CoChat
Sign Up
Cited by 371Hormonal and reproductive studiesMenopause: Health Impacts and TreatmentsThyroid Disorders and Treatments

Testosterone and Cardiovascular Disease

Open access
Kloner, Robert A., Carson, Culley, Dobs, Adrian, Kopecky, Stephen, Mohler, Emile R.·2016·Journal of the American College of Cardiology
DOI 10.1016/j.jacc.2015.12.005
Open this paper in CoChat — free accountOpen PDF

Abstract

Testosterone (T) is the principal male sex hormone. As men age, T levels typically fall. Symptoms of low T include decreased libido, vasomotor instability, and decreased bone mineral density. Other symptoms may include depression, fatigue, erectile dysfunction, and reduced muscle strength/mass. Epidemiology studies show that low levels of T are associated with more atherosclerosis, coronary artery disease, and cardiovascular events. However, treating hypogonadism in the aging male has resulted in discrepant results in regard to its effect on cardiovascular events. Emerging studies suggest that T may have a future role in treating heart failure, angina, and myocardial ischemia. A large, prospective, long-term study of T replacement, with a primary endpoint of a composite of adverse cardiovascular events including myocardial infarction, stroke, and/or cardiovascular death, is needed. The Food and Drug Administration recently put additional restrictions on T replacement therapy labeling and called for additional studies to determine its cardiac safety.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.jacc.2015.12.005

Cites

22 of 22 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Current evidence consistently shows that untreated low testosterone levels are associated with an increased risk of MACE.

    “Current evidence consistently shows that untreated low testosterone levels are associated with an increased risk of MACE”

    From Evaluation and Management of Testosterone Deficiency: AUA Guideline (2018) · cites this paper as [23]

    The ‘Low T Levels and Cardiovascular Risk’ section reports an association between low testosterone and cardiovascular disease risk, including cardiovascular events. But the review describes the evidence as observational and says ‘most’ studies suggest an association; it does not establish that evidence consistently links specifically untreated low testosterone to increased MACE risk. Page numbers were not provided in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Low testosterone levels are associated with an increased incidence of major adverse cardiac events, such as myocardial infarction, stroke, and possible cardiovascular-related mortality.

    “Currently available literature has consistently shown that low testosterone levels are associated with an increased incidence of major adverse cardiac events, such as myocardial infarction, stroke, and possible cardiovascular-related mortality”

    From Evaluation and Management of Testosterone Deficiency: AUA Guideline (2018) · cites this paper as [23]

    The “Low T Levels and Cardiovascular Risk” section (page unavailable) reports an association between low testosterone and increased cardiovascular disease risk, and says baseline testosterone was lower in those with cardiovascular mortality. The paper identifies myocardial infarction and stroke as components of a proposed study’s endpoint, but the cited passages do not establish that low testosterone is associated with increased incidence of each event individually. “Consistently shown” is also stronger than the review’s characterization that most epidemiological studies suggest an association. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Low testosterone levels are associated with an increased prevalence of certain atherosclerotic cardiovascular disease risk factors.

    “and an increased prevalence of certain atherosclerotic cardiovascular disease risk factors.”

    From Evaluation and Management of Testosterone Deficiency: AUA Guideline (2018) · cites this paper as [23]

  • Studies that measure cardiovascular benefit or harm in men on testosterone therapy have returned inconsistent and controversial results.

    “studies that measure cardiovascular benefit or harm in men on testosterone therapy have returned inconsistent and controversial results.”

    From Evaluation and Management of Testosterone Deficiency: AUA Guideline (2018) · cites this paper as [23]

  • The current scientific literature does not definitively demonstrate that testosterone therapy increases the risk of MACE.

    “the current scientific literature does not definitively demonstrate that testosterone therapy increases the risk of MACE.”

    From Evaluation and Management of Testosterone Deficiency: AUA Guideline (2018) · cites this paper as [23]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 77

  1. Mooradian AD, Morley JE, Korenman SG. Bio- logical actions of androgens. Endocr Rev 1987;8: 1-28.
  2. Walsh JP, Kitchens AC. Testosterone therapy and cardiovascular risk. Trends Cardiovasc Med 2015;25:250-7.
  3. Khera M, Bhattacharya RK, Blick G, et al. Improved sexual function with testosterone replacement therapy in hypogonadal men: real- world data from the Testim Registry in the United States (TRiUS). J Sex Med 2011;8:3204-13.
  4. Cunningham GR, Stephens-Shields AJ, Rosen RC, et al. Association of sex hormones with sexual function, vitality, and physical function of symptomatic older men with low testosterone levels at baseline in the testosterone trials. J Clin Endocrinol Metab 2015;100:1146-55.
  5. Knapp PE, Storer TW, Herbst KL, et al. Effects of a supraphysiological dose of testosterone on physical function, muscle performance, mood, and fatigue in men with HIV-associated weight loss. Am J Physiol Endocrinol Metab 2008;294: E1135-43.
  6. Travison TG, Basaria S, Storer TW, et al. Clinical meaningfulness of the changes in muscle perfor- mance and physical function associated with testosterone administration in older men with mobility limitation. J Gerontol A Biol Sci Med Sci 2011;66:1090-9.
  7. Iglesias P, Prado F, Macías MC, et al. Hypo- gonadism in aged hospitalized male patients: prevalence and clinical outcome. J Endocrinol Invest 2014;37:135-41.
  8. Langouche L, Van den Berghe G. Hypothalamic- pituitary hormones during critical illness: a dynamic neuroendocrine response. Handb Clin Neurol 2014; 124:115-26.
  9. Dhindsa S, Reddy A, Karam JS, et al. Preva- lence of subnormal testosterone concentrations in men with type 2 diabetes and chronic kidney dis- ease. Eur J Endocrinol 2015;173:359-66.
  10. Harman SM, Metter EJ, Tobin JD, et al. Lon- gitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endo- crinol Metab 2001;86:724-31.
  11. Corona G, Rastrelli G, Monami M, et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol 2011;165:687-701.
  12. Ruige JB, Mahmoud AM, De Bacquer D, et al. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart 2011;97:870-5.
  13. Hak AE, Witteman JC, de Jong FH, et al. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrin Metal 2002;87:3632-9.
  14. Rosano GM, Sheiban I, Massaro R, et al. Low testosterone levels are associated with coronary artery disease in male patients with angina. Int J Impot Res 2007;19:176-82.
  15. Ohlsson C, Barrett-Connor E, Bhasin S, et al. 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 Cardiol 2011;58: 1674-81.
  16. Hu X, Rui L, Zhu T, et al. Low testosterone level in middle-aged male patients with coronary artery disease. Eur J Intern Med 2011;22:e133-6.
  17. Li L, Guo CY, Jia EZ, et al. Testosterone is negatively associated with the severity of coro- nary atherosclerosis in men. Asian J Androl 2012; 14:875-8.
  18. Alkamel A, Shafiee A, Jalali A, et al. The association between premature coronary artery disease and level of testosterone in young adult males. Arch Iran Med 2014;17:545-50.
  19. Farias JM, Tinetti M, Khoury M, et al. Low testosterone concentration and atherosclerosis disease markers in male patients with type 2 diabetes. J Clin Endocrinol Metab 2014;99: 4698-703.
  20. Lee WC, Kim MT, Ko KT, et al. Relationship between serum testosterone and cardiovascular disease risk determined using the Framingham Risk Score in male patients with sexual dysfunction. World J Mens Health 2014;32: 139-44.
  21. Shores MM, Matsumoto AM. Testosterone, aging, and survival: biomarker or deficiency. Curr Opin Endocrinol Diabetes Obes 2014;21:209-16.
  22. Surampudi P, Swerdloff RS, Wang C. An update on male hypogonadism therapy. Expert Opin Pharmacother 2014;15:1247-64.
  23. Wu FC, Tajar A, Beynon JM, et al., for the EMAS Group. Identification of late-onset hypo- gonadism in middle aged and elderly men. N Engl J Med 2010;363:123-35.
  24. Ahmadi H, Daneshmand S. Androgen depri- vation therapy: evidence-based management of side effects. BJU Int 2013;111:543-8.
  25. Girard D, Marino FE, Cannon J. Evidence for reduced neuromuscular function in men with a history of androgen deprivation therapy for pros- tate cancer. Clin Physiol Funct Imaging 2014;34: 209-17.
  26. Lee KK, Berman N, Alexander GM, et al. A simple self-report diary for assessing psychosexual function in hypogonadal men. J Androl 2003;24:688-98.
  27. Chiang HS, Cho SL, Lin YC, et al. Testosterone gel monotherapy improves sexual function of hypogonadal men mainly through restoring erec- tion: evaluation by IIEF score. Urology 2009;73: 762-6.
  28. Corona G, Isidori AM, Buvat J, et al. Testos- terone supplementation and sexual function: a meta-analysis study. J Sex Med 2014;11:1577-92.
  29. Guay AT, Bansal S, Heatley GJ. Effect of raising endogenous testosterone levels in impo- tent men with secondary hypogonadism: double blind placebo-controlled trial with clomiphene citrate. J Clin Endocrinol Metab 1995;80:3546-52.
  30. Bhattacharya RK, Khera M, Blick G, et al. Ef- fect of 12 months of testosterone replacement therapy on metabolic syndrome components in hypogonadal men: data from the Testim Registry in the US (TRiUS). BMC Endocr Disord 2011;11:18.
  31. Greenstein A, Mabjeesh NJ, Sofer M, et al. Does sildenafil combined with testosterone gel improve erectile dysfunction in hypogonadal men in whom testosterone supplement therapy alone failed? J Urol 2005;173:530-2.
  32. Cavallini G, Caracciolo S, Vitali G, et al. Carni- tine versus androgen administration in the treat- ment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology 2004; 63:641-6.
  33. Barrett-Connor E, Von Mühlen DG, Kritz- Silverstein D. Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo Study. J Clin Endocrinol Metab 1999;84: 573-7.
  34. Orengo CA, Fullerton L, Kunik ME. Safety and efficacy of testosterone gel 1% augmentation in depressed men with partial response to antide- pressant therapy. J Geriatr Psychiatry Neurol 2005;18:20-4.
  35. Alexander GM, Swerdloff RS, Wang C, et al. Androgen-behavior correlations in hypogonadal men and eugonadal men. II. Cognitive abilities. Horm Behav 1998;33:85-94.
  36. Janowsky JS, Chavez B, Orwoll E. Sex steroids modify working memory. J Cogn Neurosci 2000; 12:407-14.
  37. Shortridge EF, Polzer P, Donga P, et al. Ex- periences and treatment pattern of hypogonadal men in the US health system. Int J Clin Pract 2014; 68:1257-63.
  38. Shortridge EF, Polzer P, Donga P, et al. Symptom report and treatment experience of hypogonadal men with and without type 2 diabetes in a United States health plan. Int J Clin Pract 2015;69:783-90.
  39. Bhasin S, Calof OM, Storer TW, et al. Drug insight: testosterone and selective androgen re- ceptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab 2006;2:146-59.
  40. Spitzer M, Huang G, Basaria S, et al. Risks and benefits of testosterone therapy in older men. Nat Rev Endocrinol 2013;9:414-24.
  41. Dabaja AA, Bryson CF, Schlegel PN, et al. The effect of hypogonadism and testosterone- enhancing therapy on alkaline phosphatase and bone mineral density. BJU Int 2015;115:480-5.
  42. Irwig MS. Bone health in hypogonadal men. Curr Opin Urol 2014;24:608-13.
  43. Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97:1802-22.
  44. Whitaker M, Guo J, Kehoe T, et al. Bisphosphonates for osteoporosis-where do we go from here? N Engl J Med 2012;366:2048-51.
  45. Laaksonen DE, Niskanen L, Punnonen K, et al. The metabolic syndrome and smoking in relation to hypogonadism in middle-aged men: a pro- spective cohort study. J Clin Endocrinol Metab 2005;90:712-9.
  46. Rolf C, von Eckardstein S, Koken U, et al. Testosterone substitution of hypogonadal men prevents the age-dependent increases in body mass index, body fat and leptin seen in healthy ageing men: results of a cross-sectional study. Eur J Endocrinol 2002;146:505-11.
  47. Corona G, Monami M, Rastrelli G, et al. Type 2 diabetes mellitus and testosterone: a meta- analysis study. Int J Androl 2011;34:528-40.
  48. Cai X, Tian Y, Wu T, et al. Metabolic effects of testosterone replacement therapy on hypo- gonadal men with type 2 diabetes mellitus: a systematic review and meta-analysis of random- ized controlled trials. Asian J Androl 2014;16: 146-52.
  49. Oskui PM, French WJ, Herring MJ, et al. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. J Am Heart Assoc 2013;2:e000272.
  50. Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005;60:1451-7.
  51. Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of random- ized placebo-controlled trials. Mayo Clin Proc 2007;82:29-39.
  52. Fernández-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: adverse effects of testos- terone therapy in adult men: a systemic review and meta-analysis. J Clin Endocrinol Metab 2010; 95:2560-75.
  53. Traish AM, Guay AT, Morgentaler A. Death by testosterone? We think not! J Sex Med 2014;11: 624-9.
  54. Goldstein I. Knowledge is power. J Sex Med 2014;11:613-5.
  55. Hwang K, Miner M. Controversies in testos- terone replacement therapy: testosterone and cardiovascular disease. Asian J Androl 2015;17: 187-91.
  56. Morgantaler A, Kacker R. Testosterone and cardiovascular risk-deciphering the statistics. Nat Rev Urol 2014;11:131-2.
  57. Kloner RA. Testosterone and cardiovascular health: safety of treatment of hypogonadism. Sex Med Rev 2015;3:56-62.
  58. Morgantaler A, Lunenfeld B. Testosterone and cardiovascular risk: world's experts take unprece- dented action to correct misinformation. Aging Male 2014;17:63-5.
  59. Layton JB, Meier CR, Sharpless JL, et al. Comparative safety of testosterone dosage forms [published erratum appears in JAMA Intern Med 2015;175:1248]. JAMA Intern Med 2015;175: 1187-96.
  60. Shores MM, Smith NL, Forsberg CW, et al. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012;97:2050-8.
  61. Shores MM, Sloan KL, Matsumoto AM, et al. Increased incidence of diagnosed depressive illness in hypogonadal older men. Arch Gen Psy- chiatry 2004;61:162-7.
  62. Baillargeon J, Urban RJ, Kuo YF, et al. Risk of myocardial infarction in older men receiving testosterone therapy. Ann Pharmacother 2014;48: 1138-44.
  63. Jones TH, Arver S, Behre HM, et al., for the TIMES 2 Investigators. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES 2 Study). Diabetes Care 2011;34:828-37.
  64. Muraleedharan V, Marsh H, Kapoor D, et al. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 2013;169:725-33.
  65. 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 2010;142: 50-5.
  66. Xu L, Freeman G, Cowling BJ, et al. Testos- terone therapy and cardiovascular events among men: a systemic review and meta-analysis of placebo-controlled randomized trails. BMC Med 2013;11:108.
  67. Corona G, Maseroli E, Rastrelli G, et al. Car- diovascular risk associated with testosterone- boosting medications: a systemic review and meta-analysis. Expert Opinion Drug Saf 2014;13: 1327-51.
  68. Grech A, Breck J, Heidelbaugh J. Adverse ef- fects of testosterone replacement therapy: an update on the evidence and controversy. Ther Adv Drug Saf 2014;5:190-200.
  69. Khera M. Controversies in testosterone sup- plementation therapy. Asian J Androl 2015;17: 175-6.
  70. Morgentaler A, Miner MM, Caliber M, et al. Testosterone therapy and cardiovascular risk: ad- vances and controversies. Mayo Clin Proc 2015; 90:224-51.
  71. Sharma R, Oni OA, Gupta K, et al. Normaliza- tion of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J 2015;36:2706-15.
  72. Snyder PJ, Ellenberg SS, Cunningham GR, et al. The Testosterone Trials: seven coordinated trials of testosterone treatment in elderly men. Clin Trials 2014;11:362-75.
  73. Naghi JJ, Philip KJ, DiLibero D, et al. Testos- terone therapy: treatment of metabolic distur- bances in heart failure. J Cardiovasc Pharmacol Ther 2011;16:14-23.
  74. Jankowska EA, Biel B, Majda J, et al. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation 2006;114:1829-37.
  75. Aukrust P, Ueland T, Gullestad L, et al. Testosterone: a novel therapeutic approach in chronic heart failure? J Am Coll Cardiol 2009;54: 928-9.
  76. Chen Q, Fu Z, Wu X. Association of serum androgen concentrations with cardiovascular risk factors in elderly male patients with chronic sys- tolic heart failure in China. Aging Male 2014;17: 155-60.
  77. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Available at: http://www.fda.gov/ downloads/AdvisoryCommittees/CommitteesMee tingMaterials/Drugs/ReproductiveHealthDrugsAd visoryCommittee/UCM424069.pdf. Accessed December 2, 2015. 120. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. U.S. Food and Drug Administration. 2015. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm4362 59.htm. Accessed December 2, 2015. 121. Matsumoto AM. Effects of chronic testosterone administration in normal men: safety and efficacy of high dosage testosterone and parallel dose- dependent suppression of luteinizing hormone, follicle-stimulating hormone, and sperm produc- tion. J Clin Endocrinol Metab 1990;70:282-7.

Cited by

Sorted by citations

Authors
Kloner, R. A., Carson, C., Dobs, A., Kopecky, S., & Mohler, E. R.
Affiliations
  • University of Southern California (US)
  • University of North Carolina at Chapel Hill (US)
  • Johns Hopkins University (US)
  • Mayo Clinic (US)
  • University of Pennsylvania (US)
Corresponding author
Kloner, Robert A.
ORCID
Venue
Journal of the American College of Cardiology
Publisher
Elsevier BV
Published
2016-02
Volume
67
Issue
5
Pages
545-557
ISSN
0735-1097 (ISSN-L)
DOI
10.1016/j.jacc.2015.12.005
OpenAlex
W2265628036
Cited by
371
References
22
Citations by year
2026: 9 · 2025: 39 · 2024: 32 · 2023: 35 · 2022: 58 · 2021: 40 · 2020: 35 · 2019: 36 · 2018: 33 · 2017: 41 · 2016: 12 · 2015: 1
FWCI
5.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American College of Cardiology (publishedVersion)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
Huntington Medical Research Institutes
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
Keywords
testosterone, cardiovascular disease, male hypogonadism, testosterone replacement therapy, older men, atherosclerosis, coronary artery disease, heart failure, angina pectoris, myocardial ischemia, cardiovascular adverse events, cardiac safety
MeSH terms
Aged, Aging, Androgens, Cardiovascular Diseases, Humans, Hypogonadism, Male, Risk Factors, Testosterone

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review