Bioidentical Hormones 101 
The Book, by Jeffrey Dach MD

26. Does Testosterone Prevent or Cause Heart Attacks ?

Chapter 26. Testosterone Found to Cause Heart Attacks ?

How Not to Do a Testosterone Clinical Trial

A testosterone study published in the New England Journal was halted early because the testosterone treated group had more heart attacks.(1)(2)(3)(4)   Doctors gave topical testosterone to obese, elderly, immobilized men with underlying heart disease. All had limitations in mobility, defined as having difficulty walking two blocks or climbing steps.  About half were obese, and 75% were heavy smokers.  More than 50% had pre-existing heart disease. Almost all had hypertension. A quarter were diabetics. 60% were on statin drugs like Lipitor.  Men younger than 65 were excluded from the study, and the average age was 74.

Starting testosterone levels were low, averaging 250 (ng/dl) for Total and 48 for Free levels. After treatment with 5 to 15 grams/day of topical testosterone gel (Testim™ or Androgel™), levels increased to 574 (ng/dl), after adjustment of the dose, while the placebo group levels remained low at 292 (ng/dl).  As you might expect, the Testosterone Group had significant improvements in leg muscle strength.

Sending Old Men Up the Hill

If we recruited a group of immobilized, obese, elderly frail men with heart disease, and then instructed them to run up a mountain hill, these men would be unable to go more than a few steps, and no harm would come from it. However, if we took this same group of men, apply testosterone gel for a few weeks, as they did, and then send them up the hill, this would be a bad thing. The testosterone would give the men the leg muscle strength to run up the hill and many would succumb to heart attacks.  In a nutshell, this is what happened in the NEJM study.

Previous Studies Show Opposite Results, Testosterone Benefits the Heart

Low Testosterone Associated with Increased Mortality

Three separate population studies have shown that low testosterone levels in men are associated with increased mortality from cardiovascular disease and all causes. (5-7)   A study by Malkin published in 2010 Heart followed 900 men with known coronary artery disease. The men were followed for 8 years, and those with low testosterone had 22% mortality compared to only 12 % for men with normal testosterone levels, almost double the mortality rate for the low testosterone group. (30)

Testosterone Reduces Cardiac Ischemia

In addition, multiple studies have shown testosterone treatment reduces cardiac ischemia in men with known heart disease. For example, an elegant study by English et al.(10)  showed less cardiac ischemia in men treated with testosterone. (9-11) Men with known heart disease were given a treadmill test and their Electrocardiogram (EKG) observed while walking up an inclined treadmill. Given enough time on the treadmill, the heart disease shows up as EKG changes and chest pain.  The doctors will then stop the test and allow the man to rest.  The testosterone group showed longer times on the treadmill before reaching chest pain or critical EKG changes.  This indicates improved blood flow with testosterone.  However, the men still reach chest pain and critical EKG changes and must be taken off the treadmill.  Continuing would bring on a heart attack.

Imagine what would happen if the doctors allowed the men to keep going, to continue up the inclined treadmill in spite of the chest pain? As you might guess, this is an excellent technique for causing heart attacks, and is not advisable. This scenario explains why the men in the NEJM Study had more heart attacks on testosterone. The testosterone gave them the strength to continue up the hill with severe underlying heart disease that caused a heart attack in some of the men.

Dr Morgentaler to the Rescue

A more reasonable approach for testosterone replacement is described by Morgentaler in his 2007 commentary, "Guidelines for Male Testosterone Therapy: A Clinician’s Perspective."  Abraham Morgentaler is a Harvard trained Urologist, who says he was taught in medical school that low testosterone was rare and treatment ineffective.(14)  Once he started clinical practice in 1988, he was surprised to find that many of his patients had low testosterone associated with erectile dysfunction (ED) which greatly improved with testosterone injections. Patients thanked him for finally "feeling normal again."   Nowadays in 2010, testosterone is accepted treatment for diminished libido and erectile dysfunction (ED).  Dr. Morgentaler actually prefers to start with transdermal gel testosterone before using the Viagra™ and Cialis™ type drugs, (the phosphodiesterase type-5 inhibitors PDE5i).

Important Point:

Low testosterone is a risk factor for coronary artery disease.  In men with known underlying coronary artery disease, lower testosterone levels are associated with higher mortality rate.

Risks of Testosterone Treatment Reviewed by Morgentaler

Dr Morgentaler’s  2004 NEJM article is also useful, covering the "Risks of testosterone-replacement therapy and recommendations for monitoring".  Dr Morgentaler says that 4 million men may be candidates for testosterone treatment, yet only 5 percent are actually treated.(15)(16)  Even though there is no large scale, long term clinical studies looking at risks and adverse effects, the number of testosterone prescriptions has increased 500 percent since 1993.

Previous Studies Contradict Bhasin’s Conclusions

In his 2004 report, Dr. Morgentaler says that previous studies of men given testosterone-replacement have not shown increased heart disease. There has been no increase rate of heart attacks, myocardial infarction, stroke, or angina (chest pain caused by narrowed coronary arteries). (15)  Increased blood count (polycythemia) is an adverse effect noted in about 3% of men after testosterone treatment. This is controlled by reducing dosage or donating blood.  Dr Morgentaler also discusses, prostate, PSA, sleep apnea, and other issues.  He finds that testosterone treatment is not associated with increased prostate cancer, although he recommends prostate surveillance.  Finally he discusses that a small percentage of men may note breast enlargement or tenderness from treatment.  For more information, I recommend Dr. Morgentaler's 2009 book, Testosterone for Life. (31)

Conclusion: Testosterone therapy for immobilized elderly men with underlying chronic conditions such as obesity, heart disease, hypertension, and cigarette smoking is not recommended.   However, for all other candidates for testosterone therapy, the health benefits clearly outweigh the risks and adverse effects which are quite manageable.

For references and links, see my web site:

References for Chapter 26. Testosterone Found to Cause Heart Attacks ?

(1) N Engl J Med. 2010 Jul 8;363(2):109-22. Adverse events associated with testosterone administration. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S.

Testosterone Gel Trial Ends After Heart Issue By RONI CARYN RABIN. July 5, 2010

(3)  Bremner WJ. Testosterone Deficiency and Replacement in Older Men. N Engl J Med;363(2):189-91.

(4) Bloomberg News 07/21/2010 - More than one-fifth of patients using a testosterone gel sold by Auxilium Pharmaceuticals Inc. developed heart problems in a study of mobility-impaired men aged 65 and older.

Testosterone gel linked to heart problems healther 2010/09/26/ 18:04

Adverse Cardiovascular Events Reported in Testosterone Trial in Older Men. Treatment Phase of Clinical Trial Halted

(7) Eur Heart J (2010) 31 (12): 1494-1501. Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20–79,  Robin Haring et al.

(8) 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.)

(9) Vol. 166 No. 15, Aug 14/28, 2006 Low Serum Testosterone and Mortality in Male Veterans . Molly M. Shores, MD; Alvin M. Matsumoto, MD; Kevin L. Sloan, MD; Daniel R. Kivlahan, PhD  Arch Intern Med. 2006;166:1660-1665.

(10) Low-Dose Transdermal Testosterone Therapy Improves Angina Threshold in Men With Chronic Stable Angina A Randomized, Double-Blind, Placebo-Controlled Study. Katherine M. English et al.

(11) Rosano GMC, Leonardo F, Pagnotta P, et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation. 1999; 99:1666 –1670.   

(12) Webb CM, Adamson DL, de Zeigler D, et al. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am J Cardiol. 1999;83:437– 439.

(13) CLINICAL STUDY Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men Atish Mathur, Christopher Malkin et al.

(14) Guideline for Male Testosterone Therapy: A Clinician’s Perspective . Abraham Morgentaler Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 2 416-417, 2007

(15) N Engl J Med. 2004 Jan 29;350(5):482-92. Risks of testosterone-replacement therapy and recommendations for monitoring. Rhoden EL, Morgentaler A.

(16) J Sex Med. 2010 Jan;7(1 Pt 1):277-83.
Symptomatic response rates to testosterone therapy and the likelihood of completing 12 months of therapy in clinical practice. Rhoden EL, Morgentaler A.

(17) Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial Chris J. Malkin et al.

(18) CLINICAL RESEARCH: HEART FAILURE Testosterone Therapy in Women With Chronic Heart Failure A Pilot Double-Blind, Randomized, Placebo-Controlled Study Ferdinando Iellamo, MD et al.

(19) Circulation. 2006;114:1829-1837. Heart Failure Anabolic Deficiency in Men With Chronic Heart Failure , Prevalence and Detrimental Impact on Survival . Wu FC, Tajar A, Beynon JM, et al.

(20) J Sex Med. 2010 Apr;7(4 Pt 1):1362-80. Epub 2009 Nov 19. Age-related changes in general and sexual health in middle-aged and older men: results from the European Male Ageing Study (EMAS.

(21) Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men. Frederick C.W. Wu, M.D., et al for the EMAS Group .  N Engl J Med 2010; 363:12 3-135 July 8, 2010

(22) Testosterone Deficiency and Men’s Health: A Crucial Connection André T. Guay, MD, and Martin Miner, MD

(23) Why Is Androgen Replacement in Males Controversial? Glenn R. Cunningham* and Shivani M. Toma Baylor College of Medicine and St. Luke's Episcopal Hospital, Houston, Texas 77030

(24) The Mel Gibson Excuse Does male menopause actually exist? By Jessica Dweck. Sept. 30, 2010.

Sunday October 3, 2010 The hormonal male Art of Healing By DR AMIR FARID ISAHAK
The ins and outs of male sex hormones.

(26) Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM, & Task Force, Endocrine Society (2010). Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism, 95 (6), 2536-59

(27) Araujo, A., Esche, G., Kupelian, V., O’Donnell, A., Travison, T., Williams, R., Clark, R., & McKinlay, J. (2007). Prevalence of Symptomatic Androgen Deficiency in Men Journal of Clinical Endocrinology & Metabolism, 92 (11), 4241-4247 DOI: 10.1210/jc.2007-1245

(28) Testosterone: The New Anti-Aging Wonder Drug? by Rebecca Shatsky, MD, 2011 

(29) Endocrine News June 2006 Article: TESTOSTERONE THERAPY FOR ANDROGEN DEFICIENT MEN New Clinical Guideline from the Endocrine Society By Cathy Kristiansen, Editor

Heart 19 October 2010, Low serum testosterone and increased mortality in men with coronary heart disease by Chris J Malkin et al

(31) Testosterone for Life: Recharge Your Vitality, Sex Drive, Muscle Mass, and Overall Health by Abraham Morgentaler  McGraw-Hill; 1st  edition (October 27, 2008)

Author: Dr Dach

Jeffrey Dach MD

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