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The relationship between testosterone levels and cardiovascular disease (CVD) has not been fully elucidated, and concerns persist. What is the relationship between hypogonadism and CVD, and what implications does that relationship present regarding screening for and treating hypogonadism and future research?

Response by Shehzad S. Basaria, MD
Epidemiologic studies have shown that low testosterone levels are independently associated with individual cardiovascular risk factors and cardiovascular mortality.1 Some of these studies are detailed below.

The Rancho Bernardo study investigated whether testosterone insufficiency in older men is associated with increased risk of death.2 During follow-up (mean, 11.8 y), 538 deaths occurred.2 Independent of age, adiposity, and lifestyle, men whose total testosterone levels were in the lowest quartile (<241 ng/dL) were 44% more likely to die than those with higher levels.2 In cause-specific analyses, low testosterone predicted increased risk of CVD-related death (hazards ratio, 1.38; 95% confidence interval, 1.02, 1.85).2 This association was independent of metabolic syndrome, diabetes, and prevalent CVD.2 Further adjustment for lipids, blood pressure, inflammatory markers, and estradiol levels did not attenuate this relationship.2 This prospective, population-based study concluded that hypogonadism in older men is associated with increased risk of death independent of multiple risk factors and several preexisting health conditions.2

The European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) is a large prospective-population study.3 Using EPIC-Norfolk data, Khaw et al conducted a nested case-control study to investigate the relationship between endogenous testosterone levels and mortality due to all causes, CVD, and cancer in middle-aged and older men.3 The authors analyzed the data for 825 men who had died of any cause and compared that with men who were still alive.3 They found that increasing quartiles of testosterone were protective, such that men in the highest quartile had a 30% lower risk of death than did those in the lowest quartile.3 Even after excluding deaths during the first 2 years of follow-up and adjusting for cardiovascular risk factors and sex hormone-binding globulin, this inverse relationship was maintained.3

A recent prospective study assessed the potential association between serum testosterone and estradiol levels and CVD mortality in men.4 Gas chromatography-mass spectrometry was used to analyze serum sex steroids at baseline in older men of the Sweden cohort (n=3014; age range, 69-80 y) of the multicenter, population-based Osteoporotic Fractures in Men (MrOS) Study.4 Analysis of mortality data after a mean follow-up period of 4.5 years suggested that elderly men in the lowest quartile for either serum testosterone or estradiol have a higher risk of mortality.4 Excluding deaths that occurred during the first 3 years of follow-up did not impact the results.4 For the 363 men whose cause of death was determinable, 40% of deaths were attributed to CVD, but the association with low testosterone was not statistically significant, unlike in the Laughlin et al and Khaw et al studies detailed above.4

Limitations of the above studies include that all used a single measurement of testosterone and all did not use mass spectrometry assay.

Patients with prostate cancer (PCa) undergoing long-term androgen deprivation therapy (ADT) are also at increased cardiovascular risk because they suffer from profound hypogonadism.5,6 Recognizing the relationship between ADT and cardiovascular events, the American Heart Association, American Cancer Society, and American Urological Association issued a science advisory, which was endorsed by the American Society for Radiation Oncology and published in the most recent issues of both Circulation and CA: A Cancer Journal for Clinicians.7,8 The advisory suggested that patients be followed by a primary care clinician after ADT is initiated.7,8 This would include monitoring patients with cardiac disease to ensure appropriate secondary preventive measures are taken, such as administering lipid- and glucose-lowering therapy, antihypertensive agents, and antithrombotic agents.7,8 Physicians should continue to discuss the risks and the benefits of ADT with their patients before initiating such therapy.6 Approximately half of men with PCa die of other causes—most commonly, CVD—and long-term ADT is associated with diabetes and metabolic syndrome.5,9 Large-scale, prospective studies are necessary to fully explain this relationship.5-8

The findings from the above studies should not be taken as a reason to initiate testosterone therapy in the clinic to treat cardiovascular risk factors or coronary heart disease. What we need are large, long-term, randomized, placebo-controlled trials to determine whether testosterone therapy has any beneficial (or harmful) influence in CVD. Until such trials are conducted, testosterone therapy should be limited to indications that have been proven to respond to androgen therapy, such as sexual dysfunction and osteoporosis.

Response by Edward D. Kim, MD
Based on my observations with cardiologists, urologists, and primary care physicians, there seems to be considerable variation in the understanding of the relationship between CVD and testosterone. For example, a cardiology colleague thought that lower levels of testosterone would have a protective effect on cardiovascular risk factors in men. The rationale was that women have lower cardiovascular risk than men, largely due to lower testosterone levels.

At the 3rd International Consultation on Sexual Medicine, which took place in Paris in July 2009, we discussed the controversy surrounding the subject of testosterone and cardiovascular health, which is fueled in part by the lack of clinical end-point data suggesting that testosterone therapy improves cardiovascular parameters in a clinically meaningful way and benefits overall mortality.10 Our discussion was tripartite, focusing on (1) endogenous testosterone as it relates to CVD risk factors, (2) endogenous serum testosterone and cardiovascular outcomes, and (3) exogenous testosterone therapy and CVD.10

Our findings are summarized here:
  • The relationship between endogenous testosterone levels and adverse cardiovascular events is consistent and inverse
  • Hypogonadism in men may contribute to higher mortality risk via arterial stiffening, endothelial dysfunction, and increased atherosclerosis
  • Low serum testosterone levels are independently associated with several risk factors for heart disease
  • There appears to be a beneficial relationship between high endogenous testosterone concentrations and mortality due to any cause, including CVD
  • Testosterone therapy appears to be relatively safe in terms of overall cardiovascular health
  • Although treating hypogonadal men with testosterone therapy may improve blood pressure, glycemic control, and all lipid fractions, whether these changes are consequential or clinically relevant is not yet supported
The clinical implications of these findings are significant. Men with clinical signs of hypogonadism and cardiovascular risk factors should be offered a serum testosterone evaluation. In the future, large-scale, long-term studies may provide the clinical end-point data needed to establish whether testosterone therapy confers protection against CVD-caused mortality and all-cause mortality.11 Meanwhile, preliminary studies have highlighted the potential benefits of testosterone therapy.11

A small (n=13) randomized, parallel-group, controlled trial assessed the long-term effect of testosterone therapy on exercise-induced ischemia, lipid profiles, carotid intima-media thickness, and body composition in hypogonadal men with stable, chronic angina.12 Throughout 12 months of treatment with injectable testosterone undecanoate (TU), a protective effect on myocardial ischemia was maintained without decrement, and the expected positive effect of testosterone on body composition was confirmed.12

In a recent randomized, controlled study (n=87; mean age, 74 y), administration of oral TU for 3 months improved serum cholesterol and triglyceride levels for patients with coronary artery disease and diabetes and significantly reduced the frequency of angina attacks, the number of ischemic episodes, and the total burden of ischemia.13 Further studies will help ascertain whether these improvements are sustained over a longer term and assess the possible connection to testosterone’s metabolic and vasoactive properties.13

Another recent randomized, controlled investigation looked at the effect of testosterone therapy on functional capacity, ventilatory efficiency, insulin resistance, and baroreflex sensitivity (BRS), an important predictor of chronic heart failure (CHF).14 Sixty-four elderly men with moderate to severe heart failure, and with or without hypogonadism, received long-acting injectable TU for 12 weeks.14 Outcomes suggested that testosterone therapy significantly improves exercise capacity; strength in large, weight-bearing muscles; glucose metabolism; and BRS for elderly patients with CHF and that measures after a longer follow-up term would be of interest.14 In addition, the long-acting testosterone therapy was well-tolerated by the patients with CHF, and the safety data were promising.14

As Aukrust et al commented on the Caminiti et al paper in Journal of the American College of Cardiology, testosterone therapy is a novel, palliative approach to CHF treatment, with the potential not only to reduce morbidity but also to improve myocardial performance and lower mortality risk.15 The promise of testosterone therapy to treat heart failure—a complex and progressive disease with high mortality—should be addressed in forthcoming studies.15 In the meantime, patients receiving testosterone therapy, and particularly those with CHF, should be monitored carefully for hematocrit level elevation.16

This topic is controversial given that the studies of testosterone and CVD to date are still in early phases. However, CVD, and heart failure in particular, are so common that the potential for testosterone therapy to improve cardiovascular risk will be viewed with great interest.


  1. Basaria S, Dobs AS. Testosterone making an entry into the cardiometabolic world [editorial]. Circulation. 2007;116(23):2658-2661.
  2. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93(1):68-75.
  3. Khaw KT, Dowsett M, Folkerd E, 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;116(23):2694-2701.
  4. Tivesten Å, Vandenput L, Labrie F, et al. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab. 2009;94(7):2482-2488.
  5. Braga-Basaria M, Dobs AS, Muller DC, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol. 2006;24(24):3979-3983.
  6. Basaria S. Androgen deprivation therapy, insulin resistance, and cardiovascular mortality: an inconvenient truth [review]. J Androl. 2008;29(5):534-539.
  7. Levine GN, D'Amico AV, Berger P, et al; American Heart Association Council on Clinical Cardiology and Council on Epidemiology and Prevention, American Cancer Society, American Urological Association. Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk. A Science Advisory From the American Heart Association, American Cancer Society, and American Urological Association. Circulation. 2010 Feb 1 [Epub ahead of print].
  8. Levine GN, D'Amico AV, Berger P, et al; American Heart Association Council on Clinical Cardiology and Council on Epidemiology and Prevention, American Cancer Society, American Urological Association. Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk: A Science Advisory From the American Heart Association, American Cancer Society, and American Urological Association: Endorsed by the American Society for Radiation Oncology. CA Cancer J Clin. 2010 Feb 2 [Epub ahead of print].
  9. Basaria S, Muller DC, Carducci MA, Egan J, Dobs AS. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer. 2006;106(3):581-588.
  10. Jackson G, Montorsi P, Adams MA, et al. Cardiovascular aspects of sexual medicine. In: Proceedings from the 3rd International Consultation on Sexual Medicine; July 10-13, 2009; Paris, France. J Sex Med. In press.
  11. Maggio M, Basaria S. Welcoming low testosterone as a cardiovascular risk factor. Int J Impot Res. 2009;21(4):261-264.
  12. 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(3):443-449.
  13. Cornoldi A, Caminiti G, Marazzi G, et al. Effects of chronic testosterone administration on myocardial ischemia, lipid metabolism and insulin resistance in elderly male diabetic patients with coronary artery disease. Int J Cardiol. 2009 Apr 8 [Epub ahead of print].
  14. Caminiti G, Volterrani M, Iellamo F, 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;54(10):919-927.
  15. Aukrust P, Ueland T, Gullestad L, Yndestad A. Testosterone: a novel therapeutic approach in chronic heart failure? [editorial]. J Am Coll Cardiol. 2009;54(10):928-929.
  16. Shabsigh R, Katz M, Yan G, Makhsida N. Cardiovascular issues in hypogonadism and testosterone therapy. Am J Cardiol. 2005;96(12B):67M-72M.

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