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Horm Metab Res 2011; 43(3): 153-164
DOI: 10.1055/s-0030-1270521
Review

© Georg Thieme Verlag KG Stuttgart · New York

Testosterone Deficiency as a Risk Factor for Cardiovascular Disease

M. I. Ullah1 , T. Washington2 , M. Kazi2 , S. Tamanna1 , 3 , C. A. Koch4
  • 1Division of General Internal Medicine, University of Mississippi Medical Center, Jackson, USA
  • 2Department of Medicine, Advocate Christ Medical Center and University of Illinois, Chicago, IL, USA
  • 3Division of Pulmonary and Sleep Medicine, University of Mississippi Medical Center, Jackson, USA
  • 4Division of Endocrinology, Department of Medicine, University of Mississippi Medical Center, Jackson, USA
Further Information

Publication History

received 22.11.2010

accepted 15.12.2010

Publication Date:
31 January 2011 (online)

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Abstract

Testosterone deficiency (TD) has become a frequently diagnosed condition in our current society with an obesity epidemic. Men diagnosed with TD often have co-morbidities including metabolic syndrome. Challenging aspects in diagnosing and treating patients with TD include intra-individual variation of symptoms combined with lack of its correlation with serum levels of testosterone. Apart from sexual aspects including libido and erectile function, replacement therapy with testosterone might have beneficial metabolic effects, whereas untreated TD might increase cardiometabolic risk and disease. In this article, we review the cardiovascular and metabolic risks associated with TD, as well as risks and benefits of testosterone replacement therapy. We also provide insights into potential mechanisms of the association between cardiometabolic risks with TD (treated and untreated) and propose an individual treatment algorithm.

Key words

testosterone - cardiovascular disease - dyslipidemia - metabolic syndrome - libido - erectile function - aging

References

  • 1 Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population.  Am Heart J. 1986;  111 383-390
    Search in Google Scholar
  • 2 Barrett-Connor E, Stuenkel C. Hormones and heart disease in women: Heart and Estrogen/Progestin Replacement Study in perspective.  J Clin Endocrinol Metab. 1999;  84 1848-1853
    Search in Google Scholar
  • 3 Kienitz T, Allolio B, Strasburger CJ, Quinkler M. Sex-specific regulation of ENaC and androgen receptor in female rat kidney.  Horm Metab Res. 2009;  41 356-362
    Search in Google Scholar
  • 4 Jones TH, Saad F. The effects of testosterone on risk factors for, and the mediators of, the atherosclerotic process.  Atherosclerosis. 2009;  207 318-327
    Search in Google Scholar
  • 5 Zitzmann M. Testosterone deficiency, insulin resistance and the metabolic syndrome.  Nat Rev Endocrinol. 2009;  5 673-681
    Search in Google Scholar
  • 6 Borst SE, Quindry JC, Yarrow JF, Conover CF, Powers SK. Testosterone administration induces protection against global myocardial ischemia.  Horm Metab Res. 2010;  42 122-129
    Search in Google Scholar
  • 7 Nettleship JE, Pugh PJ, Channer KS, Jones T, Jones RD. Inverse relationship between serum levels of interleukin-1beta and testosterone in men with stable coronary artery disease.  Horm Metab Res. 2007;  39 366-371
    Search in Google Scholar
  • 8 Yildiz O, Seyrek M. Vasodilating mechanisms of testosterone.  Exp Clin Endocrinol Diabetes. 2007;  115 1-6
    Search in Google Scholar
  • 9 Bourghardt J, Wilhelmson AS, Alexanderson C, De Gendt K, Verhoeven G, Krettek A, Ohlsson C, Tivesten A. Androgen receptor-dependent and independent atheroprotection by testosterone in male mice.  Endocrinology. 2010;  151 5428-5437
    Search in Google Scholar
  • 10 von Dehn G, von Dehn O, Volker W, Langer C, Weinbauer GF, Behre HM, Nieschlag E, Assmann G, von Eckardstein A. Atherosclerosis in apolipoprotein E-deficient mice is decreased by the suppression of endogenous sex hormones.  Horm Metab Res. 2001;  33 110-114
    Search in Google Scholar
  • 11 Tripathy D, Shah P, Lakshmy R, Reddy KS. Effect of testosterone replacement on whole body glucose utilisation and other cardiovascular risk factors in males with idiopathic hypogonadotrophic hypogonadism.  Horm Metab Res. 1998;  30 642-645
    Search in Google Scholar
  • 12 Muller M, den Tonkelaar I, Thijssen JH, Grobbee DE, van der Schouw YT. Endogenous sex hormones in men aged 40–80 years.  Eur J Endocrinol. 2003;  149 583-589
    Search in Google Scholar
  • 13 Kazi M, Geraci SA, Koch CA. Considerations for the diagnosis and treatment of testosterone deficiency in elderly men.  Am J Med. 2007;  120 835-840
    Search in Google Scholar
  • 14 Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging.  J Clin Endocrinol Metab. 2001;  86 724-731
    Search in Google Scholar
  • 15 Liu PP, Fukuoka M. Sex hormones as novel risk biomarkers for atherosclerosis in peripheral vascular disease.  J Am Coll Cardiol. 2007;  50 1077-1079
    Search in Google Scholar
  • 16 Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study.  Int J Clin Pract. 2006;  60 762-769
    Search in Google Scholar
  • 17 Araujo AB, Esche GR, Kupelian V, O’Donnell AB, Travison TG, Williams RE, Clark RV, McKinlay JB. Prevalence of symptomatic androgen deficiency in men.  J Clin Endocrinol Metab. 2007;  92 4241-4247
    Search in Google Scholar
  • 18 Bassil N, Alkaade S, Morley JE. The benefits and risks of testosterone replacement therapy: a review.  Ther Clin Risk Manag. 2009;  5 427-448
    Search in Google Scholar
  • 19 Wu FC, Tajar A, Pye SR, Silman AJ, Finn JD, O’Neill TW, Bartfai G, Casanueva F, Forti G, Giwercman A, Huhtaniemi IT, Kula K, Punab M, Boonen S, Vanderschueren D;. European Male Aging Study Group . 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 2737-2745
    Search in Google Scholar
  • 20 Veldhuis JD. Aging and hormones of the hypothalamo-pituitary axis: gonadotropic axis in men and somatotropic axes in men and women.  Ageing Res Rev. 2008;  7 189-208
    Search in Google Scholar
  • 21 Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications.  Endocr Rev. 2005;  26 833-876
    Search in Google Scholar
  • 22 Vgontzas AN, Bixler EO, Chrousos GP. Obesity-related sleepiness and fatigue: the role of the stress system and cytokines.  Ann NY Acad Sci. 2006;  1083 329-344
    Search in Google Scholar
  • 23 Merza Z. Chronic use of opioids and the endocrine system.  Horm Metab Res. 2010;  42 621-626
    Search in Google Scholar
  • 24 Diamanti-Kandarakis E, Palioura E, Kandarakis SA, Koutsilieris M. The impact of endocrine disruptors on endocrine targets.  Horm Metab Res. 2010;  42 543-552
    Search in Google Scholar
  • 25 Hanefeld MLW. Das metabolische Syndrom.  Dt Gesundh-Wesen. 1981;  36 545-551
    Search in Google Scholar
  • 26 Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, Van Pelt RE, Wang H, Eckel RH. The metabolic syndrome.  Endocr Rev. 2008;  29 777-822
    Search in Google Scholar
  • 27 Corona G, Monami M, Rastrelli G, Aversa A, Tishova Y, Saad F, Lenzi A, Forti G, Mannucci E, Maggi M. Testosterone and Metabolic Syndrome: A Meta-Analysis Study.  J Sex Med. 2011;  Jan; 8 (1) 272-283
    Search in Google Scholar
  • 28 Corona G, Monami M, Rastrelli G, Aversa A, Sforza A, Lenzi A, Forti G, Mannucci E, Maggi M. Type 2 diabetes mellitus and testosterone: a meta-analysis study.  Int J Androl. 2010;  Oct 24. doi: 10.1111/j.1365-2605.2010.01117
    Search in Google Scholar
  • 29 Corona G, Monami M, Rastrelli G, Melani C, Balzi D, Sforza A, Forti G, Mannucci E, Maggi M. Is Metabolic Syndrome a Useless Category in Subjects with High Cardiovascular Risk? Results from a Cohort Study in Men with Erectile Dysfunction.  J Sex Med. 2010;  Nov 22. doi: 10.1111/j.1743-6109.2010.02126
    Search in Google Scholar
  • 30 Schutte AE, Schutte R, Huisman HW, Rooyen JM, Malan L, Olckers A, Malan NT. Classifying Africans with the metabolic syndrome.  Horm Metab Res. 2009;  41 79-85
    Search in Google Scholar
  • 31 Hromadova M, Hacik T, Malatinsky E, Riecansky I. Alterations of lipid metabolism in men with hypotestosteronemia.  Horm Metab Res. 1991;  23 392-394
    Search in Google Scholar
  • 32 Muller M, van den Beld AW, Bots ML, Grobbee DE, Lamberts SW, van der Schouw YT. Endogenous sex hormones and progression of carotid atherosclerosis in elderly men.  Circulation. 2004;  109 2074-2079
    Search in Google Scholar
  • 33 Makinen J, Jarvisalo MJ, Pollanen P, Perheentupa A, Irjala K, Koskenvuo M, Mäkinen J, Huhtaniemi I, Raitakari OT. Increased carotid atherosclerosis in andropausal middle-aged men.  J Am Coll Cardiol. 2005;  45 1603-1608
    Search in Google Scholar
  • 34 Tomaszewski M, Charchar FJ, Maric C, Kuzniewicz R, Gola M, Grzeszczak W, Samani NJ, Zukowska-Szczechowska E. Association between lipid profile and circulating concentrations of estrogens in young men.  Atherosclerosis. 2009;  203 257-262
    Search in Google Scholar
  • 35 Corona G, Boddi V, Balercia G, Rastrelli G, De Vita G, Sforza A, Forti G, Mannucci E, Maggi M. The effect of statin therapy on testosterone levels in subjects consulting for erectile dysfunction.  J Sex Med. 2010;  7 1547-1556
    Search in Google Scholar
  • 36 Basaria S. Androgen deprivation therapy, insulin resistance, and cardiovascular mortality: an inconvenient truth.  J Androl. 2008;  29 534-539
    Search in Google Scholar
  • 37 Yeap BB. Testosterone and ill-health in aging men.  Nat Clin Pract Endocrinol Metab. 2009;  5 113-121
    Search in Google Scholar
  • 38 Lewis JG, Shand BI, Frampton CM, Elder PA, Scott RS. Plasma levels of sex hormone-binding globulin, corticosteroid-binding globulin and cortisol in overweight subjects who develop impaired fasting glucose: a 3-year prospective study.  Horm Metab Res. 2009;  41 255-259
    Search in Google Scholar
  • 39 Chubb SA, Hyde Z, Almeida OP, Flicker L, Norman PE, Jamrozik K, Hankey GJ, Yeap BB. Lower sex hormone-binding globulin is more strongly associated with metabolic syndrome than lower total testosterone in older men: the Health in Men Study.  Eur J Endocrinol. 2008;  158 785-792
    Search in Google Scholar
  • 40 Forst T, Hohberg C, Pfutzner A. Cardiovascular effects of disturbed insulin activity in metabolic syndrome and in type 2 diabetic patients.  Horm Metab Res. 2009;  41 123-131
    Search in Google Scholar
  • 41 Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen 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
    Search in Google Scholar
  • 42 Rodriguez A, Muller DC, Metter EJ, Maggio M, Harman SM, Blackman MR, Andres R. Aging, androgens, and the metabolic syndrome in a longitudinal study of aging.  J Clin Endocrinol Metab. 2007;  92 3568-3572
    Search in Google Scholar
  • 43 Kupelian V, Hayes FJ, Link CL, Rosen R, McKinlay JB. Inverse association of testosterone and the metabolic syndrome in men is consistent across race and ethnic groups.  J Clin Endocrinol Metab. 2008;  93 3403-3410
    Search in Google Scholar
  • 44 Xita N, Milionis HJ, Galidi A, Lazaros L, Katsoulis K, Elisaf MS, Georgiou I, Tsatsoulis A. The (TAAAA)n Polymorphism of the SHBG Gene in Men with the Metabolic Syndrome.  Exp Clin Endocrinol Diabetes. 2010;  Aug 5
    Search in Google Scholar
  • 45 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
    Search in Google Scholar
  • 46 Selvin E, Feinleib M, Zhang L, Rohrmann S, Rifai N, Nelson WG, Dobs A, Basaria S, Golden SH, Platz EA. Androgens and diabetes in men: results from the Third National Health and Nutrition Examination Survey (NHANES III).  Diabetes Care. 2007;  30 234-238
    Search in Google Scholar
  • 47 Zumoff B, Strain GW, Miller LK, Rosner W, Senie R, Seres DS, Rosenfeld RS. Plasma free and non-sex-hormone-binding-globulin-bound testosterone are decreased in obese men in proportion to their degree of obesity.  J Clin Endocrinol Metab. 1990;  71 929-931
    Search in Google Scholar
  • 48 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
    Search in Google Scholar
  • 49 Lichtenstein MJ, Yarnell JW, Elwood PC, Beswick AD, Sweetnam PM, Marks V, Teale D, Riad-Fahmy D. Sex hormones, insulin, lipids, and prevalent ischemic heart disease.  Am J Epidemiol. 1987;  126 647-657
    Search in Google Scholar
  • 50 Pasquali R, Casimirri F, Cantobelli S, Melchionda N, Morselli Labate AM, Fabbri R, Capelli M, Bortoluzzi L. Effect of obesity and body fat distribution on sex hormones and insulin in men.  Metabolism. 1991;  40 101-104
    Search in Google Scholar
  • 51 Simon D, Preziosi P, Barrett-Connor E, Roger M, Saint-Paul M, Nahoul K, Papoz L. Interrelation between plasma testosterone and plasma insulin in healthy adult men: the Telecom Study.  Diabetologia. 1992;  35 173-177
    Search in Google Scholar
  • 52 Friedrich N, Rosskopf D, Brabant G, Völzke H, Nauck M, Wallaschofski H. Associations of anthropometric parameters with serum TSH, prolactin, IGF-I, and testosterone levels: results of the study of health in Pomerania (SHIP).  Exp Clin Endocrinol Diabetes. 2010;  118 266-273
    Search in Google Scholar
  • 53 Maric C, Forsblom C, Thorn L, Waden J, Groop PH. Association between testosterone, estradiol and sex hormone binding globulin levels in men with type 1 diabetes with nephropathy.  Steroids. 2010;  75 772-778
    Search in Google Scholar
  • 54 Haider A, Gooren LJ, Padungtod P, Saad F. Improvement of the metabolic syndrome and of non-alcoholic liver steatosis upon treatment of hypogonadal elderly men with parenteral testosterone undecanoate.  Exp Clin Endocrinol Diabetes. 118 2010;  167-171
    Search in Google Scholar
  • 55 Grossmann M, Thomas MC, Panagiotopoulos S, Sharpe K, Macisaac RJ, Clarke S, Zajac JD, Jerums G. Low testosterone levels are common and associated with insulin resistance in men with diabetes.  J Clin Endocrinol Metab. 2008;  93 1834-1840
    Search in Google Scholar
  • 56 Miller KK, Biller BM, Schaub A, Pulaski-Liebert K, Bradwin G, Rifai N, Klibanski A. Effects of testosterone therapy on cardiovascular risk markers in androgen-deficient women with hypopituitarism.  J Clin Endocrinol Metab. 2007;  92 2474-2479
    Search in Google Scholar
  • 57 Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes.  Eur J Endocrinol. 2006;  154 899-906
    Search in Google Scholar
  • 58 Pitteloud N, Hardin M, Dwyer AA, Valassi E, Yialamas M, Elahi D, Hayes FJ. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men.  J Clin Endocrinol Metab. 2005;  90 2636-2641
    Search in Google Scholar
  • 59 Basu R, Dalla Man C, Campioni M, Basu A, Nair KS, Jensen MD, Khosla S, Klee G, Toffolo G, Cobelli C, Rizza RA. Effect of 2 years of testosterone replacement on insulin secretion, insulin action, glucose effectiveness, hepatic insulin clearance, and postprandial glucose turnover in elderly men.  Diabetes Care. 2007;  30 1972-1978
    Search in Google Scholar
  • 60 Gopal RA, Bothra N, Acharya SV, Ganesh HK, Bandgar TR, Menon PS, Shah NS. Treatment of hypogonadism with testosterone in patients with type 2 diabetes mellitus.  Endocr Pract. 2010;  16 570-576
    Search in Google Scholar
  • 61 Ishikawa T, Yamaguchi K, Kondo Y, Takenaka A, Fujisawa M. Metabolic syndrome in men with Klinefelter's syndrome.  Urology. 2008;  71 1109-1113
    Search in Google Scholar
  • 62 Bojesen A, Kristensen K, Birkebaek NH, Fedder J, Mosekilde L, Bennett P, Laurberg P, Frystyk J, Flyvbjerg A, Christiansen JS, Gravholt CH. The metabolic syndrome is frequent in Klinefelter's syndrome and is associated with abdominal obesity and hypogonadism.  Diabetes Care. 2006;  29 1591-1598
    Search in Google Scholar
  • 63 Bojesen A, Juul S, Birkebaek N, Gravholt CH. Increased mortality in Klinefelter syndrome.  J Clin Endocrinol Metab. 2004;  89 3830-3834
    Search in Google Scholar
  • 64 Pei D, Sheu WH, Jeng CY, Liao WK, Fuh MM. Insulin resistance in patients with Klinefelter's syndrome and idiopathic gonadotropin deficiency.  J Formos Med Assoc. 1998;  97 534-540
    Search in Google Scholar
  • 65 Dati E, Baroncelli GI, Mora S, Russo G, Baldinotti F, Parrini D, Erba P, Simi P, Bertelloni S. Body composition and metabolic profile in women with complete androgen insensitivity syndrome.  Sex Dev. 2009;  3 188-193
    Search in Google Scholar
  • 66 Sievers C, Klotsche J, Pieper L, Schneider HJ, März W, Wittchen HU, Stalla GK, Mantzoros C. Low testosterone levels predict all-cause mortality and cardiovascular events in women: a prospective cohort study in German primary care patients.  Eur J Endocrinol. 2010;  163 699-708
    Search in Google Scholar
  • 67 Ding EL, Song Y, Manson JE, Rifai N, Buring JE, Liu S. Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study.  Diabetologia. 2007;  50 2076-2084
    Search in Google Scholar
  • 68 Torrens JI, Sutton-Tyrrell K, Zhao X, Matthews K, Brockwell S, Sowers M, Santoro N. Relative androgen excess during the menopausal transition predicts incident metabolic syndrome in midlife women: study of Women's Health Across the Nation.  Menopause. 2009;  16 257-264
    Search in Google Scholar
  • 69 Yanase T, Fan W, Kyoya K, Min L, Takayanagi R, Kato S, Nawata H. Androgens and metabolic syndrome: lessons from androgen receptor knock out (ARKO) mice.  J Steroid Biochem Mol Biol. 2008;  109 254-257
    Search in Google Scholar
  • 70 Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH, Channer KS. Low serum testosterone and increased mortality in men with coronary heart disease.  Heart. 2010;  96 1821-1825
    Search in Google Scholar
  • 71 Akishita M, Hashimoto M, Ohike Y, Ogawa S, Iijima K, Eto M, Ouchi Y. Low testosterone level is an independent determinant of endothelial dysfunction in men.  Hypertens Res. 2007;  30 1029-1034
    Search in Google Scholar
  • 72 Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men.  J Clin Endocrinol Metab. 2008;  93 68-75
    Search in Google Scholar
  • 73 Alexandersen P, Haarbo J, Byrjalsen I, Lawaetz H, Christiansen C. Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits.  Circ Res. 1999;  84 813-819
    Search in Google Scholar
  • 74 Nettleship JE, Jones TH, Channer KS, Jones RD. Physiological testosterone replacement therapy attenuates fatty streak formation and improves high-density lipoprotein cholesterol in the Tfm mouse: an effect that is independent of the classic androgen receptor.  Circulation. 2007;  116 2427-2434
    Search in Google Scholar
  • 75 Khaw K-T, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A, Day N. 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
    Search in Google Scholar
  • 76 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
    Search in Google Scholar
  • 77 Saigal CS, Gore JL, Krupski TL, Hanley J, Schonlau M, Litwin MS. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer.  Cancer. 2007;  110 1493-1500
    Search in Google Scholar
  • 78 D’Amico AV, Denham JW, Crook J, Chen MH, Goldhaber SZ, Lamb DS, Joseph D, Tai KH, Malone S, Ludgate C, Steigler A, Kantoff PW. Influence of Androgen Suppression Therapy for Prostate Cancer on the Frequency and Timing of Fatal Myocardial Infarctions.  J Clin Oncol. 2007;  25 2420-2425
    Search in Google Scholar
  • 79 Tsai HK, D’Amico AV, Sadetsky N, Chen M-H, Carroll PR. Androgen Deprivation Therapy for Localized Prostate Cancer and the Risk of Cardiovascular Mortality.  J Natl Cancer Inst. 2007;  99 1516-1524
    Search in Google Scholar
  • 80 Anthony VDA, Ming-Hui C, Andrew AR, Marian L, Philip WK. Causes of death in men undergoing androgen suppression therapy for newly diagnosed localized or recurrent prostate cancer.  Cancer. 2008;  113 3290-3297
    Search in Google Scholar
  • 81 Levine GN, D’Amico AV, Berger P, Clark PE, Eckel RH, Keating NL, Milani RV, Sagalowsky AI, Smith MR, Zakai N. American Heart Association Council on Clinical Cardiology and Council on Epidemiology and Prevention, the American Cancer Society, and the American Urological Association . Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk: A Science Advisory From the American Heart Association, American Cancer Society, and American Urological Association: Endorsed by the American Society for Radiation Oncology.  CA Cancer J Clin. 2010;  60 194-201
    Search in Google Scholar
  • 82 Smith MR. Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer.  Urology. 2004;  63 742-745
    Search in Google Scholar
  • 83 Smith MR, Finkelstein JS, McGovern FJ, Zietman AL, Fallon MA, Schoenfeld DA, Kantoff PW. Changes in body composition during androgen deprivation therapy for prostate cancer.  J Clin Endocrinol Metab. 2002;  87 599-603
    Search in Google Scholar
  • 84 Eri LM, Urdal P, Bechensteen AG. Effects of the luteinizing hormone-releasing hormone agonist leuprolide on lipoproteins, fibrinogen and plasminogen activator inhibitor in patients with benign prostatic hyperplasia.  J Urol. 1995;  154 100-104
    Search in Google Scholar
  • 85 Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer.  J Clin Endocrinol Metab. 2006;  91 1305-1308
    Search in Google Scholar
  • 86 Braga-Basaria M, Dobs AS, Muller DC, Carducci MA, John M, Egan J, Basaria S. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy.  J Clin Oncol. 2006;  24 3979-3983
    Search in Google Scholar
  • 87 Lu JY, Huang KC, Chang LC, Huang YS, Chi YC, Su TC, Chen CL, Yang WS. Adiponectin: a biomarker of obesity-induced insulin resistance in adipose tissue and beyond.  J Biomed Sci. 2008;  15 565-576
    Search in Google Scholar
  • 88 Ahima RS. Adipose tissue as an endocrine organ.  Obesity (Silver Spring). 2006;  14 (S 05) 242S-249S
    Search in Google Scholar
  • 89 Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue: an update.  Clin Endocrinol (Oxf). 2006;  64 355-365
    Search in Google Scholar
  • 90 Lin HY, Xu Q, Yeh S, Wang RS, Sparks JD, Chang C. Insulin and leptin resistance with hyperleptinemia in mice lacking androgen receptor.  Diabetes. 2005;  54 1717-1725
    Search in Google Scholar
  • 91 Li H, Matheny M, Nicolson M, Tumer N, Scarpace PJ. Leptin gene expression increases with age independent of increasing adiposity in rats.  Diabetes. 1997;  46 2035-2039
    Search in Google Scholar
  • 92 Luukkaa V, Pesonen U, Huhtaniemi I, Lehtonen A, Tilvis R, Tuomilehto J, Koulu M, Huupponen R. Inverse correlation between serum testosterone and leptin in men.  J Clin Endocrinol Metab. 1998;  83 3243-3246
    Search in Google Scholar
  • 93 Pejovic S, Vgontzas AN, Basta M, Tsaoussoglou M, Zoumakis E, Vgontzas A, Bixler EO, Chrousos GP. Leptin and hunger levels in young healthy adults after one night of sleep loss.  J Sleep Res. 2010;  19 552-558
    Search in Google Scholar
  • 94 Cohen PG. Aromatase, adiposity, aging and disease. The hypogonadal-metabolic-atherogenic-disease and aging connection.  Med Hypotheses. 2001;  56 702-708
    Search in Google Scholar
  • 95 Axelsson J, Ingre M, Akerstedt T, Holmback U. Effects of acutely displaced sleep on testosterone.  J Clin Endocrinol Metab. 2005;  90 4530-4535
    Search in Google Scholar
  • 96 Grunstein RR, Handelsman DJ, Lawrence SJ, Blackwell C, Caterson ID, Sullivan CE. Neuroendocrine Dysfunction in Sleep Apnea: Reversal by Continuous Positive Airways Pressure Therapy.  J Clin Endocrinol Metab. 1989;  68 352-358
    Search in Google Scholar
  • 97 Saini J, Krieger J, Brandenberger G, Wittersheim G, Simon C, Follenius M. Continuous positive airway pressure treatment. Effects on growth hormone, insulin and glucose profiles in obstructive sleep apnea patients.  Horm Metab Res. 1993;  25 375-381
    Search in Google Scholar
  • 98 Gianotti L, Pivetti S, Lanfranco F, Tassone F, Navone F, Vittori E, Rossetto R, Gauna C, Destefanis S, Grottoli S, De Giorgi R, Gai V, Ghigo E, Maccario M. Concomitant impairment of growth hormone secretion and peripheral sensitivity in obese patients with obstructive sleep apnea syndrome.  J Clin Endocrinol Metab. 2002;  87 5052-5057
    Search in Google Scholar
  • 99 Makino S, Fujiwara M, Suzukawa K, Handa H, Fujie T, Ohtaka Y, Komatsu Y, Aoki Y, Maruyama H, Terada Y, Hashimoto K, Sugimoto T. Visceral obesity is associated with the metabolic syndrome and elevated plasma retinol binding protein-4 level in obstructive sleep apnea syndrome.  Horm Metab Res. 2009;  41 221-226
    Search in Google Scholar
  • 100 Luboshitzky R, Aviv A, Hefetz A, Herer P, Shen-Orr Z, Lavie L, Lavie P. Decreased pituitary-gonadal secretion in men with obstructive sleep apnea.  J Clin Endocrinol Metab. 2002;  87 3394-3398
    Search in Google Scholar
  • 101 Gonzalez-Santos MR, Gaja-Rodriguez OV, Alonso-Uriarte R, Sojo-Aranda I, Cortes-Gallegos V. Sleep deprivation and adaptive hormonal responses of healthy men.  Arch Androl. 1989;  22 203-207
    Search in Google Scholar
  • 102 Penev PD. Association between sleep and morning testosterone levels in older men.  Sleep. 2007;  30 427-432
    Search in Google Scholar
  • 103 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
    Search in Google Scholar
  • 104 Liu PY, Yee B, Wishart SM, Jimenez M, Jung DG, Grunstein RR, Handelsman DJ. The short-term effects of high-dose testosterone on sleep, breathing, and function in older men.  J Clin Endocrinol Metab. 2003;  88 3605-3613
    Search in Google Scholar
  • 105 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
    Search in Google Scholar
  • 106 Luboshitzky R, Lavie L, Shen-Orr Z, Lavie P. Pituitary-gonadal function in men with obstructive sleep apnea. The effect of continuous positive airways pressure treatment.  Neuro Endocrinol Lett. 2003;  24 463-467
    Search in Google Scholar
  • 107 Isidori AM, Giannetta E, Gianfrilli D, Greco EA, Bonifacio V, Aversa A, Isidori A, Fabbri A, Lenzi A. Effects of testosterone on sexual function in men: results of a meta-analysis.  Clin Endocrinol (Oxf). 2005;  63 381-394
    Search in Google Scholar
  • 108 Baum NH, Crespi CA. Testosterone replacement in elderly men.  Geriatrics. 2007;  62 15-18
    Search in Google Scholar
  • 109 Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, Zoeller RT, Gore AC. Endocrine-disrupting chemicals: an Endocrine Society scientific statement.  Endocr Rev. 2009;  30 293-342
    Search in Google Scholar
  • 110 Stanworth RD, Kapoor D, Channer KS, Jones TH. Statin therapy is associated with lower total but not bioavailable or free testosterone in men with type 2 diabetes.  Diabetes Care. 2009;  32 541-546
    Search in Google Scholar
  • 111 Kapoor D, Channer KS, Jones TH. Rosiglitazone increases bioactive testosterone and reduces waist circumference in hypogonadal men with type 2 diabetes.  Diab Vasc Dis Res. 2008;  5 135-137
    Search in Google Scholar
  • 112 Morley JE. Testosterone replacement and the physiologic aspects of aging in men.  Mayo Clin Proc. 2000;  75 (Suppl) S83-S87
    Search in Google Scholar
  • 113 Moore C, Huebler D, Zimmermann T, Heinemann LA, Saad F, Thai DM. The Aging Males’ Symptoms scale (AMS) as outcome measure for treatment of androgen deficiency.  Eur Urol. 2004;  46 80-87
    Search in Google Scholar
  • 114 Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Task Force, Endocrine Society . Testosterone Therapy in Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline.  J Clin Endocrinol Metab. 2010;  95 2536-2559
    Search in Google Scholar
  • 115 Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, Thompson IM, Weidner W, Wu FC. Investigation, treatment and monitoring of late-onset hypogonadism in males.  Int J Androl. 2009;  32 1-10
    Search in Google Scholar
  • 116 Jannini EA, Screponi E, Carosa E, Pepe M, Lo Giudice F, Trimarchi F, Benvenga S. Lack of sexual activity from erectile dysfunction is associated with a reversible reduction in serum testosterone.  Int J Androl. 1999;  22 385-392
    Search in Google Scholar
  • 117 Carosa E, Benvenga S, Trimarchi F, Lenzi A, Pepe M, Simonelli C, Jannini EA. Sexual inactivity results in reversible reduction of LH bioavailability.  Int J Impot Res. 2002;  14 93-99 discussion 100
    Search in Google Scholar
  • 118 Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N. Testosterone Gel Study Group . Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men.  J Clin Endocrinol Metab. 2000;  85 2839-2853
    Search in Google Scholar
  • 119 Jockenhovel F, Minnemann T, Schubert M, Freude S, Hübler D, Schumann C, Christoph A, Gooren L, Ernst M. Timetable of effects of testosterone administration to hypogonadal men on variables of sex and mood.  Aging Male. 2009;  12 113-118
    Search in Google Scholar
  • 120 Kalinchenko SY, Tishova YA, Mskhalaya GJ, Gooren LJ, Giltay EJ, Saad F. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.  Clin Endocrinol (Oxf). 2010;  73 602-612
    Search in Google Scholar
  • 121 Wackers FJ, Young LH. Lessons learned from the detection of ischemia in asymptomatic diabetics (DIAD) study.  J Nucl Cardiol. 2009;  16 855-859
    Search in Google Scholar
  • 122 Budoff MJ, Achenbach S, Blumenthal RS, Carr JJ, Goldin JG, Greenland P, Guerci AD, Lima JA, Rader DJ, Rubin GD, Shaw LJ, Wiegers SE. American Heart Association Committee on Cardiovascular Imaging and Intervention; American Heart Association Council on Cardiovascular Radiology and Intervention; American Heart Association Committee on Cardiac Imaging, Council on Clinical Cardiology . Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology.  Circulation. 2006;  114 1761-1791
    Search in Google Scholar
  • 123 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
    Search in Google Scholar
  • 124 Berg G, Schreier L, Geloso G, Otero P, Nagelberg A, Levalle O. Impact on lipoprotein profile after long-term testosterone replacement in hypogonadal men.  Horm Metab Res. 2002;  34 87-92
    Search in Google Scholar
  • 125 Singh AB, Hsia S, Alaupovic P, Sinha-Hikim I, Woodhouse L, Buchanan TA, Shen R, Bross R, Berman N, Bhasin S. The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men.  J Clin Endocrinol Metab. 2002;  87 136-143
    Search in Google Scholar
  • 126 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 1906-1911
    Search in Google Scholar
  • 127 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 3793-3796
    Search in Google Scholar
  • 128 Hobbs CJ, Plymate SR, Rosen CJ, Adler RA. Testosterone administration increases insulin-like growth factor-I levels in normal men.  J Clin Endocrinol Metab. 1993;  77 776-779
    Search in Google Scholar
  • 129 Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline.  J Clin Endocrinol Metab. 2006;  91 1995-2010
    Search in Google Scholar
  • 130 Khera M, Lipshultz LI. The role of testosterone replacement therapy following radical prostatectomy.  Urol Clin North Am. 2007;  34 549-553 vi
    Search in Google Scholar
  • 131 Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy.  Cancer. 2007;  109 536-541
    Search in Google Scholar
  • 132 Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Boloña ER, Sideras K, Uraga MV, Erwin PJ, Montori VM. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials.  Mayo Clin Proc. 2007;  82 29-39
    Search in Google Scholar
  • 133 Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA. 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 3469-3478
    Search in Google Scholar
  • 134 Santamaria JD, Prior JC, Fleetham JA. Reversible reproductive dysfunction in men with obstructive sleep apnoea.  Clin Endocrinol (Oxf). 1988;  28 461-470
    Search in Google Scholar
  • 135 Carruthers M. Time for international action on treating testosterone deficiency syndrome.  Aging Male. 2009;  12 21-28
    Search in Google Scholar
  • 136 Carruthers M. The paradox dividing testosterone deficiency symptoms and androgen assays: a closer look at the cellular and molecular mechanisms of androgen action.  J Sex Med. 2008;  5 998-1012
    Search in Google Scholar
  • 137 Crabbe P, Bogaert V, De Bacquer D, Goemaere S, Zmierczak H, Kaufman JM. Part of the interindividual variation in serum testosterone levels in healthy men reflects differences in androgen sensitivity and feedback set point: contribution of the androgen receptor polyglutamine tract polymorphism.  J Clin Endocrinol Metab. 2007;  92 3604-3610
    Search in Google Scholar
  • 138 Wang C, Christenson P, Swerdloff R. Editorial: Clinical relevance of racial and ethnic differences in sex steroids.  J Clin Endocrinol Metab. 2007;  92 2433-2435
    Search in Google Scholar
  • 139 Rohrmann S, Nelson WG, Rifai N, Brown TR, Dobs A, Kanarek N, Yager JD, Platz EA. Serum estrogen, but not testosterone, levels differ between black and white men in a nationally representative sample of Americans.  J Clin Endocrinol Metab. 2007;  92 2519-2525
    Search in Google Scholar
  • 140 Ross RK, Bernstein L, Lobo RA, Shimizu H, Stanczyk FZ, Pike MC, Henderson BE. 5-alpha-reductase activity and risk of prostate cancer among Japanese and US white and black males.  Lancet. 1992;  339 887-889
    Search in Google Scholar
  • 141 Marks LS, Hess DL, Dorey FJ, Macairan ML. Prostatic tissue testosterone and dihydrotestosterone in African-American and white men.  Urology. 2006;  68 337-341
    Search in Google Scholar

Correspondence

Prof. Dr. med. habil. C. A. KochFACP, FACE 

Division of Endocrinology

University of Mississippi

Medical Center

2500 North State Street

University of Mississippi

Medical Center

MS 39216 Jackson

USA

Phone: +1/601/984 5495

Fax: +1/601/984 5769

Email: ckoch@umc.edu