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After noticing a correlation between anabolic steroid use and increased adverse cardiovascular events such as sudden myocardial infarction in athletes, Ammar et al40 set out to investigate and determine the validity of this phenomenon in a rabbit model. It has been well established that estrogen benefits the cardiovascular system by reducing myocardial injury after ischemia and reperfusion,12–15 but few studies have examined the effects of estrogen in the presence of testosterone on the cardiovascular system. In addition, Western blots were performed to determine Kv1.5 K+ channel expression, which is responsible for IKUR, the ultra‐rapid delayed K+ rectifier.7–9 Western blots uncovered increased Kv1.5 K+ channel expression and increased IKUR in testosterone‐normal males when compared with females and testosterone‐deficient males.
In its assessment of CV risks and T therapy, the FDA identified a total of only 4 studies suggesting an increased risk, yet none provided solid evidence to support this. No definitive statement can be made regarding the effects of testosterone replacement therapy on the levels of either LDL or HDL cholesterol.11 Low T levels in men may increase their risk of developing coronary artery disease (CAD), metabolic syndrome, and type 2 diabetes. The complexity of this relationship is obvious, and thus additional basic science studies are required for a better understanding of the relationship between testosterone and the cardiovascular system.
Furthermore, it should be noted that numerous studies have shown that high pharmacological concentrations of Tes (10–100 μM) induce vasodilation in endothelium-denuded vessels, suggesting an endothelium-independent mechanism (8, 10, 12, 24, 47, 48, 60, 63, 73). Interestingly, in studies employing small vessel wire myography, it has been reported that micromolar concentrations of Tes induce vasodilation of rat pulmonary arteries (23), human subcutaneous resistance arterioles (32), and porcine small prostatic arteries (43). This acute effect of Tes and other androgens has been observed at micromolar concentrations in a variety of large arteries (aorta, coronary and umbilical arteries) as well as small resistance arteries (mesenteric, prostatic, pulmonary, and subcutaneous) from several animal species (rat, mouse, rabbit, pig, and dog) and humans (2, 8, 10, 32, 48, 60, 71). While this effect frequently has been observed in large arteries at micromolar concentrations, more recent studies have reported vasorelaxation of smaller resistance arteries at nanomolar (physiological) concentrations. Additionally, breaking a blood vessel can result in the formation of blood clots, resulting in a life-threatening situation if the blood clot travels to the lungs or heart. Testosterone plays an essential role in the maintenance of cardiovascular health. Optimal oxygen supply to the blood vessels improves their function and health and helps combat vascular stiffness.
Because of this controversy, we sought to determine the current status of basic science studies that have examined the effects of testosterone on the cardiovascular system in experimental models. This randomized controlled trial of elderly, frail men was halted early by the data safety monitoring board due to an excess of cardiovascular events noted among older men randomized to testosterone as compared with placebo. Although cross-sectional studies have demonstrated higher prevalence of CVD among men with low endogenous androgens, limited clinical data have not shown that testosterone replacement therapy (TRT) reduces CVD risk. We also take a closer look at effects of testosterone on lipids and HDL in particular, to see if this explains the cardiovascular effects seen in clinical studies. Since several recent studies have revealed that these nonaromatizable metabolites are fully capable of causing vascular relaxation (8, 10, 47, 48, 50, 73), the established concept that Tes is metabolized to inactive excretory metabolites must then be discarded when considering the effects of androgens on cardiovascular function. The well-established clinical observations that hypertension (HT) and coronary artery disease occur more frequently in men than in premenopausal women (26–28, 30, 31, 38, 69) have led to the dogmatic concept that testosterone (Tes) has deleterious effects on the heart and vasculature and exacerbates the development of CVD in males (18, 37, 54).
Nonetheless, the results of the TOM trial provide important cautionary information regarding the potential for TRT to be harmful in at least some populations of older men and points to the need for larger studies. Further, subjects in the TOM trial had higher baseline BMI, higher triglycerides, and lower HDL than individuals included in the second study. However, it is important to remember that all of these studies, regardless of findings, have methodological weaknesses that limit their interpretive value. Furthermore, another meta-analysis found that TRT appeared to confer mortality benefit specifically in hypogonadal men with Type 2 diabetes . Given the absence of a clear, causal relationship, clinical use of TRT is predicated on the presence of hypogonadal symptoms rather than cardiometabolic disease. Overall, these types of longitudinal analyses also fail to provide evidence of a direct, causal relationship between androgen exposure and CVD.
McCrohon et al38 examined human white blood cells and umbilical vein endothelial cells exposed to DHT (40 or 400 nmol/L), flutamide or control. Because VCAM‐1 expression decreased, the recruitment of white blood cells into the arterial wall was diminished, and thus atherogenesis was inhibited.37 Because VCAM‐1 plays an important role in the recruitment of white blood cells into arterial walls, the inhibition of such would attenuate atherogenesis and therefore inhibit atherosclerosis. There were no significant differences found in food intake, weight, and cholesterol levels in each group, further suggesting that DHEA may inhibit the development of atherosclerosis.35 Rabbits given a high‐cholesterol diet and DHEA showed a 48% reduction in atherosclerotic plaque size compared with rabbits given a high‐cholesterol diet and no DHEA. Gordon et al35 performed yet another study investigating atherosclerosis in rabbits fed a high‐cholesterol diet. However, DHEA‐treated rabbits had 40% less formation of fatty streaks, an early indicator of atherosclerosis, compared with control rabbits.34
The LAD was isolated and placed in either prostaglandin or potassium chloride (KCl), another contracting agent, and testosterone. This study tested the effect of endothelial denudation as well as washing the vessels with either Krebs–Henseleit bicarbonate (KHB), or N‐nitro‐l‐arginine methyl ester (l‐NAME). Deenadayalu et al18 performed a similar study using the left anterior descending (LAD) coronary arteries of swine hearts. Statistical significance was observed at both 1 and 10 μmol/L of testosterone, and there was no difference between the groups with and without endothelium.16 This suggests that testosterone has a direct smooth muscle–relaxing effect and does not require endothelium to induce vasodilation. After 7 minutes in prostaglandin, arteries were washed and exposed to testosterone or control solution. Effects of a therapy on blood vessels that have been subjected to endothelial denudation would suggest that the drug is working through an endothelium‐independent and NO‐mediated‐independent mechanism, such as directly on the tunica media (smooth muscle layer) of an artery. There is little information regarding the mechanism by which testosterone exerts its cardioprotective effect regarding ischemic injury; thus, more research is required. - http://8.133.177.112:3001/georgetrimm20
