Clinical implications

Current evidence indicates that the gender difference in the incidence ofcardiovas-cular diseases cannot be explained on the basis of ambient testosterone exposure. It has therefore been speculated that exposure to testosterone in pre- or perinatal life is responsible or contributes to the male gender disadvantage in cardiovascular disease (Liu etal. 2003). In adults, androgens can exert both beneficial and deleterious actions on a multitude of factors implicated in the pathogenesis of atherosclerosis and heart failure so that, at present, it is not possible to determine the net effect of testosterone on coronary artery disease, stroke, peripheral artery disease and heart failure.

What are the clinical implications of this ongoing uncertainty? In our view the answer to this question must differentiate between the concern for the possibility of cardiovascular side effects in androgen treatment of endocrine and non-endocrine conditions on the one hand, and whether testosterone may be used for the prevention or even treatment of coronary artery disease on the other.

Efforts to exploit the therapeutic benefits of testosterone in the treatment of hypogonadism, osteoporosis, wasting, and chronic consumptive disease or for contraception in a wider male population should not be deterred or hampered by concerns regarding increased cardiovascular risks. However, the possibility that spontaneous or induced hyperandrogenaemia may increase the risks for coronary artery disease in women needs to be seriously considered.

Some clinicians argue that androgen replacement in the elderly male, in addition to possible benefits on muscle, bone, sexual and mental functions, has the potential to prevent atherosclerotic vessel diseases. However, androgens have such an extraordinary array of effects in vivo that it is hazardous to extrapolate isolated experimental findings to the wider clinical setting. It is premature to assume clinical benefits from manipulation of the sex steroid milieu based on biologically plausible mechanisms, or indeed on cross-sectional risk factor observational data in a complex multifactorial condition such as coronary artery disease. Interpretations of effects of pharmacological doses of androgens on arterial compliance and flow-mediated dilatation in particular must also be treated with circumspection. The lessons from estrogen hormone replacement in postmenopausal women are especially salutary. Despite the overwhelmingly positive but indirect evidence on risk factors and disease incidence, controlled interventional studies recently have not confirmed estrogens to be an effective secondary preventative treatment for established coronary artery disease in women (Manson et al. 2003; Roussow et al. 2002). There is an analogous need for randomised controlled trials which assess clinical endpoints for male hormone replacement therapy. In the absence of such evidence on testosterone, priority must be given to treatment modalities of proven efficacy in the prevention or treatment of coronary artery disease (e.g. weight reduction, smoking cessation, exercise, aspirin, statins, anti-hypertensives, and vasodilators).

10.9 Key messages

Significant and independent associations between endogenous testosterone levels and cardiovascular events in men and women have not been confirmed in large prospective studies, even though cross-sectional data suggested cardiovascular diseases can be associated with low testosterone in men. However, hypoandrogenemia in men and hyperandrogenemia in women are associated with visceral obesity, insulin resistance, low HDL cholesterol, elevated triglycerides, LDL cholesterol and PAI-1. These gender differences and confounders render the precise role of endogenous testosterone in atherosclerosis unclear.

The effects of exogenous testosterone on cardiovascular mortality or morbidity have not been extensively investigated in prospective controlled studies; preliminary data suggest that supraphysiological dosages of testosterone result in short-term improvements in electrocardiographic changes in men with coronary artery disease.

In the majority of animal experiments, exogenous testosterone exerts either neutral or beneficial effects on the development of atherosclerosis in male animals, possibly by conversion into estradiol, but adverse effects in females.

Exogenous androgens 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 they may reflect accelerated reverse cholesterol transport instead.

Supraphysiological concentrations of testosterone stimulate vasorelaxation; but at physiological concentrations, beneficial, neutral, and detrimental effects on vascular reactivity have been 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 conclusion, the inconsistent data, which can only be partly explained by differences in dose and source of androgens, do not allow any meaningful assessment of the net effect of testosterone on atherosclerosis. Based on current evidence, the therapeutic use of testosterone in men need not be restricted by concerns regarding cardiovascular side effects.

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