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LE Magazine August 2004

Are major risk factors for myocardial infarction the major predictors of degree of coronary artery disease in men?
Although numerous cross-sectional studies have reported associations of hypertension, hypercholesterolemia, diabetes, smoking, and/or obesity with the presence of coronary artery disease (CAD), correlations of these risk factors for myocardial infarction (MI) with the degree or progression of CAD have been less consistent. Nevertheless, these risk factors are generally assumed to be major determinants not only of MI, but of the degree of CAD as well. The present study is an attempt to evaluate the relationship of major risk factors for MI to degree of CAD. From 182 men who underwent diagnostic coronary arteriography, the 154 with CAD were selected for study. These 154 patients were divided into 2 groups, those with hypertension, hypercholesterolemia, diabetes, smoking, and/or obesity (n = 121) and those with none of these risk factors (n = 33). The mean degree of CAD in the group with risk factors for MI (44.4%) and in the group without (50.6%) was not significantly different (P =.15); nor was the increase in CAD with age augmented by the presence of these risk factors. On multiple regression analysis, none of these risk factors was associated with degree of CAD. Three other variables that were considered in this study, age, high-density lipoprotein-cholesterol (HDL-C), and free testosterone (FT), did show an independent association with degree of CAD. These findings, together with the findings of previous studies from other laboratories, raise the possibility that in men selected for coronary arteriography, age, HDL-C, and FT may be stronger predictors of degree of CAD than are blood pressure, cholesterol, diabetes, smoking, and body mass index (BMI).

Metabolism. 2004 Mar;53(3):324-9

Endogenous sex hormones and progression of carotid atherosclerosis in elderly men.
BACKGROUND: The burden of atherosclerosis especially afflicts the increasing older segment of the population. Recent evidence has emphasized a protective role of endogenous sex hormones in the development of atherosclerosis in aging men. METHODS AND RESULTS: We studied the association between endogenous sex hormones and progression of atherosclerosis in 195 independently living elderly men. Participants underwent measurements of carotid intima-media thickness (IMT) at baseline in 1996 and again in 2000. At baseline, serum concentrations of testosterone (total and free) and estradiol (total and free E2) were measured. Serum free testosterone concentrations were inversely related to the mean progression of IMT of the common carotid artery after adjustment for age (beta=-3.57; 95% CI, -6.34 to -0.80). Higher serum total and free E2 levels were related to progression of IMT of the common carotid artery after adjustment for age (beta=0.38; 95% CI, -0.11 to 0.86; and beta=0.018; 95% CI, -0.002 to 0.038, respectively). These associations were independent of body mass index, waist-to-hip ratio, presence of hypertension and diabetes, smoking, and serum cholesterol levels CONCLUSIONS: Low free testosterone levels were related to IMT of the common carotid artery in elderly men independently of cardiovascular risk factors.

Circulation. 2004 May 4;109(17):2074-9. Epub 2004 Apr 19

The associations of endogenous testosterone and sex hormone-binding globulin with glycosylated hemoglobin levels, in community dwelling men. The Tromso Study.
OBJECTIVES: Low levels of endogenous testosterone have been associated with increased risk of cardiovascular disease and atherosclerosis in men. Long-term hyperglycemia, as measured by glycosylated hemoglobin (HbA1c), is related to cardiovascular mortality, and HbA1c across its normal range is also positively related to coronary heart and cardiovascular disease mortality in men. We therefore undertook an analysis of the cross-sectional associations of total testosterone and SHBG levels with HbA1c levels, in a general population of 1419 men aged 25-84.METHODS: Total testosterone, sex hormone-binding globulin (SHBG) and HbA1c were measured by immuno-assay. Partial correlation and multiple regression analyses were used to estimate the associations between total testosterone and SHBG with HbA1c. Analyses of variance and covariance were used to compare men with or without diabetes.RESULTS: In age-adjusted partial correlation HbA1c was inversely associated with total testosterone (p<0.01) and SHBG (p<0.001). HbA1c was positively associated with body mass index (BMI) and waist circumference (WC) (p<0.001). In multiple regression analyses total testosterone, SHBG, age, number of cigarettes smoked, BMI and WC were independently associated with HbA1c levels. Men with a history of diabetes had lower levels of total testosterone in age-adjusted analyses (p<0.05) and lower levels of SHBG in both age- and WC-adjusted analyses (p<0.001 and p<0.01, respectively).CONCLUSION: Lower levels of total testosterone and SHBG were associated with increased HbA1c levels and diabetes independent of concomitant variations in obesity and body fat distribution.

Diabetes Metab. 2004 Feb;30(1):29-34

An assessment of correlations between endogenous sex hormone levels and the extensiveness of coronary heart disease and the ejection fraction of the left ventricle in males.
This clinical study investigated the possible associations of male sex hormone with the extensiveness of coronary artery lesions, coronary heart disease risk factors and ejection fraction of the heart. Ninety six Caucasian male subjects were recruited, 76 with positive and 20 with negative coronary angiograms. Early morning, prior to haemodynamic examination all of them had determined levels of total testosterone, free testosterone, free androgen index (FAI), sex hormone-binding globulin (SHBG), oestradiol, luteinizing hormone, follicle-stimulating hormone, plasma lipids, fibrinogen and glucose. The ejection fraction and the extensiveness of coronary lesions of each subject was assessed on the basis of x-ray examination results using Quantitative Coronary Angiography (QCA) and Left Ventricular Analysis (LVA) packages on the TCS Acquisition workstation, Medcon. Men with proven coronary heart disease had significantly lower levels of total testosterone (11.9 vs 21.2 nmol/l), free testosterone (45.53 vs 86.10 pmol/l), free androgen index (36.7 vs 47.3 IU) and oestradiol (109.4 vs 146.4 pmol/l). The level of testosterone was negatively associated with the DUKE Index. The most essential negative correlation was observed between SHBG and atherogenic lipid profile (low high-density lipoprotein, high triglycerides). Ejection fraction was substantially lower in patients (51.85 vs 61.30) (without prior myocardial infarction) with low levels of free-testosterone (23.85 vs. 86.10 pmol/l) and FAI (28.4 vs 47.3 IU). A negative correlation was observed between total testosterone, free testosterone, FAI and blood pressure, especially with diastolic pressure. Men with proven coronary atherosclerosis had lower levels of endogenous androgens than the healthy controls. For the first time in clinical settings it has been demonstrated that low levels of free-testosterone was characteristic for patients with low ejection fraction. Numerous hypothesies for this action can be proposed but all require a proper evaluation process. The main determinant of atherogenic plasma lipid was low levels of SHBG suggesting its main role in developing atheroscerotic lesions.

J Med Invest. 2003 Aug;50(3-4):162-9

Acute haemodynamic effects of testosterone in men with chronic heart failure.
AIMS: Anabolic therapy with testosterone may be useful in the treatment of wasting associated with chronic heart failure but little is known about its cardiovascular actions. The aim of this study was to determine the acute haemodynamic effects of testosterone administration in men with heart failure. METHODS AND RESULTS: Twelve men with stable chronic heart failure were enrolled in a double-blind, randomised, placebo-controlled, cross-over trial. Subjects were given testosterone 60 mg or placebo via the buccal route and central haemodynamics were monitored over 6h, using a pulmonary flotation catheter. Subjects received the second treatment on day 2 and haemodynamic monitoring was repeated. Treatment was well tolerated. Compared with placebo, testosterone treatment resulted in a relative increase in cardiac output (p<0.0001, ANCOVA), with maximum treatment effect after 180 min (10.3+/-4.6% increase from baseline, p=0.035; 95% CI 0.8-19.8). This was accompanied by reduction in systemic vascular resistance compared with baseline (p<0.0001, ANCOVA), with maximum treatment effect also at 180 min (-17.4+/-9.6% from baseline, p=0.085; 95% CI -37.3 to +2.6). These maximal changes coincided with the peak elevation in serum bio-available testosterone. There was no significant change in any other haemodynamic parameter measured. CONCLUSIONS: Administration of testosterone increases cardiac output acutely, apparently via reduction of left ventricular afterload.

Eur Heart J. 2003 May;24(10):909-15

Administration of testosterone is associated with a reduced susceptibility to myocardial ischemia.
This study investigated the impact of testosterone on myocardial ischemia-reperfusion injury and corresponding intracellular calcium ([Ca2+]i) metabolism. Nonorchiectomized mature male Wistar rats were randomly assigned to placebo, a single dose of testosterone undecanoate, or 5alpha-dihydrotestosterone. In a further series, orchiectomized rats were treated with placebo. After 2 wk of treatment, the hearts were removed and placed in a Langendorff setup. The isolated, buffer-perfused hearts were subjected to 30 min of no-flow ischemia and 30 min of reperfusion. Recovery of myocardial function was measured by analyzing pre- and postischemic left ventricular ( LV) systolic/diastolic pressure and coronary perfusion pressure simultaneously, together with [Ca2+]i handling (aequorin luminescence). Calcium regulatory proteins were analyzed by Western blotting. LV weight/body weight ratio was increased after administration of testosterone vs. orchectomized rats. The recovery of contractile function was improved in testosterone-treated rats: at the end of the reperfusion, LV systolic pressure was higher and end-diastolic pressure was lower in testosterone-treated rats. End-ischemic [Ca2+]i and [Ca2+]i overload upon reperfusion was significantly lower in testosterone vs. orchiectomized rats, too. However, levels of calcium regulatory proteins remained unaffected. In conclusion, administration of testosterone significantly improves recovery from global ischemia. These beneficial effects are associated with an attenuation of reperfusion induced [Ca2+]i overload.

Endocrinology. 2003 Oct;144(10):4478-83. Epub 2003 Jul 10

High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study.
Androgens stimulate prostate cancer in vitro and in vivo. However, evidence from epidemiologic studies of an association between circulating levels of androgens and prostate cancer risk has been inconsistent. We investigated the association of serum levels of testosterone, the principal androgen in circulation, and sex hormone-binding globulin (SHBG) with risk in a case-control study nested in cohorts in Finland, Norway and Sweden of 708 men who were diagnosed with prostate cancer after blood collection and among 2,242 men who were not. In conditional logistic regression analyses, modest but significant decreases in risk were seen for increasing levels of total testosterone down to odds ratio for top vs. bottom quintile of 0.80 (95% CI = 0.59-1.06; p(trend) = 0.05); for SHBG, the corresponding odds ratio was 0.76 (95% CI = 0.57-1.01; p(trend) = 0.07). For free testosterone, calculated from total testosterone and SHBG, a bell-shaped risk pattern was seen with a decrease in odds ratio for top vs. bottom quintile of 0.82 (95% CI = 0.60-1.14; p(trend) = 0.44). No support was found for the hypothesis that high levels of circulating androgens within a physiologic range stimulate development and growth of prostate cancer.

Int J Cancer. 2004 Jan 20;108(3):418-24

Reduced circulating androgen bioactivity in patients with prostate cancer.
BACKGROUND: Previous studies on immunoreactive androgen levels in serum have revealed equivocal associations with the risk of prostate cancer (CaP). The aim of this study was to compare serum biological androgen activity between men with newly diagnosed CaP and age-matched men with benign prostatic hyperplasia (BPH). METHODS: Caucasian men with newly diagnosed, untreated CaP (n = 101) and age-matched patients with BPH (n = 103) were investigated. Serum androgen bioactivity ( ABA) levels were measured using a recently developed recombinant cell bioassay. RESULTS: In comparison to men with BPH, CaP patients with Gleason score >or=8 (n = 16) had lower serum ABA (P < 0.05), and patients with Gleason score <or=5 (P < 0.05) or >or=8 (P = 0.07) displayed suppressed ABA levels in relation to serum testosterone. As the entire group, men with CaP (n = 101) had significantly lower serum ABA than age-matched men with BPH (n = 103): median 3.0 nM (range, 0.8-6.4 nM) versus 3.2 nM (range, 0.8-7.9 nM) testosterone equivalents, respectively (P < 0.005). By contrast, serum immunoreactive testosterone and SHBG concentrations and free androgen indices did not differ significantly between the two groups. CONCLUSIONS: Patients with CaP have lower serum ABA than controls with BPH, and men with low or high Gleason score display suppressed circulating ABA-to-testosterone ratio. These features may reflect interaction between variables such as the degree of tumor differentiation and tumor volume with androgen metabolism.

Prostate. 2003 May 15;55(3):194-8

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