip strength. However, individual studies, such as a randomized, placebo-controlled, doubleblind study [15], have found that hand grip strength improved after testosterone administration. Other studies [7, 26] that showed improved hand grip strength after testosterone supplementation could not be included in the analysis because they only presented data in figures.


Fig. 1
Forest plot showing the weighted mean differences (WMDs) and 95% confidence intervals (CIs) for hand grip strength in kilograms as derived from available randomized controlled trials on the effect of testosterone replacement therapy vs. placebo.
Click for larger imageDownload as PowerPoint slide

2. Leg muscle strength

Seven studies included in the analysis measured leg muscle strength. All 7 studies included information for the knee extensor muscles, consisting of a total of 780 participants. Three studies were conducted in the United States, 2 in the United Kingdom, 1 in New Zealand, and 1 in the Netherlands. The study conducted in the Netherlands [20] did not include measurements for the knee flexor muscles, so only 6 of the 7 studies included for the knee extensor analysis were included in the analysis of knee flexor strength. This resulted in a total of 543 participants for the knee flexor analysis. The intervention period varied from 12 weeks to 1 year. Lower muscle strength measurements were expressed as 1-RM in kilograms, newton-meters per second, or watts. Although marginal effects were shown for increased knee extensor strength (Fig. 2), when combined with the outcomes for knee flexor strength, the overall results showed no significant difference.


Fig. 2
Forest plot showing standardized mean differences (SMDs) and 95% confidence intervals (CIs) for leg muscle strength as derived from available randomized controlled trials on the effect of testosterone replacement therapy vs. placebo.
Click for larger imageDownload as PowerPoint slide

TESTOSTERONE REPLACEMENT THERAPY AND PHYSICAL FUNCTION

Physical function was commonly measured by the 6-minute walk test [28], the Physical Activity Scale for the Elderly (PASE) questionnaire [29], the physical-function domain (PF-10) of the Medical Outcomes Study 36-Item Short-Form Health Survey [30], a physical performance test (PPT) [31], and the Short Physical Performance Battery (ability to rise from a chair, static balance, and 8-foot walk) [32]. Other tests performed in some studies that were not included in our analyses included the supine-to-stand test [33], and the Get-Up- and-Go test [34].

1. 6-minute walk test

Three studies included in the analysis showed results of the 6-minute walk test. Two of these studies were conducted in the United States, and 1 in New Zealand. A total of 733 participants were included in the analysis. The intervention period varied from 6 months to 1 year. All TRT interventions were done using transdermal testosterone gel, although the dosages differed between studies. The overall results (Fig. 3) showed that TRT improved the 6-minute walking distance by 9.35 m (95% confidence interval [CI], 0.64–18.07 m).


Fig. 3
Forest plot showing weighted mean differences (WMDs) and 95% confidence intervals (CIs) for the 6-minute walk test in meters as derived from available randomized controlled trials on the effect of testosterone replacement therapy vs. placebo.
Click for larger imageDownload as PowerPoint slide

2. Physical Activity Scale for the Elderly score

Three studies included results from the PASE questionnaire [23, 24, 27], which is known to be a reliable instrument for assessing physical activity in older people [29]. Two studies were conducted in the United States, and 1 was conducted in New Zealand. A total of 504 participants were included in the analysis. The intervention period varied from 6 months to 1 year, and the participants in all 3 studies received transdermal testosterone supplementation. Two studies [23, 24] administered 5 mg per day for 12 months, while another [27] administered 50 mg per day for 6 months. Even though each of the individual studies did not show statistically significant improvements in the PASE score, when the individual results were combined, the overall results (Fig. 4) showed that there was an increase of 18.22 points (95% CI, 1.27–35.18 points) in the PASE score with TRT.


Fig. 4
Forest plot showing weighted mean differences (WMDs) and 95% confidence intervals (CIs) for physical activity scale for the elderly (PASE) scale as derived from available randomized controlled trials on the effect of testosterone replacement therapy vs. placebo.
Click for larger imageDownload as PowerPoint slide

3. Physical performance test

Three studies were combined to analyze the effects of TRT on physical performance. Two studies were conducted in the United States, and 1 was conducted in New Zealand. A total of 733 participants were included. All interventions consisted of transdermal testosterone, and the intervention period varied from 6 months to 1 year. The overall results (Fig. 5) showed improved physical performance after TRT. Other studies that also showed improved physical performance after testosterone supplementation could not be included in the analysis because they only presented data in figures for a timed PPT [26] or gait speed [19] and did not provide exact measurements. Another study did not report outcomes for the functional assessment tests that were conducted, such as maximal reach, standing balance, fast walk, and chair rise [9], and hence, could not be included.


Fig. 5
Forest plot showing standardized mean differences (SMDs) and 95% confidence intervals (CIs) for physical performance test scores as derived from available randomized controlled trials on the effect of testosterone replacement therapy vs. placebo.
Click for larger imageDownload as PowerPoint slide

SUMMARY

The overall analyses showed that TRT is not associated with increased muscle strength, whereas it does increase physical function. This is in accordance with previous findings [7, 8, 9]. However, as the number of studies included in some analyses was limited, these results are not generalizable to elderly men in general as a whole. Additionally, most of the reviewed RCTs were conducted in the United States or Europe, and there was no mention of the inclusion of participants from other ethnic backgrounds, such as Asians. Therefore, further studies are needed to investigate the effects of TRT on muscle strength and physical function in populations with a broader ethnic background.

Some difficulties were encountered during the review. For instance, when comparing results for muscle strength, some studies included exercise training and some did not. Moreover, some studies measured isokinetic muscle strength and some measured isometric muscle strength with different dynamometers, which made them difficult to compare. Additionally, the muscle strength evaluation protocols differed for each study. The lack of a standardized, validated exercise protocol to evaluate muscle strength made it difficult to compare the results and suggests that further studies are needed to develop a standardized protocol to be disseminated and widely used.

SEARCH STRATEGIES

We performed 2 sets of searches, one as a rapid SR and an additional traditional SR, because the latest published SR included studies published up to April 9, 2016. The results for the rapid and traditional SRs and meta-analyses were reported following the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [35] (Fig. 6).


Fig. 6
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. SR: systematic review, RCT: randomized controlled trial.
Click for larger imageDownload as PowerPoint slide

For the rapid SR, the PubMed Central, MEDLINE, and Embase databases were searched for studies published up to October 30, 2017. The initial search was conducted using the following keywords: elderly men aged at least 60 years (for participants), testosterone replacement (for intervention), placebo (for comparison), physical performance (for outcome), and SR (for study design) (see Supplementary Table 1 for the complete list of the search terms). We only included articles published in English. Studies were considered eligible for the rapid SR if they met the following inclusion criteria: 1) being a SR; 2) including elderly men at least 60 years of age; 3) reporting physical function, physical performance, and/or muscle strength; 4) having TRT as the major intervention; and 5) including a comparison with a placebo. Although we searched for healthy elderly men, we did not exclude studies if they included participants with hypogonadism, but studies of other specific diseases, such as diabetes mellitus and Parkinson disease, were excluded from the analysis. We included interventions that compared testosterone supplementation vs. placebo or other substances, such as growth hormone. As a result, 1 SR [13] was retrieved for assessment. The other 3 SRs were excluded because 2 [10, 11] included inappropriate populations and one [12] had inappropriate outcomes. We then applied AMSTAR [36], a measurement tool for assessing the methodological quality of the retrieved SR, which gave a score of 4 out of 11 (see Appendix 1 for details).

For the additional traditional SR, as the retrieved SR used for the rapid SR included studies between January 1, 1950, and April 9, 2016, we searched for additional RCTs from January 1, 2015, to October 30, 2017 through the PubMed Central, MEDLINE, and Embase databases. We used the same search terms as were used for the rapid SR except for the study design, which was RCTs (see Supplementary Table 2 for a complete list of the search terms). After excluding studies that did not match our inclusion criteria, we included a total of 17 studies and added the 4 RCTs retrieved from the additional search. Subsequently, a total of 21 full-text articles were reviewed for the analysis and 3 studies were further excluded because their population [37, 38] and outcome measures [39] did not meet our criteria. A total of 18 studies were included in the final analysis.

STATISTICAL ANALYSIS

Statistical analyses were performed using STATA ver. 15.0 (StataCorp, College Station, TX, USA) using the metan command with a random effect. When outcome measurements were given in the same units or the units could be converted, weighted mean differences were calculated, whereas if outcome measurements were given in different, non-convertible units, standardized mean differences were calculated instead.

Supplementary Materials

Supplementary materials can be found via https://doi.org/10.5534/wjmh.182001.

Supplementary Table 1

Search Queries for Systematic Reviews (SR)

Click here to view.(0, pdf)
Supplementary Table 2

Search Queries for Randomized Control Trials (RCTs)

Click here to view.(41K, pdf)

Notes

Disclosure:The authors have no potential conflicts of interest to disclose.

Author Contribution:Drafting of the manuscript: Nam YS. Data acquisition: Lee G, Yun JM. Data analysis and interpretation: Lee G, Nam YS, Yun JM. Statistical analysis: Lee G. Critical revision of the manuscript: Yun JM, Cho B. Approval of final manuscript: all authors.

Appendix 1

AMSTAR – a measurement tool to assess the methodological quality of systematic reviews

References
Buckinx F, Reginster JY, Petermans J, Croisier JL, Beaudart C, Brunois T, et al. Relationship between frailty, physical performance and quality of life among nursing home residents: the SENIOR cohort. Aging Clin Exp Res 2016;28:1149–1157.
Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med 2016;374:611–624.
Shores MM, Moceri VM, Gruenewald DA, Brodkin KI, Matsumoto AM, Kivlahan DR. Low testosterone is associated with decreased function and increased mortality risk: a preliminary study of men in a geriatric rehabilitation unit. J Am Geriatr Soc 2004;52:2077–2081.
Chou CH, Hwang CL, Wu YT. Effect of exercise on physical function, daily living activities, and quality of life in the frail older adults: a meta-analysis. Arch Phys Med Rehabil 2012;93:237–244.
Narici MV, Maffulli N. Sarcopenia: characteristics, mechanisms and functional significance. Br Med Bull 2010;95:139–159.
Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 1999;107:123–136.
Sih R, Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab 1997;82:1661–1667.
Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci 2003;58:618–625.
Ly LP, Jimenez M, Zhuang TN, Celermajer DS, Conway AJ, Handelsman DJ. A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency. J Clin Endocrinol Metab 2001;86:4078–4088.
Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf) 2005;63:280–293.
Vigano A, Piccioni M, Trutschnigg B, Hornby L, Chaudhury P, Kilgour R. Male hypogonadism associated with advanced cancer: a systematic review. Lancet Oncol 2010;11:679–684.
Corona G, Giagulli VA, Maseroli E, Vignozzi L, Aversa A, Zitzmann M, et al. Therapy of endocrine disease: testosterone supplementation and body composition: results from a meta-analysis study. Eur J Endocrinol 2016;174:R99–R116.
Huo S, Scialli AR, McGarvey S, Hill E, Tügertimur B, Hogenmiller A, et al. Treatment of men for “Low Testosterone”: a systematic review. PLoS One 2016;11:e0162480
Storer TW, Basaria S, Traustadottir T, Harman SM, Pencina K, Li Z, et al. Effects of testosterone supplementation for 3 years on muscle performance and physical function in older men. J Clin Endocrinol Metab 2017;102:583–593.
Bakhshi V, Elliott M, Gentili A, Godschalk M, Mulligan T. Testosterone improves rehabilitation outcomes in ill older men. J Am Geriatr Soc 2000;48:550–553.
Borst SE, Yarrow JF, Conover CF, Nseyo U, Meuleman JR, Lipinska JA, et al. Musculoskeletal and prostate effects of combined testosterone and finasteride administration in older hypogonadal men: a randomized, controlled trial. Am J Physiol Endocrinol Metab 2014;306:E433–E442.
Brill KT, Weltman AL, Gentili A, Patrie JT, Fryburg DA, Hanks JB, et al. Single and combined effects of growth hormone and testosterone administration on measures of body composition, physical performance, mood, sexual function, bone turnover, and muscle gene expression in healthy older men. J Clin Endocrinol Metab 2002;87:5649–5657.
Clague JE, Wu FC, Horan MA. Difficulties in measuring the effect of testosterone replacement therapy on muscle function in older men. Int J Androl 1999;22:261–265.
Dias JP, Melvin D, Simonsick EM, Carlson O, Shardell MD, Ferrucci L, et al. Effects of aromatase inhibition vs. testosterone in older men with low testosterone: randomized-controlled trial. Andrology 2016;4:33–40.
Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM, Bosch JL, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA 2008;299:39–52.
Giannoulis MG, Sonksen PH, Umpleby M, Breen L, Pentecost C, Whyte M, et al. The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial. J Clin Endocrinol Metab 2006;91:477–484.
Hildreth KL, Barry DW, Moreau KL, Vande Griend J, Meacham RB, Nakamura T, et al. Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low-normal testosterone levels. J Clin Endocrinol Metab 2013;98:1891–1900.
Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 2001;56:M266–M272.
Kenny AM, Kleppinger A, Annis K, Rathier M, Browner B, Judge JO, 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;58:1134–1143.
Nair KS, Rizza RA, O'Brien P, Dhatariya K, Short KR, Nehra A, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006;355:1647–1659.
Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ, 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;90:1502–1510.
Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, Adams JE, Oldham JA, 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;95:639–650.
Committee ATS.ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111–117.
Washburn RA, Smith KW, Jette AM, Janney CA. The Physical Activity Scale for the Elderly (PASE): development and evaluation. J Clin Epidemiol 1993;46:153–162.
Ware JE, Kosinski M, Gandek B. In: SF-36 health survey: manual and interpretation guide. Lincoln (RI): QualityMetric Inc; 2000.
Reuben DB, Siu AL. An objective measure of physical function of elderly outpatients. The Physical Performance Test. J Am Geriatr Soc 1990;38:1105–1112.
Guralnik JM, Branch LG, Cummings SR, Curb JD. Physical performance measures in aging research. J Gerontol 1989;44:M141–M146.
Alexander NB, Ulbrich J, Raheja A, Channer D. Rising from the floor in older adults. J Am Geriatr Soc 1997;45:564–569.
Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 1991;39:142–148.
Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. PLoS Med 2009;6:e1000097
Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol 2007;7:10.
Travison TG, Basaria S, Storer TW, Jette AM, Miciek R, Farwell WR, 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;66:1090–1099.
Magnussen LV. Testosterone therapy of men with type 2 diabetes mellitus: a randomized, double-blinded, placebo-controlled study. Dan Med J 2017;64:B5396
Sullivan DH, Roberson PK, Johnson LE, Bishara O, Evans WJ, Smith ES, et al. Effects of muscle strength training and testosterone in frail elderly males. Med Sci Sports Exerc 2005;37:1664–1672.