Cardiovascular risk associated with testosterone-boosting medications: A systematic review and meta-Analysis

Expert Opinion on Drug Safety

Volumn 13, Issue 10, 2014, Pages 1327-1351

  Corona, Giovanni ^a   Maseroli, Elisa ^b   Rastrelli, Giulia ^b   Isidori, Andrea M ^c   Sforza, Alessandra ^a   Mannucci, Edoardo ^d   Maggi, Mario ^b  

^a BELLARIA HOSPITAL   (Italy)

^b UNIVERSITY OF FLORENCE   (Italy)

^c SAPIENZA UNIVERSITY OF ROME   (Italy)

^d CAREGGI UNIVERSITY HOSPITAL   (Italy)

Author keywords

Cardiovascular risk; Mortality; Randomized clinical trial; Testosterone

Indexed keywords

PLACEBO; TESTOSTERONE; ANDROGEN;

BODY FAT; CARDIOVASCULAR RISK; HEART DISEASE; HUMAN; HYPOGONADISM; INTERVENTION STUDY; META ANALYSIS; MUSCLE MASS; OUTCOME ASSESSMENT; QUALITY CONTROL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RETROSPECTIVE STUDY; REVIEW; SYSTEMATIC REVIEW; CARDIOVASCULAR DISEASES; MALE; RISK FACTOR;

ANDROGENS; CARDIOVASCULAR DISEASES; HUMANS; HYPOGONADISM; MALE; RISK FACTORS; TESTOSTERONE;

EID: 84907276116     PISSN: 14740338     EISSN: 1744764X     Source Type: Journal    
DOI: 10.1517/14740338.2014.950653     Document Type: Review

References (143)

1. Buvat J, Maggi M, Guay A, Torres LO. Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. J Sex Med 2013;10:245-84
2. Corona G, Rastrelli G, Vignozzi L, et al. Emerging medication for the treatment of male hypogonadism. Expert Opin Emerg Drugs 2012;17:239-59
3. Corona G, Rastrelli G, Maggi M. Diagnosis and treatment of late-onset hypogonadism: systematic review and meta-Analysis of TRT outcomes. Best Pract Res Clin Endocrinol Metab 2013;27:557-79
4. Handelsman DJ. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription Drug misuse. Med J Aust 2013;199:548-51
5. Wu FC, Tajar A, Beynon JM, et al. EMAS Group. Identification of late-onset hypogonadism in middle-Aged and elderly men. N Engl J Med 2010;363:123-35
6. Jain P, Rademaker AW, McVary KT. Testosterone supplementation for erectile dysfunction: results of a meta-Analysis. J Urol 2000;164:371-5
7. Boloña ER, Uraga MV, Haddad RM, et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-Analysis of randomized placebo-controlled trials. Mayo Clin Proc 2007;82:20-8
8. Isidori AM, Giannetta E, Gianfrilli D, et al. Effects of testosterone on sexual function in men: results of a meta-Analysis. Clin Endocrinol (Oxf) 2005;63:381-94
9. Corona G, Isidori AM, Buvat J, et al. Testosterone supplementation and sexual function: a meta-Analysis study. J Sex Med 2014;11:1577-92
10. Is it low T. Available from: www. IsItLowT.com [Last accessed 22 July 2014]
11. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010;363:109-22
12. Vigen R, O'Donnell CI, Baroán AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829-36
13. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014;9:e85805
14. The Risk of Cardiovascular Events in Men Receiving Testosterone Therapy. An Endocrine Society Statement. Available from: https://www.endocrine. org/~/media/endosociety/Files/Advocacy %20and%20Outreach/Position% 20Statements/Other%20Statements/The %20Risk%20of%20Cardiovascular% 20Events%20in%20Men%20Receiving% 20Testosterone%20Therapy.pdf [Last accessed 22 July 2014]
15. Min KJ, Lee CK, Park HN. The lifespan of Korean eunuchs. Curr Biol 2012;22:R792-3
16. Hamilton JB, Mestler GE. Mortality and survival: comparison of eunuchs with intact men and women in a mentally retarded population. J Gerontol 1969;24:395-411
17. Nieschlag E, Nieschlag S, Behre HM. Lifespan and testosterone. Nature 1993;366:215
18. Shores MM, Smith NL, Forsberg CW, et al. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012;97:2050-8
19. Muraleedharan V, Marsh H, Kapoor D, et al. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 2013;169:725-33
20. Corona G, Rastrelli G, Monami M, et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a metaanalytic study. Eur J Endocrinol 2011;165:687-701
21. Araujo AB, Dixon JM, Suarez EA, et al. Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-Analysis. J Clin Endocrinol Metab 2011;96:3007-19
22. Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM. Endogenous testosterone and cardiovascular disease in healthy men: a meta-Analysis. Heart 2011;97:870-5
23. Rastrelli G, Corona G, Lotti F, et al. Relationship of testis size and LH levels with incidence of major adverse cardiovascular events in older men with sexual dysfunction. J Sex Med 2013;10:2761-73
24. Toma M, McAlister FA, Coglianese EE, et al. Testosterone supplementation in heart failure: a meta-Analysis. Circ Heart Fail 2012;5:315-21
25. Calof OM, Singh AB, Lee ML, 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
26. Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and metaanalysis of randomized placebo-controlled trials. Mayo Clin Proc 2007;82:29-39
27. Fernaández-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-Analysis. J Clin Endocrinol Metab 2010;95:2560-75
28. Xu L, Freeman G, Cowling BJ, et al. Testosterone therapy and cardiovascular events among men: a systematic review and meta-Analysis of placebo-controlled randomized trials. BMC Med 2013;11:108
29. U.S. Food and Drug Administration. Available from: http://www.fda.gov/ [Last accessed 22 July 2014]
30. Prisma checklist. Available from: http:/ www.prisma-statement.org [Last accessed 22 July 2014]
31. Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. The Copenhagen Study Group for Liver Diseases. Hepatology 1986;6:807-13
32. Drinka PJ, Jochen AL, Cuisinier M, et al. Polycythemia as a complication of testosterone replacement therapy in nursing home men with low testosterone levels. J Am Geriatr Soc 1995;43:899-901
33. Aydin S, Odabaş O, Ercan M, et al. Efficacy of testosterone, trazodone and hypnotic suggestion in the treatment of non-organic male sexual dysfunction. Br J Urol 1996;77:256-60
34. Hall GM, Larbre JP, Spector TD, et al. A randomized trial of testosterone therapy in males with rheumatoid arthritis. Br J Rheumatol 1996;35:568-73
35. Coodley GO, Coodley MK. A trial of testosterone therapy for HIV-Associated weight loss. AIDS 1997;11:1347-52
36. Sih R, Morley JE, Kaiser FE, et al. Testosterone replacement in older hypogonadal men: a 12- month randomized controlled trial. J Clin Endocrinol Metab 1997;82:1661-7
37. Bhasin S, Storer TW, Asbel-Sethi N, et al. Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab 1998;83:3155-62
38. Grinspoon S, Corcoran C, Askari H, et al. Effects of androgen administration in men with the AIDS wasting syndrome. Ann Intern Med 1998;129:18-26
39. Clague 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
40. Snyder 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
41. Bhasin S, Storer TW, Javanbakht M, et al. Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels. JAMA 2000;283:763-70
42. English KM, Steeds RP, Jones TH, et al. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, doubleblind,placebocontrolled study. Circulation 2000;102:1906-11
43. Grinspoon S, Corcoran C, Parlman K, et al. Effects of testosterone and progressive resistance training in eugonadal men with AIDS wasting. A randomized, controlled trial. Ann Intern Med 2000;133:348-55
44. Rabkin JG, Wagner GJ, Rabkin R. A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Arch Gen Psychiatry 2000;57:141-7; discussion 155-6
45. Münzer T, Harman SM, Hees P, et al. Effects of GH and/or sex steroid administration on abdominal subcutaneous and visceral fat in healthy aged women and men. J Clin Endocrinol Metab 2001;86:3604-10
46. Howell SJ, Radford JA, Adams JE, et al. Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy. Clin Endocrinol (Oxf) 2001;55:315-24
47. Seidman SN, Spatz E, Rizzo C, et al. Testosterone replacement therapy for hypogonadal men with major depressive disorder: a randomized, placebocontrolled clinical trial. J Clin Psychiatry 2001;62:406-12
48. Simon D, Charles MA, Lahlou N, et al. Androgen therapy improves insulin sensitivity and decreases leptin level in healthy adult men with low plasma total testosterone: a 3-month randomized placebo-controlled trial. Diabetes Care 2001;24:2149-51
49. Amory JK, Chansky HA, Chansky KL, et al. Preoperative supraphysiological testosterone in older men undergoing knee replacement surgery. J Am Geriatr Soc 2002;50:1698-701
50. Ferrando 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
51. Pope HG Jr, Cohane GH, Kanayama G, et al. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry 2003;160:105-11
52. Steidle C, Schwartz S, Jacoby K, et al. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab 2003;88:2673-81
53. Tan RS, Pu SJ. A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer's disease. Aging Male 2003;6:13-17
54. Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 2004;89:503-10
55. Cavallini G, Caracciolo S, Vitali G, et al. Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology 2004;63:641-6
56. Kenny AM, Fabregas G, Song C, et al. 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
57. Malkin CJ, Pugh PJ, Morris PD, et al. Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life. Heart 2004;90:871-6
58. Malkin CJ, Pugh PJ, Jones RD, et al. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab 2004;89:3313-18
59. Rabkin JG, Wagner GJ, McElhiney MC, et al. Testosterone versus fluoxetine for depression and fatigue in HIV/AIDS: a placebo-controlled trial. J Clin Psychopharmacol 2004;24:379-85
60. Svartberg J, Aasebø U, Hjalmarsen A, et al. Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial. Respir Med 2004;98:906-13
61. Seidman SN, Miyazaki M, Roose SP. Intramuscular testosterone supplementation to selective serotonin reuptake inhibitor in treatment-resistant depressed men: randomized placebocontrolled clinical trial. J Clin Psychopharmacol 2005;25:584-8
62. Sullivan DH, Roberson PK, Johnson LE, et al. Effects of muscle strength training and testosterone in frail elderly males. Med Sci Sports Exerc 2005;37:1664-72
63. Brockenbrough AT, Dittrich MO, Page ST, et al. Transdermal androgen therapy to augment EPO in the treatment of anemia of chronic renal disease. Am J Kidney Dis 2006;47:251-62
64. Giannoulis MG, Sonksen PH, Umpleby M, et al. The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial. J Clin Endocrinol Metab 2006;91:477-84
65. Gold J, Batterham MJ, Rekers H, et al. Effects of nandrolone decanoate compared with placebo or testosterone on HIV-Associated wasting. HIV Med 2006;7:146-55
66. Kapoor D, Goodwin E, Channer KS, et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006;154:899-06
67. Katznelson L, Robinson MW, Coyle CL, et al. Effects of modest testosterone supplementation and exercise for 12 weeks on body composition and quality of life in elderly men. Eur J Endocrinol 2006;155:867-75
68. Lu 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
69. Malkin CJ, Pugh PJ, West JN, et al. Testosterone therapy in men with moderate severity heart failure: a doubleblind randomized placebo controlled trial. Eur Heart J 2006;27:57-64
70. Marks LS, Mazer NA, Mostaghel E, 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
71. Merza Z, Blumsohn A, Mah PM, et al. Double-blind placebo-controlled study of testosterone patch therapy on bone turnover in men with borderline hypogonadism. Int J Androl 2006;29:381-91
72. Nair 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
73. Okun MS, Fernandez HH, Rodriguez RL, et al. Testosterone therapy in men with Parkinson Disease: results of the TEST-PD Study. Arch Neurol 2006;63:729-35
74. Bhasin S, Parker RA, Sattler F, et al. Effects of testosterone supplementation on whole body and regional fat mass and distribution in human immunodeficiency virus-infected men with abdominal obesity. J Clin Endocrinol Metab 2007;92:1049-57
75. Chiang HS, Hwang TI, Hsui YS, et al. Transdermal testosterone gel increases serum testosterone levels in hypogonadal men in Taiwan with improvements in sexual function. Int J Impot Res 2007;19:411-17
76. Agledahl I, Hansen JB, Svartberg J. Impact of testosterone treatment on postprandial triglyceride metabolism in elderly men with subnormal testosterone levels. Scand J Clin Lab Invest 2008;68:641-8
77. Allan CA, Strauss BJ, Burger HG, et al. 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
78. Basurto L, Zarate A, Gomez R, et al. Effect of testosterone therapy on lumbar spine and hip mineral density in elderly men. Aging Male 2008;11:140-5
79. Emmelot-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
80. Knapp PE, Storer TW, Herbst KL, et al. Effects of a supra-physiological dose of testosterone on physical function, muscle performance, mood, and fatigue in men with HIV-Associated weight loss. Am J Physiol Endocrinol Metab 2008;294:E1135-43
81. Svartberg J, Agledahl I, Figenschau Y, 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
82. Caminiti G, Volterrani M, Iellamo F, 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
83. Chiang HS, Cho SL, Lin YC, et al. Testosterone gel monotherapy improves sexual function of hypogonadal men mainly through restoring erection: evaluation by IIEF score. Urology 2009;73:762-6
84. Chapman IM, Visvanathan R, Hammond AJ, et al. Effect of testosterone and a nutritional supplement, alone and in combination, on hospital admissions in undernourished older men and women. Am J Clin Nutr 2009;89:880-9
85. Legros JJ, Meuleman EJ, Elbers JM, et al. Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study. Eur J Endocrinol 2009;160:821-31
86. Mathur A, Malkin C, Saeed B, et al. Long-Term benefits of testosterone replacement therapy on angina threshold and atheroma in men. Eur J Endocrinol 2009;161:443-9
87. Seidman SN, Orr G, Raviv G, et al. Effects of testosterone replacement in middle-Aged men with dysthymia: a randomized, placebo-controlled clinical trial. J Clin Psychopharmacol 2009;29:216-21
88. Shores MM, Kivlahan DR, Sadak TI, et al. A randomized, double-blind, placebo-controlled study of testosterone treatment in hypogonadal older men with subthreshold depression (dysthymia or minor depression). J Clin Psychiatry 2009;70:1009-16
89. Aversa A, Bruzziches R, Francomano D, et al. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-Aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebocontrolled study. J Sex Med 2010;7:3495-503
90. Aversa A, Bruzziches R, Francomano D, et al. Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. J Endocrinol Invest 2010;33:776-83
91. Gopal RA, Bothra N, Acharya SV, et al. Treatment of hypogonadism with testosterone in patients with type 2 diabetes mellitus. Endocr Pract 2010;16:570-6
92. Kalinchenko SY, Tishova YA, Mskhalaya GJ, et al. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the doubleblinded placebo-controlled Moscow study. Clin Endocrinol (Oxf) 2010;73:602-12
93. Srinivas-Shankar U, Roberts SA, Connolly MJ, 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;95:639-50
94. Amiaz R, Pope HG Jr, Mahne T, et al. Testosterone gel replacement improves sexual function in Depressed men taking serotonergic antidepressants: a randomized, placebo-controlled clinical trial. J Sex Marital Ther 2011;37:243-54
95. Ho CC, Tong SF, Low WY, et al. A randomized, double-blind, placebocontrolled trial on the effect of longacting testosterone treatment as assessed by the Aging Male Symptoms scale. BJU Int 2012;110:260-5
96. Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011;34:828-37
97. Kaufman JM, Miller MG, Garwin JL, et al. Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men. J Sex Med 2011;8:2079-89
98. Hoyos CM, Yee BJ, Phillips CL, et al. Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial. Eur J Endocrinol 2012;167:531-41
99. Behre HM, Tammela TL, Arver S, et al. A randomized, double-blind, placebocontrolled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen Deficiency over 6 months with 12 months open-label follow-up. Aging Male 2012;15:198-207
100. Hackett G, Cole N, Bhartia M, et al. Testosterone replacement therapy with long-Acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes. J Sex Med 2013;10:1612-27
101. Hildreth KL, Barry DW, Moreau KL, et al. Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with lownormal testosterone levels. J Clin Endocrinol Metab 2013;98:1891-900
102. Maggio M, Snyder PJ, Ceda GP, et al. Is the haematopoietic effect of testosterone mediated by erythropoietin?. The results of a clinical trial in older men. Andrology 2013;1:24-8
103. Johnsen SG, Bennett EP, Jensen VG. Therapeutic effectiveness of oral testosterone. Lancet 1974;2:1473-5
104. Benkert O, Witt W, Adam W, Leitz A. Effects of testosterone undecanoate on sexual potency and the hypothalamic-pituitary-gonadal axis of impotent males. Arch Sex Behav 1979;8:471-9
105. Davidson JM, Camargo CA, Smith ER. Effects of androgen on sexual behavior in hypogonadal men. J Clin Endocrinol Metab 1979;48:955-8
106. Skakkebaek NE, Bancroft J, Davidson DW, Warner P. Androgen replacement with oral testosterone undecanoate in hypogonadal men: a double blind controlled study. Clin Endocrinol (Oxf) 1981;14:49-61
107. Bancroft J, Wu FC. Changes in erectile responsiveness during androgen replacement therapy. Arch Sex Behav 1983;12:59-66
108. Kwan M, Greenleaf WJ, Mann J, et al. The nature of androgen action on male sexuality: a combined laboratory-selfreport study on hypogonadal men. J Clin Endocrinol Metab 1983;57:557-62
109. O'Carroll R, Bancroft J. Testosterone therapy for low sexual interest and erectile dysfunction in men: a controlled study. Br J Psychiatry 1984;145:146-51
110. Nankin HR, Lin T, Osterman J. Chronic testosterone cypionate therapy in men with secondary impotence. Fertil Steril 1986;46:300-7
111. Gluud C, Wantzin P, Eriksen J. No effect of oral testosterone treatment on sexual dysfunction in alcoholic cirrhotic men. Gastroenterology 1988;95:1582-7
112. Carani C, Zini D, Baldini A, et al. Effects of androgen treatment in impotent men with normal and low levels of free testosterone. Arch Sex Behav 1990;19:223-34
113. Mårin P, Holmäng S, J€onsson L, et al. The effects of testosterone treatment on body composition and metabolism in middle-Aged obese men. Int J Obes Relat Metab Disord 1992;16:991-7
114. Clopper RR, Voorhess ML, MacGillivray MH, et al. Psychosexual behavior in hypopituitary men: a controlled comparison of gonadotropin and testosterone replacement. Psychoneuroendocrinology 1993;18:149-61
115. 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;26:231-41
116. Dobs AS, Hoover DR, Chen MC, Allen R. Pharmacokinetic characteristics, efficacy, and safety of buccal testosterone in hypogonadal males: a pilot study. J Clin Endocrinol Metab 1998;83:33-9
117. Anderson RA, Bancroft J, Wu FC. The effects of exogenous testosterone on sexuality and mood of normal men. J Clin Endocrinol Metab 1999;75:1503-7
118. Wolf OT, Preut R, Hellhammer DH, et al. Testosterone and cognition in elderly men: a single testosterone injection blocks the practice effect in verbal fluency, but has no effect on spatial or verbal memory. Biol Psychiatry 2000;47:650-4
119. Kenny AM, Prestwood KM, Gruman CA, et al. Effects of transdermal testosterone on lipids and vascular reactivity in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 2002;57:M460-5
120. O'Connor DB, Archer J, Hair WM, Wu FC. Exogenous testosterone, aggression, and mood in eugonadal and hypogonadal men. Physiol Behav 2002;75:557-66
121. Malkin CJ, Morris PD, Pugh PJ, et al. Effect of testosterone therapy on QT dispersion in men with heart failure. Am J Cardiol 2003;92:1241-3
122. Haren M, Chapman I, Coates P, et al. Effect of 12 month oral testosterone on testosterone deficiency symptoms in symptomatic elderly males with lownormal gonadal status. Age Ageing 2005;34:125-30
123. Sheffield-Moore M, Dillon EL, Casperson SL, et al. A randomized pilot study of monthly cycled testosterone replacement or continuous testosterone replacement versus placebo in older men. J Clin Endocrinol Metab 2011;96:E1831-7
124. Frederiksen L, Højlund K, Hougaard DM, et al. Testosterone therapy decreases subcutaneous fat and adiponectin in aging men. Eur J Endocrinol 2012;166:469-76
125. Corona G, Mondaini N, Ungar A, et al. Phosphodiesterase type 5 (PDE5) inhibitors in erectile dysfunction: the proper drug for the proper patient. J Sex Med 2011;8:3418-32
126. Corona G, Razzoli E, Forti G, et al. The use of phosphodiesterase 5 inhibitors with concomitant medications. J Endocrinol Invest 2008;31:799-808
127. Giannetta E, Isidori AM, Galea N, et al. Chronic inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation 2012;125:2323-33
128. Aversa A, Isidori AM, Spera G, et al. Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. Clin Endocrinol (Oxf) 2003;58:632-8
129. 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
130. Buvat J, Montorsi F, Maggi M, et al. Hypogonadal men non responders to the PDE5 inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST study). J Sex Med 2011;8:284-93
131. Spitzer M, Basaria S, Travison TG, et al. Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med 2012;157:681-91
132. Cochrane Handbook for Systematic Reviews of Interventions. Available from: www.cochrane-handbook.org [Last accessed 22 July 2014]
133. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials 1996;17:1-12
134. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088-101
135. Egger M, Davey SG, Schneider M, et al. Bias in meta-Analysis detected by a simple, graphical test. BMJ 1997;315:629-34
136. Corona G, Monami M, Rastrelli G, et al. Type 2 diabetes mellitus and testosterone: a meta-Analysis study. Int J Androl 2011;34(6 Pt 1):528-40
137. Cai X, Tian Y, Wu T, et al. Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: a systematic review and meta-Analysis of randomized controlled trials. Asian J Androl 2014;16:146-52
138. Corona G, Vignozzi L, Sforza A, Maggi M. Risks and benefits of late onset hypogonadism treatment: an expert opinion. World J Mens Health 2013;31:103-25
139. Grimes DA, Schulz KF. False alarms and pseudo-epidemics: the limitations of observational epidemiology. Obstet Gynecol 2012;120:920-7
140. Corona G, Rastrelli G, Vignozzi L, et al. Testosterone, cardiovascular disease and the metabolic syndrome. Best Pract Res Clin Endocrinol Metab 2011;25:337-53
141. Corona G, Mannucci E, Lotti F, et al. Pulse pressure, an index of arterial stiffness, is associated with androgen Deficiency and impaired penile blood flow in men with ED. J Sex Med 2009;6:285-93
142. Antithrombotic Trialists' (ATT) Collaboration. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-Analysis of individual participant data from randomised trials. Lancet 2009;373:1849-60
143. Saad F, Aversa A, Isidori AM, Gooren LJ. Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Curr Diabetes Rev 2012;8:131-43