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      Association of Testosterone and Sex Hormone–Binding Globulin With Metabolic Syndrome and Insulin Resistance in Men

      research-article
      , MD, PHD 1 , , MD, MPH 1 , , MD, PHD 2 , , MD, MS 1 , , MD, SCD 3
      Diabetes Care
      American Diabetes Association

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          Abstract

          OBJECTIVE

          We sought to assess the associations of testosterones and sex hormone–binding globulin (SHBG) with metabolic syndrome and insulin resistance in men.

          RESEARCH DESIGN AND METHODS

          We defined metabolic syndrome according to the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Among men aged ≥20 years who participated in the Third National Health and Nutrition Examination Survey ( n = 1,226), the Cox proportional hazards model was used to estimate the prevalence ratio and 95% CI of metabolic syndrome according to circulating concentrations of testosterones and SHBG.

          RESULTS

          After adjustment for age, race/ethnicity, smoking status, alcohol intake, physical activity level, LDL cholesterol, C-reactive protein, and insulin resistance, men in the first quartile (lowest) (prevalence ratio 2.16 [95% CI 1.53–3.06]) and second quartile of total testosterone (2.51 [1.86–3.37]) were more likely to have metabolic syndrome than men in the fourth quartile (highest, referent group) ( P < 0.001 for linear trend). Similarly, men in the first quartile of SHBG (2.17 [1.32–3.56]) were more likely to have metabolic syndrome than men in the fourth quartile ( P = 0.02 for linear trend). No significant associations of calculated free testosterone ( P = 0.31 for linear trend) and bioavailable testosterone ( P = 0.11 for linear trend) with metabolic syndrome were detected after adjustment for all possible confounders.

          CONCLUSIONS

          Low concentrations of total testosterone and SHBG were strongly associated with increased likelihood of having metabolic syndrome, independent of traditional cardiovascular risk factors and insulin resistance.

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          Most cited references18

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          Compendium of physical activities: classification of energy costs of human physical activities.

          A coding scheme is presented for classifying physical activity by rate of energy expenditure, i.e., by intensity. Energy cost was established by a review of published and unpublished data. This coding scheme employs five digits that classify activity by purpose (i.e., sports, occupation, self-care), the specific type of activity, and its intensity as the ratio of work metabolic rate to resting metabolic rate (METs). Energy expenditure in kilocalories or kilocalories per kilogram body weight can be estimated for all activities, specific activities, or activity types. General use of this coding system would enhance the comparability of results across studies using self reports of physical activity.
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            Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study.

            We used longitudinal data from the Massachusetts Male Aging Study, a large population-based random-sample cohort of men aged 40-70 yr at baseline, to establish normative age trends for serum level of T and related hormones in middle-aged men and to test whether general health status affected the age trends. Of 1,709 men enrolled in 1987-1989, 1,156 were followed up 7-10 yr afterward. By repeated-measures statistical analysis, we estimated simultaneously the cross-sectional age trend of each hormone between subjects within the baseline data, the cross-sectional trend between subjects within the follow-up data, and the longitudinal trend within subjects between baseline and follow-up. Total T declined cross-sectionally at 0.8%/yr of age within the follow-up data, whereas both free and albumin-bound T declined at about 2%/yr, all significantly more steeply than within the baseline data. Sex hormone-binding globulin increased cross-sectionally at 1.6%/yr in the follow-up data, similarly to baseline. The longitudinal decline within subjects between baseline and follow-up was considerably steeper than the cross-sectional trend within measurement times for total T (1.6%/yr) and bioavailable T (2-3%/yr). Dehydroepiandrosterone, dehydroepiandrosterone sulfate, cortisol, and estrone showed significant longitudinal declines, whereas dihydrotestosterone, pituitary gonadotropins, and PRL rose longitudinally. Apparent good health, defined as absence of chronic illness, prescription medication, obesity, or excessive drinking, added 10-15% to the level of several androgens and attenuated the cross-sectional trends in T and LH but did not otherwise affect longitudinal or cross-sectional trends. The paradoxical finding that longitudinal age trends were steeper than cross-sectional trends suggests that incident poor health may accelerate the age-related decline in androgen levels.
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              Sex hormone-binding globulin and risk of type 2 diabetes in women and men.

              Circulating sex hormone-binding globulin levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain. We performed a nested case-control study of postmenopausal women in the Women's Health Study who were not using hormone therapy (359 with newly diagnosed type 2 diabetes and 359 controls). Plasma levels of sex hormone-binding globulin were measured; two polymorphisms of the gene encoding sex hormone-binding globulin, SHBG, that were robustly associated with the protein levels were genotyped and applied in mendelian randomization analyses. We then conducted a replication study in an independent cohort of men from the Physicians' Health Study II (170 with newly diagnosed type 2 diabetes and 170 controls). Among women, higher plasma levels of sex hormone-binding globulin were prospectively associated with a lower risk of type 2 diabetes: multivariable odds ratios were 1.00 for the first (lowest) quartile of plasma levels, 0.16 (95% confidence interval [CI], 0.08 to 0.33) for the second quartile, 0.04 (95% CI, 0.01 to 0.12) for the third quartile, and 0.09 (95% CI, 0.03 to 0.21) for the fourth (highest) quartile (P<0.001 for trend). These prospective associations were replicated among men (odds ratio for the highest quartile of plasma levels vs. the lowest quartile, 0.10; 95% CI, 0.03 to 0.36; P<0.001 for trend). As compared with homozygotes of the respective wild-type allele, carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 had 10% higher sex hormone-binding globulin levels (P=0.005), and carriers of an rs6257 variant had 10% lower plasma levels (P=0.004); variants of both SNPs were also associated with a risk of type 2 diabetes in directions corresponding to their associated sex hormone-binding globulin levels. In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard-deviation increase in the plasma level of sex hormone-binding globulin was 0.28 (95% CI, 0.13 to 0.58) among women and 0.29 (95% CI, 0.15 to 0.58) among men, a finding that suggests that sex hormone-binding globulin may have a causal role in the risk of type 2 diabetes. Low circulating levels of sex hormone-binding globulin are a strong predictor of the risk of type 2 diabetes in women and men. The clinical usefulness of both SHBG genotypes and plasma levels in stratification and intervention for the risk of type 2 diabetes warrants further examination. 2009 Massachusetts Medical Society
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                Author and article information

                Journal
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                July 2010
                5 April 2010
                : 33
                : 7
                : 1618-1624
                Affiliations
                [1] 1Division of Adult and Community Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia;
                [2] 2Department of Urology, University of Kansas Medical Center, Kansas City, Kansas;
                [3] 3Departments of Epidemiology and Medicine, Center for Metabolic Disease Prevention, University of California, Los Angeles, Los Angeles, California.
                Author notes
                Corresponding author: Chaoyang Li, cli@ 123456cdc.gov .
                Article
                1788
                10.2337/dc09-1788
                2890370
                20368409
                6e6a4a43-33f8-4b0c-a9be-42e31d0ef3b6
                © 2010 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 23 September 2009
                : 24 March 2010
                Categories
                Original Research
                Cardiovascular and Metabolic Risk

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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