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In contrast, the A-ring bends 90° relative to the steroid nucleus when the C5 hydrogen is β/cis oriented, as in the case of 5β-reduced androgens such as 5β-DHT (see structural conformations in Fig. 2). We have observed that the A-ring of the steroid nucleus is planar in the structure of Tes and in the α/trans configuration at C5 of reduced metabolites such as 5α-DHT. Nevertheless, the dramatic difference in vasorelaxing potency between Tes and its dihydro-metabolites deserves further consideration, based on their different structural conformations. However, to our knowledge, there is no information available on the plasma concentrations of 5β-DHT; consequently, further research is urgently needed to determine the range of normal plasma concentrations of 5β-DHT. Whereas the circulating plasma concentration of Tes in adult men ranges 11–36 nmol/l, its 5α-reduced metabolite (5α-DHT) is present in the plasma at levels of only about 10% that of Tes (1.0–2.9 nmol/l). As a nonaromatizable dihydro-androgen metabolite of Tes, 5α-DHT has been frequently used as a tool to verify that the aromatization of Tes to estrogen is not required for this androgen to produce vasorelaxation (3, 8, 10, 64, 73).
Of the patients in the TRT group, 35% (20 of 57) experienced an improvement of ≥ 1 NYHA class in their functional capacity compared to only 9.8% of patients in the placebo group (5 of 51). Although T was shown to significantly improve exercise capacity, none of the studies found a significant change in LVEF, although NYHA class was shown to improve in two of the studies. Toma et al. performed a meta-analysis of these studies and discovered that there was a net pooled improvement of 0.52 standard deviations in exercise capacity among those who received TRT. Testosterone replacement therapy has been shown to significantly improve exercise capacity without affecting left ventricular ejection fraction (LVEF). The authors also verified that the odds ratio for having hypogonadism was significantly higher in obese men, and there was a statistically significant negative correlation between total T level and BMI.15 Testosterone replacement therapy (TRT) has been shown to decrease fat mass.
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.
When compared with the control (intact) males, both groups of treated males showed decreases in proapoptotic signaling, suggesting that testosterone is proapoptotic and is harmful to cardiomyocytes during ischemia and reperfusion.56 Researchers found that after ischemia and reperfusion, castrated male and flutamide‐treated male hearts showed decreased caspase‐1, caspase‐3, caspase‐11, TNF‐α, IL‐1β, IL‐6, and activated p38 MAPK in conjunction with increased Bcl‐2 expression. Western blot analysis revealed upregulation of caspase‐3 (apoptotic) and downregulation of Bcl‐2 (antiapoptotic) in the testosterone group compared with the controls.44 Estrada et al and Jia et al found similar effects of testosterone in the caspase‐3 and Bcl‐2 pathways, respectively, further suggesting a proapoptotic function of testosterone.54–55 Heart disease is the leading cause of death in both sexes.53 The concept of cardiomyocyte death signaling during ischemic heart disease and the role of testosterone merits investigation.
Second, the modulation of intracellular cAMP by Tes may occur via the sex hormone-binding globulin-Tes complex and may be biologically active via its binding to cell-surface sex hormone-binding globulin receptors that evoke an increase in intracellular cAMP. First, in VSM cells, Tes stimulates NO production (via neuronal NOS), which in turn evokes the formation of cGMP (via guanylyl cyclase) to induce vasorelaxation (8, 68). Moreover, Tes may also cause vasorelaxation by modulating intracellular signal transduction pathways such as increasing the levels of cGMP (8) and cAMP (41), which may indeed evoke vasorelaxation. In porcine coronary myocytes, 200 nM Tes very dramatically activated BKCa channels, increasing the open probability by more than 10-fold (8). Furthermore, the authors (41) presented data revealing that the vasodilatory action of the 5β-reduced metabolite of Tes, 5β-DHT, involves the inhibition of VOCCs from nanomolar to micromolar concentrations (100 nM–32 μM).
Male rabbits were given a weekly intramuscular injection of testosterone (25 mg/kg) or no treatment. Results of this study showed that treatment with DHT caused upregulation of 27 proatherosclerotic genes in macrophages from male donors, with negative functional consequences. Ng et al39 examined the effect of DHT on human macrophages from both male and female donors in a similar study. There were significantly fewer lesions in the testes‐intact group and the orchiectomy plus testosterone group than in the testes‐intact plus aromatase inhibitor group, the orchiectomized plus placebo group, and the orchiectomized plus testosterone plus aromatase inhibitor group, suggesting that testosterone and aromatase are both necessary for attenuating atherosclerosis.
All four studies included in this meta-analysis evaluated the effects of TRT on LVEF as well. The meta-analysis revealed that patients treated with T experienced a 16.7% increase (equivalent to ~ 54 m) in the 6-minute walk test, a 15.9% increase in the isometric walk test, and a 22.7% increase in peak VO2. Emerging evidence indicates that congestive heart failure (CHF) is more than just a syndrome affecting a failing heart. In their 2013 review, Oskui and colleagues reported on evidence suggesting that men with lower levels of endogenous T are more likely to develop CAD during their lifetimes.11 The severity of CAD has also been investigated as a function of serum T concentrations. Populations at high risk for TD include men with CHF, type 2 diabetes, obesity, chronic obstructive pulmonary disorder, HIV, and chronic opioid use.7 Studies have reported a reduced CV risk with higher endogenous T concentration, improvement of known CV risk factors with T therapy, and reduced mortality in T-deficient men who underwent T replacement therapy versus untreated men.
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.
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