Intake of Selected Micronutrients and the Risk of Surgically Treated Benign Prostatic Hyperplasia: A Case-Control Study from Italy

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1 european urology xxx (2006) xxx xxx available at journal homepage: Benign Prostatic Hyperplasia Intake of Selected Micronutrients and the Risk of Surgically Treated Benign Prostatic Hyperplasia: A Case-Control Study from Italy Alessandra Tavani a, *, Elisa Longoni a, Cristina Bosetti a, Luigino Dal Maso b, Jerry Polesel b, Maurizio Montella c, Valerio Ramazzotti d, Eva Negri a, Silvia Franceschi e, Carlo La Vecchia a,f a Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy b Unità di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Aviano (PN), Italy c Servizio di Epidemiologia, Istituto Tumori Fondazione Pascale, Naples, Italy d Servizio Integrato di Epidemiologia e Sistemi Informativi, Istituto Nazionale Tumori Regina Elena, Rome, Italy e International Agency for Research on Cancer, Lyon Cedex, France f Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milan, Italy Article info Article history: Accepted November 21, 2005 Published online ahead of print on December 28, 2005 Keywords: Antioxidants Benign prostatic hyperplasia Micronutrients Risk factors Vitamins Abstract Objective: To analyze the relationship between surgically treated benign prostatic hyperplasia (BPH) and intake of selected micronutrients. Methods: A multicentric case-control study was conducted in Italy between 1991 and Cases were 1369 men with histologically confirmed, surgically treated BPH and controls were 1451 men younger than 75 yr, frequency matched by quinquennium of age and study center, admitted to the hospital for acute nonneoplastic diseases. Information was collected by trained interviewers using a structured validated food-frequency questionnaire. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional multiple logistic regression models. Results: The risk of BPH significantly decreased with increasing intake of carotene (OR = 0.80 for an increment equal to the difference between the 80th and 20th percentile of intake), a-carotene (OR = 0.83), b-carotene (OR = 0.82), and cis b-carotene (OR = 0.82) and tended to decrease with the intake of vitamin C (OR = 0.89) and iron (OR = 0.79). The OR tended to increase with the intake of sodium (OR = 1.30) and zinc (OR = 1.10). No systematic heterogeneity was observed across strata of age, education, and body mass index. No meaningful associations emerged for other antioxidants, such as folic acid, lycopene, lutein/zeaxanthin, vitamin E, vitamin D, nor for retinol. Conclusions: Our results suggest a protective effect of carotene on the risk of BPH. The risk tended to decrease also with the intake of vitamin C and iron and tended to increase with the intake of sodium and zinc. Results also indicate that other antioxidants, including folic acid, lycopene, lutein/zeaxanthin, and vitamins D and E, and retinol were not related to the risk for this disease. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, Milan, Italy. Tel ; Fax: address: tavani@marionegri.it (A. Tavani) /$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo EURURO-1079; No of Pages 6

2 2 european urology xxx (2006) xxx xxx 1. Introduction Although benign prostatic hyperplasia (BPH) is a very common disease in older men [1,2], little is known about its etiology [3,4], except for an involvement of androgens in its development and maintenance [5 7]. Very few studies have considered a potential association of the disease with dietary micronutrients [8]. A Greek case-control study found an increased risk of BPH with dietary intake of zinc, but no association with several other micronutrients, including b-carotene and retinol [9]. We investigated the association between various micronutrients and BPH risk using data from a multicentric case-control study conducted in Italy, where dietary habits were collected by a foodfrequency questionnaire tested for reproducibility and validity [10,11]. 2. Methods 2.1. Subjects and procedures The data were derived from a case-control study of BPH [12,13], conducted between 1991 and 2002 in four Italian areas: the provinces of Pordenone and Gorizia (northeastern Italy), the greater Milan area (northern Italy), the province of Latina (central Italy), and the urban area of Naples (southern Italy). All interviews were conducted in the hospital by trained interviewers using a structured questionnaire; <5% of cases and controls approached refused the interview, and the response rates did not vary across hospitals and geographic areas. Cases were 1369 men (median age, 66 yr; range, yr) with surgically treated BPH, admitted to the major teaching and general hospitals in the areas under surveillance. Indication for surgical treatment of BPH included low urinary tract symptoms refractory to medical management, in the presence or risk of refractory urinary retention, renal insufficiency, bladder stones, recurrent urinary tract infections, or recurrent hematuria [14]. Controls were 1451 men (median age, 63 yr; range, yr), residing in the same geographic areas and admitted to the same network of hospitals as cases for a wide spectrum of acute conditions unrelated to smoking and long-term modification of diet. Controls were frequency matched for study center and quinquennium of age. Among controls, 21% had traumatic conditions, 32% nontraumatic orthopedic disorders, 17% acute surgical conditions, and 29% miscellaneous other illnesses (such as eye, ear, nose, throat, and dental disorders). The structured questionnaire included information on sociodemographic factors, anthropometric variables, general lifestyle habits (eg, smoking, alcohol, and coffee consumption), physical activity at work, family history of cancer, and personal history of selected diseases [12,13]. The subjects usual diet during the 2 yr prior to BPH diagnosis or hospital admission (for controls) was investigated through an interviewer-administered food-frequency questionnaire, including 78 foods, recipes, and beverages. Subjects were asked to indicate the average weekly frequency of consumption of several dietary items; intakes lower than once a week, but at least once a month, were coded as 0.5/wk. To estimate total energy and nutrient intake, an Italian food composition database was used [15]. Losses due to cooking were subtracted for the computation of vitamin content when appropriate, except for specific carotenoids, where such information was not available. The sum of carotenes (ie, b- and a-carotene, b-cryptoxanthin) weighted by their vitamin activity was thus different from the value of carotene. All major sources of lycopene and other micronutrients are included in our estimate because our food-frequency questionnaire included information on the consumption of many common Italian foods and recipes. The food frequency questionnaire was satisfactorily reproducible [10] and valid [11]; the correlation coefficients for reproducibility ranged from 0.48 to 0.69 [10] and for validity from 0.34 to 0.56 [11] Data analysis Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for each nutrient were estimated using unconditional multiple logistic regression models [16], including terms for study center, quinquennia of age, years of education, total energy intake, occupational physical activity at age yr, body mass index before diagnosis, smoking, and alcohol intake. Micronutrients were entered in the models as quintiles of intake based on the distribution of controls. In alternative models, micronutrients were entered as continuous variables, with a measurement unit equal to the difference between the 80th and 20th percentile, that is, between the upper cut-point of the fourth quintile and that of the first one. Tests for trend were based on the likelihood ratio test between models with and without a linear term for each micronutrient. 3. Results The distribution of cases and controls according to age and other selected covariates is shown in Table 1. Cases were more educated and less physically active than controls; they smoked fewer cigarettes and consumed less alcohol. Table 2 gives the mean daily intake of selected micronutrients among controls and the ORs of BPH according to quintile of intake. For instance, the upper cut-off points for carotene were 2471 mg for the first quintile, 3228 mg for the second one, 3994 mg for the third one, and 5101 mg for the forth quintile. The risk of BPH decreased with increasing intake of carotene (OR = 0.80 for an increase equal to the difference between the 80th and 20th percentile of intake, 2630 mg), a-carotene (OR = 0.83, for an increase of 828 mg), b-carotene (OR = 0.82, for an increase of 3078 mg), and cis b-carotene (OR = 0.82, for an increase of mg) and tended to decrease

3 european urology xxx (2006) xxx xxx 3 Table 1 Distribution of 1369 cases of benign prostatic hyperplasia (BPH) and 1451 controls according to age and other selected covariates and corresponding odds ratios (OR) with 95% confidence intervals (CI). Italy, No. BPH cases No. Controls OR a (95% CI) Age (yr) < Education (yr) b < c ( ) ( ) x 2 trend = 11.40, p trend = Body mass index (kg/m 2 ) < c ( ) ( ) ( ) ( ) x 2 trend = 4.54, p trend = Physical activity b Very active c Moderately active ( ) Inactive ( ) x 2 trend = 26.11, p trend < Total calorie intake (kcal/d) < c ( ) ( ) ( ) ( ) x 2 trend < 0.01, p trend = Smoking habit b,d Never smoker c Ex smoker ( ) Current smoker <15 cigarettes/d ( ) cigarettes/d ( ) 25 cigarettes/d ( ) x 2 trend = 28.57, p trend < Alcohol consumption habit b Abstainer c Ex drinker ( ) Current drinker <14 drinks/wk ( ) drinks/wk ( ) drinks/wk ( ) 35 drinks/wk ( ) a Adjusted for age and study center. b The sum does not add up to the total because of some missing values. c Reference category. d One cigar equals three cigarettes; one g of pipe tobacco equals one cigarette. with the intake of vitamin C (OR = 0.89, for an increase of mg) and iron (OR = 0.79, for an increase of 7.81 mg). The OR tended to increase with the intake of sodium (OR = 1.30, for an increase of 1305 mg) and zinc (OR = 1.10, for an increase of 5.72 mg). No meaningful associations emerged for other antioxidants, such as folic acid, lycopene, lutein/zeaxanthin, vitamin E, vitamin D, nor for retinol. Table 3 presents the ORs for an increment of intake corresponding to the difference between the 80th and 20th percentile of intake, in different strata

4 4 european urology xxx (2006) xxx xxx Table 2 Mean intake and odds ratios (OR) of benign prostatic hyperplasia (BPH) and corresponding 95% confidence intervals (CI) according to the intake of selected micronutrients. Italy, Nutrient Mean OR b for quintiles of intake x 2 intake (SD) a trend ( p value) OR (95% CI) for a continuous term c Carotene (mg) 3929 (1949) (<0.001) 0.80 ( ) a Carotene (mg) (696.2) (<0.001) 0.83 ( ) b Carotene (mg) 4515 (2234) (<0.001) 0.82 ( ) Cis b Carotene (mg) (48.4) (0.002) 0.82 ( ) g Carotene (mg) 1689 (874) (0.76) 0.97 ( ) b Criptoxanthin (mg) (311.1) (0.019) 0.92 ( ) Retinol (mg) (976.2) (0.39) 0.89 ( ) Lycopene (mg) 7487 (3473) (0.63) 0.99 ( ) Lutein/Zeaxanthin (mg) 4704 (2497) (0.58) 1.01 ( ) Vitamin E (mg) (6.51) (0.75) 0.97 ( ) Vitamin D (mg) 3.07 (1.33) (0.36) 1.14 ( ) Thiamin (mg) (247.2) (0.64) 0.98 ( ) Riboflavin (mg) 1559 (529) (0.99) 1.08 ( ) Niacin (mg) (4.67) (0.97) 1.07 ( ) Vitamin B 6 (mg) 1922 (528) (0.17) 0.96 ( ) Vitamin C (mg) (73.1) (0.03) 0.89 ( ) Folic acid (mg) (78.6) (0.26) 0.95 ( ) Calcium (mg) 1020 (425) (0.27) 1.05 ( ) Sodium (mg) 2422 (826) (0.07) 1.30 ( ) Potassium (mg) 3911 (1014) (0.24) 0.97 ( ) Phosphorus (mg) 1568 (457) (0.72) 1.10 ( ) Zinc (mg) (3.69) (0.28) 1.10 ( ) Iron (mg) (4.96) (0.001) 0.79 ( ) a Mean intake and standard deviation (SD) among controls. b Estimated by multiple logistic regression equations including terms for study center, age, education, total energy, physical activity, body mass index, smoking and alcohol. Reference category was the lowest quintile of intake for each nutrient. c OR for an increment corresponding to the difference between 80th and 20th percentile, i.e. between the upper cut-point of the 4th quintile and that of the 1st one. Table 3 Odds ratios (OR) and corresponding 95% confidence intervals (CI) of benign prostatic hyperplasia (BPH) for a continuous term according to the intake of selected micronutrients in strata of age, education and body mass index. Italy, Nutrient OR for a continuous term a (95% CI) Age (yr) Education (yr) Body mass index (kg/m 2 ) <65 65 <7 7 <26 26 Carotene (mg) 0.83 ( ) 0.78 ( ) 0.79 ( ) 0.83 ( ) 0.71 ( ) 0.90 ( ) a-carotene (mg) 0.86 ( ) 0.80 ( ) 0.79 ( ) 0.89 ( ) 0.75 ( ) 0.91 ( ) b-carotene (mg) 0.84 ( ) 0.80 ( ) 0.83 ( ) 0.82 ( ) 0.74 ( ) 0.90 ( ) Cis b Carotene (mg) 0.94 ( ) 0.67 ( ) 0.88 ( ) 0.73 ( ) 0.82 ( ) 0.81 ( ) Sodium (mg) 1.16 ( ) 1.51 ( ) 1.34 ( ) 1.18 ( ) 1.36 ( ) 1.23 ( ) Zinc (mg) 1.15 ( ) 1.02 ( ) 1.29 ( ) 0.84 ( ) 1.16 ( ) 1.06 ( ) Iron (mg) 0.74 ( ) 0.84 ( ) 0.89 ( ) 0.62 ( ) 0.75 ( ) 0.81 ( ) a OR for an increment corresponding to the difference between the 80th and 20th percentile, that is, between the upper cut-point of the 4th quintile and that of the 1st one. Estimated by multiple logistic regression equations including terms for study center, age, education, total energy, physical activity, body mass index, smoking and alcohol, as appropriate. of age, education, and body mass index. Although there was no systematic heterogeneity across strata of these covariates, the OR for sodium tended to be higher in men aged 65 yr, in those with a lower education, and with a body mass index <26 kg/m 2 ; the OR for zinc tended to be higher in men with a lower education, and the inverse association of cis b- carotene was apparently stronger in men aged 65 yr. 4. Discussion This uniquely large case-control study of BPH found an inverse association of dietary intake of various carotenes and iron with the risk of the disease. A nonsignificant inverse association was found also for vitamin C dietary intake, whereas a weak direct association was found for sodium and zinc intake.

5 european urology xxx (2006) xxx xxx 5 The intake of selected other antioxidants (including lycopene, lutein/zeaxanthin, folic acid, and vitamins D and E) and that of retinol were not related to the risk of BPH. A potential weakness of this study on BPH is that no uniform case definition of the disease has been established [4]. In this study, only surgically treated men, that is, those with the most severe and histologically confirmed disease, were considered. However, the risk of prostatic surgery may depend on previous medical treatment of the disease [17], and the use of surgical intervention is progressively diminishing, while medical therapy takes a more prominent role [2]. Another potential source of bias could derive from undetected cases of BPH in the control group, mainly among the elderly [18], although the similarity of results in younger and older men weighs against a major role of any such bias. Moreover, strict allowance was made for education, because a higher prevalence of prostate-specific antigen (PSA) testing among more educated men is likely. Dietary habits of hospital controls may differ from those of the general population [16]. Thus, all diagnoses that might have involved long-term modifications of diet were carefully excluded from the control group. Our information on diet refers to the previous 2 yr, that is, to the latest stages of BPH, a chronic disease developing over decades [2]. Other possible sources of bias should be limited because cases and controls were drawn from the same catchment areas, participation was almost complete, and allowance for several confounding factors did not notably modify the risk estimates. The results were consistent when comparison was made with different diagnostic categories of controls. Among the strengths of the study was the use of a validated and reproducible foodfrequency questionnaire [10,11], which allowed a comprehensive assessment of major nutrient sources in the Italian diet. Further, total calorie intake and major potential confounding factors have been accounted for in the analysis. The inverse association observed for several carotenes, but not for carotenoids without vitamin activity, may suggest that vitamin A is responsible for the protection on BPH risk. However, the lack of association of retinol with BPH risk works against this hypothesis. Carotene and vitamin C have antioxidant properties and may have a role in the host defense against reactive oxygen, DNA damage, and cell proliferation [23]. Because b-carotene and vitamin C derive from plant foods, their protective effect on BPH may be due to a more generic beneficial role of vegetables and fruit [8,9]. However, no association was found for several other antioxidants mainly contained in vegetables and fruit, including folic acid, lutein plus zeaxanthin, and particularly lycopene, whose concentration in the prostate gland is relatively high [24]. It has been suggested that zinc intake is important in the etiology of BPH, because the prostate gland is very rich in zinc and zinc content is increased in periurethral adenomas, but decreased in prostatitis and prostate cancer [19,20]. Moreover, zinc concentration increases in BPH [19,20], plasma zinc concentrations rise in men older than 55 years, and cellular and mitochondrial zinc levels are increased by testosterone [19] (an important permissive factor for the development of BPH) [21]. Further, zinc appears to modulate the 5-a-reduction of testosterone, and the addition of zinc enhances androgen uptake by the prostate [22]. The results of Lagiou et al. [9] of a positive association of zinc intake with BPH risk support this hypothesis. Our findings also point to a potential link between zinc and BPH risk, although in the absence of linear association. The inverse association of iron intake with BPH risk could partly depend on the overall beneficial effect of wine, as one of the major sources of iron in the Italian diet is wine [25], which tended to be inversely related to BPH risk in this [12] and other studies [26 30]. However, the OR for an increment corresponding to the difference between the 80th and 20th percentile of iron intake on BPH risk was 0.55 in men drinking <14 drinks/wk of total alcohol (mainly wine in the Italian diet), 0.60 in men drinking 14 to <21 drinks/wk, 0.66 in drinkers of 21 to <35 drinks/wk, and 0.91 in drinkers of 35 drinks/wk, suggesting that the inverse association with iron intake may be independent from that of wine. Thus, interpretation for this potential inverse association remains unclear, as well as for the positive association found with sodium intake. However, when multiple comparisons are performed, some of them could turn out to be statistically significant by chance alone; thus our findings need to be replicated in other studies and populations, because very few epidemiologic studies have explored the nutritional etiology of BPH, in particular the role of micronutrients [8,9]. Acknowledgments This work was conducted with the contribution the Italian Association for Cancer Research, the Italian League Against Cancer and the Italian Ministry of Education (COFIN 2003). The authors thank Mrs O. Volpato for study coordination; Ms. M. P. Bonifacino for editorial assistance; and Drs G. Laconca, M.

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