journal of men's health
Volume 6, Issue 3 , Pages 169-176 , September 2009

Testosterone in men's health: a new role for an old hormone

  • Robert J. Feeley, MA

      Affiliations

    • Department of Biochemistry and Urology, Boston University School of Medicine, Boston, MA, USA
  • ,
  • Farid Saad, DVM

      Affiliations

    • Bayer-Schering Pharma, Men's Healthcare, Berlin, Germany and Gulf Medical University Ajman, UAE
  • ,
  • Andre Guay, MD

      Affiliations

    • Department of Endocrinology, Center for Sexual Function, Lahey Clinic, Peabody, MA, USA
  • ,
  • Abdulmaged M. Traish, MBA, PHD

      Affiliations

    • Laboratories for Sexual Medicine, Institute for Sexual Medicine, Boston University School of Medicine, Center for Advanced Biomedical Research, 700 Albany Street, W607, Boston, MA 02118, USA
    • Corresponding Author InformationCorresponding author.

Received 23 May 2009 ,Revised 23 June 2009 ,Accepted 23 June 2009.

References 

  1. Taskinen MR. Is metabolic syndrome the main threat to human health in the twenty-first century?. Arterioscler Thromb Vasc Biol. 2007;27:2275
  2. Bataille V, Perret B, Dallongeville J, Arveiler D, Yarnell J, Ducimetiere P, et al. Metabolic syndrome and coronary heart disease risk in a population-based study of middle-aged men from France and Northern Ireland. Diabetes Metab. 2006;32:475–479
  3. Imam SK, Shahid SK, Hassan A, Alvi Z. Frequency of the metabolic syndrome in type 2 diabetic subjects attending the diabetes clinic of a tertiary care hospital. J Pak Med Assoc. 2007;57:239–242
  4. Rodriguez A, Muller DC, Metter EJ, Maggio M, Harman SM, Blackman MR, et al. Aging, androgens, and the metabolic syndrome in a longitudinal study of aging. J Clin Endocrinol Metab. 2007;92:3568–3572
  5. Muller M, Grobbee DE, den Tonkelaar I, Lamberts SW, van der Schouw YT. Endogenous sex hormones and metabolic syndrome in aging men. J Clin Endocrinol Metab. 2005;90:2618–2623
  6. Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab. 2006;91:843–850
  7. Kupelian V, Shabsigh R, Araujo AB, O’Donnell AB, McKinlay JB. Erectile dysfunction as a predictor of the metabolic syndrome in aging men: results from the Massachusetts Male Aging Study. J Urol. 2006;176:222–226
  8. Miner MM, Sadovsky R. Evolving issues in male hypogonadism: evaluation, management, and related comorbidities. Clin J Med. 2007;74:S38–S46
  9. Miner MM, Seftel AD. Testosterone and aging: what we have learned since the Institute of Medicine and what lies ahead. Int J Clin Prac. 2007;61:622–632
  10. Blouin K, Despres JP, Couillard C, Tremblay A, Prud’homme D, Bouchard C, et al. Contribution of age and declining androgen levels to features of the metabolic syndrome in men. Metabolism. 2005;54:1034–1040
  11. Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen TP, Valkonen VP, et al. The metabolic syndrome and smoking in relation to hypogonadism in middle-aged men: a prospective cohort study. J Clin Endocrinol Metab. 2005;90:712–719
  12. Kaplan SA, Meehan AG, Shah A. The age related decrease in testosterone is significantly exacerbated in obese men with the metabolic syndrome. What are the implications for the relatively high incidence of erectile dysfunction observed in these men?. J Urol. 2006;176:1524–1528
  13. Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen TP, Salonen R, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol. 2003;149:601–608
  14. Pasquali R, Macor C, Vicennati V, Novo F, De Lasio R, Mesini P, et al. Effects of acute hyperinsulinemia on testosterone serum concentrations in adult obese and normal-weight men. Metabolism. 1997;46:526–529
  15. Svartberg J. Epidemiology: testosterone and the metabolic syndrome. Int J Impot Res. 2007;19:124–128
  16. Osuna JA, Gomez-Perez R, Arata-Bellabarba G, Villaroel V. Relationship between BMI, total testosterone, sex hormone-binding-globulin, leptin, insulin and insulin resistance in obese men. Arch Androl. 2006;52:355–361
  17. Svartberg J, von Muhlen D, Sundsfjord J, Jorde R. Waist circumference and testosterone levels in community dwelling men. The Tromso Study. Eur J Epidemiol. 2004;19:657–663
  18. Isidori AM, Caprio M, Strollo F, Moretti C, Frajese G, Isidori A, et al. Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab. 1999;84:3673–3680
  19. Rosmond R, Wallerius S, Wanger P, Martin L, Holm G, Bjorntorp P. A 5 year follow-up study of disease incidence in men with an abnormal hormone pattern. J Intern Med. 2003;254:386–390
  20. Kalyani RR, Dobs AS. Androgen deficiency, diabetes and the metabolic syndrome in men. Curr Opin Endocrinol Diabetes Obes. 2007;14:226–234
  21. D’Amico AV, Denham JW, Crook J, Chen MH, Goldhaber SZ, Lamb DS, et al. Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarction. J Clin Oncol. 2007;25:2420–2425
  22. Braga-Basaria M, Dobs AS, Muller DC, Carducci MA, John M, Egan J, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol. 2006;24:3979–3983
  23. Chen Z, Maricic M, Nguyen P, Ahmann FR, Bruhn R, Dalkin BL. Low bone density and high percentage of body fat among men who were treated with androgen deprivation therapy for prostate carcinoma. Cancer. 2002;95:2136–2144
  24. Smith MR, Finkelstein JS, McGovern FJ, Zietman AL, Fallon MA, Schoenfeld DA, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab. 2002;87:599–603
  25. Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006;91:1305–1308
  26. Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, Hayes FJ. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2007;92:4254–4259
  27. Lee SJ, Gungor N, Bacha F, Arslanian S. Insulin resistance: link to the components of the metabolic syndrome and biomarkers of endothelial dysfunction in youth. Diabetes Care. 2007;30:2091–2097
  28. 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
  29. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab. 1992;75:1092–1098
  30. Swerdloff RS, Wang C. Three-year follow-up of androgen treatment in hypogonadal men: preliminary report with testosterone gel. Aging Male. 2003;6:207–211
  31. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, 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;89:2085–2098
  32. Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, et al. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes Relat Metab Disord. 1992;16:991–997
  33. 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
  34. 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
  35. Parikh NI, Pencine MJ, Wang TJ, Lanier KJ, Fox CS, d’Agostino RB, et al. Increasing trends in incidence of overweight and obesity over 5 decades. Am J Med. 2007;120:242–250
  36. Steinbrook R. Facing the diabetes epidemic – mandatory reporting of glycosylated hemoglobin values in New York City. N Engl J Med. 2006;354:545–548
  37. Ford ES, Li C, Zhao G, Pearson WS, Mokdad AH. Prevalence of the metabolic syndrome among US adolescents using the definition from the international diabetes federation. Diabetes Care. 2008;31:587–589
  38. Haffner SM, Miettinen H, Karhapa P, Mykkanen L, Laakso M. Leptin concentrations, sex hormones, and cortisol in nondiabetic men. J Clin Endocrinol Metab. 1997;82:1807–1809
  39. 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
  40. Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. Rancho Bernardo Study. Endogenous sex hormones and the development of type 2 diabetes in older men and women; the Rancho Bernardo study. Diabetes Care. 2002;25:55–60
  41. Rhoden EL, Ribeiro EP, Teloken C, Souto CA. Diabetes mellitus is associated with subnormal serum levels of free testosterone in men. BJU Int. 2005;96:867–870
  42. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006;166:1660–1665
  43. Selvin E, Feinleib M, Zhang L, Rohrmann S, Rifai N, Nelson W, et al. Androgens and diabetes in men. Diabetes Care. 2007;30:234–238
  44. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2006;295:1288–1299
  45. Simon D, Charles MA, Nahoul K, Orssaud G, Kremski J, Hully V, et al. Association between plasma total testosterone and cardiovascular risk factors in healthy adult men: The Telecom Study. J Clin Endocrinol Metab. 1997;82:682–685
  46. Pitteloud N, Hardin M, Dwyer AA, Valassi E, Yialamas M, Elahi D, et al. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab. 2005;90:2636–2641
  47. Pitteloud N, Mootha VK, Dwyer AA, Hardin M, Lee H, Eriksson KF, et al Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care. 2005;28:1636–1642
  48. Basaria S, Muller DC, Carducci MA, Egan J, Dobs AS. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer. 2006;106:581–588
  49. Lage MJ, Barber BL, Markus RA. Association between androgen-deprivation therapy and incidence of diabetes among males with prostate cancer. Urology. 2007;70:1104–1108
  50. Haidar A, Yassin A, Saad F, Shabsigh R. Effects of androgen deprivation on glycaemic control and on cardiovascular biochemical risk factors in men with advanced prostate cancer with diabetes. Aging Male. 2007;10:189–196
  51. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab. 2004;89:5462–5468
  52. Kapoor D, Aldred H, Clark S, Channer K, Jones T. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes. Diabetes Care. 2007;30:911–917
  53. Pasquali R, Casimirri F, Cantobelli S, Melchionda N, Morselli Labate AM, Fabbri R, et al. Effect of obesity and body fat distribution on sex hormones and insulin in men. Metabolism. 1991;40:101–104
  54. Pagotto U, Gambineri A, Pelusi C, Genghini S, Cacciari M, Otto B, et al. Testosterone replacement therapy restores normal ghrelin in hypogonadal men. J Clin Endocrinol Metab. 2003;88:4139–4143
  55. Naharci MI, Pinar M, Bolu E, Olgun A. Effect of testosterone on insulin sensitivity in men with idiopathic hypogonadotropic hypogonaidsm. Endocr Pract. 2007;13:629–635
  56. Hutson JC, Stocco DM, Campbell GT, Wagoner J. Sertoli cell function in diabetic, insulin-treated diabetic, and semi-starved rats. Diabetes. 1983;32:112–116
  57. Wabitsch M, Blum WF, Muche R, Braun M, Hube F, Rascher W, et al. Contribution of androgens to the gender difference in leptin production in obese children and adolescents. J Clin Invest. 1997;100:808–813
  58. Maggio M, Blackford A, Taub D, Carducci M, Ble A, Metter EJ, et al. Circulating inflammatory cytokine expression in men with prostate cancer undergoing androgen deprivation therapy. J Androl. 2006;27:725–728
  59. Maggio M, Lauretani F, Ceda GP, Bandinelli S, Ling SM, Metter EJ, 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;167:2249–2254
  60. Khaw K, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, 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;116:2694–2701
  61. Carrero JJ, Qureshi AR, Parini P, Arver S, Lindholm B, Barany P, et al. Low serum testosterone increases mortality risk among male dialysis patients. J Am Soc Nephrol. 2009;20(3):613–620
  62. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93:68–75
  63. Basaria S. Androgen deprivation therapy, insulin resistance, and cardiovascular mortality: an inconvenient truth. J Androl. 2008;29:534–539
  64. Smith G, Ben-Shlomo Y, Beswick A, Yarnell J, Lightman S, Elwood P. Cortisol, testosterone, and coronary heart disease prospective evidence from the Caperhill Study. Circulation. 2005;112:332–340
  65. Hak A, Witteman J, de Jong F, Geerlings M, Hofman A, Pols H. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab. 2002;87:3632–3639
  66. Phillips G, Pinkernell B, Jing T. The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb. 1994;14:701–706
  67. Dunajska K, Milewicz A, Szymczak J, Jedrzejuk D, Kuliczkowski W, Salomon P, et al. Evaluation of sex hormone levels and some metabolic factors in men with coronary atherosclerosis. Aging Male. 2004;7:197–204
  68. Makinen JI, Perheentupa A, Irjala K, Pollanen P, Makinen J, Huhtaniemi I, et al. Endogenous testosterone and serum lipids in middle-aged men. Atherosclerosis. 2008;197:688–693
  69. Traish AM, Guay AT, Feeley R, Saad F. The dark side of testosterone deficiency: I. metabolic syndrome and erectile dysfunction. J Androl. 2009;30:10–22
  70. Traish AM, Saad F, Guay AT. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl. 2009;30:23–32
  71. Traish AM, Saad F, Guay AT. The dark side of testosterone deficiency: III. Cardiovascular disease. J Androl 2009 Apr 2.[Epub ahead of print].
  72. Smith MR, Bennett S, Evans L, Kynaton H, Parmar M, Mason M, et al. The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J Clin Endocrinol Metab. 2001;86:4261–4267
  73. 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;92:3844–3853
  74. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448–4456
  75. Dockery F, Bulpitt CJ, Agarwal S, Donaldson M, Rajkumar C. Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Clin Sci. 2003;104:195–201
  76. Marin P, Holmang S, Gustafsson C, Jonsson L, Kvist H, Elander A, et al. Androgen treatment of abdominally obese men. Obesity Res. 1993;1:245–251
  77. Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serium T. J Clin Endocrinol Metab. 2005;90:1502–1510
  78. Heufelder AE, Saad F, Bunck MC, Gooren L. 52-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. Andrology 2009; in press.
  79. Lu YL, Kuang L, Zhu H, Wu H, Wang XF, Pang YP, et al. Changes in aortic endothelium ultrastructure in male rats following castration, replacement with testosterone and administration of 5-alpha-reductase inhibitor. Asian J Androl. 2007;9:843–847
  80. Akishita M, Hashimoto M, Ohike Y, Ogawa S, Iijima K, Eto M, et al. Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertens Res. 2007;30:1029–1034
  81. Foresta C, Caretta N, Lana A, De Toni L, Biagioli A, Ferlin A, et al. Reduced number of circulating endothelial progenitor cells in hypogonadal men. J Clin Endocrin Metab. 2006;91:4599–4602
  82. Malkin CJ, Pugh PJ, Morris PD, Kerry KE, Jones RD, Jones TH, et al. Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life. Heart. 2004;90:871–876
  83. Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J. 2006;27:57–64
  84. Webb C, Elkington A, Kraidly M, Keenan N, Pennell D, Collins P. Effects of oral testosterone treatment on myocardial perfusion and vascular function in men with low plasma testosterone and coronary heart disease. Am J Cardiol. 2008;101:618–624
  85. Makinen J, Jarvisalo M, Pollanen P, Perheentupa A, Irjala K, Koskenvuo M, et al. Increased carotid atherosclerosis in andropausal middle-aged men. J Am Coll Cardiol. 2005;45:1603–1608
  86. De Pergola G, Pannacciulli N, Ciccone M, Tartagni M, Rizzon P, Giorgino R. Free testosterone plasma levels are negatively associated with the intima-media thickness of the common carotid artery in overweight and obese glucose-tolerant young adult men. Int J Obes. 2003;27:803–807
  87. Stattin P, Lumme S, Tekanen L, Alfthan H, Jellum E, Hallmans G, et al. High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study. Int J Cancer. 2004;108:418–424
  88. Travis RC, Key TJ, Allen NE, Appleby PN, Roddam AW, Rinaldi S, et al. Serum androgens and prostate cancer among 643 cases and 643 controls in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 2007;121:1331–1338
  89. Roddam AW, Allen NE, Appleby P, Key TJ. Endogenous Hormones, Prostate Cancer Collaborative Group. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst. 2008;100:170–183
  90. Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab. 2004;89:3313–3318
  91. Haffner SM, Mykkanen L, Valdez RA, Katz MS. Relationship of sex hormones to lipids and lipoproteins in nondiabetic men. J Clin Endocrinol Metab. 1993;77:1610–1615
  92. Pugh PJ, Jones TH, Channer KS. Acute haemodynamic effects of testosterone in men with chronic heart failure. Eur Heart J. 2003;24:909–915
  93. Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men: a 13 year follow-up of former multiple risk factor intervention trial participants. Am J Epidemiol. 1997;146:609–617
  94. Gyllenborg J, Rasmussen S, Borch-Johnsen K, Heitmann BL, Skakkebaek NE, Juul A. Cardiovascular risk factors in men: the role of gonadal steroids and sex hormone-binding globulin. Metabolism. 2001;50:882–888
  95. Dubey RK, Oparil S, Imthurn B, Jackson EK. Sex hormones and hypertension. Cardiovasc Res. 2002;53:688–708
  96. Makhsida N, Shah J, Yan G, Fisch H, Shabsigh R. Hypogonadism and metabolic syndrome: implications for testosterone therapy. J Urol. 2005;174:827–834
  97. Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Bolona ER, Sideras K, 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

PII: S1875-6867(09)00074-8

doi: 10.1016/j.jomh.2009.06.005

journal of men's health
Volume 6, Issue 3 , Pages 169-176 , September 2009