Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Risks and benefits of testosterone therapy in older men

Abstract

In young men (defined as age <50 years) with classic hypogonadism caused by known diseases of the hypothalamus, pituitary or testes, testosterone replacement therapy induces a number of beneficial effects, for example, the development of secondary sex characteristics, improvement and maintenance of sexual function, and increases in skeletal muscle mass and BMD. Moreover, testosterone treatment in this patient population is associated with a low frequency of adverse events. Circulating testosterone levels decline progressively with age, starting in the second and third decade of life, owing to defects at all levels of the hypothalamic–pituitary–testicular axis. In cohort studies, testosterone levels are associated weakly but consistently with muscle mass, strength, physical function, anaemia, BMD and bone quality, visceral adiposity, and with the risk of diabetes mellitus, coronary artery disease, falls, fractures and mortality. However, the clinical benefits and long-term risks of testosterone therapy—especially prostate-related and cardiovascular-related adverse events—have not been adequately assessed in large, randomized clinical trials involving older men (defined as age >65 years) with androgen deficiency. Therefore, a general policy of testosterone replacement in all older men with age-related decline in testosterone levels is not justified.

Key Points

  • Effects of testosterone therapy must be distinguished in the context of the various clinical conditions for which testosterone therapy can be used

  • In young men (<50 years) with classic hypogonadism caused by known diseases of the hypothalamus, pituitary or the testes, the benefit to risk ratio for testosterone replacement therapy is favourable

  • Testosterone levels decline with advancing age, and clustering of sexual and some physical symptoms, for example, erectile dysfunction and reduced vigorous activity, occurs in association with testosterone levels <8 nmol/l

  • Clinical benefits of testosterone therapy in men aged >65 years with age-associated decline in testosterone levels and with conditions associated with low testosterone levels have yet to be demonstrated in randomized trials

  • Long-term effects of testosterone therapy on the risk of prostate-related and cardiovascular-related adverse events remain unknown

  • In the absence of clear evidence regarding benefits or risks of testosterone therapy, a general recommendation about testosterone administration to all men over the age of 65 years with age-related decline in testosterone levels is not justified

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Effects of testosterone therapy on body composition and muscle strength, bone health, and sexual function in intervention trials.
Figure 2: Effects of testosterone administration on maximal voluntary strength in the leg-press and chest-press exercises and on loaded stair-climbing power in a randomized testosterone trial in older men with mobility limitation (TOM trial).
Figure 3: Adverse events associated with testosterone therapy in randomized trials.

Similar content being viewed by others

References

  1. Auxilium Pharmaceuticals Form 10-K Annual Report [online], (2011).

  2. Liverman, C. T. & Blazer, D. G. (Eds) Testosterone and Aging: Clinical Research Directions (National Academies Press, Washington, 2004).

    Google Scholar 

  3. Gan, E., Pattman, S., Pearce, S. & Quinton, R. A UK epidemic of testosterone prescribing, 2001–2010. Clin. Endocrinol. (Oxf.) http://dx.doi.org/10.1111/cen.12178.

  4. Bhasin, S. et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 95, 2536–2559 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Cunningham, G. R. & Toma, S. M. Clinical review: Why is androgen replacement in males controversial? J. Clin. Endocrinol. Metab. 96, 38–52 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Araujo, A. B. et al. Prevalence of symptomatic androgen deficiency in men. J. Clin. Endocrinol. Metab. 92, 4241–4247 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Bhasin, S. et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J. Clin. Endocrinol. Metab. 96, 2430–2439 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dai, W. S. et al. The epidemiology of plasma testosterone levels in middle-aged men. Am. J. Epidemiol. 114, 804–816 (1981).

    Article  CAS  PubMed  Google Scholar 

  9. Feldman, H. A. et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J. Clin. Endocrinol. Metab. 87, 589–598 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Ferrini, R. L. & Barrett-Connor, E. Sex hormones and age: a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. Am. J. Epidemiol. 147, 750–754 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Harman, S. M., Metter, E. J., Tobin, J. D., Pearson, J. & Blackman, M. R. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J. Clin. Endocrinol. Metab. 86, 724–731 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Mohr, B. A., Bhasin, S., Link, C. L., O'Donnell, A. B. & McKinlay, J. B. The effect of changes in adiposity on testosterone levels in older men: longitudinal results from the Massachusetts Male Aging Study. Eur. J. Endocrinol. 155, 443–452 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Orwoll, E. et al. Testosterone and estradiol among older men. J. Clin. Endocrinol. Metab. 91, 1336–1344 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Wu, F. C. et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N. Engl. J. Med. 363, 123–135 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Wu, F. C. et al. 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. 93, 2737–2745 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Yeap, B. B. et al. Reference ranges and determinants of testosterone, dihydrotestosterone, and estradiol levels measured using liquid chromatography-tandem mass spectrometry in a population-based cohort of older men. J. Clin. Endocrinol. Metab. 97, 4030–4039 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Zmuda, J. M. et al. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants. Am. J. Epidemiol. 146, 609–617 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Tajar, A. et al. Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). J. Clin. Endocrinol. Metab. 97, 1508–1516 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Wang, C. et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J. Androl. 30, 1–9 (2009).

    Article  PubMed  Google Scholar 

  20. Tajar, A. et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J. Clin. Endocrinol. Metab. 95, 1810–1818 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Roy, T. A. et al. Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men. Am. J. Physiol. Endocrinol. Metab. 283, E284–E294 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. van den Beld, A. W., de Jong, F. H., Grobbee, D. E., Pols, H. A. & Lamberts, S. W. 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. 85, 3276–3282 (2000).

    CAS  PubMed  Google Scholar 

  23. Orwoll, E. et al. Endogenous testosterone levels, physical performance, and fall risk in older men. Arch. Intern. Med. 166, 2124–2131 (2006).

    Article  PubMed  Google Scholar 

  24. Travison, T. G., Morley, J. E., Araujo, A. B., O'Donnell, A. B. & McKinlay, J. B. The relationship between libido and testosterone levels in aging men. J. Clin. Endocrinol. Metab. 91, 2509–2513 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Benito, M. et al. Deterioration of trabecular architecture in hypogonadal men. J. Clin. Endocrinol. Metab. 88, 1497–1502 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Benito, M. et al. Effect of testosterone replacement on trabecular architecture in hypogonadal men. J. Bone Miner. Res. 20, 1785–1791 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Cauley, J. A. et al. Sex steroid hormones in older men: longitudinal associations with 4.5-year change in hip bone mineral density--the osteoporotic fractures in men study. J. Clin. Endocrinol. Metab. 95, 4314–4323 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fink, H. A. et al. Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. J. Clin. Endocrinol. Metab. 91, 3908–3915 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Greendale, G. A., Edelstein, S. & Barrett-Connor, E. Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo Study. J. Bone Miner. Res. 12, 1833–1843 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Khosla, S., Melton, L. J. 3rd, Atkinson, E. J. & O'Fallon, W. M. Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J. Clin. Endocrinol. Metab. 86, 3555–3561 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Khosla, S. et al. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J. Clin. Endocrinol. Metab. 83, 2266–2274 (1998).

    CAS  PubMed  Google Scholar 

  32. Khosla, S. et al. Relationship of volumetric BMD and structural parameters at different skeletal sites to sex steroid levels in men. J. Bone Miner. Res. 20, 730–740 (2005).

    Article  PubMed  Google Scholar 

  33. Meier, C. et al. Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study. Arch. Intern. Med. 168, 47–54 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Ferrucci, L. et al. Low testosterone levels and the risk of anemia in older men and women. Arch. Intern. Med. 166, 1380–1388 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Paller, C. J. et al. Association between sex steroid hormones and hematocrit in a nationally representative sample of men. J. Androl. 33, 1332–1341 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cawthon, P. M. et al. Sex hormones and frailty in older men: the osteoporotic fractures in men (MrOS) study. J. Clin. Endocrinol. Metab. 94, 3806–3815 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Krasnoff, J. B. 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. 95, 2790–2799 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Amin, S. et al. Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study. Ann. Intern. Med. 133, 951–963 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Ding, E. L., Song, Y., Malik, V. S. & Liu, S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 295, 1288–1299 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Bhasin, S. et al. Sex hormone-binding globulin, but not testosterone, is associated prospectively and independently with incident metabolic syndrome in men: the Framingham Heart study. Diabetes Care 34, 2464–2470 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Laaksonen, D. E. et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 27, 1036–1041 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Corona, G. et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur. J. Endocrinol. 165, 687–701 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Wu, F. C. & von Eckardstein, A. Androgens and coronary artery disease. Endocr. Rev. 24, 183–217 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Ohlsson, C. et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J. Am. Coll. Cardiol. 58, 1674–1681 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Araujo, A. B. et al. Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 96, 3007–3019 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Markianos, M., Tripodianakis, J., Sarantidis, D. & Hatzimanolis, J. Plasma testosterone and dehydroepiandrosterone sulfate in male and female patients with dysthymic disorder. J. Affect. Disord. 101, 255–258 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Seidman, S. N. et al. Low testosterone levels in elderly men with dysthymic disorder. Am. J. Psychiatry 159, 456–459 (2002).

    Article  PubMed  Google Scholar 

  48. Seidman, S. N., Araujo, A. B., Roose, S. P. & McKinlay, J. B. Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men. Biol. Psychiatry 50, 371–376 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. T'Sjoen, G. G. et al. Sex steroid level, androgen receptor polymorphism, and depressive symptoms in healthy elderly men. J. Am. Geriatr. Soc. 53, 636–642 (2005).

    Article  PubMed  Google Scholar 

  50. Alexander, G. M. et al. Androgen-behavior correlations in hypogonadal men and eugonadal men. I. Mood and response to auditory sexual stimuli. Horm. Behav. 31, 110–119 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Bancroft, J. & Wu, F. C. Changes in erectile responsiveness during androgen replacement therapy. Arch. Sex Behav. 12, 59–66 (1983).

    Article  CAS  PubMed  Google Scholar 

  52. Boloña, E. R. et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin. Proc. 82, 20–28 (2007).

    Article  PubMed  Google Scholar 

  53. Carani, C. et al. The endocrine effects of visual erotic stimuli in normal men. Psychoneuroendocrinology 15, 207–216 (1990).

    Article  CAS  PubMed  Google Scholar 

  54. Hirshkowitz, M., Moore, C. A., O'Connor, S., Bellamy, M. & Cunningham, G. R. Androgen and sleep-related erections. J. Psychosom. Res. 42, 541–546 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Kwan, M., Greenleaf, W. J., Mann, J., Crapo, L. & Davidson, J. M. The nature of androgen action on male sexuality: a combined laboratory-self-report study on hypogonadal men. J. Clin. Endocrinol. Metab. 57, 557–562 (1983).

    Article  CAS  PubMed  Google Scholar 

  56. Steidle, C. et al. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J. Clin. Endocrinol. Metab. 88, 2673–2681 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Wang, C. et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J. Clin. Endocrinol. Metab. 85, 2839–2853 (2000).

    CAS  PubMed  Google Scholar 

  58. Shabsigh, R., Kaufman, J. M., Steidle, C. & Padma-Nathan, H. Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J. Urol. 172, 658–663 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Corona, G. et al. The age-related decline of testosterone is associated with different specific symptoms and signs in patients with sexual dysfunction. Int. J. Androl. 32, 720–728 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Isidori, A. M. et al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin. Endocrinol. (Oxf.) 63, 381–394 (2005).

    Article  CAS  Google Scholar 

  61. Legros, J. J. et al. Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study. Eur. J. Endocrinol. 160, 821–831 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Cavallini, G., Caracciolo, S., Vitali, G., Modenini, F. & Biagiotti, G. Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology 63, 641–646 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Bhasin, S., Enzlin, P., Coviello, A. & Basson, R. Sexual dysfunction in men and women with endocrine disorders. Lancet 369, 597–611 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Korenman, S. G. et al. Secondary hypogonadism in older men: its relation to impotence. J. Clin. Endocrinol. Metab. 71, 963–969 (1990).

    Article  CAS  PubMed  Google Scholar 

  65. Köhler, T. S. et al. Prevalence of androgen deficiency in men with erectile dysfunction. Urology 71, 693–697 (2008).

    Article  PubMed  Google Scholar 

  66. Jain, P., Rademaker, A. W. & McVary, K. T. Testosterone supplementation for erectile dysfunction: results of a meta-analysis. J. Urol. 164, 371–375 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Aversa, A., Isidori, A. M., Spera, G., Lenzi, A. & Fabbri, A. Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. Clin. Endocrinol. (Oxf.) 58, 632–638 (2003).

    Article  CAS  Google Scholar 

  68. Buvat, J. et al. Hypogonadal men nonresponders to the PDE5 inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST study). J. Sex. Med. 8, 284–293 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Kalinchenko, S. Y., Kozlov, G. I., Gontcharov, N. P. & Katsiya, G. V. Oral testosterone undecanoate reverses erectile dysfunction associated with diabetes mellitus in patients failing on sildenafil citrate therapy alone. Aging Male 6, 94–99 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Spitzer, M. et al. Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann. Intern. Med. 157, 681–691 (2012).

    Article  PubMed  Google Scholar 

  71. Schaap, L. A. et al. Low testosterone levels and decline in physical performance and muscle strength in older men: findings from two prospective cohort studies. Clin. Endocrinol. (Oxf.) 68, 42–50 (2008).

    Article  CAS  Google Scholar 

  72. O'Donnell, A. B., Travison, T. G., Harris, S. S., Tenover, J. L. & McKinlay, J. B. Testosterone, dehydroepiandrosterone, and physical performance in older men: results from the Massachusetts Male Aging Study. J. Clin. Endocrinol. Metab. 91, 425–431 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Mauras, N. et al. Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity. J. Clin. Endocrinol. Metab. 83, 1886–1892 (1998).

    CAS  PubMed  Google Scholar 

  74. Bhasin, S. et al. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J. Clin. Endocrinol. Metab. 82, 407–413 (1997).

    CAS  PubMed  Google Scholar 

  75. Brodsky, I. G., Balagopal, P. & Nair, K. S. Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men—a clinical research center study. J. Clin. Endocrinol. Metab. 81, 3469–3475 (1996).

    CAS  PubMed  Google Scholar 

  76. Katznelson, L. et al. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J. Clin. Endocrinol. Metab. 81, 4358–4365 (1996).

    CAS  PubMed  Google Scholar 

  77. Snyder, P. J. et al. Effects of testosterone replacement in hypogonadal men. J. Clin. Endocrinol. Metab. 85, 2670–2677 (2000).

    CAS  PubMed  Google Scholar 

  78. Wang, C. et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J. Clin. Endocrinol. Metab. 89, 2085–2098 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Bhasin, S. et al. Drug insight: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat. Clin. Pract. Endocrinol. Metab. 2, 146–159 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ferrando, A. A. et al. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am. J. Physiol. Endocrinol. Metab. 282, E601–E607 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Kenny, A. M., Prestwood, K. M., Gruman, C. A., Marcello, K. M. & Raisz, L. G. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J. Gerontol. A. Biol. Sci. Med. Sci. 56, M266–M272 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Nair, K. S. et al. DHEA in elderly women and DHEA or testosterone in elderly men. N. Engl. J. Med. 355, 1647–1659 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Page, S. T. 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. 90, 1502–1510 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Sih, R. et al. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J. Clin. Endocrinol. Metab. 82, 1661–1667 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Snyder, P. J. et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J. Clin. Endocrinol. Metab. 84, 2647–2653 (1999).

    CAS  PubMed  Google Scholar 

  86. Tenover, J. S. Effects of testosterone supplementation in the aging male. J. Clin. Endocrinol. Metab. 75, 1092–1098 (1992).

    CAS  PubMed  Google Scholar 

  87. Wittert, G. A. 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. 58, 618–625 (2003).

    Article  PubMed  Google Scholar 

  88. Bhasin, S. et al. Testosterone dose-response relationships in healthy young men. Am. J. Physiol. Endocrinol. Metab. 281, E1172–E1181 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Storer, T. W. et al. Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension. J. Clin. Endocrinol. Metab. 88, 1478–1485 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Travison, T. G. 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. 66, 1090–1099 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Bhasin, S. et al. The mechanisms of androgen effects on body composition: mesenchymal pluripotent cell as the target of androgen action. J. Gerontol. A. Biol. Sci. Med. Sci. 58, M1103–M1110 (2003).

    Article  PubMed  Google Scholar 

  92. Sinha-Hikim, I. et al. Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy. Am. J. Physiol. Endocrinol. Metab. 283, E154–E164 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Sinha-Hikim, I., Cornford, M., Gaytan, H., Lee, M. L. & Bhasin, S. Effects of testosterone supplementation on skeletal muscle fiber hypertrophy and satellite cells in community-dwelling older men. J. Clin. Endocrinol. Metab. 91, 3024–3033 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Sinha-Hikim, I., Roth, S. M., Lee, M. I. & Bhasin, S. Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men. Am. J. Physiol. Endocrinol. Metab. 285, E197–E205 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. 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. 350, 39–52 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Singh, R. et al. Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with β-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors. Endocrinology 147, 141–154 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Singh, R. et al. Regulation of myogenic differentiation by androgens: cross talk between androgen receptor/ β-catenin and follistatin/transforming growth factor-β signaling pathways. Endocrinology 150, 1259–1268 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Woodhouse, L. J. et al. Dose-dependent effects of testosterone on regional adipose tissue distribution in healthy young men. J. Clin. Endocrinol. Metab. 89, 718–726 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Ferrando, A. A., Sheffield-Moore, M., Paddon-Jones, D., Wolfe, R. R. & Urban, R. J. Differential anabolic effects of testosterone and amino acid feeding in older men. J. Clin. Endocrinol. Metab. 88, 358–362 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Sheffield-Moore, M. et al. Short-term oxandrolone administration stimulates net muscle protein synthesis in young men. J. Clin. Endocrinol. Metab. 84, 2705–2711 (1999).

    CAS  PubMed  Google Scholar 

  101. Urban, R. J. et al. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am. J. Physiol. 269, E820–E826 (1995).

    CAS  PubMed  Google Scholar 

  102. Basaria, S. et al. Adverse events associated with testosterone administration. N. Engl. J. Med. 363, 109–122 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kenny, A. M. 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. 58, 1134–1143 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Srinivas-Shankar, U. 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. 95, 639–650 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Fried, L. P. et al. Frailty in older adults: evidence for a phenotype. J. Gerontol. A. Biol. Sci. Med. Sci. 56, M146–M156 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Barrett-Connor, E., Von Mühlen, D. G. & Kritz-Silverstein, D. Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo Study. J. Clin. Endocrinol. Metab. 84, 573–577 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. Pope, H. G. Jr, Cohane, G. H., Kanayama, G., Siegel, A. J. & Hudson, J. I. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am. J. Psychiatry 160, 105–111 (2003).

    Article  PubMed  Google Scholar 

  108. Seidman, S. N. et al. Effects of testosterone replacement in middle-aged men with dysthymia: a randomized, placebo-controlled clinical trial. J. Clin. Psychopharmacol. 29, 216–221 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Seidman, S. N., Spatz, E., Rizzo, C. & Roose, S. P. Testosterone replacement therapy for hypogonadal men with major depressive disorder: a randomized, placebo-controlled clinical trial. J. Clin. Psychiatry 62, 406–412 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Shores, M. M., Kivlahan, D. R., Sadak, T. I., Li, E. J. & Matsumoto, A. M. A randomized, double-blind, placebo-controlled study of testosterone treatment in hypogonadal older men with subthreshold depression (dysthymia or minor depression). J. Clin. Psychiatry 70, 1009–1016 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Wang, C. et al. Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study. J. Clin. Endocrinol. Metab. 81, 3578–3583 (1996).

    CAS  PubMed  Google Scholar 

  112. Pope, H. G. Jr et al. Parallel-group placebo-controlled trial of testosterone gel in men with major depressive disorder displaying an incomplete response to standard antidepressant treatment. J. Clin. Psychopharmacol. 30, 126–134 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Fleurence, R. et al. A systematic review of augmentation strategies for patients with major depressive disorder. Psychopharmacol. Bull. 42, 57–90 (2009).

    PubMed  Google Scholar 

  114. Gray, P. B. et al. Dose-dependent effects of testosterone on sexual function, mood, and visuospatial cognition in older men. J. Clin. Endocrinol. Metab. 90, 3838–3846 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Haren, M. T., Wittert, G. A., Chapman, I. M., Coates, P. & Morley, J. E. Effect of oral testosterone undecanoate on visuospatial cognition, mood and quality of life in elderly men with low-normal gonadal status. Maturitas 50, 124–133 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Vaughan, C., Goldstein, F. C. & Tenover, J. L. Exogenous testosterone alone or with finasteride does not improve measurements of cognition in healthy older men with low serum testosterone. J. Androl. 28, 875–882 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Cherrier, M. M. et al. Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology 64, 2063–2068 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Lu, P. H. et al. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch. Neurol. 63, 177–185 (2006).

    Article  PubMed  Google Scholar 

  119. Maki, P. M. et al. Intramuscular testosterone treatment in elderly men: evidence of memory decline and altered brain function. J. Clin. Endocrinol. Metab. 92, 4107–4114 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Azad, N., Pitale, S., Barnes, W. E. & Friedman, N. Testosterone treatment enhances regional brain perfusion in hypogonadal men. J. Clin. Endocrinol. Metab. 88, 3064–3068 (2003).

    Article  CAS  PubMed  Google Scholar 

  121. Tracz, M. J. et al. Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials. J. Clin. Endocrinol. Metab. 91, 2011–2016 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Aversa, A. et al. Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study. Aging Male 15, 96–102 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. Amory, J. K. et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J. Clin. Endocrinol. Metab. 89, 503–510 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Dhindsa, S. et al. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J. Clin. Endocrinol. Metab. 89, 5462–5468 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Lakshman, K. M., Bhasin, S. & Araujo, A. B. Sex hormone-binding globulin as an independent predictor of incident type 2 diabetes mellitus in men. J. Gerontol. A. Biol. Sci. Med. Sci. 65, 503–509 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Basaria, S., Muller, D. C., Carducci, M. A., Egan, J. & Dobs, A. S. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer 106, 581–588 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Yialamas, M. A. et al. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab. 92, 4254–4259 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Jones, T. H. et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 34, 828–837 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Corona, G. et al. Type 2 diabetes mellitus and testosterone: a meta-analysis study. Int. J. Androl. 34, 528–540 (2011).

    Article  CAS  PubMed  Google Scholar 

  130. Huang, G. et al. Effect of testosterone administration on liver fat in older men with mobility limitation: results from a randomized controlled trial. J. Gerontol. A. Biol. Sci. Med. Sci. http://dx.doi.org/10.1093/gerona/gls259.

  131. Emmelot-Vonk, M. H. et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA 299, 39–52 (2008).

    CAS  PubMed  Google Scholar 

  132. Akamatsu, H., Zouboulis, C. C. & Orfanos, C. E. Control of human sebocyte proliferation in vitro by testosterone and 5-α-dihydrotestosterone is dependent on the localization of the sebaceous glands. J. Invest. Dermatol. 99, 509–511 (1992).

    Article  CAS  PubMed  Google Scholar 

  133. Liang, T. et al. Immunocytochemical localization of androgen receptors in human skin using monoclonal antibodies against the androgen receptor. J. Invest. Dermatol. 100, 663–666 (1993).

    Article  CAS  PubMed  Google Scholar 

  134. Anderson, R. A. & Wu, F. C. Comparison between testosterone enanthate-induced azoospermia and oligozoospermia in a male contraceptive study. II. Pharmacokinetics and pharmacodynamics of once weekly administration of testosterone enanthate. J. Clin. Endocrinol. Metab. 81, 896–901 (1996).

    CAS  PubMed  Google Scholar 

  135. Liu, P. Y. et al. Determinants of the rate and extent of spermatogenic suppression during hormonal male contraception: an integrated analysis. J. Clin. Endocrinol. Metab. 93, 1774–1783 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Coviello, A. D., Lakshman, K., Mazer, N. A. & Bhasin, S. Differences in the apparent metabolic clearance rate of testosterone in young and older men with gonadotropin suppression receiving graded doses of testosterone. J. Clin. Endocrinol. Metab. 91, 4669–4675 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Coviello, A. D. et al. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J. Clin. Endocrinol. Metab. 93, 914–919 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Bachman, E. et al. Testosterone suppresses hepcidin in men: a potential mechanism for testosterone-induced erythrocytosis. J. Clin. Endocrinol. Metab. 95, 4743–4747 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Calof, O. M. 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. 60, 1451–1457 (2005).

    Article  PubMed  Google Scholar 

  140. Fernández-Balsells, M. M. et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 95, 2560–2575 (2010).

    Article  CAS  PubMed  Google Scholar 

  141. Gagnon, D. R., Zhang, T. J., Brand, F. N. & Kannel, W. B. Hematocrit and the risk of cardiovascular disease--the Framingham study: a 34-year follow-up. Am. Heart J. 127, 674–682 (1994).

    Article  CAS  PubMed  Google Scholar 

  142. Strand, A. et al. Increased hematocrit before blood pressure in men who develop hypertension over 20 years. J. Am. Soc. Hypertens. 1, 400–406 (2007).

    Article  PubMed  Google Scholar 

  143. Burch, G. E. & DePasquale, N. P. Hematocrit, viscosity and coronary blood flow. Dis. Chest 48, 225–232 (1965).

    Article  CAS  PubMed  Google Scholar 

  144. Danesh, J., Collins, R., Peto, R. & Lowe, G. D. Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease. Eur. Heart J. 21, 515–520 (2000).

    Article  CAS  PubMed  Google Scholar 

  145. Hagl, S. et al. The effect of hemodilution on regional myocardial function in the presence of coronary stenosis. Basic Res. Cardiol. 72, 344–364 (1977).

    Article  CAS  PubMed  Google Scholar 

  146. Woodward, M., Rumley, A., Tunstall-Pedoe, H. & Lowe, G. D. Does sticky blood predict a sticky end? Associations of blood viscosity, haematocrit and fibrinogen with mortality in the West of Scotland. Br. J. Haematol. 122, 645–650 (2003).

    Article  PubMed  Google Scholar 

  147. Roddam, A. W., Allen, N. E., Appleby, P. & Key, T. J. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J. Natl Cancer Inst. 100, 170–183 (2008).

    Article  CAS  PubMed  Google Scholar 

  148. Bhasin, S. et al. Managing the risks of prostate disease during testosterone replacement therapy in older men: recommendations for a standardized monitoring plan. J. Androl. 24, 299–311 (2003).

    Article  PubMed  Google Scholar 

  149. Gormley, G. J. et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. N. Engl. J. Med. 327, 1185–1191 (1992).

    Article  CAS  PubMed  Google Scholar 

  150. Brand, J. S., van der Tweel, I., Grobbee, D. E., Emmelot-Vonk, M. H. & van der Schouw, Y. T. Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. Int. J. Epidemiol. 40, 189–207 (2010).

    Article  PubMed  Google Scholar 

  151. Seidell, J. C., Björntorp, P., Sjöström, L., Kvist, H. & Sannerstedt, R. Visceral fat accumulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels. Metabolism 39, 897–901 (1990).

    Article  CAS  PubMed  Google Scholar 

  152. Eckardstein, A. & Wu, F. C. Testosterone and atherosclerosis. Growth Horm. IGF Res. 13 (Suppl. A), S72–S84 (2003).

    Article  CAS  PubMed  Google Scholar 

  153. Liu, P. Y., Death, A. K. & Handelsman, D. J. Androgens and cardiovascular disease. Endocr. Rev. 24, 313–340 (2003).

    Article  CAS  PubMed  Google Scholar 

  154. Muller, M., van der Schouw, Y. T., Thijssen, J. H. & Grobbee, D. E. Endogenous sex hormones and cardiovascular disease in men. J. Clin. Endocrinol. Metab. 88, 5076–5086 (2003).

    Article  CAS  PubMed  Google Scholar 

  155. Firtser, S. et al. Relation of total and free testosterone and sex hormone-binding globulin with cardiovascular risk factors in men aged 24–45 years. The Cardiovascular Risk in Young Finns Study. Atherosclerosis 222, 257–262 (2012).

    Article  CAS  PubMed  Google Scholar 

  156. Soisson, V. et al. Low plasma testosterone and elevated carotid intima-media thickness: importance of low-grade inflammation in elderly men. Atherosclerosis 223, 244–249 (2012).

    Article  CAS  PubMed  Google Scholar 

  157. Barrett-Connor, E. & Khaw, K. T. Endogenous sex hormones and cardiovascular disease in men. A prospective population-based study. Circulation 78, 539–545 (1988).

    Article  CAS  PubMed  Google Scholar 

  158. Cauley, J. A., Gutai, J. P., Kuller, L. H. & Dai, W. S. Usefulness of sex steroid hormone levels in predicting coronary artery disease in men. Am. J. Cardiol. 60, 771–777 (1987).

    Article  CAS  PubMed  Google Scholar 

  159. Lovejoy, J. C. et al. Oral anabolic steroid treatment, but not parenteral androgen treatment, decreases abdominal fat in obese, older men. Int. J. Obes. Relat. Metab. Disord. 19, 614–624 (1995).

    CAS  PubMed  Google Scholar 

  160. English, K. M., Steeds, R. P., Jones, T. H., Diver, M. J. & Channer, K. S. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation 102, 1906–1911 (2000).

    Article  CAS  PubMed  Google Scholar 

  161. Hall, J., Jones, R. D., Jones, T. H., Channer, K. S. & Peers, C. Selective inhibition of L-type Ca2+ channels in A7r5 cells by physiological levels of testosterone. Endocrinology 147, 2675–2680 (2006).

    Article  CAS  PubMed  Google Scholar 

  162. Haddad, R. M. et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin. Proc. 82, 29–39 (2007).

    Article  CAS  PubMed  Google Scholar 

  163. Snyder, P. J. et al. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Am. J. Med. 111, 255–260 (2001).

    Article  CAS  PubMed  Google Scholar 

  164. Brockenbrough, A. T. et al. Transdermal androgen therapy to augment EPO in the treatment of anemia of chronic renal disease. Am. J. Kidney Dis. 47, 251–262 (2006).

    Article  CAS  PubMed  Google Scholar 

  165. Sattler, F. R. et al. Testosterone and growth hormone improve body composition and muscle performance in older men. J. Clin. Endocrinol. Metab. 94, 1991–2001 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Shores, M. M., Smith, N. L., Forsberg, C. W., Anawalt, B. D. & Matsumoto, A. M. Testosterone treatment and mortality in men with low testosterone levels. J. Clin. Endocrinol. Metab. 97, 2050–2058 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Sandblom, R. E. et al. Obstructive sleep apnea syndrome induced by testosterone administration. N. Engl. J. Med. 308, 508–510 (1983).

    Article  CAS  PubMed  Google Scholar 

  168. Hoyos, C. M., Killick, R., Yee, B. J., Grunstein, R. R. & Liu, P. Y. Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnoea: a randomized placebo-controlled trial. Clin. Endocrinol. (Oxf.) 77, 599–607 (2012).

    Article  CAS  Google Scholar 

  169. Hoyos, C. M. et al. Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial. Eur. J. Endocrinol. 167, 531–541 (2012).

    Article  CAS  PubMed  Google Scholar 

  170. Emery, M. J., Hlastala, M. P. & Matsumoto, A. M. Depression of hypercapnic ventilatory drive by testosterone in the sleeping infant primate. J. Appl. Physiol. 76, 1786–1793 (1994).

    Article  CAS  PubMed  Google Scholar 

  171. Liu, P. Y. et al. The short-term effects of high-dose testosterone on sleep, breathing, and function in older men. J. Clin. Endocrinol. Metab. 88, 3605–3613 (2003).

    Article  CAS  PubMed  Google Scholar 

  172. Kirbas, G. et al. Obstructive sleep apnoea, cigarette smoking and serum testosterone levels in a male sleep clinic cohort. J. Int. Med. Res. 35, 38–45 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

M. Spitzer, G. Huang, T. G. Travison and S. Bhasin researched the data for the article. All authors provided a substantial contribution to discussions of the content, contributed to writing the article, and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Shalender Bhasin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spitzer, M., Huang, G., Basaria, S. et al. Risks and benefits of testosterone therapy in older men. Nat Rev Endocrinol 9, 414–424 (2013). https://doi.org/10.1038/nrendo.2013.73

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2013.73

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing