A few days ago, Jan 29th 2014, a controversial study was published showing that men aged 65 years and older, had a two-fold increase in the risk of heart attack in the 90 days after filling an initial testosterone therapy (TT) prescription, regardless of cardiovascular disease history. Among younger men below 65 years of age with a history of heart disease, the study reported two to three-fold increased risk of MI in the 90 days following an initial TT prescription (and no excess risk was found in younger men without such a history).
This study has stirred up heated discussions and media headlines. Let’s dissect it and look under the hood…
The study analyzed over 55,000 patients in a health-care database, which did not include information on blood work nor diagnostic indications for treatment.
Thus, it is lacking critical information on baseline hormone levels and potential risk factors which could have contributed to the heart attacks. The study also lacks data on what type of testosterone treatments that were used, and dosages.
In addition, it should be noted that this study was not a randomized controlled trial, which is the gold standard in medical research.
Testosterone replacement therapy (TRT) increases both estradiol and DHT (dihydrotestosterone). When men take testosterone, a significant amount of it can be converted into estradiol by aromatase in just a few months, especially in older men over 59 years of age.
Excess estrogen promotes abnormal clot formation  and several studies have shown that even slightly elevated estradiol levels increases risk of CVD (cardiovascular disease), and cardiovascular/all-cause mortality. [4-6] For example, compared to having estradiol in the optimal range of 21.80 – 30.11 pg/mL, men with an estradiol level over 37.40 pg/mL were found in one study to have over a two-fold increase risk of dying during a 3 year follow-up. Therefore, levels of all relevant hormones have to be monitored and taking into account before drawing conclusions. While acknowledging that estradiol elevations might contribute to cardiovascular events, the study authors did not point out that this could have been an important contributing factor to the rise in heart attacks.
Another issue that not many doctors are aware of is that the metabolic clearance of testosterone slows down with age. This means that any given testosterone supplementation dose will cause a higher elevation in blood testosterone levels in older men over 59 years of age, compared to young men below 35 years. Thus, replacement doses have to be titrated accurately in older men to minimize the risk of adverse events during TRT.
The most common side-effect of TRT is elevation of hematocrit (aka polycythemia) , ie. an increase in the percentage of the volume of whole blood that is made up of red blood cells. Elevated hematocrit, which increases the blood’s viscosity (ie. makes the blood thicker), can itself give rise to heart attacks. The risk of hematocrit elevation varies widely depending on mode of testosterone administration: 15% with gel and up to 44% with intramuscular injections.[10, 11] Thus, when evaluating safety of TRT, the different modes of testosterone delivery need to be analyzed separately. This was another important factor left out in this study.
What do other studies show?
The study’s ignorance of these issues completely discredits the conclusion that “evidence supports an association between testosterone therapy and risk of serious, adverse cardiovascular related events – including non-fatal myocardial infarction – in men.”
A plethora of randomized controlled trials contradicts this conclusion. Three meta-analyses of a total of 100 well conducted randomized controlled trials found no significant difference between the TRT and placebo groups for all cardiovascular events, nor for each type of event (all cause and CV death, fatal and non-fatal myocardial infarction, revascularization procedures, arrhythmia, cerebrovascular events).[8, 12, 13]
Why doesn’t this make it to the media headlines?
Current available evidence generated from well designed randomized controlled trials show overall that TRT in men is not associated with an increase in cardiovascular adverse events.
Garbage in, garbage out!
1. Finkle, W.D., et al., Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men. PLoS ONE 9(1): e85805. doi:10.1371/journal.pone.0085805, 2014.
2. Lakshman, K.M., 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, 2010. 95(8): p. 3955-64.
3. Bracamonte, M.P. and V.M. Miller, Vascular effects of estrogens: arterial protection versus venous thrombotic risk. Trends Endocrinol Metab, 2001. 12(5): p. 204-9.
4. Corona, G., et al., Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol, 2011. 165(5): p. 687-701.
5. Jankowska, E.A., et al., Circulating estradiol and mortality in men with systolic chronic heart failure. JAMA, 2009. 301(18): p. 1892-901.
6. Abbott, R.D., et al., Serum estradiol and risk of stroke in elderly men. Neurology, 2007. 68(8): p. 563-8.
7. Coviello, A.D., et al., Differences in the apparent metabolic clearance rate of testosterone in young and older men with gonadotropin suppression receiving graded doses of testosterone. J Clin Endocrinol Metab, 2006. 91(11): p. 4669-75.
8. Calof, O.M., 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(11): p. 1451-7.
9. Stergiopoulos, K., et al., Anabolic steroids, acute myocardial infarction and polycythemia: a case report and review of the literature. Vasc Health Risk Manag, 2008. 4(6): p. 1475-80.
10. Seftel, A., Testosterone replacement therapy for male hypogonadism: part III. Pharmacologic and clinical profiles, monitoring, safety issues, and potential future agents. Int J Impot Res, 2007. 19(1): p. 2-24.
11. Dobs, A.S., et al., Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab, 1999. 84(10): p. 3469-78.
12. Fernandez-Balsells, M.M., et al., Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab, 2010. 95(6): p. 2560-75.
13. Haddad, R.M., et al., Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc, 2007. 82(1): p. 29-39.