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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-0970
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 2 712-719
Copyright © 2005 by The Endocrine Society

The Metabolic Syndrome and Smoking in Relation to Hypogonadism in Middle-Aged Men: A Prospective Cohort Study

David E. Laaksonen, Leo Niskanen, Kari Punnonen, Kristiina Nyyssönen, Tomi-Pekka Tuomainen, Veli-Pekka Valkonen and Jukka T. Salonen

Departments of Medicine (D.E.L., L.N.) and Clinical Chemistry (K.P.), Kuopio University Hospital, Kuopio, Finland; Research Institute of Public Health (K.N., T.-P.T., V.-P.V., J.T.S.), Departments of Physiology (D.E.L.) and Public Health and General Practice (J.T.S.), University of Kuopio, FIN-70211 Kuopio, Finland; and Oy Jurilab Ltd. (J.T.S.), FIN-70211 Kuopio, Finland

Address all correspondence and requests for reprints to: Kristiina Nyyssönen, Ph.D., Research Institute of Public Health, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail: Kristiina. Nyyssonen{at}uku.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
In men, hypoandrogenism is associated with features of the metabolic syndrome. It is not known whether men with the metabolic syndrome are at a higher risk of developing hypogonadism. We therefore assessed whether the metabolic syndrome predicts development of hypogonadism 11 yr later in 651 middle-aged Finnish men participating in a population-based cohort study. Men with the metabolic syndrome at baseline as defined by the World Health Organization (n = 114, 20%) had a 2.6-fold increased risk of developing hypogonadism as defined by total testosterone levels less than 11 nmol/liter at the 11-yr follow-up independent of age, smoking, and other potential confounders. Further adjustment for body mass index (OR, 2.0; 95% CI, 1.1–3.8) or baseline total testosterone levels (OR, 1.9; 95% CI, 1.0–3.4) attenuated the association. The association of the metabolic syndrome with hypogonadism as defined by calculated free testosterone levels less than 225 pmol/liter was similar, but weaker. The adjusted decrease in testosterone concentrations during the 11-yr follow-up was also greater in men with than without the metabolic syndrome. Smokers had a nonsignificantly lower risk of developing hypogonadism during follow-up, whereas a decrease in smoking increased the risk of hypogonadism. The metabolic syndrome predisposes to development of hypogonadism in middle-aged men. Prevention of abdominal obesity and the accompanying metabolic syndrome in middle age may decrease the risk of hypogonadism in men, especially in those who quit smoking.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN CROSS-SECTIONAL STUDIES, low levels of total and free testosterone and SHBG in men have consistently been associated not only with type 2 diabetes, but also with visceral obesity, insulin resistance or hyperinsulinemia and dyslipidemia (1, 2, 3, 4, 5, 6, 7, 8), and more recently, with the metabolic syndrome itself (7). 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).

We have recently shown that low concentrations of total testosterone, SHBG, and to a lesser extent calculated free testosterone predict development of the metabolic syndrome in middle-aged men (9). We (9) and others (10, 11, 12) have also shown that low testosterone levels predict development of type 2 diabetes. Little is known, however, about whether the metabolic syndrome itself may predict development of hypogonadism. Because low testosterone levels may have negative metabolic consequences in addition to adverse effects on physical, cognitive, and sexual well-being, a better understanding of the risk factors predisposing to hypogonadism is necessary to improve the treatment and possibly even prevention of hypogonadism.

We (13) and others (14) have recently shown that weight loss and weight maintenance brings about sustained increases in concentrations of free testosterone and, to a lesser extent, total testosterone in men with mainly generalized obesity (14) or abdominal obesity and the metabolic syndrome (13). Moreover, the prevalence of hypogonadism as defined by total testosterone levels or free testosterone levels decreased from 48 and 32% at baseline to 21 and 16%, respectively, after weight loss and 12 months of successful weight maintenance (13).

The mechanisms by which weight loss and weight maintenance may increase testosterone levels and improve hypogonadism are unclear. Obesity dampens LH release (15), at least in severe obesity (16). Overall or abdominal obesity increases glucocorticoid turnover and production (17), which may disturb regulation of the hypothalamic-pituitary-adrenal axis (18, 19) and contribute to mild hypoandrogenism in men. Suppression of insulin levels by diazoxide has reduced testosterone and increased SHBG blood concentrations, and conversely, an acute insulin infusion increases testosterone levels in obese men (20, 21).

Male smokers have consistently had higher testosterone levels than nonsmokers in cross-sectional analyses (22, 23, 24, 25, 26). Smoking is associated with a lower body weight, but possibly increased insulin resistance (27). Complicating the issue, smoking cessation leads to weight gain and increases in abdominal obesity, which could also contribute to decreased testosterone levels.

We therefore examined the role of the metabolic syndrome in the prediction of hypogonadism and decreases in concentrations of total and calculated free testosterone during an 11-yr follow-up in nondiabetic middle-aged men without hypogonadism at baseline. To provide further insight into the role of the metabolic syndrome in the development of hypogonadism, we also carried out analyses taking into account development of the metabolic syndrome during the follow-up and examined the role of individual components of the metabolic syndrome and their changes. A secondary aim was to evaluate the role of smoking in the development of hypogonadism in middle-aged men.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

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 (28). The study population was a random age-stratified sample of men living in Eastern Finland who were 42, 48, 54, or 60 yr old at baseline examinations during 1987–1989, of whom 854 underwent repeat examination during 1998–2001. The Research Ethics Committee of the University of Kuopio and Kuopio University Hospital approved the study. All subjects gave their written informed consent. The study was carried out in accordance with the Declaration of Helsinki. Subject recruitment has been described previously in detail (28). There were 777 men without diabetes at baseline for whom complete information on the metabolic syndrome and sex hormones was available. In analyses with hypogonadism as defined by total testosterone levels less than 11 nmol/liter as an endpoint, 651 men who at baseline were nondiabetic and whose total testosterone levels were at least 11 nmol/liter at baseline were included. In analyses with hypogonadism as defined by calculated free testosterone concentrations less than 225 pmol/liter as an endpoint, 668 men who at baseline were nondiabetic and whose calculated free testosterone concentrations were at least 225 pmol/liter at baseline were included.

Anthropometric and biochemical measurements

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

Blood pressure was measured with a random-zero mercury sphygmomanometer (Hawksley & Sons Ltd., Lansing, UK). The mean of three measurements in supine, one in standing, and two in the sitting position was used as systolic and diastolic blood pressure.

Subjects were asked to fast for 12 h before blood sampling, which was done between 0800 and 1000 h. They were also asked to refrain from smoking for 12 h and from consuming alcohol for 3 d 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 RIA kit (Novo Nordisk, Bagsvaerd, Denmark). High-density lipoprotein (HDL) fractions were separated from fresh serum by combined ultracentrifugation and precipitation. The cholesterol contents of lipoprotein fractions and serum triglycerides were measured enzymatically.

Definition of the metabolic syndrome

The metabolic syndrome was defined according to recommendations by the National Cholesterol Education Program (NCEP) and the World Health Organization (WHO). The metabolic syndrome as defined by the NCEP was three or more of the following: fasting blood glucose levels at least 5.6 mmol/liter (equivalent to plasma glucose levels at least 6.1 mmol/liter (29), serum triglycerides at least 1.7 mmol/liter, serum HDL less than 1.0 mmol/liter, blood pressure at least 130/85 mm Hg or medication, and waist girth greater than 102 cm (30).

The WHO definition of the metabolic syndrome was modified as described before (31, 32) and defined as the presence of hyperinsulinemia (fasting serum insulin concentration in the top 25% of these nondiabetic men), impaired fasting glucose, or diabetes and the presence of at least two of the following: abdominal obesity (waist-to-hip ratio > 0.90 or BMI ≥ 30 kg/m2), dyslipidemia (serum triglycerides ≥ 1.7 mmol/liter or serum HDL cholesterol < 0.9 mmol/liter), or hypertension (blood pressure ≥ 140/90 mm Hg or blood pressure medication) (29). Impaired fasting glucose was defined as a fasting blood glucose 5.6–6.0 mmol/liter, equivalent to a plasma glucose of 6.1–6.9 mmol/liter (29). Diabetes was defined as fasting blood glucose concentration at least 6.1 mmol/liter (equivalent to plasma glucose ≥ 7.0 mmol/liter) or a clinical diagnosis of diabetes with either dietary, oral, or insulin treatment (29). In the present study, men with diabetes at baseline were excluded.

Measurement of sex hormones and SHBG

SHBG was determined at baseline and at the 11-yr follow-up using the 1235 AutoDelfia automatic system based on a time-resolved fluoroimmunoassay (AutoDelfia SHBG, Wallac Co., Turku, Finland). The total testosterone measurements of the baseline samples were performed within 3 months in 2003 using AutoDelfia assay system (Wallac), whereas the 11-yr follow-up samples were analyzed within 3 months in 2001 using the Spectria RIA (Orion Diagnostica, Espoo, Finalnd). The standards for both assays are produced by Orion Diagnostica, and the current assay systems have been found to correlate well with each other (r = 0.82; data provided by the manufacturers). Because there was a systematic difference between the two kits, especially at the low end of values, baseline total testosterone values measured by the Auto-Delfia kit were corrected using the regression equation derived from data provided by the manufacturer (n = 123 men; y = 1.12 x –4.05). The stability of both assay systems was monitored over the analysis period using the data from routine external quality control schemes. At each time point, the samples were assayed in random order in batches of 100 samples.

Free testosterone was calculated as described by Vermeulen (33) using a second-order equation based on SHBG and total testosterone concentrations and assuming an albumin concentration of 43 g/liter. In this cohort, this formula has a correlation of r = 0.98–0.99 with that of Anderson et al. (34) and Nanjee and Wheeler (35). Cutoffs for biochemical hypogonadism were defined as total testosterone less than 11 mmol/liter or calculated free testosterone less than 225 pmol/liter.

Other assessments

Assessments of medical history and medications, smoking, alcohol intake, adult socioeconomic status, and leisure-time physical activity have been described previously (36, 37, 38).

Statistical analyses

Differences in baseline clinical and biochemical characteristics between men who developed hypogonadism based on total testosterone concentrations and those who did not were tested for statistical significance with Student’s t test and, where indicated, the {chi}2 test. To assess the associations of the metabolic syndrome and other variables with hypogonadism, logistic regression was used. To test the association with continuous outcome variables, analysis of covariance models or linear regression was used. The covariates for the logistic and linear regression analyses were forced into the model. Variables are given as means ± SD, except for variables with a skewed distribution (SHBG, total and calculated free testosterone, insulin, triglycerides, and 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 transformed by taking the square root (for SHBG and calculated free testosterone concentrations) or the log. Statistical significance was considered to be P < 0.05. All statistical analyses were performed with SPSS 11.0 for Windows (Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline clinical characteristics

During the 11-yr follow-up, men who developed hypogonadism as defined by total testosterone concentrations less than 11 nmol/liter were heavier, had a larger waist and waist-to-hip ratio, and were more dyslipidemic at baseline (Table 1Go). For differences in blood pressure and blood pressure medication, there was only a nonsignificant trend. Baseline concentrations of serum total and calculated free testosterone and SHBG were also lower in men who developed hypogonadism during follow-up. The prevalence of the metabolic syndrome at baseline was much higher in men who later developed hypogonadism. Men with the metabolic syndrome at baseline already had lower total [WHO, n = 114, 17.4 (5.1) vs. 21.1 (7.2) nmol/liter, P < 0.001; NCEP, n = 51, 18.3 (6.3) vs. 20.6 (7.1) nmol/liter, P = 0.016) and free (WHO, 367 (102) vs. 409 (120) pmol/liter, P < 0.001; NCEP, 381 (108) vs. 404 (118) pmol/liter, P = 0.18) testosterone and SHBG (WHO, 31.4 (11.4) vs. 38.9 (15.5) nmol/liter, P < 0.001; NCEP, 32.5 (67) vs. 37.9 (71) nmol/liter, P = 0.097] levels at baseline than other men.


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  		TABLE 1. Baseline characteristics of men who developed hypogonadism (serum testosterone < 11 nmol/liter) during follow-up and those who did not

 
Metabolic syndrome and hypogonadism

Men with the metabolic syndrome were 2.8–3.2 times more likely to develop hypogonadism as defined by total testosterone levels less than 11 nmol/liter (Table 2Go). Adjustment for potential confounding lifestyle factors (model 2) had little effect on the association. Men with the metabolic syndrome were still more likely to develop hypogonadism after further adjustment for BMI (model 3) or levels of total testosterone (model 4) at baseline.


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  		TABLE 2. OR (95% CI) for developing hypogonadism as defined by total testosterone concentrations less than 11 nmol/liter or calculated free testosterone concentrations less than 160 pmol/liter during the 11-yr follow-up according to the presence of the metabolic syndrome at baseline in men without hypogonadism by the respective definition at baseline

 
There was a nonsignificant trend for men with the metabolic syndrome as defined by the WHO to develop hypogonadism as defined by calculated free testosterone levels less than 225 pmol/liter, but the NCEP definition was not significantly associated with development of hypogonadism as defined by free testosterone levels (Table 2Go).

Metabolic syndrome, change in metabolic status, and hypogonadism

Men who had the metabolic syndrome as defined by the WHO or NCEP both at baseline and at the 11-yr follow-up were about twice as likely to develop hypogonadism as defined by total testosterone concentrations less than 11 nmol/liter during the follow-up after adjustment for age (Fig. 1Go, A and B). Men who developed the metabolic syndrome during the follow-up were also at increased risk. In contrast, those who had the metabolic syndrome at baseline but not at follow-up were not at increased risk.



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  		FIG. 1. OR for developing hypogonadism as defined by total testosterone concentrations less than 11 nmol/liter during the 11-yr follow-up according to the presence of the metabolic syndrome (MSy) at baseline (BL) but not follow-up (FU), at both baseline and follow-up, and at follow-up only. The metabolic syndrome is as defined by the WHO (A) or NCEP (B). For a given category of metabolic status, the OR and 95% CI are displayed after adjustment for the following models: model 1, adjusted for age and the other classifications of metabolic status; model 2, adjusted for model 1 and the presence of cardiovascular disease, smoking (none, 1–19 cigarettes/d, or ≥20 cigarettes/d), alcohol consumption (abstinence and two levels of alcohol intake), sedentary lifestyle, socioeconomic status and changes in smoking, alcohol consumption, and leisure-time physical activity during the follow-up; model 3, adjusted for variables in model 2 and BMI; and model 4, adjusted for variables in model 2 and total testosterone levels at baseline.

 
For hypogonadism as defined by free testosterone levels, men who had the metabolic syndrome as defined by the WHO both at baseline and follow-up were about twice as likely to develop hypogonadism, with some attenuation of the association after adjustment for baseline concentrations of calculated free testosterone (Fig. 2Go, A and B). Having the metabolic syndrome at baseline or developing the metabolic syndrome during follow-up was not associated with a significantly increased risk. In corresponding analyses using the NCEP definition, metabolic status was not significantly associated with development of hypogonadism based on free testosterone levels.



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  		FIG. 2. Or for developing hypogonadism as defined by calculated free testosterone concentrations less than 225 pmol/liter during the 11-yr follow-up according to the presence of the metabolic syndrome at baseline but not follow-up, at both baseline and follow-up, and at follow-up only. The metabolic syndrome is as defined by criteria from the WHO (A) or NCEP (B). Abbreviations and models are as in Fig. 1Go (except for model 4, in which adjustment for free testosterone levels was done).

 
Metabolic syndrome and changes in sex hormones

Total testosterone decreased most in men who had the metabolic syndrome as defined by the NCEP both at baseline and follow-up and in men who developed the metabolic syndrome during follow-up (Table 3Go). Findings for the changes in free testosterone were similar. In contrast, SHBG increased with age in men who did not have the metabolic syndrome at the follow-up but decreased in men who had the metabolic syndrome both at baseline and follow-up or who developed the metabolic syndrome during follow-up.


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  		TABLE 3. Change in the concentrations of total testosterone, calculated free testosterone, and SHBG during the 11-yr follow-up in 651 men with total testosterone levels at least 11 nmol/liter at baseline according to the presence of the metabolic syndrome (WHO definition) at both baseline and follow-up, at baseline but not follow-up, and at follow-up but not baseline

 
Components of the metabolic syndrome and their changes

Of the components of the metabolic syndrome (waist circumference; insulin, glucose, and triglyceride concentrations; systolic blood pressure; and blood pressure medication) at baseline, only baseline insulin concentrations predicted hypogonadism as defined by total testosterone levels. Of the changes in components of the metabolic syndrome, only the increase in waist predicted the decrease in testosterone levels. For a model with baseline total testosterone levels and waist circumference; insulin, glucose, and triglyceride concentrations; systolic blood pressure and their changes during the follow-up in addition to potential confounding factors (age, smoking, alcohol intake, socioeconomic status, presence of cardiovascular disease, sedentary lifestyle, and changes in smoking, alcohol intake, and moderate-to-vigorous physical activity), a 1-SD increase in the log of baseline insulin concentrations [odds ratio (OR), 2.59; 95% confidence interval (CI), 1.12–1.83], a 1-mmol/liter increase in blood glucose concentrations (OR, 1.39; 95% CI, 1.03–1.87), and a 5-cm increase in waist girth (OR, 1.70; 95% CI, 1.34–2.15) predicted hypogonadism as defined by total testosterone levels less than 11 nmol/liter at the 11-yr follow-up. In corresponding analyses, baseline insulin concentrations (for a 1-SD increase in the log-transformed values, OR, 1.91; 95% CI, 0.97–3.74) and baseline HDL concentrations (for a 1-SD increase, OR, 0.65; 95% CI, 0.47–0.89) were associated with hypogonadism as defined by calculated free testosterone levels.

In analyses of individual variables and their changes during the 11-yr follow-up, baseline waist circumference was inversely associated with the change in SHBG concentrations and changes in waist girth were inversely associated with total testosterone and SHBG concentrations (Table 4Go). Glucose concentrations at baseline were negatively associated with the change in total and free testosterone levels, and the changes in glucose levels were inversely associated with total testosterone and SHBG levels. Triglyceride concentrations at baseline and the changes in HDL cholesterol levels during follow-up were positively associated with changes in SHBG. Insulin levels tended to be inversely associated with total and calculated free testosterone concentrations.


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  		TABLE 4. Standardized ß-correlation coefficients for the association of selected variables related to the metabolic syndrome and lifestyle with changes in total testosterone, calculated free testosterone, or SHBG during the 11-yr follow-up in 651 middle-aged men

 
Smoking and its changes

In the entire cohort, smokers had higher total (21.9 ± 7.2 vs. 19.8 ± 6.9 nmol/liter; P < 0.001) and free (427 ± 113 vs. 391 ± 113 pmol/liter; P < 0.001) testosterone levels at baseline than nonsmokers. Smoking at baseline seemed to be inversely associated with a lower risk of hypogonadism as defined by total (at least 20 cigarettes/d vs. nonsmoker, OR, 0.44; 95% CI, 0.16–1.22; trend across smoking categories, P = 0.11) and free testosterone levels (at least 20 cigarettes/d vs. nonsmoker, OR, 0.64; 95% CI, 0.29–1.44), but the association was attenuated even further by adjustment for respective baseline testosterone levels. A decrease in smoking during follow-up was even more clearly associated with the risk for hypogonadism as defined by total (for a 10-cigarette decrease per day, OR, 1.68; 95% CI, 0.97–2.92) and especially free testosterone levels (for a 10-cigarette decrease, OR, 1.80; 95% CI, 1.16–2.79), with only minor attenuation when adjusting further for baseline testosterone levels. Although the increase in risk with decreased cigarette smoking during the follow-up was independent of changes in waist circumference and other characteristics of the metabolic syndrome, it is noteworthy that men who quit smoking during the follow-up had a larger increase in waist girth than men who remained smokers (9.6 ± 0.6 cm vs. 7.3 ± 0.5 cm; P = 0.007). In analyses with total testosterone and free testosterone as continuous outcome variables, the change in the daily number of cigarettes smoked was also consistently positively and independently associated with changes in total and free testosterone levels during follow-up (Table 4Go).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Men with the metabolic syndrome were 2.6–2.9 times more likely to develop hypogonadism as defined by total testosterone levels less than 11 nmol/liter, independently of potential confounding factors such as smoking or alcohol intake. Disturbed insulin, lipid, and glucose metabolism and an increase in waist girth during the follow-up also individually increased the risk of hypogonadism during follow-up.

We also took into account changes in the metabolic status during the follow-up, which is a unique and important feature of this study. Men with the metabolic syndrome both at baseline and follow-up had a 5.7–7.4 times higher risk of developing hypogonadism based on total testosterone levels, even after adjustment for confounding factors such as smoking or alcohol intake. Development of the metabolic syndrome during the follow-up also increased the risk of hypogonadism by approximately 3-fold. In contrast, men who no longer had the metabolic syndrome at follow-up were not at increased risk. These findings have several important implications.

First, the findings suggest that successful treatment of the metabolic syndrome mitigates the risk of hypogonadism associated with it. Second, men without the metabolic syndrome but at risk for it may also benefit from treatment. Third, even if the findings are in part explained by misclassification of the metabolic syndrome at baseline, it is evident that the metabolic syndrome entails a high risk for developing hypogonadism when longstanding and correctly classified.

The association of the metabolic syndrome with incident hypogonadism as defined by calculated free testosterone levels less than 225 pmol/liter was weaker than that based on total testosterone levels, and significant only for the WHO definition of the metabolic syndrome. Lower total testosterone levels are in part because SHBG levels are lower in obesity, and SHBG levels are also reflected in total testosterone levels (16). Even so, there is some evidence that androgens may also mediate some of their effects through SHBG bound to the SHBG receptor (39). The lack of association of hypogonadism based on calculated free testosterone concentrations with the NCEP definition of the metabolic syndrome may be because the NCEP definition is rather poorly associated with insulin resistance (40, 41). The WHO definition, on the other hand, is strongly based on directly or indirectly measured insulin resistance (29, 31, 42).

The association of the metabolic syndrome with hypogonadism was attenuated by adjustment for baseline testosterone levels. This suggests that part of the association may be because baseline concentrations of total testosterone, free testosterone, and SHBG were lower already at baseline in men with the metabolic syndrome. This is unlikely to be the sole explanation of the association, however, because the decrease in total and free testosterone levels was greater in men who had the metabolic syndrome than in those who did not when taking into account baseline testosterone levels.

Increased insulin and glucose concentrations at baseline and an increase in glucose levels and waist girth during follow-up were associated with greater decreases in total testosterone or with the development of hypogonadism as defined by total testosterone levels during follow-up. Even for the decline in free testosterone during follow-up and hypogonadism as defined by calculated free testosterone, abnormal insulin, glucose, and lipid metabolism was a risk factor. The mechanisms by which abdominal obesity or insulin and glucose dysregulation may decrease testosterone levels are unresolved. Possible mechanisms include increased glucocorticoid turnover and production (17) and disturbed regulation of the hypothalamic-pituitary-adrenal axis (18, 19) with possible secondary hypoandrogenism in men. Insulin also appears to regulate testosterone and SHBG production (20, 21). The association of triglyceride and HDL cholesterol levels at baseline and changes in HDL cholesterol levels during the follow-up with hypogonadism and changes in SHBG levels seem unlikely to be direct, but may represent more complex processes related to hepatic and adipose insulin resistance, including ectopic fat distribution.

These findings combined with previous studies (13, 14) showing that weight loss in obese men with generalized obesity or abdominal obesity and the metabolic syndrome increases total and free testosterone levels and corrects hypogonadism (13) over 12 months of weight maintenance indicate that a lifestyle intervention may prevent not only the metabolic syndrome in high risk men (42) but also hypogonadism. Physical activity and cardiorespiratory fitness has appeared to decrease the risk of the metabolic syndrome in this same cohort (38). In the Finnish Diabetes Prevention Study, dietary changes, moderate physical activity, and moderate weight loss have improved components of the metabolic syndrome and decreased the risk for diabetes in persons with impaired glucose tolerance, a condition that overlaps the metabolic syndrome (43).

Smoking seemed to decrease the risk of hypogonadism, but the association was not significant. Decreased cigarette smoking during follow-up increased the risk of hypogonadism, at least as defined by total testosterone levels, and was also associated with larger decreases in testosterone during follow-up. Most cross-sectional studies have shown a positive association of smoking with total or free testosterone levels (22, 23, 24, 25, 26), present already at 12–14 yr of age (26). Of the sparse prospective data available, baseline smoking predicted larger declines in testosterone during a 13-yr follow-up of the Multiple Risk Factor Intervention Trial study (44). On the other hand, smoking cessation decreased testosterone levels in 1104 men followed for idiopathic infertility (24).

The mechanisms by which cigarette smoking may increase testosterone levels are unclear, but nicotine-mediated inhibition of aromatase (45) has been suggested to explain low estrogen and high androgen levels in women smokers (46). Consistent with this hypothesis, the aromatase inhibitor anastrozole has been shown to increase total and bioavailable testosterone levels in elderly men with low testosterone levels (47). The decrease in testosterone and increase in hypogonadism as a result of decreased smoking could also be secondary to weight gain and increased abdominal obesity, but adjustment for waist girth and its changes did not attenuate the relationship. Weight control through diet and exercise should nonetheless be actively encouraged for men who quit smoking, as increased abdominal obesity and its accompanying negative health consequences may partially offset the substantial health gains of smoking cessation.

The strengths of this study include its large, population-based design and detailed assessment of potentially confounding factors and features related to insulin resistance. Moreover, we examined the changes in metabolic status and other risk factors during the follow-up, which provides unique and important insight into the role of the metabolic syndrome in the development of hypogonadism. Measurement of total testosterone with different kits at baseline and follow-up is a shortcoming, but adjustment by linear regression from data comparing the two kits is likely to remove any major systematic bias this might cause. 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 (33, 48). The concept of male andropause is increasingly recognized, but strong epidemiological and clinical evidence for the preferential use of total or free testosterone levels in the diagnosis of hypogonadism does not yet exist. As a consequence, some experts advocate use of cutoffs based on total testosterone concentrations (49), whereas others favor free testosterone levels (50). More epidemiological studies and clinical trials are needed to resolve these issues.

Our results suggest that the metabolic syndrome is not only the consequence of low testosterone levels (9) but also a cause of low total and free testosterone levels and hypogonadism in middle-aged men. Lifestyle interventions including physical activity, diet, and weight loss in men with or at risk for the metabolic syndrome may aid not only in the prevention of diabetes but also in the prevention of hypogonadism. Furthermore, the presence of the metabolic syndrome or abdominal obesity should be assessed in men who are evaluated for hypogonadism.


   Acknowledgments
 
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
 
First Published Online November 9, 2004

Abbreviations: BMI, Body mass index; CI, confidence interval; HDL, high-density lipoprotein; OR, odds ratio.

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 (Grant HL44199).

Received May 21, 2004.

Accepted November 3, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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