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Notably, substantial decreases in HDL-c concentrations have mainly been demonstrated with supraphysiologic doses of androgens administered to young men and the use of anabolic androgens among athletes . Interestingly, these authors reported that when T concentrations were tracked over time, a greater decline was evident among men with multiple CVD risk factors than men without risk factors, with T levels in some subjects reaching the hypogonadal range. However, in an analysis in older men from the Framingham heart study , no association between plasma lipids and T concentrations was observed. A positive correlation exists between HDL-c and circulating T concentrations, as seen in multiple studies including the San Antonito Heart study , the Tromso study , the Turku Male Aging study , the Rancho Bernardo study , MRFIT and a study from Ghent, Belgium . Therefore, the higher rate of cardiovascular events noted in the TOM trial might be attributable to a poorer baseline cardiometabolic profile among the participants. In fact, a similar study of comparable size and design did not observe such an increase in CVD events among men randomized to the T arm . The authors further suggested that the Xu meta-analysis may have noted an association because their definition of cardiovascular events was more inclusive than typical restriction to major adverse cardiovascular events.
The authors also found higher vascular and all-cause mortality among men with low plasma T levels when compared with men without androgen deficiency. In lieu of such data, small randomized trials to date have been performed that evaluate CVD risk factors rather than events as study endpoints, and these demonstrate mixed effects of TRT. Testosterone prescriptions have risen steadily and sharply in the USA despite a lack of clear understanding of the relationship between androgens and cardiovascular disease. Finally, it is well known that the serum levels of Tes fall markedly with increasing age in otherwise normal men, and there is increasing evidence that Tes replacement therapy significantly improves cardiovascular and metabolic functions in hypogonadal aging men (28, 33, 34, 53, 62).
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.
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).
All three found that in men with CAD, testosterone prolongs the time to exercise-induced ST-segment depression as measured on treadmill stress testing.24–26 Testosterone has been reported to have direct vasodilatory effects on coronary arteries in men with CAD.26 Whether low T and increased mortality are simply covariates or a causal relationship remains to be proven. 9 Finally, Corona et al. screened 1,178 articles and found 70 in their meta-analysis that showed a clear association between low T/high estradiol levels and CV disease.10 Longitudinal studies demonstrated that overall mortality and CV mortality were highest in those with low T levels. Some biological effects of testosterone may result from its aromatization to estradiol and subsequent interaction with the estrogen receptor. Only 1% to 2% of testosterone circulates in blood as unbound "free" testosterone, but this fraction exhibits the most potent biological activity. Testosterone (T) is the principal male sex hormone, secreted primarily by the testes and transported in the blood by the carrier protein, sex-hormone binding globulin (SHBG).
We have previously demonstrated that TRT in older, hypogonadal men confers changes to the protein composition of HDL without altering HDL-c concentrations or its cholesterol efflux capacity suggesting a neutral effect with regard to HDL-related cardiovascular risk. Importantly too, HDL-c concentrations in isolation may not be a reliable marker of CVD risk, since no long-term clinical data have established a link between the lower HDL-c concentrations caused specifically by TRT and increased incidence of CVD. The study endpoints include coronary artery plaque volume as measured by CT scan as well as serum lipids; thus, although resultant data merit interest, this study is underpowered to provide additional information regarding cardiovascular events. Recently, larger cross-sectional studies have been undertaken to better define the cardiovascular effects of TRT. Accordingly, clinical intervention studies have been performed to investigate whether TRT can mitigate CVD risk factors among men with low endogenous T concentrations; however, none of these have been powered to examine CVD event rates. The Rancho Bernardo study followed 1000 men aged 40–79 years over a 12-year period and found no association between plasma T levels and either extant CVD or subsequent cardiovascular morbidity and mortality .
Testosterone and the more potent DHT bind to cytoplasmic androgen receptors (AR) that are chaperoned by heat shock proteins. There are no large long-term, placebo-controlled, randomized clinical trials to provide definitive conclusions about TRT and CV risk. Male and female rats were either left intact, underwent a gonadectomy, or underwent a gonadectomy plus exogenous hormone treatment. The results of this second investigation showed that additional IL‐10 is synthesized by CD4+ lymphocytes. In males, the only significant difference was between the sham‐castration plus placebo group and the castration plus placebo group. In contrast, no proatherosclerotic genes were upregulated in macrophages from female donors. This suggests that there is an important mechanism that occurs within the tunica media, a layer not found in veins, of the artery that attenuates atherogenesis and 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. - http://106.13.112.233:8085/sammiebleakley
