Hostname: page-component-76fb5796d-vfjqv Total loading time: 0 Render date: 2024-04-25T17:25:27.840Z Has data issue: false hasContentIssue false
  • English
  • Français

Testosterone: clinical relevance in ageing men

Part of: Bespoke shallow archive Weizmann

Published online by Cambridge University Press:  24 December 2009

Risto Huupponen ,
Ilpo Huhtaniemi  and
Aapo Lehtonen
Risto Huupponen*
Affiliation:
Department of Pharmacology, Drug Development and Therapeutics, University of Turku and Unit of Clinical Pharmacology, Turku University Hospital, Finland
Ilpo Huhtaniemi
Affiliation:
Department of Reproductive Biology, Imperial College of London, UK and Department of Physiology, University of Turku, Finland
Aapo Lehtonen
Affiliation:
Department of Geriatrics, University of Turku, and Turku City Hospital, Finland
*
Address for correspondence: Risto Huupponen, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Itäinen Pitkäkatu 4B, FIN-200014 Turun yliopisto, Finland. E-mail: risto.huupponen@utu.fi
Get access Rights & Permissions [Opens in a new window]

Summary

Testosterone production declines with age in men. The decline is associated with several risk factors and diseases, including obesity and cardiovascular and metabolic diseases, diminished muscular, cognitive and sexual function and changes in body composition. Androgen treatment in elderly men has mostly been addressed in small short-term studies, and larger long-term investigations with sufficient statistical power are still needed for a proper evaluation of the benefit-risk-ratio of testosterone treatment. Current data do not support testosterone supplementation in healthy, asymptomatic older men with normal or low-normal testosterone levels. Treatment may be beneficial in older men with clear hypoandrogenic symptoms, especially reduced libido, erectile dysfunction and decreased muscle strength, if testosterone concentration is consistently low, and the patient selection, counselling and follow-up are adequate.

Keywords

testosteroneagedmortalitymacrovascular diseaseobesitydiabetes mellituscognitive functionfrailtyfractureslate-onset hypogonadism
Type
Clinical geriatrics
Information
Reviews in Clinical Gerontology , Volume 19 , Issue 4 , November 2009 , pp. 249 - 261
Copyright
Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Yeap, BB. Are declining testosterone levels a major risk factor for ill-health in ageing men? Review. Int J Impot Res 2009; 21: 24–36.CrossRefGoogle Scholar
2Jones, TH. Late onset hypogonadism (editorial). BMJ 2009; 338: b352.CrossRefGoogle Scholar
3Nieschlag, E, Behre, HM (eds) (2004). Testosterone: Action, Deficiency Substitution, 3rd edn.Cambridge: Cambridge University Press, 2004: 747 pp.Google Scholar
4Azhar, S, Reaven, E. Regulation of Leydig cell cholesterol metabolism. In Payne, AH, Hardy, MP (eds). The Leydig Cell in Health and Disease. Tonowa: Humana Press, 2007; 135–48.CrossRefGoogle Scholar
5Clark, BJ, Stocco, DM. StAR – A tissue specific acute mediator of steroidogenesis. Trends Endocrinol Metab 1996; 7: 227–33.CrossRefGoogle Scholar
6Papadopoulos, V, Liu, J, Culty, M. Is there a mitochondrial signaling complex facilitating cholesterol import? Mol Cell Endocrinol 2007; 265–266: 59–64.CrossRefGoogle Scholar
7Payne, AH, Hales, DB. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Rev 2004; 25: 947–70.CrossRefGoogle ScholarPubMed
8Spratt, DI, O'Dea, LStL, Schoenfeld, D, Butler, J, Rao, PN, Crowley, WF Jr.Neuroendocrine–gonadal axis in men: frequent sampling of LH, FSH, and testosterone. Am J Physiol 1988; 254: E658–66.Google ScholarPubMed
9Martikainen, H, Huhtaniemi, I, Vihko, R. Response of peripheral serum sex steroids and some of their precursors to a single injection of hCG in adult men. Clin Endocrinol 1980; 13: 157–66.CrossRefGoogle ScholarPubMed
10Bhasin, S. Disorders of the testis and the male reproductive tract. In Kronenberg, H, Melmed, S, Polonski, K, Wilson, JD, Larsen, PR (eds). Williams Textbook of Endocrinology, 11th edn.Philadelphia: WB Saunders, 2007; 645–700.Google Scholar
11Heemers, HV, Tindall, DJ. Androgen receptor (AR) coregulators: A diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev 2007; 28: 778–808.CrossRefGoogle ScholarPubMed
12Rosner, W, Auchus, RJ, Azziz, R, Sluss, PM, Raff, H. Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab 2007; 92: 405–13.CrossRefGoogle ScholarPubMed
13Vermeulen, A, Verdonck, L, Kaufman, JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999; 84: 3666–72.CrossRefGoogle ScholarPubMed
14Wu, FC, Tajar, A, Pye, SR et al. Hypothalamic–pituitary–testicular axis disruptions in older men are differentially linked to age and modifiable risk factors. J Clin Endocrinol Metab 2008; 93: 2737–45.CrossRefGoogle ScholarPubMed
15Kaufman, JM, Vermeulen, A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005; 26: 833–76.CrossRefGoogle ScholarPubMed
16Perheentupa, A, Huhtaniemi, I. Ageing of the human ovary and testis. Mol Cell Endocrinol 2009; 299: 2–13.CrossRefGoogle ScholarPubMed
17Travison, TG, Araujo, AB, Hall, SA, McKinlay, JB. Temporal trends in testosterone levels and treatment in older men. Curr Opin Endocrinol Diab Obes 2009; 16: 211–17.CrossRefGoogle ScholarPubMed
18Feldman, HA, Longcope, C, Derby, CA et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male ageing study. J Clin Endocrinol Metab 2002; 87: 589–98.CrossRefGoogle Scholar
19Laaksonen, DE, Niskanen, L, Punnonen, K et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004; 27: 1036–41.CrossRefGoogle ScholarPubMed
20Dobs, AS, Schrott, H, Davidson, MH et al. Effects of high-dose simvastatin on adrenal and gonadal steroidogenesis in men with hypercholesterolemia. Metabolism 2000; 49: 1234–38.CrossRefGoogle ScholarPubMed
21Hyyppä, MT, Kronholm, E, Virtanen, A, Leino, A, Jula, A. Does simvastatin affect mood and steroid hormone levels in hypercholesterolemic men? A randomomized double-blind trial. Psychoneuroendocrinology 2003; 28: 181–94.CrossRefGoogle Scholar
22Hall, SA, Page, ST, Travison, TG, Montgomery, RB, Link, CL, McKinlay, JB. Do statins affect androgen levels in men? Results from the Boston area community health survey. Cancer Epidemiol Biomarkers Prev 2007; 16: 1587–94.CrossRefGoogle ScholarPubMed
23Lehtonen, A, Huupponen, R, Tuomilehto, J et al. Serum testosterone but not leptin predicts mortality in elderly men. Age Ageing 2008; 37: 461–4.CrossRefGoogle Scholar
24Laughlin, GA, Barrett-Connor, E, Bergstrom, J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008; 93: 68–75.CrossRefGoogle ScholarPubMed
25Khaw, K-T, Dowsett, M, Folkerd, E et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease and cancer in men. European prospective investigation into cancer in Norfolk (EPIC-Norfolk) prospective population study. Circulation 2007; 116: 2694–701.CrossRefGoogle ScholarPubMed
26Maggio, M, Lauretani, F, Ceda, GP et al. Relationship between low levels of anabolic hormones and 6-year mortality in older men. Arch Intern Med 2007; 167: 2249–54.CrossRefGoogle ScholarPubMed
27Shores, MM, Matsumoto, AM, Sloan, KL, Kivlahan, DR. Low serum testosterone and mortality in male veterans. Arch Intern Med 2006; 166: 1660–5.CrossRefGoogle ScholarPubMed
28Shores, MM, Moceri, VM, Gruenewald, DA, Brodkin, KI, Matsumoto, AM, Kivlahan, DR. Low testosterone is associated with decreased function and increased mortality risk: a preliminary study of men in a geriatric rehabilitation unit. J Am Geriatr Soc 2004; 52: 2077–81.CrossRefGoogle Scholar
29Smith, GD, Ben-Shlomo, Y, Beswick, A, Yarnell, J, Lightman, S, Elwood, P. Cortisol, testosterone, and coronary heart disease: prospective evidence from the Caerphilly study. Circulation 2005; 112: 332–40.CrossRefGoogle ScholarPubMed
30Araujo, AB, Kupelian, V, Page, ST, Handelsman, DJ, Bremner, WJ, McKinley, JB. Sex steroids and all-cause and cause-specific mortality in men. Arch Intern Med 2007; 167: 1252–60.CrossRefGoogle ScholarPubMed
31Liu, Py, Death, AK, Handelsman, DJ. Androgens and cardiovascular disease. Endocr Rev 2003; 24: 313–40.CrossRefGoogle ScholarPubMed
32Wu, FC, von Eckardstein, A. Androgens and coronary artery disease. Endocr Rev 2003; 24: 183–217.CrossRefGoogle ScholarPubMed
33Phillips, GB. Is atherosclerotic cardiovascular disease an endocrinological disorder? The estrogen-androgen paradox. J Clin Endocrinol Metab 2005; 90: 2708–11.CrossRefGoogle ScholarPubMed
34Muller, M, van der Schouw, YT, Thijssen, JH, Grobbee, DF. Endogenous sex hormones and cardiovascular disease in men. J Clin Endocrinol Metab 2003; 88: 5076–86.CrossRefGoogle ScholarPubMed
35Mendelsohn, ME, Karas, RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340: 1801–11.CrossRefGoogle ScholarPubMed
36Yarnell, JW, Beswick, AD, Sweetnam, PM, Riad-Fahmy, D. Endogenous sex hormones and ischemic heart disease in men. The Caerphilly prospective study. Arterioscler Thromb Vasc Biol 1993; 13: 517–20.CrossRefGoogle ScholarPubMed
37Barrett-Connor, E, Khaw, KT. Endogenous sex hormones and cardiovascular disease in men. A prospective population-based study. Circulation 1988; 78: 539–45.CrossRefGoogle Scholar
38Harman, SM, Metter, EJ, Tobin, JD, Pearson, J, Blackman, MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001; 86: 724–31.CrossRefGoogle ScholarPubMed
39Hak, AE, Witteman, JC, de Jong, FH, Geerlings, MI, Hofman, A, Pols, HA. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab 2002; 87: 3632–39.CrossRefGoogle ScholarPubMed
40Muller, M, van den Beld, AW, Bots, ML, Grobbee, DE, Lamberts, SW, Van Der Schouw, YT. Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation 2004; 109: 2074–79.CrossRefGoogle ScholarPubMed
41Mäkinen, J, Järvisalo, MJ, Pöllänen, P et al. Increased carotid atherosclerosis in andropausal middle-aged men. J Am Coll Cardiol 2005; 45: 1603–8.CrossRefGoogle ScholarPubMed
42Phillips, GB, Pinkernell, BH, Jing, TY. The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 1994; 14: 701–6.CrossRefGoogle ScholarPubMed
43Price, JF, Lee, AJ, Foekes, FG. Steroid sex hormones and peripheral arterial disease in the Edinburgh Artery Study. Steroids 1997; 62: 789–94.CrossRefGoogle ScholarPubMed
44Phillips, GB, Yano, K, Stemmermann, GN. Serum sex hormone levels and myocardial infarction in the Honolulu Heart Program. Pitfalls in prospective studies on sex hormones. J Clin Epidemiol 1988; 41: 1151–6.CrossRefGoogle ScholarPubMed
45Contoreggi, CS, Blackman, MR, Andres, R et al. Plasma levels of estradiol, testosterone, and DHEAS do not predict risk of coronary artery disease in men. J Androl 1990; 11: 460–70.CrossRefGoogle Scholar
46Hautanen, A, Mänttäri, M, Manninen, V et al. Adrenal androgens and testosterone as coronary risk factors in the Helsinki Heart Study. Atherosclerosis 1994; 105: 191–200.CrossRefGoogle ScholarPubMed
47Ärnlöv, J, Pencina, MJ, Amin, S et al. Endogenous sex hormones and cardiovascular disease incidence in men. Ann Intern Med 2006; 145: 176–84.CrossRefGoogle ScholarPubMed
48Yeap, BB, Hyde, Z, Almeida, OP et al. Lower testosterone levels predict incident stroke and transient ischemic attack in older men. J Clin Endocrinol Metab 2009; 94: 2353–9.CrossRefGoogle ScholarPubMed
49Hougaku, H, Fleg, JL, Najjar, SS et al. Relationship between androgenic hormones and arterial stiffness, based on longitudinal hormone measurements. Am J Physiol Endocrinol Metab 2006; 290: 234–42.CrossRefGoogle ScholarPubMed
50Snyder, PJ, Peachey, H, Hannoush, P et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 1999; 84: 1966–72.Google Scholar
51Snyder, PJ, Peachey, H, Berlin, JA et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab 2000; 85: 2670–7.Google ScholarPubMed
52Sih, 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: 1661–7.CrossRefGoogle Scholar
53Snyder, PJ, Peachey, H, Berlin, JA et al. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Am J Med 2001; 111: 255–60.CrossRefGoogle ScholarPubMed
54Cherrier, MM, Asthana, S, Plymate, S et al. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology 2001; 57: 80–8.CrossRefGoogle ScholarPubMed
55Moffat, SD, Zonderman, AB, Metter, EJ, Blackman, MR, Harman, SM, Resnick, SM. Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab 2002; 87: 5001–7.CrossRefGoogle ScholarPubMed
56Rhoden, EL, Morgentaler, A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004; 350: 482–92.CrossRefGoogle ScholarPubMed
57English, KM, Steeds, RP, Jones, TH, Diver, MJ, Channer, KS. Low-dose testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation 2000; 102: 1906–11.CrossRefGoogle ScholarPubMed
58Webb, CM, Adamson, DL, de Zeigler, D, Collins, P. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am J Cardiol 1999; 83: 437–39.CrossRefGoogle ScholarPubMed
59Webb, CM, McNeill, JG, Hayward, CS, de Zeigler, D, Collins, P. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation 1999; 100: 1690–96.CrossRefGoogle ScholarPubMed
60Rosano, GMC, Leonardo, F, Pagnotta, P et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 1999; 99: 1666–70.CrossRefGoogle ScholarPubMed
61Jaffe, MD. Effect of testosterone cypionate on postexercise ST segment depression. Br Heart J 1977; 39: 1217–22.CrossRefGoogle ScholarPubMed
62Hajjar, RR, Kaiser, FE, Morley, JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab 1997; 82: 3793–6.CrossRefGoogle ScholarPubMed
63Nair, KS, Rizza, RA, O'Brien, P et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006; 355: 1647–59.CrossRefGoogle ScholarPubMed
64Reaven, GM. Banting Lecture 1988: role of insulin resistance in human disease. Diabetes 1988; 37: 1595–607.CrossRefGoogle ScholarPubMed
65Alberti, KG, Zimmet, P, Shaw, J, for the IDF Epidemiology Task Force Consensus Group. The metabolic syndrome – a new worldwide definition. Lancet 2005; 366: 1059–62.CrossRefGoogle ScholarPubMed
66Gould, DC, Kirby, RS, Amoroso, P. Hypoandrogen-metabolic syndrome: a potentially common and underdiagnosed condition in men. Int J Clin Practice 2007; 61: 341–44.CrossRefGoogle ScholarPubMed
67Hofstra, J, Loves, S, van Wageningen, B, Ruinemans-Koerts, J, Jansse, I, de Boer, H. High prevalence of hypogonadotropic hypogonadism in men referred for obesity treatment. Netherlands J Med 2008; 66: 103–9.Google ScholarPubMed
68Fukui, M, Soh, J, Tanaka, M, Kitagawa, Y, Hasegawa, G, Yoshikawa, T, Miki, T, Nakamura, N. Low serum testosterone concentration in middle-aged men with type 2 diabetes. Endocr J 2007; 6: 871–7.CrossRefGoogle Scholar
69Pitteloud, N, Mootha, VK, Dwyer, AA et al. Relationship between testosterone levels, insulin sensitivity and mitochondrial function in men. Diabetes Care 2005; 28: 1636–42.CrossRefGoogle ScholarPubMed
70Yialamas, MA, Dwyer, AA, Hanley, E, Lee, H, Pitteloud, N, Hayes, FJ. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2007; 92: 4254–59.CrossRefGoogle ScholarPubMed
71Kupelian, V, Page, ST, Araujo, AB, Travison, TG, Bremner, WJ, McKinlay, JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endicrinol Metab 2006; 91: 843–50.CrossRefGoogle ScholarPubMed
72Laaksonen, DE, Niskanen, L, Punnonen, K, Nyyssönen, K, Tuomainen, T-P, Valkonen, V-P, Salonen, JT. The metabolic syndrome and smoking in relation to hypogonadism in middle-aged men: a prospective cohort study. J Clin Endocrinol Metab 2005; 90: 712–19.CrossRefGoogle ScholarPubMed
73Hakimian, P, Blute, M Jr, Kashanian, J, Chan, S, Silver, D, Shabsigh, R. Metabolic and cardiovascular effects of androgen deprivation therapy. BJU Int 2008; 102: 1509–14.CrossRefGoogle ScholarPubMed
74Allan, CA, Strauss, BJG, Burger, HG, Forbes, EA, McLachlan, RI. Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men. J Clin Endocrinol Metab 2008; 93: 139–46.CrossRefGoogle ScholarPubMed
75Kapoor, D, Goodwin, E, Channer, KS, Jones, TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006; 154: 899–906.CrossRefGoogle ScholarPubMed
76Cohen, PG. The hypogonadal-obesity cycle: role of aromatase in modulating the testosterone-estradiol shunt – a major factor in the genesis of morbid obesity. Med Hypotheses 1999; 52: 49–51.CrossRefGoogle Scholar
77Kapoor, D, Jones, TH. Androgen deficiency as a predictor of metabolic syndrome in aging men. An opportunity for intervention? Drugs Aging 2008; 25: 357–69.CrossRefGoogle ScholarPubMed
78Pitteloud, N, Hardin, M, Dwyer, AA et al. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab 2005; 90: 2636–41.CrossRefGoogle ScholarPubMed
79Bhasin, S, Tenover, JS. Age-associated sarcopenia – issues in the use of testosterone as an anabolic agent in older men. J Clin Endocrinol Metab 1997; 82: 1659–60.Google ScholarPubMed
80Morley, JE, Baumgartner, RN, Roubenoff, R, Mayer, J, Nair, KS. Sarcopenia. J Lab Clin Med 2001; 137: 231–43.CrossRefGoogle ScholarPubMed
81Baumgartner, 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.CrossRefGoogle ScholarPubMed
82Roy, TA, Blackman, MR, Harman, SM, Tobin, JD, Schrager, M, Metter, EJ. Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men. Am J Physiol Endocrinol Metab 2002; 283: E284–94.CrossRefGoogle ScholarPubMed
83Knutzen, KM, Brilla, L, Caine, D, Chalmers, G, Gunter, K, Schot, P. Absolute vs. relative machine strength as predictors of function in older adults. J Strength Cond Res 2002; 16: 628–40.Google ScholarPubMed
84Breuer, B, Trungold, S, Martucci, C et al. Relationships of sex hormone levels to dependence in activities of daily living in the frail elderly. Maturitas 2001; 39: 147–59.CrossRefGoogle ScholarPubMed
85Morley, JE, Kaiser, FE, Sih, R, Hajjar, R, Perry, HM 3rd. Testosterone and frailty. Clin Geriatr Med 1997; 13: 685–95.CrossRefGoogle ScholarPubMed
86Dong, Q, Hawker, F, McWilliam, D, Bangah, M, Burger, H, Handelsman, DJ. Circulating immunoreactive inhibin and testosterone levels in men with critical illness. Clin Endocrinol 1992; 36: 399–404.CrossRefGoogle ScholarPubMed
87Schaap, LA, Pluijm, SM, Smit, JH 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 2005; 63: 152–60.CrossRefGoogle ScholarPubMed
88Orwoll, E, Lambert, LC, Marshall, LM et al. Endogenous testosterone levels, physical performance, and fall risk in older men. Arch Intern Med 2006; 166: 2124–31.CrossRefGoogle ScholarPubMed
89Mohr, BA, Bhasin, S, Kupelian, V, Araujo, AB, O'Donnell, AB, McKinlay, JB. Testosterone, sex hormone-binding globulin, and frailty in older men. J Am Geriatr Soc 2007; 55: 548–55.CrossRefGoogle ScholarPubMed
90Urban, RJ, Bodenburg, YH, Gilkison, C et al. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol 1995; 269: E820–6.Google ScholarPubMed
91Ferrando, AA, Sheffield-Moore, M, Yeckel, CW et al. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am J Physiol Endocrinol Metab 2002; 282: E601–7.CrossRefGoogle ScholarPubMed
92Bhasin, S, Woodhouse, L, Casaburi, R et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 2005; 90: 678–88.CrossRefGoogle Scholar
93Snyder, PJ, Peachey, H, Hannoush, P et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 1999; 84: 2647–53.Google ScholarPubMed
94Araujo, AB, Travison, TG, Bhasin, S 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.CrossRefGoogle Scholar
95Chu, LW, Tam, S, Kung, AW et al. Serum total and bioavailable testosterone levels, central obesity, and muscle strength changes with aging in healthy Chinese men. J Am Geriatr Soc 2008; 56: 1286–91.CrossRefGoogle ScholarPubMed
96Bhasin, S, Storer, TW, Berman, N 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.CrossRefGoogle ScholarPubMed
97Storer, TW, Magliano, L, Woodhouse, L et al. Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension. J Clin Endocrinol Metab 2003; 88: 1478–85.CrossRefGoogle ScholarPubMed
98Brill, KT, Weltman, AL, Gentili, A 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.CrossRefGoogle ScholarPubMed
99Page, ST, Amory, JK, Bowman, FD et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 2005; 90: 1502–10.CrossRefGoogle ScholarPubMed
100Clague, 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.CrossRefGoogle ScholarPubMed
101Storer, TW, Woodhouse, L, Magliano, L et al. Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men. J Am Geriatr Soc 2008; 56: 1991–99.CrossRefGoogle Scholar
102Ottenbacher, KJ, Ottenbacher, ME, Ottenbacher, AJ, Acha, AA, Ostir, GV. Androgen treatment and muscle strength in elderly men: A meta-analysis. J Am Geriatr Soc 2006; 54: 1666–73.CrossRefGoogle ScholarPubMed
103Ebeling, PR. Osteoporosis in men. N Engl J Med 2009; 258: 1474–82.Google Scholar
104Clarke, BL, Khosla, S. Androgens and bone. Steroids 2009; 74: 296–305.CrossRefGoogle ScholarPubMed
105Vandenput, L, Ohlsson, C. Estrogens as regulators of bone health in men. Nat Rev Endocrinol 2009; 5: 437–43.CrossRefGoogle ScholarPubMed
106Paller, CJ, Shiels, MS, Rohrmann, S et al. Relationship of sex steroid hormones with bone mineral density (BMD) in a nationally representative sample of men. Clin Endocrinol 2009; 70: 26–34.CrossRefGoogle Scholar
107Travison, TG, Araujo, AB, Beck, TJ et al. Relation between serum testosterone, serum estradiol, sex hormone-binding globulin and geometrical measures of adult male proximal femur strength. J Clin Endocrinol Metab 2009; 94: 853–60.CrossRefGoogle ScholarPubMed
108LeBlanc, ES, Nielson, CM, Marshall, LM et al. The effects of serum testosterone, estradiol and sex hormone binding globulin levels on fracture risk in older men. J Clin Endocrinol Metab 2009; 94: 3337–46.CrossRefGoogle ScholarPubMed
109Mellström, D, Vandenput, L, Mallmin, H et al. Older men with low serum estradiol and high serum SHBG have an increased risk of fractures. J Bone Miner Res 2008; 23: 1552–60.CrossRefGoogle ScholarPubMed
110Jankowsky, CM, Gozansky, WS, Kittelson, JM, Van Pelt, RE, Schwartz, RS, Kohrt, WM. Increases in bone mineral density in response to oral dehydroepiandrosterone replacement in older adults appear to be mediated by serum estrogens. J Clin Endocrinol Metab 2008; 93: 4767–73.CrossRefGoogle Scholar
111Weiss, EP, Shah, K, Fontana, L, Lambert, CP, Holloszy, JO, Villareal, DT. Dehydroepiandrosterone replacement therapy in older adults: 1- and 2-year effects on bone. Am J Clin Nutr 2009; 89: 1459–67.CrossRefGoogle Scholar
112Basurto, L, Zarate, A, Gomez, R, Vargas, C, Saucedo, R, Galvan, R. Effect of testosterone therapy on lumbar spine and hip mineral density in elderly men. Aging Male 2008; 11: 140–45.CrossRefGoogle Scholar
113Tracz, MJ, Sideras, K, Bolona, ER et al. Clinical review: 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 2006; 91: 2011–16.CrossRefGoogle Scholar
114Simerly, RB, Chang, C, Muramatsu, M, Swanson, LW. Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. J Comp Neurol 1990; 294: 76–95.CrossRefGoogle Scholar
115Lamberts, SW, Van Den Beld, AW, Van Der Lely, AJ. The endocrinology of aging. Science 1997; 278: 419–24.CrossRefGoogle ScholarPubMed
116Hogervorst, E, Lehmann, DJ, Warden, DR, McBroom, J, Smith, AD. Apolipoprotein E ϵ4 and testosterone interact in the risk of Alzheimer's disease in men. Int J Geriatr Psychiatry 2002; 17: 938–40.CrossRefGoogle Scholar
117Barrett-Connor, E, Goodman-Gruen, D, Patay, B. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab 1999; 84: 3681–5.Google ScholarPubMed
118Yaffe, K, Lui, Ly, Zmuda, J, Cauley, J. Sex hormones and cognitive function in older men. J Am Geriatr Soc 2002; 50: 707–12.CrossRefGoogle ScholarPubMed
119Moffat, SD, Zonderman, AB, Metter, EJ et al. Free testosterone and risk for Alzheimer disease in older men. Neurology 2004; 62: 188–93.CrossRefGoogle ScholarPubMed
120Muller, M, Aleman, A, Grobbee, DE, de Haan, EH, van der Schouw, YT. Endogenous sex hormone levels and cognitive function in aging men: is there an optimal level? Neurology 2005; 64: 866–71.CrossRefGoogle ScholarPubMed
121Gandy, S, Almeida, OP, Fonte, J et al. Chemical andropause and amyloid-beta peptide. JAMA 2001; 285: 2195–96.CrossRefGoogle ScholarPubMed
122Hammond, J, Le, Q, Goodyer, C, Gelfand, M, Trifiro, M, LeBlanc, A. Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons. J Neurochem 2001; 77: 1319–26.CrossRefGoogle ScholarPubMed
123Moffat, SD, Hampson, E. A curvilinear relationship between testosterone and spatial cognition in humans: possible influence of hand preference. Psychoneuroendocrinology 1996; 21: 323–37.CrossRefGoogle ScholarPubMed
124Emmelot-Vonk, MH, Verhaar, HJ, Nakhai Pour, HR 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.CrossRefGoogle ScholarPubMed
125Janowsky, JS, Oviatt, SK, Orwoll, ES. Testosterone influences spatial cognition in older men. Behav Neurosci 1994; 108: 325–32.CrossRefGoogle ScholarPubMed
126Haren, MT, Wittert, GA, Chapman, IM, Coates, P, Morley, JE. Effect of oral testosterone undecanoate on visuospatial cognition, mood and quality of life in elderly men with low-normal gonadal status. Maturitas 2005; 50: 124–33.CrossRefGoogle ScholarPubMed
127Cherrier, MM, Matsumoto, AM, Amory, JK et al. Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology 2005; 64: 2063–8.CrossRefGoogle ScholarPubMed
128Kenny, AM, Fabregas, G, Song, C, Biskup, B, Bellantonio, S. Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss. J Gerontol A Biol Sci Med Sci 2004; 59: 75–8.CrossRefGoogle ScholarPubMed
129Lu, PH, Masterman, DA, Mulnard, R et al. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol 2006; 63: 177–85.CrossRefGoogle ScholarPubMed
130Camacho, ME, Reyes-Ortiz, CA. Sexual dysfunction in the elderly: age or disease? Int J Impot Res 2005; 17: S52–56.CrossRefGoogle ScholarPubMed
131Travison, TG, Morley, JE, Araujo, AB, O'Donnel, AB, McKinlay, JB. The relationship between libido and testosterone levels in ageing men. J Clin Endocrinol Metab 2006; 91: 2509–13.CrossRefGoogle Scholar
132Rosen, RC. Reproductive health problems in ageing men. Lancet 2005; 366: 183–85.CrossRefGoogle ScholarPubMed
133Shiri, R, Koskimäki, J, Hakama, M et al. Prevalence and severity of erectile dysfunction in 50- to 75-year-old Finnish men. J Urol 2003; 170: 2342–44.CrossRefGoogle ScholarPubMed
134Halden, CA, McLachlan, RI, Pitts, M et al. Men in Australia telephone Survey (MATeS): a national survey of the reproductive health and concerns of middle-aged and older Australian men. Lancet 2005; 366: 218–24.CrossRefGoogle Scholar
135O'Connor, DB, Corona, G, Forti, G et al. Assessment of sexual health in ageing men in Europe: development and validation of the European Male Ageing Study Sexual Functioning Questionnaire. J Sex Med 2008; 5: 1374–85.CrossRefGoogle Scholar
136Isidori, AM, Giannetta, E, Gianfrilli, D et al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol 2005; 63: 381–94.CrossRefGoogle ScholarPubMed
137Wang, C, Nieschlag, E, Swerdloff, E et al. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. J Androl 2009; 30: 1–9.CrossRefGoogle ScholarPubMed