Outcomes of testosterone therapy in men with testosterone deficiency (TD) part II, "Beyond the Abstract," by Abdulmaged M. Traish, PhD, MBA

BERKELEY, CA (UroToday.com) - As far back as 1940, testosterone (T) therapy in men with T deficiency (TD), when administered in the physiological range, was deemed beneficial to overall health and had no demonstrable side effects.1, 2 These early observations pointed out that if T treatment was in the physiological range, no harm of T therapy was noted.1, 2 Over the past seven decades a large number of studies were published on T therapy in men with TD. While some of these studies had small numbers of patients, or were of short duration, and others may have been observational in nature, many of these studies have provided a wealth of information on the improvements in the overall health of men with TD.

T therapy in men with TD increases insulin sensitivity, attenuates inflammation, increases muscle mass, and reduces fat mass and adiposity. T therapy improves lipid profiles and endothelial function and reduces systolic and diastolic blood pressure. T therapy improves bone mineral density and increases energy and vitality and improves mood and sexual function and overall quality of life (see Figure). Furthermore, T therapy may reduce risk of vascular disease and mortality (see Figure). T therapy appears to be safe if treatment and monitoring are appropriately executed. The evidence available to date does not support alleged concerns regarding risk of cardiovascular disease (CVD) and prostate cancer.

bta traish part2Beneficial Effects of Testosterone Therapy in Men with TD

T Therapy Reduces Inflammatory Biomarkers in Men with TD

Recently we have reported that T therapy reduces activities of liver enzymes and reduces C-reactive protein (CRP) levels in obese and diabetic men with TD, suggesting attenuation of the inflammatory response and improvement in various physiological functions.3-7 Long-term T therapy in men with TD markedly and significantly reduced CRP levels, suggesting T therapy reduces inflammatory responses.

T Therapy Improves Insulin Sensitivity and Reduces Glucose and HbA1c Levels

T therapy elicits positive effects on blood glucose levels, insulin sensitivity, and glycated hemoglobin (HbA1c) levels,8-21 suggesting that T therapy ameliorates hyperglycemia and insulin resistance (IR) in subjects with type 2 diabetes mellitus (T2DM).3, 7, 21, 22, 23 Hackett et al.,22 and Grossman et al.,23 reinforced the benefits of T in reducing IR and regulating hyperglycemia and HbA1c22, 23 These findings, together with data from other studies, strongly suggest that T therapy improves glycemic control and improves fasting blood sugar and also improves insulin sensitivity.

T Therapy Improves Body Weight, Waist Circumference (WC) and Body Mass Index (BMI) Men with TD

T therapy in men with TD produced significant decrease in weight, WC, and BMI,3-6 suggesting that T therapy produces improvement in metabolic function and results in lifestyle and behavioral modifications, such as increased energy and motivation and increased physical activity that are translated into changes in body composition, which are accompanied with increases in lean body mass and reduction in fat mass, as discussed previously.3-6 Reduced fat mass and increased lean body mass are the most common reported observations in men with TD treated with T.3-6, 20, 24, 25-43

T Therapy Improves Lipid Profile in Men with TD

Long-term T therapy in men with TD is associated with reduced levels of total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TGs) coupled with beneficial increase in high-density lipoprotein (HDL).3, 7, 8, 13, 14, 20, 24, 44-53 Thus, T therapy appears to have a favorable impact on the lipid profile in men with TD. Treatment with intramuscular T undecanoate maintained LDL levels low and HDL levels high in men with TD for up to 9.5 years.44 The clinical implication of reduction in LDL and TGs and increased HDL is reduced CVD risk.3-8

T Therapy Improves Systolic and Diastolic Blood Pressure

In a study of 1 548 men aged 25–84 years, Svartberg et al.,54 reported that systolic blood pressure was inversely associated with T levels, inferring that TD is associated with higher blood pressure. Data from TRiUS (Testim® Registry study showed that blood pressure is reduced in response to T therapy after 12 months,20 supporting previous findings.16, 55 On the contrary, men treated with androgen deprivation therapy (ADT) for prostate cancer showed marked increased arterial stiffness,56, 57

T Therapy Improves CVD Risk in Men with TD

Although epidemiological studies have suggested that reduced T levels are associated with greater CVD risk,58 this area of investigation remained controversial.59 Hoyos et al.10 reported that T treatment decreased arterial stiffness and decreased the respiratory quotient compared with placebo. T therapy in men with TD reduced CVD risk factors with concomitant improvement in insulin sensitivity and glycemic control, even in studies of shorter duration.60, 61 Further, a marked decrease in visceral fat mass and circulating inflammatory cytokines concomitant with improvement in endothelial cell function have been reported.48, 62 T is well known to regulate a host of metabolic functions in liver, adipose tissue, muscles, coronary arteries, and the heart. Thus, it is not surprising that T therapy reduces the risk of CVD. An inverse relationship exists between T and obesity and TD is associated with dyslipidaemia, atherosclerosis, cardiovascular diseases, metabolic syndrome (MetS) and diabetes.63, 64, 65

T therapy Reduces Mortality and Improves Survival in Men with TD

Two recent studies demonstrated reduced mortality in men with TD who were treated with T.66, 67 Shores et al.66 demonstrated that mortality in T-treated men was 10.3% compared with 20.7% in untreated men (P < 0.0001). Muraleedharan et al.67 demonstrated increased mortality of 19.2% versus 9.0% in men with normal T and in men with low T receiving T therapy, mortality was reduced to 8.4%, compared with 19.2% in untreated men (P=0.002). These findings are consistent with several studies.34, 58, 68-87 CV benefits of T therapy have been shown in interventional studies, including benefits of in men with congestive heart failure (CHF), cardiac ischemia/angina, and reduced carotid intima media thickness (CIMT).59, 60, 61, 87-99 Most studies identified an inverse association between serum T concentration and all-cause or cardiovascular mortality.

T therapy Improves Sexual Function and Quality of Life in men with TD

T therapy in men with TD increases vigor and vitality.21 This, together with improvement in quality of life, explains, in part, the noted increase in physical activity subsequent to T treatment. Furthermore, the increased motivation, level of energy, and vigor associated with T treatment may explain the marked reduction in BW attributed to increased energy expenditure. Similar observations were made by Tong et al.,100 who examined the effect of long-acting T undecanoate therapy on quality of life in men with TD. After 48 weeks, the QoL of men treated with T improved significantly in five out of the eight domains on SF-12. The mental health composite scores also improved in the T group. After adjusting for baseline differences, significant improvement was observed only in mental health composite scores. Erectile dysfunction (ED) is thought to be one of the relevant signs and symptoms of TD deficiency. The role of T in erectile physiology has been the subject of a recent comprehensive review and it is clear that androgens play critical role in erections.101 The readers are advised to consult this review.101 For brevity’s sake, we will not elaborate on the relationship between erectile dysfunction and TD, since this topic is covered in detail in this current review.101

In summary, TD is a common clinical condition, which contributes to sexual dysfunction and is associated with a number of co-morbidities.102 In observational studies, long-term T therapy in men with TD restores physiological T levels and produced significant WL, reduced WC, and BMI. T therapy reduced inflammatory cytokines and fasting blood glucose and HbA1c levels concomitant with increased insulin sensitivity. More importantly, T therapy reduced TC, LDL, triglycerides and increased HDL levels and improved systolic and diastolic blood pressure.103-134 Finally, T therapy improved mineral bone density and increased energy and vitality and improved mood and sexual function and overall quality of life. T therapy appears to be safe, and risks, such as erythrocytosis, require appropriate monitoring.

References:

  1. Aub JC. The use of Testosterone . N Engl J Med. 1940; 222: 877-881.
  2. Aub JC and Kety, Seymour S. Recent Advances in Testosterone Therapy. N Engl J Med 1943; 228:338-343.
  3. Saad F, Haider A, Doros G, Traish A. Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring). 2013 ;21:1975-1981.
  4. Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and withoutdiabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study.  Obesity Research & Clinical Practice (2013).
  5. Haider A, Yassin A, Doros G, Saad F. Effects of Long-Term Testosterone Therapy on Patients with “Diabesity”: Results of Observational Studies of Pooled Analyses in Obese Hypogonadal Men with Type 2 Diabetes.  International Endocrinology, in press 2014.
  6. Yassin A, Doros G. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clin Obes. 2013;3:73-83.
  7. Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract. 2013 (in press)
  8. Francomano D, Ilacqua A, Bruzziches R, Lenzi A, Aversa A. Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Urology. 2014 Jan;83(1):167-74.
  9. Wang C, Jackson G, Jones TH, Matsumoto AM, Nehra A, Perelman MA, Swerdloff RS, Traish A, Zitzmann M, Cunningham G.Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. Diabetes Care. 2011;34:1669-1675.
  10. Hoyos CM, Yee BJ, Phillips CL, Machan EA, Grunstein RR, Liu PY. 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;167:531-541.
  11. Pagotto U, Gambineri A, Pelusi C, Genghini S, Cacciari M, Otto B, Castaneda T, Tschop M, Pasquali R. Testosterone replacement therapy restores normal ghrelin in hypogonadal men. J Clin Endocrinol Metab. 2003; 88: 4139-4143.
  12. 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.
  13. Mårin P, Krotkiewski M, Björntorp P. Androgen treatment of middle-aged, obese men: effects on metabolism, muscle and adipose tissues. Eur J Med. 1992 ;1:329-336.
  14. Mårin P, Holmäng S, Gustafsson C, Jönsson L, Kvist H, Elander A, Eldh J, Sjöström L, Holm G, Björntorp P. Androgen treatment of abdominally obese men. Obes Res. 1993;1:245-251.
  15. Heufelder AE, Saad F, Bunck MC, Gooren L. 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.
  16. Boyanov, M.A., Boneva, Z. & Christov, V.G. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male. 2003; 6, 1-7.
  17. Naharci, M.I., Pinar, M., Bolu, E. & Olgun, A. Effect of testosterone on insulin sensitivity in men with idiopathic hypogonadotropic hypogonadism. Endocrine Practice. 2007;13:629-635.
  18. 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.
  19. Pitteloud N, Mootha VK, Dwyer AA, Hardin M, Lee H, Eriksson KF, Tripathy D, Yialamas M, Groop L, Elahi D, Hayes FJ. Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care. 2005 ;28:1636-1642.
  20. Bhattacharya RK, Khera M, Blick G, Kushner H, Nguyen D, Miner MM. Effect of 12 months of testosterone replacement therapy on metabolic syndrome components in hypogonadal men: data from the Testim Registry in the US (TRiUS). BMC Endocrine Disorders. 2011; 11: 18-29.
  21. Zitzmann M, Mattern A, Hanisch J, Gooren L, Jones H, Maggi M. IPASS: A Study on the Tolerability and Effectiveness of Injectable Testosterone Undecanoate for the Treatment of Male Hypogonadism in a Worldwide Sample of 1,438 Men. J Sex Med. 2013; 10:579-588.
  22. Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P, and the BLAST Study Group. Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetesbut not in men with coexisting depression: The BLAST study. J Sex Med 2013 (in press)
  23. Grossmann M Testosterone and Glucose Metabolism in Men: Current Concepts and Controversies. Journal of Endocrinology (2013) in press.
  24. 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.
  25. Svartberg J, Agledahl I, Figenschau Y, Sildnes T, Waterloo K, Jorde R. Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. Int J Impot Res. 2008; 20:378-387.
  26. Allan CA, Strauss BJ, Burger HG, Forbes EA, McLachlan RI. Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in non-obese aging men. J Clin Endocrinol Metab. 2008; 93:139-146.
  27. Behre HM, Tammela TL, Arver S, Tolrá JR, Bonifacio V, Lamche M, Kelly J, Hiemeyer F; European Testogel® Study Team, Giltay EJ, Gooren LJ. A randomized, double-blind, placebo-controlled 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.
  28. Aversa A, Bruzziches R, Francomano D, Greco EA, Fornari R, Di Luigi L, Lenzi A, Migliaccio S. Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study. Aging Male. 2012; 15:96-102.
  29. Hamilton EJ, Gianatti E, Strauss BJ, Wentworth J, Lim-Joon D, Bolton D, et al. Increase in visceral and subcutaneous abdominal fat in men with prostate cancer treated with androgen deprivation therapy. Clin Endocrinol 2011; 74: 377-383.
  30. De Maddalena C, Vodo S, Petroni A, Aloisi AM. Impact of testosterone on body fat composition. J Cell Physiol. 2012; 227:3744-3748.
  31. Bhasin S, Travison TG, Storer TW, Lakshman K, Kaushik M, Mazer NA, et al. Effect of testosterone supplementation with and without a dual 5α-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial. JAMA. 2012; 307:931-939.
  32. Finkelstein JS, Lee H, Burnett-Bowie SA, Pallais JC, Yu EW, Borges LF, Jones BF, Barry CV, Wulczyn KE, Thomas BJ, Leder BZ. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013 ;369:1011-1022.
  33. Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, Adams JE, Oldham JA, Wu FC. 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: 639-650.
  34. Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, Lenzi A, Fabbri A. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf). 2005 Sep;63(3):280-93.
  35. Traish A Rami A, Kypreos KE Androgen deficiency and atherosclerosis: The lipid link.  Vascular Pharmacology 51 (2009) 303–313.
  36. Emmelot-Vonk, M.H., Verhaar, H.J.J., Nakhai Pour, H.R., Aleman, A., Lock, T.M.T.W., Ruud Bosch, J.L.H., Grobbee, D.E., van der Schouw, Y.T., 2008. Effect of testosterone supplementation on functionalmobility, cognition, and other parameters in older age. A randomized controlled trial. J. Amer. Med. Assoc. 299, 39–52
  37. Saad, F., Gooren, L., Haider, A., Yassin, A., 2007. An exploratory study of the effects of 12-month administration of the novel long-acting testosteroneundecanoate onmeasures of sexual function and the metabolic syndrome. Arch. Androl. 53, 353–357.
  38. Saad, F., Gooren, L.J., Haider, A., Yassin, A., 2008. A dose–response study of testosterone on sexual dysfunction and features of the metabolic syndrome using testosterone gel and parenteral testosterone undecanoate. J. Androl. 29, 102–105.,
  39. Zitzmann, M., Nieschlag, E., 2007. Androgen receptor gene CAG repeat length and body mass index modulate the safety of long term intramuscular testosterone undecanoae therapy in hypogonadal men. J. Clin. Endocrinol. Metab. 92, 3844–3853.,
  40. Page, S.T., Amory, J.K., Bowman, F.D., Anawalt, B.D., Matsumoto, A.M., Bremner, W.J., Tenover, J.L., 2005. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J. Clin. Endocrinol. Metab. 90, 1502–1510.
  41. Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profile in hypogonadal men. J Clin Endocrinol Metab. 2004;89:3313–3318.
  42. Dobs, A.S., Bachorik, P.S., Arver, S., Meikle, A.W., Sanders, S.W., Caramelli, K.E., Mazer, N.A., 2001. Interrelationships among lipoprotein levels, sex hormones, anthropometric parameters, and age in hypogonadal men treated for 1 year with a permeation-enhanced testosterone transdermal system. J. Clin. Endocrinol. Metab. 86, 1026–1033.].
  43. Chen, K.C., Peng, C.C., Hsieh, H.M., Peng, C.H., Hseih, C.L., Hunag, C.N., Chyau, C.C., Wang, H.E., Peng, R.Y., 2005. Antiandrogenic therapy can cause coronary arterial disease. Int. J. Urol. 12, 886–891.
  44. 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: 3844-5360.
  45. Page ST, Herbst KL, Amory JK, et al. Testosterone administration suppresses adiponectin levels in men. J Androl 2005; 26: 85-92.
  46. Monroe AK, Dobs AS. The effect of androgens on lipids. Curr Opin Endocrinol Diabetes Obes. 2013;20:132-139.
  47. Permpongkosol, S., Tantirangsee, N. & Ratana-olarn, K. Treatment of 161 men with symptomatic late onset hypogonadism with long-acting parenteral testosterone undecanoate: effects on body composition, lipids, and psychosexual complaints. Journal of Sexual Medicine 2010;7:3765-3674.
  48. Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, Morales AM, Volterrani M, Yellowlees A, Howell JD, Channer KS; TIMES2 Investigators. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 Study). Diabetes Care. 2011;34:828–837.
  49. Jones TH. Effects of testosterone on Type 2 diabetes and components of the metabolic syndrome. J Diabetes. 2010;2:146-156.
  50. Mårin P. Testosterone and regional fat distribution. Obesity Research. 1995;3 Suppl 4:S609-S612.
  51. Mårin P, Lonn L, Andersson B, Oden B, Olbe L, Bengtsson BA, Bjorntorp P. Assimilation of triglycerides in subcutaneous and intraabdominal adipose tissues in vivo in men: effects of testosterone. The Journal of Clinical Endocrinology and Metabolism. 1996;81:1018-1022.
  52. 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.
  53. Zgliczynski S, Ossowski M, Slowinska-Srzednicka J, Brzezinska A, Zgliczynski W, Soszynski P, Chotkowska E, Srzednicki M, Sadowski Z. Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men. Atherosclerosis. 1996;121:35-43.
  54. Svartberg J, von Mühlen D, Schirmer H, Barrett-Connor E, Sundfjord J, Jorde R. Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromsø Study. European Journal of Endocrinology. 2004; 150: 65–71.
  55. Li JY, Zhu JC, Dou JT et al., “Effects of androgen supplementation therapy on partial androgen deficiency in the aging male: a preliminary study,” Aging Male, vol. 2002; 5: 47-51
  56. Smith, J. C., Bennett, S., Evans, L. M., Kynaston, H. G., Parmar, M., Mason, M. D. 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.
  57. Dockery, F., Bulpitt, C. J., Agarwal, S., Donaldson, M. and Rajkumar, C.: Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Clin Sci, 200; 104: 195-201.
  58. Ohlsson C, Barrett-Connor E, Bhasin S, Orwoll E, Labrie F, Karlsson M,Ljunggren O, Vandenput L, Mellstrom D, Tivesten A. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic fractures in men) study in Sweden. J Am Coll Cardiology. 2011;58:1674–1682.
  59. Ullah MI1, Washington T, Kazi M, Tamanna S, Koch CA.Testosterone deficiency as a risk factor for cardiovascular disease. Horm Metab Res. 2011 Mar;43(3):153-64. doi: 10.1055/s-0030-1270521. Epub 2011 Jan 31.
  60. Aversa A, Bruzziches R, Francomano D, Rosano G, Isidori AM, Lenzi A, Spera G. 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.
  61. Aversa A, Bruzziches R, Francomano D, Spera G, Lenzi A. Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. J Endocrinol Invest 2010; 33:776-783.
  62. Lemieux I, Lamarche B, Couillard C, Pascot A, Cantin B, Bergeron J, Dagenais GR, Després JP. Total cholesterol/HDL cholesterol ratio vs LDL cholesterol/HDL cholesterol ratio as indices of ischemic heart disease risk in men: the Quebec Cardiovascular Study. Arch Intern Med. 2001 ;161:2685-2692.
  63. Kelly DM and Jones TH. “Testosterone: a vascular hormone in health and disease,” Journal of Endocrinology, vol. 217, no. 3, pp. R47-71, 2013.
  64. Kelly DM and Jones TH. “Testosterone: a metabolic hormone in health and disease,“ Journal of Endocrinology, vol. 217, no. 3, pp. R25-45, 2013.
  65. Rao PM, Kelly DM, Jones TH. “Testosterone and insulin resistance in the metabolic syndrome and T2DM in men,” Nature Reviews Endocrinology, vol. 9, no. 8, pp. 479-493, 2013.
  66. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012 ;97:2050-2058.
  67. Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol. 2013;169:725-733.
  68. Zhao SP, Li XP.The association of low plasma testosterone level with coronary artery disease in Chinese men. Int J Cardiol. 1998;63:161-164.
  69. Dobrzycki S, Serwatka W, Nadlewski S, Korecki J, Jackowski R, Paruk J, Ladny JR, Hirnle T. An assessment of correlations between endogenous sex hormone levels and the extensiveness of coronary heart disease and the ejection fraction of the left ventricle in males. J Med Invest. 2003 ;50:162-169.
  70. Akishita M, Hashimoto M, Ohike Y, Ogawa S, Iijima K, Eto M, Ouchi Y. Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors. Atherosclerosis. 2010;210:232-236.
  71. Hu X, Rui L, Zhu T, Xia H, Yang X, Wang X, Liu H, Lu Z, Jiang H. Low testosterone level in middle-aged male patients with coronary artery disease. Eur J Intern Med. 2011;22:e133-136.
  72. Li L, Guo CY, Jia EZ, Zhu TB, Wang LS, Cao KJ, Ma WZ, Yang ZJ. Testosterone is negatively associated with the severity of coronary atherosclerosis in men. Asian J Androl. 2012; 14:875-878.
  73. Phillips GB, Pinkernell BH, Jing TY. The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb. 1994;14:701-706.
  74. Hackett G, Kirby M, Sinclair AJ. Testosterone Deficiency, Cardiac Health, and Older Men. Int J Endocrinol. 2014; 2014: 143763.
  75. 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
  76. Khurana KK, Navaneethan SD, Arrigain S, Schold JD, Nally JV Jr, Shoskes DA Serum Testosterone Levels and Mortality in Men With CKD Stages 3-4. Am J Kidney Dis. 2014 Apr 10.
  77. Toma M, McAlister FA, Coglianese EE, Vidi V, Vasaiwala S, Bakal JA, Armstrong PW, Ezekowitz JA.Testosterone supplementation in heart failure: a meta-analysis. Circ Heart Fail. 2012;5:315-321
  78. Corona G, Rastrelli G, Monami M, Guay A, Buvat J, Sforza A, Forti G, Mannucci E, Maggi M. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol. 2011;165:687-701.
  79. Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA. Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96:3007-3019
  80. Corona G, Rastrelli G, Vignozzi L, Mannucci E, Maggi M. Testosterone, cardiovascular disease and the metabolic syndrome. Best Pract Res Clin Endocrinol Metab. 2011;25:337-353.
  81. Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart. 2011;97:870-875.
  82. 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.
  83. Fernández-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, Elamin MB, Gallegos-Orozco JF, Wang AT, Erwin PJ, Bhasin S, Montori VM.Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2010;95:2560-2575.
  84. Oskui PM, French WJ, Herring MJ, Mayeda GS, Burstein S, Kloner RA. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. J Am Heart Assoc. 2013;2:e000272.
  85. Jones TH. Testosterone deficiency: a risk factor for cardiovascular disease? Trends Endocrinol Metab. 2010;21:496-503.
  86. Carson CC and Rosano G. Exogenous testosterone, cardiovascular events, and cardiovascular risk factors in elderly men: A review of trial data. J Sex Med 2012;9: 54–67.
  87. Stout M, Tew GA, Doll H, Zwierska I, Woodroofe N, Channer KS, Saxton JM. Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study. Am Heart J. 2012;164:893-901.
  88. Makinen J, Jarvisalo M, Pollanen P, Perheentupa A, Irjala K, Koskenvuo M, Makinen J, Huhtaniemi I, Raitakari O. Increased carotid atherosclerosis in andropausal middle-aged men. J Am Coll Cardiol. 2005;45:1603–1608.
  89. van den Beld AW, Bots ML, Janssen JAMLL, Pols HAP, Lamberts SWJ, Grobbee DE. Endogenous hormones and carotid atherosclerosis in elderly men. Am J Epidemiol. 2003;157:25–31.
  90. 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 Relat Metab Disord. 2003; 27:803–807.
  91. Fu L, Gao QP, Shen JX. Relationship between testosterone and indexes indicating endothelial function in male coronary heart disease patients. Asian J Androl. 2008;10:214–218.
  92. Svartberg J, Von Muhlen D, Mathiesen E, Joakimsen O, Bonaa KH, Stensland-Bugge E. Low testosterone levels are associated with carotid atherosclerosis in men. J Intern Med. 2006;259:576–582.
  93. Fukui M, Kitagawa Y, Nakamura N, Kadono M, Mogami S, Hirata C, Ichio N, Wada K, Hasegawa G, Yoshikawa T. Association between serum testosterone concentration and carotid atherosclerosis in men with type 2 diabetes. Diabetes Care. 2003;26:1869–1873.
  94. Naghi JJ, Philip KJ, DiLibero D, Willix R, Schwarz ER. Testosterone therapy: treatment of metabolic disturbances in heart failure. J Cardiovasc Pharmacol Ther. 2011;16:14-23.
  95. Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, Mammi C, Piepoli M, Fini M, Rosano GM. 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 ;54:919-927.
  96. Mathur A, Malkin C, Saeed B, Muthusamy R, Jones TH, Channer K. Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men. Eur J Endocrinol 2009;161: 443–449.
  97. 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.
  98. Pugh PJ, Jones RD, West JN, Jones TH, Channer KS Testosterone treatment for men with chronic heart failure. Heart. 2004 ;90:446-447.
  99. Aukrust P, Ueland T, Gullestad L, Yndestad A. Testosterone: a novel therapeutic approach in chronic heart failure? J Am Coll Cardiol. 2009;54: 928-929.
  100. Tong S-F, Ng C-J, Lee B-C, Lee V-K, Khoo E-M, Lee E-G, Tan H-M. Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial. Asian J Androl 2012; 14:604–611.
  101. Isidori AM, Buvat J, Corona G, Goldstein I, Jannini EA, Lenzi A, Porst H, Salonia A, Traish AM, Maggi M. A critical analysis of the role of testosterone in erectile function: from pathophysiology to treatment-a systematic review. Eur Urol. 2014 ;65:99-112.
  102. Traish A. Adverse Effects of Testosterone Deficiency on Men’s Health (Submitted to Steroids, 2014)
  103. Kang J 2nd, Ham BK, Oh MM, Kim JJ, Moon du G. Correlation between serum total testosterone and the AMS and IIEF questionnaires in patients with erectile dysfunction with testosterone deficiency syndrome. Korean J Urol. 2011;52:416-420.
  104. Jacob BC. Testosterone replacement therapy in males with erectile dysfunction. J Pharm Pract. 2011;24:298-306.
  105. Morales A. Androgens are fundamental in the maintenance of male sexual health. Curr Urol Rep. 2011;12:453-460.
  106. Traish AM, Goldstein I, Kim NN. Testosterone and erectile function: from basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction. Eur Urol. 2007;52:54-70.
  107. Saad F, Grahl AS, Aversa A, Yassin AA, Kadioglu A, Moncada I, Eardley I Effects of testosterone on erectile function: implications for the therapy of erectile dysfunction. BJU Int. 2007;99:988-92.
  108. Boloña ER, Uraga MV, Haddad RM, Tracz MJ, Sideras K, Kennedy CC, Caples SM, Erwin PJ, Montori VM. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007;82:20-28.
  109. Mitkov MD, Aleksandrova IY, Orbetzova MM. Effect of transdermal testosterone or alpha-lipoic acid on erectile dysfunction and quality of life in patients with type 2 diabetes mellitus. Folia Med (Plovdiv). 2013;55:55-63.
  110. Allan CA, Forbes EA, Strauss BJ, McLachlan RI. Testosterone therapy increases sexual desire in ageing men with low-normal testosterone levels and symptoms of androgen deficiency. Int J Impot Res. 2008;20:396-401.
  111. Yeap BB. Testosterone and sex in older men. Med J Aust. 2011;195:61-62.
  112. Pexman-Fieth C, Behre HM, Morales A, Kan-Dobrosky N, Miller MG. A 6-month observational study of energy, sexual desire, and body proportions in hypogonadal men treated with a testosterone 1% gel. Aging Male. 2013 Nov 25.
  113. Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P. 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;10:1612-1627.
  114. Amiaz R, Pope HG Jr, Mahne T, Kelly JF, Brennan BP, Kanayama G, Weiser M, Hudson JI, Seidman SN. Testosterone gel replacement improves sexual function in depressed men taking serotonergic antidepressants: a randomized, placebo-controlled clinical trial. J Sex Marital Ther. 2011;37:243-254.
  115. Kido Y, Sakazume S, Abe Y, Oto Y, Itabashi H, Shiraishi M, Yoshino A, Tanaka Y, Obata K, Murakami N, Nagai T. Testosterone replacement therapy to improve secondary sexual characteristics and body composition without adverse behavioral problems in adult male patients with Prader-Willi syndrome: an observational study. Am J Med Genet A. 2013;161:2167-2173.
  116. Ho CC, Tong SF, Low WY, Ng CJ, Khoo EM, Lee VK, Zainuddin ZM, Tan HM. A randomized, double-blind, placebo-controlled trial on the effect of long-acting testosterone treatment as assessed by the Aging Male Symptoms scale. BJU Int. 2012;110:260-265.
  117. Tsujimura A. The Relationship between Testosterone Deficiency and Men's Health. World J Mens Health. 2013;31:126-135.
  118. Seidman SN, Weiser M. Testosterone and mood in aging men. Psychiatr Clin North Am. 2013;36:177-182.
  119. Yeap BB. Are declining testosterone levels a major risk factor for ill-health in aging men? Int J Impot Res. 2009 ;21:24-36.
  120. Glintborg D, Nielsen TL, Wraae K, Hougaard D, Gudex C, Brixen K, Andersen M. The relationship between health-related quality of life, obesity and testosterone levels in older men. Age Ageing. 2013 Dec 29.
  121. Lašaitė L, Ceponis J, Preikša RT, Zilaitienė B Impaired emotional state, quality of life and cognitive functions in young hypogonadal men. Andrologia. 2013 Dec 8.
  122. Pearl JA, Berhanu D, François N, Masson P, Zargaroff S, Cashy J, McVary KT. Testosterone supplementation does not worsen lower urinary tract symptoms. J Urol. 2013 ;190:1828-1833.
  123. Strollo F, Strollo G, Morè M, Magni P, Macchi C, Masini MA, Carucci I, Celotti F, Ruscica M, Gentile S. Low-intermediate dose testosterone replacement therapy by different pharmaceutical preparations improves frailty score in elderly hypogonadal hyperglycaemic patients. Aging Male. 2013;16:33-37.
  124. Amore M, Innamorati M, Costi S, Sher L, Girardi P, Pompili M. Partial androgen deficiency, depression, and testosterone supplementation in aging men. Int J Endocrinol. 2012;2012:280724.
  125. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93: 68–75.
  126. Khaw KT, 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.
  127. Haring R, Volzke H, Steveling A, Krebs A, Felix SB, Schofl C, Dorr M, Nauck M, Wallaschofski H. Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79. Eur Heart J. 2010;31:1494–1501.
  128. 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.
  129. Tivesten A, Vandenput L, Labrie F, Karlsson MK, Ljunggren O, Mellstrom D, Ohlsson C. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab. 2009;94:2482–2488.
  130. Menke A, Guallar E, Rohrmann S, Nelson WG, Rifai N, Kanarek N, Feinleib M, Michos ED, Dobs A, Platz EA. Sex steroid hormone concentrations and risk of death in US men. Am J Epidemiol. 2010;171:583–592.
  131. Vikan T, Schirmer H, Njolstad I, Svartberg J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromso Study. Eur J Endocrinol. 2009;161:435–442.
  132. Corona G, Monami M, Boddi V, Cameron-Smith M, Fisher AD, de Vita G, Melani C, Balzi D, Sforza A, Forti G, Mannucci E, Maggi M. Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. J Sex Med. 2010;7:1557-1564.
  133. Hyde Z, Norman PE, Flicker L, Hankey GJ, Almeida OP, McCaul KA, Chubb SA, Yeap BB.Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. J Clin Endocrinol Metab. 2012;97:179-189.
  134. S. R. Pye, I. T. Huhtaniemi, J. D. Finn, D. M. Lee, T. W. O’Neill, A. Tajar, G. Bartfai, S. Boonen, F. F. Casanueva, G. Forti, A. Giwercman, T. S. Han, K. Kula, M. E. Lean, N. Pendleton, M. Punab, M. K. Rutter, D. Vanderschueren, F. C. W. Wu, and the EMAS Study Group. Late-Onset Hypogonadism and Mortality in Aging Men. J Clin Endocrin Metab. December 11, 2013 (Ahead of Print)

Written by:
Abdulmaged M. Traish, PhD, MBA as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Department of Biochemistry, Boston University School of Medicine, Boston, MA USA; Department of Urology, Boston University School of Medicine, Boston, MA USA

Outcomes of testosterone therapy in men with testosterone deficiency (TD) part II - Abstract

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