Testosterone and atherosclerosis

https://doi.org/10.1016/S1096-6374(03)00059-5Get rights and content

Abstract

Hypoandrogenemia in men and hyperandrogenemia in women are associated with increased risk of coronary artery disease but also with visceral obesity, insulin resistance, low high-density lipoprotein (HDL) cholesterol, elevated triglycerides, low-density lipoprotein (LDL) cholesterol and plasminogen activator inhibitor (PAI-1). These gender differences and confounders render the precise role of endogenous androgens in atherosclerosis unclear.

Exogenous androgens, on the other hand, induce both apparently beneficial and deleterious effects on cardiovascular risk factors by decreasing serum levels of HDL-C, PAI-1 (apparently deleterious), Lp(a), fibrinogen, insulin, leptin and visceral fat mass (apparently beneficial) in men as well as women. However, androgen-induced declines in circulating HDL-C should not automatically be assumed to be pro-atherogenic, since it may reflect accelerated reverse cholesterol transport instead.

Short-term application of supraphysiological doses of exogenous T can reduce the severity and frequency of angina pectoris and improve the electrocardiographic signs of myocardial ischaemia; long-term effects have not been investigated. Nonetheless, interpretations of the effects of pharmacological doses of androgens on arterial compliance and flow-mediated dilatation in particular must be treated with circumspection also because at physiological concentrations, beneficial, neutral, and detrimental effects on vascular reactivity can be observed.

Testosterone exerts ‘pro-atherogenic’ effects on macrophage function by facilitating the uptake of modified lipoproteins and an ‘anti-atherogenic’ effect by stimulating efflux of cellular cholesterol to HDL.

In the majority of animal experiments, exogenous testosterone exerted neutral or beneficial effects on the development of atherosclerosis.

In conclusion, the overall effect of administration of testosterone on cardiovascular-disease risk is difficult to assess because androgens have such an extraordinary array of effects in vivo. When dealing with a complex multifactorial condition such as CAD, it is premature to assume that clinical benefits can be derived from manipulation of the sex steroid milieu – even when these assumptions are based on biologically plausible mechanisms or, indeed, on cross-sectional risk-factor observational data. Neither needs the therapeutic use of testosterone in men be restricted by concerns regarding cardiovascular side effects.

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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