Q J Med 2003; 96: 521-529
© 2003 Association of Physicians
Commentary |
Testosterone for secondary prevention in men with ischaemic heart disease?
From the 1Department of Cardiology, Royal Hallamshire Hospital, Sheffield, and 2Academic Unit of Endocrinology, Division of Genomic Medicine, University of Sheffield Medical School, Sheffield, UK
 |
Introduction |
|---|
 Top Introduction Lipids and apoproteinsBlood pressureTestosterone and the haemostatic...Testosterone and obesityTestosterone and insulin...Testosterone and atherosclerosisConclusionsReferences |
|---|
Atherosclerotic coronary artery disease (CAD) is a leading cause of mortality and morbidity in the western world. It is a chronic progressive condition, and treatment is required indefinitely. Men are more than twice as likely as women to develop CAD:1 this ratio is consistent in all populations and is not related to differences in risk factors. Pre-menopausal females have a lower incidence of CAD, but this rises after the menopause, so that the risk of CAD rapidly approaches that of males after about 10 years. One explanation for these epidemiological observations is that female hormones protect against the development of CAD. Observational studies of hormone replacement therapies in women have suggested some benefit,2 but large randomized controlled trials have failed to show protective effects.3,4
Little attention has been paid to the role of testosterone in the pathogenesis of CAD. Males do not have a menopause equivalent, but sex hormones do fall with advancing age.5,6 The more elderly population, in which the prevalence of CAD is highest, has relatively low testosterone levels. Furthermore, males with CAD have lower testosterone levels than men with normal coronary angiograms males of the same age.7 Moreover, there is evidence that testosterone therapy delays the onset of cardiac ischaemia,8 probably as a consequence of a coronary vasodilator mechanism,8 improving the symptom of angina.8,10
The ability of testosterone replacement therapy to alter disease progression to reduce events or mortality has not been examined. In this article, we review the effects of testosterone therapy on factors known to influence cardiovascular risk, and propose a justification for further studies into its use for males with coronary disease as secondary prevention.
Testosterone has well-established functions in the adult male. It induces secondary sexual characteristics, and is important for preserving sexual function, muscle strength, bone mineral density and mood in the post-pubertal male.6 The hormone has a circadian and circannual rhythm, with peak blood levels in the morning and in the spring, respectively. The majority (68%) is tightly bound to sex-hormone-binding globulin, with about 30% loosely bound to albumin and only 2–3% free. The biologically active moiety is the albumin and free testosterone; this is called the ‘bio-available’ portion.11 It is important to bear this in mind when interpreting the studies on testosterone in the literature. Earlier studies only measured total testosterone, which is influenced largely by the level of sex-hormone-binding globulin. As a carrier protein manufactured in the liver, this is in turn influenced by many factors.
Hypogonadism, the state of testosterone deficiency, has a prevalence of 7% in the general population, rising to 20% in very elderly males.5 However, males with CAD have lower testosterone levels than unaffected males of the same age. In a small observational study comparing men presenting for scheduled angiography, the bio-available measurement of testosterone was significantly lower in males with CAD compared to men with normal coronaries.7 The mean bio-available testosterone of the CAD group was 2.55 nmol/l; the lower limit of normal range for the bio-available testosterone with this assay is 2.5 nmol/l. This would suggest that a significant proportion of males with CAD may have testosterone levels lower than the normal range, and that the prevalence of frank hypogonadism may be high in the CAD population. Larger studies on the prevalence of hypogonadism in males with CAD have yet to be published. However data have been presented to suggest that the prevalence of bio-chemical hypogonadism in these patients, as defined by a total testosterone < 7.5 nmol/l or a bio-available testosterone < 2.5 nmol/l, may be as high as 23.4%.12 Patients with overt hypogonadism clearly require treatment. However, given that a substantial proportion of men male with CAD appear to have relative androgen deficiency, would correcting this afford any benefit to them? Preliminary studies have suggested objective improvements in symptoms, but would male HRT have beneficial effects on established risk factors, and would this be translated into a clinically relevant reduction in cardiovascular endpoints?
|
Lipids and apoproteins |
|---|
|
TopIntroductionLipids and apoproteinsBlood pressureTestosterone and the haemostatic...Testosterone and obesityTestosterone and insulin...Testosterone and atherosclerosisConclusionsReferences |
|---|
Different patterns of lipid levels and apoproteins are associated with CAD. In particular, high total cholesterol, high LDL fraction hypertriglyceridaemia and elevated lipoprotein-A are pro-atherogenic, whereas HDL is protective. The ratio of total cholesterol to HDL has been used to estimate risk in primary prevention in clinical practice.13 In patients with overt vascular disease, virtually all patients benefit from lipid-lowering with statins, whatever their baseline cholesterol level.14 The majority of cross-sectional studies have found a positive correlation of endogenous testosterone with HDL15–19 and a negative correlation with total cholesterol, LDL and triglycerides.20–23 Thus normal men with low testosterone appear to have adverse lipid profiles, and hypogonadal men have a potentially atherogenic dyslipidaemia prior to treatment.24 A few observational/cross-section studies have found no correlation with endogenous androgens and lipid profiles.25–27 It is difficult to account for this variation in the literature other than to comment on the relatively modest numbers of patients in the studies involved, and the use of total testosterone rather than free or bio-available measurements of testosterone.26 There has only been one major longitudinal follow up study of androgens and lipid levels. In the MRFIT study,28 serum was taken from patients at baseline and after an average of 13 years. A small reduction in testosterone level over time was reported and this correlated with a significant increase in triglycerides and HDL. These findings remained positive after controlling for obesity. No significant changes were reported in other lipid fractions but the reduction in testosterone was small.
There have been a number of small studies of androgen therapy using several preparations of testosterone in a variety of populations. These studies can be grouped either in terms of their population (hypogonadal men, young men/athletes and healthy elderly men) or the level of androgen therapy (physiological or supra-physiological). Testosterone therapy in most populations causes a reduction in HDL,29–31 but this effect is smaller in elderly or hypogonadal men.32,33 This finding contrasts with data from cross-sectional and longitudinal studies. The relationship of androgens and HDL is complex. In the juvenile male, the rise of endogenous androgens at puberty causes a reduction in HDL.34 Experimental hypogonadism induced with GnRH agonists or withdrawal of maintenance testosterone causes an increase in HDL; this effect is suppressed if testosterone is administered at physiological doses.31,35 There is therefore evidence that androgens suppress HDL, but this is not supported by cross-sectional data. The reason for this disparity in the literature is probably related to obesity and insulin resistance. Testosterone has an inverse relationship with obesity,36,37 and obesity has an inverse relationship with HDL (see later section).16 Thus in cross-sectional analysis testosterone may appear to have a positive relation with HDL. This also explains why the reduction in HDL in young men or athletes is greater than that in old or hypogonadal men. Young men or athletes are lean and insulin-sensitive. Elderly or hypogonadal men have higher body mass index and a degree of insulin resistance—the testosterone has positive effects on body mass index and insulin resistance and this abrogates the reduction of HDL seen with testosterone therapy in the younger populations.
There is a more consistent relationship with testosterone and other lipid fractions. Most studies of elderly or hypogonadal populations report reductions in total cholesterol, LDL and apo-protein B,18,32,33,38,39 although there has been at least one conflicting report.40 Testosterone treatment has also been shown to reduce lipoprotein-A level.41 In the hypogonadal and elderly cohorts, testosterone therapy is associated with reported reductions of up to 22% in total cholesterol and 15% LDL.33 This was recently confirmed in a meta-analysis of 19 trials encompassing 272 hypogonadal men receiving intra-muscular testosterone preparations. This study demonstrated significant reductions in total cholesterol and LDL fractions.42 There was also an expected dose-dependent reduction in HDL cholesterol, but this was small and less than that seen in normal men or young athletes.
Testosterone replacement in elderly or hypogonadal men would thus appear to improve the dyslipidaemia associated with atherosclerosis. The effects may be sizeable (up to 15% reduction in LDL reported) and approach those seen in the large lipid-lowering trials (for example the 4S study with a 20% reduction in LDL).43
|
Blood pressure |
|---|
|
TopIntroductionLipids and apoproteinsBlood pressureTestosterone and the haemostatic...Testosterone and obesityTestosterone and insulin...Testosterone and atherosclerosisConclusionsReferences |
|---|
Hypertension is another established risk factor for CAD, and lowering high blood pressure reduces the risk of cardiovascular events. Testosterone is lower in populations of men with hypertension than in normal men,44 and case-controlled studies have demonstrated a relationship between hypotestosteronaemia and high blood pressure.20,22 However, the relationship of testosterone and blood pressure is uncertain. Testosterone has direct vasodilating properties in resistance arterioles by a calcium antagonistic action yet to be fully characterized.45 A study of testosterone therapy in men with heart failure reported an increase in cardiac output, primarily as a result of reducing peripheral vascular resistance, lending support to the action of testosterone as a natural vasodilator.47 In addition, a low testosterone:oestrodiol ratio is linked to activation of the renin-angiotensin system,48 which further increases peripheral vascular resistance. A handful of small trials have recorded blood pressure after testosterone therapy. None have reported increases, but some have reported modest reductions,49,50 of around 4–5 mmHg diastolic. These reductions compare favourably to the effect of anti-hypertensive treatments in major blood pressure trials.51
|
Testosterone and the haemostatic system |
|---|
|
TopIntroductionLipids and apoproteinsBlood pressureTestosterone and the haemostatic...Testosterone and obesityTestosterone and insulin...Testosterone and atherosclerosisConclusionsReferences |
|---|
Myocardial infarction is caused by thrombosis of the coronary artery in 90% of cases. The trigger for the thrombosis occurs when a coronary plaque erodes or ruptures and the endothelium is breached. Thrombosis is a complicated process with its own intrinsic promoters and antagonists which together determine the prevailing coagulation status.
Fibrinogen is the precursor of fibrin, which is the final component of the coagulation cascade and the building block of a stable clot. Fibrinogen is also an acute-phase protein and is raised in any disease characterized by inflammation. Some 19 studies have found an association between elevated fibrinogen and atherosclerotic disease, and fibrinogen has been confirmed in meta-analysis to be an independent risk factor for CAD (for review see reference 52). It is not known whether treatments directed at reducing fibrinogen reduce the risk of subsequent vascular disease. However, several of the treatments widely used in cardiac medicine such as fibrates, ß-blockers, smoking cessation and physical exercise are associated with fibrinogen reduction,52 and all are associated with improved clinical outcomes and a reduced risk of acute events. Androgens and in particular testosterone have an inverse relationship with fibrinogen such that low endogenous testosterone is associated with elevated fibrinogen.53–55 Moreover, testosterone administration causes a significant fall in fibrinogen,56 which is similar to the reduction with fibrates, for example.57 It is not known how testosterone reduces fibrinogen. Androgens are metabolized extensively in the liver, and androgen therapy may alter coagulation protein production, for example a high factor VII has been associated with low serum testosterone.44,58 An alternative explanation is that testosterone by its intrinsic immune-modulating properties, damps down the inflammation in atherosclerotic plaques causing the reduction of acute-phase proteins in general, including fibrinogen.
Testosterone has a number of actions on the haemostatic/fibrinolytic system separate from the effects on fibrinogen. Androgens and testosterone in particular have anti-thrombotic actions, and have been used as therapy in thrombotic diseases.59 Observational studies have consistently found a positive association between testosterone levels and tPA (a major endogenous stimulator of thrombolysis) and a negative association with factor VIIa (a coagulation protein) and PAI-1 (an inhibitor of thrombolysis).48,54,55 Evidence is emerging that PAI-1 in particular is of major importance in coronary disease, since elevated PAI-1 predicts myocardial infarction and progression of atheroma in stable CAD patients60,61 and is associated with a failure of reperfusion with thrombolysis following AMI.62 Hypogonadal men have elevated PAI-1; replacement of testosterone in hypogonadal men and therapy with testosterone or the adrenal androgen dehydroepiandrosterone in normal men leads to a reduction in circulating PAI-1 level.63,64
The fibrinolytic system is of critical importance in the pathogenesis of myocardial infarction. The goal of therapy in this medical emergency is to reopen the thrombosed artery. Therapeutic thrombolysis works by triggering or delivering a large external supply of tPA. Unfortunately, in about 60% of patients it is impossible to dissolve the clot and reopen the artery quickly. One of the reasons for this is thrombolysis resistance, and PAI-1 is one of the blood proteins responsible, because PAI-1 inhibits tPA and stabilizes the clot. During myocardial infarction, testosterone levels fall dramatically and this corresponds with a rise in PAI-1.65 In essence, all men suffering with AMI are temporarily hypogonadal, and this phenomenon leads to a prothrombotic state that may prevent thrombolysis or cause re-infarction.
|
Testosterone and obesity |
|---|
|
TopIntroductionLipids and apoproteinsBlood pressureTestosterone and the haemostatic...Testosterone and obesityTestosterone and insulin...Testosterone and atherosclerosisConclusionsReferences |
|---|
Obesity is a heterogeneous condition, and certain patterns of obesity are more strongly linked to ischaemic heart disease. In particular, abdominal or visceral obesity, as measured by waist:hip ratio, is most strongly linked to cardiac disease and is an independent coronary risk factor.66 Visceral adipose tissue is more highly metabolically active than non-visceral fat.67 Visceral adipocytes produce large amounts of free fatty acids, and their flux of free fatty acids in the portal blood can cause disturbances of hepatic metabolism. In particular, in obese men there is reduced insulin extraction by hepatocytes,68 increased hepatic insulin resistance69 and increased hepatic gluconeogenesis.70 These factors contribute to systemic hyperinsulinaemia and ultimately insulin resistance (see next section). Testosterone blood levels are inversely related to the degree of visceral obesity.37 Visceral fat has a high density of androgen receptors, and these appear to inhibit the action of lipoprotein lipase and fatty acid/triglyceride uptake; the androgen receptors thus limit fat accumulation.71 In the ageing male, the natural diminution of testosterone may allow an increase in fat mass (middle-aged spread), hypogonadal men are also recognized to have increased obesity. Moreover, adipose tissue extensively metabolizes testosterone to oestrodiol, thus obese men also have increased extraction of testosterone because of aromatization.72 Whatever the causal relationship of obesity and testosterone, there is little doubt that testosterone therapy in elderly, hypogonadal, or obese men reduces visceral obesity.50,73,74 Most of these studies also report beneficial effects on other aspects of the metabolic syndrome and an increase in lean mass.
|
Testosterone and insulin resistance |
|---|
|
TopIntroductionLipids and apoproteinsBlood pressureTestosterone and the haemostatic...Testosterone and obesityTestosterone and insulin...Testosterone and atherosclerosisConclusionsReferences |
|---|
The ability of insulin to stimulate glucose uptake is variable. Insulin resistance at peripheral receptors is compensated by an exaggerated release of insulin. Insulin resistance and consequent hyperinsulinaemia are the key components of the metabolic syndrome.75 The other features are type 2 diabetes, hypertension, male pattern (visceral) obesity, impaired fibrinolysis and dyslipidaemia. The dyslipidaemia is characterized by high triglycerides and low HDL. All of these separate conditions are associated with an increased risk of CAD. The metabolic syndrome is complex, and the pathophysiology is incompletely understood. Hyperinsulinaemia is itself a separate risk factor for CAD and mortality,76 but the cardiovascular impact of hyperinsulinaemia is due mainly to the clustering of several potent risk factors in individual patients. The beneficial effects of testosterone on blood pressure, cholesterol, fibrinolysis and obesity have been discussed. Given these earlier reports, testosterone would be expected to have positive effects on the metabolic syndrome.
Observational and animal studies have consistently found an inverse correlation between endogenous testosterone and fasting glucose or fasting insulin.20,77,78 Both hyperinsulinaemia and low testosterone separately predict the onset of type 2 diabetes.79 Patients with overt diabetes appear to have lower testosterone levels than normal males.80 A population study of 110 men with type 2 diabetes found that the level of testosterone was inversely related to glycaemic control, and that twice as many men with diabetes had a testosterone in the hypogonadal range than matched controls.81 Intervention studies with testosterone treatment to within the physiological range document improved insulin sensitivity in elderly and obese men.82 These reports concur with animal models.77
Although the risk of the metabolic syndrome is mainly related to the accumulation of cardiovascular risk factors, it seems clear that it is the hyperinsulinaemia that drives the metabolic syndrome. Testosterone inhibits this hyperinsulinaemia, and a general improvement in all associated risk factors is therefore expected; this may include delaying the onset of diabetes mellitus and even improving diabetic control.
|
Testosterone and atherosclerosis |
|---|
|
TopIntroductionLipids and apoproteinsBlood pressureTestosterone and the haemostatic...Testosterone and obesityTestosterone and insulin...Testosterone and atherosclerosisConclusionsReferences |
|---|
In men, endogenous levels or testosterone are inversely related to the severity of aortic atheroma and to the progression of aortic atheroma when assessed radiologically.83 Testosterone may have beneficial effects on a number of the risk factors for atherosclerotic heart disease, and these have already been discussed. In addition testosterone may have specific properties that inhibit the progression of atherosclerosis, separate from its effects on acknowledged risk factors. These observations originate from animal models. Castrated male animals rapidly develop atheroma, which is abrogated by testosterone replacement.84 The mechanisms are the subject of extensive investigation, but the key to the whole process may be inflammation. Coronary plaques responsible for angina and the acute coronary syndrome are areas of chronic inflammation. Inflammatory cells are present,85 levels of inflammatory cytokines are high,86 and nuclear mechanisms controlling inflammatory messengers are up-regulated.87 Myocardial infarction is caused when the internal surface of a plaque erodes or ruptures. The plaques most likely to rupture and thus cause AMI are those that are most inflamed.88 The inflammatory process weakens the plaque structure by stimulating matrix metalloproteinase enzymes89 and by triggering apoptosis in vascular smooth muscle cells.90 There are numerous biochemical markers of inflammation, the most recognized and best known is C-reactive protein. A high sensitive assay of CRP is the single best predictor of atherosclerotic disease in otherwise healthy people.91 A high CRP after a coronary event predicts death.92 This reinforces the importance of inflammation, and has led to commentators suggesting the use of hs-CRP to guide stepwise therapy in CAD.93 Testosterone has innate immune modulating properties. There is in vitro and animal evidence that testosterone reduces inflammation and reduces inflammatory cytokines.94,95 Men are less likely to suffer from autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosis, and hypogonadal or eugonadal men suffering with chronic inflammatory diseases have been shown to improve following testosterone administration.96,97 Since males with coronary disease have relative androgen deficiency, it is plausible that testosterone therapy would reduce plaque inflammation and therefore limit the progression of atheroma.
|
Conclusions |
|---|
|
TopIntroductionLipids and apoproteinsBlood pressureTestosterone and the haemostatic...Testosterone and obesityTestosterone and insulin...Testosterone and atherosclerosisConclusionsReferences |
|---|
The purpose of secondary prevention in patients with overt vascular disease is to reduce the incidence of subsequent events or complications, thus prolonging the duration and quality of life. There are well-established therapies for coronary disease that target the known cardiovascular risk factors. A sound evidence base supports these measures. We have studied the influence that endogenous testosterone may have on these risk factors, and we suggest that testosterone treatment in men has potentially beneficial effects on virtually all of the coronary risk factors, as well as an independent anti-atherogenic action. In addition, testosterone therapy improves the ischaemic threshold, quality of life and depression scores in patients with symptomatic coronary disease. This should not be underestimated, since it is rare that a secondary prevention treatment makes a patient feel better, and this may improve compliance.
However, before testosterone replacement therapy can be widely used two questions must be addressed. First, what is the efficacy? Does testosterone actually reduce the incidence of myocardial infarction, stroke and death? Second, what are the adverse effects, such as the risk of prostatic hyperplasisa and malignancy? The evidence linking endogenous serum androgen levels with risk of prostate cancer is not conclusive98 and recent meta-analyses are conflicting.99,100 Equally, there is no clear evidence that appropriate exogenous testosterone replacement therapy increases the incidence of prostate malignancy, although this is based on a relatively small number of patients.101 Despite this, many physicians would regard androgen therapy as a risk factor for prostate malignancy since prostate tissue is highly androgen-sensitive. Testosterone replacement causes an increase in prostate size and in prostate specific antigen (PSA) levels. Testosterone therapy within the normal range causes increased growth of cancer cells in vitro102 and may cause a ‘flare’ of cancer in affected patients. Chemically or surgically induced hypogonadism where possible is a mainstay of therapy for patients with prostate cancer. Conversely, hypogonadal men may have concealed prostate cancer that only becomes detectable clinically or biochemically after testosterone therapy is initiated.103 In these patients, the prostate cancer may be detected earlier than would be normal because of screening protocols. Currently endocrinologists initiating testosterone therapy in men check PSA levels in all patients at baseline and at regular subsequent intervals, and some physicians routinely perform digital prostate examinations. Thus prostate disease may be diagnosed earlier in patients on testosterone therapy, but it is not known whether these patients have better or worse outcomes with respect to their prostate cancer.
Thus testosterone therapy in men is likely to lead to an increased detection of prostate cancer, but this may merely be a lead time bias, and outcomes in terms of mortality may be little different. The questions relating to efficacy and safety of male hormone replacement in men with coronary disease can only be answered by an appropriately powered trial.
|
Footnotes |
|---|
Address correspondence to Dr K.S. Channer, Department of Cardiology, M131, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF. e-mail: Kevin.Channer{at}sth.nhs.uk
|
References |
|---|
|
TopIntroductionLipids and apoproteinsBlood pressureTestosterone and the haemostatic...Testosterone and obesityTestosterone and insulin...Testosterone and atherosclerosisConclusionsReferences |
|---|
1. British Heart Foundation Statistics database. BHF 1996:21–2.
2. Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Post menopausal estrogen therapy and cardiovascular disease. Ten-year follow up from the nurses health study. N Engl J Med 1991; 325:756–62.[Abstract]
3. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Group. JAMA 1998; 280:605–13.
4. Working group for the womens health initiative investigators. Risks and benefits of Estrogen plus Progestin in healthy post-menopausal women. Principal results from the womens health initiative randomised controlled trial. JAMA 2002; 288:321–33.
5. Vermeulen A, Kaufman JM. Ageing of the Hypothalamo-Pituitary-Testicular Axis in Men. Horm Res 1995; 43:25–8.[Web of Science][Medline]
6. Wu FCW. Endocrine Aspects of anabolic steroids. Clin Chem 1997; 43:1289–92.
7. English KM, Mandour O, Steeds RP, Diver MJ, Jones TH, Channer KS. Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms. Eur Heart J 2000; 21:890–4.
8. English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: A randomized double-blind placebo controlled study. Circulation 2000; 102:1906–11.
9. Webb CM, McNeill JG, Hayward CS, de Zeigler D, Collins P. Effects of Testosterone on Coronary Vasomotor Regulation in men with Coronary Heart Disease. Circulation 1999; 100:1690–6.
10. Levine Sa, Likoff WB. The therapeutic value of testosterone propionate in angina pectoris. N Engl J Med 1943; 229:770–2.[Web of Science]
11. Tremblay RR, Dube JY. Plasma concentrations of free and non Te-BG bound testosterone in women on oral contraceptives. Contraception 1974; 10:599–605.[CrossRef][Web of Science][Medline]
12. Pugh PJ, Malkin CJ, Morris PD, Asif S, Jones RD, Jones TH, Channer KS. The prevalence of hypogonadism in men coronary heart disease. Am Coll Cardiol Sci Sessions 2003; in Press.
13. Ramsay LE, Haq IU, Jackson PR, Yeo WW. The Sheffield table for the prevention of coronary heart disease: corrected. Lancet 1996; 348:1251.[Web of Science][Medline]
14. MRC/BHF Heart Protection Study of cholesterol lowering with Simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Heart Protection Study Collaborative Group. Lancet 2002; 360:7–22.[CrossRef][Web of Science][Medline]
15. Dai WS, Gutai JP, Kuller LH, Falvo-Gerard L. Relation between plasma high-density lipoprotein cholesterol and sex hormone concentrations in men. Am J Cardiol 1984; 53:1259–63.[CrossRef][Web of Science][Medline]
16. Lichtenstsin MJ, Yarnell JWG, Elwood PC, Beswick AD, Sweetnam PM, Marks V, Teale D, Riad-Fahmy D. Sex hormones, insulin, lipids and prevalent ischemic heart disease. Am J of Epidemiol 1987; 126:647–57.
17. Hamalainen E, Adlercreutz H, Ehnholm C, Puska P. Relationship of serum lipoproteins and apoproteins to sex hormones and to binding capacity of sex hormone binding globulin in healthy Finnish men. Metabolism 1986; 35:535–41.[CrossRef][Web of Science][Medline]
18. Hromadova M, Hacik T, Malatinsky E, Riecansky I. Alterations of lipid metabolism in men with hypotestosteronemia. Horm Metab Res 1991; 32:392–4.
19. Heller RF, Wheeler MJ, Micallef J, Miller NE, Lewis B. Relationship of high density lipoprotein with total and free testosterone and sex hormone binding globulin. Acta Endocrinol (Copenh) 1983; 104:253–6.
20. Simon D, Charles M-A, Nahoul K, Orssaud G, Kremski J, Joubert E, Papoz L, Eschwege E. Association between plasma total testosterone and cardiovascular risk factors on healthy adult men: The Telecom Study. J Clin Endocrinol Metab 1997; 82:682–5.
21. Haffner SM, Mykkanen l, Valdez RA, Katz MS. Relationship of sex hormones to lipids and lipoproteins in nondiabetic men. J Clin Endocrinol Metab 1993; 77:1610–15.[Abstract]
22. Barrett-Connor E, Khaw KT. Endogenous sex hormones and cardiovascular disease in men. a prospective population-based study. Circulation 1988; 78:539–45.
23. Barrett-Connor E. Lower endogenous androgen levels and dyslipidaemia in men with non-insulin-dependent diabetes mellitus. Ann Intern Med 1992; 117:807–11.
24. Oppenheim DS, Greenspan SL, Zervas NT et al. Elevated serum lipids in hypogonadal men with and without hyperprolactinaemia. Ann Intern Med 1989; 111:288–92.
25. Denti L, Pasolini G, Sanfelici L, Benedetti R, Cecchetti A, Ceda GP, Ablondi F, Valenti G. Aging-related decline of gonodal function in healthy men: correlation with body composition and lipoproteins. J Am Geriatr Soc 2000; 48:51–8.[Web of Science][Medline]
26. Kiel DP, Baron JA, Plymate SR, Chute CG. Sex hormones and lipoproteins in men. Am J Med 1989; 87:35–9.[Web of Science][Medline]
27. Duall PB, Bierman EL. The relationship between sex hormones and high-density lipoprotein cholesterol levels in healthy adult men. Arch Intern Med 1990; 150:2317–20.
28. Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. Am J Epidemiol 1997; 246:609–17.
29. Meriggiola MC, Marcovina S, Paulsen CA, Bremenr WJ. Testosterone enanthate at a dose of 200mg/week decreases HDL-cholesterol in healthy men. Int J Androl 1995; 18:237–42.[Web of Science][Medline]
30. Contrasting effects of Testosterone and Stanozolol on serum lipoprotein levels. Thompson PD, Cullinane EM, Sady SP, Chenevert C, Saritelli AL, Sady MA, Herbert PN. JAMA 1989; 261:1165.
31. Dobs AS, Bachorik PS, Arver S, Meikle W, Sanders SW, Caramelli KE, Mazer NA. Interrelationships among lipoprotein levels, sex hormones, anthropomorphic parameters, and age on hypogonadal men treated for 1 year with a permeation-enhanced testosterone transdermal system. J Clin Endocrinol Metab 2001; 86:1026–33.
32. Tenover JS. Effects of testosterone in the aging male. J Clin Endocrinol Metab 1992; 75:1092–8.[Abstract]
33. Zgliczynski S, Ossowski M, Slowinska-Srzednicka J, Brzezinska A, Zglicznski W, Soszynski P, Chotkowska E, Srzednicki M, Sadowski Z. Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men. Atherosclerosis 1996; 121:35–43.[CrossRef][Web of Science][Medline]
34. Kirkland RT, Keenan BS, Probstfield JL, Patsch W, Lin TL, Clayton GW. Decreases in plasma high density lipoprotein cholesterol levels at puberty in boys with delayed adolescence. JAMA 1987; 257:502–7.
35. Bagatell CJ, Knopp RH, Vale WW, Rivier JE, Bremner WJ. Physiologic testosterone levels in normal men suppress high-density lipoprotein cholesterol levels. Ann Intern Med 1992; 116:967–73.[CrossRef][Web of Science][Medline]
36. Vermeulen A, Kaufman JM, Gagulli VA. Influence on some biological indices on sex hormone binding globulin and androgen levels in aging or obese males. J Clin Endocrinol Metab 1996; 81:1821–6.[Abstract]
37. Vermeulen A, Goemaere S, Kaufman JM. Testosterone, body composition and aging. J Endocrinol Invest 1999; 22:110–16.[Medline]
38. Morley JE, Peryy HM, Kaiser FE, Kraenzle D, Jensen J, Houston K, Mattammal M, Perry HM Jr. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc 1993; 41:149–52.[Web of Science][Medline]
39. Uyanik BS, Ari Z, Gumus B, Yigitoglu MR, Arslan T. Beneficial effects of testosterone undecanoate on the lipoprotein profiles in healthy elderly men. A placebo controlled study. Jpn Heart J 1997; 38:73–82.[Medline]
40. Jockenhovel F, Bullman C, Schubert M, Vogel E, Reinhardt W, Reinwein D, Muller-Wieland D, Krone W. Ifluence of various modes of androgen substitution on serum lipids in hypogonadal men. Metabolism 1999; 48:590–6.[CrossRef][Web of Science][Medline]
41. Zmunda JM, Thompson PD, Dickenson, Bausserman LL. Testosterone decreases lipoprotein (A) in men. Am J Cardiol 1996; 77:1244–7.[CrossRef][Web of Science][Medline]
42. Whitsel EA, Boyko EJ, Matsumoto AM, Anawalt BD, Siscovivk DS. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. Am J Med 2001; 111:261–9.[CrossRef][Web of Science][Medline]
43. Scandanavian Simvastatin Survival Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383–9.[CrossRef][Web of Science][Medline]
44. Phillips GB, Jing TY, Resnick, Barbagallo M, Laragh JH, Sealey JE LM. Sex hormones and hemostatic risk factors for coronary heart disease in men with hypertension. J Hypertens 1993; 11:699–702.[CrossRef][Web of Science][Medline]
45. Chou TM, Sudhir K, Hutchinson SJ, Ko E, Amidon TM, Collins P, Chatterjee K. Testosterone induces dilation of canine coronary conductance and resistance arteries in vivo. Circulation 1996; 94:2614–19.
46. Testosterone acts as a coronary vasodilator by a calcium antagonistic action. English KM, Jones RJ, Jones TH, Morrice AH, Channer KS. J Endocrinol Invest 2002; 25:455–8.[Web of Science][Medline]
47. Pugh PJ, Jones TH, Channer KS. Acute haemodynamic effects of testosterone administration in men with heart failure. European Society of cardiology XXIV congress Berlin 2002. Eur Heart J 2002; 23(suppl.):28.
48. Phillips GB, Jing TY, Laragh JH et al. Serum sex hormone levels and Renin-sodium profile in men with hypertension. Am J Hypertens 1995; 8:626–9.[CrossRef][Web of Science][Medline]
49. Anderson FH, Francis RM, Faulkner K. Androgen supplementation in eugonadal men with osteoporosis-effects of 6 months of treatment on bone mineral density and cardiovascular risk factors. Bone 1996; 18:171–7.[Medline]
50. Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, Bjorntorp P. The effects of testosterone treatment on body composition and metabolism in middle aged obese men. Int J Obes Relat Metab Disord 1992; 16:991–7.[Web of Science][Medline]
51. Systolic Hypertension in Europe Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350:757–64.[CrossRef][Web of Science][Medline]
52. Maresca G, Blasio AD, Marchioli R, Di Minno G. Measuring plasma fibrinogen to predict stroke and myocardial infarction an update. Arterioscler Thromb Vasc Biol 1999; 19:1368–77.
53. De Pergola G, De Mitrio V, Sciaraffia M, Pannacciulli N, Minenna A, Giorgino F, Petronelli M, Laudadio E, Giorgino R. Lower androgenicity is associated with higher plasma levels of pro-thrombotic factors irrespective of age, obesity, body fat distribution, and related metabolic parameters in men. Metabolism 1997; 46:1287–93.[CrossRef][Web of Science][Medline]
54. Glueck CJ, Glueck HI, Stroop D, Spiers J, Hamer T, Tracy T. Endogenous testosterone, fibrinolysis, and coronary heart disease risk in hyperlipidaemic men. J Lab Clin Med 1993; 122:412–20.[Web of Science][Medline]
55. Phillips GB, Pinkernell BH, Jing TY. The association of hypotestosteronaemia with coronary disease in men. Arterioscler Thromb 1994; 14:701–6.
56. Anderson RA, Ludlam CA, Wu FCW. Haemostatic effects of supraphysiological levels of testosterone in normal men. Thromb Haemost 1995; 74:693–7.[Web of Science][Medline]
57. Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B, de Faire U. Angiographic assessments of the effects of benzafibrate on progression of coronary artery disease on young male post-infarction patients. Lancet 1996; 347:849–53.[CrossRef][Web of Science][Medline]
58. Bonithon-Kopp C, Scarabin PY, Bara L, Castanier M, Jacqueson A, Roger M. Relationship between sex hormones and haemostatic factors in healthy middle-aged men. Atherosclerosis 1988; 71:71–6.[CrossRef][Web of Science][Medline]
59. Noll G, Lammle B, Duckert F. Treatment with Stanozolol before thrombolysis in patients with arterial occlusions. Thrombosis Research 1985; 37:529–32.[CrossRef][Web of Science][Medline]
60. Thogerson AM, Jansson JH, Boman K, Nilsson TK, Weinehall L, huhtasaari F, Hallmans G. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98:2241–7
61. Bavenholm P, de Faire U, Landou C, Efendic S, Nilsson J, Wiman B, Hamsten A. Progression of coronary artery disease in young male post-infarction is linked to disturbances of carbohydrate and lipoprotein metabolism and to impaired fibrinolytic function. Eur Heart J 1998; 19:402–10.
62. Sinkovic A. Pre treatment plasminogen activator inhibitor-1 (PAI-1) levels and the outcome of thrombolysis with streptokinase in patients with acute myocardial infarction. Am Heart J 1998; 136:406–11.[CrossRef][Web of Science][Medline]
63. Beer NA, Jakubowicz DJ, Matt DW, Beer RM, Nestler JE. Dehydroepiandrosterone Reduces Plasma Plasminogen Activator Inhibitor type 1 and tissue plasminogen activator antigen in men. Am J Med Sci 1996; 311:205–10.[CrossRef][Web of Science][Medline]
64. Caron P, Bennett A, Camare R et al. Plasminogen activator inhibitor in plasma is related to testosterone in men. Metabolism 1989; 38:1010–15.[CrossRef][Web of Science][Medline]
65. Pugh PJ, Channer KS, Parry H, Downes T, Jones TH. Bio-available testosterone levels fall acutely following myocardial infarction: association with fibrinolytic factors. Endocr Res 2002; 28:161–73.[CrossRef][Web of Science][Medline]
66. Huang B, Rodriguez BL, Burchfiel CM, Chyou PH, Curb JD, Sharp DS. Associations of adiposity with prevalent coronary heart disease among elderly men: the Honolulu Heart Programme. Int J Relat Metab Disord 1997; 21:340–8.
67. Rebuffe-Scrive M, Anderson B, Olbe L, Bjorntop P. Metabolism of adipose tissue in intra-abdominal depots of non obese men and women. Metabolism 1989; 38:453–8.[CrossRef][Web of Science][Medline]
68. Svedburg J, Bjorntorp P, Smith U et al. Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes. Diabetes 1990; 39:570–4.[Abstract]
69. Boden G, Cheung P, Stein TP, Kresge K, Mozzoli M. FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. Am J Physiol Endocrinol Metab 2002; 283:E12-19.
70. Boden G. Role of Fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997; 46:3–10.[Abstract]
71. Marin P, Oden B, Bjorntorp P. Assimilation and mobilization of triglycerides in sub cutaneous abdominal and femoral adipose tissue in vivo in men: effects of androgens. J Clin Endocrinol Metab 1995; 80:239–43.[Abstract]
72. Schneider G, Kirshner A, Berkowitz R, Ertel NH. Increased estrogen production in obese men. J Clin Endocrinol Metab 1979; 48:633–8.
73. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Lenrow DA, Holmes JH, Dlewati A, Santanna J, Rosen CJ, Strom BL. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 1999; 84:2647–53.
74. Wang C, Swerdloff S, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto Am, Weber T, Berman N. Transdermal Testosterone Gel Improves Sexual Function, Mood, Muscle Strength, and body Composition Parameters in Hypogonadal Men. J Clin Endocrinol Metab 2000; 85:2839–2853.
75. Reaven G. Metabolic Syndrome, Pathophysiology and Implications for management of cardiovascular disease. Circulation 2002; 106:286–8.
76. Haffner SM. Epidemiology of insulin resistance and its relation to coronary heart disease. Am J Cardiol 1999; 84(1A):11–14J.
77. Holmang A, Bjorntorp P. The effects of testosterone on insulin sensitivity in male rats. Acta Physiol Scand 1992; 146:505–10.[Web of Science][Medline]
78. Haffner SM, Valdez RA, Mykkanen L, Stern MP, Katz MS. Decreased testosterone and dehydroepiandrosterone sulfate concentrations are associated with increased insulin and glucose concentrations in non diabetic men. Metabolism 1994; 43:599–603.[CrossRef][Web of Science][Medline]
79. Haffner SM, Karhapaa P, Mykkanen L, Laakso M. Insulin resistance, body fat distribution and sex hormones in men. Diabetes 1994; 43:212–19.[Abstract]
80. Stellato RK, Feldman HA, Hamdy O Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 2000; 23:490–4.[Abstract]
81. Barrett-Connor E, Khaw KT, Yen SS. Endogenous sex hormone levels in older adult men with diabetes mellitus. Am J Epidemiol 1990; 132:895–901.
82. Marin P, Krotkiewski M, Bjorntorp P. Androgen treatment of middle-aged obese men: effects on metabolism, muscle and adipose tissues. Eur J Med 1992; 1:329–36.[Medline]
83. Hak AE, Witteman JCM, Jong FH de, Geerlings MI, Hofman A, Pols HAP. Low levels of androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab 2002; 87:3632–9.
84. Hanke H, Lenz C, Hess B, Spindler KD, Weideman W. Effect of Testosterone on plaque Development and Androgen receptor Expression in the Arterial Vessel Wall. Circulation 2001; 103:1382–5.
85. Kohchi K, Takebayashi S, Hiroki T, Nobuyoshi M. Significance of adventitial inflammation of the coronary artery in patients with unstable angina: results of autopsy. Circulation 1985; 71:709–16
86. Tipping PG, Hancock WW. Production of tumour necrosis factor and Interleukin-1 by macrophages from human atheromatous plaques. Am J Pathol 1993; 142:1721–8.[Abstract]
87. Valen G, Y Zhong-qun, Hansson GK. Nuclear Factor Kappa-B and the heart. J Am Coll Cardiol 2001; 38:307–14.
88. Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes: implications for plaque rupture. Circulation 1994; 90:775–8.
89. George SJ. Tissue inhibitors of metalloproteinases and metalloproteinases in atherosclerosis. Curr Opin Lipidol 1998; 9:413–23.[CrossRef][Web of Science][Medline]
90. Geng YJ, Wu Q, Muszynski M, Hansson GK, Libby P. Apoptosis of vascular smoth muscle cells induced by in vitro stimulation with interferon gamma, tumour necrosis factor alpha and Interleukin-1 Beta. Arterioscler Thromb Vasc Biol 1996; 16:19–27.
91. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336:973–9.
92. Tommasi S, Carluccio E, Bentivoglio M, Mariotti M, Politano M, Corea L. C-reactive protein as a marker for cardiac ischaemic events the year after a first uncomplicated myocardial infarction. Am J Cardiol 1999; 83:1595–9.[CrossRef][Web of Science][Medline]
93. Rifai N, Ridker PM. Proposed cardiovascular Risk Assessment Algorithm using high sensitivity C-Reactive Protein and Lipid Screening. Clin Chem 2001; 47:28–30.
94. Gornstein RA, Lapp CA, Bustos-Valdes SM, Zamorano P. Androgens modulate interleukin-6 production by gingival fibroblasts in vitro. J Periodontol 1999; 70:604–9.[CrossRef][Web of Science][Medline]
95. Khosla S, Atkinson EJ, Dunstan CR, O’Fallon WM. Effect of estrogen versus testosterone on circulating osteoprotegerin and other cytokine levels in normal elderly men. J Clin Endocrinol Metab 2002; 87:1550–4.
96. Cutulo M, Balleari E, Giusti M, et al. Androgen Replacement Therapy in Male Patients with Rheumatoid Arthritis. Arthritis Rheumatism 1991; 34:1–5.[Web of Science][Medline]
97. Bizzarro A, Valentini G, Di Martino, DaPonte A, De Bellis A, Iacono G. Influence of testosterone therapy on clinical and immunological features of autoimmune diseases associated with Klinefelter’s syndrome. J Clin Endocrinol Metab 1987; 64:32–6.
98. Slater S, Oliver RT. Testosterone: its role in the development of prostate cancer and potential risk from use as hormone replacement therapy. Drugs Aging 2000; 17:431–9.[CrossRef][Web of Science][Medline]
99. Shaneyfelt T, Husein R, Bubley G, Mantzoros CS. Hormonal predictors of prostate cancer: a meta-analysis. J Clin Oncol 2000; 18:847–53.
100. Eaton NE, Reeves GK, Appleby PN, Key TJ. Endogenous sex hormones and prostate cancer review of prospective studies. Br J Cancer; 80:930–4.
101. Morales A. Androgen replacement therapy and prostate safety. Eur Urol 2002; 41:113–20.[CrossRef][Web of Science][Medline]
102. Lee C. Cellular interactions in Prostate Cancer. Br J Urol 1997; 79:21–7.
103. Guay AT, Perez JB, Fitaihi WA, et al. Testosterone treatment in hypogonadal men: prostate-specific antigen level and risk of prostate cancer. Endocr Pract 2000; 6:218–21.[Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Mathur, C. Malkin, B. Saeed, R Muthusamy, T H. Jones, and K. Channer Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men Eur. J. Endocrinol., September 1, 2009; 161(3): 443 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Traish, F. Saad, R. J. Feeley, and A. Guay The Dark Side of Testosterone Deficiency: III. Cardiovascular Disease J Androl, September 1, 2009; 30(5): 477 - 494. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||