Affiliations of authors: M. F. Leitzmann, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; M. J. Stampfer, W. C. Willett, E. L. Giovannucci, Departments of Epidemiology and Nutrition, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Womens Hospital, Boston, MA; K. Wu, Department of Nutrition, Harvard School of Public Health; G. A. Colditz, Department of Epidemiology, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Womens Hospital.
Corresponding author: Michael F. Leitzmann, M.D., Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Blvd., EPS-MSC 7232, Bethesda, MD 20892 (e-mail: leitzmann{at}mail.nih.gov).
ABSTRACT
The high concentration of zinc in the prostate suggests that zinc may play a role in prostate health. We examined the association between supplemental zinc intake and prostate cancer risk among 46 974 U.S. men participating in the Health Professionals Follow-Up Study. During 14 years of follow-up from 1986 through 2000, 2901 new cases of prostate cancer were ascertained, of which 434 cases were diagnosed as advanced cancer. Supplemental zinc intake at doses of up to 100 mg/day was not associated with prostate cancer risk. However, compared with nonusers, men who consumed more than 100 mg/day of supplemental zinc had a relative risk of advanced prostate cancer of 2.29 (95% confidence interval = 1.06 to 4.95; Ptrend = .003), and men who took supplemental zinc for 10 or more years had a relative risk of 2.37 (95% confidence interval = 1.42 to 3.95; Ptrend<.001). Although we cannot rule out residual confounding by supplemental calcium intake or some unmeasured correlate of zinc supplement use, our findings, that chronic zinc oversupply may play a role in prostate carcinogenesis, warrant further investigation.
The concentration of zinc in the prostate is higher than that in any other soft tissue in the body (3). Zinc levels in prostate adenocarcinoma are markedly lower than those in the surrounding normal prostate tissues (3). Several findings that link zinc with the suppression of prostate cancer cell growth (46) and inhibition of prostate tumor cell invasion (7,8) suggest that high intraprostatic zinc levels may protect against prostate carcinogenesis. However, results of other studies suggest that high intraprostatic zinc concentrations may adversely affect prostate cancer risk. For example, zinc enhances the activity of telomerase (9), an enzyme thought to be responsible for unlimited proliferation of tumor cells and whose activity is increased in prostate cancer (10). Zinc has also been found to antagonize the potential inhibitory effect of bisphosphonates on prostate tumor cell invasion (11).
Whether dietary zinc intake affects intraprostatic zinc levels is unknown. However, ingestion of 150 mg/day or more of zinc has undesirable metabolic effects, such as immune dysfunction (12) and impaired antioxidant defense (13), that are potentially related to prostate cancer. In animal studies, subtoxic zinc levels at doses of 200 parts per million of zinc in supply water may interfere with a cancer-protecting activity associated with selenium intake (14). In humans, zinc intake is positively correlated with circulating levels of insulin-like growth factor-I (15) and testosterone (16), growth factors that are directly related to prostate carcinogenesis. Thus, results of studies that have addressed the systemic effects of dietary zinc suggest that high zinc intakes may be positively associated with prostate cancer risk (1216). To address this issue, we examined the relationship between supplemental zinc intake and prostate cancer risk among participants in the Health Professionals Follow-Up Study. The Health Professionals Follow-Up Study was initiated in 1986, when 51 529 U.S. male health professionals aged 40 to 75 years responded to a mailed questionnaire concerning their medical history and disease risk factors. Since then, follow-up questionnaires have been mailed biennially to cohort members to update information on newly diagnosed illnesses. The Health Professionals Follow-Up Study was approved by the institutional review board on the use of human subjects in research of the Harvard School of Public Health.
Dietary intake was assessed in 1986 with the use of a 131-item semiquantitative food-frequency questionnaire that requested detailed information on the amount and duration of supplement use, including questions on the brand of multivitamin used and the use of vitamins A, C, and E, zinc, iron, and calcium. The Pearson correlation coefficient between zinc intake reported in this questionnaire and in two 1-week dietary records was 0.71 (17), indicating reasonable validity of our questionnaire-based assessment of zinc intake. On each follow-up questionnaire, participants were asked to report whether they had been diagnosed with prostate cancer during the previous 2 years. We requested permission from men who reported a prostate cancer diagnosis (or from the next of kin for decedents) to obtain medical records and pathology reports, which were used to confirm the diagnosis and to determine the stage of the cases of prostate cancer. Multivariable relative risks (RRs) were computed using the Cox proportional hazards model (18). The proportional hazards assumption was satisfied. All statistical tests were two-sided.
During 587 444 person-years of follow-up, we documented 2901 new cases of prostate cancer. Among the men in our study population, supplemental zinc provided 32% of total zinc intake and thus represented by far the major source of zinc. Other sources of zinc included beef and breakfast cereals, which provided 11% and 5%, respectively, of zinc intake. The median value of the highest category of supplemental zinc intake (reported by approximately 1% of the study population) was 143 mg/day, a dose that exceeds the current recommended dietary allowance by 13-fold. We examined supplemental zinc use in relation to various risk factors for prostate cancer (Table 1). Compared with nonusers, men who consumed supplemental zinc also consumed more multivitamins, supplemental calcium, supplemental vitamin E, lycopene, copper, iron, folate, and fish, but had lower intakes of red meat, and were slightly less likely to have had a history of prostate-specific antigen screening.
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NOTES
Supported by Public Health Service research grants CA55075 from the National Cancer Institute (to W. C. Willett) and HL35464 from the National Heart, Lung, and Blood Institute (to W. C. Willett), National Institutes of Health (NIH), Department of Human Services (DHHS), and by Cancer Epidemiology Training Grant 5T32 CA09001-26 (to M. F. Leitzmann) from the National Cancer Institute, NIH, DHHS.
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Manuscript received October 21, 2002; revised April 9, 2003; accepted April 16, 2003.
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