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Clinical Section / Viewpoint

Editor's Choice - Free Access

Testosterone Deficiency and Testosterone Treatment in Older Men

Saad F.a, b · Röhrig G.c, d · von Haehling S.e · Traish A.f, g

Author affiliations

aGlobal Medical Affairs Andrology, Bayer AG, Berlin, Germany; bGulf Medical University, Ajman, United Arab Emirates; cAgeing Clinical Research, Department II Internal Medicine, University Hospital Cologne, and dClinic for Geriatrics at St. Marien-Hospital, Cologne, and eDepartment of Cardiology and Pneumology, University of Göttingen Medical School, Göttingen, Germany; Departments of fBiochemistry and gUrology, Boston University School of Medicine, Boston, MA, USA

Corresponding Author

Farid Saad

Global Medical Affairs Andrology, Bayer AG

Muellerstr. 178

DE-13353 Berlin (Germany)

E-Mail farid.saad@bayer.com

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Gerontology 2017;63:144-156

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Abstract

Frailty is a clinical condition related to changes in metabolism, to sarcopenia, and to decline in muscle mass and strength, bone mineral density, and physical function with aging. The pathophysiology of frailty is multifactorial and associated with comorbidities. Testosterone is implicated in regulating metabolic functions, maintenance of muscle and bone, and inhibition of adipogenesis. In older individuals, reduced testosterone is thought to contribute to an altered state of metabolism, loss of muscle and bone, and increased fat, leading to sarcopenia, sarcopenic obesity, and frailty. While no direct relationship between testosterone deficiency (commonly known as hypogonadism) and frailty has been established (due to the multifactorial nature of frailty), clinical evidence suggests that testosterone deficiency is associated with increased sarcopenia and obesity. Testosterone treatment in frail older men with limited mobility and with testosterone deficiency improved insulin resistance, glucose metabolism, and body composition. These changes contribute to better physical function and improved quality of life. Because frailty increases disability, comorbidities, and the risk of hospitalization, institutionalization, and mortality in older men, it is warranted to explore the potential usefulness of testosterone treatment in frail men with hypogonadism in order to attenuate the progression of sarcopenia and frailty. In this paper, we will discuss the impact of testosterone deficiency on frailty and the potential role of testosterone treatment in ameliorating and reducing the progression of frailty. Such an approach may reduce disability and the risk of hospitalization and increase functional independence and quality of life.

© 2016 S. Karger AG, Basel


References

  1. 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.
  2. Saad F: The relationship between testosterone deficiency and frailty in elderly men. Horm Mol Biol Clin Investig 2010;4:529-538.
  3. Afilalo J: Androgen deficiency as a biological determinant of frailty: hope or hype? J Am Geriatr Soc 2014;62:1174-1178.
  4. Tian S, Xu Y: Association of sarcopenic obesity with the risk of all-cause mortality: a meta-analysis of prospective cohort studies. Geriatr Gerontol Int 2016;16:155-166.
  5. Morley JE: Frailty, falls, and fractures. J Am Med Dir Assoc 2013;14:149-151.
  6. Baillargeon J, Deer RR, Kuo YF, Zhang D, Goodwin JS, Volpi E: Androgen therapy and rehospitalization in older men with testosterone deficiency. Mayo Clin Proc 2016;91:587-595.
  7. Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA: Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2011;96:3007-3019.
  8. Svartberg J, Agledahl I, Figenschau Y, Sildnes T, Waterloo K, Jorde R: Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. Int J Impot Res 2008;20:378-387.
  9. Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL: 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.
  10. Hyde Z, Flicker L, Almeida OP, Hankey GJ, McCaul KA, Chubb SA, Yeap BB: Low free testosterone predicts frailty in older men: the Health in Men Study. J Clin Endocrinol Metab 2010;95:3165-3172.
  11. Krasnoff JB, Basaria S, Pencina MJ, Jasuja GK, Vasan RS, Ulloor J, Zhang A, Coviello A, Kelly-Hayes M, D'Agostino RB, Wolf PA, Bhasin S, Murabito JM: Free testosterone levels are associated with mobility limitation and physical performance in community-dwelling men: the Framingham Offspring Study. J Clin Endocrinol Metab 2010;95:2790-2799.
  12. Eichholzer M, Barbir A, Basaria S, Dobs AS, Feinleib M, Guallar E, Menke A, Nelson WG, Rifai N, Platz EA, Rohrmann S: Serum sex steroid hormones and frailty in older American men of the Third National Health and Nutrition Examination Survey (NHANES III). Aging Male 2012;15:208-215.
  13. Ferrucci L, Maggio M, Bandinelli S, Basaria S, Lauretani F, Ble A, Valenti G, Ershler WB, Guralnik JM, Longo DL: Low testosterone levels and the risk of anemia in older men and women. Arch Intern Med 2006;166:1380-1388.
  14. Morley JE, von Haehling S, Anker SD, Vellas B: From sarcopenia to frailty: a road less traveled. J Cachexia Sarcopenia Muscle 2014;5:5-8.
  15. von Haehling S, Morley JE, Anker SD: From muscle wasting to sarcopenia and myopenia: update 2012. J Cachexia Sarcopenia Muscle 2012;3:213-217.
  16. Kenny AM, Kleppinger A, Annis K, Rathier M, Browner B, Judge JO, McGee D: 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.
  17. Kvorning T, Christensen LL, Madsen K, Nielsen JL, Gejl KD, Brixen K, Andersen M: 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;61:957-962.
  18. Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, Adams JE, Oldham JA, Wu FCW: 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.
  19. Bhasin S: Testosterone supplementation for aging-associated sarcopenia. J Gerontol A Biol Sci Med Sci 2003;58:1002-1008.
  20. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Lenrow DA, Holmes JH, Dlewati A, Santanna J, Rosen CJ, Strom BL: Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 1999;84:2647-2653.
  21. Ferrando AA, Sheffield-Moore M, Yeckel CW, Gilkison C, Jiang J, Achacosa A, Lieberman SA, Tipton K, Wolfe RR, Urban RJ: Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am J Physiol Endocrinol Metab 2002;282:E601-E607.
  22. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S: Adverse events associated with testosterone administration. N Engl J Med 2010;363:109-122.
  23. Sheffield-Moore M, Dillon EL, Casperson SL, Gilkison CR, Paddon-Jones D, Durham WJ, Grady JJ, Urban RJ: A randomized pilot study of monthly cycled testosterone replacement or continuous testosterone replacement versus placebo in older men. J Clin Endocrinol Metab 2011;96:E1831-E1837.
  24. Orwoll E, Lambert LC, Marshall LM, Blank J, Barrett-Connor E, Cauley J, Ensrud K, Cummings SR; Osteoporotic Fractures in Men Study Group: Endogenous testosterone levels, physical performance, and fall risk in older men. Arch Intern Med 2006;166:2124-2131.
  25. Bischoff-Ferrari HA, Orav EJ, Dawson-Hughes B: Additive benefit of higher testosterone levels and vitamin D plus calcium supplementation in regard to fall risk reduction among older men and women. Osteoporos Int 2008;19:1307-1314.
  26. Ucak S, Basat O, Karatemiz G: Functional and nutritional state in elderly men with compensated hypogonadism. J Am Med Dir Assoc 2013;14:433-436.
  27. Guralnik JM, Eisenstaedt RS, Ferrucci L, Klein HG, Woodman RC: Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood 2004;104:2263-2268.
  28. Gaskell H, Derry S, Andrew Moore R, McQuay HJ: Prevalence of anaemia in older persons: systematic review. BMC Geriatr 2008; 8:1.
  29. Röhrig G, Hörter M, Becker I, Adams A, Schulz RJ, Lenzen-Grossimlinghaus R, Willschrei HP, Gebauer S, Modreker MK, Jäger M, Wirth R: Anemia prevalence and hematologic findings in German geriatric inpatients - results of the prospective cross-sectional multicenter study “GeriAnaemie2013.” Eur Geriatr Med 2016;7:328-332.
  30. Skjelbakken T, Langbakk B, Dahl IM, Løchen ML; Tromsø Study: Haemoglobin and anaemia in a gender perspective: the Tromsø Study. Eur J Haematol 2005;74:381-388.
  31. Zhang LT, Shin YS, Kim JY, Park JK: Could testosterone replacement therapy in hypogonadal men ameliorate anemia, a cardiovascular risk factor? An observational, 54-week cumulative registry study. J Urol 2016;195:1057-1064.
  32. Maggio M, De Vita F, Fisichella A, Lauretani F, Ticinesi A, Ceresini G, Cappola A, Ferrucci L, Ceda GP: The role of the multiple hormonal dysregulation in the onset of “anemia of aging”: focus on testosterone, IGF-1, and thyroid hormones. Int J Endocrinol 2015;2015:292574.
  33. Röhrig G, Becker I, Schulz RJ, Lenzen-Grossimlinghaus R, Willschrei P, Gebauer S, Modreker M, Jäger M, Wirth R: Association between hematologic parameters and functional impairment among geriatric inpatients: data of a prospective cross-sectional multicenter study (“GeriPrävalenz2013”). Maturitas 2016;90:37-41.
  34. Romero-Ruperto S, Pérez-Bocanegra MC, Duran-Taberna M, Toscano-Rivera A, Barbé-Gil Ortega J, San José-Laporte A: Anemia in elderly patients admitted to an acute geriatric ward. Rev Esp Geriatr Gerontol 2015;50:122-125.
  35. Fukai S, Akishita M, Yamada S, Hama T, Ogawa S, Iijima K, Eto M, Kozaki K, Toba K, Ouchi Y: Association of plasma sex hormone levels with functional decline in elderly men and women. Geriatr Gerontol Int 2009;9:282-289.
  36. Dos Santos MR, Sayegh AL, Bacurau AV, Arap MA, Brum PC, Pereira RM, Takayama L, Barretto AC, Negrão CE, Alves MJ: Effect of exercise training and testosterone replacement on skeletal muscle wasting in patients with heart failure with testosterone deficiency. Mayo Clin Proc 2016;91:575-586.
  37. Fülster S, Tacke M, Sandek A, Ebner N, Tschöpe C, Doehner W, Anker SD, von Haehling S: Muscle wasting in patients with chronic heart failure: results from the Studies Investigating Co-Morbidities Aggravating Heart Failure (SICA-HF). Eur Heart J 2013;34:512-519.
  38. Bekfani T, Pellicori P, Morris DA, Ebner N, Valentova M, Steinbeck L, Wachter R, Elsner S, Sliziuk V, Schefold JC, Sandek A, Doehner W, Cleland JG, Lainscak M, Anker SD, von Haehling S: Sarcopenia in patients with heart failure with preserved ejection fraction: impact on muscle strength, exercise capacity and quality of life. Int J Cardiol 2016;222:41-46.
  39. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, Gill TM, Barrett-Connor E, Swerdloff RS, Wang C, Ensrud KE, Lewis CE, Farrar JT, Cella D, Rosen RC, Pahor M, Crandall JP, Molitch ME, Cifelli D, Dougar D, Fluharty L, Resnick SM, Storer TW, Anton S, Basaria S, Diem SJ, Hou X, Mohler ER 3rd, Parsons JK, Wenger NK, Zeldow B, Landis JR, Ellenberg SS; Testosterone Trials Investigators: Effects of testosterone treatment in older men. N Engl J Med 2016;374:611-624.
  40. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; Authors/Task Force Members; Document Reviewers: 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;8:891-975.
  41. Traish AM: Testosterone therapy in men with testosterone deficiency: are the benefits and cardiovascular risks real or imagined? Am J Physiol Regul Integr Comp Physiol 2016;31:R566-R573.
  42. Traish AM: Testosterone therapy in men with testosterone deficiency: are we beyond the point of no return? Investig Clin Urol 2016, in press.
  43. Morgentaler A, Zitzmann M, Traish AM, Fox AW, Jones TH, Maggi M, Arver S, Aversa A, Chan JC, Dobs AS, Hackett GI, Hellstrom WJ, Lim P, Lunenfeld B, Mskhalaya G, Schulman CC, Torres LO: Fundamental concepts regarding testosterone deficiency and treatment: International Expert Consensus Resolutions. Mayo Clin Proc 2016;91:881-896.
  44. Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM: Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc 2015;90:224-251.
  45. Morgentaler A, Feibus A, Baum N: Testosterone and cardiovascular disease - the controversy and the facts. Postgrad Med 2015;127:159-165.
  46. Morgentaler A: Controversies and advances with testosterone therapy: a 40-year perspective. Urology 2016;89:27-32.
  47. Morgentaler A: Testosterone, cardiovascular risk, and hormonophobia. J Sex Med 2014;11:1362-1366.
  48. Vigen R, O'Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM: Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829-1836.
  49. Vigen R, O'Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM: Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels (erratum). JAMA 2014;311:967.
  50. Xu L, Freeman G, Cowling BJ, Schooling CM: Testosterone therapy and cardiovascular events among men: a systematic review and metaanalysis of placebo-controlled randomized trials. BMC Med 2013;11:108.
  51. Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. The Copenhagen Study Group for Liver Diseases. Hepatology 1986;6:807-813.
  52. Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, Fraumeni JF Jr, Hoover RN: Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014;9: e85805.
  53. US Food and Drug Administration: Citizen Petition Denial Response from FDA CDER to Public Citizen. Published July 16, 2014 (accessed August 31, 2014). http://www.citizen.org/documents/2184_FDA%20Denial%20of%20Petition_July%2016,%202014.pdf (accessed April 28, 2016).
  54. Baillargeon J, Urban RJ, Morgentaler A, Glueck CJ, Baillargeon G, Sharma G, Kuo YF: Risk of venous thromboembolism in men receiving testosterone therapy. Mayo Clin Proc 2015;90:1038-1045.
  55. Blackman MR, Sorkin JD, Münzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE, Jayme J, O'Connor KG, Christmas C, Tobin JD, Stewart KJ, Cottrell E, St Clair C, Pabst KM, Harman SM: Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA 2002;288:2282-2292.
  56. Brill KT, Weltman AL, Gentili A, Patrie JT, Fryburg DA, Hanks JB, Urban RJ, Veldhuis JD: 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.
  57. Clague JE, Wu FCW, Horan MA: Difficulties in measuring the effect of testosterone replacement therapy on muscle function in older men. Int J Androl 1999;22:261-265.
  58. Emmelot-Vonk MH, Verhaar HJJ, Nakhai Pour HR, Aleman A, Lock TMTW, Bosch JLHR, Grobbee DE, van der Schouw YT: Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA 2008;299:39-52.
  59. Giannoulis MG, Sonksen PH, Umpleby M, Breen L, Pentecost C, Whyte M, McMillan CV, Bradley C, Martin FC: The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial. J Clin Endocrinol Metab 2006;91:477-484.
  60. 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;87:3125-3135.
  61. 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.
  62. Morley JE, Perry HM 3rd, Kaiser FE, Kraenzle D, Jensen J, Houston K, Mattammal M, Perry HM Jr: Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc 1993;41:149-152.
  63. Nair KS, Rizza RA, O'Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R, Cobelli C, Toffolo G, Dalla Man C, Tindall DJ, Melton LJ 3rd, Smith GE, Khosla S, Jensen MD: DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006;355:1647-1659.
  64. Sattler FR, Castaneda-Sceppa C, Binder EF, Schroeder ET, Wang Y, Bhasin S, Kawakubo M, Stewart Y, Yarasheski KE, Ulloor J, Colletti P, Roubenoff R, Azen SP: Testosterone and growth hormone improve body composition and muscle performance in older men. J Clin Endocrinol Metab 2009;94:1991-2001.
  65. 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.
  66. Tenover JS: Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992;75:1092-1098.
  67. Urban RJ, Bodenburg YH, Gilkison C, Foxworth J, Coggan AR, Wolfe RR, Ferrando A: Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol Endocrinol Metab 1995;269(pt 1):E820-E826.
  68. 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.

Article / Publication Details

First-Page Preview
Abstract of Clinical Section / Viewpoint

Received: August 23, 2016
Accepted: October 15, 2016
Published online: November 18, 2016
Issue release date: February 2017

Number of Print Pages: 13
Number of Figures: 5
Number of Tables: 1

ISSN: 0304-324X (Print)
eISSN: 1423-0003 (Online)

For additional information: https://www.karger.com/GER


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