Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis

Corona, Giovanni; Maseroli, Elisa; Rastrelli, Giulia; Isidori, Andrea M.; Sforza, Alessandra; Mannucci, Edoardo; Maggi, Mario

doi:10.1517/14740338.2014.950653

Cited by 265 publications

(191 citation statements)

References 135 publications

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“…The results of several large meta-analyses have generally not supported a causal role between testosterone treatment and cardiovascular events. [21][22][23][24] These metaanalyses are limited by the quality of the included studies, the heterogeneity of the testosterone levels in the populations assessed, and the use of different doses and routes of administration of testosterone replacement products.…”

Section: Treatmentmentioning

confidence: 99%

Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline

Morales

Bebb

Manjoo

et al. 2015

CMAJ

196

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Section: Treatmentmentioning

confidence: 99%

Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline

Morales

Bebb

Manjoo

et al. 2015

CMAJ

196

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“…Results of a recent metaanalysis (Xu et al 2013) that included the Testosterone in Older Men (TOM) trial (Basaria et al 2010) indicated that exogenous testosterone increased the risk of cardiovascularrelated events. However, the results of a more recent metaanalysis indicated that testosterone supplementation wasn't related to any increase in cardiovascular risk, supporting the hypothesis that there isn't a causal link between testosterone supplementation and adverse cardiovascular events (Corona et al 2014). Although much work has been reported recently in this field, the potential of testosterone replacement therapy to improve outcomes is still an uncertain matter.…”

Section: Introductionmentioning

confidence: 99%

Testosterone replacement attenuates mitochondrial damage in a rat model of myocardial infarction

Wang¹,

Yang²,

Sun³

et al. 2015

Journal of Endocrinology

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Testosterone can affect cardiovascular disease, but its effects on mitochondrial dynamics in the post-infarct myocardium remain unclear. To observe the effects of testosterone replacement, a rat model of castration-myocardial infarction (MI) was established by ligating the left anterior descending coronary artery 2 weeks after castration with or without testosterone treatment. Expression of mitochondrial fission and fusion proteins was detected by western blot and immunofluorescence 14 days after MI. Cardiac function, myocardial inflammatory infiltration and fibrosis, cardiomyocyte apoptosis, mitochondrial microstructure, and ATP levels were also assessed. Compared with MI rats, castrated rats showed aggravated mitochondrial and myocardial insults, including mitochondrial swelling and disordered arrangement; loss of cristae, reduced mitochondrial length; decreased ATP levels; cardiomyocyte apoptosis; and impaired cardiac function. Results of western blotting analyses indicated that castration downregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) and mitofusin 2, but upregulated dynamin-related protein 1. The results were also supported by results obtained using immunofluorescence. However, these detrimental effects were reversed by testosterone supplementation, which also elevated the upstream AMP-activated protein kinase (AMPK) activation of PGC1A. Thus, testosterone can protect mitochondria in the post-infarct myocardium, partly via the AMPK-PGC1A pathway, thereby decreasing mitochondrial dysfunction and cardiomyocyte apoptosis. The effects of testosterone were confirmed by the results of ELISA analyses.

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“…One study reported an excess of cardiovascular events in older men without pathological hypogonadism,6 but subsequent meta-analyses of randomised placebo controlled trials of adverse cardiovascular effects from testosterone treatment have provided discrepant interpretations 78 9 10 11 12 However, the overall risk ratios were 1.0 or greater in each trial, suggesting that these relatively short term analyses with wide confidence intervals were still too under-powered to be decisive 13. On the basis of congruent considerations, in June 2014 the US Food and Drug Administration and Health Canada required a new general label warning in the product information of all approved testosterone products about risk of venous thromboembolism after testosterone treatment 14…”

Section: Introductionmentioning

confidence: 99%

Testosterone treatment and risk of venous thromboembolism: population based case-control study

Martínez¹,

Suissa

Rietbrock³

et al. 2016

BMJ

138

119

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Objective To determine the risk of venous thromboembolism associated with use of testosterone treatment in men, focusing particularly on the timing of the risk.Design Population based case-control studySetting 370 general practices in UK primary care with linked hospital discharge diagnoses and in-hospital procedures and information on all cause mortality.Participants 19 215 patients with confirmed venous thromboembolism (comprising deep venous thrombosis and pulmonary embolism) and 909 530 age matched controls from source population including more than 2.22 million men between January 2001 and May 2013.Exposure of interest Three mutually exclusive testosterone exposure groups were identified: current treatment, recent (but not current) treatment, and no treatment in the previous two years. Current treatment was subdivided into duration of more or less than six months.Main outcome measure Rate ratios of venous thromboembolism in association with current testosterone treatment compared with no treatment were estimated using conditional logistic regression and adjusted for comorbidities and all matching factors.Results The adjusted rate ratio of venous thromboembolism was 1.25 (95% confidence interval 0.94 to 1.66) for current versus no testosterone treatment. In the first six months of testosterone treatment, the rate ratio of venous thromboembolism was 1.63 (1.12 to 2.37), corresponding to 10.0 (1.9 to 21.6) additional venous thromboembolisms above the base rate of 15.8 per 10 000 person years. The rate ratio after more than six months’ treatment was 1.00 (0.68 to 1.47), and after treatment cessation it was 0.68 (0.43 to 1.07). Increased rate ratios within the first six months of treatment were observed in all strata: the rate ratio was 1.52 (0.94 to 2.46) for patients with pathological hypogonadism and 1.88 (1.02 to 3.45) for those without it, and 1.41 (0.82 to 2.41) for those with a known risk factor for venous thromboembolism and 1.91 (1.13 to 3.23) for those without one.Conclusions Starting testosterone treatment was associated with an increased risk of venous thromboembolism, which peaked within six months and declined thereafter.

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Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis

Cited by 265 publications

References 135 publications

Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline

Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline

Testosterone replacement attenuates mitochondrial damage in a rat model of myocardial infarction

Testosterone treatment and risk of venous thromboembolism: population based case-control study

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