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ABSTRACT The associations between androgens and cardiovascular risk factors in men are controversial. A nested case-control study was used to compare the levels of cardiovascular risk factors in two groups (n ϭ 25 each) of healthy men contrasted by their plasma total testosterone (PTT) concentration, matched by age and ethnic origin. Compared to the men with normal PTT (mean Ϯ SEM, 19.8 Ϯ 0.7 nmol/L), the men with low PTT (10.1 Ϯ 0.3 nmol/L) had a significantly higher body mass index (P Ͻ 0.01), waist/hip ratio (P Ͻ 0.001), systolic blood pressure (P Ͻ 0.05), fasting and 2-h plasma glucose (P Ͻ 0.04 and P Ͻ 0.02 respectively), serum triglycerides (P Ͻ 0.001), total cholesterol (P Ͻ 0.04), low density lipoprotein cholesterol (P Ͻ 0.01), apolipoprotein B (P Ͻ 0.01), fasting and 2-h plasma insulin (both P Ͻ 0.0001), and lower values of serum high density lipoprotein cholesterol (P Ͻ 0.01) and apolipoprotein A1 (P Ͻ 0.05). After adjustment for both body mass index and waist/ hip ratio, fasting and 2-h plasma insulin and triglyceride levels remained significantly different between the two groups (P Ͻ 0.04, P Ͻ 0.001, and P Ͻ 0.03 respectively). Plasma sex hormone-binding globulin was markedly decreased in the low PTT group (P Ͻ 0.0001), whereas bioavailable testosterone was not significantly different. This case-control study provides further and stronger evidence of a negative association between PTT and plasma insulin in men, as suggested by cross-sectional studies. Because these are observational data, neither causality nor the direction of the associations among PTT, sex hormone-binding globulin, and insulin sensitivity can be determined. Intervention studies are needed to better assess the metabolic and cardiovascular benefits of androgen treatment that have been suggested by preliminary clinical trials. (J Clin Endocrinol Metab 82: 682-685, 1997) F OR A LONG time, androgens have been considered to decrease glucose tolerance, induce hyperinsulinemia, and increase cardiovascular risk in women (1) as well as in men (2). Recently, these effects have been questioned in men. Indeed, from recent cross-sectional studies in healthy men, lower plasma total testosterone (PTT) levels seem to be associated with hyperinsulinemia, decreased glucose tolerance, and a higher level of cardiovascular risk factors (3-5). To investigate the role of endogenous testosterone and sex hormone-binding globulin (SHBG) in the association between sex hormones and cardiovascular risk factors in healthy males, in 1992-1993 we selected from the large male occupation-based population examined in the Telecom Study in 1985-1987 (3, 6), two groups of men contrasted by their PTT concentrations to compare their levels of cardiovascular risk factors, plasma SHBG, and plasma bioavailable testosterone. Materials and Methods Study design This study used a nested case-control design. The levels of plasma SHBG, plasma bioavailable testosterone, and cardiovascular risk factors were compared between males with low and normal PTT. As age and ethnicity influence cardiovascular risk factors (7-9), the subjects were matched on these covariates (Ϯ1 yr for age). Selection of subjects For the low PTT group, we selected healthy men not treated for diabetes, dyslipidemia, or hypertension from the lower percentiles of the PTT distribution of the 1718 adult men who participated in the crosssectional study of 1985-1987 (3, 6). We recruited all healthy men with PTT levels of 11.8 nmol/L or less in 1985-1987 who could be traced and who agreed to be reexamined in 1992-1993. The fifth percentile of the PTT distribution in the background population was 11.8 nmol/L When a case with a confirmed low PTT level had been included, we then recruited a matched control subject, with PTT levels between 17. 3-24.3 nmol/L in 1985-1987 and 13.9 -28.4 nmol/L in 1992-1993. When several controls were available for a given case, we systematically chose the control who had been examined at the date closest to that of the case in [1985][1986][1987]. To obtain the a priori calculated sample size of 25 men by group (see Statistical methods), we contacted 147 subjects (65 with low PTT in 198