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Response To Media Reports Associating Testosterone Treatment With Greater Heart Attack Risk

March 2014

By William Faloon

Additional Studies Demonstrate The Benefits Of Maintaining Higher Testosterone Levels

Additional Studies Demonstrate The Benefits Of Maintaining Higher Testosterone Levels  

Another study found the threshold level for benefit with testosterone replacement therapy was >500 ng/dL. This randomized, double-blind, placebo-controlled trial on 50 male subjects with low testosterone and metabolic syndrome found that testosterone administration reduced fasting glucose and waist circumference, and improved markers of atherosclerosis. The authors concluded: “Clinical efficacy of T [testosterone] replacement therapy in hypogonadal men with MS [metabolic syndrome] is reached when its plasmatic levels approach into the medium-high range of normality ( >5 ng/mL [or >500 ng/dL]).”19

Asymmetric dimethylarginine (ADMA) is a metabolic compound that contributes to atherosclerosis and cardiovascular disease. In a study of 10 men with low testosterone levels at baseline (115.27 ng/dL), testosterone administration for 2 weeks caused testosterone levels to rise to 648.41 ng/dL and ADMA levels to drop a statistically significant degree. The study authors noted: “The outcome of this study may be viewed as a favorable effect of normalization of plasma testosterone on plasma ADMA since even small elevations of plasma ADMA significantly increase cardiovascular risk.”7

Study Conflicts with Previous Research

The authors of the JAMA study note, “The association between testosterone therapy use and adverse outcomes observed in this study differs from the association observed in a prior retrospective VA study.”

  • In the JAMA study, investigators noted a 39% reduction in mortality risk among patients treated with testosterone therapy.21 Unfortunately, the testosterone levels achieved in this study were not reported.
  • A comprehensive review of data from 4 randomized controlled trials on men with chronic heart failure found that testosterone therapy was associated with improved functional capacity with no adverse events reported after up to 52 weeks of treatment.22
  • French researchers found that lower bioavailable testosterone levels (i.e., the fraction of circulating testosterone that readily enters cells [free testosterone plus weakly bound testosterone]) in men 65 and older were linked to increased carotid artery intima-media thickness, which is a known marker of cardiovascular risk.23
  • A randomized, controlled, 12-month study on 13 men with low testosterone levels and chest pain (i.e., angina) found that testosterone restoration therapy resulted in greater reductions in carotid artery plaques and improvements in time to myocardial ischemia (i.e., decreased blood flow to the heart) during exercise testing; the benefits were maintained throughout the duration of the study.24 The average range of total testosterone achieved during the 12-month period was approximately 461 ng/dL to548 ng/dL .
  • In a study of 24 men with low baseline testosterone, intramuscular injections with 200 mg of testosterone every 2 weeks for 3 months were associated with improvements in insulin sensitivity and glycemic control as well as a reduction in total cholesterol and visceral adiposity. The scientists noted, “ Improvements in [glycemic] control, insulin resistance, cholesterol and visceral adiposity together represent an overall reduction in cardiovascular risk. 28
  • A 2013 study confirmed the increase of metabolic syndrome in men that are testosterone deficient.17Metabolic syndrome is a cluster of cardiovascular risk factors that include insulin resistance, hypertension, elevated triglycerides/LDL, and low HDL. This study found that men treated with testosterone showed across the board improvements as indicated by:
  • Study Conflicts with Previous Research  

    • Reduced LDL
    • Reduced triglycerides
    • Reduced glucose
    • Reduced C-reactive protein
    • Reduced liver enzymes
    • Reduced blood pressure
    • Reduced hemoglobin A1c
    • Increased HDL (removes cholesterol buildup from arterial walls)

Retrospective Observational Study - Unmeasured Confounding Or Hidden Bias Might Exist

The study by JAMA was retrospective and observational. This study design limits the interpretation of the findings because subjects were treated in a clinical setting and not randomized to treatment. Bias may be introduced if confounding factors (e.g., those associated with both treatment initiation and mortality) are not adequately accounted for. Although the authors attempted to control for confounding factors, unmeasured or hidden factors likely still exist. The extent that these unmeasured variables bias the association reported is unknown.

Based upon an analysis of this study and the existing research, Life Extension continues to recommend male members restore testosterone levels to youthful ranges for optimal health.

Unnatural Forms Of Testosterone Used By 1/3 Of Subjects

Of men receiving testosterone therapy in the study by JAMA, only 1.1% were prescribed testosterone gel, 63.3% received patches, and 35.7% received injections. Commonly prescribed testosterone injectables can produce a peak, often supraphysiologic, level of testosterone that then declines slowly to an often subnormal level in 1 to 2 weeks.29,30 This “peak and trough” effect is an unnatural rhythm for testosterone. A testosterone cream or gel, on the other hand, gradually releases into the bloodstream, which is more analogous to the natural secretion of testosterone by the testes. More than a third of men in this analysis received testosterone injections, which may cause unusual fluctuations in testosterone levels. In addition, testosterone injectables are comprised of non-bioidentical testosterone compounds. Life Extension advocates that men use a daily bioidentical testosterone gel (e.g., Androgel® or compounded version) to avoid unnatural fluctuations in testosterone levels.

Summary

Headline news stories on November 5, 2013, parroted a study proclaiming that aging men using testosterone drugs suffer greater heart attack risk.1-3 The study suggests testosterone therapy may increase risk of death and certain cardiovascular events.5 However, there are several significant shortcomings in the study’s design and methodology, and the results conflict with an existing body of research. The media’s portrayal of this flawed study may discourage aging men from properly restoring their testosterone levels and potentially endanger their health.

Over the years, several studies have shown that testosterone replacement therapy improves multiple measures of men’s vitality, especially related to cardio-metabolic health.4,15-24 The precipitous decline of men’s testosterone levels over the years is inevitable. Unless aging men replace their diminishing testosterone, they could succumb to any of the numerous health problems linked to low testosterone levels: frailty, muscle loss, weight gain, impaired cognition, fatigue, loss of self-confidence, depression, declining bone health, increased risk of type II diabetes, stroke, and cardiovascular disease.15,16

Based on many published studies, Life Extension has recommended for decades that aging men restore testosterone to a youthful range. We’ve always warned that for some men restoring one’s testosterone to more youthful levels could create excessive levels of estrogen, which is readily detectable by blood testing and reversible using aromatase-inhibiting therapies.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

  1. Available at: http://www.usatoday.com/story/news/nation/2013/11/05/testosterone-heart-attacks/3448543/. Accessed November 25, 2013.
  2. Available at: http://www.cbsnews.com/news/testosterone-therapy-increases-risk-of-heart-attack-stroke-or-death-by-29-percent-study-says/. Accessed November 25, 2013.
  3. Available at: http://www.nydailynews.com/life-style/health/testosterone-linked-heart-risks-men-study-article-1.1507645. Accessed November 25, 2013.
  4. 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 Oct 11;58(16):1674-81.
  5. Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-36.
  6. Cohen PG. Aromatase, adiposity, aging and disease. The hypogonadal-metabolic-atherogenic-disease and aging connection. Med Hypotheses. 2001 Jun;56(6):702-8.
  7. Cohen PG. The hypogonadal-obesity cycle: role of aromatase in modulating the testosterone-estradiol shunt—a major factor in the genesis of morbid obesity. Med Hypotheses. 1999 Jan;52(1):49-51.
  8. Mendelsohn ME. Protective effects of estrogen on the cardiovascular system. Am J Cardiol. 2002 Jun 20;89(12A):12E-17E; discussion 17E-8E.
  9. Colmou A. Estrogens and vascular thrombosis. Soins Gynecol Obstet Pueric Pediatr. Sep 1982(16):39-41.
  10. Abbott RD, Launer LJ, Rodriguez BL, et al. Serum estradiol and risk of stroke in elderly men. Neurology. Feb 20 2007;68(8):563-8.
  11. Mohamad MJ, Mohammad MA, Karayyem M, Hairi A, Hader AA. Serum levels of sex hormones in men with acute myocardial infarction. Neuro Endocrinol Lett. 2007 Apr;28(2):182-6.
  12. Mechlin CW, Frankel J, McCullough A. Coadministration of anastrozole sustains therapeutic testosterone levels in hypogonadal men undergoing testosterone pellet insertion. J Sex Med. 2013 Oct 9.
  13. Saad F. Androgen therapy in men with testosterone deficiency: can testosterone reduce the risk of cardiovascular disease? Diabetes Metab Res Rev. 2012 Dec;28 Suppl 2:52-9.
  14. Cattabiani C, Basaria S, Ceda GP, etal. Relationship between testosterone deficiency and cardiovascular risk and mortality in adult men. J Endocrinol Invest. 2012 Jan;35(1):104-20.
  15. Bain J. Testosterone and the aging male: to treat or not to treat? Maturitas. 2010 May;66(1):16-22.
  16. Tsujimura A. The relationship between testosterone deficiency and men’s health. World J Mens Health. 2013 Aug;31(2):126-35.
  17. 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. 2013;Oct 15.
  18. 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(1):57-64.
  19. Aversa A, Bruzziches R, Francomano D, et al. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med. 2010 Oct;7(10):3495-503.
  20. Leifke E, Kinzel M, Tsikas D, Gooren L, Frolich JC, Brabant G. Effects of normalization of plasma testosterone levels in hypogonadal men on plasma levels and urinary excretion of asymmetric dimethylarginine (ADMA). Horm Metab Res. 2008 Jan;40(1):56-9.
  21. 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(6):2050-8.
  22. Toma M, McAlister FA, Coglianese EE, et al. Testosterone supplementation in heart failure: a meta-analysis. Circ Heart Fail. 2012 May 1;5(3):315-21.
  23. Soisson V, Brailly-Tabard S, Empana JP, et al. Low plasma testosterone and elevated carotid intima-media thickness: importance of low-grade inflammation in elderly men. Atherosclerosis. 2012 Jul;223(1):244-9.
  24. 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 Sep;161(3):443-9.
  25. Jasuja GK, Travison TG, Davda M, et al. Age trends in estradiol and estrone levels measured using liquid chromatography tandem mass spectrometry in community-dwelling men of the Framingham Heart Study. J Gerontol A Biol Sci Med Sci. 2013 Jun;68(6):733-40.
  26. Jankowska EA, Rozentryt P, Ponikowska B, et al. Circulating estradiol and mortality in men with systolic chronic heart failure. JAMA. 2009; May 13 301(18):1892-1901.
  27. Lakshman KM, Kaplan B, Travison TG, et al. The effects of injected testosterone dose and age on the conversion of testosterone to estradiol and dihydrotestosterone in young and older men. J Clin Endocrinol Metab. Aug 2010;95(8):3955-64.
  28. Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. Jun 2006;154(6):899-906.
  29. Edelstein D, Dobs A, Basaria S. Emerging drugs for hypogonadism. Expert Opin Emerg Drugs. Nov 2006;11(4):685-707.
  30. Snyder PJ. Clinical use of androgens. Annu Rev Med. 1984;35:207-17.