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Diabetes Care 27:1036-1041, 2004
© 2004 by the American Diabetes Association, Inc.

Clinical Care/Education/Nutrition
Original Article

Testosterone and Sex Hormone–Binding Globulin Predict the Metabolic Syndrome and Diabetes in Middle-Aged Men

David E. Laaksonen, MD, PHD, MPH1,2, Leo Niskanen, MD, PHD1, Kari Punnonen, MD, PHD3, Kristiina Nyyssönen, PHD4, Tomi-Pekka Tuomainen, MD4, Veli-Pekka Valkonen, MD4, Riitta Salonen, MD, PHD4,5 and Jukka T. Salonen, MD, PHD, MSCPH4,5,6

1 Department of Medicine, Kuopio University Hospital, Kuopio, Finland
2 Department of Physiology, Research Institute of Public Health, University of Kuopio, Kuopio, Finland
3 Department of Clinical Chemistry, Kuopio University Hospital, Kuopio, Finland
4 Research Institute of Public Health, University of Kuopio, Kuopio, Finland
5 Department of Public Health and General Practice, Research Institute of Public Health, University of Kuopio, Kuopio, Finland
6 Inner Savo Health Center, Suonenjoki, Finland

Address correspondence and reprint requests to Professor Jukka T. Salonen, MD, PhD, MScPH, Research Institute of Public Health, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail: jukka.salonen{at}uku.fi


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
OBJECTIVE—In men, hypoandrogenism is associated with features of the metabolic syndrome, but the role of sex hormones in the pathogenesis of the metabolic syndrome and diabetes is not well understood. We assessed the association of low levels of testosterone and sex hormone–binding globulin (SHBG) with the development of the metabolic syndrome and diabetes in men.

RESEARCH DESIGN AND METHODS—Concentrations of SHBG and total and calculated free testosterone and factors related to insulin resistance were determined at baseline in 702 middle-aged Finnish men participating in a population-based cohort study. These men had neither diabetes nor the metabolic syndrome.

RESULTS—After 11 years of follow-up, 147 men had developed the metabolic syndrome (National Cholesterol Education Program criteria) and 57 men diabetes. Men with total testosterone, calculated free testosterone, and SHBG levels in the lower fourth had a severalfold increased risk of developing the metabolic syndrome (odds ratio [OR] 2.3, 95% CI 1.5–3.4; 1.7, 1.2–2.5; and 2.8, 1.9–4.1, respectively) and diabetes (2.3, 1.3–4.1; 1.7, 0.9–3.0; and 4.3, 2.4–7.7, respectively) after adjustment for age. Adjustment for potential confounders such as cardiovascular disease, smoking, alcohol intake, and socioeconomic status did not alter the associations. Factors related to insulin resistance attenuated the associations, but they remained significant, except for free testosterone.

CONCLUSIONS—Low total testosterone and SHBG levels independently predict development of the metabolic syndrome and diabetes in middle-aged men. Thus, hypoandrogenism is an early marker for disturbances in insulin and glucose metabolism that may progress to the metabolic syndrome or frank diabetes and may contribute to their pathogenesis.

Abbreviations: NCEP, National Cholesterol Education Program • SHBG, sex hormone–binding globulin • WHR, waist-to-hip ratio


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
In cross-sectional studies, low levels of total and free testosterone and sex hormone–binding globulin (SHBG) in men have consistently been associated not only with type 2 diabetes, but also with visceral obesity, insulin resistance or hyperinsulinemia, dyslipidemia (1–7), and, more recently, the metabolic syndrome itself (6). The association of testosterone and SHBG with an altered lipid profile is partly secondary to abdominal fat accumulation, but there also appears to be an independent relationship between low levels of testosterone and hyperinsulinemia (4) and dyslipidemia (8). Low levels of testosterone have also predicted worsening abdominal obesity (9).

Testosterone itself may have a central or permissive role in the pathogenesis of the metabolic syndrome and type 2 diabetes by increasing skeletal muscle tissue and decreasing abdominal obesity and nonesterified fatty acids, consequently improving insulin sensitivity (10). Overall or abdominal obesity increases glucocorticoid turnover and production, which disturbs regulation of the hypothalamic-pituitary-adrenal axis (11,12) and may contribute to mild hypoandrogenism in men. An imbalance between levels of testosterone and its metabolite dihydrotestosterone could also contribute (13).

Orchiectomized rats show marked insulin resistance, confined to peripheral tissues, and these metabolic abnormalities are corrected by physiological doses of testosterone (14). In relatively small randomized controlled trials, androgen treatment has improved insulin sensitivity in middle-aged abdominally obese men (10,15), although findings have not been completely consistent (16). Diabetes or the metabolic syndrome as an end point has not been investigated.

Epidemiological evidence suggests that low levels of testosterone or SHBG may predispose to type 2 diabetes, but the few prospective nested case-control (17) or cohort (18,19) studies reported have not controlled adequately for potentially confounding factors such as fasting glucose and insulin levels (18,19), were not population-based (17,19), or used self-reported diabetes as an end point (18). No studies with the metabolic syndrome as an end point have to our knowledge been published. We therefore examined the role of total and free testosterone and SHBG in the prediction of the metabolic syndrome and diabetes in 702 middle-aged men who at baseline had neither the metabolic syndrome nor diabetes.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
The subjects were participants of the Kuopio Ischemic Heart Disease Risk Factor Study, which is an ongoing prospective population-based study designed to investigate risk factors for chronic diseases, including type 2 diabetes and cardiovascular diseases, among middle-aged men (20). The study population was a random age-stratified sample of men living in Eastern Finland who were 42, 48, 54, or 60 years old at baseline examinations in 1987–1989, of whom 854 underwent repeat examination in 1998–2001. The Research Ethics Committee of the University of Kuopio and Kuopio University Hospital approved the study. All study subjects gave their written informed consent. The recruitment of the subjects has been previously described in detail (20). The present study included 702 men who at baseline did not have the metabolic syndrome or diabetes and who had complete data on sex hormones.

Anthropometric and biochemical measurements
BMI was computed as the ratio of weight to the square of height (kg/m2). Waist girth was taken as the average of two measurements taken after inspiration and expiration at the midpoint between the lowest rib and the iliac crest. Waist-to-hip ratio (WHR) was defined as the ratio of waist girth to the circumference of the hips measured at the trochanter major.

Blood pressure was measured with a random zero mercury sphygmomanometer (Hawksley, West Sussex, U.K.). The measurement protocol included three measurements in supine, one in standing, and two in a sitting position with 5-min intervals. The mean of all six measurements was used as systolic and diastolic blood pressure.

Subjects were asked to fast for 12 h before blood sampling, which was done between 8:00 and 10:00 A.M. They were also asked to refrain from smoking for 12 h and from consuming alcohol for 3 days before blood draws. Blood glucose was measured using a glucose dehydrogenase method after precipitation of proteins by trichloroacetic acid. The serum samples for insulin determination were stored frozen at –80°C. Serum insulin was determined with a Novo Biolabs radioimmunoassay kit (Novo Nordisk, Bagsvaerd, Denmark). HDL fractions were separated from fresh serum by combined ultracentrifugation and precipitation. The cholesterol contents of lipoprotein fractions and serum triglycerides were measured enzymatically.

Measurement of sex hormones and SHBG
SHBG was determined using the 1235 AutoDELFIA automatic system based on a time-resolved fluoroimmunoassay (AutoDELFIA SHBG; Wallac, Turku, Finland). Total testosterone levels were measured with the AutoDELFIA Testosterone kit (Wallac). Non–SHBG-bound free testosterone (fT) was calculated as follows (21,22): proportion (%) of fT (fT%) = 2.28 – 1.38 x log(SHBG nmol/1/10), and serum fT (pmol/l) = fT% x T (nmol/l) x 10.

In this cohort, this formula has a correlation of r = 0.998 with that of Nanjee and Wheeler (23). Cutoffs for biochemical hypogonadism were defined as total testosterone <11 nmol/l or calculated free testosterone <160 pmol/l.

Definition of the metabolic syndrome and diabetes
The metabolic syndrome as defined by the National Cholesterol Education Program (NCEP) was three or more of the following: fasting blood glucose levels >=5.6 mmol/l (equivalent to plasma glucose levels >=6.1 mmol/l [24]), serum triglycerides >=1.7 mmol/l, serum HDL <1.0 mmol/l, blood pressure >=130/85 mmHg, and waist girth >102 cm (25). Diabetes at baseline and follow-up was defined as a fasting blood glucose concentration >=6.1 mmol/l (equivalent to plasma glucose >=7.0 mmol/l) or a clinical diagnosis of diabetes with treatment by diet, oral medications, or insulin (24).

Other assessments
Assessments of medical history and medications, smoking, alcohol consumption, adult socioeconomic status, and moderate-to-vigorous leisure-time physical activity have been described previously (26–28).

Statistical analysis
Differences in baseline clinical and biochemical characteristics between men who developed diabetes and those who did not were tested for statistical significance with the Student’s t test and, where indicated, the {chi}2 test. To assess the associations of testosterone and SHBG with diabetes, concentrations of testosterone and SHBG were dichotomized by the lower quartile and entered into logistic regression models adjusting for 1) age; 2) age, smoking, alcohol intake, adult socioeconomic status, leisure-time physical activity, and presence of cardiovascular disease; 3) variables in model 2 and BMI; 4) variables in model 2 and waist (for the metabolic syndrome) or WHR (for diabetes); 5) concentrations of insulin, glucose, and triglycerides; and 6) systolic blood pressure and use of blood pressure medication. Waist girth was used as a covariate in models with the metabolic syndrome as an end point and the WHR in models with diabetes as an end point, because these respective measures were stronger predictors than the other measures of obesity and fat distribution. Clinically used cutoffs for hypogonadism (total testosterone <11 nmol/l, calculated free testosterone <160 pmol/l) were similarly analyzed. To assess the association of low testosterone levels with a three-variable metabolic outcome (neither the metabolic syndrome nor diabetes, either the metabolic syndrome or diabetes, or both the metabolic syndrome and diabetes at the 11-year follow-up), polynomial logistic regression was used. The covariates for the logistic regression models were forced into the model.

Variables are given as means ± SD, except for variables with a skewed distribution (SHBG, insulin, triglycerides, physical activity), which are given as medians and interquartile ranges, and proportions, which are given as percentages. In analyses using continuous variables, these variables were log transformed. Statistical significance was considered to be P < 0.05. All statistical analyses were performed with SPSS 11.0 for Windows (SPSS, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
Baseline clinical characteristics
Men who developed the metabolic syndrome or diabetes during the 11-year follow-up were heavier, had a larger waist and higher WHR, had higher glucose and insulin concentrations, and were more hypertensive and dyslipidemic at baseline (Table 1). Baseline concentrations of serum total and calculated free testosterone and SHBG were lower in men who developed the metabolic syndrome or diabetes during follow-up, but for calculated free testosterone, the difference was statistically significant only for men who developed the metabolic syndrome. Men who developed diabetes more often had hypogonadism as defined by low total testosterone levels, but the proportion of men with hypogonadism, as defined by calculated free testosterone levels, did not differ between men who developed or did not develop diabetes.


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  		Table 1— Baseline characteristics of the entire cohort, who did not have the metabolic syndrome or diabetes at baseline, and men who developed the metabolic syndrome or diabetes during follow-up

 
Testosterone, SHBG, and development of the metabolic syndrome and diabetes
After adjustment for age, men with concentrations of total testosterone, calculated free testosterone, or SHBG in the lower fourth were 1.7–2.8 times more likely to develop the metabolic syndrome than other men during the 11-year follow-up (Table 2). Adjustment for potentially confounding factors such as smoking, alcohol intake, socioeconomic status, cardiovascular disease, and amount of moderate- or vigorous-intensity leisure-time physical activity (model 2) had little effect on the association. After further adjustment for BMI, the predictive value of low testosterone and SHBG concentrations was attenuated. After further adjustment for features related to insulin resistance (model 4), new cases of the metabolic syndrome were still 1.7-fold more common in men with low levels of total testosterone and SHBG, but the association of calculated free testosterone levels only tended to be significant. Other significant predictors of the metabolic syndrome were triglycerides (e.g., for the model with total testosterone, for a 1-SD log change, odds ratio [OR] 3.3, 95% CI 2.0–5.4), waist (1-SD change, 2.2, 1.7–2.8), systolic blood pressure (1-SD change, 1.3, 1.0–1.6), blood glucose (1-SD change, 1.3, 1.0–1.6), and smoking (>=20 cigarettes/day versus none, 2.3, 1.2–4.3). The association of insulin concentrations with subsequent development of the metabolic syndrome was not significant in model 4 but became significant when omitting waist circumference from the model (not shown). The presence or absence of testosterone or SHBG concentrations in the model did not materially influence the association of insulin or the other variables with development of the metabolic syndrome. The association of hypogonadism as defined by total testosterone <11 nmol/l or calculated free testosterone <160 pmol/l with the development of the metabolic syndrome was not significant.


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  		Table 2— ORs for developing the metabolic syndrome or diabetes during the 11-year follow-up for men in the lowest fourth of concentrations of serum total and calculated free testosterone and SHBG at baseline in 702 men initially without the metabolic syndrome or diabetes

 
Likewise, adjusting for age concentrations of total testosterone, calculated free testosterone, or SHBG in the lower fourth increased the risk of incident diabetes by 1.7- to 4.3-fold, although the association with calculated free testosterone did not reach statistical significance (Table 2). Adjusting for potentially confounding factors (model 2) had little effect on the association. After further adjustment for BMI (model 3) or for other features related to the metabolic syndrome (model 4), the associations were attenuated. Other significant predictors of incident diabetes were blood glucose (e.g., for the model with total testosterone, for a 1-SD change, OR 7.8, 95% CI 3.6–16), WHR (1-SD change, 1.6, 1.1–2.2), triglycerides (1-SD change, 2.2, 1.1–4.4), and insulin (1-SD log change, 2.3, 1.0–5.5). The association of hypogonadism as defined by total testosterone <11 nmol/l with incident diabetes was qualitatively similar as that for total testosterone dichotomized by the lower quartile when using the models shown in Table 2 (model 2, OR 2.94, 95% CI 1.11–7.75; model 3, 2.40, 0.89–6.44; model 4, 2.70, 0.92–7.91), although the association only tended to be significant for models 3 and 4. The association of hypogonadism as defined by calculated free testosterone <160 pmol/l with incident diabetes was not significant (not shown).

We also examined the association of low total testosterone levels at baseline with the metabolic outcome at the 11-year follow-up (neither the metabolic syndrome nor diabetes, either the metabolic syndrome or diabetes, or both the metabolic syndrome and diabetes; Fig. 1). In these analyses, low total testosterone levels at baseline were associated with a worse outcome at 11 years. Men who developed both the metabolic syndrome and diabetes were especially likely to have had low testosterone levels already at baseline.



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  		Figure 1— Percentage of men with total testosterone levels at baseline in the lowest fourth (<15.6 nmol/l) according to metabolic status at the 11-year follow-up. DM, diabetes; MSy, metabolic syndrome. P = 0.005 for the overall association of baseline testosterone levels <15.6 nmol/l with the metabolic status (neither the metabolic syndrome nor diabetes, either the metabolic syndrome or diabetes, or both the metabolic syndrome and diabetes) at the 11-year follow-up after adjustment for age and baseline cardiovascular disease, smoking, alcohol intake, socioeconomic status, WHR, insulin and glucose concentrations, triglyceride levels, systolic blood pressure, and blood pressure medication.

 

   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
This is the first study to show that total testosterone and SHBG concentrations in the low-normal range predict not only diabetes, but also the development of the metabolic syndrome as defined by the NCEP in middle-aged men, independently of BMI and other factors related to insulin resistance. Calculated free testosterone levels likewise predicted the metabolic syndrome, but not independently of BMI.

Men with total testosterone levels in the lower fourth were 2.3-fold more likely to develop the metabolic syndrome or diabetes than other men. Importantly, the increase in likelihood was nearly two times greater even after adjusting for baseline abdominal obesity and insulin and glucose levels in addition to other factors related to insulin resistance. Accordingly, men with hypogonadism based on a total testosterone concentration <11 nmol/l had an increased risk for incident diabetes. A few previous studies have assessed the prospective association of testosterone with the incidence of type 2 diabetes (17–19). In a prospective nested case-control study from the Multiple Risk Factor Intervention Trial, total and free testosterone levels were lower in the 176 men who developed diabetes than in the 176 control men (17). Even after matching for fasting glucose levels and BMI, free testosterone, but not total testosterone, was still associated with incident diabetes in multivariate models including glucose, BMI, and insulin (17). In that study, free testosterone concentrations were measured with a double antibody system instead of equilibrium dialysis. This antibody method may be influenced by SHBG concentrations (29). In a Massachusetts population-based study, low levels of centrifugal ultrafiltration-measured free testosterone, but not total testosterone, were determinants of incident type 2 diabetes 7–10 years later in 1,156 men independently of BMI and the presence of hypertension and cardiovascular disease (18). However, diabetes was diagnosed based on self-report or the use of insulin, and glucose and insulin levels were not measured. In 294 middle-aged and elderly men, total testosterone levels were lower in the 26 men who developed diabetes during the 8-year follow-up, but adjustment was made for only age, BMI, and systolic blood pressure (19). To our knowledge, the association of testosterone levels with the metabolic syndrome as defined by the NCEP has not been previously reported.

Testosterone itself may contribute to the pathogenesis of insulin resistance and diabetes by increasing skeletal muscle mass at the expense of fat mass and decreasing abdominal obesity through inhibition of lipoprotein lipase activity (10). Low levels of free or total testosterone have been consistently associated with overall or abdominal obesity, insulin resistance or hyperinsulinemia, hyperglycemia, and dyslipidemia (1–7). The associations have in some studies persisted even after adjustment for adiposity (4,6,8). Furthermore, low testosterone levels have predicted an increase in visceral fat during follow-up (9).

On the other hand, overall or abdominal obesity may decrease free and total testosterone levels. Consistent with abdominal or overall obesity playing a contributing role, we found that the association of free testosterone with diabetes was abolished and the association of total testosterone attenuated after adjustment for BMI, WHR, and other factors related to insulin resistance. The effect of weight loss on free and total testosterone and SHBG has been inconsistent, but overall or abdominal obesity increases glucocorticoid turnover and production (11,12), resulting in abnormal control of hypothalamic-pituitary-adrenal axis and possibly mild hypoandrogenism in men. Furthermore, obesity is associated with abnormally increased expression and activity of enzyme 11ß-hydroxysteroid dehydogenase type 1 in adipose tissue (30–32). 11ß-Hydroxysteroid dehydogenase type 1 determines local glucocorticoid concentrations through interconversion of cortisol and its inactive counterpart cortisone.

In multivariate analyses including BMI, calculated free testosterone did not predict development of the metabolic syndrome or diabetes, although our study is underpowered to rule out a small increase in risk with mildly decreased free testosterone levels. These findings agree with previous studies (18). Because total testosterone is also a function of SHBG, it may be that SHBG may be more important than testosterone itself, either as a risk marker for or as a contributor to the development of the metabolic syndrome or diabetes.

SHBG has been previously shown to be inversely related to components related to insulin resistance (3,5). Low SHBG concentrations have also predicted development of diabetes (18). Inhibition of insulin secretion by diazoxide leads to increased SHBG levels (33), suggesting that SHBG production in the liver is regulated by insulin. Furthermore, in cell cultures, insulin inhibits, whereas testosterone stimulates, SHBG production (34). Androgens may also mediate some of their effects through SHBG bound to the SHBG receptor (35). Regardless of the mechanism, SHBG seems at the very least to be a good risk marker for the metabolic syndrome or diabetes.

Our findings raise the following question: Can lifestyle or pharmacological intervention in overweight men at risk for type 2 diabetes and who have relatively low testosterone levels prevent or delay development of the metabolic syndrome or diabetes? We (36) and others (37) have found that weight loss and successful weight maintenance increase free and total testosterone and SHBG in men with general obesity (37) or abdominal obesity and the metabolic syndrome (36). Although effects on sex hormones were not reported, recent evidence from the Finnish Diabetes Prevention Study and U.S. Diabetes Prevention Program suggest that even relatively modest lifestyle interventions can have a major impact in decreasing the risk for diabetes in glucose-intolerant individuals (38,39). Furthermore, some studies have found that administration of testosterone improves insulin sensitivity, possibly via improvements in body composition and a reduction in circulating nonesterified fatty acids (10,15).

The strengths of this study include its large population-based design and detailed assessment of features related to insulin resistance. We calculated free testosterone levels rather than directly determining bioavailable testosterone, but calculation of free testosterone from total testosterone and SHBG seems to be valid in healthy individuals and in several pathological conditions (22,29).

Low total testosterone and SHBG levels predict development of the metabolic syndrome and diabetes in middle-aged men, independently of other factors related to insulin resistance. Calculated free testosterone concentrations also identify men at risk for the metabolic syndrome, but not independently of obesity or insulin resistance. Thus, hypoandrogenism is an early marker for disturbances in insulin and glucose metabolism that may progress to the metabolic syndrome and frank diabetes and may contribute to their pathogeneses.


   Acknowledgments
 
The Kuopio Ischemic Heart Disease Risk Factor Study was supported by grants from the Academy of Finland (grants 41471, 1041086, and 2041022), the Ministry of Education of Finland (grants 167/722/96, 157/722/97, and 156/722/98), and the National Heart, Lung and Blood Institute in the U.S. (grant HL44199).

We thank the staff of the Research Institute of Public Health, University of Kuopio, and Kuopio Research Institute of Exercise Medicine for data collection in the Kuopio Ischemic Heart Disease Risk Factor Study.


   Footnotes
 
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Received for publication October 26, 2003. Accepted for publication February 3, 2004.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

  1. Phillips GB: Relationship between serum sex hormones and glucose, insulin and lipid abnormalities in men with myocardial infarction. Proc Natl Acad Sci U S A 74:1729–1733, 1977[Abstract/Free Full Text]
  2. Phillips GB: Relationship between serum sex hormones and the glucose-insulin-lipid defect in men with obesity. Metabolism 42:116–120, 1993[Medline]
  3. Haffner SM, Karhapaa P, Mykkanen L, Laakso M: Insulin resistance, body fat distribution, and sex hormones in men. Diabetes 43:212–219, 1994[Abstract]
  4. Haffner SM, Valdez RA, Mykkanen L, Stern MP, Katz MS: Decreased testosterone and dehydroepiandrosterone sulfate concentrations are associated with increased insulin and glucose concentrations in nondiabetic men. Metabolism 43:599–603, 1994[Medline]
  5. Haffner SM: Sex hormones, obesity, fat distribution, type 2 diabetes and insulin resistance: epidemiological and clinical correlation. Int J Obes Relat Metab Disord 24(Suppl. 2):S56–S58, 2000
  6. Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen T-P, Salonen R, Rauramaa R, Salonen JT: Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol 149:601–608, 2003[Abstract]
  7. Phillips GB, Jing T, Heymsfield SB: Relationships in men of sex hormones, insulin, adiposity, and risk factors for myocardial infarction. Metabolism 52:784–790, 2003[Medline]
  8. Haffner SM, Mykkanen L, Valdez RA, Katz MS: Relationship of sex hormones to lipids and lipoproteins in nondiabetic men. J Clin Endocrinol Metab 77:1610–1615, 1993[Abstract]
  9. Tsai EC, Boyko EJ, Leonetti DL, Fujimoto WY: Low serum testosterone level as a predictor of increased visceral fat in Japanese-American men. Int J Obes Relat Metab Disord 24:485–491, 2000[Medline]
  10. Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, Bjorntorp P: The effects of testosterone treat-ment on body composition and metabolism in middle-aged obese men. Int J Obes Relat Metab Disord 16:991–997, 1992[Medline]
  11. Walker BR: Steroid metabolism in metabolic syndrome X. Best Pract Res Clin Endocrinol Metab 15:111–122, 2001[Medline]
  12. Rask E, Olsson T, Soderberg S, Andrew R, Livingstone DE, Johnson O, Walker BR: Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 86:1418–1421, 2001[Abstract/Free Full Text]
  13. Matilainen V, Koskela P, Keinanen-Kiukaanniemi S: Early androgenetic alopecia as a marker of insulin resistance (Letter). Lancet 356:1165–1166, 2000[Medline]
  14. Holmang A, Bjorntorp P: The effects of testosterone on insulin sensitivity in male rats. Acta Physiol Scand 146:505–510, 1992[Medline]
  15. Marin P: Testosterone and regional fat distribution. Obes Res 3(Suppl. 4):609S–612S, 1995
  16. Liu PY, Wishart SM, Celermajer DS, Jimenez M, Pierro ID, Conway AJ, Handelsman DJ: Do reproductive hormones modify insulin sensitivity and metabolism in older men? A randomized, placebo-controlled clinical trial of recombinant human chorionic gonadotropin. Eur J Endocrinol 148:55–66, 2003[Abstract]
  17. Haffner SM, Shaten J, Stern MP, Smith GD, Kuller L: Low levels of sex hormone-binding globulin and testosterone predict the development of non-insulin-dependent diabetes mellitus in men: MRFIT Research Group: Multiple Risk Factor Intervention Trial. Am J Epidemiol 143:889–897, 1996[Abstract/Free Full Text]
  18. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB: Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts Male Aging Study. Diabetes Care 23:490–494, 2000[Abstract]
  19. Oh JY, Barrett-Connor E, Wedick NM, Wingard DL: Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo Study. Diabetes Care 25:55–60, 2002[Abstract/Free Full Text]
  20. Salonen JT: Is there a continuing need for longitudinal epidemiologic research? The Kuopio Ischaemic Heart Disease Risk Factor Study. Ann Clin Res 20:46–50, 1988[Medline]
  21. Anderson DC, Thorne MO, Fisher RA, Woodham JP, Goble HL, Besser CM: Effects of hormonal treatment on plasma unbound androgen levels in hirsute women (Abstract). Acta Endocrinol (Copenh) 90:224, 1975
  22. Wheeler MJ: The determination of bio-available testosterone. Ann Clin Biochem 32:345–357, 1995[Medline]
  23. Nanjee MN, Wheeler MJ: Plasma free testosterone: is an index sufficient? Ann Clin Biochem 22:387–390, 1985[Medline]
  24. Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus: provisional report of a WHO consultation. Diabet Med 15:539–553, 1998[Medline]
  25. National Cholesterol Education Program: Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486–2497, 2001[Free Full Text]
  26. Lakka TA, Venäläinen JM, Rauramaa R, Salonen R, Tuomilehto J, Salonen JT: Relation of leisure-time physical activity and cardiorespiratory fitness to the risk of acute myocardial infarction. N Engl J Med 330:1549–1554, 1994[Abstract/Free Full Text]
  27. Lynch JW, Kaplan GA, Cohen RD, Kauhanen J, Wilson TW, Smith NL, Salonen JT: Childhood and adult socioeconomic status as predictors of mortality in Finland. Lancet 343:524–527, 1994[Medline]
  28. Laaksonen DE, Lakka HM, Salonen JT, Niskanen LK, Rauramaa R, Lakka TA: Low levels of leisure-time physical activity and cardiorespiratory fitness predict development of the metabolic syndrome. Diabetes Care 25:1612–1618, 2002[Abstract/Free Full Text]
  29. Vermeulen A, Verdonck L, Kaufman JM: A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 84:3666–3672, 1999[Abstract/Free Full Text]
  30. Davani B, Khan A, Hult M, Martensson E, Okret S, Efendic S, Jornvall H, Oppermann UC: Type 1 11beta-hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets. J Biol Chem 275:34841–34844, 2000[Abstract/Free Full Text]
  31. Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS: A transgenic model of visceral obesity and the metabolic syndrome. Science 294:2166–2170, 2001[Abstract/Free Full Text]
  32. Dotsch J, Rascher W: The role of 11beta-hydroxysteroid dehydrogenase activity in the metabolic syndrome: lessons learned from the animal model. Eur J Endocrinol 146:603–605, 2002[Medline]
  33. Pasquali R, Casimirri F, De Iasio R, Mesini P, Boschi S, Chierici R, Flamia R, Biscotti M, Vicennati V: Insulin regulates testosterone and sex hormone-binding globulin concentrations in adult normal weight and obese men. J Clin Endocrinol Metab 80:654–658, 1995[Abstract]
  34. Plymate SR, Matej LA, Jones RE, Friedl KE: Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab 67:460–464, 1988[Abstract]
  35. Heinlein CA, Chang C: The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol Endocrinol 16:2181–2187, 2002[Abstract/Free Full Text]
  36. Niskanen L, Laaksonen DE, Punnonen K, Mustajoki P, Kaukua J, Rissanen A: Changes in sex hormone binding globulin and testosterone during weight loss and weight maintenance in abdominally obese men with the metabolic syndrome. Diabetes Obes Metab In press
  37. Kaukua J, Pekkarinen T, Sane T, Mustajoki P: Sex hormones and sexual function in obese men losing weight. Obes Res 11:689–694, 2003[Medline]
  38. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343–1350, 2001[Abstract/Free Full Text]
  39. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403, 2002[Abstract/Free Full Text]

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