Androgens and male aging: Current evidence of safety and efficacy

Asian Journal of Andrology

Volumn 12, Issue 2, 2010, Pages 136-151

  Gooren, Louis J ^a,b  

^a VU UNIVERSITY AMSTERDAM   (Netherlands)

^b NONE   (Thailand)

Author keywords

Aging; Bone mineral density; Metabolic syndrome; Polycythemia; Prostate disease; Sexual dysfunction; Sleep apnea; Testosterone

Indexed keywords

ANASTROZOLE; ANDROGEN; ANTIDEPRESSANT AGENT; PHOSPHODIESTERASE V INHIBITOR; PLACEBO; TESTOSTERONE;

AGING; ALZHEIMER DISEASE; ANDROGEN DEFICIENCY; BLOOD ANALYSIS; BONE DENSITY; CARDIOVASCULAR DISEASE; CLINICAL TRIAL; DISEASE ASSOCIATION; DISEASE COURSE; DOSE RESPONSE; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; DRUG SAFETY; ERECTILE DYSFUNCTION; HIGH RISK POPULATION; HUMAN; HYPOGONADISM; LOWER URINARY TRACT SYMPTOM; MAJOR DEPRESSION; MALE; MALE SEXUAL DYSFUNCTION; MASS SPECTROMETRY; MEMORY DISORDER; MEN'S HEALTH; METABOLIC SYNDROME X; MILD COGNITIVE IMPAIRMENT; MOOD CHANGE; MUSCLE MASS; MUSCLE STRENGTH; NON INSULIN DEPENDENT DIABETES MELLITUS; OBESITY; PATIENT MONITORING; POLYCYTHEMIA; PROSTATE CANCER; PROSTATE DISEASE; REVIEW; SEXUAL DYSFUNCTION; SLEEP APNEA SYNDROME; TESTOSTERONE BLOOD LEVEL; URINE RETENTION;

AGED; AGING; HUMANS; HYPOGONADISM; MALE; TESTOSTERONE;

EID: 77749283792     PISSN: 1008682X     EISSN: 17457262     Source Type: Journal    
DOI: 10.1038/aja.2010.4     Document Type: Review

References (178)

1. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005; 26: 833-76.
2. Araujo AB, O'Donnell AB, Brambilla DJ, Simpson WB, Longcope C, et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2004; 89: 5920-6.
3. Liu PY, Beilin J, Meier C, Nguyen TV, Center JR, et al. Age-related changes in serum testosterone and sex hormone binding globulin in Australian men: longitudinal analyses of two geographically separate regional cohorts. J Clin Endocrinol Metab 2007; 92: 3599-603.
4. Yassin AA, Saad F, Gooren LJ. Metabolic syndrome, testosterone deficiency and erectile dysfunction never come alone. Andrologia 2008; 40: 259-64.
5. Tenover JL. Testosterone replacement therapy in older adult men. Int J Androl 1999; 22: 300-6.
6. Traish AM, Saad F, Guay A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl 2009; 30: 23-32.
7. Traish AM, Feeley RJ, Guay A. Mechanisms of obesity and related pathologies: androgen deficiency and endothelial dysfunction may be the link between obesity and erectile dysfunction. Febs J 2009; 276: 5755-67.
8. Saad F, Gooren L. The role of testosterone in the metabolic syndrome: a review. J Steroid Biochem Mol Biol 2009; 114: 40-3.
9. Traish AM, Goldstein I, Kim NN. Testosterone and erectile function: from basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction. Eur Urol 2007; 52: 54-70.
10. McVary K. Lower urinary tract symptoms and sexual dysfunction: epidemiology and pathophysiology. BJU Int 2006; 97 Suppl 2: 23-8; discussion 44-5.
11. Haider A, Gooren LJ, Padungtod P, Saad F. Concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of plasma testosterone levels in hypogonadal elderly men. Andrologia 2009; 41: 7-13.
12. Handelsman DJ, Liu PY. Andropause: invention, prevention, rejuvenation. Trends Endocrinol Metab 2005; 16: 39-45.
13. Kelleher S, Conway AJ, Handelsman DJ. Blood testosterone threshold for androgen deficiency symptoms. J Clin Endocrinol Metab 2004; 89: 3813-7.
14. Zitzmann M, Nieschlag E. The CAG repeat polymorphism within the androgen receptor gene and maleness. Int J Androl 2003; 26: 76-83.
15. Zitzmann M. Mechanisms of disease: pharmacogenetics of testosterone therapy in hypogonadal men. Nat Clin Pract Urol 2007; 4: 161-6.
16. Mohr BA, Guay AT, O'Donnell AB, McKinlay JB. Normal, bound and nonbound testosterone levels in normally ageing men: results from the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf) 2005; 62: 64-73.
17. Wu FC, Tajar A, Pye SR, Silman AJ, Finn JD, 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 2008; 93: 2737-45.
18. Gooren LJ. Androgen levels and sex functions in testosterone-treated hypogonadal men. Arch Sex Behav 1987; 16: 463-73.
19. Bagatell CJ, Heiman JR, Rivier JE, Bremner WJ. Effects of endogenous testosterone and estradiol on sexual behavior in normal young men. J Clin Endocrinol Metab 1994; 78: 711-6.
20. Woodhouse LJ, Reisz-Porszasz S, Javanbakht M, Storer TW, Lee M, et al. Development of models to predict anabolic response to testosterone administration in healthy young men. Am J Physiol Endocrinol Metab 2003; 284: E1009-17.
21. Saad F, Gooren LJ, Haider A, Yassin A. A dose-response study of testosterone on sexual dysfunction and features of the metabolic syndrome using testosterone gel and parenteral testosterone undecanoate. J Androl 2008; 29: 102-5.
22. Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab 2006; 91: 4335-43.
23. Bancroft J. The endocrinology of sexual arousal. J Endocrinol 2005; 186: 411-27.
24. Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A. Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. Clin Endocrinol (Oxf) 2003; 58: 632-8.
25. O'Donnell AB, Araujo AB, McKinlay JB. The health of normally aging men: The Massachusetts Male Aging Study (1987-2004). Exp Gerontol 2004; 39: 975-84.
26. Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. ISA, ISSAM, and EAU recommendations. Eur Urol 2005; 48: 1-4.
27. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, 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 2002; 87: 589-98.
28. Nieschlag E, Behre HM, Bouchard P, Corrales JJ, Jones TH, et al. Testosterone replacement therapy: current trends and future directions. Hum Reprod Update 2004; 10: 409-19.
29. Kshirsagar A, Seftel A, Ross L, Mohamed M, Niederberger C. Predicting hypogonadism in men based upon age, presence of erectile dysfunction, and depression. Int J Impot Res 2006; 18: 47-51.
30. Black AM, Day AG, Morales A. The reliability of clinical and biochemical assessment in symptomatic late-onset hypogonadism: can a case be made for a 3-month therapeutic trial? BJU Int 2004; 94: 1066-70.
31. Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA Recommendations. Eur Urol 2009; 55: 121-30.
32. Reyes-Vallejo L, Lazarou S, Morgentaler A. Subjective sexual response to testosterone replacement therapy based on initial serum levels of total testosterone. J Sex Med 2007; 4: 1757-62.
33. Sartorius G, Ly LP, Sikaris K, McLachlan R, Handelsman DJ. Predictive accuracy and sources of variability in calculated free testosterone estimates. Ann Clin Biochem 2009; 46: 137-43.
34. Allan CA, Strauss BJ, 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.
35. Swerdloff RS, Wang C. Three-year follow-up of androgen treatment in hypogonadal men: preliminary report with testosterone gel. Aging Male 2003; 6: 207-11.
36. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Mac RP, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 2005; 90: 678-88.
37. Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 2005; 90: 1502-10.
38. Muller M, van den Beld AW, Bots ML, Grobbee DE, Lamberts SW, et al. Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation 2004; 109: 2074-9.
39. Tivesten A, Mellstrom D, Jutberger H, Fagerberg B, Lernfelt B, et al. Low serum testosterone and high serum estradiol associate with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden. J Am Coll Cardiol 2007; 50: 1070-6.
40. Hak AE, Witteman JC, de Jong FH, Geerlings MI, Hofman A, et al. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab 2002; 87: 3632-9.
41. Pitteloud N, Mootha VK, Dwyer AA, Hardin M, Lee H, et al. Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care 2005; 28: 1636-42.
42. Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006; 154: 899-906.
43. Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 2009; 30: 726-33.
44. Marin P, Lonn L, Andersson B, Oden B, Olbe L, et al. Assimilation of triglycerides in subcutaneous and intraabdominal adipose tissues in vivo in men: effects of testosterone. J Clin Endocrinol Metab 1996; 81: 1018-22.
45. Aversa A, Isidori AM, Greco EA, Giannetta E, Gianfrilli D, et al. Hormonal supplementation and erectile dysfunction. Eur Urol 2004; 45: 535-8.
46. Phillips GB, Pinkernell BH, Jing T Y. The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb 1994; 14: 701-6.
47. Seidell JC, Bjorntorp P, Sjostrom 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 1990; 39: 897-901.
48. Tchernof A, Labrie F, Belanger A, Prud'homme D, Bouchard C, et al. Relationships between endogenous steroid hormone, sex hormone-binding globulin and lipoprotein levels in men: contribution of visceral obesity, insulin levels and other metabolic variables. Atherosclerosis 1997; 133: 235-44.
49. Kabakci G, Yildirir A, Can I, Unsal I, Erbas B. Relationship between endogenous sex hormone levels, lipoproteins and coronary atherosclerosis in men undergoing coronary angiography. Cardiology 1999; 92: 221-5.
50. Hajjar 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.
51. Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Bolona ER, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 2007; 82: 29-39.
52. Allan CA, McLachlan RI. Age-related changes in testosterone and the role of replacement therapy in older men. Clin Endocrinol (Oxf) 2004; 60: 653-70.
53. 4 in relation to ischemic heart disease mortality in diabetic subjects. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabetes Care 1996; 19: 1045-50.
54. Barrett-Connor E, Khaw KT. Endogenous sex hormones and cardiovascular disease in men. A prospective population-based study. Circulation 1988; 78: 539-45.
55. Cauley JA, Gutai JP, Kuller LH, Dai WS. Usefulness of sex steroid hormone levels in predicting coronary artery disease in men. Am J Cardiol 1987; 60: 771-7.
56. Goldberg RB, Rabin D, Alexander AN, Doelle GC, Getz GS. Suppression of plasma testosterone leads to an increase in serum total and high density lipoprotein cholesterol and apoproteins A-I and B. J Clin Endocrinol Metab 1985; 60: 203-7.
57. Meier C, Nguyen TV, Handelsman DJ, Schindler C, Kushnir MM, et al. Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study. Arch Intern Med 2008; 168: 47-54.
58. Fink HA, Ewing SK, Ensrud KE, Barrett-Connor E, Taylor BC, et al. Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. J Clin Endocrinol Metab 2006; 91: 3908-15.
59. Compston JE. Sex steroids and bone. Physiol Rev 2001; 81: 419-47.
60. Svartberg J, Agledahl I, Figenschau Y, Sildnes T, Waterloo K, et al. Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. Int J Impot Res 2008; 20: 378-87.
61. Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab 1997; 82: 2386-90.
62. Saggese G, Bertelloni S, Baroncelli GI. Sex steroids and the acquisition of bone mass. Horm Res 1997; 48 Suppl 5: 65-71.
63. van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab 2000; 85: 3276-82.
64. Michael H, Harkonen PL, Vaananen HK, Hentunen TA. Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption. J Bone Miner Res 2005; 20: 2224-32.
65. Center JR, Nguyen TV, Sambrook PN, Eisman JA. Hormonal and biochemical parameters in the determination of osteoporosis in elderly men. J Clin Endocrinol Metab 1999; 84: 3626-35.
66. Bhasin S. Regulation of body composition by androgens. J Endocrinol Invest 2003; 26: 814-22.
67. Frontera WR, Hughes VA, Fielding RA, Fiatarone MA, Evans WJ, et al. Aging of skeletal muscle: a 12-yr longitudinal study. J Appl Physiol 2000; 88: 1321-6.
68. Reed RL, Pearlmutter L, Yochum K, Meredith KE, Mooradian AD. The relationship between muscle mass and muscle strength in the elderly. J Am Geriatr Soc 1991; 39: 555-61.
69. Mauras N, Hayes V, Welch S, Rini A, Helgeson K, et al. Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity. J Clin Endocrinol Metab 1998; 83: 1886-92.
70. Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 1999; 107: 123-36.
71. Mudali S, Dobs AS. Effects of testosterone on body composition of the aging male. Mech Ageing Dev 2004; 125: 297-304.
72. Ferrando AA, Sheffield-Moore M, Paddon-Jones D, Wolfe RR, Urban RJ. Differential anabolic effects of testosterone and amino acid feeding in older men. J Clin Endocrinol Metab 2003; 88: 358-62.
73. Harman SM, Blackman MR. The effects of growth hormone and sex steroid on lean body mass, fat mass, muscle strength, cardiovascular endurance and adverse events in healthy elderly women and men. Horm Res 2003; 60: 121-4.
74. Sih R, Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, et al. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab 1997; 82: 1661-7.
75. Morley JE, Perry HM 3rd, Kaiser FE, Kraenzle D, Jensen J, et al. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc 1993; 41: 149-52.
76. Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol 2009; 54: 919-27.
77. Srinivas-Shankar U, Roberts SA, Connolly MJ, MD OC, Adams JE, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2010 Jan 8. Epub ahead of print.
78. Perry HM 3rd, Miller DK, Patrick P, Morley JE. Testosterone and leptin in older African-American men: relationship to age, strength, function, and season. Metabolism 2000; 49: 1085-91.
79. Breuer B, Trungold S, Martucci C, Wallenstein S, Likourezos A, et al. Relationships of sex hormone levels to dependence in activities of daily living in the frail elderly. Maturitas 2001; 39: 147-59.
80. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 1999; 84: 2647-53.
81. Bhasin S. Testosterone supplementation for aging-associated sarcopenia. J Gerontol A Biol Sci Med Sci 2003; 58: 1002-8.
82. Lyngdorf P, Hemmingsen L. Epidemiology of erectile dysfunction and its risk factors: a practice-based study in Denmark. Int J Impot Res 2004; 16: 105-11.
83. Selvin E, Burnett AL, Platz EA. Prevalence and risk factors for erectile dysfunction in the US. Am J Med 2007; 120: 151-7.
84. Schiavi RC, Rehman J. Sexuality and aging. Urol Clin North Am 1995; 22: 711-26.
85. Gray PB, Singh AB, Woodhouse LJ, Storer TW, Casaburi R, et al. Dose-dependent effects of testosterone on sexual function, mood, and visuospatial cognition in older men. J Clin Endocrinol Metab 2005; 90: 3838-46.
86. Morales A, Buvat J, Gooren LJ, Guay AT, Kaufman JM, et al. Endocrine aspects of sexual dysfunction in men. J Sex Med 2004; 1: 69-81.
87. Yassin AA, Saad F. Dramatic improvement of penile venous leakage upon testosterone administration. A case report and review of literature. Andrologia 2006; 38: 34-7.
88. Krause W, Mueller U, Mazur A. Testosterone supplementation in the aging male: which questions have been answered? Aging Male 2005; 8: 31-8.
89. Shabsigh R. The effects of testosterone on the cavernous tissue and erectile function. World J Urol 1997; 15: 21-6.
90. Meikle AW, Arver S, Dobs A, Sanders SW, Mazer NA. Androderm: A Permeation-Enhanced, Non-Scrotal Testosterone Transdermal System for the Treatment of Male Hypogonadism. In: Bhasin S, editor. Phatmacology, Biology, and Clinical Applications of Androgens. New York: Wiley Liss, Inc.; 1996. p449-57.
91. Shabsigh R, Kaufman JM, 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 2004; 172: 658-63.
92. Greenstein A, Mabjeesh NJ, Sofer M, Kaver I, Matzkin H, et al. Does sildenafil combined with testosterone gel improve erectile dysfunction in hypogonadal men in whom testosterone supplement therapy alone failed? J Urol 2005; 173: 530-2.
93. Greco EA, Spera G, Aversa A. Combining testosterone and PDE5 inhibitors in erectile dysfunction: basic rationale and clinical evidences. Eur Urol 2006; 50: 940-7.
94. Karazindiyanoglu S, Cayan S. The effect of testosterone therapy on lower urinary tract symptoms/bladder and sexual functions in men with symptomatic late-onset hypogonadism. Aging Male 2008; 11: 146-9.
95. Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab 2000; 85: 2839-53.
96. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, 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 2004; 89: 2085-98.
97. Barrett-Connor E, Von Muhlen DG, Kritz-Silverstein D. Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo Study. J Clin Endocrinol Metab 1999; 84: 573-7.
98. Schmidt PJ, Berlin KL, Danaceau MA, Neeren A, Haq NA, et al. The effects of pharmacologically induced hypogonadism on mood in healthy men. Arch Gen Psychiatry 2004; 61: 997-1004.
99. Seidman SN, Spatz E, Rizzo C, Roose SP. Testosterone replacement therapy for hypogonadal men with major depressive disorder: a randomized, placebo-controlled clinical trial. J Clin Psychiatry 2001; 62: 406-12.
100. English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation 2000; 102: 1906-11.
101. Tricker R, Casaburi R, Storer TW, Clevenger B, Berman N, et al. The effects of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men - a clinical research center study. J Clin Endocrinol Metab 1996; 81: 3754-8.
102. Haren 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.
103. Wang C, Alexander G, Berman N, Salehian B, Davidson T, et al. Testosterone replacement therapy improves mood in hypogonadal men - a clinical research center study. J Clin Endocrinol Metab 1996; 81: 3578-83.
104. Lunenfeld B, Nieschlag E. Testosterone therapy in the aging male. Aging Male 2007; 10: 139-53.
105. Morley JE. Testosterone replacement in older men and women. J Gend Specif Med 2001; 4: 49-53.
106. Livermann CT, Blazer DG, editors. Tetosterone and Aging: Clinical Research Directions. Washington, DC: National Academies Press; 2004.
107. Gruenewald DA, Matsumoto AM. Testosterone supplementation therapy for older men: potential benefits and risks. J Am Geriatr Soc 2003; 51: 101-15; discussion 15.
108. Rabkin JG, Wagner GJ, Rabkin R. Testosterone therapy for human immunodeficiency virus-positive men with and without hypogonadism. J Clin Psychopharmacol 1999; 19: 19-27.
109. Grinspoon S, Corcoran C, Stanley T, Baaj A, Basgoz N, et al. Effects of hypogonadism and testosterone administration on depression indices in HIV-infected men. J Clin Endocrinol Metab 2000; 85: 60-5.
110. Seidman SN, Araujo AB, Roose SP, McKinlay JB. Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men. Biol Psychiatry 2001; 50: 371-6.
111. Harkonen K, Huhtaniemi I, Makinen J, Hubler D, Irjala K, et al. The polymorphic androgen receptor gene CAG repeat, pituitary-testicular function and andropausal symptoms in ageing men. Int J Androl 2003; 26: 187-94.
112. Barrett-Connor E, Goodman-Gruen D, Patay B. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab 1999; 84: 3681-5.
113. Yaffe K, Lui LY, Zmuda J, Cauley J. Sex hormones and cognitive function in older men. J Am Geriatr Soc 2002; 50: 707-12.
114. Yeap BB, Almeida OP, Hyde Z, Chubb SA, Hankey GJ, et al. Higher serum free testosterone is associated with better cognitive function in older men, while total testosterone is not. The Health In Men Study. Clin Endocrinol (Oxf) 2008; 68: 404-12.
115. Cherrier MM, Rose AL, Higano C. The effects of combined androgen blockade on cognitive function during the first cycle of intermittent androgen suppression in patients with prostate cancer. J Urol 2003; 170: 1808-11.
116. Hogervorst E, Bandelow S, Combrinck M, Smith AD. Low free testosterone is an independent risk factor for Alzheimer's disease. Exp Gerontol 2004; 39: 1633-9.
117. Beauchet O. Testosterone and cognitive function: current clinical evidence of a relationship. Eur J Endocrinol 2006; 155: 773-81.
118. Cherrier MM, Craft S, Matsumoto AH. Cognitive changes associated with supplementation of testosterone or dihydrotestosterone in mildly hypogonadal men: a preliminary report. J Androl 2003; 24: 568-76.
119. Cherrier MM, Matsumoto AM, Amory JK, Asthana S, Bremner W, et al. Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology 2005; 64: 2063-8.
120. Spivak JL. The blood in systemic disorders. Lancet 2000; 355: 1707-12.
121. Coviello AD, Kaplan B, Lakshman KM, Chen T, Singh AB, et al. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab 2008; 93: 914-9.
122. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006; 91: 1995-2010.
123. Cui YG, Tong JS, Pan QQ, Di FS, Jia Y, et al. [Effect of androgen on erythropoietin in patients with hypogonadism]. Zhonghua Nan Ke Xue 2003; 9: 248-51.
124. Kozlov VA, Tsyrlova IG, Zhuravkin IN. [Different effect of testosterone on polypotential stem hematopoietic stem cells and immunocompetent B-lymphocytes]. Zh Mikrobiol Epidemiol Immunobiol 1979: 72-6.
125. Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, et al. Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab 1999; 84: 3469-78.
126. Ip FF, di Pierro I, Brown R, Cunningham I, Handelsman DJ, et al. Trough serum testosterone predicts the development of polycythemia in hypogonadal men treated for up to 21 years with subcutaneous testosterone pellets. Eur J Endocrinol 2010; 162: 385-90.
127. Zitzmann M, Nieschlag E. Androgen receptor gene CAG repeat length and body mass index modulate the safety of long-term intramuscular testosterone undecanoate therapy in hypogonadal men. J Clin Endocrinol Metab 2007; 92: 3844-53.
128. Kiyohara Y, Ueda K, Hasuo Y, Fujii I, Yanai T, et al. Hematocrit as a risk factor of cerebral infarction: long-term prospective population survey in a Japanese rural community. Stroke 1986; 17: 687-92.
129. Lee BI, Nam HS, Heo JH, Kim DI. Yonsei Stroke Registry. Analysis of 1,000 patients with acute cerebral infarctions. Cerebrovasc Dis 2001; 12: 145-51.
130. Brown DW, Giles WH, Croft JB. Hematocrit and the risk of coronary heart disease mortality. Am Heart J 2001; 142: 657-63.
131. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005; 60: 1451-7.
132. Schultheiss D, Machtens S, Jonas U. Testosterone therapy in the ageing male: what about the prostate? Andrologia 2004; 36: 355-65.
133. Morales A. Testosterone treatment for the aging man: the controversy. Curr Urol Rep 2004; 5: 472-7.
134. Ebling DW, Ruffer J, Whittington R, Vanarsdalen K, Broderick GA, et al. Development of prostate cancer after pituitary dysfunction: a report of 8 patients. Urology 1997; 49: 564-8.
135. Loughlin KR, Richie JP. Prostate cancer after exogenous testosterone treatment for impotence. J Urol 1997; 157: 1845.
136. Curran MJ, Bihrle W 3rd. Dramatic rise in prostate-specific antigen after androgen replacement in a hypogonadal man with occult adenocarcinoma of the prostate. Urology 1999; 53: 423-4.
137. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004; 350: 482-92.
138. Sengupta S, Duncan HJ, Macgregor RJ, Russell JM. The development of prostate cancer despite late onset androgen deficiency. Int J Urol 2005; 12: 847-8.
139. Carter HB, Pearson JD, Metter EJ, Chan DW, Andres R, et al. Longitudinal evaluation of serum androgen levels in men with and without prostate cancer. Prostate 1995; 27: 25-31.
140. Heikkila R, Aho K, Heliovaara M, Hakama M, Marniemi J, et al. Serum testosterone and sex hormone-binding globulin concentrations and the risk of prostate carcinoma: a longitudinal study. Cancer 1999; 86: 312-5.
141. Hsing AW. Hormones and prostate cancer: what's next? Epidemiol Rev 2001; 23: 42-58.
142. Morgentaler A, Bruning CO 3rd, DeWolf WC. Occult prostate cancer in men with low serum testosterone levels. Jama 1996; 276: 1904-6.
143. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349: 215-24.
144. Andriole G, Bostwick D, Brawley O, Gomella L, Marberger M, et al. Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial. J Urol 2004; 172: 1314-7.
145. Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, et al. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. J Clin Endocrinol Metab 2004; 89: 2179-84.
146. Andriole GL, Roehrborn C, Schulman C, Slawin KM, Somerville M, et al. Effect of dutasteride on the detection of prostate cancer in men with benign prostatic hyperplasia. Urology 2004; 64: 537-41; discussion 42-3.
147. Giovannucci E, Stampfer MJ, Krithivas K, Brown M, Dahl D, et al. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci U S A 1997; 94: 3320-3.
148. Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 1994; 22: 3181-6.
149. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992; 75: 1092-8.
150. Marks LS, Mazer NA, Mostaghel E, Hess DL, Dorey FJ, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. Jama 2006; 296: 2351-61.
151. Morgentaler A. Testosterone replacement therapy and prostate cancer. Urol Clin North Am 2007; 34: 555-63.
152. Yassin A, Saad F. Testosterone treatment in hypogonadal patients does not cause higher incidence of prostate cancer. J Urol 2008; 179: 301.
153. Yassin AA, Saad F. Improvement of sexual function in men with late-onset hypogonadism treated with testosterone only. J Sex Med 2007; 4: 497-501.
154. Coward RM, Simhan J, Carson CC 3rd. Prostate-specific antigen changes and prostate cancer in hypogonadal men treated with testosterone replacement therapy. BJU Int 2009; 103: 1179-83.
155. Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol 2004; 172: 920-2.
156. Agarwal PK, Oefelein MG. Testosterone replacement therapy after primary treatment for prostate cancer. J Urol 2005; 173: 533-6.
157. Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer 2007; 109: 536-41.
158. Morgentaler A. Two years of testosterone therapy associated with decline in prostate-specific antigen in a man with untreated prostate cancer. J Sex Med 2009; 6: 574-7.
159. Wu FC, von Eckardstein A. Androgens and coronary artery disease. Endocr Rev 2003; 24: 183-217.
160. Liu PY, Death AK, Handelsman DJ. Androgens and cardiovascular disease. Endocr Rev 2003; 24: 313-40.
161. Jones RD, Nettleship JE, Kapoor D, Jones HT, Channer KS. Testosterone and atherosclerosis in aging men: purported association and clinical implications. Am J Cardiovasc Drugs 2005; 5: 141-54.
162. Shabsigh R, Rajfer J, Aversa A, Traish AM, Yassin A, et al. The evolving role of testosterone in the treatment of erectile dysfunction. Int J Clin Pract 2006; 60: 1087-92.
163. Shabsigh R, Katz M, Yan G, Makhsida N. Cardiovascular issues in hypogonadism and testosterone therapy. Am J Cardiol 2005; 96: 67M-72M.
164. Shores MM, Moceri VM, Gruenewald DA, Brodkin KI, Matsumoto AM, et al. 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.
165. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med 2006; 166: 1660-5.
166. Maggio M, Lauretani F, Ceda GP, Bandinelli S, Ling SM, et al. Relationship between low levels of anabolic hormones and 6-year mortality in older men: the aging in the Chianti Area (InCHIANTI) study. Arch Intern Med 2007; 167: 2249-54.
167. Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, 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.
168. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008; 93: 68-75.
169. Corona G, Forti G, Maggi M. Why can patients with erectile dysfunction be considered lucky? The association with testosterone deficiency and metabolic syndrome. Aging Male 2008; 11: 193-9.
170. Lopez-Jimenez F, Sert Kuniyoshi FH, Gami A, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. Chest 2008; 133: 793-804.
171. Hoekema A, Stel AL, Stegenga B, van der Hoeven JH, Wijkstra PJ, et al. Sexual function and obstructive sleep apnea-hypopnea: a randomized clinical trial evaluating the effects of oral-appliance and continuous positive airway pressure therapy. J Sex Med 2007; 4: 1153-62.
172. Karkoulias K, Perimenis P, Charokopos N, Efremidis G, Sampsonas F, et al. Does CPAP therapy improve erectile dysfunction in patients with obstructive sleep apnea syndrome? Clin Ter 2007; 158: 515-8.
173. de Sousa AG, Cercato C, Mancini MC, Halpern A. Obesity and obstructive sleep apnea-hypopnea syndrome. Obes Rev 2008; 9: 340-54.
174. Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000; 85: 1151-8.
175. Shabsigh R, Arver S, Channer KS, Eardley I, Fabbri A, et al. The triad of erectile dysfunction, hypogonadism and the metabolic syndrome. Int J Clin Pract 2008; 62: 791-8.
176. Traish AM, Guay A, Feeley R, Saad F. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. J Androl 2009; 30: 10-22.
177. Barrett-Connor E, Dam TT, Stone K, Harrison SL, Redline S, et al. The association of testosterone levels with overall sleep quality, sleep architecture, and sleep-disordered breathing. J Clin Endocrinol Metab 2008; 93: 2602-9.
178. Goncharov NP, Katsya GV, Chagina NA, Gooren LJ. Three definitions of metabolic syndrome applied to a sample of young obese men and their relation with plasma testosterone. Aging Male 2008; 11: 118-22.