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American Journal of Epidemiology Advance Access originally published online on September 12, 2006
American Journal of Epidemiology 2006 164(11):1094-1102; doi:10.1093/aje/kwj320
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American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

ORIGINAL CONTRIBUTIONS

The Metabolic Syndrome Is Associated with Reduced Risk of Prostate Cancer

Aaron J. Tande1, Elizabeth A. Platz2 and Aaron R. Folsom1

1 Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN
2 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Correspondence to Dr. Aaron R. Folsom, Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, 1300 South 2nd Street, Suite 300, Minneapolis, MN 55454 (e-mail: folsom{at}epi.umn.edu).

Received for publication January 27, 2006. Accepted for publication April 20, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Diabetes is associated with reduced risk of prostate cancer, but whether the metabolic syndrome is associated with prostate cancer is not established. The authors assessed this association in the Atherosclerosis Risk in Communities (ARIC) Study, comprising 6,429 men in four US communities initially with no history of cancer and aged 45–64 years. Metabolic syndrome and other risk factors were assessed in 1987–1989. Follow-up for prostate cancer incidence (n = 385 through 2000) was accomplished through cancer registry and hospital linkage. At baseline, 1,871 men (29.5%) had the metabolic syndrome. After the authors adjusted for other risk factors, men with the metabolic syndrome (≥3 components) were significantly less likely to develop prostate cancer (relative risk = 0.77, 95% confidence interval: 0.60, 0.98) than men without the metabolic syndrome. Diabetes was negatively associated with prostate cancer, although the confidence interval included 1 (relative risk = 0.73, 95% confidence interval: 0.51, 1.05). When diabetic participants were excluded, the inverse association between metabolic syndrome and prostate cancer incidence was slightly strengthened. In this study, the metabolic syndrome was associated with decreased prostate cancer incidence. The authors hypothesize that this finding reflects a decrease in bioavailable (free and albumin-bound) testosterone with the metabolic syndrome and a concomitant reduction in prostate cancer risk.

diabetes mellitus; metabolic syndrome X; prospective studies; prostatic neoplasms

Abbreviations: ARIC, Atherosclerosis Risk in Communities


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The metabolic syndrome (or insulin resistance syndrome) is a cluster of risk factors associated with increased risk of cardiovascular disease and diabetes. Components include insulin resistance, dyslipidemia, elevated blood pressure, abdominal obesity, and proinflammatory and prothrombotic states (1). The prevalence of the metabolic syndrome was 26.7 percent among US adults in the 1999–2000 National Health and Nutrition Examination Survey, and it appears that it may continue to increase (2). Although the primary outcome of the metabolic syndrome is cardiovascular disease, it has been proposed as a risk factor for increased prostate cancer incidence (3, 4). On the other hand, diabetes has repeatedly been observed to be associated with reduced risk of prostate cancer, including in large prospective cohort studies (5, 6). The purpose of this study was to evaluate whether there is any association between the metabolic syndrome and incident prostate cancer using data from the Atherosclerosis Risk in Communities (ARIC) Study, a multicenter prospective cohort.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
The ARIC Study was funded by the National Heart, Lung, and Blood Institute and the cancer component by the National Cancer Institute. National Heart, Lung, and Blood Institute staff helped design the ARIC Study and approved this manuscript. The ARIC Study protocol was approved by the institutional review board of each participating university.

Population
The ARIC Study is a cohort study of cardiovascular disease in four US communities. Between 1987 and 1989, 7,082 men and 8,710 women aged 45–64 years were recruited from Forsyth County, North Carolina; Jackson, Mississippi (African Americans only); suburban Minneapolis, Minnesota; and Washington County, Maryland. There was a 46 percent response in the Jackson cohort and a 65–67 percent response in the other three cohorts. After written informed consent was obtained, participants underwent a baseline clinical examination (visit 1). Follow-up examinations of the cohort occurred three times, at intervals of roughly 3 years. The response rates for visits 2 (1990–1992), 3 (1993–1995), and 4 (1996–1998) were 93 percent, 86 percent, and 80 percent, respectively. Participants completed annual telephone interviews between visits and following visit 4. Between 1994 and 1996, 90 percent of the cohort completed a telephone interview that included history of cancer in first-degree relatives and recall of nonsteroidal antiinflammatory drug or aspirin use at ARIC Study visit 1.

Measurements
Risk factors examined in these analyses were ascertained at visit 1 or during the 1994–1996 medical history interview. Data collection and quality control methods are described in detail in the ARIC Study manuals of operation (7).

Anthropometrics were assessed with the subject wearing a scrub suit and no shoes. Body weight was measured by using a calibrated scale (model #437; Detecto, Jericho, New York). Standing height was measured with a vertical metal ruler. Body mass index was also calculated (weight in kilograms/height in meters squared). Waist (at the level of the umbilicus) and hips (maximum girth) were measured once with an anthropometric tape. The ratio of waist/hip was calculated. Anthropometric measures in the ARIC Study have been shown to be reliable (8).

After subjects rested for 5 minutes, their sitting blood pressure was taken three times with a random zero sphygmomanometer. The second and third readings were averaged.

Participants were asked to fast for 12 hours prior to the clinical examination. Fasting blood was drawn from an antecubital vein of seated participants into vacuum tubes containing ethylenediaminetetraacetic acid (for measurement of lipids) or a serum separator gel (glucose and insulin). Serum and plasma aliquots were stored at –70°C and were shipped to central laboratories for analyses. Total triglycerides were measured by enzymatic methods, and high density lipoprotein cholesterol was measured after dextran-magnesium precipitation. Serum glucose was assayed by a hexokinase/glucose-6-phosphate dehydrogenase method, and serum insulin was measured by radioimmunoassay (123Insulin Kit; Cambridge Medical Diagnostics, Inc., Billerica, Massachusetts). Fasting hyperglycemia was defined as a fasting glucose level of ≥110 mg/dl; prevalent diabetes mellitus was defined as a fasting glucose level of ≥126 mg/dl (9) or a self-reported history of or treatment for diabetes.

Information assessed by questionnaire included years of education, smoking status (current, former, never), number of cigarettes smoked per day and duration of smoking, alcohol drinking status (current, former, never), and usual consumption of wine, beer, and hard liquor. Pack-years of cigarette smoking and usual intake of alcohol (grams per day) were calculated. Usual food intake during the previous year was collected by using a validated 61-item semiquantitative food frequency questionnaire (10). Physical activity was assessed by the Baecke Questionnaire (11, 12). Three indices of physical activity were derived, encompassing occupational activity, leisure-time participation in sports, and nonsport leisure activity. Participants were asked to bring to the clinic all medications taken during the 2 weeks prior to the examination.

Participants were categorized according to the number of components of the Adult Treatment Panel III definition of the metabolic syndrome (1) present at baseline and were classified as having the metabolic syndrome if they had three or more of the following components: 1) high blood pressure (≥130 mmHg systolic or ≥85 mmHg diastolic or self-reported antihypertensive medication use); 2) central obesity (waist circumference ≥102 cm in men or ≥88 cm in women); 3) high triglyceride level (≥150 mg/dl); 4) low high density lipoprotein cholesterol (<40 mg/dl); 5) or fasting hyperglycemia (≥110 mg/dl)/diabetes.

Prostate cancer ascertainment
During each clinical examination, participants were asked whether they had ever been diagnosed with cancer. Among men not reporting baseline cancer, incident cancers were identified between January 1, 1987, and December 31, 2000. Minneapolis, Forsyth County, and Washington County had well-established state or county cancer registries between 1987 and 2000. After 1995, a state registry also covered Jackson. Cohort identifiers were linked to each cancer registry's database to obtain data regarding cancer occurrence, primary site, and diagnosis date. The Mississippi registry reported 90 percent completeness in 1999 and 96 percent in 2000. The Minnesota Cancer Surveillance System had a "gold standard" rating, with data completeness estimated at 99.7 percent (13). The Washington County registry was estimated to be at least 90 percent complete and was supplemented by the Maryland Cancer Registry to ensure coverage. For 1987–1989, the North Carolina Central Cancer Registry was incomplete on a statewide basis, but it was complete for the major hospitals in Forsyth County; statewide data are available beginning in 1990.

In addition to a search of cancer registries, the ARIC Study asked participants to report all hospitalizations, and hospital surveillance was carried out in each community. Cancer-related hospital discharges not identified by cancer registries were retrieved in each community. Because of the lack of a state registry prior to 1995, cases that occurred in Jackson in that period were identified by hospital surveillance only. Two records for possible prostate cancer in Jackson were not located, so these two were considered nonevents. Hospital information related to the cancer diagnosis—including primary site, date of diagnosis, and source of diagnosis information (e.g., a pathology report)—was copied from the medical records. Study investigators reviewed these records and added verified cases to the database. Information on Gleason grade and stage were not uniformly available from the registries or hospital records.

As a check on completeness of identification of incident prostate cancer, we examined all listed causes or contributors on the death certificates of ARIC participants who had not been lost to follow up and died before 2001. Only four additional prostate cancer deaths were found, suggesting reasonable completeness of ascertainment.

Data analysis and statistical methods
From the original ARIC cohort (n = 15,792), women (n = 8,710) were excluded. Of the men (n = 7,082), participants who did not provide sufficient data to determine baseline cancer status (n = 70), who had any prevalent cancer (n = 310), or who did not fast at least 8 hours (n = 273) were excluded, leaving 6,429 men in the cohort at risk. For 6,332 of these men, data on the metabolic syndrome were complete.

Statistical analysis was performed by using SAS software (v. 8.02; SAS Institute, Inc., Cary, North Carolina). Person-years at risk were calculated from the time of baseline clinical examination until the date of prostate cancer diagnosis, death, loss to follow-up, or December 31, 2000, whichever occurred first. Participants were stratified by baseline clinical characteristics, and crude incidence rates (per 1,000 person-years) were calculated. Adjusted relative risks for the association of the metabolic syndrome and other risk factors with prostate cancer incidence were calculated by using Cox proportional hazards regression (SAS procedure PHREG). A test for trend across the relative risks was performed by treating the components of the metabolic syndrome as an ordinal variable (0–5 metabolic syndrome components). The proportional hazards assumption of the Cox model was found not to be violated by testing an interaction between metabolic syndrome and time.

The potential for confounding was investigated for several variables, and the variables were included in the multivariable Cox model if they changed the relative risk estimate for the metabolic syndrome by at least 10 percent. First, an age- and race-adjusted model was explored. The final multivariable model included adjustment for age (continuous), race (African American, other), first-degree family history of prostate cancer (yes, no, unknown), educational level (<high school, high school, >high school), pack-years of smoking (quartiles), grams of ethanol per week (quartiles), energy intake (quartiles), and milk intake (quartiles). Additional variables that were tested for confounding but ultimately were not included were nonsteroidal antiinflammatory drug use, aspirin use, physical activity, height, waist/hip ratio, and intakes of animal fat, red meat, vitamin D, and calcium.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
At the ARIC baseline visit, 1,871 men (29.5 percent) had the metabolic syndrome (≥3 components). As shown in table 1, a higher proportion of participants with the metabolic syndrome were at least age 55 years, had a body mass index of at least 25 kg/m2, were in the highest quartile of animal fat and red meat intake, were taking aspirin or nonsteroidal antiinflammatory drugs, and had smoked for ≥20 pack-years, although intake of animal fat and red meat and use of aspirin and nonsteroidal antiinflammatory drugs were not associated with prostate cancer in this cohort. A lower proportion of participants with the metabolic syndrome had a family history of prostate cancer, and there were fewer in the highest quartiles of physical activity and energy intake. As expected, hyperinsulinemia was more common in men with the metabolic syndrome.


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  		TABLE 1 Prevalence (%) of selected characteristics by number of metabolic syndrome components present at baseline, ARIC* Study men, United States, 1987–1989 or 1994–1996

 
During 78,076 person-years of follow-up (mean, 12.1 years), 385 incident prostate cancers were recorded in 6,429 participants. Among men aged 45–64 years at baseline, the age-adjusted incidence rates of prostate cancer (adjusted to the 2000 US population) were 3.62 and 7.25 per 1,000 person-years for Whites and African Americans, respectively. In comparison, estimates of incidence rates at ages 45–64 years in the United States were 2.22 and 4.23 per 1,000 person-years for White and African-American men, respectively (14). For men aged 60–64 years, the incidence rate was four times higher than for those aged 45–49 years (table 2). The incidence among African Americans was twice that of Caucasians. Participants with a family history had a 1.8 times higher age- and race-adjusted incidence than those without. For participants with greater than a high school education and those in the highest milk intake group, prostate cancer incidence was 50 percent higher than for those in their reference groups. In contrast, incidence did not differ significantly across quartiles of lipids, body measurements, serum insulin, or glucose.


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  		TABLE 2 Crude incidence rate and relative risk of prostate cancer in relation to selected baseline characteristics, ARIC* Study men, United States, 1987–2000

 
Prostate cancer incidence rates in relation to individual metabolic syndrome components are presented in table 3. Possible inverse associations with prostate cancer were observed for high triglycerides, low high density lipoprotein cholesterol, high blood pressure, and fasting hyperglycemia/diabetes, but not waist circumference. However, none of the relative risk estimates for the individual components was statistically significant.


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  		TABLE 3 Incidence rate and relative risk of prostate cancer by individual components of the metabolic syndrome, ARIC* Study men, United States, 1987–2000

 
As shown in table 3, diabetes was the component most inversely associated with prostate cancer (relative risk = 0.73, 95 percent confidence interval: 0.51, 1.05). In a supplemental analysis, the adjusted relative risks (compared with no diabetes) were reduced for each diabetes subgroup: 0.49 (95 percent confidence interval: 0.12, 1.99) for diabetes treated with insulin, 0.77 (95 percent confidence interval: 0.42, 1.42) for diabetes treated with oral medication, 0.81 (95 percent confidence interval: 0.36, 1.82) for self-reported diabetes, and 0.72 (95 percent confidence interval: 0.42, 1.23) for diabetes defined only by a glucose level of ≥126 mg/dl.

The inverse association with prostate cancer seemed stronger for the composite metabolic syndrome than for any of its individual components. The adjusted relative risk of developing prostate cancer for those with the metabolic syndrome versus those without (≥3 vs. <3 components) was 0.77 (95 percent confidence interval: 0.60, 0.98) (table 4 and figure 1). When data for African-American (relative risk = 0.78, 95 percent confidence interval: 0.50, 1.22) and White (relative risk = 0.79, 95 percent confidence interval: 0.59, 1.05) participants were analyzed separately, we observed a similar inverse association, although it was not statistically significant because of smaller sample sizes.


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  		TABLE 4 Incidence rate and relative risk of prostate cancer by metabolic syndrome and number of components, ARIC* Study men, 1987–2000

 

Figure 1
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  		FIGURE 1 Cumulative incidence of prostate cancer in men with and without the metabolic syndrome, adjusted for age, race, family history, educational level, pack-years of smoking, grams of ethanol per week, total caloric intake, and milk intake, Atherosclerosis Risk in Communities Study men, United States, 1987–2000.

 
We repeated the analysis by excluding all diabetic participants. Results were similar but slightly stronger (table 4). The multivariate-adjusted relative risk of developing prostate cancer for those with the metabolic syndrome versus those without was 0.71 (95 percent confidence interval: 0.54, 0.94). The relative risk of prostate cancer decreased with increasing number of metabolic syndrome components present (p for trend = 0.05).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
This prospective study showed that men with the metabolic syndrome had a significantly, approximately 25 percent, lower risk of developing prostate cancer than those without. In contrast, individual components of the metabolic syndrome were not, in isolation, appreciably related to prostate cancer risk. Most notable among the components, diabetes was also inversely, albeit not statistically significantly, associated with prostate cancer incidence. In addition, there tended to be a dose-response relation between prostate cancer and number of metabolic syndrome components present. Thus, our data suggest that a combination of metabolic syndrome components identifies men at reduced risk of prostate cancer. The consistency of inverse associations between prostate cancer and both the metabolic syndrome, which often leads to diabetes, and diabetes itself suggests potential etiologic links.

To our knowledge, only one previous study has examined the relation between the metabolic syndrome and prostate cancer. In contrast with our results, Laukkanen et al. (3) reported that nondiabetic men with the metabolic syndrome were 1.9 times more likely to develop prostate cancer than those without, after multivariable adjustment. Although that study and the current one had similarly aged participants and lacked systematic prostate-specific antigen screening programs, a key difference was the definition of the metabolic syndrome used. The Finnish study used a modified version of the World Health Organization definition (3, 15). In addition, all diabetic participants were excluded from their study. We used the Adult Treatment Panel III definition (1). It seems unlikely that this alone could account for the difference in results between the two studies because there is a moderate degree of concordance between the World Health Organization and Adult Treatment Panel III definitions of the metabolic syndrome (16). However, an inverse association, as we found, seems plausible given consistent literature suggesting that diabetes is associated with reduced risk of prostate cancer. For example, a meta-analysis of 14 studies suggested a pooled relative risk between diabetes and prostate cancer of 0.91 (95 percent confidence interval: 0.86, 0.96) (5). This finding may be related to the blood insulin profiles of type 2 diabetic patients, which are initially elevated as a result of insulin resistance but later fall below normal because of damage to pancreatic ß cells. This occurrence was reflected by several studies finding that diabetic men had an increased risk of prostate cancer early in the course of their disease but a lowered risk later (6, 17). Our results revealed that, for men with diabetes, the relative risk of developing prostate cancer was 0.73.

A possible link between the metabolic syndrome (and diabetes) and prostate cancer is via altered androgen levels. High testosterone levels have been associated with prostate cancer in vitro (18) and in vivo (19); however, population-based studies have been inconsistent (20, 21), highlighting potentially complex interactions between testosterone, sex hormone-binding globulin, and insulin (22). Men with diabetes or the metabolic syndrome have been reported to have decreased testosterone levels (23, 24); conversely, men with decreased testosterone levels are at significantly higher risk of developing diabetes (25–27) or the metabolic syndrome (28, 29). Taken together, these observations suggest that the metabolic syndrome reflects a state of low circulating testosterone, which in turn decreases risk of prostate cancer.

Although the metabolic syndrome was associated with fasting hyperinsulinemia in our study, fasting insulin level was not itself associated with prostate cancer incidence. This finding suggests that insulin alone is not the culprit mediator of the inverse association between the metabolic syndrome and prostate cancer. In fact, if anything, hyperinsulinemia in isolation might be expected to increase prostate cancer risk. Insulin can cross-react with the insulin-like growth factor-1 receptor. High insulin-like growth factor-1 concentrations are associated with increased risk of prostate cancer (30), and insulin-like growth factor-1 has mitogenic and antiapoptotic effects on prostate cancer cells (31). Findings from two previous studies of the association between insulin resistance and prostate cancer, as determined by the ratio of fasting insulin to fasting glucose, have been inconsistent (32, 33). Similar to our study, Hubbard et al. (33) found no relation between insulin resistance and risk of prostate cancer in the Baltimore Longitudinal Study of Aging cohort. In contrast, a case-control study of Chinese men reported that men in the highest tertile of insulin resistance had a significantly increased risk of developing prostate cancer (32). However, the Chinese study participants had a low mean body mass index compared with that of US men, suggesting that high insulin levels may be a risk factor for prostate cancer in nonobese men only.

The present study has several important strengths. It used data from a large prospective study with careful physiologic measures and follow-up. In addition, the participants were from four distinct geographic sites in the United States and included a large proportion of African Americans.

A limitation was the reliance on cancer registries and hospital surveillance for cancer data. This factor may have led to missing cases, especially in the Mississippi cohort. However, missing cases should not be associated with the metabolic syndrome and therefore should not bias relative risk estimates. We also lacked data on the Gleason sum or cancer stage. Depending on the nature of the exposure, risk factor associations often have been stronger for advanced prostate cancer than for earlier cases of the disease. No such variation in the association has been observed for diabetes and prostate cancer in previous large cohort studies (6, 17). Our study did not measure testosterone levels, which would have been useful in examining their relation to prostate cancer and to the metabolic syndrome. Our fasting insulin assay was a nonspecific radioimmunoassay; use of a specific insulin assay or a more direct marker of insulin resistance may have demonstrated a different association of insulin with prostate cancer. Finally, the current study may have been subject to detection bias. It is possible, though perhaps unlikely, that the prostate-specific antigen test, which is used to screen for prostate cancer, was ordered less often for men with the metabolic syndrome than for those without. In addition, prostate-specific antigen is influenced by testosterone (34). Thus, men with the metabolic syndrome and associated lower testosterone levels may have lower prostate-specific antigen levels and presumably less further testing for prostate cancer. These scenarios could lower the observed incidence rates of prostate cancer in men with the metabolic syndrome compared with other men.

In conclusion, our results suggest that the metabolic syndrome is a marker of decreased risk of prostate cancer. We hypothesize that this finding reflects a decrease in bioavailable testosterone in men with the metabolic syndrome and a concomitant reduction in prostate cancer risk.


   ACKNOWLEDGMENTS
 
This research was sponsored by National Cancer Institute grant R03-CA65473 and by National Heart, Lung, and Blood Institute contracts N01-HC–55015, 55016, 55018, 55019, 55020, 55021, and 55022. Aaron Tande was supported by a grant from the Minnesota Medical Foundation, Minneapolis, Minnesota. The funding agencies had no role in the preparation of this manuscript.

Dr. Aaron Folsom had full access to all of the study data and takes responsibility for the integrity of the data and the accuracy of the data analysis. Some data were supplied by the Maryland Cancer Registry, Department of Mental Hygiene, which specifically disclaims responsibility for any analyses, interpretations, or conclusions.

The investigators thank the ARIC Study staff for their important contributions and William Baker and Lori Boland for technical assistance.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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