Testosterone and atherosclerosis
Introduction
Male gender is one of the classic risk factors for coronary artery disease (CAD), and the average life expectancy for men with CAD is about 8 years less than that of women. The presence of androgens and the lack of estrogens are often regarded as proximate causes for the disproportionately shorter duration of survival among men. With the prospect of much wider therapeutic application of androgens (e.g., for contraception; treatment of aplastic anaemia or sarcopenic, osteopenic and dysphoric states, and chronic systemic conditions; and treatment of physiologic ageing), one important question is whether androgen treatment might increase the risk for, or severity, of CAD.
This review addresses five questions related to androgens and coronary artery disease: (1) Do observational studies provide any evidence for associations between serum levels of endogenous androgens and CAD endpoints? (2) Which effects on CAD endpoints or symptoms are exerted by application of exogenous testosterone (T) or suppression of endogenous T? (3) What can be learned from animal studies of the effects of androgens on atherosclerosis? (4) How do androgens affect cardiovascular-disease risk factors? (5) How do androgens affect the function of vascular cells involved in the pathogenesis of atherosclerosis [1]?
Section snippets
Lessons learned from observational studies
It is important to emphasize the limitations of observational studies in demonstrating the associations between serum levels of endogenous androgens and CAD. These studies have been characterized by extremely variable CAD endpoints (e.g., mortality; morbid conditions such as myocardial infarction [MI] and angina; and angiography-, ultrasound- or postmortem-based diagnosis or unspecified cardiac events), heterogeneous study groups, and diverse selection criteria. For example, most CAD patients
Androgen deprivation
Historic studies comparing the life spans of castrated inmates and castrated singers with that of their intact counterparts did not reveal any differences in the incidence of total or cardiovascular-disease-related mortality [12], [13]. Cross-gender sex-hormone treatment of 816 male-to-female transsexuals aged 18–86 years with administration of ethinyl E2 100 μg/day and cyproterone acetate 100 mg/day for 7734 patient-years was not associated with any significant difference in
Animal studies
The influence of androgens on the development and progression of experimentally induced atherosclerosis has been investigated in five animal models with diet-induced atherosclerosis and in three mouse models genetically susceptible to atherosclerosis.
Larsen et al. [19] compared the effects of im injections of T enanthate or placebo on atherosclerosis in castrated male rabbits. Serum cholesterol levels were titrated by a cholesterol-rich diet. After 17 weeks of treatment, there was no difference
Effects of T on cardiovascular-disease risk factors
The net effect of T on cardiovascular-disease risk is difficult to assess for at least six main reasons. First, the effects of T on cardiovascular-disease risk factors are contradictory, depending on whether associations with endogenous T or effects of exogenous T have been investigated. Second, the associations between serum concentrations of endogenous T and cardiovascular-disease risk factors are confounded by mutual interactions between endogenous androgens, body fat distribution, and
Effects of androgens on vascular reactivity
An early hallmark of atherosclerosis is decreased vascular responsiveness to various hormonal stimuli, which is either due to endothelial dysfunction or to endothelium-independent disturbances in vascular smooth muscle cell physiology. As a result, decreased vasodilatation and enhanced vasoconstriction can lead to vasospasm and angina pectoris. Moreover, endothelial dysfunction also contributes to coronary events by promoting plaque rupture and thrombosis [63]. T can induce vasodilatation or
Estrogens and cardiovascular disease in men
There is compelling evidence indicating that the physiological actions of T in men can be mediated by the estrogen receptors (ERs) following conversion to E2 by site-specific aromatases in target tissues [85]. The existence of two nuclear ER subtypes, α and β, as well as a membrane ER encoded by the same transcript as the α nuclear receptor, attest to the potential for many different biological estrogen effects. ERα, ERβ, and aromatase are detectable in the coronary arteries of the monkey and
Conclusions and therapeutic implications
Current evidence indicates that the difference between genders in the incidence of CAD cannot be explained on the basis of ambient T exposure. Androgens can exert both beneficial and deleterious effects on a multitude of factors implicated in the pathogenesis of atherosclerosis and CAD. Thus, at present, it is not possible to determine the net effect of T on CAD.
What are the clinical implications of this ongoing uncertainty? In our view, the answer to this question must differentiate between
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2012, Journal of Sexual MedicineCitation Excerpt :Whether testosterone plays a similar role in other forms of CVD remains to be determined. Attempting to predict the overall effect of testosterone administration on cardiovascular events and risk of CVD is difficult, based on the diverse and contradictory array of in vitro and in vivo effects that this hormone exerts [18]. The results of such studies provide biologically plausible mechanisms for virtually any observation, according to the model tested.
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2009, European UrologyCitation Excerpt :In the last two decades, growing epidemiologic, clinical, and experimental evidence have shown a marked sexual dimorphism in cardiovascular function and in the pathogenesis of cardiovascular disease. Numerous studies have correlated reduced circulating levels of testosterone to severe coronary artery disease (CAD) [1], atherosclerotic risk [2,3], and other pathologies, including hypertension, diabetes and insulinaemia [4], implicating a possible beneficial effect of testosterone on the cardiovascular system. In addition, it has been reported that chronic testosterone treatment reduces serum levels of IL-1 beta, TNF alpha, and increases the levels of the anti-inflammatory cytokine IL-10 [5,6], conferring to this hormone long lasting cardiovascular benefits.