Testosterone Deficiency and Risk Factors in the Metabolic Syndrome: Implications for Erectile Dysfunction

Urologic Clinics of North America

Volumn 38, Issue 2, 2011, Pages 175-183

  Guay, Andre T ^a,b   Traish, Abdulmaged ^c  

^a LAHEY HOSPITAL AND MEDICAL CENTER   (United States)

^b TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Endothelial dysfunction; Erectile dysfunction; Hypogonadism; Metabolic syndrome; Testosterone

Indexed keywords

GONADORELIN ANTAGONIST; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; INSULIN; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PLACEBO; SEX HORMONE BINDING PROTEIN; TESTOSTERONE; TESTOSTERONE ESTER; TESTOSTERONE UNDECANOATE;

ABDOMINAL OBESITY; ANDROGEN DEFICIENCY; ANDROGEN THERAPY; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; DISEASE ASSOCIATION; DRUG EFFECT; DYSLIPIDEMIA; ENDOTHELIAL DYSFUNCTION; ERECTILE DYSFUNCTION; HIGH RISK PATIENT; HUMAN; HYPERTENSION; HYPOGONADISM; INSULIN BLOOD LEVEL; INSULIN RESISTANCE; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROSTATE CANCER; REVIEW; RISK FACTOR; RISK MANAGEMENT; RISK REDUCTION; VASCULAR ENDOTHELIUM;

ERECTILE DYSFUNCTION; HORMONE REPLACEMENT THERAPY; HUMANS; HYPOGONADISM; MALE; METABOLIC SYNDROME X; RISK FACTORS; TESTOSTERONE;

EID: 79957491763     PISSN: 00940143     EISSN: 1558318X     Source Type: Journal    
DOI: 10.1016/j.ucl.2011.02.004     Document Type: Review

References (82)

1. Muller M., Grobbee D.E., den Tonkelar I., et al. Endogenous sex hormones and metabolic syndrome in aging men. J Clin Endocrinol Metab 2005, 90:2618-2623.
2. Kupelian V., Page S.T., Araujo A.B., et al. 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.
3. Kupelian V., Shabsigh R., Araujo A.B., et al. 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.
4. Miner M.M., Sadovsky R. Evolving issues in male hypogonadism: evaluation, management, and related comorbidities. Cleve Clin J Med 2007, 74:S38-S46.
5. Miner M.M., Seftel A.D. Testosterone and aging: what we have learned since the Institute of Medicine and what lies ahead. Int J Clin Pract 2007, 61:622-632.
6. Blouin K., Despres J.P., Couillard C., et al. Contribution of age and declining androgen levels to features of the metabolic syndrome in men. Metabolism 2005, 54:1034-1040.
7. Blouin K., Richard C., Brochu G., et al. Androgen inactivation and steroid converting enzyme expression in abdominal adipose tissue in men. J Endocrinol 2006, 191:637-649.
8. Laaksonen D.E., Niskanen L., Punnonen K., et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol 2003, 149:601-608.
9. Kaplan S.A., Meehan A.G., 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.
10. Rodriguez A., Muller D.C., Metter E.J., et al. Aging, androgens, and the metabolic syndrome in a longitudinal study of aging. J Clin Endocrinol Metab 2007, 92:3568-3572.
11. Laaksonen D.E., Niskanen L., Punnonen K., 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. Chen R.Y., Wittert G.A., Andrews G.R. Relative androgen deficiency in relation to obesity and metabolic status in older men. Diabetes Obes Metab 2006, 8:429-435.
13. Hu G., Qiao Q., Tuomilehto J. DECODE Study Group. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med 2004, 164:1066-1076.
14. Steinbrook R. Facing the diabetes epidemic-mandatory reporting of glycosylated hemoglobin values in New York City. N Engl J Med 2006, 354:545-548.
15. Parikh N.I., Pencine M.J., Wang T.J., et al. Increasing trends in incidence of overweight and obesity over 5 decades. Am J Med 2007, 120:242-250.
16. Ford E.S., Li C., Zhao G., et al. Prevalence of the metabolic syndrome among US adolescents using the definition from the International Diabetes Federation. Diabetes Care 2008, 31:587-589.
17. Haffner S.M., Miettinen H., Karhapää P., et al. Leptin concentrations, sex hormones, and cortisol in nondiabetic men. J Clin Endocrinol Metab 1997, 82:1807-1809.
18. Stellato R.K., Feldman H.A., Hamdy O., et al. 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.
19. Selvin E., Feinleib M., Zhang L., et al. Androgens and diabetes in men. Diabetes Care 2007, 30:234-238.
20. Ding E.L., Song Y., Malik V.S., et al. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006, 295:1288-1299.
21. Haffner S.M., Shaten J., Stern M.P., et al. Low levels of sex hormone-binding globulin and testosterone predict the development of non-insulin-dependent diabetes mellitus in men. MRFIT Research Group. Multiple Risk Factor Intervention Trial. Am J Epidemiol 1996, 143:889-897.
22. Grossman M., Thomas M.C., Panagiotopoulos S., et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab 2008, 93(5):1834-1840.
23. Fukui M., Soh J., Tanaka M., et al. Low serum testosterone concentration in middle-aged men with type 2 diabetes. Endocr J 2007, 54:871-877.
24. Simon D., Charles M.A., Nahoul K., 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.
25. Pitteloud N., Hardin M., Dwyer A.A., 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.
26. Basaria S., Muller D.C., Carducci M.A., et al. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer 2006, 106:581-588.
27. Svartberg J., von Muhlen D., Schirmer H., et al. Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromsø Study. Eur J Endocrinol 2004, 150:65-71.
28. Svartberg J., von Muhlen D., Sundsfjord J., et al. Waist circumference and testosterone levels in community dwelling men. The Tromsø Study. Eur J Epidemiol 2004, 19:657-663.
29. Phillips G.B., Jing T.Y., Resnick L.M., et al. Sex hormones and hemostatic risk factors for coronary heart disease in men with hypertension. J Hypertens 1993, 11:699-702.
30. Smith M.R., Bennett S., Evans L., 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.
31. Marin P., Holmang S., Gustafsson C., et al. Androgen treatment of abdominally obese men. Obes Res 1993, 1:245-251.
32. 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.
33. Anderson F.H., Francis R.M., Faulkner K. Androgen supplementation in eugonadal men with osteoporosis-effects of 6 months of treatment on bone mineral density and cardiovascular risk factors. Bone 1996, 18:171-177.
34. Kaufman J.M., Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005, 26:833-876.
35. Ng M.K. New perspectives on Mars and Venus: unraveling the role of androgens in gender differences in cardiovascular biology and disease. Heart Lung Circ 2007, 16:185-192.
36. Traish A.M., Guay A., Feely R., et al. The dark side of testosterone deficiency: I. metabolic syndrome and erectile dysfunction. J Androl 2009, 30:10-22.
37. Traish A.M., Saad F., Guay A. The dark side of testosterone deficiency: II. type 2 diabetes and insulin resistance. J Androl 2009, 30:23-32.
38. Traish A.M., Guay A., Feely R., et al. The dark side of testosterone deficiency: III. vascular disease. J Androl 2009, 30:477-494.
39. Kalyani R.R., Dobs A.S. Androgen deficiency, diabetes, and the metabolic syndrome in men. Curr Opin Endocrinol Diabetes Obes 2007, 14:226-234.
40. Kapoor D., Jones T.H. Androgen deficiency as a predictor of metabolic syndrome in aging men: an opportunity for investigation?. Drugs Aging 2008, 5:357-369.
41. Wu F.C., von Eckardstein A. Androgens and coronary artery disease. Endocr Rev 2003, 24:183-217.
42. Barrett-Connor E. Lower endogenous androgen levels and dyslipidemia in men with non-insulin-dependent diabetes mellitus. Ann Intern Med 1992, 117:807-811.
43. Haffner S.M., Mykkänen L., Valdez R.A., et al. Relationship of sex hormones to lipids and lipoproteins in nondiabetic men. J Clin Endocrinol Metab 1993, 77:1610-1615.
44. Saad F., Gooren L.J., Haider A., et al. A dose-response study of testosterone on sexual dysfunction and features of the metabolic syndrome using testosterone gel and parenteral testosterone undecanoate. J Androl 2008, 29:102-105.
45. Tenover J.S. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992, 75(4):1092-1098.
46. Ly L.P., Jimenez M., Zhuang T.N., et al. A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency. J Clin Endocrinol Metab 2001, 86:4078-4088.
47. Saad F., Gooren L., Haider A., et al. An exploratory study of the effects of 12-month administration of the novel long-acting testosterone undecanoate on measures of sexual function and the metabolic syndrome. Arch Androl 2007, 53:353-357.
48. Zgliczynski S., Ossowski M., Slowinska-Srzednicka J., et al. Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men. Atherosclerosis 1996, 121:35-43.
49. Uyanik B.S., Ari Z., Gumus B., et al. Beneficial effects of testosterone undecanoate on the lipoprotein profiles in healthy elderly men. Jpn Heart J 1997, 38:73-82.
50. Thompson P.D., Cullinane E.M., Sady S.P., et al. Contrasting effects of testosterone and stanozolol on serum lipoprotein levels. JAMA 1989, 261:1165-1168.
51. Bagatell C.J., Heiman J.R., Matsumoto A.M., et al. Metabolic and behavioral effects of high dose exogenous testosterone in healthy men. J Clin Endocrinol Metab 1994, 79:561-567.
52. Isidori A.M., Giannetta E., Greco E.A., et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol 2005, 63:280-293.
53. Traish A.M., Abdou R., Kypreos K.E. Androgen deficiency and atherosclerosis: the lipid link. Vascul Pharmacol 2009, 51:303-313.
54. Tomaszewski M., Charchar F.J., Maric C., et al. Association between lipid profile and circulating concentrations of estrogens in young men. Atherosclerosis 2009, 203:257-262.
55. Tivesten A., Mellström D., Jutberger H., et al. Low serum testosterone and high serum estradiol associate with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden. J Am Coll Cardiol 2007, 50:1070-1076.
56. Corona G., Mannucci E., Petrone L., et al. A comparison of NCEP ATPIII and IDF metabolic syndrome definitions with relation to metabolic syndrome-associated sexual dysfunction. J Sex Med 2007, 4:789-796.
57. Corona G., Mannucci E., Schulman C., et al. Psychobiologic correlates of the metabolic syndrome and associated sexual dysfunction. Eur Urol 2006, 50:595-604.
58. Wannamethee S.G., Shaper A.G., Morris R.W., et al. Measures of adiposity in the identification of metabolic abnormalities in elderly men. Am J Clin Nutr 2005, 81:1313-1321.
59. Osuna J.A., Gomez-Perez R., Arata-Bellabarba G., et al. Relationship between BMI, total testosterone, sex hormonebinding-globulin, leptin, insulin and insulin resistance in obese men. Arch Androl 2006, 52:355-361.
60. Pasquali R., Macor C., Vicennati V., et al. Effects of acute hyperinsulinemia on testosterone serum concentrations in adult obese and normal weight men. Metabolism 1997, 46:526-529.
61. Isidori A.M., Caprio M., Strollo F., et al. Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab 1999, 84:3673-3680.
62. Rosmond R., Wallerius S., Wanger P., et al. A 5 year follow-up study of disease incidence in men with an abnormal hormone pattern. J Intern Med 2003, 254:386-390.
63. Esposito K., Giugliano F., Martedi E., et al. High proportions of erectile dysfunction in men with the metabolic syndrome. Diabetes Care 2004, 28:1201-1203.
64. Heidler S., Temml C., Broessner C., et al. Is the metabolic syndrome an independent risk factor for erectile dysfunction?. J Urol 2007, 177:651-654.
65. Demir T., Demir O., Kefi A., et al. Prevalence of erectile dysfunction in patients with metabolic syndrome. Int J Urol 2006, 13:385-388.
66. Zhody W., Kamal E.E., Ibrahim Y. Androgen deficiency and abnormal penile duplex parameters in obese men with erectile dysfunction. J Sex Med 2007, 4:797-808.
67. Traish A.M., Guay A.T. Are androgens critical for penile erections in humans? Examining the clinical and preclinical evidence. J Sex Med 2006, 3:382-407.
68. Miller V.M., Mulvagh S.L. Sex steroids and endothelial function: translating basic science to clinical practice. Trends Pharmacol Sci 2007, 28:263-270.
69. Sader M.A., Griffiths K.A., Skilton M.R., et al. Physiological testosterone replacement and arterial endothelial function in men. Clin Endocrinol (Oxf) 2003, 59:62-67.
70. Akishita M., Hashimoto M., Ohike Y., et al. Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertens Res 2007, 30:1029-1034.
71. Van den Beld A.W., Bots M.L., Janssen J.A., et al. Endogenous hormones and carotid atherosclerosis in elderly men. Am J Epidemiol 2003, 157:25-31.
72. Demirbag R., Yilmaz R., Ulucay A., et al. The inverse relationship between thoracic aortic intima media thickness and testosterone level. Endocr Res 2005, 31:335-344.
73. Lu Y.L., Zhu H., Wu H., 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.
74. Mäkinen J., Järvisalo M.J., Pöllänen P., et al. Increased carotid atherosclerosis in andropausal middle-aged men. J Am Coll Cardiol 2005, 45:1603-1608.
75. Malkin C.J., Pugh P.J., Jones R.D., et al. Testosterone as a protective factor against atherosclerosis-immunomodulation and influence upon plaque development and stability. J Endocrinol 2003, 178:373-380.
76. Malkin C.J., Pugh P.J., Jones R.D., et al. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab 2004, 89:3313-3318.
77. Makhsida N., Shah J., Yan G., et al. Hypogonadism and metabolic syndrome: implications for testosterone therapy. J Urol 2005, 174:827-834.
78. Kapoor D., Goodwin E., Channer K.S., et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006, 154:899-906.
79. Heufelder A.E., Saad F., Bunck M.C., et al. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 2009, 30:726-733.
80. 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, placebo-controlled study. J Sex Med 2010, 7:3495-3503.
81. 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, 161:443-449.
82. 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(11):776-783.