Relationships between endogenous steroid hormone, sex hormone-binding globulin and lipoprotein levels in men: contribution of visceral obesity, insulin levels and other metabolic variables
Introduction
The relationships of endogenous steroid hormone levels to plasma lipoprotein concentrations in men have been widely studied in numerous populations. Testosterone levels have generally been positively associated with HDL-cholesterol (HDL-C) concentrations 1, 2. Conflicting results have been reported regarding the associations between testosterone levels and plasma triglyceride (TG), total cholesterol, LDL-C and apolipoprotein (apo) B concentrations 1, 3, 4, 5, 6, 7. Relationships between endogenous sex steroid hormone levels and coronary heart disease (CHD) have also been studied in men and although there is no general consensus 7, 8it has been suggested that reduced testosterone could be associated with a deterioration of the metabolic profile leading to an increased CHD risk [7]. On the other hand, plasma sex hormone-binding globulin (SHBG) concentrations have been shown to be correlated with HDL-C and apo A-I levels [9].
It is well established that excess visceral adipose tissue (AT) accumulation as well as hyperinsulinemia are conditions associated with alterations in the lipoprotein lipid profile which include elevated TG, apo B and LDL-apo B levels as well as reduced HDL-C and HDL2-C concentrations [10]. Furthermore, obesity, visceral AT accumulation and hyperinsulinemia are also associated with changes in sex steroid hormone and SHBG concentrations 11, 12.
In previous reports on the association between steroid hormones, SHBG, plasma lipoproteins and coronary heart disease in men, taking obesity and body fat distribution (using the waist-to-hip ratio) into account have generated controversial results [9]. In an attempt to provide further insight into the independent relationships of steroid hormones and SHBG to plasma lipoprotein concentrations, we have examined the associations between plasma testosterone, adrenal C19 steroids, SHBG and lipoprotein concentrations in a sample of men, taking into account the concomitant variations in obesity, visceral AT accumulation measured by computed tomography, and plasma insulin levels.
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Subjects
Seventy-six male subjects were recruited by solicitation through the media for a study on excess body weight, on the basis of their BMI values (lean men BMI≤25kg/m2 and obese men BMI>27kg/m2). Total body fat mass values were, however, continuously distributed from 6.4 to 37.3 kg. All subjects had a complete physical examination and had to be non-smokers to be included in the study. Individuals with diabetes, endocrine disorders or coronary heart disease were excluded. Subjects signed an
Measurement of body fatness and adipose tissue distribution
Body density was determined by hydrostatic weighing [13], with measurement of the pulmonary residual volume by the helium dilution method [14]before immersion in a hydrostatic tank. The equation of Siri [15]was used to derive body fat mass values from the mean of 6 body density measurements.
Measurements of cross-sectional abdominal adipose tissue areas were performed by computed tomography as previously described 16, 17with a Somatom DHR scanner (Siemens, Erlangen, Germany). Subjects were
Fasting lipid, lipoprotein and insulin measurements
Blood samples were drawn from an antecubital vein into vacutainer tubes containing EDTA between 07:00 and 09:00. Triglyceride [18]as well as cholesterol [19]concentrations in the plasma and lipoprotein fractions were measured on an Auto-Analyser (Technicon RA-1000) using enzymatic reagents obtained from Miles Laboratories. Plasma VLDLs (d<1.006) were separated by ultracentrifugation [20]and the HDL fraction was obtained by precipitation of the LDLs from the infranatant (d>1.006), with heparin
Plasma steroid measurements
The following steroids were measured: testosterone, androstenedione (Δ4-DIONE), androstene-3β,17β-diol (Δ5-DIOL), dehydroepiandrosterone (DHEA), estradiol and estrone. Plasma was obtained after centrifugation of blood at 2000×g for 15 min and samples were frozen at −80°C until the steroids were assayed. Steroids were extracted from plasma with ethanol before centrifugation at 2200×g for 15 min as previously described [26]. The resulting pellet was resuspended in ethanol before recentrifugation.
Statistical analyses
Log10 transformation of TG, HDL2-C, and the HDL2-C/HDL3-C ratio was performed to reduce the skewness in the distribution of these variables. Pearson correlation coefficients were computed to quantify the relationships between lipid and lipoprotein variables with steroids and SHBG levels. Covariance analyses were performed to eliminate the contribution of visceral AT and metabolic variables to these correlations. Multiple regression analyses were performed to quantify the contributions of each
Results
Table 1 shows the characteristics of the study sample. Men in the present study had a wide and continuous range of total body fat mass values.
Fig. 1 shows the Pearson correlation coefficients between testosterone and SHBG concentrations and plasma lipid-lipoprotein levels. Testosterone concentrations were negatively correlated with TG, apo B, total and LDL-C and positively with the HDL-C/total cholesterol ratio. No significant correlation was found between plasma testosterone concentrations and
Discussion
The purpose of this study was to characterize the possible associations between steroid hormones, SHBG and lipoprotein concentrations with control over potential confounders known to affect lipoprotein metabolism such as visceral adipose tissue accumulation, plasma insulin and free fatty acid levels as well as total body fat mass. Results indicate that increased testosterone and adrenal C19 steroid levels were associated with a more favorable lipid profile in men. Indeed, as reflected by the
Acknowledgements
The authors would like to thank the staff of the MRC group in Molecular Endocrinology for performing the steroid assays. We also acknowledge the excellent collaboration of the subjects and the dedicated work of the staff of the Lipid Research Center, the Physical Activity Sciences Laboratory and the Diabetes Research Unit. This work was supported by the Medical Research Council of Canada, and by the Québec Heart Foundation. André Tchernof is a fellow from Le Fonds de la Recherche en Santé du
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