Erectile Dysfunction, Metabolic Syndrome, and Cardiovascular Risks

Facts and Controversies

Edward Sanchez; Alexander W. Pastuszak; Mohit Khera

Disclosures

Transl Androl Urol. 2017;6(1):28-36. 

In This Article

Testosterone's Role in CVD

Our knowledge of the intersection between testosterone and cardiovascular risk continues to evolve. Animal studies suggest that testosterone plays a role in coronary artery vasodilation.[36–38] Recently, multiple randomized, placebo-controlled trials have shown that testosterone therapy improves myocardial ischemia in men with CAD.[39–41] English et al. observed that testosterone therapy decreased exercised-induced myocardial ischemia in men with stable angina. In addition, a significant decrease in pain perception, as well as role limitation due to physical problems was noted in the testosterone therapy group.[39] Similarly, Rosano et al. demonstrated an increased time to 1 mm ST-segment depression in men with CAD receiving intravenous testosterone prior to exercise stress testing.[40] It is important to note that these changes were seen with both transdermal and intravenous testosterone formulations.

The mechanism by which testosterone affects vasomotor response remains under investigation. Webb et al. demonstrated that physiologic levels of intracoronary testosterone led to increased coronary artery dilation as well as increased coronary blood flow in men with established CAD via an endothelium-independent pathway.[42] Additional studies suggest that the most likely mechanism of action of testosterone on vascular smooth muscle is via modulation of non-ATP-sensitive potassium ion channels, calcium-activated potassium ion channels, voltage-sensitive potassium ion channels, and finally L-type calcium ion channels.[43]

Testosterone is also thought to play a role in regulating ventricular repolarization. Prolongation of heart rate corrected QT interval (QTc), an accepted measure of ventricular repolarization, is associated with increased incidence of ventricular arrhythmias, including torsades de pointes.[44] Charbit et al. examined the QTc interval in hypogonadal men and observed a significant negative correlation between QTc length and total testosterone levels, a finding echoed by van Noord et al..[45,46] Charbit et al. also examined the effects of a single intramuscular injection of testosterone enanthate on QTc and found that testosterone therapy shortened QTc. Its greatest effect was noted 2 days after administration, with statistically significant differences noted up to 4–6 weeks after administration.[45]

An inverse correlation between testosterone levels and carotid intima-media thickness (IMT) has been demonstrated by several studies.[47–49] IMT is considered a marker for preclinical atherosclerosis and is generally considered a risk factor for adverse cardiovascular events.[50,51] The mechanism of action by which testosterone affects IMT remains unclear, but current data suggests endogenous testosterone may be protective against the development of atherosclerosis.

In addition to direct effects on the coronary vasculature, testosterone replacement may further affect CVD risk by modulating known CVD risk factors. Kalinchenko et al. showed that intramuscular testosterone therapy led to significant improvements in the BMIs of men with metabolic syndrome (MetS).[52] Corona et al. also revealed a reduction in fat mass after testosterone replacement therapy. Additionally, this same analysis revealed that testosterone therapy lowered hemoglobin A1c and fasting plasma glucose.[53] Whitsel et al. demonstrated that intramuscular testosterone led to a reduction in both HDL and LDL, although studies published by Haddad and Isidori reported conflicting results.[54–56]

A study done by Basaria et al. in 2010 was stopped prematurely due to an increased rate of adverse cardiovascular events observed in men receiving transdermal testosterone, raising concern that testosterone may carry significant cardiovascular risk.[57] However, several limitations in this study have been pointed out. For example, the mean age of the study population was 74 years, with a very high percentage of the population suffering from serious chronic illnesses including diabetes, dyslipidemia, obesity, hypertension, and pre-existing heart disease. Significant limitations in mobility existed at baseline, as the purpose of this study was to measure improvement in physical strength. A number of adverse events reported may have been minor phenomena and not true cardiac events. Finally the sample size was thought to be relatively small. Several meta-analyses have investigated the association between testosterone therapy and adverse events. Calof et al. analyzed 19 randomized placebo controlled trials. No significant difference in rate of cardiovascular events was noted. An increased combined incidence of all prostate related adverse events was noted. These included combined prostate events such as all incidents of prostate biopsies, PSA >4 ng/mL or an increase of 1.5 ng/mL during the study, prostate cancer, acute urinary frequency, and an increase in international prostate symptom score. Of note, none of these individual adverse events were significantly different than those observed in the placebo group. A significant rise in hematocrit >50% was observed in the testosterone group. Finally, skin irritation at the site of testosterone application was noted in studies using topical testosterone.[58] A second analysis by Haddad et al. also failed to find a statistically significant difference in adverse cardiovascular events.[56] Fernández-Balsells et al. analyzed 51 studies which included men receiving testosterone therapy for over 3 months. Again, a significant increase in hemoglobin and hematocrit levels was seen in the therapy group compared to those receiving placebo. No difference was found when comparing rate of death, MI, coronary revascularization procedures, or arrhythmias. No difference was seen in rates of prostate cancer, need for prostate biopsy, international prostate symptom score, increase in PSA, or combined prostate related adverse events.[59]

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