World J Mens Health.  2019 Jan;37(1):31-44. 10.5534/wjmh.180027.

Type 2 Diabetes and Testosterone Therapy

• Hackett G

• KMID: 2429720
• DOI: http://doi.org/10.5534/wjmh.180027

Abstract

A third of men with type 2 diabetes (T2DM) have hypogonadotrophic hypogonadism (HH) and associated increased risk of cardiovascular and all-cause mortality. Men with HH are at increased risk of developing incident T2DM. We conducted MEDLINE, EMBASE, and COCHRANE reviews on T2DM, HH, testosterone deficiency, cardiovascular and all-cause mortality from May 2005 to October 2017, yielding 1,714 articles, 52 clinical trials and 32 randomized controlled trials (RCT). Studies with testosterone therapy suggest significant benefits in sexual function, quality of life, glycaemic control, anaemia, bone density, fat, and lean muscle mass. Meta-analyses of RCT, rather than providing clarification, have further confused the issue by including under-powered studies of inadequate duration, multiple regimes, some discontinued, and inbuilt bias in terms of studies included or excluded from analysis.

Keyword

Cardiovascular diseases; Diabetes mellitus, type 2; Hypogonadism; Major adverse coronary events; Testosterone deficiency

MeSH Terms

Bias (Epidemiology)
Bone Density
Cardiovascular Diseases
Diabetes Mellitus, Type 2
Humans
Hypogonadism
Male
Mortality
Quality of Life
Testosterone*
Testosterone

Figure

• 

  Fig. 1 Changes from baseline in body composition after 56 weeks treatment with intramuscular testosterone undecanoate (plus intense exercise) or placebo (plus intensive exercise). Data from Ng Tang Fui et al (BMC Med 2016;14:153) [41].

• 

  Fig. 2 Changes in HbA1c from baseline with 30 weeks double blind therapy with intramuscular testosterone undecanoate or placebo in poorly controlled type 2 diabetes (T2DM) (HbA1c= or >7.5%) vs. well controlled (HbA1c<7.5%). Data from Hackett et al (Int J Clin Pract 2014;68:203–15) [46].

• 

  Fig. 3 Changes in international index of erectile function (IIEF) from baseline with 30 weeks double blind therapy with intramuscular testosterone undecanoate (TU) or placebo (P) in men with type 2 diabetes and mild hypogonadism (HG) (8–12 nmol/L) or severe HG (<8 nmol/L). Data from Hackett et al (Int J Clin Pract 2014;68:203–15) [46].

• 

  Fig. 4 Meta-analysis of 59 randomized controlled trials of testosterone substitution in hypogonadism (3,029 treated vs. 2,049 controls) (mean duration=32.5 weeks). Highlight boxes indicate significant changes. diff: difference, LL: lower limit, UL: upper limit, BMI: body mass index, HOMA: homeostatic model assessment, HDL: high density lipoprotein, SBP: systolic blood pressure, DBP: diastolic blood pressure. Cited from Corona et al (Eur J Endocrinol 2016;174:R99–116) [70].

• 

  Fig. 5 Estimated mortality probability and 95% confidence intervals (CIs) from the fitted logistic regression: Men stratified by testosterone (T) replacement therapy. Data from Hackett et al (World J Diabetes 2017;8:104–11) [67].

• 

  Fig. 6 Estimated mortality probability and 95% confidence intervals (CIs) from fitted logistic regression: men on all or none of the treatments testosterone replacement therapy, phosphodiesterase type 5 inhibitor, or statin). Data from Hackett et al (World J Diabetes 2017;8:104–11) [67].

Reference

1. Diabetes UK. More people than ever have diabetes. More people than ever are at risk of type 2 diabetes. If nothing changes, more than five million people will have diabetes in the UK by 2025 [Internet]. London: Diabetes UK;c2017. cited 2018 Apr 1. Available from: https://www.diabetes.org.uk/Professionals/Position-statements-reports/Statistics.

2. American Diabetes Association. Statistics about Diabetes [Internet]. Arlington (VA): American Diabetes Association;cited 2018 Apr 1. Available from: http://www.diabetes.org/diabetes-basics/statistics/.

3. Hackett GI, Cole NS, Deshpande AA, Popple MD, Kennedy D, Wilkinson P. Biochemical hypogonadism in men with type 2 diabetes in primary care practice. Br J Diabetes Vasc Dis. 2009; 9:226–231.

4. Goodman N, Guay A, Dandona P, Dhindsa S, Faiman C, Cunningham GR, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of testosterone and cardiovascular risk. Endocr Pract. 2015; 21:1066–1073. PMID: 26355962.

5. Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, et al. Testosterone therapy in men with hypogonadism: an endocrine society guideline. J Clin Endocrinol Metab. 2018; 103:1715–1744. PMID: 29562364.

6. Corona G, Rastrelli G, Maggi M. Diagnosis and treatment of late-onset hypogonadism: systematic review and meta-analysis of TRT outcomes. Best Pract Res Clin Endocrinol Metab. 2013; 27:557–579. PMID: 24054931.

7. Kelly DM, Jones TH. Testosterone: a vascular hormone in health and disease. J Endocrinol. 2013; 217:R47–R71. PMID: 23549841.

8. Selvin E, Feinleib M, Zhang L, Rohrmann S, Rifai N, Nelson WG, et al. Androgens and diabetes in men: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care. 2007; 30:234–238. PMID: 17259487.

9. Haffner SM, Shaten J, Stern MP, Smith GD, Kuller L. 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. PMID: 8610702.

10. Ding EL, Song Y, Manson JE, Hunter DJ, Lee CC, Rifai N, et al. Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med. 2009; 361:1152–1163. PMID: 19657112.

11. Corona G, Monami M, Rastrelli G, Aversa A, Tishova Y, Saad F, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med. 2011; 8:272–283. PMID: 20807333.

12. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care. 2000; 23:490–494. PMID: 10857940.

13. Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. Rancho Bernardo Study. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care. 2002; 25:55–60. PMID: 11772901.

14. Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Valkonen VP, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004; 27:1036–1041. PMID: 15111517.

15. Vikan T, Schirmer H, Njølstad I, Svartberg J. Low testosterone and sex hormone-binding globulin levels and high estradiol levels are independent predictors of type 2 diabetes in men. Eur J Endocrinol. 2010; 162:747–754. PMID: 20061333.

16. Lakshman KM, Bhasin S, Araujo AB. Sex hormone-binding globulin as an independent predictor of incident type 2 diabetes mellitus in men. J Gerontol A Biol Sci Med Sci. 2010; 65:503–509. PMID: 20106959.

17. Li C, Ford ES, Li B, Giles WH, Liu S. Association of testosterone and sex hormone-binding globulin with metabolic syndrome and insulin resistance in men. Diabetes Care. 2010; 33:1618–1624. PMID: 20368409.

18. Antonio L, Wu FC, O'Neill TW, Pye SR, Carter EL, Finn JD, et al. Associations between sex steroids and the development of metabolic syndrome: a longitudinal study in European men. J Clin Endocrinol Metab. 2015; 100:1396–1404. PMID: 25636052.

19. Holmboe SA, Jensen TK, Linneberg A, Scheike T, Thuesen BH, Skakkebaek NE, et al. Low testosterone: a risk marker rather than a risk factor for type 2 diabetes. J Clin Endocrinol Metab. 2016; 101:3180–3190. PMID: 27285294.

20. 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. PMID: 21816776.

21. 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. PMID: 21177660.

22. Haring R, Völzke HV, Steveling A, Krebs A, Felix SB, Schöfl C, et al. 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. PMID: 20164245.

23. 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. PMID: 23999642.

24. Yeap BB, Alfonso H, Chubb SA, Handelsman DJ, Hankey GJ, Almeida OP, et al. In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality. J Clin Endocrinol Metab. 2014; 99:E9–E18. PMID: 24257908.

25. Daka B, Langer RD, Larsson CA, Rosén T, Jansson PA, Råstam L, et al. Low concentrations of serum testosterone predict acute myocardial infarction in men with type 2 diabetes mellitus. BMC Endocr Disord. 2015; 15:35. PMID: 26209521.

26. Hackett GI. Testosterone replacement therapy and mortality in older men. Drug Saf. 2016; 39:117–130. PMID: 26482385.

27. Muraleedharan V, Jones TH. Testosterone and mortality. Clin Endocrinol (Oxf). 2014; 81:477–487. PMID: 25041142.

28. 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. PMID: 24242682.

29. Home P, Mant J, Diaz J, Turner C. Guideline Development Group. Management of type 2 diabetes: summary of updated NICE guidance. BMJ. 2008; 336:1306–1308. PMID: 18535074.

30. Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L, et al. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona diabetes complications study. Diabetes Care. 2002; 25:1135–1141. PMID: 12087010.

31. Stratton IM, Cull CA, Adler AI, Matthews DR, Neil HA, Holman RR. Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75). Diabetologia. 2006; 49:1761–1769. PMID: 16736131.

32. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359:1577–1589. PMID: 18784090.

33. Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Valkonen VP, et al. The metabolic syndrome and smoking in relation to hypogonadism in middle-aged men: a prospective cohort study. J Clin Endocrinol Metab. 2005; 90:712–719. PMID: 15536158.

34. Tsai EC, Boyko EJ, Leonetti DL, Fujimoto WY. Low serum testosterone level as a predictor of increased visceral fat in Japanese-American men. Int J Obes Relat Metab Disord. 2000; 24:485–491. PMID: 10805506.

35. Travison TG, Araujo AB, O'Donnell AB, Kupelian V, McKinlay JB. A population-level decline in serum testosterone levels in American men. J Clin Endocrinol Metab. 2007; 92:196–202. PMID: 17062768.

36. Haring R, Ittermann T, Völzke H, Krebs A, Zygmunt M, Felix SB, et al. Prevalence, incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania. Aging Male. 2010; 13:247–257. PMID: 20504090.

37. Kumagai H, Zempo-Miyaki A, Yoshikawa T, Tsujimoto T, Tanaka K, Maeda S. Lifestyle modification increases serum testosterone level and decrease central blood pressure in overweight and obese men. Endocr J. 2015; 62:423–430. PMID: 25753766.

38. Gloy VL, Briel M, Bhatt DL, Kashyap SR, Schauer PR, Mingrone G, et al. Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised controlled trials. BMJ. 2013; 347:f5934. PMID: 24149519.

39. Rastrelli G, Carter EL, Ahern T, Finn JD, Antonio L, O'Neill TW, et al. Development of and recovery from secondary hypogonadism in aging men: prospective results from the EMAS. J Clin Endocrinol Metab. 2015; 100:3172–3182. PMID: 26000545.

40. Ng Tang Fui M, Hoermann R, Prendergast LA, Zajac JD, Grossmann M. Symptomatic response to testosterone treatment in dieting obese men with low testosterone levels in a randomized, placebo-controlled clinical trial. Int J Obes (Lond. Int J Obes (Lond). 2017; 41:420–426. PMID: 28028318.

41. Ng Tang Fui M, Prendergast LA, Dupuis P, Raval M, Strauss BJ, Zajac JD, et al. Effects of testosterone treatment on body fat and lean mass in obese men on a hypocaloric diet: a randomised controlled trial. BMC Med. 2016; 14:153. PMID: 27716209.

42. The T4DM [Internet]. Sydney: The T4DM;cited 2018 Apr 1. Available from: www.t4dm.org.au.

43. Kapoor D, Clarke S, Stanworth R, Channer KS, Jones TH. The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2007; 156:595–602. PMID: 17468196.

44. 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. PMID: 20718771.

45. Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011; 34:828–837. PMID: 21386088.

46. Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract. 2014; 68:203–215. PMID: 24355040.

47. Dhindsa S, Ghanim H, Batra M, Kuhadiya ND, Abuaysheh S, Sandhu S, et al. Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes care. 2016; 39:82–91. PMID: 26622051.

48. Francomano D, Lenzi A, Aversa A. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. Int J Endocrinol. 2014; 2014:527470. PMID: 24688542.

49. 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. PMID: 22812645.

50. Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorate elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract. 2014; 68:314–329. PMID: 24127736.

51. Gianatti EJ, Dupuis P, Hoermann R, Strauss BJ, Wentworth JM, Zajac JD, et al. Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2014; 37:2098–2107. PMID: 24804695.

52. Hackett GI. Erectile dysfunction, diabetes and cardiovascular risk. Br J Diabetes. 2016; 16:52–57.

53. Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab. 2006; 91:4335–4343. PMID: 16926258.

54. Buvat J, Montorsi F, Maggi M, Porst H, Kaipia A, Colson MH, et al. Hypogonadal men nonresponders to the PDE5 inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST study). J Sex Med. 2011; 8:284–293. PMID: 20704642.

55. Lowe G, Bahnson R. Non-invasive management of primary phosphodiesterase type 5 inhibitor failure in patients with erectile dysfunction. Ther Adv Urol. 2009; 1:235–242. PMID: 21789070.

56. Hackett G, Cole N, Saghir A, Jones P, Strange RC, Ramachandran S, et al. Testosterone undecanoate improves sexual function in men with type 2 diabetes and severe hypogonadism: results from a 30-week randomized placebo-controlled study. BJU Int. 2016; 118:804–813. PMID: 27124889.

57. 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. PMID: 23551886.

58. de Groot M, Anderson R, Freedland KE, Clouse RE, Lustman PJ. Association of depression and diabetes complications: a meta-analysis. Psychosom Med. 2001; 63:619–630. PMID: 11485116.

59. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016; 374:611–624. PMID: 26886521.

60. Spitzer M, Bhasin S, Travison TG, Davda MN, Stroh H, Basaria S. Sildenafil increases serum testosterone levels by a direct action on the testes. Andrology. 2013; 1:913–918. PMID: 24106072.

61. Hackett G. Should PDE5Is be prescribed routinely for all men with newly diagnosed type 2 diabetes? Br J Diabetes Vasc Dis. 2015; 15:184–186.

62. Hackett G, Heald AH, Sinclair A, Jones PW, Strange RC, Ramachandran S. Serum testosterone, testosterone replacement therapy and all-cause mortality in men with type 2 diabetes: retrospective consideration of the impact of PDE5 inhibitors and statins. Int J Clin Pract. 2016; 70:244–253. PMID: 26916621.

63. Grossmann M, Hoermann R, Wittert G, Yeap BB. Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. Clin Endocrinol (Oxf). 2015; 83:344–351. PMID: 25557752.

64. Corona G, Maseroli E, Rastrelli G, Isidori AM, Sforza A, Mannucci E, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf. 2014; 13:1327–1351. PMID: 25139126.

65. Corona G, Rastrelli G, Morgentaler A, Sforza A, Mannucci E, Maggi M. Meta-analysis of results of testosterone therapy on sexual function based on international index of erectile function scores. Eur Urol. 2017; 72:1000–1011. PMID: 28434676.

66. Borst SE, Yarrow JF. Injection of testosterone may be safer and more effective than transdermal administration for combating loss of muscle and bone in older men. Am J Physiol Endocrinol Metab. 2015; 308:E1035–E1042. PMID: 25898953.

67. Hackett G, Jones PW, Strange RC, Ramachandran S. Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes. World J Diabetes. 2017; 8:104–111. PMID: 28344753.

68. Huo S, Scialli AR, McGarvey S, Hill E, Tügertimur B, Hogenmiller A, et al. Treatment of men for “low testosterone”: a systematic review. PLoS One. 2016; 11:e0162480. PMID: 27655114.

69. Ponce OJ, Spencer-Bonilla G, Alvarez-Villalobos N, Serrano V, Singh-Ospina N, Rodriguez-Gutierrez R, et al. The efficacy and adverse events of testosterone replacement therapy in hypogonadal men: a systematic review and meta-analysis of randomized, placebo-controlled trials. J Clin Endocrinol Metab. 2018; [Epub]. DOI: 10.1210/jc.2018-00404.

70. Corona G, Giagulli VA, Maseroli E, Vignozzi L, Aversa A, Zitzmann M, et al. Therapy of endocrine disease: testosterone supplementation and body composition: results from a meta-analysis study. Eur J Endocrinol. 2016; 174:R99–R116. PMID: 26537862.

71. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013; 11:108. PMID: 23597181.

72. Doğan BA, Karakılıç E, Tuna MM, Arduç A, Berker D, Güler S. Effect of androgen replacement therapy on atherosclerotic risk markers in young-to-middle-aged men with idiopathic hypogonadotropic hypogonadism. Clin Endocrinol (Oxf). 2015; 82:422–428. PMID: 25280063.

73. Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013; 173:1465–1466. PMID: 23939517.

74. Vigen R, O'Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013; 310:1829–1836. PMID: 24193080.

75. Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014; 9:e85805. PMID: 24489673.

76. Kloner RA, Carson C 3rd, Dobs A, Kopecky S, Mohler ER 3rd. Testosterone and cardiovascular disease. J Am Coll Cardiol. 2016; 67:545–557. PMID: 26846952.

77. Anderson SG, Hutchings DC, Woodward M, Rahimi K, Rutter MK, Kirby M, et al. Phosphodiesterase type-5 inhibitor use in type 2 diabetes is associated with a reduction in all-cause mortality. Heart. 2016; 102:1750–1756. PMID: 27465053.

78. Pofi R, Gianfrilli D, Badagliacca R, Di Dato C, Venneri MA, Giannetta E. Everything you ever wanted to know about phosphodiesterase 5 inhibitors and the heart (but never dared ask): how do they work? J Endocrinol Invest. 2016; 39:131–142. PMID: 26142740.

79. Andersson DP, Trolle Lagerros Y, Grotta A, Bellocco R, Lehtihet M, Holzmann MJ. Association between treatment for erectile dysfunction and death or cardiovascular outcomes after myocardial infarction. Heart. 2017; 103:1264–1270. PMID: 28280146.

80. 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. PMID: 22496507.

81. Anderson JL, May HT, Lappé DL, Bair T, Le V, Carlquist JF, et al. Impact of testosterone replacement therapy on myocardial infarction, stroke, and death in men with low testosterone concentrations in an integrated health care system. Am J Cardiol. 2016; 117:794–799. PMID: 26772440.

82. Sharma R, Oni OA, Gupta K, Chen G, Sharma M, Dawn B, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015; 36:2706–2715. PMID: 26248567.

83. Wallis CJ, Lo K, Lee Y, Krakowsky Y, Garbens A, Satkunasivam R, et al. Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. Lancet Diabetes Endocrinol. 2016; 4:498–506. PMID: 27165609.