Conference 2005 back to Programme TESTOSTERONE, ANGINA AND HEART FAILURE Channer, K.S. Consultant Cardiologist, Royal Hallamshire Hospital, Sheffield S10 2JF Hon Professor of Cardiovascular Medicine, Sheffield Hallam University. Despite wide variation in the prevalence of coronary artery disease in different countries, the ratio of mortality between male to female remains remarkably constant at around 3 to 1. This difference is not due to differences in underlying cardiovascular risk factors (Wingard et al. 1983; Jousilahti et al. 1998) and the difference is only compatible with an intrinsic advantage of female gender or a disadvantage of male gender. Sex hormones determine gender and recent evidence has shown that sex hormones influence cardiovascular risk. In women endogenous female sex hormones appear to be protective (Colditz et al. 1987) although the reduction of female sex hormones at the menopause does not increase the risk of vascular disease.(Barrett-Connor and Stuenkel 1999) Female sex hormone replacement following the menopause increases the risk of vascular disease; this risk is most marked in the first year and is probably due to increased thrombotic events.(Hulley et al. 1998 WHI NEJM 2003) The evidence base on male sex hormones is less developed than for female sex hormones. Androgens have been presumed to have a detrimental effect on the cardiovascular system, largely due to case reports of adverse events with anabolic alkylated androgens used by male athletes.(Bagatell and Bremner 1996) In fact prospective follow up studies based on serum androgen levels have either found no relationship or an inverse relationship with the risk of developing vascular disease. Approximately 40 cross-sectional studies using a variety of experimental designs have also found no link between a high level of male sex hormones and cardiovascular disease. On the basis of these data, high levels of male sex hormones do not appear to adversely affect the risk of vascular disease (reviewed in (Alexandersen et al. 1996)) In addition physiological testosterone replacement therapy given to men with low or low-normal testosterone levels imparts favourable changes in cardiovascular risk factors Although modifications to these cardiovascular risk factors have been demonstrated in a number of small studies, it is currently unknown whether androgen manipulation will have a measurable effect on cardiovascular endpoints and whether these effects are mediated by risk factor modification. Cardiovascular disease is caused by atherosclerosis. Atherogenesis is an inflammatory process that results in a deposition of fibro-fatty 'plaque' on the internal aspect of affected arteries. Progressive plaque development causes obstruction and blood flow limitation. In cholesterol fed animals, castrated males develop aggressive atheroma but this effect is abrogated by physiological testosterone replacement.(Alexandersen et al. 1999) These effects do not appear to be mediated simply by improvement of cholesterol profiles and the effect is likely to involve modulation of inflammatory cytokines that stimulate nascent atheroma. Testosterone is an immune-modulator that has been shown in vivo and in vitro to inhibit the expression of inflammatory cytokines such as TNF-a and potentiate the expression of anti-inflammatory cytokines such as IL-10. (Yesilova et al. 2000; Hatakeyama et al. 2002; Malkin et al. 2003) The immuno-modulating effect of testosterone may account for the positive effects on atheroma observed in animals, (Malkin et al. 2003) however this hypothesis has never been tested in humans in-vivo. Angina is a symptom of coronary atheroma and is caused by blood flow limitation to the myocardium through the coronary arteries. There is evidence that men with angina and angiographic proven coronary disease have lower testosterone levels than men with normal coronary arteries.(English et al. 2000) Testosterone is an arterial vasodilator (Jones et al. 2003) and has been shown in animal and human studies to reduce coronary blood vessel tone and increase coronary blood flow.(Chou et al. 1996; Webb et al. 1999) Testosterone is therefore a potential therapy for angina. Of the 12 published studies since 1942, all but one has reported a positive effect on coronary ischaemia (the other was neutral). In the past 4 years our research group has completed 2 studies on the effect of testosterone therapy on exercise induced coronary ischaemia. We have shown that testosterone replacement therapy improved exercise duration on the treadmill and prolonged time to ischaemia (ischaemic threshold). Moreover, we demonstrated a dose response relationship between the increase in exercise duration and the baseline testosterone level. So that men with lower baseline testosterone level derived the greatest symptomatic benefit from replacement therapy. Importantly we have also demonstrated that the effects of testosterone are maintained in the presence of concomitant anti-anginal drug therapy and at physiological levels of testosterone therapy.(English et al. 2000; Malkin 2004). Furthermore we have found that the prevalence of men with coronary disease and low serum testosterone levels to be approximately 25%. This represents a large population of men with low testosterone levels that may benefit symptomatically from testosterone therapy. These men qualify for androgen replacement therapy per se simply to relieve hypogonadal symptoms and maintain bone mineral density and there are clinical guidelines recommending physiological testosterone replacement in this cohort. (Morales and Lunenfeld 2002) The safety issues relating to testosterone treatment which comprise a theoretical increased risk of prostate neoplasia and increased erythropoiesis are of limited relevance in this population because replacement therapy only returns the testosterone level to the physiological range. Indeed, there is no evidence that appropriate testosterone therapy increases the risk of prostate cancer. More importantly, prostate cancer can be identified early by screening for prostate specific antigen allowing careful surveillance during replacement therapy. We have also demonstrated that testosterone is an acute vasodilator (Pugh PJ. 2003) and improves haemodynamics in men with heart failure when given acutely. More importantly we have shown in 2 randomised controlled trials that replacement doses of testosterone improve symptoms and effort tolerance in men with heart failure over 3 (Pugh PJ et al 2004) and 12 months (submitted). 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