The optimal level of testosterone is important for improving blood flow, supporting overall heart function, and promoting healthy energy levels. Restoring optimal levels of testosterone helps address vascular stiffness and improve cardiovascular health. According to research, men with low levels of testosterone have a higher chance of experiencing vascular stiffness and other related cardiovascular issues. Testosterone has several effects on cardiovascular physiology and has directly affects the blood vessels of the heart and cardiovascular system. On the other hand, a potential risk of high levels of testosterone is cardiac hypertrophy, a thickening of the heart muscles. One of the many effects of testosterone on the blood vessels is to dilate the arteries, including the coronary arteries of the aorta and the heart, to help reduce blood pressure. Data from clinical studies indicate that, in men, androgen replacement may provide beneficial effects when coronary artery disease is present.
However, there currently is no credible evidence that T therapy increases CV risk and substantial evidence that it does not. Testosterone replacement therapy (TRT) has been shown to improve myocardial ischemia in men with CAD, improve exercise capacity in patients with CHF, and improve serum glucose levels, HbA1c, and insulin resistance in men with diabetes and prediabetes. We review the evidence for a role of testosterone in vascular health, its therapeutic potential and safety in hypogonadal men with CVD, and some of the possible underlying mechanisms. Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis.
This study suggests that DHT, a nonaromatizable form of testosterone that has a high affinity for the androgen receptor, only alters macrophage genes in males.39 This may be an important part of the testosterone–atherosclerosis relationship, which was overlooked in this study, as the aromatization of testosterone to estrogens has been shown to inhibit atherosclerosis in male mice.36 In this study, white blood cells were more likely to adhere to endothelial cells in the presence of testosterone compared with control. DHEA increased very‐low‐density lipoprotein (VLDL), intermediate‐density lipoprotein (IDL), and low‐density lipoprotein (LDL) levels compared with levels before initiation of the high‐cholesterol diet in tested rabbits. In a study by Jackson and Hutson, diabetes was chemically induced in rats of both sexes.27 Diabetic rats showed significantly higher blood glucose levels accompanied by statistically lower levels of luteinizing hormone (LH), follicle‐stimulating hormone (FSH), insulin, and testosterone than control rats. Testosterone and 5α‐dihydrotestosterone administration yielded increased coronary blood flow independent of dose in intact animals, suggesting that vessels were dilated. At testosterone concentrations between 10−5 and 10−4 mol/L, the vessels treated with KCl showed greater contraction than those contracted with prostaglandin, but the trend of reduced contraction with increased testosterone concentration was still seen, suggesting that testosterone may be a vasodilator.20
This suggestion is consistent with previous findings showing markedly increased plasma levels of DHEA, androstenedione, and Tes throughout pregnancy (16, 35). Notably, the endogenous Tes metabolite 5β-DHT is an efficacious and potent vasorelaxant that acts at nanomolar to micromolar concentrations without estrogenic and androgenic side effects, thus increasing its potential for use in the treatment of HT. While previous studies identified the potential of androgens to elicit vasorelaxation at pharmacological concentrations, more recent studies on the mechanism(s) of action at near physiological (11–36 nmol/l) concentrations strongly suggest that Tes-induced vasorelaxation is a physiologically relevant phenomenon (55, 64, 68). For this reason, the 5β-reduced C19 steroids and/or functional 5β-DHT analogs, which do not exert estrogenic or androgenic effects, could have useful roles in vascular therapeutics. These molecular conformations reveal that minor changes in the orientation of C5 in the A-ring can result in major changes in the efficacy and potency of nongenomic vascular effects of the androgen molecule (e.g., 5α-DHT vs. 5β-DHT; see text for details). Indeed, androgens may both inactivate inward Ca2+ currents carried by VOCCs (at physiological concentrations, 11–36 nM) and/or activate outward K+ currents carried by K+ channels (at physiological concentrations, 1–100 nM) in the VSM cell at different concentrations; however, a definitive answer will require more comprehensive studies that examine the roles of both mechanisms simultaneously. It has been reported that Tes increases cGMP accumulation and stimulates BKCa channel activity at micromolar concentrations (10–50 μM) in porcine coronary artery and at nanomolar concentrations (100 nM) in rat mesenteric myocytes to induce vasorelaxation (8, 68).
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.
Orchiectomized rats were given either testosterone treatment or served as controls. In a study by Liu et al,8 male rats were subjected to an orchiectomy or a sham orchiectomy. Whether by increasing K+ channel expression to better stabilize the cardiomyocyte7 or a as yet unexamined or undiscovered mechanism, testosterone may create an antiarrhythmic substrate. Therefore, testosterone‐shortened ventricular repolarization duration and the mechanism of testosterone may have involved increasing expression of the Kv1.5 K+ channels.7–9 Hopefully, a randomized controlled trial, sufficiently powered to look at cardiovascular outcomes in a wide range of hypogonadal men receiving TRT, will be under way.
The direct vasorelaxing effect of Tes on VSM cells has also been examined in electrophysiological experiments using the patch-clamp technique, which have confirmed the findings from vascular function studies, i.e., that Tes inactivates VOCCs and/or activates Kv and BKCa. 5α-DHT has the highest affinity for the AR and mediates many androgenic effects, whereas 5β-DHT has little affinity and is without biological effects (14). Structure-function studies employing a variety of Tes analogs and metabolites have revealed that Tes-induced vasodilation is a structurally specific nongenomic effect that is fundamentally different than the genomic effects of Tes on reproductive targets (10, 51, 73). A variety of studies has clearly established that androgen-induced vasorelaxation is a rapid, nongenomic effect on the vascular wall (5, 11, 22, 46).

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