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• W2022894974 abstract "Objective. To study the relationship between endogenous sex hormone levels and intima-media thickness (IMT) of the carotid artery measured by ultrasonography. Design. Population-based cross-sectional study. Methods. Sex hormone levels measured by immunoassay, anthropometric measurements and IMT was studied in 1482 men aged 25–84 years participating in the 1994–1995 Tromsø study. The data were analysed with partial correlation, multiple linear regression and logistic regression analysis. Results. Linear regression models showed that total testosterone and sex hormone-binding globulin levels, but not calculated free testosterone, serum oestradiol or dehydroepiandrosterone sulphate levels were inversely associated with the age-adjusted IMT (P = 0.008 and P < 0.001 respectively). These associations were independent of smoking, physical activity, blood pressure and lipid levels, but were not independent of body mass index (BMI). Excluding men with cardiovascular disease (CVD) did not materially change these results. In a logistic regression model adjusted for the confounding effect of CVD risk factors, men with testosterone levels in the lowest quintile (<9.0 nmol L−1) had an independent OR = 1.51 (P = 0.015) of being in the highest IMT quintile. Conclusions. We found an inverse association between total testosterone levels and IMT of the carotid artery in men that was present also after excluding men with CVD, but was not independent of BMI. The clinical relevance of this, however, is uncertain and needs to be investigated in a clinical setting. The role of testosterone in the development of cardiovascular disease (CVD) is controversial. Men have a higher incidence of CVD than women of similar age, and it has been suggested that testosterone may influence the development of CVD [1]. However, endogenous testosterone levels are inversely associated with several cardiovascular risk factors, i.e. abdominal obesity [2, 3], blood pressure [4, 5], lipid levels [6] and left ventricular mass [5]. Lower testosterone levels have been found in men with hypertension [5, 7], stroke [8] and diabetes mellitus [9, 10], but so far no relation has been found between endogenous testosterone and cardiovascular events [11-13]. Results from earlier studies on endogenous androgen levels and atherosclerosis have been inconsistent [14-22]. In two recent cross-sectional studies of elderly men, intima-media thickness (IMT), an indicator of general atherosclerosis, was associated with lower testosterone levels [19, 20]. Free, but not total, testosterone levels were inversely related to IMT in a recent prospective population-based study [21], and higher levels of oestradiol have been reported in men with coronary stenosis in two case–control studies [23, 24], whilst another study did not [25]. The present study, including 1482 men from a general population with a wide age range (25–84 years), is so far the largest population-based study investigating the relationships between endogenous sex hormone levels and IMT of the carotid artery in men. The participants of the study were men recruited from a population-based health study, the fourth survey of the Tromsø Study (1994–1995) [8]. The study population has been described in detail previously [8]. In a random sample of 1605 nonfasting men, aged 25–84 years, blood samples were drawn between 08.00 hours and 16.00 hours. Serum samples were stored at −70 °C, until they were first thawed for analyses of sex hormones in 2001. Determination of total testosterone, oestradiol, dehydroepiandrosterone sulphate (DHEAS) and sex hormone-binding globulin (SHBG) was performed on Immulite 2000 (Diagnostic Product Corp., Los Angeles, CA, USA). The intra- and inter-assay coefficients of variation (CV) for the analyses were between 5% and 10%. Free testosterone values were calculated from total testosterone and SHBG using a fixed albumin according to Vermeulen et al. [26]. Height, weight and waist girth were measured in standing subjects wearing light clothing without shoes; waist circumference (WC) was measured at the umbilical line according to written protocol. Body mass index (BMI) (kg m−2) was calculated. Self-administered questionnaires that included information about smoking habits, physical activity, alcohol consumption and medical history were completed and checked by trained nurses. CVD was defined as a history of myocardial infarction and/or angina pectoris and/or stroke. A physical activity score was calculated from the questionnaires by adding the hours of easy and vigorous physical activity, with the hours of vigorous activity receiving double weight. The alcohol intake of beer, wine and hard liquor consumed during a 2-week period was also scored, assuming an equal amount of alcohol in one glass of each type. High-resolution B-mode and colour Doppler/pulsed-wave Doppler ultrasonography of the right carotid artery was performed as described previously [27]. In short, the examinations were performed with a high-resolution ultrasound Acuson 128 XP/10c ART-upgraded scanner (Mountain View, CA, USA) equipped with a linear transducer with 7 MHz in B-mode. IMT was measured in 10-mm segments in three locations of the carotid artery: the near and far wall of the common carotid artery (CCA) and the far wall of the bifurcation. Frozen images from each segment were stored on high-resolution videotapes. The loss of parallel configuration of the near and far walls of the CCA served as a reference point for the start of the carotid bifurcation. The ultrasonic images were analysed off-line with a computerized technique for automated ultrasonic image analysis. The average IMT from the three preselected images was calculated for each location. Plaques were included in the measurements of IMT if they were located in areas predefined for IMT registrations. The reproducibility of the ultrasound measurements was acceptable [27]. Of the 1605 men initially selected for sex hormone analyses, 1482 men had both complete sex hormone values and IMT data, and are included in this study. The Regional Ethics Committee approved the study, and all participants gave written informed consent. Normal distribution was evaluated with determination of skewness and histograms, and average IMT and sex hormones were considered normally distributed. Age was used as a confounder in all models as a previous study in the same population showed the expected strong association between age and sex hormones [8]. Partial correlations were used to determine the cross-sectional associations between IMT and covariates adjusted for age. Multiple linear regression analyses, with IMT as the dependent variable, were performed to evaluate the independent contribution of sex hormones, age, BMI, blood pressure, lipids and lifestyle factors. The independent relationship between CVD risk factors (see below), age, testosterone levels and IMT was also tested with logistic regression analysis, where IMT was treated as the dependent variable. CVD risk factors were dichotomized based on risk levels according to the following cut points: BMI > 25 kg cm−2, systolic blood pressure >160 mmHg, cholesterol >5.2 mmol L−1, HDL cholesterol <0.9 mmol L−1, current smoking and lack of physical activity <3 h week−1. Age was used as a continuous variable and the testosterone cut point was being in the lowest testosterone quintile (<9.0 nmol L−1). The model calculates the OR for being in the highest IMT quintile (>1.04 mm). All statistical tests were two-tailed with statistical significance defined as P < 0.05. The data were analysed using the SPSS statistical package for Windows version 12.0 (SPSS Inc., Chicago, IL, USA). As shown in Table 1, the mean age of the study population was 60.3 years and the mean BMI was 26.1 kg m−2. The average mean IMT was 0.90 mm and a history of CVD was reported by 17.5%. Table 1 also shows mean levels of total testosterone (13.2 nmol L−1), free testosterone (205 pmol L−1), total oestradiol (0.06 nmol L−1), DHEAS (3.4 μmol L−1) and SHBG (52.3 nmol L−1). In age-adjusted correlations, higher testosterone levels were associated with lower BMI (r = −0.31, P < 0.001), WC (r = −0.34, P < 0.001), systolic and diastolic blood pressure (r = −0.13, P < 0.001; and r = −0.10, P < 0.001 respectively) and triglycerides (r = −0.19, P < 0.001), higher HDL levels (r = 0.11, P < 0.001) and current smoking (r = 0.15, P < 0.001). IMT was positively associated with BMI (r = 0.16, P < 0.001), WC (r = 0.14, P < 0.001), smoking (r = 0.08, P < 0.01), systolic and diastolic blood pressure (r = 0.19, P < 0.001; and r = 0.06, P < 0.05 respectively), cholesterol (r = 0.08, P < 0.01) and triglycerides (r = 0.13, P < 0.001), and negatively associated with HDL cholesterol (r = −0.08, P < 0.01) and physical activity (r = −0.08, P < 0.01). In linear regression analyses, total testosterone and SHBG levels, but not calculated free testosterone, serum oestradiol or DHEAS levels, were inversely associated with the age-adjusted average IMT (β = −0.07, P = 0.008; and β = −0.09, P < 0.001 respectively). These associations were independent of smoking, physical activity, blood pressure and lipid levels, but were not independent of BMI or WC (Table 2). Excluding men with CVD did not materially change these results. Table 3 shows that men with a testosterone level in the lowest quintile (<9.0 nmol L−1) were more likely (OR = 1.51, P = 0.015) to be in the highest average IMT quintile (>1.04 mm) independently of age and the CVD risk factors. Age (OR = 1.11 year−1), BMI > 25 kg cm−2 (OR = 1.47), systolic blood pressure >160 mmHg (OR = 1.87), cholesterol >5.2 mmol L−1 (OR = 1.59), HDL cholesterol <0.90 mmol L−1 (OR = 2.51), smoking (OR = 1.44) and exercising <3 times week−1 (OR = 1.46) were also independently associated with being in the highest average IMT quintile. In this population-based study of 1482 men we found that total testosterone levels were significantly related to the carotid IMT. The association was independent of age, CVD risk factors and lifestyle factors but was not independent of BMI. Excluding men with a self-reported history of CVD from the analyses did not change the association. A similar association was also found with SHBG but not with free testosterone, DHEAS or oestradiol. The association between lower levels of testosterone and increased IMT is supported by previous studies. Hak et al. [19] reported an inverse association between levels of testosterone and aortic atherosclerosis in 504 nonsmoking men, aged 55 years and over, participating in the Rotterdam Study. Another recently published study by van den Beld et al. [20] reported that testosterone appeared to be linearly inversely related to the IMT of the carotid artery in 403 independently living elderly men, aged 73–94 years. Both studies [19, 20] also evaluated the possible relationship between DHEAS and atherosclerosis and in one of the studies [20] the relationship between oestradiol and atherosclerosis was also investigated. In agreement with our study no association was observed. Lower free testosterone levels were recently reported to be associated with IMT of the carotid artery [21, 22]. In the report by Muller et al. [21] free testosterone, but not total testosterone, was associated with progression of atherosclerosis in older men, aged 77–94 years. The study by De Pergola et al. [22] was performed in a group of 127 highly selected overweight or obese younger men, making a comparison between our studies difficult. Free testosterone represents a small part of total testosterone (1–2%) and is influenced by both total testosterone and SHBG levels [28]. If SHBG, as in our study, decreases in parallel with total testosterone, the amount of free testosterone may remain unaffected. An important risk factor for total morbidity and mortality is the increase in total adipose tissue mass and the redistribution of fat mass from peripheral to central, intra-abdominal deposits [29, 30]. The consequences of these changes are significant, and include CVD [31]. The testosterone and IMT association seen in our study was not independent of BMI or WC, suggesting that the relationship between total testosterone and IMT is at least partly mediated by body fat or body fat distribution. In comparison, increased central adiposity is seen in hypogonadal men [32]. Lower endogenous androgens predict central obesity 12 years later [2], and low-dose testosterone administration to hypogonadal men has been found to reduce fat mass and increase lean body mass regardless of the cause of hypogonadism [33, 34]. HDL cholesterol is inversely associated with the risk of CVD, and we find the same direction of association between HDL cholesterol and IMT in our study. In addition, both cholesterol and triglycerides were positively associated with IMT. High testosterone levels have been found to be associated with high HDL cholesterol and low triglyceride levels in several cross-sectional [6, 19] and one longitudinal [35] study in agreement with our results. Furthermore, a decrease in endogenous testosterone was associated with an increase in triglycerides [35]. Besides the possible modulating effect of testosterone on CVD risk factors, a few other possible explanations for the association between testosterone and atherosclerosis have been suggested. A direct beneficial effect of testosterone on plaque development, probably mediated by the vascular androgen receptor, has been reported in a recent animal study [36]. Testosterone induces endothelium-independent relaxation of isolated rabbit [37] and rat [38] aorta, and seems to have a beneficial effect on myocardial ischaemia [39] and coronary blood flow in men with coronary disease [40]. In addition, long-term oral administration of testosterone has also been shown to enhance endothelium-dependent and endothelium-independent vasodilation [41]. However, the evidence for a role of androgens in CVD as a whole is far from complete (for a review, see [1]), and the precise mechanism underlying the relationship between testosterone and atherosclerosis is still elusive. This is the largest population-based study of the relationship between endogenous sex hormones and carotid IMT in men, but it does have several limitations. Hormone levels were based on a single serum sample drawn between 08.00 hours and 1600 hours. Preferably samples should have been drawn in the morning because of the diurnal variation of total and free testosterone, and sample time was associated with both total and free testosterone, with expected higher levels of testosterone in the morning. Adjusting for time of venepuncture, however, did not change our results. Our samples were kept frozen for approximately 6.5 years at −70 °C, and hormone levels were measured when samples were thawed for the first time. Levels of steroid hormones have been shown to be relatively stable in frozen serum for up to 10 years [42, 43]. We did not measure free testosterone but used calculated values. This calculation was recently evaluated by two different investigators, and found to be a reliable index of free testosterone [26, 44]. The medical history in this study is based on self-report, and we cannot exclude that some men had a silent CVD. However, as the results were unchanged, whether men with CVD were included in the analyses or not, we do not believe this weakens our findings. The most important limitation, of course, is that the results of this study are obtained from cross-sectional data and do not provide direct evidence of cause and effect. Thus, low testosterone could lead to an increase in IMT or vice versa; whatever is true, well-conducted prospective studies are needed to determine the direction of the association. In conclusion, we found an inverse association between total testosterone levels and atherosclerosis, as measured by IMT of the carotid artery that was present also after excluding men with CVD. The association was independent of age, CVD risk factors and lifestyle factors but was not independent of BMI. The clinical relevance of this, however, is uncertain and needs to be investigated in a clinical setting. No conflict of interest was declared. This study was supported by local funds from the University Hospital of North Norway." @default.
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• W2022894974 title "Low testosterone levels are associated with carotid atherosclerosis in men" @default.
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