It is important to emphasize that the dihydro- and tetrahydro-androgens are nonaromatizable; thus, they cannot be bioconverted into estrogens (Fig. 2). Androstanediol (a 3α,5α-androgen) via 17β-hydroxysteroid dehydrogenase is then converted into androsterone, a major excretory metabolite of Tes, and both androstanediol and androsterone are genomically inactive in reproductive targets. Apart from its irreversible bioconversion to 17β-estradiol via the enzyme aromatase (CYP19), Tes can also be converted to the 5-reduced dihydro-metabolites (5α and 5β reductions; Ref. 65), which include 5α-DHT via the enzyme 5α-reductase type 1 and 2 (56) and 5β-DHT via the enzyme 5β-reductase, a member of AKR superfamily (9). Moreover, the Tes metabolite 5β-DHT is also more potent than 17β-estradiol in producing relaxation of the rat aorta (50), and both Tes and 5β-DHT are more effective than 17β-estradiol in blocking inward Ca2+ currents in rat aortic myocytes (41). However, this possibility has been excluded for several reasons, 1) inhibition of P-450 aromatase does not prevent Tes-induced vasorelaxation (8, 63, 64, 73), 2) estrogen receptor antagonism does not alter Tes-induced vasodilation (3, 22, 48), and 3) nonaromatizable metabolites of Tes (e.g., DHT) cause vasorelaxation (8, 10, 47, 48). Since 17β-estradiol causes acute and long-term vasodilation and Tes and estrogens share the same biosynthetic pathway, it has been suggested that Tes-induced vasorelaxation might be an indirect effect mediated by the local conversion of Tes to 17β-estradiol by vascular P-450 aromatase (see Fig. 2).
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.
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.
In males, the testes‐intact plus placebo group had a significantly higher neutrophil density than the testes‐intact male plus estrogen group for the first 2 days after MI, suggesting estrogen inhibited neutrophil infiltration. Testosterone was given at 208 μg/day for 60 days to achieve approximately normal male physiological levels. They suggested that the discrepancies in results are a result of differences in the way testosterone interacts with different parts of the vessel. Vessels dilated with adenosine showed significantly more dilation than with adenosine plus testosterone. Ceballos et al41 conceded that testosterone can induce relaxation of the aorta and coronary arteries, but they also believed that testosterone may facilitate vasoconstriction. When treated with 5‐HT, aortas from the testosterone group displayed statistically significantly higher contraction percentages than those from the control group.
However, it should be emphasized that most of these observations are anecdotal or come from small-scale clinical studies, and limited information is available in women. The authors have completed and submitted the Methodist DeBakey Cardiovascular Journal Conflict of Interest Statement and none were reported. Many authors of systematic reviews on the CV risks of TRT call for a large randomized multicenter trial on this issue. Among the subjects with elevated hematocrit, there was only one incident of serious complication (cerebral hemorrhage).34 The most recent meta-analysis examining the adverse effects of TRT was performed by Fernandez-Balsells et al. in 2010. However, none of the individual prostate-related adverse events significantly differed between groups, including incident prostate cancer, which showed no difference between the TRT group and placebo.34 In 2016, Boyle et al. reported results of a meta-analysis on prostate cancer in TRT trials. The TRT group had a significantly greater incidence of all prostate-related adverse events, with a pooled odds ratio of 1.78 (95% CI, 1.07–2.95).

Gender: Female

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