ISA, ISSAM and EAU recommendations for the investigation, treatment and monitoring of late-onset hypogonadism in males: Scientific background and rationale

Aging Male

Volumn 8, Issue 2, 2005, Pages 59-74

  Lunenfeld, Bruno ^a   Saad, F ^b   Hoesl, C E ^c  

^a BAR ILAN UNIVERSITY   (Israel)

^b BAYER PHARMA AG   (Germany)

^c NONE

Author keywords

Aging; Androgen deficiency; Late onset hypogonadism; Testosterone

Indexed keywords

FLUOXYMESTERONE; GROWTH HORMONE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HYDROCORTISONE; LUTEINIZING HORMONE; MESTEROLONE; METHYLTESTOSTERONE; PHOSPHODIESTERASE V INHIBITOR; PLACEBO; PRASTERONE; PRASTERONE SULFATE; SEX HORMONE BINDING GLOBULIN; SILDENAFIL; TADALAFIL; TESTOSTERONE; TESTOSTERONE CIPIONATE; TESTOSTERONE PROPIONATE; TESTOSTERONE UNDECANOATE;

ACNE; AGING; ANDROGEN DEFICIENCY; BODY FAT; BONE DENSITY; BREAST CARCINOMA; COGNITION; DRUG CONTRAINDICATION; EDEMA; ERECTILE DYSFUNCTION; ERYTHROCYTOSIS; GYNECOMASTIA; HAIR; HEART FAILURE; HORMONE DETERMINATION; HORMONE SUBSTITUTION; HUMAN; HYPOGONADISM; LIVER TOXICITY; MEDICAL SOCIETY; METABOLIC SYNDROME X; MOOD; MUSCLE STRENGTH; NON INSULIN DEPENDENT DIABETES MELLITUS; POLYCYTHEMIA; PRACTICE GUIDELINE; PREVALENCE; PRIORITY JOURNAL; PROSTATE CARCINOMA; PROSTATE HYPERTROPHY; REVIEW; SEXUAL FUNCTION; SKIN; SKIN IRRITATION; SLEEP APNEA SYNDROME; SYSTEMATIC REVIEW; URINARY TRACT OBSTRUCTION;

AGE FACTORS; AGE OF ONSET; AGED; AGING; ANDROGENS; HORMONE REPLACEMENT THERAPY; HUMANS; HYPOGONADISM; MALE; MIDDLE AGED; MONITORING, PHYSIOLOGIC; RISK ASSESSMENT; RISK FACTORS; TESTOSTERONE; TIME FACTORS;

EID: 22144480281     PISSN: 13685538     EISSN: None     Source Type: Journal    
DOI: 10.1080/13685530500163416     Document Type: Review

References (201)

1. Morales A, Lunenfeld B; International Society for the Study of the Aging Male. Investigation, treatment and monitoring of late-onset hypogonadism in males. Official recommendations of ISSAM. International Society for the Study of the Aging Male. Aging Male 2002;5:74-86.
2. Morales A, Lunenfeld B. Androgen replacement therapy in aging men with secondary hypogonadism. Draft recommendations for endorsement by ISSAM. Aging Male 2001;4:1.
3. Gray A, Feldman HA, McKinlay JB, Longcope C. Age, disease, and changing sex hormone levels in middle-aged men: Results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab 1991;73:1016-1025.
4. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB. 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: 589-598.
5. Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, Morley PM, Stauber PM, Vellas B, Baumgartner RN, Garry PJ. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism 1997;46:410-413.
6. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR; Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86:724-731.
7. McClure RD. Androgen deficiency and the aging male: new urologic perspectives. Curr Urol Rep 2001;2:453-459.
8. Araujo AB, O'Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM, McKinlay JB. Prevalence and incidence of androgen deficiency in middle-aged and older men: Estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2004;89:5920-596.
9. Morley JE, Charlton E, Patrick P, Kaiser FE, Cadeau P, McCready D, Perry HM 3rd. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism 2000;49:1239-1242.
10. Smith KW, Feldman HA, McKinlay JB. Construction and field validation of a self-administered screener for testosterone deficiency (hypogonadism) in ageing men. Clin Endocrinol (Oxf) 2000;53:703-711.
11. Tancredi A, Reginster JY, Schleich F, Pire G, Maassen P, Luyckx F, Legros JJ. Interest of the androgen deficiency in aging males (ADAM) questionnaire for the identification of hypogonadism in elderly community-dwelling male volunteers. Eur J Endocrinol 2004;151:355-360.
12. Lunenfeld B. Androgen therapy in the aging male. World J Urol 2003;21:292-305.
13. Davidson JM, Chen JJ, Crapo L, Gray GD, Greenleaf WJ, Catania JA. Hormonal changes and sexual function in aging men. J Clin Endocrinol Metab 1983;57:71-77.
14. Schiavi RC, Schreiner-Engel P, White D, Mandeli J. The relationship between pituitary-gonadal function and sexual behavior in healthy aging men. Psychosom Med 1991;53: 363-374.
15. Schiavi RC, White D, Mandeli J, Levine AC. Effect of testosterone administration on sexual behavior and mood in men with erectile dysfunction. Arch Sex Behav 1997;26:231-241.
16. O'Carroll R, Bancroft J. Testosterone therapy for low sexual interest and erectile dysfunction in men: a controlled study. Br J Psychiatry 1984;145:146-151.
17. Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB. Incidence of erectile dysfunction in men 40 to 69 years old: Longitudinal results from the Massachusetts male aging study. J Urol 2000;163:460-463.
18. Bacon CG, Mittleman MA, Kawachi I, Giovannucci E, Glasser DB, Rimm EB. Sexual function in men older than 50 years of age: Results from the health professionals follow-up study. Ann Intern Med 2003;139:161-168.
19. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. J Urol 1994;151:54-61.
20. Mills TM, Lewis RW. The role of androgens in the erectile response: A 1999 perspective. Mol Urol 1999;3:75-86.
21. Korenman SG, Morley JE, Mooradian AD, Davis SS, Kaiser FE, Silver AJ, Viosca SP, Garza D. Secondary hypogonadism in older men: its relation to impotence. J Clin Endocrinol Metab 1990;71:963-969.
22. Nickel JC, Morales A, Condra M, Fenemore J, Surridge DH. Endocrine dysfunction in impotence: Incidence, significance and cost-effective screening. J Urol 1984;132:40-43.
23. Slag MF, Morley JE, Elson MK, Trence DL, Nelson CJ, Nelson AE, Kinlaw WB, Beyer HS, Nuttall FQ, Shafer RB. JAMA 1983;249:1736-1740.
24. Bodie J, Lewis J, Schow D, Monga M. Laboratory evaluations of erectile dysfunction: An evidence based approach. J Urol 2003;169:2262-2264.
25. Guay AT, Perez JB, Jacobson J, Newton RA. Efficacy and safety of sildenafil citrate for treatment of erectile dysfunction in a population with associated organic risk factors. J Androl 2001;22:793-797.
26. Corona G, Mannucci E, Mansani R, Petrone L, Bartolini M, Giommi R, Forti G, Maggi M. Organic, relational and psychological factors in erectile dysfunction in men with diabetes mellitus. Eur Urol 2004;46:222-228.
27. Traish AM, Park K, Dhir V, Kim NN, Moreland RB, Goldstein I. Effects of castration and androgen replacement on erectile function in a rabbit model. Endocrinology 1999;140:1861-1858.
28. Traish AM, Munarriz R, O'Connell L, Choi S, Kim SW, Kim NN, Huang YH, Goldstein I. Effects of medical or surgical castration on erectile function in an animal model. J Androl 2003;24:381-387.
29. Reilly CM, Lewis RW, Stopper VS, Mills TM. Androgenic maintenance of the rat erectile response via a non-nitric-oxide-dependent pathway. J Androl 1997;18:588-594.
30. Aversa A, Isidori AM, De Martino MU, Caprio M, Fabbrini E, Rocchietti-March M, Frajese G, Fabbri A. Androgens and penile erection: evidence for a direct relationship between free testosterone and cavernous vasodilation in men with erectile dysfunction. Clin Endocrinol (Oxf) 2000;53:517-522.
31. Tsujimura A, Matsumiya K, Matsuoka Y, Takahashi T, Koga M, Iwasa A, Takeyama M, Okuyama A. Bioavailable testosterone with age and erectile dysfunction. J Urol 2003; 170(6 Pt 1):2345-2347.
32. Rhoden EL, Teloken C, Sogari PR, Souto CA. The relationship of serum testosterone to erectile function in normal aging men. J Urol 2002;167:1745-1748.
33. Park K, Ku JH, Kim SW, Paick JS. Risk factors in predicting a poor response to sildenafil citrate in elderly men with erectile dysfunction. BJU Int 2005;95:366-370.
34. 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;58:632-638.
35. 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; 172:658-663.
36. Yassin A, Saad F, Diede HE. Combination therapy for erectile dysfunction with testosterone & tadalafil in hypogonadal patients who failed to respond to tadalafil alone. AJU 2003;1:10-12.
37. Kalinchenko SY, Kozlov GI, Gontcharov NP, Katsiya GV. Oral testosterone undecanoate reverses erectile dysfunction associated with diabetes mellitus in patients failing on sildenafil citrate therapy alone. Aging Male 2003;6:94-99.
38. 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;58:632-638.
39. Greenstein A, Mabjeesh NJ, Sofer M, Kaver I, Matzkin H, Chen J. Does sildenafil combined with testosterone gel improve erectile dysfunction in hypogonadal men in whom testosterone supplement therapy alone failed? J Urol 2005; 173:530-532.
40. Carani C, Granata AR, Bancroft J, Marrama P. The effects of testosterone replacement on nocturnal penile tumescence and rigidity and erectile response to visual erotic stimuli in hypogonadal men. Psychoneuroendocrinology 1995;20:743-753.
41. Buvat J, Lemaire A. Endocrine screening in 1,022 men with erectile dysfunction: clinical significance and cost-effective strategy. J Urol 1997;158:1764-1767.
42. Jain P, Rademaker AW, McVary KT. Testosterone supplementation for erectile dysfunction: results of a meta-analysis. J Urol 2000;164:371-375.
43. Schultheiss D, Hiltl DM, Meschi MR, Machtens SA, Truss MC, Stief CG, Jonas U. Pilot study of the transdermal application of testosterone gel to the penile skin for the treatment of hypogonadotropic men with erectile dysfunction. World J Urol 2000;18:431-435.
44. Foresta C, Caretta N, Rossato M, Garolla A, Ferlin A. Role of androgens in erectile function. J Urol 2004;171(6 Pt 1):2358-2362.
45. Mulhall JP, Valenzuela R, Aviv N, Parker M. Effect of testosterone supplementation on sexual function in hypogonadal men with erectile dysfunction. Urology 2004;63:348-352.
46. Seftel AD, Sun P, Swindle R. The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in men with erectile dysfunction. J Urol 2004;171(6 Pt 1):2341-2345.
47. Penson DF, Latini DM, Lubeck DP, Wallace KL, Henning JM, Lue TF; Comprehensive Evaluation of Erectile Dysfunction (ExCEED) database. Do impotent men with diabetes have more severe erectile dysfunction and worse quality of life than the general population of impotent patients? Results from the Exploratory Comprehensive Evaluation of Erectile Dysfunction (ExCEED) database. Diabetes Care 2003;26: 1093-1099.
48. Sullivan ME, Keoghane SR, Miller MA. Vascular risk factors and erectile dysfunction. BJU Int 2001;87:838-845.
49. Araujo AB, Johannes CB, Feldman HA, Derby CA, McKinlay JB. Relation between psychosocial risk factors and incident erectile dysfunction: prospective results from the Massachusetts Male Aging Study. Am J Epidemiol 2000; 152:533-541.
50. Braun MH, Sommer F, Haupt G, Mathers MJ, Reifenrath B, Engelmann UH. Lower urinary tract symptoms and erectile dysfunction: co-morbidity or typical "Aging Male" symptoms? Results of the "Cologne Male Survey". Eur Urol 2003;44:588-594.
51. Hoesl CE, WoIl EM, Burkart M, Altwein JE. Erectile Dysfunction (ED) is prevalent, bothersome and underdiagnosed in patients consulting urologists for Benign Prostatic Syndrome (BPS). Eur Urol 2005;47:511-517.
52. Russell ST, Khandheria BK, Nehra A. Erectile dysfunction and cardiovascular disease. Mayo Clin Proc 2004;79:782-794.
53. Morley JE. Testosterone and behavior. Clin Geriatr Med 2003;19:605-16.
54. Moffat SD, Hampson E. A curvilinear relationship between testosterone and spatial cognition in humans: possible influence of hand preference. Psychoneuroendocrinology 1996;21:323-337.
55. Barrett-Connor E, Goodman-Gruen D, Patay B. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab 1999;84:3681-3685.
56. Moffat 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;87:5001-5007.
57. Yaffe K, Lui LY, Zmuda J, Cauley J. Sex hormones and cognitive function in older men. J Am Geriatr Soc 2002;50:707-712.
58. Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, Raskind MA, Brodkin K, Bremner W, Petrova A, et al. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology 2001;57:80-88.
59. O'Connor DB, Archer J, Hair WM, Wu FC. Activational effects of testosterone on cognitive function in men. Neuropsychologia 2001;39:1385-1394.
60. 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;50:124-133.
61. Kenny 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;59:75-78.
62. Janowsky JS, Oviatt SK, Orwoll ES. Testosterone influences spatial cognition in older men. Behav Neurosci 1994;108:325-332.
63. Janowsky JS, Chavez B, Orwoll E. Sex steroids modify working memory. J Cogn Neurosci 2000;12:407-414.
64. Almeida OP, Waterreus A, Spry N, Corica T, Martins G, Martins RN, Flicker L. Effect of testosterone deprivation on the cognitive performance of a patient with Alzheimer's disease. Int J Geriatr Psychiatry 2001;16:823-825.
65. Almeida OP, Waterreus A, Spry N, Flicker L, Martins RN. One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men. Psychoneuroendocrinology 2004;29:1071-1081.
66. Gouras GK, Xu H, Gross RS, Greenfield JP, Hai B, Wang R, Greengard P. Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides. Proc Natl Acad Sci USA 2000;97:1202-1205.
67. Goodenough S, Engert S, Behl C. Testosterone stimulates rapid secretory amyloid precursor protein release from rat hypothalamic cells via the activation of the mitogen-activated protein kinase pathway. Neurosci Lett 2000;296:49-52.
68. Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, Resnick SM. Free testosterone and risk for Alzheimer disease in older men. Neurology 2004;62:188-193.
69. Bialek M, Zaremba P, Borowicz KK, Czuczwar SJ. Neuroprotective role of testosterone in the nervous system. Pol J Pharmacol 2004;56:509-518.
70. Carnahan RM, Perry PJ. Depression in aging men: the role of testosterone. Drugs Aging 2004;21:361-376.
71. Sachar EJ, Halpern F, Rosenfeld RS, Galligher TF, Hellman L. Plasma and urinary testosterone levels in depressed men. Arch Gen Psychiatry 1973;28:15-18.
72. Shaw DM, Francis AF, Groom GV, Riad-Fahmy D. A pilot endocrine study in depression. Postgrad Med J 1977;53 Suppl 4:172-174.
73. Steiger A, von Bardeleben U, Wiedemann K, Holsboer F. Sleep EEG and nocturnal secretion of testosterone and cortisol in patients with major endogenous depression during acute phase and after remission. J Psychiatr Res 1991; 25:169-177.
74. 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;62:406-412.
75. Shores MM, Moceri VM, Sloan KL, Matsumoto AM, Kivlahan DR. Low testosterone levels predict incident depressive illness in older men: effects of age and medical morbidity. J Clin Psychiatry 2005;66:7-14.
76. 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;84:573-577.
77. Perry PJ, Lund BC, Arndt S, Holman T, Bever-Stille KA, Paulsen J, Demers LM. Bioavailable testosterone as a correlate of cognition, psychological status, quality of life, and sexual function in aging males: implications for testosterone replacement therapy. Ann Clin Psychiatry 2001;13:75-80.
78. Seidman SN, Araujo AB, Roose SP, Devanand DP, Xie S, Cooper TB, McKinlay JB. Low testosterone levels in elderly men with dysthymic disorder. Am J Psychiatry 2002;159: 456-459.
79. Shores MM, Sloan KL, Matsumoto AM, Moceri VM, Felker B, Kivlahan DR. Increased incidence of diagnosed depressive illness in hypogonadal older men. Arch Gen Psychiatry 2004;61:162-167.
80. Seidman SN, Araujo AB, Roose SP, McKinlay JB. Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men. Biol Psychiatry 2001;50:371-376.
81. Krithivas K, Yurgalevitch SM, Mohr BA, Wilcox CJ, Batter SJ, Brown M, Longcope C, McKinlay JB, Kantoff PW. Evidence that the CAG repeat in the androgen receptor gene is associated with the age-related decline in serum androgen levels in men. J Endocrinol 1999;162:137-142.
82. Wang C, Alexander G, Berman N, Salehian B, Davidson T, McDonald V, Steiner B, Hull L, Callegari C, Swerdloff RS. Testosterone replacement therapy improves mood in hypogonadal men-a clinical research center study. J Clin Endocrinol Metab 1996;81:3578-3583.
83. Perry PJ, Yates WR, Williams RD, Andersen AE, Maclndoe JH, Lund BC, Holman TL. Testosterone therapy in late-life major depression in males. J Clin Psychiatry 2002;63:1096-1101.
84. Seidman SN, Rabkin JG. Testosterone replacement therapy for hypogonadal men with SSRI-refractory depression. J Affect Disord 1998;48:157-161.
85. Pope HG Jr, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry 2003;160:105-111.
86. Visser M, Kritchevsky SB, Goodpaster BH, Newman AB, Nevitt M, Stamm E, Harris TB. Leg muscle mass and composition in relation to lower extremity performance in men and women aged 70 to 79: the health, aging and body composition study. J Am Geriatr Soc 2002;50:897-904.
87. Newman AB, Kupelian V, Visser M, Simonsick E, Goodpaster B, Nevitt M, Kritchevsky SB, Tylavsky FA, Rubin SM, Harris TB; Health ABC Study Investigators. Sarcopenia: alternative definitions and associations with lower extremity function. J Am Geriatr Soc 2003;51:1602-1609.
88. Baumgartner RN, Stauber PM, McHugh D, Koehler KM, Garry PJ. Cross-sectional age differences in body composition in persons 60 + years of age. J Gerontol A Biol Sci Med Sci 1995;50:M307-M316.
89. Kyle UG, Genton L, Hans D, Karsegard VL, Michel JP, Slosman DO, Pichard C. Total body mass, fat mass, fat-free mass, and skeletal muscle in older people: cross-sectional differences in 60-year-old persons. J Am Geriatr Soc 2001; 49:1633-1640.
90. Baumgartner RN, Wayne SJ, Waters DL, Janssen I, Gallagher D, Morley JE. Sarcopenic obesity predicts instrumental activities of daily living disability in the elderly. Obes Res 2004;12:1995-2004.
91. Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 1999;107:123-136.
92. Szulc P, Duboeuf F, Marchand F, Delmas PD. Hormonal and lifestyle determinants of appendicular skeletal muscle mass in men: the MINOS study. Am J Clin Nutr 2004; 80:496-503.
93. 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: 1085-1091.
94. Morley JE, Kaiser FE, Sih R, Hajjar R, Perry HM. Testosterone and frailty. Clin Geriatr Med 1997;13:685-695.
95. Breuer B, Trungold S, Martucci C, Wallenstein S, Likourezos A, Libow LS, Zumoff B. Relationships of sex hormone levels to dependence in activities of daily living in the frail elderly. Maturitas 2001;39:147-159.
96. 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;85:3276-3282.
97. Bhasin S, Storer TW, Berman N, Yarasheski KE, Clevenger B, Phillips J, Lee WP, Bunnell TJ, Casaburi R. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab 1997;82:407-413.
98. Sih R, Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab 1997;82:1661-1667.
99. Morley JE, Perry HM 3rd, Kaiser FE, Kraenzle D, Jensen J, Houston K, Mattammal M, Perry HM Jr. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc 1993;41:149-152.
100. Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 1996;81: 4358-4365.
101. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Lenrow DA, Holmes JH, Dlewati A, Santanna J, Rosen CJ, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 1999;84:2647-2653.
102. Lovejoy JC, Bray GA, Greeson CS, Klemperer M, Morris J, Partington C, Tulley R. Oral anabolic steroid treatment, but not parenteral androgen treatment, decreases abdominal fat in obese, older men. Int J Obes Relat Metab Disord 1995;19: 614-624.
103. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992;75:1092-1098.
104. Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci 2003;58:618-625.
105. Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 2005;90:1502-1510.
106. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, Chen X, Yarasheski KE, Magliano L, Dzekov C, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab 2001;281: E1172-E1181.
107. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Mac RP, Lee M, Yarasheski KE, Sinha-Hikim I, Dzekov C, Dzekov J, 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;90:678-688.
108. Bhasin S, Storer TW, Singh AB, Woodhouse L, Singh R, Artaza J, Taylor WE, Sinha-Hikim I, Jasuja R, Gonzalez-Cadavid N. In: Nieschlag E, Behre HM, editors. Testosterone: action, deficiency, substitution. Cambridge: Cambridge University Press; 2004. pp 641-664.
109. Van Pottelbergh I, Braeckman L, De Bacquer D, De Backer G, Kaufman JM. Differential contribution of testosterone and estradiol in the determination of cholesterol and lipoprotein profile in healthy middle-aged men. Atherosclerosis 2003;166:95-102.
110. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 2000;23:490-494.
111. Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen TP, Valkonen VP, Salonen R, Salonen JT. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004;27:1036-1041.
112. Tsai EC, Matsumoto AM, Fujimoto WY, Boyko EJ. Association of bioavailable, free, and total testosterone with insulin resistance: influence of sex hormone-binding globulin and body fat. Diabetes Care 2004;27:861-868.
113. Tchernof A, Despres JP, Dupont A, Belanger A, Nadeau A, Prud'homme D, Moorjani S, Lupien PJ, Labrie F. Relation of steroid hormones to glucose tolerance and plasma insulin levels in men. Importance of visceral adipose tissue. Diabetes Car 1995;18:292-299.
114. Abate N, Haffher SM, Garg A, Peshock RM, Grundy SM. Sex steroid hormones, upper body obesity, and insulin resistance. J Clin Endocrinol Metab 2002;87:4522-4527.
115. Marin P, Krotkiewski M, Bjorntorp P. Androgen treatment of middle-aged, obese men: effects on metabolism, muscle and adipose tissues. Eur J Med 1992;1:329-336.
116. Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male 2003;6:1-7.
117. Zouboulis CC, Degitz K. Androgen action on human skin - from basic research to clinical significance. Exp Dermatol 2004;13 Suppl 4:5-10.
118. Deslypere JP, Vermeulen A. Aging and tissue androgens. J Clin Endocrinol Metab 1981;53:430-434.
119. Zouboulis C, Chen W, Alestas T, Makrantonaki E, Seltmann H, Muller-Decker K. Sexual hormones utilize complex mechanisms to modulate sebocyte differentiation. Exp Dermatol 2005;14:156.
120. Akamatsu H, Zouboulis CC, Orfanos CE. Control of human sebocyte proliferation in vitro by testosterone and 5-alpha-dihydrotestosterone is dependent on the localization of the sebaceous glands. J Invest Dermatol 1992;99:509-511.
121. Rosenfield RL, Lucky AW. Acne, hirsutism, and alopecia in adolescent girls. Clinical expressions of androgen excess. Endocrinol Metab Clin North Am 1993;22:507-532.
122. Shaw JC. Acne: effect of hormones on pathogenesis and management. Am J Clin Dermatol 2002;3:571-578.
123. Kaufman KD. Androgens and alopecia. Mol Cell Endocrinol 2002;198:89-95.
124. Starka L, Cermakova I, Duskova M, Hill M, Dolezal M, Polacek V. Hormonal profile of men with premature balding. Exp Clin Endocrinol Diabetes 2004;112:24-28.
125. Fritsch M, Orfanos CE, Zouboulis CC. Sebocytes are the key regulators of androgen homeostasis in human skin. J Invest Dermatol 2001;116:793-800.
126. Zouboulis CC. Human skin: an independent peripheral endocrine organ. Horm Res 2000;54:230-242.
127. Deslypere JP, Vermeulen A. Influence of age on steroid concentrations in skin and striated muscle in women and in cardiac muscle and lung tissue in men. J Clin Endocrinol Metab 1985;61:648-653.
128. Heaton JP, Morales A. Andropause-a multisystem disease. Can J Urol 2001;8:1213-1222.
129. Zouboulis ChC. Intrinsic skin aging. A critical appraisal of the role of hormones. Hautarzt 2003;54:825-832.
130. Wu CY, Yu TJ, Chen MJ. Age related testosterone level changes and male andropause syndrome. Chang Gung Med J 2000;23:348-353.
131. Campion JM, Maricic MJ. Osteoporosis in men. Am Earn Physician 2003;67:1521-1526.
132. Conde FA, Aronson WJ. Risk factors for male osteoporosis. Urol Oncol 2003;21:380-383.
133. Peris P, Guanabens N. Male osteoporosis. Curr Opin Rheumatol 1996;8:357-364.
134. Boonen S, Vanderschueren D, Geusens P, Bouillon R. Age-associated endocrine deficiencies as potential determinants of femoral neck (type II) osteoporotic fracture occurrence in elderly men. Int J Androl 1997;20:134-143.
135. Khosla S, Melton LJ 3rd, Atkinson EJ, O'Fallon WM, Klee GG, Riggs BL. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. Clin Endocrinol Metab 1998;83:2266-2274.
136. Gurlek A, Gedik O. Endogenous sex steroid, GH and IGF-I levels in normal elderly men: relationships with bone mineral density and markers of bone turnover. J Endocrinol Invest 2001;24:408-414.
137. Stanley HL, Schmitt BP, Poses RM, Deiss WP. Does hypogonadism contribute to the occurrence of a minimal trauma hip fracture in elderly men? J Am Geriatr Soc 1991;39:766-771.
138. Jackson JA, Riggs MW, Spiekerman AM. Testosterone deficiency as a risk factor for hip fractures in men: a case-control study. Am J Med Sci 1992;304:4-8.
139. Rucker D, Ezzat S, Diamandi A, Khosravi J, Hanley DA. IGF-I and testosterone levels as predictors of bone mineral density in healthy, community-dwelling men. Clin Endocrinol (Oxf) 2004;60:491-499.
140. Pietschmann P, Kudlacek S, Grisar J, Spitzauer S, Woloszczuk W, Willvonseder. Bone turnover markers and sex hormones in men with idiopathic osteoporosis. Eur J Clin Invest 2001;31:444-451.
141. Kenny AM, Prestwood KM, Marcello KM, Raisz LG. Determinants of bone density in healthy older men with low testosterone levels. J Gerontol A Biol Sci Med Sci 2000;55:M492-M497.
142. Szulc P, Claustrat B, Marchand F, Delmas PD. Increased risk of falls and increased bone resorption in elderly men with partial androgen deficiency: the MINOS study. J Clin Endocrinol Metab 2003;88:5240-5247.
143. Greendale GA, 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 1997; 12:1833-1843.
144. Gennari L, Merlotti D, Martini G, Gonnelli S, Franci B, Campagna S, Lucani B, Dal Canto N, Valenti R, Gennari C, et al. Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men. J Clin Endocrinol Metab 2003;88:5327-5333.
145. 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;82:2386-2390.
146. Zacharin MR, Pua J, Kanumakala S. Bone mineral density outcomes following long-term treatment with subcutaneous testosterone pellet implants in male hypogonadism. Clin Endocrinol (Oxf) 2003;58:691-695.
147. Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N. Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men. Clin Endocrinol (Oxf) 2001;54:739-750.
148. Leifke E, Korner HC, Link TM, Behre HM, Peters PE, Nieschlag E. Effects of testosterone replacement therapy on cortical and trabecular bone mineral density, vertebral body area and paraspinal muscle area in hypogonadal men. Eur J Endocrinol 1998;138:51-58.
149. Medras M, Jankowska EA, Rogucka E. Effects of long-term testosterone substitutive therapy on bone mineral content in men with hypergonadotrophic hypogonadism. Andrologia 2001;33:47-52.
150. Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 2001;56:M266-M272.
151. Francis RM. Androgen replacement in aging men. Calcif Tissue Int 2001;69:235-238.
152. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Holmes JH, Dlewati A, Staley J, Santanna J, Kapoor SC, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 1999; 84:1966-1972.
153. Amory JK, Watts NB, Easley KA, Sutton PR, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 2004;89:503-510.
154. Crawford BA, Liu PY, Kean MT, Bleasel JF, Handelsman DJ. Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment. J Clin Endocrinol Metab 2003;88: 3167-3176.
155. Morales A. Andropause (or symptomatic late-onset hypogonadism): facts, fiction and controversies. Aging Male 2004;7:297-303.
156. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999;84:3666-3672.
157. Barini A, Liberale I, Menini E. Simultaneous determination of free testosterone and testosterone bound to non-sex-hormone-binding globulin by equilibrium dialysis. Clin Chem 1993;39:938-941.
158. Morley JE, Patrick P, Perry HM 3rd. Evaluation of assays available to measure free testosterone. Metabolism 2002;51:554-559.
159. Taieb J, Mathian B, Millot F, Patricot MC, Mathieu E, Queyrel N, Lacroix I, Somma-Delpero C, Boudou P. Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children. Clin Chem 2003;49:1381-1395.
160. Matsumoto AM, Bremner WJ. Serum testosterone assays-accuracy matters. J Clin Endocrinol Metab 2004;89:520-524.
161. Simoni M. Methodology for measuring testosterone, DHT and SHBG in a clinical setting. In: Nieschlag E, Behre HM, editors. Testosterone: action, deficiency, substitution. Cambridge: Cambridge University Press; 2004. pp 641-664.
162. De Rosa M, Zarrilli S, Di Sarno A, Milano N, Gaccione M, Boggia B, Lombardi G, Colao A. Hyperprolactinemia in men: clinical and biochemical features and response to treatment. Endocrine 2003;20:75-82.
163. Jockenhovel F. Testosterone therapy-what, when and to whom? Aging Male 2004;7:319-324.
164. Lunenfeld B. Replacement therapy in the aging male. J Endocrinol Invest 2002;25(10 Suppl):2-9.
165. Gooren LJ, Bunck MC. Androgen replacement therapy: present and future. Drugs 2004;64:1861-1891.
166. Schubert M, Minnemann T, Hubler D, Rouskova D, Christoph A, Oettel M, Ernst M, Mellinger U, Krone W, Jockenhovel F. Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism. J Clin Endocrinol Metab 2004;89:5429-5434.
167. Cunningham GR, Cordero E, Thornby JI. Testosterone replacement with transdermal therapeutic systems. Physiological serum testosterone and elevated dihydrotestosterone levels. JAMA 1989;261:2525-2530.
168. Raynaud JP, Legros JJ, Rollet J, Auges M, Bunouf P. Testosterone therapy of hypogonadism: Long-term efficacy and safety of a new testosterone-in-adhesive matrix patch applied every two days. Aging Male 2005;in press.
169. Swerdloff RS, Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Longstreth J, Berman N. Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J Clin Endocrinol Metab 2000;85:4500-4510.
170. Heywood R, Chesterman H, Ball SA, Wadsworth PF. Toxicity of methyl testosterone in the beagle dog. Toxicology 1977;7:357-365.
171. Welder AA, Robertson JW, Melchert RB. Toxic effects of anabolic-androgenic steroids in primary rat hepatic cell cultures. J Pharmacol Toxicol Methods 1995;33:187-195.
172. Kohn FM, Schill WB. A new oral testosterone undecanoate formulation. World J Urol 2003;21:311-315.
173. Labrie F, Bélanger A, Cusan L, Candas B. Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites. Intracrinology. J Clin Endocrinol Metab 1997; 82:2403-409.
174. Johnson MD, Bebb RA, Sirrs SM. Uses of DHEA in aging and other disease states. Ageing Res Rev 2002;1:29-41.
175. Saad F, Hoesl CE, Oettel M, Fauteck J-D, Römmler A. Dehydroepiandrosterone (DHEA) and successful male aging: Significance for the urologist. Eur Urol 2005, submitted.
176. Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol 2000;161:73-88.
177. Acevedo HF. Human chorionic gonadotropin (hCG), the hormone of life and death: a review. J Exp Ther Oncol 2002;2:133-145.
178. Meier C, Liu PY, Ly LP, de Winter-Modzelewski J, Jimenez M, Handelsman DJ, Seibel MJ. Recombinant human chorionic gonadotropin but not dihydrotestosterone alone stimulates osteoblastic collagen synthesis in older men with partial age-related androgen deficiency. J Clin Endocrinol Metab 2004;89:3033-3041.
179. Liu PY, Wishart SM, Handelsman DJ. A double-blind, placebo-controlled, randomized clinical trial of recombinant human chorionic gonadotropin on muscle strength and physical function and activity in older men with partial age-related androgen deficiency. J Clin Endocrinol Metab 2002;87:3125-3135.
180. Liu PY, Wishart SM, Celermajer DS, Jimenez M, Pierro ID, Conway AJ, Handelsman DJ. Do reproductive hormones modify insulin sensitivity and metabolism in older men? A randomized, placebo-controlled clinical trial of recombinant human chorionic gonadotropin. Eur J Endocrinol 2003;148: 55-66.
181. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004;350:482-492.
182. Schroder FH. EORTC Genitourinary Group: prostate cancer studies. Prog Clin Biol Res 1990;357:73-81.
183. Huggins C, Stevens RE, Hodges CV. Studies on prostatic cancer: The effects of castration on advanced carcinoma of the prostate gland. Arch Surg 1941;43:209-223.
184. Miyamoto H, Messing EM, Chang C. Androgen deprivation therapy for prostate cancer: current status and future prospects. Prostate 2004;61:332-353.
185. Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman JD. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 1993; 150(2 Pt 1):379-385.
186. 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;53:423-424.
187. Loughlin KR, Richie JP. Prostate cancer after exogenous testosterone treatment for impotence. J Urol 1997;157:1845.
188. Rhoden EL, Morgentaler A. Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia. J Urol 2003;170(6 Pt 1):2348-2351.
189. Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol 2004;172:920-922.
190. Agarwal PK, Oefelein MG. Testosterone replacement therapy after primary treatment for prostate cancer. J Urol 2005;173:533-536.
191. Luboldt HJ, Altwein JE, Bichler KH, Czaja D, Husing J, Fornara P, Jockei KH, Lubben G, Schalkhauser K, Weissbach L, et al. Early recognition of prostate carcinoma. Initial results of a prospective multicenter study in Germany. Project Group for Early Detection DGU-BDU Laboratory diagnosis Professional Circle. Urologe A 1999;38:114-123.
192. Djavan B, Zlotta A, Kratzik C, Remzi M, Seitz C, Schulman CC, Marberger M. PSA, PSA density, PSA density of transition zone, free/total PSA ratio, and PSA velocity for early detection of prostate cancer in men with serum PSA 2.5 to 4.0 ng/mL. Urology 1999;54:517-522.
193. Shahidi NT. Androgens and erythropoiesis. N Engl J Med 1973;289:72-80.
194. Basaria S, Dobs AS. Risks versus benefits of testosterone therapy in elderly men. Drugs Aging 1999;15:131-142.
195. Schneider BK, Pickett CK, Zwillich CW, Weil JV, McDermott MT, Santen RJ, Varano LA, White DP. Influence of testosterone on breathing during sleep. J Appl Physiol 1986;61:618-623.
196. Matsumoto AM, Sandblom RE, Schoene RB, Lee KA, Giblin EC, Pierson DJ, Bremner WJ. Testosterone replacement in hypogonadal men: effects on obstructive sleep apnoea, respiratory drives, and sleep. Clin Endocrinol (Oxf) 1985;22:713-721.
197. Kouri EM, Lukas SE, Pope HG Jr, Oliva PS. Increased aggressive responding in male volunteers following the administration of gradually increasing doses of testosterone cypionate. Drug Alcohol Depend 1995;40:73-79.
198. Pope HG Jr, Kouri EM, Hudson JI. Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial. Arch Gen Psychiatry 2000;57:133-140.
199. O'Connor DB, Archer J, Wu FC. Effects of testosterone on mood, aggression, and sexual behavior in young men: a double-blind, placebo-controlled, cross-over study. J Clin Endocrinol Metab 2004;89:2837-2845.
200. O'Connor DB, Archer J, Hair WM, Wu FC. Exogenous testosterone, aggression, and mood in eugonadal and hypogonadal men. Physiol Behav 2002;75:557-566.
201. Orengo C, Kunik ME, Molinari V, Wristers K, Yudofsky SC. Do testosterone levels relate to aggression in elderly men with dementia? J Neuropsychiatry Clin Neurosci 2002;14:161-166.