Update on hypogonadism and cardiovascular risk

Description

According to the FDA and Australian guidelines the benefits and safety of testosterone therapy in aging men have not been established and should only be used for treatment of classical hypogonadism. The questions is, is this correct? What is the real evidence?

A meta-analysis published in 2011 examined whether hypogonadism is a risk factor for cardiovascular morbidity and mortality, and whether testosterone therapy improves cardiovascular parameters in subjects with known cardiovascular disease.1 70 studies were included in the analysis. In cross-sectional studies, men with cardiovascular disease had significantly lower testosterone and higher estradiol levels. In longitudinal studies, baseline testosterone level was significantly lower among patients with incident overall and cardiovascular mortality. Testosterone therapy was associated with a significant increase in treadmill test duration and time to 1 mm ST segment depression. Another meta-analysis published the same year also showed that low endogenous testosterone levels are associated with increased risk of all-cause and cardiovascular death in community-based studies of men.2

Of 9 meta-analyses3,4 of randomised controlled trials investigating the effect of testosterone therapy and cardiovascular disease, only 1 – by Xu et al. - showed increased risk. However, the meta-analysis by Xu et al included questionable studies, such as the Copenhagen Study which was performed with a non-approved preparation of micronised testosterone which was administered orally in a dose of 600 mg daily to men with alcoholic liver cirrhosis. This dosage resulted in supraphysiological testosterone levels of a maximum of 745 nmol/L (21 486 ng/dl) which is about 20 times the upper limit of normal. This clearly invalidates the conclusion by Xu et al. that testosterone therapy increases risk of cardiovascular disease.

Cardiovascular safety concerns related to testosterone therapy are essentially based on a limited number of observational and randomized controlled trials which present important methodological flaws.5 When hypogonadism is properly diagnosed and testosterone therapy correctly given, no cardiovascular disease or prostate risk have been documented.5 Based on all available data, the European Medicines Agency has correctly concluded that there is “No consistent evidence of an increased risk of heart problems with testosterone medicines.”6

In 2017 new concerns arose when the TTrials reported that among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography.7 However, this trial was not sufficiently powered to analyse cardiovascular safety. Dr Corona and his group recently performed an updated meta-analysis, again showing that testosterone therapy does not increase cardiovascular disease risk.4 In fact, in obese men testosterone therapy was found to reduce cardiovascular disease risk.

In conclusion:

  • Low testosterone can be considered a possible risk factor for cardiovascular disease.
  • Testosterone therapy might reduce cardiovascular disease risk (in pharmaco-epidemiological studies).
  • Testosterone therapy does NOT increase cardiovascular disease risk (in meta-analysed randomised controlled trials)
  • Testosterone therapy is especially beneficial for hypogonadal men with metabolic diseases (obesity, metabolic syndrome, type 2 diabetes).

 

Speakers

Giovanni Corona, MD, PhD

Giovanni Corona, MD, PhD
Endocrinology Unity Medical Department
Ospedale Maggiore Bologna,
Italy

References

  • Corona G, Rastrelli G, Monami M, Guay A, Buvat J, Sforza A, Forti G, Mannucci E, Maggi M. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol. 2011 Nov;165(5):687-701 Return to content
  • 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. J Clin Endocrinol Metab. 2011 Oct;96(10):3007-19. Return to content
  • Corona G, Rastrelli G, Reisman Y, Sforza A, Maggi M. The safety of available treatments of male hypogonadism in organic and functional hypogonadism. Expert Opin Drug Saf. 2018 Mar;17(3):277-292 Return to content
  • Corona G, Rastrelli G, Di Pasquale G, Sforza A, Mannucci E, Maggi M. Testosterone and Cardiovascular Risk: Meta-Analysis of Interventional Studies. J Sex Med. 2018 Jun;15(6):820-838. Return to content
  • Corona G, Sforza A, Maggi M. Testosterone Replacement Therapy: Long-Term Safety and Efficacy. World J Mens Health. 2017 Aug;35(2):65-76. Return to content
  • http://www.ema.europa.eu/ema/index.jsp%3Fcurl%3Dpages/medicines/human/referrals/Testosterone-containing_medicines/human_referral_prac_000037.jsp%26mid%3DWC0b01ac05805c516f Return to content
  • Budoff MJ, Ellenberg SS, Lewis CE, Mohler ER 3rd, Wenger NK, Bhasin S, Barrett-Connor E, Swerdloff RS, Stephens-Shields A, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Gill TM, Matsumoto AM, Molitch ME, Nakanishi R, Nezarat N, Matsumoto S, Hou X, Basaria S, Diem SJ, Wang C, Cifelli D, Snyder PJ. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. JAMA. 2017 Feb 21;317(7):708-716 Return to content