Androgen effects on skeletal muscle: Implications for the development and management of frailty

Asian Journal of Andrology

Volumn 16, Issue 2, 2014, Pages 203-212

  O'Connell, Matthew D L ^a   Wu, Frederick C W ^b  

^a TRINITY COLLEGE DUBLIN   (Ireland)

^b UNIVERSITY OF MANCHESTER   (United Kingdom)

Author keywords

Ageing; Androgens; Body composition; Frailty; Muscle; Physical function; Sarcopenia; Selective androgen receptor modulators; Sex hormones; Testosterone

Indexed keywords

ANDROGEN; SELECTIVE ANDROGEN RECEPTOR MODULATOR;

AGING; ANDROGEN BLOOD LEVEL; ANDROGEN THERAPY; BODY COMPOSITION; CARDIOVASCULAR RISK; EXERCISE; FRAIL ELDERLY; HUMAN; INTERVENTION STUDY; KINESIOTHERAPY; MUSCLE MASS; MUSCLE STRENGTH; NONHUMAN; OBSERVATIONAL STUDY; REVIEW; SARCOPENIA; SKELETAL MUSCLE;

AGED; AGING; ANDROGENS; FRAIL ELDERLY; HORMONE REPLACEMENT THERAPY; HUMANS; MUSCLE, SKELETAL; TESTOSTERONE;

EID: 84896798304     PISSN: 1008682X     EISSN: 17457262     Source Type: Journal    
DOI: 10.4103/1008-682X.122581     Document Type: Review

References (153)

1. Available from: http: //ec.europa.eu/eurostat [Last accessed date on 12 August, 2012].
2. Cesari M, Leeuwenburgh C, Lauretani F, Onder G, Bandinelli S, et al. Frailty syndrome and skeletal muscle: Results from the Invecchiare in Chianti study. Am J Clin Nutr 2006; 83: 1142-8. (Pubitemid 44713116)
3. Gielen E, Verschueren S, O'Neill TW, Pye SR, O'Connell MD, et al. Musculoskeletal frailty: a geriatric syndrome at the core of fracture occurrence in older age. Calcif Tissue Int 2012; 91: 161-77.
4. Fried LP, Hadley EC, Walston JD, Newman AB, Guralnik JM, et al. From bedside to bench: research agenda for frailty. Sci Aging Knowledge Environ 2005: p.24.
5. O'Connell MD, Tajar A, Roberts SA, Wu FC. Do androgens play any role in the physical frailty of ageing men? Int J Androl 2011; 34: 195-211.
6. Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996; 335: 1-7. (Pubitemid 26230806)
7. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab 2001; 281: E1172-81.
8. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Mac RP, 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: 678-88. (Pubitemid 40279179)
9. Camacho EM, Huhtaniemi IT, O'Neill TW, Finn JD, Pye SR, et al. EMAS Group. Age- associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol 2013; 168: 445-55.
10. Wu FC, Tajar A, Pye SR, Silman AJ, Finn JD, et al. European Male Aging Study Group. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab 2008; 93: 2737-45. (Pubitemid 352008544)
11. Yeap BB, Almeida OP, Hyde Z, Norman PE, Chubb SA, et al. In men older than 70 years, total testosterone remains stable while free testosterone declines with age. The Health in Men Study. Eur J Endocrinol 2007; 156: 585-94. (Pubitemid 46796526)
12. Travison TG, Araujo AB, Kupelian V, O'Donnell AB, McKinlay JB. The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab 2007; 92: 549-55.
13. Sinha-Hikim I, Artaza J, Woodhouse L, Gonzalez-Cadavid N, Singh AB, Lee MI, et al. Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy. Am J Physiol Endocrinol Metab 2002; 283: E154-64. (Pubitemid 34686681)
14. Sinha-Hikim I, Cornford M, Gaytan H, Lee ML, Bhasin S. Effects of testosterone supplementation on skeletal muscle fiber hypertrophy and satellite cells in community-dwelling older men. J Clin Endocrinol Metab 2006; 91: 3024-33. (Pubitemid 44271751)
15. Storer TW, Magliano L, Woodhouse L, Lee ML, Dzekov C, 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: 1478-85. (Pubitemid 36636978)
16. Schroeder ET, Terk M, Sattler FR. Androgen therapy improves muscle mass and strength but not muscle quality: results from two studies. Am J Physiol Endocrinol Metab 2003; 285: E16-24. (Pubitemid 36736357)
17. Dubois V, Laurent M, Boonen S, Vanderschueren D, Claessens F. Androgens and skeletal muscle: cellular and molecular action mechanisms underlying the anabolic actions. Cell Mol Life Sci 2012; 69: 1651-67.
18. Ferrando AA, Sheffield-Moore M, Yeckel CW, Gilkison C, Jiang J, et al. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am J Physiol Endocrinol Metab 2002; 282: E601-7. (Pubitemid 34654776)
19. Ferrando AA, Tipton KD, Doyle D, Phillips SM, Cortiella J, et al. Testosterone injection stimulates net protein synthesis but not tissue amino acid transport. Am J Physiol 1998; 275: E864-71.
20. Sinha-Hikim I, Roth SM, Lee MI, Bhasin S. Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men. Am J Physiol Endocrinol Metab 2003; 285: E197-205. (Pubitemid 36736377)
21. Urban RJ, Bodenburg YH, Gilkison C, Foxworth J, Coggan AR, et al. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol 1995; 269: E820-6. (Pubitemid 3005899)
22. Singh R, Artaza JN, Taylor WE, Gonzalez-Cadavid NF, Bhasin S. Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology 2003; 144: 5081-8. (Pubitemid 37378423)
23. Sinha-Hikim I, Taylor WE, Gonzalez-Cadavid NF, Zheng W, Bhasin S. Androgen receptor in human skeletal muscle and cultured muscle satellite cells: Up-regulation by androgen treatment. J Clin Endocrinol Metab 2004; 89: 5245-55. (Pubitemid 39391474)
24. Singh R, Bhasin S, Braga M, Artaza JN, Pervin S, et al. Regulation of myogenic differentiation by androgens: cross talk between androgen receptor/β-Catenin and follistatin/transforming growth factor-β signaling pathways. Endocrinology 2009; 150: 1259-68.
25. Braga M, Bhasin S, Jasuja R, Pervin S, Singh R. Testosterone inhibits transforming growth factor-β signaling during myogenic differentiation and proliferation of mouse satellite cells: potential role of follistatin in mediating testosterone action. Mol Cell Endocrinol 2012; 350: 39-52.
26. Brown D, Hikim AP, Kovacheva EL, Sinha-Hikim I. Mouse model of testosterone- induced muscle fiber hypertrophy: involvement of p38 mitogen-activated protein kinase-mediated Notch signaling. J Endocrinol 2009; 201: 129-39.
27. Kovacheva EL, Sinha Hikim AP, Shen R, Sinha I, Sinha-Hikim I. Testosterone supplementation reverses sarcopenia in aging through regulation of myostatin, c-Jun NH2-terminal kinase, notch, and akt signaling pathways. Endocrinology 2010; 151: 628-38.
28. Serra C, Bhasin S, Tangherlini F, Barton ER, Ganno M, et al. The Role of GH and IGF-I in mediating anabolic effects of testosterone on androgen-responsive muscle. Endocrinology 2010; 152: 193-206.
29. White JP, Gao S, Puppa MJ, Sato S, Welle SL, et al. Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle. Mol Cell Endocrinol 2013; 365: 174-86.
30. Wu Y, Bauman WA, Blitzer RD, Cardozo C. Testosterone-induced hypertrophy of L6 myoblasts is dependent upon Erk and mTOR. Biochem Biophys Res Commun 2010; 400: 679-83.
31. Delmonico MJ, Harris TB, Visser M, Park SW, Conroy MB, et al. Longitudinal study of muscle strength, quality, and adipose tissue infiltration. Am J Clin Nutr 2009; 90: 1579-85.
32. Koster A, Ding J, Stenholm S, Caserotti P, Houston DK, et al. Health ABC study. Does the amount of fat mass predict age-related loss of lean mass, muscle strength, and muscle quality in older adults? J Gerontol A Biol Sci Med Sci 2011; 66A: 888-95.
33. Koster A, Visser M, Simonsick EM, Yu B, Allison DB, et al. Health, Aging and Body Composition Study. Association between fitness and changes in body composition and muscle strength. J Am Geriatr Soc 2010; 58: 219-26.
34. Narici MV, Maffulli N, Maganaris CN. Ageing of human muscles and tendons. Disabil Rehabil 2008; 30: 1548-54.
35. Tomlinson BE, Irving D. The numbers of limb motor neurons in the human lumbosacral cord throughout life. J Neurol Sci 1977; 34: 213-9. (Pubitemid 8188068)
36. Mitchell WK, Atherton PJ, Williams J, Larvin M, Lund JN, et al. Sarcopenia, dynapenia and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. Front Physiol 2012; 3: 260.
37. Russ D, Gregg-Cornell K, Conaway M, Clark BC. Evolving concepts on the age-related changes in "muscle quality". J Cachexia Sarcopenia Muscle 2012; 3: 95-109.
38. Baumgartner RN, Koehler KM, Gallagher D, Romero L, Heymsfield SB, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol 1998; 147: 755-63. (Pubitemid 28183275)
39. Janssen I, Heymsfield SB, Ross R. Low relative skeletal muscle mass (Sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc 2002; 50: 889-96. (Pubitemid 34496687)
40. Delmonico MJ, Harris TB, Lee JS, Visser M, Nevitt M, et al. Health, Aging and Body Composition Study. Alternative definitions of sarcopenia, lower extremity performance, and functional impairment with aging in older men and women. J Am Geriatr Soc 2007; 55: 769-74. (Pubitemid 46668965)
41. Newman AB, Kupelian V, Visser M, Simonsick E, Goodpaster B, et al. Health ABC Study Investigators. Sarcopenia: alternative definitions and associations with lower extremity function. J Am Geriatr Soc 2003; 51: 1602-9. (Pubitemid 37409595)
42. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, et al. European Working Group on Sarcopenia in Older People. Sarcopenia: european consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010; 39: 412-23.
43. Fielding RA, Vellas B, Evans WJ, Bhasin S, Morley JE, et al. Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. international working group on sarcopenia. J Am Med Dir Assoc 2011; 12: 249-56.
44. Morley JE, Abbatecola AM, Argiles JM, Baracos V, Bauer J, et al. Society on Sarcopenia, Cachexia and Wasting Disorders Trialist Workshop. Sarcopenia with limited mobility: an international consensus. J Am Med Dir Assoc 2011; 12: 403-9.
45. Muscaritoli M, Anker SD, Argiles J, Aversa Z, Bauer JM, et al. Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) "cachexia-anorexia in chronic wasting diseases" and "nutrition in geriatrics". Clin Nutr 2010; 29: 154-9.
46. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, et al. Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001; 56: M146-56. (Pubitemid 32187141)
47. Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci 2007; 62: 722-7. (Pubitemid 350143602)
48. Abellan van Kan G, Rolland Y, Bergman H, Morley JE, Kritchevsky SB, et al. The I.A.N.A. task force on frailty assessment of older people in clinical practice. J Nutr Health Aging 2008; 12: 29-37. (Pubitemid 351156012)
49. Ensrud KE, Ewing SK, Taylor BC, Fink HA, Cawthon PM, et al. Comparison of 2 frailty indexes for prediction of falls, disability, fractures, and death in older women. Arch Intern Med 2008; 168: 382-9. (Pubitemid 351347130)
50. Abellan van Kan G, Cesari M, Gillette-Guyonnet S, Dupuy C, Nourhashemi F, et al. Sarcopenia and cognitive impairment in elderly women: results from the EPIDOS cohort. Age Ageing 2013; 42: 196-202.
51. Bijlsma AY, Meskers CG, Ling CH, Narici M, Kurrle SE, et al. Defining sarcopenia: the impact of different diagnostic criteria on the prevalence of sarcopenia in a large middle aged cohort. Age (Dordr) 2013; 35: 871-81.
52. Narici MV, Maffulli N. Sarcopenia: characteristics, mechanisms and functional significance. Br Med Bull 2010; 95: 139-59.
53. Bijlsma AY, Meskers CG, van Heemst D, Westendorp RG, de Craen AM, et al. Diagnostic criteria for sarcopenia relate differently to insulin resistance. Age (Dordr) 2013; 35: 2367-75.
54. Clark BC, Manini TM. Sarcopenia =/= Dynapenia. J Gerontol A Biol Sci Med Sci 2008; 63: 829-34.
55. Morley JE. Sarcopenia in the elderly. Fam Pract 2012; 29: i44-8.
56. Bergman H, Ferrucci L, Guralnik J, Hogan DB, Hummel S, et al. Frailty: an emerging research and clinical paradigm issues and controversies. J Gerontol A Biol Sci Med Sci 2007; 62: 731-7. (Pubitemid 350143604)
57. Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci 2004; 59: 255-63. (Pubitemid 38375339)
58. Walston J, Hadley EC, Ferrucci L, Guralnik JM, Newman AB, et al. Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc 2006; 54: 991-1001. (Pubitemid 43847040)
59. Ensrud KE, Ewing SK, Cawthon PM, Fink HA, Taylor BC, et al. Osteoporotic Fractures in Men Research Group. A comparison of frailty indexes for the prediction of falls, disability, fractures, and mortality in older men. J Am Geriatr Soc 2009; 57: 492-8.
60. Ravaglia G, Forti P, Lucicesare A, Pisacane N, Rietti E, et al. Development of an easy prognostic score for frailty outcomes in the aged. Age Ageing 2008; 37: 161-6. (Pubitemid 351445186)
61. Rolfson DB, Majumdar SR, Tsuyuki RT, Tahir A, Rockwood K. Validity and reliability of the edmonton frail scale. Age Ageing 2006; 35: 526-9. (Pubitemid 44295645)
62. Strawbridge WJ, Shema SJ, Balfour JL, Higby HR, Kaplan GA. Antecedents of frailty over three decades in an older cohort. J Gerontol B Psychol Sci Soc Sci 1998; 53: S9-16.
63. Cawthon PM, Marshall LM, Michael Y, Dam TT, Ensrud KE, et al. Osteoporotic Fractures in Men Research Group. Frailty in older men: prevalence, progression, and relationship with mortality. J Am Geriatr Soc 2007; 55: 1216-23. (Pubitemid 47106689)
64. Ensrud KE, Ewing SK, Taylor BC, Fink HA, Stone KL, et al. Study of Osteoporotic Fractures Research Group. Frailty and risk of falls, fracture, and mortality in older women: the study of osteoporotic fractures. J Gerontol A Biol Sci Med Sci 2007; 62: 744-51. (Pubitemid 350143606)
65. Woods NF, LaCroix AZ, Gray SL, Aragaki A, Cochrane BB, et al. Women's Health Initiative. Frailty: emergence and consequences in women aged 65 and older in the women's health initiative observational study. J Am Geriatr Soc 2005; 53: 1321-30. (Pubitemid 41602477)
66. O'Connell MD, Tajar A, O'Neill TW, Roberts SA, Lee DM, et al. Frailty is associated with impaired quality of life and falls in middle-aged and older european men. J Frailt Aging 2013; 2: 77-83.
67. Rochat S, Cumming RG, Blyth F, Creasey H, Handelsman D, et al. Frailty and use of health and community services by community-dwelling older men: the Concord Health and Ageing in Men Project. Age Ageing 2010; 39: 228-33.
68. Searle S, Mitnitski A, Gahbauer E, Gill TM, Rockwood K. A standard procedure for creating a frailty index. BMC Geriatr 2008; 8: 24.
69. Mitnitski A, Rockwood K. Decrease in the relative heterogeneity of health with age: a cross-national comparison. Mech Ageing Dev 2006; 127: 70-2. (Pubitemid 41713516)
70. Mitnitski A, Song X, Skoog I, Broe GA, Cox JL, et al. Relative fitness and frailty of elderly men and women in developed countries and their relationship with mortality. J Am Geriatr Soc 2005; 53: 2184-9. (Pubitemid 43001203)
71. Rockwood K, Mitnitski A. Limits to deficit accumulation in elderly people. Mech Ageing Dev 2006; 127: 494-6.
72. Abellan van Kan G, Rolland YM, Morley JE, Vellas B. Frailty: toward a clinical definition. J Am Med Dir Assoc 2008; 9: 71-2. (Pubitemid 351189169)
73. Cawthon PM, Ensrud KE, Laughlin GA, Cauley JA, Dam TT, et al. Osteoporotic Fractures in Men (MrOS) Research Group. Sex hormones and frailty in older men: the osteoporotic fractures in men (MrOS) study. J Clin Endocrinol Metab 2009; 94: 3806-15.
74. Carcaillon L, Blanco C, Alonso-Bouzon C, Alfaro-Acha A, Garcia-Garcia FJ, et al. Sex differences in the association between serum levels of testosterone and frailty in an elderly population: the Toledo Study for Healthy Aging. PLoS One 2012; 7: e32401.
75. Wu IC, Lin XZ, Liu PF, Tsai WL, Shiesh SC. Low serum testosterone and frailty in older men and women. Maturitas 2010; 67: 348-52.
76. Travison TG, Nguyen AH, Naganathan V, Stanaway FF, Blyth FM, et al. Changes in reproductive hormone concentrations predict the prevalence and progression of the frailty syndrome in older men: the concord health and ageing in men project. J Clinl Endocrinol Metab 2011; 96: 2464-74.
77. Eichholzer M, Barbir A, Basaria S, Dobs AS, Feinleib M, et al. Serum sex steroid hormones and frailty in older American men of the Third National Health and Nutrition Examination Survey (NHANES III). Aging Male 2012; 15: 208-15.
78. Mohr BA, Bhasin S, Kupelian V, Araujo AB, O'Donnell AB, et al. Testosterone, sex hormone-binding globulin, and frailty in older men. J Am Geriatr Soc 2007; 55: 548-55. (Pubitemid 46496587)
79. Hyde Z, Flicker L, Almeida OP, Hankey GJ, McCaul KA, et al. Low free testosterone predicts frailty in older men: the health in men study. J Clin Endocrinol Metab 2010; 95: 3165-72.
80. Tajar A, O'Connell MD, Mitnitski AB, O'Neill TW, Searle SD, et al. European Male Aging Study Group. Frailty in relation to variations in hormone levels of the hypothalamic-pituitary-testicular axis in older men: results from the european male aging study. J Am Geriatr Soc 2011; 59: 814-21.
81. Araujo AB, Travison TG, Bhasin S, Esche GR, Williams RE, et al. Association between testosterone and estradiol and age-related decline in physical function in a diverse sample of men. J Am Geriatr Soc 2008; 56: 2000-8.
82. Auyeung TW, Lee JS, Kwok T, Leung J, Ohlsson C, et al. Testosterone but not estradiol level is positively related to muscle strength and physical performance independent of muscle mass: a cross-sectional study in 1489 older men. Eur J Endocrinol 2011; 164: 811-7.
83. 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: 123-36. (Pubitemid 29138849)
84. Chin KY, Soelaiman IN, Naina Mohamed I, Shahar S, Teng NI, et al. Testosterone is associated with age-related changes in bone health status, muscle strength and body composition in men. Aging Male 2012; 15: 240-5.
85. Iannuzzi-Sucich M, Prestwood KM, Kenny AM. Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women. J Gerontol A Biol Sci Med Sci 2002; 57: M772-7. (Pubitemid 35470952)
86. Szulc P, Duboeuf F, Marchand F, Delmas PD. Hormonal and lifestyle determinants of appendicular skeletal muscle mass in men: the MINOS study. Am J Clin Nutr 2004; 80: 496-503.
87. van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab 2000; 85: 3276-82.
88. Waters DL, Yau CL, Montoya GD, Baumgartner RN. Serum sex hormones, IGF-1, and IGFBP3 exert a sexually dimorphic effect on lean body mass in aging. J Gerontol A Biol Sci Med Sci 2003; 58: 648-52. (Pubitemid 36900173)
89. Roy TA, Blackman MR, Harman SM, Tobin JD, Schrager M, et al. Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men. Am J Physiol Endocrinol Metab 2002; 283: E284-94. (Pubitemid 34827443)
90. Folland JP, Mc Cauley TM, Phypers C, Hanson B, Mastana SS. The relationship of testosterone and AR CAG repeat genotype with knee extensor muscle function of young and older men. Exp Gerontol 2012; 47: 437-43.
91. Vandenput L, Mellstrom D, Karlsson MK, Orwoll E, Labrie F, et al. Serum estradiol is associated with lean mass in elderly Swedish men. Eur J Endocrinol 2010; 162: 737-45.
92. Orwoll E, Lambert LC, Marshall LM, Blank J, Barrett-Connor E, et al. Endogenous testosterone levels, physical performance, and fall risk in older men. Arch Intern Med 2006; 166: 2124-31. (Pubitemid 44631401)
93. Maggio M, Ceda GP, Lauretani F, Bandinelli S, Metter EJ, et al. Gonadal status and physical performance in older men. Aging Male 2011; 14: 42-7.
94. Trabert B, Graubard B, Nyante SJ, Rifai N, Bradwin G, et al. Relationship of sex steroid hormones with body size and with body composition measured by dual-energy X-ray absorptiometry in US men. Cancer Causes Control 2012; 23: 1881-91.
95. Gates MA, Mekary RA, Chiu GR, Ding EL, Wittert GA, et al. Sex steroid hormone levels and body composition in men. J Clin Endocrinol Metab 2013; 98: 2442-50.
96. Miljkovic I, Cauley JA, Dressen AS, Gordon CL, Goodpaster BH, et al. Bioactive androgens and glucuronidated androgen metabolites are associated with subcutaneous and ectopic skeletal muscle adiposity among older black men. Metabolism 2011; 60: 1178-85.
97. LeBlanc ES, Wang PY, Lee CG, Barrett-Connor E, Cauley JA, et al. Higher testosterone levels are associated with less loss of lean body mass in older men. J Clin Endocrinol Metab 2011; 96: 3855-63.
98. Yuki A, Otsuka R, Kozakai R, Kitamura I, Okura T, et al. Relationship between low free testosterone levels and loss of muscle mass. Sci Rep 2013; 3: 1818.
99. Syddall H, Cooper C, Martin F, Briggs R, Aihie Sayer A. Is grip strength a useful single marker of frailty? Age Ageing 2003; 32: 650-6. (Pubitemid 37461574)
100. Perry HM 3rd, Miller DK, Patrick P, Morley JE. Testosterone and leptin in older African-American men: relationship to age, strength, function, and season. Metabolism 2000; 49: 1085-91. (Pubitemid 30641450)
101. Schaap LA, Pluijm SM, Smit JH, van Schoor NM, Visser M, et al. The association of sex hormone levels with poor mobility, low muscle strength and incidence of falls among older men and women. Clin Endocrinol (Oxf) 2005; 63: 152-60. (Pubitemid 41097983)
102. O'Donnell AB, Travison TG, Harris SS, Tenover JL, McKinlay JB. Testosterone, Dehydroepiandrosterone, and physical performance in older men: results from the massachusetts male aging study. J Clin Endocrinol Metab 2006; 91: 425-31. (Pubitemid 43236905)
103. Schaap LA, Pluijm SM, Deeg DJ, Penninx BW, Nicklas BJ, et al. Health ABC study. Low testosterone levels and decline in physical performance and muscle strength in older men: findings from two prospective cohort studies. Clin Endocrinol (Oxf) 2008; 68: 42-50. (Pubitemid 350243480)
104. Krasnoff JB, Basaria S, Pencina MJ, Jasuja GK, Vasan RS, 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: 2790-9.
105. Blackman MR, Sorkin JD, Munzer T, Bellantoni MF, Busby-Whitehead J, et al. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA 2002; 288: 2282-92. (Pubitemid 35291758)
106. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM, 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.
107. Kenny AM, Kleppinger A, Annis K, Rathier M, Browner B, 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: 1134-43.
108. 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: M266-72. (Pubitemid 32381803)
109. Liu PY, Wishart SM, Handelsman DJ. A double-blind, placebo-controlled, randomized clinical trial of recombinant human chorionic gonadotropin on muscle strength and physical function and activity in older men with partial age-related androgen deficiency. J Clin Endocrinol Metab 2002; 87: 3125-35. (Pubitemid 34816354)
110. Nair KS, Rizza RA, O'Brien P, Dhatariya K, Short KR, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006; 355: 1647-59. (Pubitemid 44583955)
111. Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, 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: 1502-10. (Pubitemid 40464011)
112. Sattler FR, Castaneda-Sceppa C, Binder EF, Schroeder ET, Wang Y, et al. Testosterone and growth hormone improve body composition and muscle performance in older men. J Clin Endocrinol Metab 2009; 94: 1991-2001.
113. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, 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: 2647-53. (Pubitemid 30641987)
114. Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, Adams JE, 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: 639-50.
115. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992; 75: 1092-8.
116. Travison TG, Basaria S, Storer TW, Jette AM, Miciek R, 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; 66A: 1090-9.
117. Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, et al. 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: 618-25. (Pubitemid 36900168)
118. Frederiksen L, Hojlund K, Hougaard DM, Brixen K, Andersen M. Testosterone therapy increased muscle mass and lipid oxidation in aging men. Age (Dorodr) 2012; 34: 145-56.
119. Brill KT, Weltman AL, Gentili A, Patrie JT, Fryburg DA, 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: 5649-57. (Pubitemid 36034373)
120. 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: 261-5. (Pubitemid 29361240)
121. Giannoulis MG, Sonksen PH, Umpleby M, Breen L, Pentecost C, et al. The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial. J Clin Endocrinol Metab 2006; 91: 477-84. (Pubitemid 43236912)
122. Storer TW, Woodhouse L, Magliano L, Singh AB, Dzekov C, 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: 1991-9.
123. Bean JF, Kiely DK, Herman S, Leveille SG, Mizer K, et al. The relationship between leg power and physical performance in mobility-limited older people. J Am Geriatr Soc 2002; 50: 461-7. (Pubitemid 34229401)
124. Macaluso A, Vito G. Muscle strength, power and adaptations to resistance training in older people. Eur J Appl Physiol 2004; 91: 450-72. (Pubitemid 38488736)
125. Morley JE, Perry HM 3rd, Kaiser FE, Kraenzle D, Jensen J, et al. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc 1993; 41: 149-52. (Pubitemid 23051423)
126. Sih R, Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, et al. Testosterone replacement in older hypogonadal men: a 12-Month randomized controlled trial. J Clin Endocrinol Metab 1997; 82: 1661-7. (Pubitemid 127495166)
127. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, et al. Adverse events associated with testosterone administration. N Engl J Med 2010; 363: 109-22.
128. Ly LP, Jimenez M, Zhuang TN, Celermajer DS, Conway AJ, et al. 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: 4078-88. (Pubitemid 32848516)
129. Schroeder ET, He J, Yarasheski KE, Binder EF, Castaneda-Sceppa C, et al. Value of measuring muscle performance to assess changes in lean mass with testosterone and growth hormone supplementation. Eur J Appl Physiol 2012; 112: 1123-31.
130. Sattler F, Bhasin S, He J, Chou CP, Castaneda-Sceppa C, et al. Testosterone threshold levels and lean tissue mass targets needed to enhance skeletal muscle strength and function: the HORMA trial. J Gerontol A Biol Sci Med Sci 2011; 66: 122-9.
131. Verdijk LB, van Loon L, Meijer K, Savelberg HH. One-repetition maximum strength test represents a valid means to assess leg strength in vivo in humans. J Sports Sci 2009; 27: 59-68.
132. Becker R, Berth A, Nehring M, Awiszus F. Neuromuscular quadriceps dysfunction prior to osteoarthritis of the knee. J Orthop Res 2004; 22: 768-73. (Pubitemid 38756255)
133. Roos MR, Rice CL, Connelly DM, Vandervoort AA. Quadriceps muscle strength, contractile properties, and motor unit firing rates in young and old men. Muscle Nerve 1999; 22: 1094-103. (Pubitemid 29360256)
134. Buchner DM, Larson EB, Wagner EH, Koepsell TD, De Lateur BJ. Evidence for a non- linear relationship between leg strength and gait speed. Age Ageing 1996; 25: 386-91. (Pubitemid 26381771)
135. Kwon IS, Oldaker S, Schrager M, Talbot LA, Fozard JL, et al. Relationship between muscle strength and the time taken to complete a standardized walk-turn-walk test. J Gerontol A Biol Sci Med Sci 2001; 56: B398-404. (Pubitemid 32816730)
136. Rantanen T, Guralnik JM, Izmirlian G, Williamson JD, Simonsick EM, et al. Association of muscle strength with maximum walking speed in diisabled older women. Am J Phys Med Rehabil 1998; 77: 299-305. (Pubitemid 28377945)
137. Lord SR, Murray SM, Chapman K, Munro B, Tiedemann A. Sit-to-Stand performance depends on sensation, speed, balance, and psychological status in addition to strength in older people. J Gerontol A Biol Sci Med Sci 2002; 57: M539-43. (Pubitemid 35006100)
138. Bhasin S. The brave new world of function-promoting anabolic therapies: testosterone and frailty. J Clin Endocrinol Metab 2010; 95: 509-11.
139. O'Connell MD, Roberts SA, Srinivas-Shankar U, Tajar A, Connolly MJ, et al. Do the effects of testosterone on muscle strength, physical function, body composition and quality of life persist six months post-treatment in intermediate-frail and frail elderly men? J Clin Endocrinol Metab 2011; 96: 454-8.
140. Sattler FR, Bhasin S, He J, Yarasheski KE, Binder EF, et al. Durability of the effects of testosterone and growth hormone supplementation in older community-dwelling men: the HORMA Trial. Clin Endocrinol 2011; 75: 103-11.
141. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, 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: 1451-7. (Pubitemid 41798454)
142. Fernandez-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, et al. Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010; 95: 2560-75.
143. Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Bolona ER, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 2007; 82: 29-39. (Pubitemid 46036319)
144. Basaria S, Davda MN, Travison TG, Ulloor J, Singh R, et al. Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation. J Gerontol A Biol Sci Med Sci 2013; 68: 153-60.
145. Bhasin S, Jasuja R. Selective androgen receptor modulators as function promoting therapies. Curr Opin Clin Nutr Metab Care 2009; 12: 232-40.
146. Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, et al. Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem 2009; 52: 3597-617.
147. Dalton J, Barnette K, Bohl C, Hancock M, Rodriguez D, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle 2011; 2: 153-61.
148. Dobs AS, Boccia RV, Croot CC, Gabrail NY, Dalton JT, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol 2013; 14: 335-45.
149. Papanicolaou DA, Ather SN, Zhu H, Zhou Y, Lutkiewicz J, et al. A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia. J Nutr Health Aging 2013; 17: 533-43.
150. Basaria S, Collins L, Dillon EL, Orwoll K, Storer TW, Miciek R, et al. The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men. J Gerontol A Biol Sci Med Sci 2013; 68: 87-95.
151. Raue U, Slivka D, Minchev K, Trappe S. Improvements in whole muscle and myocellular function are limited with high-intensity resistance training in octogenarian women. J Appl Physiol (1985) 2009; 106: 1611-7.
152. Hildreth KL, Barry DW, Moreau KL, Vande Griend J, Meacham RB, 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: 1891-900.
153. Kvorning T, Christensen LL, Madsen K, Nielsen JL, Gejl KD, et al. Mechanical Muscle function and lean body mass during supervised strength training and testosterone therapy in aging men with low-normal testosterone levels. J Am Geriatr Soc 2013; 61: 957-62.