Testosterone therapy and mortality in older men

December 2015

Hackett GI. Testosterone Therapy and Mortality in Older Men. Drug Saf. 2016;39(2):117-130.

Despite a large prevalence of hypogonadism and increased testosterone prescribing over the past decade1-3, population-based (BACH, Boston Area Community Health)4 and clinical-based studies (HIM, Health In Men)5 report that only 10-12% of hypogonadal patients (comprising 40-45% of studied populations) are receiving treatment.

One important reason for the under-treatment of men with testosterone deficiency is the widespread misperception about testosterone therapy on risk of cardiovascular disease. In this editorial we summarize a review paper by Hackett, which addresses the effects of testosterone therapy on cardiovascular risk factors, as well as mortality.6


  • There is a high level of evidence that hypogonadism is associated with increased all-cause mortality and reduced quality of life.
  • A large body of evidence shows that testosterone therapy according to expert guidelines is safe and effective for men suffering from testosterone deficiency.
  • Emerging evidence shows that testosterone therapy in hypogonadal men may reduce all-cause mortality.
  • Recent studies suggesting that testosterone therapy may increase cardiovascular risk are severely flawed and do not exclude the possibility that the increased risk is related to hypogonadism and not the testosterone treatment.

What is known

Some well-established benefits of testosterone therapy in hypogonadal men are improvements in sexual function, mood, well-being, muscle mass and bone mineral density.7-9 Testosterone therapy improves body composition and glycometabolic profile, particularly in younger hypogonadal men and in those with metabolic disturbances.9

Despite concerns among clinicians and hypogonadal men, there is no evidence that testosterone therapy is associated with increased risk of prostate cancer10-12 or symptomatic benign prostatic hyperplasia.13 Currently, the main controversy surrounding testosterone therapy is its effect on heart disease.

What this review adds

The controversy about testosterone therapy and its putative negative impact on heart disease is based on a few fundamentally flawed studies.14-17 The review by Hackett points out their methodological problems and concludes that despite suggesting that testosterone therapy may increase cardiovascular risk, these studies do not exclude the possibility that the increased risk is related to hypogonadism and not the testosterone treatment.6 Along the same line, the European Medicines Agency (EMA) concluded that "there is no consistent evidence of increased cardiovascular risk with testosterone products".18 This was based on a European Union-wide review of testosterone medications, which did not find consistent evidence that testosterone therapy in men with hypogonadism increases the risk of heart problems.18

These conclusions are supported by a large body of research evidence from both epidemiological studies and clinical trials, accumulated over several decades. Multiple long-term studies show that hypogonadism is associated with increased cardiovascular and all-cause mortality.19-23 A recent study with a 14-year follow-up suggested a strong association between low baseline testosterone and incident myocardial infarction.24 One meta-analysis of community-based studies found that low testosterone levels at baseline are associated with a 35% and 25% increased risk of all-cause and cardiovascular mortality, respectively, 9 years later.25 The association between low testosterone levels and mortality risk persists even after strict adjustment for comorbidities.

A recent meta-analysis, performed on the largest number of studies collected so far, concludes that testosterone therapy is not related to any increase in cardiovascular risk, and that present data do not support a causal role between testosterone therapy and cardiovascular events.26 In accordance with another more recent meta-analysis9, in subjects with metabolic derangements a protective effect of testosterone therapy on cardiovascular risk is observed.26 This has also been demonstrated in several long-term registry studies lasting up to 8 years, where great improvements where seen in cardiovascular risk factors, including reductions in BMI, waist circumference, LDL, triglycerides, blood pressure, blood glucose, HbA1c and C-reactive protein.27-33

If testosterone was truly bad for the heart – as the flawed studies suggested - one would expect that hypogonadal men with preexisting heart disease would be especially vulnerable to testosterone therapy. To the contrary, several studies show that testosterone therapy in men with chronic heart failure and angina is beneficial. In men with chronic stable angina pectoris, the ischemic threshold increased after 334 and 12 months35 of testosterone therapy. Notably, in the 12 month study, CIMT (a marker of atherosclerosis) tendentially decreased in the testosterone group more than in the placebo group, and the protective effect of testosterone therapy on myocardial ischemia was maintained throughout the 12 month treatment period without decrement.35 In men with chronic heart failure, testosterone therapy increased exercise capacity after 12 weeks36,37, predominantly through improvement in skeletal muscle performance.38

Ultimately, the goal with any medical treatment is to reduce mortality and increase longevity. As of this writing, two prospective studies have demonstrated reduced mortality in men treated with testosterone.20,39 In a study of 1031 men, testosterone treatment was initiated in 398 men (39%) during routine clinical care.20 After a follow-up of 20 months, mortality was 21% among untreated men versus 10% among testosterone treated men, with the greatest mortality reduction in younger men and those with type 2 diabetes.20 The second study of 587 men with type 2 diabetes had a follow-up of 5.8 years. 51 men were treated with testosterone for 2 years or more (mean testosterone therapy duration 3.5 years). Mortality rate was 20% in untreated hypogonadal diabetic men and 8.6 % in hypogonadal diabetic men who received testosterone therapy.39 Both of these studies show that testosterone therapy reduces death by half and increases longevity in treated men.

In summary, the multiple beneficial effects of testosterone therapy can add up to a considerable benefit to the patient that may be underestimated by the physician primarily concerned with his own specialty. Testosterone therapy in hypogonadal men can be a valuable strategy to improve the metabolic profile, reduce body fat and increase muscle mass, which would ultimately reduce the risk of heart disease and increase longevity.


  • 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 Aug 12;173:1465-6. Return to content
  • Gan EH, Pattman S, S HSP, Quinton R. A UK epidemic of testosterone prescribing, 2001-2010. Clin Endocrinol (Oxf). 2013 Oct;79:564-70. Return to content
  • Layton JB, Li D, Meier CR, Sharpless JL, Sturmer T, Jick SS, et al. Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011. J Clin Endocrinol Metab. 2014 Mar;99:835-42. Return to content
  • Hall SA, Araujo AB, Esche GR, Williams RE, Clark RV, Travison TG, et al. Treatment of symptomatic androgen deficiency: results from the Boston Area Community Health Survey. Arch Intern Med. 2008 May 26;168:1070-6. Return to content
  • 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 Jul;60:762-9. Return to content
  • Hackett GI. Testosterone Therapy and Mortality in Older Men. Drug Saf.2016;39(2):117-130. Return to content
  • Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf). 2005 Sep;63:280-93. Return to content
  • Saad F, Aversa A, Isidori AM, Zafalon L, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol. 2011 Nov;165:675-85. Return to content
  • 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. 2015 Nov 4. Return to content
  • Khera M, Crawford D, Morales A, Salonia A, Morgentaler A. A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur Urol. 2014 Jan;65:115-23. Return to content
  • Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol. 2006 Nov;50:935-9. Return to content
  • Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol. 2009 Feb;55:310-20. Return to content
  • 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;83:167-73. Return to content
  • Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010 Jul 8;363:109-22. Return to content
  • 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. Return to content
  • Vigen R, ODonnell CI, Baron 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 Nov 6;310:1829-36. Return to content
  • 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. Return to content
  • European Medicines Agency. PRAC review does not confirm increase in heart problems with testosterone medicines - Committee recommends medicines can continue to be given for their authorised uses. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2014/10/WC500175207.pdf Accessed Dec 14, 2015. 2014. Return to content
  • Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation. 2007 Dec 4;116:2694-701. Return to content
  • 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 Jun;97:2050-8. Return to content
  • Tivesten A, Vandenput L, Labrie F, Karlsson MK, Ljunggren O, Mellstrom D, et al. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab. 2009 Jul;94:2482-8. Return to content
  • Corona G, Monami M, Boddi V, Cameron-Smith M, Fisher AD, de Vita G, et al. Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. J Sex Med. 2010 Apr;7:1557-64. Return to content
  • 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 Sep;161:435-42. Return to content
  • Daka B, Langer RD, Larsson CA, Rosen T, Jansson PA, Rastam 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. Return to content
  • 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 Oct;96:3007-19. Return to content
  • 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 Oct;13:1327-51. Return to content
  • Saad F, Yassin A, Doros G, Haider A. Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity Classes I-III: Observational data from two registry studies. Int J Obes (Lond). 2015;Jul 29 [Epub ahead of print]. Return to content
  • 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. 2014 Mar;68:314-29. Return to content
  • Francomano D, Lenzi A, Aversa A. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in aging men with metabolic syndrome. Int J Endocrinol. 2014;2014:527470. Return to content
  • Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study. Obes Res Clin Pract. 2014 Jul-Aug;8:e339-49. Return to content
  • 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. Int J Endocrinol. 2014;2014:683515. Return to content
  • 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 Oct;21:1975-81. Return to content
  • Yassin A, Doros G. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clin Obes. 2013 Jun;3:73-83. Return to content
  • 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 Oct 17;102:1906-11. Return to content
  • Mathur A, Malkin C, Saeed B, Muthusamy R, Jones TH, Channer K. Long-term benefits of testosterone therapy on angina threshold and atheroma in men. Eur J Endocrinol. 2009 Sep;161:443−9. Return to content
  • Pugh PJ, Jones RD, West JN, Jones TH, Channer KS. Testosterone treatment for men with chronic heart failure. Heart. 2004 Apr;90:446-7. Return to content
  • 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 Jan;27:57-64. Return to content
  • Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, et al. 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 Sep 1;54:919-27. Return to content
  • 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 Dec;169:725-33. Return to content