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Testosterone Boosting Medications and Cardiovascular Risk - a systematic review and meta-analysis

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Accumulating evidence shows beneficial effect of testosterone therapy on a wide range of health outcomes, including inflammation, insulin sensitivity, muscle mass, body fat mass, lipid profiles,  endothelial, bone mineral density, energy and vitality, mood, sexual function and overall quality of life. [1-9]
 
Despite this, concerns have been raised that testosterone therapy could have detrimental effects on cardiovascular disease.
 
In this article I summarize results from a comprehensive systematic review and meta-analysis, the largest to date, of all placebo-controlled randomized clinical trials (RCTs) on the effect of testosterone therapy on cardiovascular-related outcomes.[10] 
 

KEY POINTS  

 
* This new systematic review and meta-analysis of randomized controlled trials reporting the effects of testosterone therapy on different cardiovascular outcomes, included 75 RCTs with a total of 3016 patients on testosterone therapy and 2448 patients on placebo, for mean duration of 34 weeks.[10]
 
* The principal outcome of this analysis was the effect of testosterone therapy, as compared with placebo, on the incidence of a new major adverse cardiovascular event (MACE). MACE was defined as the composite of cardiovascular death, non-fatal acute myocardial infarction and stroke, and acute coronary syndromes and/or heart failure reported as serious adverse events. This was done to comply with requirements for drug safety assessment, as required by regulatory agencies.
 
* The meta-analysis took into consideration baseline hypogonadism status (total testosterone levels below or over 346 ng/dL or 12 nmol/L), trial duration (≤ 12 weeks and > 12 weeks), clinical conditions (elderly men, men with cardiovascular disease, frail men and men with metabolic diseases) and industry-funding vs. non-industry-funding.
 
* The mean age, baseline testosterone level and body mass index (BMI) of enrolled patients were 60 years, 11.2 nmol/L (323 ng/dL) and 28 kg/m2 (overweight). 
 
* Testosterone was administered in different doses, preparations (oral, intramuscular and transdermal) and in mixed populations of hypogonadal and eugonadal (non-hypogonadal) men. 
 
* This analysis, performed on the largest number of studies collected so far, indicate that testosterone therapy is not related to any increase in cardiovascular risk, even when composite or single adverse events were considered. 
 
* Present data clearly refute the notion that testosterone therapy would increase risk of cardiovascular events.
 
* In studies performed in subjects with metabolic derangements, a protective effect of testosterone therapy on cardiovascular risk was observed.
 
* No sponsorship bias was detected, because no difference in MACE risk was found when the analysis was performed according to the presence or absence of drug company support.
 
* Testosterone therapy in hypogonadal men can be a valuable strategy to improve metabolic profile, reduce body fat and increase lean muscle mass, which would ultimately reduce the risk of heart disease.
 
 

What is known

 
The notion that testosterone is "bad for the heart" arose from the well documented simple observation that heart diseases are more prevalent in men than in women.[11-18] Acute coronary heart disease and ischaemic stroke events appears approximately 10 years earlier in men than in women, and these rates remain higher in men than in women in all age groups.[11] More men are living with and dying of coronary heart disease than women, and have more hospital discharges for cardiovascular diseases and.[19] The prevalence of coronary heart disease is higher in men within each age stratum, which contributed to the perception that heart disease is a “man’s disease”.[19] A recent analysis found that the age-standardized risk of death from cardiovascular diseases is 80% higher for men (442/100 000) than for women (246/100 000).[12] Because men have higher testosterone, it was automatically assumed that testosterone may be the culprit. Further support for this notion comes from case reports of sudden cardiovascular death amongst male athletes abusing anabolic steroids (which are synthetic compounds similar to testosterone) [20-24], and observations that testosterone dose-dependently increases hematocrit [25, 26] and reduces HDL-cholesterol at supra-physiological levels.[27-29]
 
However, longitudinal observational studies demonstrate that it is reduced, rather than increased testosterone levels, which are associated with elevated risk of cardiovascular disease, cardiovascular mortality and all-cause mortality.[30, 31] This can be explained by the well documented strong associations of hypogonadism with a number of cardiovascular risk factors, including adiposity and increased waist circumference, insulin resistance and type 2 diabetes mellitus, hypertension and inflammation.[32-37] 
In line with this, androgen deprivation therapy for prostate cancer causes worsening of these risk factors and co-morbidities [38], and a growing body of research demonstrates that testosterone therapy improves them.[1-9, 39] This indicates that hypogonadism is causally related to disease development and progression.
 

What this meta-analysis adds

 
The results from the comprehensive systematic review and meta-analysis presented here show that testosterone therapy is not related to any increase in cardiovascular risk, and that it may have a protective effect on cardiovascular risk in men with metabolic derangements.[10] This conclusion is based on an analysis of the largest number of studies collected so far, which clearly refutes the previously purported causal role between testosterone therapy and cardiovascular events.
 
A strength of this meta-analysis is that its principal outcome was the effect of testosterone therapy, as compared with placebo, on the incidence of a new major adverse cardiovascular event (MACE).[10] A previous meta-analysis, which concluded that testosterone therapy increased the risk of cardiovascular-related events [40], included many events which are not typically considered for the assessment of cardiovascular risk (e.g., peripheral edema, self-reported syncope etc.). This can be grossly misleading due to the limited reliability of diagnostic criteria used to attribute these events as drug-related. It should be recognized that the use of MACE, instead of a broader ambiguous definition of cardiovascular side effects, has the advantage of a clearer diagnostic definition and precise diagnosis, which is less dependent on investigators’ subjective opinions. Therefore, the assessments of cardiovascular safety of any therapy should be based on the incidence of MACE, which are easier to detect and less controversial in diagnosis. It should be underscored that regulatory agencies assessing the safety of drugs require analyses of MACE and not of broadly defined cardiovascular side effects.[41] 
 
This meta-analysis also did not observe any sponsorship bias, because no difference in cardiovascular risk was found when the analysis was performed according to the presence or absence of drug company funding.[10] This is also in contrast to the meta-analysis just mentioned, which reported that the effects of testosterone on cardiovascular-related events varied with source of funding.[40]
 
Comparison to previous meta-analyses
 
As of this writing, only one previous meta-analysis concluded that testosterone therapy increases the risk of cardiovascular-related events.[40] However, this meta-analysis has been criticized on several grounds. The authors specifically included only studies in which cardiovascular events were reported; therefore studies without any cardiovascular events were excluded. Importantly, two studies were included that were performed with off-label use of the respective testosterone preparation [42, 43] and one study used non-approved preparation of testosterone (oral micronized testosterone) which resulted in supra-physiological serum testosterone levels reaching as high as 745 nmol/L (21 486 ng/dl), which is about 20 times the upper limit of normal.[44]  Since oral forms of testosterone are known to cause liver toxicity it is no surprise that such a high testosterone dose would be harmful, especially in a study population of patients with liver cirrhosis.[44]  
 
These three studies accounted for 39% of events in the testosterone treated group and 18% in the placebo group.[44] After excluding them from the analysis, there would have been a similar rate of events among testosterone and placebo groups; 70/1570 (4.5%) events in the testosterone group and 53/1001 (5.3%) events in the placebo group.
 
Notably, results from three other large meta-analyses which included a more representative set of studies, and that specifically focused on identifying potential adverse effects of testosterone treatment, are in line with the conclusions from the most recent meta-analysis reported here; none of them found increased cardiovascular risks with testosterone therapy versus placebo.[45-47] More specifically, their conclusions were:
 
* The frequency of cardiovascular events, sleep apnea or death is not significantly different between the testosterone and placebo treated groups.[45]
 
* Currently (as of 2007) available evidence weakly supports the inference that testosterone use in men is not associated with important cardiovascular effects.[47]
 
* There is no significant negative effect of testosterone therapy on mortality, prostate, or cardiovascular outcomes.[46]
 
Supporting data from other recent studies
 
Multiple other lines of evidence concur with the conclusions in this meta-analysis. Two notable studies demonstrated that testosterone therapy decreases mortality compared with no testosterone treatment [48], and improves survival in hypogonadal men with type 2 diabetes.[49] Further support comes from The MrOS (Osteoporotic Fractures in Men) study which after a 5-year follow-up found that an apparent threshold of ≥550 ng/dL (approximately 19 nmol/L) needs to be reached in order to reduce risk of cardiovascular events..[50] In this study, men in the highest quartile of testosterone (≥550 ng/dL) had a 30% lower risk of cardiovascular events (hazard ratio: 0.70) compared with men in the 3 lower quartiles, where no protective effect was noted. [50] This association remained after adjustment for traditional cardiovascular risk factors and was not materially changed in analyses excluding men with known cardiovascular disease at.[50] 
 
Additional support refuting the notion that testosterone therapy would be pro-atherogenic comes from a notable recent dose-response study which assessed the effects of graded doses of testosterone on serum markers of oxidative stress, chemotaxis, adhesion, and inflammation in healthy younger and older men.[51] Weekly injections of 25, 50, 125, 300, or 600 mg of testosterone enanthate were administrated for 20 weeks in 121 eugonadal men (n = 61, 18-35 years of age and n = 60, 60-75 years of age). No significant linear associations were observed between testosterone dose and MCP-1 (chemokine monocyte chemotactic protein-1), sICAM-1 (soluble intracellular adhesion molecule-1), or CRP (high-sensitivity C-reactive protein)[51] Also, levels of the oxidative stress marker 8-isoprostane PGF2-alpha (8-iso-PGF2-alpha) were not negatively impacted.[51] As MCP-1 [52],  sICAM-1 [53] and  CRP [54] are atherogenic markers which independently predict risk of cardiovascular disease or acute myocardial infarction, the results from this study are strongly congruent with the conclusions that testosterone therapy does not increase atherosclerosis.
 
Reflections 
 
A few flawed studies of epidemiological observations induced an epidemic of sensational and misleading media coverage and false claims alleging potential dangerous effect of testosterone therapy on the cardiovascular system.[55, 56] The popular press is terrifying the general public on a daily basis with announcements of serious testosterone associated cardiac hazards. However, as outlined here, results from randomized placebo controlled clinical trials, which are golden standard in medical research, show that testosterone therapy does not increase cardiovascular events, and to the contrary, that it protects against cardiovascular events in hypogonadal men with metabolic risk factors.[10] According to expert opinion, testosterone therapy in hypogonadal men can be a valuable strategy to improve metabolic profile, reduce body fat and increase lean muscle mass, which would ultimately reduce the risk of heart disease.[10]
 
 
References:
 

1.         Francomano, D., et al., Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Urology, 2014. 83(1): p. 167-73.

2.         Haider, A., et al., Progressive Improvement of T-Scores in Men with Osteoporosis and Subnormal Serum Testosterone Levels upon Treatment with Testosterone over Six Years. Int J Endocrinol, 2014. 2014: p. 496948.

3.         Haider, A., et al., Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study. Obes Res Clin Pract, 2014. 8(4): p. e339-49.

4.         Haider, A., et al., Effects of long-term testosterone therapy on patients with "diabesity": results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. Int J Endocrinol, 2014. 2014: p. 683515.

5.         Haider, A., et al., Incidence of Prostate Cancer in Hypogonadal Men Receiving Testosterone Therapy: Observations from Five Year-median Follow-up of Three Registries. J Urol, 2014.

6.         Saad, F., et al., Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring), 2013. 21(10): p. 1975-81.

7.         Traish, A.M., et al., Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract, 2014. 68(3): p. 314-29.

8.         Yassin, A. and G. Doros, Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clin Obes, 2013. 3(3-4): p. 73-83.

9.         Traish, A.M., Outcomes of testosterone therapy in men with testosterone deficiency (TD): Part II. Steroids, 2014. 88C: p. 117-126.

10.       Corona, G., et al., Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf, 2014. 13(10): p. 1327-51.

11.       Hyvarinen, M., et al., The difference between acute coronary heart disease and ischaemic stroke risk with regard to gender and age in Finnish and Swedish populations. Int J Stroke, 2010. 5(3): p. 152-6.

12.       Mikkola, T.S., et al., Sex differences in age-related cardiovascular mortality. PLoS One, 2013. 8(5): p. e63347.

13.       Ng, M.K., New perspectives on Mars and Venus: unravelling the role of androgens in gender differences in cardiovascular biology and disease. Heart Lung Circ, 2007. 16(3): p. 185-92.

14.       Perez-Lopez, F.R., et al., Gender differences in cardiovascular disease: hormonal and biochemical influences. Reprod Sci, 2010. 17(6): p. 511-31.

15.       Phillips, G.B., Is atherosclerotic cardiovascular disease an endocrinological disorder? The estrogen-androgen paradox. J Clin Endocrinol Metab, 2005. 90(5): p. 2708-11.

16.       Rosano, G.M., Androgens and coronary artery disease. A sex-specific effect of sex hormones? Eur Heart J, 2000. 21(11): p. 868-71.

17.       Seifarth, J.E., C.L. McGowan, and K.J. Milne, Sex and life expectancy. Gend Med, 2012. 9(6): p. 390-401.

18.       Vitale, C., M.E. Mendelsohn, and G.M. Rosano, Gender differences in the cardiovascular effect of sex hormones. Nat Rev Cardiol, 2009. 6(8): p. 532-42.

19.       Mosca, L., E. Barrett-Connor, and N.K. Wenger, Sex/gender differences in cardiovascular disease prevention: what a difference a decade makes. Circulation, 2011. 124(19): p. 2145-54.

20.       Payne, J.R., P.J. Kotwinski, and H.E. Montgomery, Cardiac effects of anabolic steroids. Heart, 2004. 90(5): p. 473-5.

21.       Nieminen, M.S., et al., Serious cardiovascular side effects of large doses of anabolic steroids in weight lifters. Eur Heart J, 1996. 17(10): p. 1576-83.

22.       Baggish, A.L., et al., Long-term anabolic-androgenic steroid use is associated with left ventricular dysfunction. Circ Heart Fail, 2010. 3(4): p. 472-6.

23.       Kersey, R.D., et al., National Athletic Trainers' Association position statement: anabolic-androgenic steroids. J Athl Train, 2012. 47(5): p. 567-88.

24.       Rothman, R.D., et al., Anabolic androgenic steroid induced myocardial toxicity: an evolving problem in an ageing population. BMJ Case Rep, 2011. 2011.

25.       Coviello, A.D., et al., Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. Journal of Clinical Endocrinology and Metabolism, 2008. 93(3): p. 914-9.

26.       Anderson, R.A., C.A. Ludlam, and F.C. Wu, Haemostatic effects of supraphysiological levels of testosterone in normal men. Thrombosis and Haemostasis, 1995. 74(2): p. 693-7.

27.       Bhasin, S., et al., Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab, 2001. 281(6): p. E1172-81.

28.       Singh, A.B., et al., The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men. Journal of Clinical Endocrinology and Metabolism, 2002. 87(1): p. 136-43.

29.       Bhasin, S., et al., Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. Journal of Clinical Endocrinology and Metabolism, 2005. 90(2): p. 678-88.

30.       Corona, G., et al., Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. European Journal of Endocrinology / European Federation of Endocrine Societies, 2011. 165(5): p. 687-701.

31.       Araujo, A.B., et al., Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab, 2011. 96(10): p. 3007-19.

32.       Traish, A.M., Adverse health effects of testosterone deficiency (TD) in men. Steroids, 2014. 88C: p. 106-116.

33.       Traish, A.M., et al., Testosterone deficiency. Am J Med, 2011. 124(7): p. 578-87.

34.       Ullah, M.I., et al., Testosterone deficiency as a risk factor for cardiovascular disease. Horm Metab Res, 2011. 43(3): p. 153-64.

35.       Tsujimura, A., The Relationship between Testosterone Deficiency and Men's Health. World J Mens Health, 2013. 31(2): p. 126-35.

36.       Maggio, M. and S. Basaria, Welcoming low testosterone as a cardiovascular risk factor. Int J Impot Res, 2009. 21(4): p. 261-4.

37.       Yeap, B.B., Are declining testosterone levels a major risk factor for ill-health in aging men? Int J Impot Res, 2009. 21(1): p. 24-36.

38.       Saylor, P.J. and M.R. Smith, Adverse effects of androgen deprivation therapy: defining the problem and promoting health among men with prostate cancer. J Natl Compr Canc Netw, 2010. 8(2): p. 211-23.

39.       Saad, F., et al., Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Curr Diabetes Rev, 2012. 8(2): p. 131-43.

40.       Xu, L., et al., Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med, 2013. 11: p. 108.

41.       U.S. Food and Drug Administration (FDA). Available at: http://www.fda.govAccessed Sept 29, 2014.

42.       Basaria, S., et al., Adverse events associated with testosterone administration. N Engl J Med, 2010. 363(2): p. 109-22.

43.       Spitzer, M., et al., Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med, 2012. 157(10): p. 681-91.

44.       Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. The Copenhagen Study Group for Liver Diseases. Hepatology, 1986. 6(5): p. 807-13.

45.       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.

46.       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.

47.       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.

48.       Shores, M.M., et al., Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab, 2012. 97(6): p. 2050-8.

49.       Muraleedharan, V., et al., Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol, 2013. 169(6): p. 725-33.

50.       Ohlsson, C., 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. 58(16): p. 1674-81.

51.       Roberts, C.K., et al., Effects of varying doses of testosterone on atherogenic markers in healthy younger and older men. Am J Physiol Regul Integr Comp Physiol, 2014. 306(2): p. R118-23.

52.       Deo, R., et al., Association among plasma levels of monocyte chemoattractant protein-1, traditional cardiovascular risk factors, and subclinical atherosclerosis. Journal of the American College of Cardiology, 2004. 44(9): p. 1812-8.

53.       Ridker, P.M., et al., Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet, 1998. 351(9096): p. 88-92.

54.       Ridker, P.M., et al., C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. New England Journal of Medicine, 2000. 342(12): p. 836-43.

55.       Finkle, W.D., et al., Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One, 2014. 9(1): p. e85805.

56.       Vigen, R., et al., Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA, 2013. 310(17): p. 1829-36.

 
Last modified on Tuesday, 30 September 2014 22:46
Monica

Medical Writer & Nutritionist

MSc Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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