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Testosterone and Cardiovascular Risk

Men and their doctors may want to think twice the next time they consider testosterone replacement therapies.  Often advertised in television commercials and magazines, these products are aimed at treating men with “Low T” (low testosterone), typically due to hypogonadism.  Testosterone therapies have experienced their fair share of controversy in the medical community for decades.  Recent studies have amassed significant media attention and public awareness, particularly related to potential links between testosterone therapies and cardiovascular deaths.

Concerns of Testosterone Therapy and Cardiovascular Risk

Two prior studies of testosterone replacement therapy that have gained the media attention were published in the New England Journal of Medicine in July 2010 and published in PLOS One in January 2014. 

The former study was stopped early due to an increased risk of cardiovascular events in men older than 65 undergoing testosterone therapy versus placebo.  Cardiovascular events however were not planned endpoints of the study, and the patients had high prevalence of cardiovascular risk at baseline.1 

The latter report was a retrospective cohort study that analyzed 55,593 health records and found that men with heart disease had a higher risk of myocardial infarction during 90 days after starting testosterone therapy when compared with the risk during the year prior to initiating testosterone (RR 1.36, 95% CI: 1.03-1.81).2  This risk was even higher for men older than 65 (RR 2.19, 95% CI: 1.27-3.77). 

It is unlikely, however, that patients with excess cardiovascular risk would have been excluded from receiving testosterone as the study authors stated, “there is no reason to suspect that physicians excluded high-risk individuals from testosterone therapy prescription or monitored them more closely, since the hypothesis relating testosterone therapy prescription to adverse cardiovascular events was not widely known during the study period.”2 

With evidence from large randomized trials lacking, a group of researchers at The University of Hong Kong performed a meta-analysis of cardiovascular risk associated with testosterone therapy, results of which were published in an April 2013 issue of BMC Medicine.  After evaluating 27 clinical trials which included 2,994 mostly older men, the researchers showed that those receiving testosterone therapy had one and a half greater odds of developing a cardiovascular event than those taking placebo (95% CI: 1.09–2.18).3  Overall, the authors indicated a number needed to harm of 90 per year of testosterone therapy, at most. 

Exogenous Testosterone and Blood Viscosity

The PLOS One study that prompted a statement from the Endocrine Society on February 7, 2014 also raised concern from the FDA.  When asked about the study in an interview, lead author and epidemiologist William Finkle explained that testosterone increases red blood development.  He stated that, “the increase in red blood cells can coagulate, and cause an increase in viscosity, or thickening in the blood.  An increase in viscosity of the blood means thicker blood.  If the blood is thicker, then that increases the risk of clotting, and hence the risk of blockage and so forth.” 4 

Testosterone treatments are known to stimulate erythropoiesis (production of red blood cells).  In fact, hematocrit and hemoglobin increases are dose-dependent in both young and older men (p = 0.0001) with older men experiencing more significant increases than younger men.5  This coincides with a 15-20% increase in hemoglobin and a parallel increase in testosterone levels in males at puberty.6  Left unchecked, hematocrit, the concentration of red blood cells (RBCs), can exceed beyond normal ranges. 

Small increases in hematocrit have demonstrated exponential increases in whole blood viscosity.7  Elevated hematocrit and blood viscosity, which directly cause increased vascular resistance and reduced blood flow, have been linked to cardiovascular and cerebrovascular disorders such as carotid atherosclerosis, ischemic heart disease, thrombosis, and stroke.  Such erythrocytosis (elevated hematocrit) has been explained by various mechanisms including increased erythropoietin (EPO) levels, decreased ferritin concentrations due to iron utilization for RBC production, and stiffening of RBC membranes which impedes flow within small capillaries. 8-10

Implications for Clinical Practice

It is important that testosterone replacement therapy be used only in those with verifiable testosterone deficiencies and not those who are symptomatic of hypogonadism with normal testosterone levels.  When choosing a testosterone regimen, practitioners should know that injectable preparations carry the greatest risk of erythrocytosis when compared with transdermal preparations. 

Supraphysiologic doses are also significantly associated with erythrocytosis.  Hematocrit and hemoglobin elevations associated with testosterone therapy are dose-dependent in men of all ages; meanwhile, older men are likely to experience the greatest elevations.5

Testosterone replacement therapy should be suspended if hematocrit rises above 54%.11  Therapy should not be reinitiated until hematocrit reaches a safe level (i.e. 45%).  Once hematocrit is normalized, a low-dose testosterone regimen may be initiated. 

Hematocrit greater than 45% may cause elevated blood viscosity and increased risk of cardiovascular death and major thrombosis.  Therefore, it is important to determine a baseline measurement of hematocrit, testosterone levels, and other safety parameters such as prostate specific antigen (PSA) and a digital rectal exam, prior to initiating therapy.  These safety parameters should be monitored at 3 months, 6 months, and then yearly after initiation of therapy.11

Potential Consequences of Not Addressing Low Testosterone Levels

Naturally occurring testosterone deficiency has been correlated with increased cardiovascular risk in one meta-analysis, and a separate meta-analysis demonstrated increased cardiovascular risk only in elderly men. 12,13   Both of these studies agreed that low endogenous testosterone levels may be a poor indicator of overall health as endogenous testosterone levels are often lower in patients with chronic conditions such as chronic heart failure, chronic obstructive pulmonary disease (COPD), type 2 diabetes mellitus, obesity, and end-stage renal disease.14  Furthermore, low endogenous testosterone levels have been associated with increased overall risk of death and cardiovascular-related death.

Conclusions

These findings are still inconclusive for a number of reasons.  Many studies favoring testosterone therapy may actually go unpublished.3  Further, criteria for cardiovascular event reporting can differ among studies.  Differences in baseline cardiovascular risk and risk factors can also complicate interpretations of testosterone therapy studies.  The recognition of testosterone metabolites having related biological functions such as dihydrotestosterone and estrogens can further complicate the interpretation of results. 15

New research is needed to determine differences in the effects of endogenous and exogenous testosterone. 


References:

1. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. Jul 8 2010;363(2):109-122.

2. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9(1):e85805.

3. 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.

4. Gibb G. FDA to Review Risk of Testosterone Heart Attack, Stroke.  http://www.lawyersandsettlements.com/articles/testosterone/testosterone-lawsuit-side-effects-2-19525.html#.UxcrDj9dV8E. Accessed March 5, 2014.

5. Coviello AD, Kaplan B, Lakshman KM, Chen T, Singh AB, Bhasin S. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab. Mar 2008;93(3):914-919.

6. Bassil N, Alkaade S, Morley JE. The benefits and risks of testosterone replacement therapy: a review. Therapeutics and clinical risk management. Jun 2009;5(3):427-448.

7. Lowe GD. Rheological influences on thrombosis. Baillieres Best Pract Res Clin Haematol. Sep 1999;12(3):435-449.

8. Guo W, Bachman E, Li M, et al. Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells. Aging cell. Apr 2013;12(2):280-291.

9. Bachman E, Travison TG, Basaria S, et al. Testosterone Induces Erythrocytosis via Increased Erythropoietin and Suppressed Hepcidin: Evidence for a New Erythropoietin/Hemoglobin Set Point. The journals of gerontology. Series A, Biological sciences and medical sciences. Oct 24 2013.

10. Panin LE, Mokrushnikov PV, Kunitsyn VG, Zaitsev BN. Interaction mechanism of anabolic steroid hormones with structural components of erythrocyte membranes. The journal of physical chemistry. B. Dec 22 2011;115(50):14969-14979.

11. Ullah MI, Riche DM, Koch CA. Transdermal testosterone replacement therapy in men. Drug design, development and therapy. 2014;8:101-112.

12. 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. The Journal of clinical endocrinology and metabolism. Oct 2011;96(10):3007-3019.

13. Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart. Jun 2011;97(11):870-875.

14. Oskui PM, French WJ, Herring MJ, Mayeda GS, Burstein S, Kloner RA. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. Journal of the American Heart Association. Dec 2013;2(6):e000272.

15. Stergiopoulos K, Brennan JJ, Mathews R, Setaro JF, Kort S. Anabolic steroids, acute myocardial infarction and polycythemia: a case report and review of the literature. Vasc Health Risk Manag. 2008;4(6):1475-1480.

 

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