In this hospital-based case-control study, men who used zinc for 10 or more years, either in a multivitamin or as a single supplement, had an approximately two-fold increased risk of prostate cancer. Use of vitamin E, beta-carotene, folate, and selenium were not associated with increased risk of prostate cancer. We found little evidence to support an effect of multivitamins on the risk of prostate cancer.
Evidence on the relation of multivitamin use to the risk of prostate is conflicting (10
). In a population-based case-control study (10
), the use of a multivitamin more than 7 times per week was not associated with risk of prostate cancer compared to no use (OR=0.96, 95% CI: 0.73, 1.26); results did not differ by stage of disease or by histological grade. In seven years of follow-up of 454,000 men in the Cancer Prevention Study II cohort (CPS-II), the risk of death from prostate cancer was not associated with use of multivitamins overall; however, mortality was increased by 30% (OR=1.31, 95% CI: 1.04,1.66) among participants who had used multivitamins for 5 or more years (19
). In an up-dated analysis of the CPS-II cohort over 18 years of follow-up, the use of multivitamins for 15 or more times/month was weakly and insignificantly associated with prostate cancer mortality (RR=1.07, 95% CI: 0.99,1.15) (20
). Multivitamins were not assessed according to the presence or absence of zinc in these studies. In the prospective AARP Diet and Heath Study, Lawson et al (17
) found that men reporting use of multivitamins more than seven time per week had a 30% increase in the risk of advanced and fatal prostate cancer compared with never users (RR=1.32, 95% CI: 1.04,1.67). Our results do not confirm the AARP finding of a stronger association of multivitamin use with advanced than with early stage cancer. In the AARP study, an increased risk was more pronounced among men with a family history of prostate cancer or who took individual supplements, including selenium, beta-carotene, or zinc in addition to a multivitamin. The number of men with a family history of prostate cancer in our study was relatively small (n=248); thus we were unable to obtain a robust estimate of the effect of multivitamin use among men with a positive family history.
Findings on the relation of single vitamin or mineral supplements to the risk of prostate cancer are conflicting. Vitamin E has been associated with a decreased risk of prostate cancer (9
), with a more pronounced effect among smokers (15
). In the Male Health Professional Study, Chan and colleagues found no association between vitamin E use and risk of total and metastatic or fatal prostate cancer (11
). However, among current smokers and recent quitters, those who consumed at least 100 IU of supplement vitamin E per day had a reduced risk (RR=0.44, 95% CI: 0.18–1.07) for metastatic or fatal prostate cancer compared with nonusers. Results from two large prospective cohort studies (13
), however, did not find an association between vitamin E supplement and risk of prostate cancer, and its effect was not significantly modified by smoking status. In our study, there was no association between vitamin E use and risk of prostate cancer regardless of smoking status. More recently, results from the Selenium and Vitamin E cancer Prevention Trial suggest there was no beneficial effect of either vitamin E or selenium on the prevention of prostate cancer (31
The few studies that have evaluated the effects of beta-carotene (15
) and selenium (22
) on the risk of prostate cancer have been inconclusive. In the Alpha-Tocopherol, Beta- Carotene Cancer Prevention Trial, participants who received beta-carotene had a slightly higher risk of prostate cancer than those who did not receive beta-carotene (27
). However, in the Physicians’ Health Study, beta-carotene supplementation of 50 mg on alternative days was not associated with risk of prostate cancer (18
). We found an inverse association of 10 or more years of beta-carotene supplement use with prostate cancer risk, but there was not a significant trend.
Several epidemiologic studies have examined folate in relation to the risk of prostate cancer, with inconclusive findings (24
). Of three case-control studies evaluating plasma concentrations of folate in relation to prostate cancer (33
), two (33
) found that high circulating folate levels were associated with a small but non-significant increase in risk and one (35
) reported no effect of folate on prostate cancer risk. In a large dietary case-control study with 1,294 incident prostate cancer cases, folate intake was associated with a decreased risk of prostate cancer, with an adjusted OR of 0.66 (95% CI: 0.51, 0.85) for the highest vs.
the lowest quintile of folate intake (26
). While there was no effect of dietary intake of folate on overall prostate cancer risk among the male participants in the CPS-II, high dietary folate intake was marginally associated with reduced risk of advanced prostate cancer (25
). In a smaller European case-control study, however, high dietary intake of folate was associated with a non-significant increased risk of prostate cancer (24
). In our study, no apparent effect of folate supplement use was found on prostate cancer risk.
In a population-based case-control study of 697 incident prostate cancer cases and 666 controls (10
), prostate cancer risk was inversely associated with zinc use. However, in the Health Professionals Follow-up Study (12
) use of zinc supplements for 10 years or more was associated with more than a doubling in the risk of advanced prostate cancer (RR=2.3, 95% CI: 1.1, 5.0) compared with nonuse. In a large case-control study (1294 prostate cancer cases and 1451 controls) conduced in Italy, Gallus et al (8
) reported that the OR of prostate cancer was 1.56 for men with the highest quintile of dietary zinc as compared with those in the lowest quintile (p for trend =0.04). Two other studies also suggested that zinc intake was associated with an increased risk of prostate cancer (23
). In the current study, we also observed a 2-fold increased risk of prostate cancer among men who used zinc for 10 or more years. Considering that zinc has long been linked to prostate health, some men with long-standing prostate symptoms may be self-medicating with zinc supplements which may account for, at least in part, these positive findings.
Some studies have suggested that high intraprostatic zinc levels may decrease the risk of prostate cancer by suppression of prostate cancer cell growth (36
) or inhibition of tumor cell invasion (37
). Studies comparing zinc concentrations in normal and malignant prostate tissue have found that zinc content is 60–70% lower in cancer cells (38
). These findings raised the possibility that a high intake of dietary zinc and use of supplement zinc could be efficacious in the prevention of prostate cancer (39
). However, other studies have shown that zinc may enhance the activity of telomerase, an enzyme that has been associated with the proliferation of prostate cancer cells (40
). An excess of zinc has also been shown to reverse the potential inhibitory effect of biophosphonate on prostate tumor cell invasion (41
). Studies have also demonstrated that zinc intake is positively associated with levels of serum insulin-like growth factor (42
) and testosterone (43
), both of which may be risk factors for prostate cancer (44
Selection of appropriate hospital controls in a case-control study is a challenge, especially for the evaluation of lifestyle factors like multivitamin use. If hospital patients were less likely to take multivitamins than the general population, an adverse effect of multivitamin use on risk of prostate cancer would be exaggerated. We selected controls from men with diagnoses that we judged to be unrelated to multivitamin use. Results were unchanged in a sensitivity analysis which removed the controls with the lowest prevalence of vitamin and supplement use. Finally, the number of advanced prostate cancer cases in the current study is relatively small, which limited our ability to assess the effect of multivitamin or single vitamin or mineral use on advanced disease.
Important prostate cancer risk factors, such as family history of cancer, were controlled simultaneously in multivariable analysis. The data on multivitamin use were collected in the context of questions about many drug indications, and the participants and interviewers were unaware of the hypotheses at issue; thus, it is unlikely that biased reporting of multivitamin use accounts for the present results.
Approximately 16% of subjects did not know the name of the multivitamin they had taken and they were excluded from the analysis of specific vitamins or minerals. Similar to most previous studies, we did not collect data on dietary intake and therefore could not take into account vitamin and mineral intake from food. Finally, our study did not collect information on dosage of either multivitamins/minerals or single supplements. Thus, we were unable to assess the effect of doses of either multivitamins/minerals or single supplements.
In summary, the present study found that long-term use of multivitamins that did not contain zinc was not associated with increased risk of prostate cancer. Long-term zinc intake from multivitamins or single supplements was associated with a doubling in risk. This finding together with other epidemiologic evidence suggests that that there is an unfavorable effect of zinc use on prostate carcinogenesis.