Dr. Ron’s Research Review – June 5, 2013

© 2013

This week’s research review is part 3 of the adverse effects of testosterone use.

A recent meta-analysis found testosterone therapy increased the risk of a cardiovascular-related event (odds ratio 1.54, 95% confidence interval 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). (Xu, Freeman et al. 2013)

These comments made regarding the 2010 study published in New England Journal of Medicine are also relevant to this meta-analysis. (Basaria, Coviello et al. 2010)

Doses that were higher than those recommended by the manufacturer as starting doses, and an upper threshold almost twice the level recommended by the Endocrine Society: 1000 ng per deciliter vs 4-500. (Khoo 2010)

More than doubling of the testosterone level results in a superimposition of a rise of approximately 40% in estradiol, which might account for the atherosclerosis-related events reported. If so, these events might be prevented by the administration of an aromatase inhibitor. (Phillips 2010)

Notice the confidence intervals (CI). The precision of the estimate is revealed by the confidence interval. The last two columns show the confidence interval expressed as a percentage (CI÷ORx100).


Odds Ratio

95% CI

Difference

%

Overall

1.54

1.09 to 2.18

1.09

70%

Non-pharmaceutical

2.06

1.34 to 3.17

0.977

47%

Pharmaceutical funded

0.89

0.50 to 1.60

1.1

123%

Dr. Ron


Article

Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials

         (Xu, Freeman et al. 2013) Download

BACKGROUND: Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease. METHODS: A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using "("testosterone" or "androgen") and trial and ("random*")" with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. RESULTS: Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). CONCLUSIONS: The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy.


References

Basaria, S., A. D. Coviello, et al. (2010). "Adverse Events Associated with Testosterone Administration." N Engl J Med. [PMID: 20592293]

Khoo, T. K. (2010). "Adverse events associated with testosterone administration." N Engl J Med 363(19): 1865-6; author reply 1866-7. [PMID: 21047235]

Phillips, G. B. (2010). "Adverse events associated with testosterone administration." N Engl J Med 363(19): 1866; author reply 1866-7. [PMID: 21047234]

Xu, L., G. Freeman, et al. (2013). "Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials." BMC Med 11(1): 108. [PMID: 23597181]