Vitamin D and prostate cancer risk: a review of the epidemiological literature

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1 REVIEW (2009) 12, & 2009 Nature Publishing Group All rights reserved /09 $ : a review of the epidemiological literature D Gupta, CA Lammersfeld, K Trukova and CG Lis Cancer Treatment Centers of America s at Midwestern Regional Medical Center, Zion, IL, USA Prostate cancer is the most commonly diagnosed cancer in the. Prostate cells contain vitamin D receptors as well as enzymes necessary for vitamin D metabolism. Vitamin D metabolites have an antiproliferative and a pro-differentiating effect on prostate cancer cell lines in vitro and in vivo. As a result, there has been an emerging interest in the potential role of vitamin D in the etiology of prostate cancer. This review summarizes all available epidemiological literature on the association between dietary vitamin D, circulating levels of vitamin D and sunlight exposure in relation to prostate cancer risk. To place these studies in context, we also provide some background information on vitamin D, such as its dietary sources, metabolism, optimal levels, hypovitaminosis and relationship with the prostate. (2009) 12, ; doi: /pcan ; published online 7 April 2009 Keywords: vitamin D; sunlight; risk Introduction Prostate cancer is the sixth most common cancer in the world, the third most common cancer in men worldwide and the most common cancer in men in Europe and North America, 1 5 with a new case diagnosed every 3 min. 6 The increasing incidence of prostate cancer is because of its strong association with age in combination with the rising average age of American men, improvements in detection techniques and programs for the early detection of prostate cancer. 7 9 Each year in the United States, approximately new cases of prostate cancer are diagnosed, and men die of the disease. 9 The mean age of patients with this disorder is years, and about 85% of patients are diagnosed after 65 years of age. 5 Prostate cancer is the second leading cause of cancer death among US men after lung cancer. 6,10 Similar to most other cancer types, prostate cancer epidemiology is not fully known. The available information does not completely explain the causation and pathogenesis of the disease. Research is in progress to establish the missing links in the association of etiologic factors, such as dietary habits, with prostate carcinogenesis. A high intake of red meat is one such dietary habit that has been linked to prostate cancer The incidence varies among different racial/ethnic populations and is the lowest among Asians (Japanese, 39/ ; Chinese, 28/ ) 16 and vegetarians. 5,17 The Correspondence: Dr D Gupta, Cancer Treatment Centers of America s, Operations Center, Office of Research, 2610 Sheridan Road, Zion, IL 60099, USA. gupta_digant@yahoo.com Received 28 January 2009; accepted 18 February 2009; published online 7 April 2009 highest incidence of prostate cancer is seen in North America and Scandinavia, especially in African-American men in the (137 per per year). 5 In Uganda 18 and Nigeria, 19,20 prostate cancer is very common, and in Nigeria it is the most common cancer in men. Another factor that influences the occurrence of the disease is obesity. 21 Both body mass index and lean body mass were positively associated with the risk of prostate cancer and were more strongly related to mortality than to incidence. Other factors that influence the occurrence of the disease are dietary habits (diet that includes a high intake of fat, meat and dairy products), 22,23 pattern of sexual behavior, alcohol consumption, 24 exposure to ultraviolet radiation, 22,25 28 occupational exposure 29 and familial genetic inheritance. 5,30 35 Finally, factors such as smoking, 36 vasectomy 37 and physical activity 38 have been investigated in several studies, but the general consensus is that they do not affect risk of prostate cancer. It is known that prostate cells contain vitamin D receptors (VDRs) as well as enzymes necessary for vitamin D metabolism. In vitro studies show the anticarcinogenic properties of vitamin D. Vitamin D metabolites have an antiproliferative and a pro-differentiating effect on prostate cancer cell lines in vitro and in vivo The physiological levels of 1,25-dihydroxyvitamin D (1,25(OH)2D 3 ) reveal impressive antimetastatic effects on prostate cancer cells in vivo. 45 In 1993, Skowronski et al. 46 discovered that all three of the prostate cancer cell lines they studied possessed a VDR and that the active form of vitamin D, calcitriol, dramatically inhibited the growth of two of the three cell lines. From the abovementioned studies, it was suggested that the expression of functional VDR is necessary, but not sufficient, for maximal growth inhibition by 1,25(OH)2D The finding that 1,25(OH)2D 3 shows antiproliferative, pro-differentiation

2 216 and antimetastatic effects could open new avenues to the development and targeting of chemopreventive interventions. However, 1,25(OH)2D 3 may not be a suitable agent for use as a chemopreventive agent because of the risk of hypercalcemia. 48 These findings, combined with the epidemiological evidence on the association between low prostate cancer risk and high levels of vitamin D, warrant additional avenues of investigation in this field. Given the emerging interest in the potential role of vitamin D in the etiology of prostate cancer, we review here the current epidemiological literature on vitamin D in relation to prostate cancer risk. We start by providing some background information on vitamin D, such as its dietary sources, metabolism, optimal levels, hypovitaminosis and relationship with the prostate. Basic facts about vitamin D Vitamin D is a fat-soluble steroid prohormone well known for its role in maintaining bone health. 49 Vitamin D is available in small amounts in foods such as fish, eggs and fortified dairy products. In addition, many multivitamins and supplements containing vitamin D are available. 50 Vitamin D 3 is also produced in skin when exposed to sunlight, specifically ultraviolet B radiation. 7-Dehydrocholestrol is converted into vitamin D 3, when skin is exposed to sun. 51 Vitamin D 3 is more efficient than vitamin D 2 in increasing serum 25-hydroxyvitamin D (25(OH)D), the precursor of the biologically active form of vitamin D, 1,25(OH)2D. 52 In the, the dietary reference intake for vitamin D is 200, 400 and 600 IU for adults with age o50, and 470 years, respectively. 50 The prohormone vitamin D, in the form of vitamin D 2 or D 3, is first metabolized to 25(OH)D in the liver and then further metabolized to 1,25(OH)2D by 1-a hydroxylase in the kidneys and other target tissues, such as prostate and colon. 53 Both 25(OH)D and 1,25(OH)2D can be degraded through the catalysis of vitamin D 24- hydroxylase in these tissues Circulating 25(OH)D concentration varies with dietary intake and exposure to sunlight and is considered to be the best indicator of vitamin D status. 50 Therefore, vitamin D status in the circulation depends on exogenous vitamin D sources (from dietary and supplemental intake), endogenous production (through synthesis in the skin) and activities of vitamin D metabolic enzymes. A blood calcidiol [25(OH)D] level is the most accepted way to determine vitamin D nutritional status. The appropriate thresholds to define vitamin D deficiency are debated. 57,58 The most widely accepted optimal level of serum 25(OH)D is ng ml 1. A study showed that for all health-related end points, the most advantageous serum levels for 25(OH)D appeared to be at least 75 nmol l 1 (30 ng ml 1 ) and for cancer prevention, desirable 25(OH)D levels are between 90 and 120 nmol l 1 (36 48 ng ml 1 ). 59 The average older man and woman need intakes of at least mcg ( IU) per day of vitamin D to reach a serum 25(OH)D level of 75 nmol l 1 (30 ng ml 1 ). 57 Hypovitaminosis D The prevalence of vitamin D inadequacy is defined by a low serum 25(OH)D, the major circulating form of vitamin D and a standard indicator of vitamin D status. Lower vitamin D levels are associated with advancing age, 60,61 female sex history of diabetes, 65 hypertension, greater body mass index 66 and a lower estimated glomerular filtration rate. 67 Mean vitamin D levels vary by race/ethnicity, 65 with the highest levels in non- Hispanic whites, intermediate levels in Mexican Americans and the lowest levels in non-hispanic blacks. Vitamin D levels vary by region and are greater in summer than in winter months. 68,69 Higher skin melanin levels increase the risk of vitamin D deficiency. African Americans are more prone to be deficient because of higher skin melanin levels. 70 Vitamin D inadequacy constitutes a largely unrecognized epidemic in many populations worldwide It has been reported in healthy children, 74 adolescents 75 and adults. 76,77 Vitamin D and prostate health Normal and malignant prostate cells contain VDRs, which mediate the antiproliferative action of 1,25(OH)2D. 1,25(OH)2D, the biologically active form of vitamin D, binds to nuclear VDRs in the epithelial cells of the prostate. It has a specific affinity for specific DNA sequences, namely vitamin D response elements. 81 1,25(OH)2D is capable of acting through both nongenomic signaling pathways involving a membraneassociated receptor and genomic pathways involving the nuclear VDR. The binding of vitamin D to these response elements evokes a cascade of genetic events, thus becoming responsible for the formation of proteins. 82 1,25(OH)2D diffuses passively into the cells to bind to the receptor causing a conformational change in the VDR, allowing dimerization with the retinoid receptor. Dimerization enables interaction with the vitamin D response element on target genes, initiating transcription. Vitamin D response element is also found on genes related to cellular differentiation and proliferation, including p21, transforming growth factor-b2, fibronectin, urokinase plasminogen activator and b integrin. These gene products interact with and inhibit cyclindependent kinases, preventing uncontrolled progression through the cell cycle. Vitamin D response elements have also been identified as the promoters of insulin-like growth factor-binding protein-3 and insulin receptor genes. 1,25(OH)2D, therefore, plays an important role in the growth and function of the normal prostate, as well as in prostate carcinogenesis. 10 The reason is that most of the actions of vitamin D are mediated through an intracellular receptor in the prostate that has a much higher affinity for 1,25(OH)2D than for other metabolites. In addition to the antiproliferative action of 1,25(OH)2D, it can cause apoptosis, 39 induce differentiation, 83 inhibit telomerase expression, 84 inhibit tumor cell invasiveness 45 and suppress tumor-induced angiogenesis. 85 Epidemiological studies of vitamin D and prostate cancer risk Search strategy and selection criteria We conducted MEDLINE searches to identify epidemiological studies on the relationship between vitamin D

3 and prostate cancer risk. To identify the studies of prostate cancer risk in relation to vitamin D, we searched using the terms prostate cancer and prostate cancer risk in combination with the following terms: epidemiology, incidence, prevalence, risk factors, vitamin D, sunlight exposure, ultraviolet radiation, geography, dairy, dietary, diet, micronutrients, nutrition, serum vitamin D, serum 1,25(OH)2D3 and serum 25-dihydroxyvitamin D. We also searched the bibliography of the selected papers to identify relevant articles that we might have missed during the primary MEDLINE search. To be included in the review, a study must have been published in English, reported on data collected in humans with prostate cancer, had prostate cancer risk as the primary outcome measure, had vitamin D as one of the or the only risk factor measured as follows (dietary intake, sunlight exposure and serum levels) and had any of the following study designs (case control, cohort, cross-sectional, prospective, retrospective, nested case control, ecological, clinical trial and meta-analysis). There were no restrictions according to age, ethnicity or stage of prostate cancer. Dietary vitamin D and prostate cancer risk The association between dietary factors and prostate cancer has been investigated in several epidemiological studies. The results of these studies are mostly conflicting or negative, 12,15,86 but some dietary components are consistently associated with prostate cancer, for example, high intakes of linolenic acid (a polyunsaturated fatty acid in vegetables and dairy products) 14,87 90 and calcium. 91,92 Table 1 summarizes the epidemiological studies on the association between vitamin D intake and prostate cancer risk. A study found that there is an increased incidence of prostate cancer in migrant Asians as they adopt a Western diet, that is, lacking the large amount of vitamin-d-rich fish oil. 93 In 1992, Hanchette and Schwartz 22 pointed out that men in the were 10 times more likely to develop prostate cancer than men in Japan, where men consume higher amounts of vitamin D because of their consumption of fatty fish. Furthermore, traditional Japanese men consume higher quantities of omega-3 fatty acids than their American counterparts. These fats are known to dissociate vitamin D metabolites from their binding protein, thus raising active levels of those metabolites in the blood. A study found that a high calcium consumption, largely from dairy products, increases the risk of prostate cancer by lowering the levels of circulating 1,25(OH)D. It is the bioactive metabolite of vitamin D that was thought to protect against prostate carcinogenesis, and the conversion of the precursor 25(OH)D to 1,25(OH)2D is inhibited by high calcium intake. However, continuous measures of dietary vitamin D intake were not associated with risk of prostate cancer. 91 The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study investigated the associations between various nutrients hypothesized to influence 1,25(OH)2D (calcium, phosphorus, fructose and animal protein), as well as other aspects of diet, and prostate cancer risk. The study examined six major food groups (dairy, red meat, fish and poultry, vegetables, fruits (including berries) and cereals), the three major macronutrients (fat, protein and carbohydrates), total energy, calcium, phosphorus, vitamin D and fructose. None of the foods or nutrients examined were significantly associated with the risk. 94 Another study assessing the relationship between calcium, phosphorus and vitamin D dietary intake and prostate cancer risk, taking into account the potential confounding effect of several covariates, found no association between selfreported measures of vitamin D intake (obtained retrospectively) and the risk of prostate cancer. 95 Similarly, a prospective study of 3612 men followed from to 1992 for the first National Health and Nutrition Examination Epidemiologic Follow-up Study was conducted to examine the association of dairy, calcium and vitamin D intake with prostate cancer. Dietary calcium was strongly associated with increased risk (relative risk (RR) ¼ 2.2; 95% confidence interval (CI) ¼ 1.4, 3.5; third compared with first tertile; trend P ¼ 0.001). After adjustment for calcium intake, neither vitamin D nor phosphorus was associated with risk. 96 A multiethnic cohort study ( ) examined the association of high intakes of calcium and dairy products with prostate cancer risk among men who completed a detailed quantitative food frequency questionnaire. Nutrient and food intakes were divided into quintiles and no association was found between calcium and vitamin D intake and total, advanced or high-grade prostate cancer risk. In analyses of food groups, dairy product and total milk consumption were not associated with prostate cancer risk. However, low-/non-fat milk was related to an increased risk and whole milk to a decreased risk of total prostate cancer. After stratification, these effects were limited to localized or low-grade tumors. 97 Another study examined the available evidence and sources of heterogeneity for studies of dairy products, calcium, and vitamin D intake and the risk of prostate cancer. The study collected data from 45 observational studies using a general variance-based, meta-analytic method employing CIs. Cohort studies showed no evidence of an association between dairy (RR ¼ 1.06; 95% CI ¼ ) or milk intake (RR ¼ 1.06; 95% CI ¼ ) and the risk of prostate cancer. This was supported by pooled results of case control analyses (RR ¼ 1.14; 95% CI ¼ ), although studies using milk as the exposure of interest were heterogeneous and could not be combined. Dietary intake of vitamin D was not related to prostate cancer risk. 98 The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial study prospectively examined the association of dairy products and calcium intake with prostate cancer risk in men, including 1910 cases. A greater intake of dairy products, particularly low-fat dairy products, was weakly associated with increased risk of prostate cancer. Dietary vitamin D was not associated with prostate cancer; however, risk tends to decrease with greater vitamin D from supplemental sources, with a 40% reduction in men who used 4600 IU of supplemental vitamin D compared with men not using vitamin D supplements. 99 Another study analyzed 454 male participants in the Baltimore Longitudinal Study of Aging who were years old at the time of completion of a food frequency questionnaire. The adjusted odds ratio (OR) of prostate cancer for the highest tertile compared with that for the lowest tertile of vitamin D was 1.21 (95% CI ¼ ; P-trend ¼ 0.46). Likewise, no significant trends were found for phosphorus, fructose or animal 217

4 218 Table 1 Vitamin D intake and prostate cancer risk First author, year, study place Data collection Study design No. of cases/ controls (cohort) RR (95% CI), P-value Conclusion Variables adjusted for Chan, , Sweden Chan, , Finland Tavani, , Italy Tseng, , Park, , Huncharek, , United States Ahn, , Berndt, , United States Kristal, , United States January 1989 to July 1994 Populationbased case control Randomized, doubleblinded placebocontrolled 526/ ( ), Case control 1294/ ( ), and 1992 Prospective cohort Cohort 4404/ Review meta-analysis Cohort 1910/ Dairy-related nutrients, including fat, protein, retinol, phosphorous and vitamin D, were not associated with risk of prostate cancer 184/ ( ), 0.86 Of all the foods and nutrients examined, none was significantly associated with risk No material association of dietary intake of calcium, vitamin D and phosphorus with prostate cancer risk 131/ (0.3, 1.2), 0.16 After adjustment for calcium intake, neither vitamin D nor phosphorus was clearly associated with risk 1.09 ( ), 0.64 There is no association between the intakes of calcium and vitamin D and prostate cancer risk, an association with milk consumption may vary by fat content, particularly for early forms of cancer ( ) Dietary intake of vitamin D was not related to prostate cancer risk 0.61 ( ), Cohort 69/ ( ), January 1993 to 31 December 1996 Populationbased case control 605/592 Local disease 1.06 ( ), 0.98; regional or distant disease 1.13 ( ), 0.19 Risks tended to decrease with greater vitamin D from supplemental sources, with a 40% reduction in men who used 4600 IU of supplemental vitamin D compared with men not using vitamin D supplements No associations between prostate cancer and dietary vitamin D intake were found No associations of vitamin D, total polyunsaturated fatty acids or the highly unsaturated, long-chain eicosapentenoic and docosahexaenoic fatty acids with prostate cancer risk Age, family history of prostate cancer, smoking, and total energy and phosphorous intakes Age, smoking, BMI, total energy, education and supplementation group Age, center, education, BMI (kg m 2 ), tobacco smoking, physical activity, total energy and family history of prostate cancer in firstdegree relatives Age, race, energy intake, US region, education, sun exposure, physical activity, smoking and alcohol Ethnicity, time since cohort entry, BMI, education, family history of prostate cancer and smoking status Not stated Race, study center, family history of prostate cancer, BMI, smoking status, physical activity, red meat intake, total energy intake, history of diabetes and education Tertiles of foods and energyadjusted nutrients, age, total energy, physical activity and intake of phosphorus and fat Age, race, family history of prostate cancer, education, BMI, number of screening PSA tests within 5 years before reference date, the number of servings/day of vegetables and for use of supplemental vitamin E, vitamin C, and zinc Abbreviations: BMI, body mass index; CI, confidence interval; PSA, prostate-specific antigen; RR, relative risk. protein intake. Dairy products, including milk, were not associated with an increased risk of prostate cancer. 100 Finally, one additional study examined the associations of energy, fat, vitamin D and calcium with risk of prostate cancer in 605 incident cases of prostate cancer and 592 controls. Self-administered food frequency questionnaires were used to assess diet over the 3- to 5- year period before diagnosis or interview date. Total energy was associated with increased risk for both local and regional/distant-stage disease. The adjusted ORs contrasting highest to lowest quintile of energy intake were 2.15 (95% CI ¼ ) for local and 1.96 (95% CI ¼ ) for regional/distant disease. Fat was associated with regional/distant disease only. However, there were no associations of vitamin D, total polyunsaturated fatty acids or the highly unsaturated, longchain eicosapentenoic and docosahexaenoic fatty acids with prostate cancer risk. 101

5 Table 2 Serum levels of vitamin D and prostate cancer risk 219 First author, year, study place Data collection Study design No. of cases/ controls (cohort) RR (95% CI), P-value Conclusion Variables adjusted for Ahonen, , Finland Li, , Nomura, , Hawaii, Ahn, , Platz, , Tuohimaa, , Norway, Finland and Sweden Gann, , to the end of 1995 Nested case control Case control 1066/ ( ), 0.91 a 0.91 ( ), 0.74 b Nested case control November 1993 to October 2003 Nested case control 149/ ( ), 0.01 a Low levels of 25-VD were associated with an increased risk of prostate cancer 136/ (CI: ), 0.87 b 0.8 ( ), 0.68 a Case control 460/ ( ), 0.16 b 1.19 ( ), 0.59 a Finland, 1981 to 1982; Norway, 1973; Sweden, Longitudinal nested case control Nested case control Vitamin D status, measured by 25(OH)D in plasma, interacts with the VDR FokI polymorphism and modifies prostate cancer risk There is a lack of a strong association between vitamin D and prostate cancer 749/ ( ), 0.15 a Serum 25(OH)D was not associated with risk for nonaggressive disease 622/ ( ) for highest and 1.5 ( ) for lowest quintile of vitamin D a 232/ ( ), 0.50 b 0.92 ( ), 0.82 a No inverse association between plasma concentrations of 1,25(OH)2D or 25(OH)D and incident prostate cancer was observed Both low (o19 nmol l 1 ) and high (480 nmol l 1 ) 25(OH)- vitamin D serum concentrations are associated with higher prostate cancer risk Analysis of risk for increasing quartiles of total or free metabolites did not reveal a pattern of decreasing risk Age, time of sample retrieval, residence, smoking, treatment with gemfibrozil, factors related to insulin resistance syndrome Age, smoking status, exercise and race Age at examination, month and year of examination BMI, vigorous physical activity, calcium intake, study center, history of diabetes, family history of prostate cancer, 25(OH)D assay batch, vigorous physical activity, daily aspirin and/or ibuprofen use, smoking status, total energy, and dairy product, vitamin D and calcium intake Age, history of a PSA test before blood draw, time of day, season and year of blood draw. Father or brother with prostate cancer, height, vigorous physical activity, diabetes mellitus, vasectomy, cigarette smoking in the past 10 years, intake of energy, red meat and fish, intake of energyadjusted lycopene, fructose and a-linolenic acid, and use of vitamin E and selenium supplements Age, date of blood sampling, country and the region inside the country Smoking status, age, season of blood collection Abbreviations: BMI, body mass index; CI, confidence interval; PSA, prostate-specific antigen; RR, relative risk; VDR, vitamin D receptor. a 25(OH)D. b 1,25(OH)2D. Serum vitamin D and prostate cancer risk To date, several observational studies have been conducted to investigate the association between endogenous vitamin D levels and prostate cancer as shown in Table 2. In 1990, Schwartz proposed that vitamin D deficiency may underlie the major risk factors for prostate cancer, including age, black race and northern latitudes. He pointed out that all these factors were associated with a decreased synthesis of vitamin D. The initial hypothesis that vitamin D may have a protective effect against developing prostate carcinoma was raised by Schwartz and Hulka 93. They showed that prostate cancer incidence increases with age, and the elderly are known to have lower levels of vitamin D. Mortality rates from prostate cancer in the were inversely correlated with ultraviolet blue radiation (UVB), the principal source of vitamin D.

6 220 A study conducted to evaluate the association between serum 25(OH)D level and the risk of prostate cancer found that low levels of 25(OH)D were associated with an increased risk for subsequent earlier exposure and more aggressive development of prostate cancer, especially before andropause. Men with a 25(OH)D concentration below the median had an adjusted relative risk (OR) of 1.7 compared with men with 25(OH)D level above the median. The prostate cancer risk was highest among younger men (o52 years) at entry and with low serum 25(OH)D (OR ¼ 3.1 non-adjusted and 3.5 adjusted). Among those younger men (o52 years), a low 25(OH)D entailed a higher risk of non-localized cancers (OR ¼ 6.3). 78 A nested case control study within the Physicians Health Study evaluated 1066 prostate cancer patients and 1618 cancer-free, age- and smokingmatched control participants. The median plasma 25(OH)D levels were 25 ng ml 1 in the blood samples collected during the winter or spring and 32 ng ml 1 in samples collected during the summer or fall. Plasma levels of 1,25(OH)2D did not vary by season. Men whose levels for both 25(OH)D and 1,25(OH)2D were below the median had a significantly increased risk of aggressive prostate cancer (OR ¼ 2.1, 95% CI ¼ ), although the interaction between the two vitamin D metabolites was not statistically significant (P-interaction ¼ 0.23). 102 Another study examined a cohort of 3737 Japanese- American men from 1967 to 1970, and after a surveillance period of over 23 years, the researchers identified 136 tissue-confirmed incident cases of prostate cancer. Their stored sera and those of 136 matched controls were measured for the following: 25(OH)D, 1,25(OH)2D, calcium, phosphorus and parathyroid hormone. Subjects with high serum levels of both 25(OH)D and 1,25(OH)2D had an OR of 0.5 compared with subjects who had a low level of both vitamin D metabolites, but the difference was not statistically significant. 103 However, it is to be noted that there was a one-time blood draw and 23 years in between in which changes could have occurred in vitamin D levels. Similarly, another nested case control study investigated the association between vitamin D status, as determined by serum 25(OH)D level, and the risk of prostate cancer within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. No statistically significant trend in overall prostate cancer risk was observed with increasing season standardized serum 25(OH)D level. The findings of this large prospective study did not support the hypothesis that high levels of vitamin D are associated with decreased risk of prostate cancer. Instead, they postulated that higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease. 104 Yet another study was conducted to determine the levels of plasma 1,25(OH)2D and 25(OH)D and subsequent risk of prostate cancer. The OR of prostate cancer comparing men in the top to bottom quartile of 1,25(OH)2D was 1.25 (95% CI ¼ , P-trend ¼ 0.16). For 25(OH)D, the OR of prostate cancer comparing the top and bottom quartiles was 1.19 (95% CI ¼ , P-trend ¼ 0.59). These findings did not vary by level of the other metabolite, age at diagnosis, family history of prostate cancer or factors that are thought to influence 25(OH)D levels. 105 In a yet another study, serum 25(OH)D levels of 622 prostate cancer cases and 1451 matched controls were investigated, and it was found that both low (o19 nmol l 1 ) and high (480 nmol l 1 ) 25(OH)D serum concentrations are associated with a higher prostate cancer risk. 106 A study by Clemens et al. 107 reported high incidence of prostate cancer in blacks who are known to have relative low levels of vitamin D. A nested case control study evaluated the relationship between plasma levels of the two major vitamin D metabolites, 25(OH)D and 1,25(OH)2D, and subsequent diagnosis of prostate cancer. Plasma samples from participants in the Physicians Health Study were collected and frozen in This analysis included 232 cases diagnosed up to 1992 and 414 age-matched control participants. Analysis for increasing quartiles of total or free metabolites did not reveal a pattern of decreasing risk. 108 Sunlight exposure and prostate cancer risk Ultraviolet blue radiation promotes the endogenous synthesis of vitamin D 3, and a number of studies show that UVB radiation plays an important role in vitamin D 3 status in humans, even at northern latitudes Thus, indirectly, sunlight exposure plays an important role as a factor affecting prostate cancer risk. 112,113. Several studies have been conducted to evaluate this association as shown in Table 3. One study compared UVB exposure between 210 cases and 155 controls. Childhood sunburn, regular foreign holidays, sunbathing score and low exposure to UVB were associated with the development of prostate cancer. Furthermore, cases with low UVB exposure developed cancer at a younger median age than cases with higher exposure. Thus, it was concluded that UVB had a protective effect against development of prostate cancer. 28 In 1992, Hanchette and Schwartz 22 proposed that sunlight and vitamin D may play a role in prostate cancer. Mortality rates in the from prostate cancer showed a negative correlation with UVB exposure. To support their hypothesis, Hanchette and Schwartz analyzed American prostate cancer deaths in relation to sunlight and discovered a negative correlation. That is, they found that men who received more sunlight were less likely to die from prostate cancer. In the same year, Schwartz discovered that death rates from prostate cancer were correlated with death rates from multiple sclerosis, another disease known to be associated with a lack of sunlight. Again, he proposed that lack of vitamin D may be a causative factor in both diseases. 114 Another study conducted to determine the association of sunlight exposure with prostate cancer risk showed that sun exposure and VDR polymorphisms together play an important role in the etiology of prostate cancer. Interview data on lifetime sun exposure and other risk factors were collected for 905 non-hispanic white men (450 cases and 455 controls). A reduced risk of advanced prostate cancer was associated with high sun exposure determined by reflectometry and high occupational outdoor activity. 26 Yet another study analyzed data from the first National Health and Nutrition Examination Survey to test the hypothesis that residential sunlight exposure reduces the risk of prostate cancer and found that residence in the southern at baseline (RR ¼ 0.68, CI ¼ ), the state of longest residence in the south (RR ¼ 0.62, CI ¼ ) and high solar radiation in the state of birth (RR ¼ 0.49, CI ¼ )

7 Table 3 Sunlight exposure and prostate cancer risk 221 First author, year, study place Data collection Study design No. of cases/ controls (cohort) RR (95% CI), P-value Conclusion Variables adjusted for Luscombe, , UK Hanchette, , United States John, , John, , John, , Rukin, , UK De Vries, , Netherlands Colli, , Bodiwala, , UK Luscombe, , UK 2001 Case control 210/155 Childhood sunburn, 0 18 ( ); regular foreign holidays, (0.41, ); sunbathing score, (0.83, ); and low exposure to UVB, (3.03, ) Ecological (r ¼ 0.25, P ¼ ) for epidemiological index and (r ¼ 0.15, Po0.0001) for UV count July 1997 to December to to 1992 Case control 450/455 High sun exposure determined by reflectometry, 0.51 ( ), 0.02; and high occupational outdoor activity, 0.73 ( ), 0.3 UVB radiation protects against the development of prostate cancer UVB radiation may protect against clinical prostate cancer. Vitamin D may have an important role in the natural history of prostate cancer Sun exposure and VDR polymorphisms together play important roles in the etiology of prostate cancer Cohort 153/ ( ) Sunlight exposure reduces the risk of prostate cancer and has important implications for prostate cancer prevention Cohort 161/3367 For men born in a region of high solar radiation, 0.49 ( ); recreational sun exposure in adulthood, 0.47 ( ) Case control 528/365 Regular foreign holidays, 0.64 ( ), 0.010; childhood sunburn, 0.35 ( ), o Populationbased cohort (incidence) and (mortality) August 2001 to April 2002 October 1999 to May No direct relationship between UV radiation exposure and prostate cancer was measured Ecological _ (r ¼ 0.42, Po0.01) for white men and (r ¼ 0.40, Po0.05) for black men Case control 212/135 Positive childhood sunburn, 0.42 ( ), 0.014; regular foreign holidays, 0.56 ( ), 0.02; adult sunbathing 0.79, ( ), ; living abroad in a hot country for more than 6 months 0.89 ( ), Case control 210/155 Childhood sunburn, 0.13 ( ), o0.001; adult sunbathing score, 0.84 ( ), o0.001; foreign holidays, 0.44 ( ), In addition to sun exposure in adulthood, sun exposure in early life protects against prostate cancer Sunlight exposure patterns determine reduced prostate cancer risk Exposure to ultraviolet radiation protects against prostate cancer development and possibly against its progression Increased solar UVB radiation might reduce the risk of prostate cancer, but the efficacy depends on the season of UVB irradiance Although the parameters of exposure were significantly associated with prostate cancer, living abroad in a hot climate for 6 months or more was not linked with risk Chronic and acute UV exposure and, genes associated with response to UV were associated with risk of prostate cancer Vasectomy status and diet Geographical region Race, family history of prostate cancer and age Age, family history of prostate cancer, and dietary intake of fat and calcium Family history of prostate cancer, fat intake or calcium intake Age, skin type Age and calendar period of the skin cancer diagnosis Season of the year and race Age at diagnosis Age at diagnosis Abbreviations: CI, confidence interval; RR, relative risk; UVB, ultraviolet blue radiation; VDR, vitamin D receptor. were associated with significant and substantial reductions in prostate cancer risk. 25 Analysis of data from the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study was conducted to examine associations of prostate cancer risk with earlylife and adult residential sun exposure and adult sun exposures. Solar radiation in the state of birth was used as a measure of sun exposure in early life. Significant inverse associations were found for men born in a region of high solar radiation, with a slightly greater reduction for fatal than for non-fatal prostate cancer. Frequent recreational sun exposure in adulthood was associated

8 222 with a significantly reduced risk of fatal prostate cancer only. These findings suggest that, in addition to sun exposure in adulthood, sun exposure in early life protects against prostate cancer. 27 Yet another study was conducted to investigate the effects of sunlight exposure on prostate cancer and basalcell carcinoma risk. It found that skin type 1 (OR ¼ 0.47, 95% CI ¼ ), childhood sunburn (OR ¼ 0.38, 95% CI ¼ ), occasional/frequent sunbathing (OR ¼ 0.21, 95% CI ¼ ), lifetime weekday (OR ¼ 0.85, 95% CI ¼ ) and weekend exposure (OR ¼ 0.79, 95% CI ¼ ) were associated with reduced prostate cancer risk. Combinations of one or two parameters were associated with a progressive decrease in the ORs for prostate cancer risk (OR ¼ ), with a corresponding increase in BCC risk (OR ¼ ). 115 In a cohort study, the incidence rates of prostate cancer among skin cancer patients were compared with those in the reference population. Skin cancer patients were at a decreased risk of developing prostate cancer compared with the general population (standardized incidence ratio (SIR) ¼ 0.89, 95% CI ¼ 0.78, 0.99), especially shortly after diagnosis. The risk of advanced prostate cancer was significantly decreased (SIR ¼ 0.73, 95% CI ¼ 0.56, 0.94), indicating a possible antiprogressive effect of UVB. Patients with a skin cancer in the chronically UVBexposed head and neck area (SIR ¼ 0.84, 95% CI ¼ 0.73, 0.97) and those diagnosed after the age of 60 years (SIR ¼ 0.86, 95% CI ¼ 0.75, 0.97) had decreased prostate cancer incidence rates. These results supported the hypothesis that UVB protects against prostate cancer. 116 Another study was conducted to assess whether patients with skin cancer have an altered risk of developing other cancers. The study cohort consisted of cases of skin cancer and cases of nonskin cancer as a first cancer extracted from 13 cancer registries. The observed numbers (O) of 46 types of second primary cancer after skin melanoma, basal cell carcinoma or non-basal cell carcinoma, and of skin cancers following non-skin cancers, were compared with the expected numbers (E) derived from the age-, sex- and calendar period-specific cancer incidence rates in each of the cancer registries (O/E ¼ SIR). Rates from cancer registries classified to sunny countries (Australia, Singapore and Spain) and less sunny countries (Canada, Denmark, Finland, Iceland, Norway, Scotland, Slovenia and Sweden) were compared with each other. SIR of all second solid primary cancers (except skin and lip) after skin melanoma were significantly lower for the sunny countries (SIR(S) ¼ 1.03; 95% CI ¼ ) than that for the less sunny countries (SIR(L) ¼ 1.14; 95% CI ¼ ). The study concluded that vitamin D production in the skin decreased the risk of several solid cancers (especially stomach, colorectal, liver and gallbladder, pancreas, lung, female breast, prostate, bladder and kidney cancers). 117 Similarly, another study was conducted to investigate whether the incidence of prostate cancer and mortality rates in the correlated inversely with UVB radiation levels computed from a mathematical model using forecasted ozone levels, cloud levels and elevation. The authors found an inverse correlation between the UVB levels and prostate cancer incidence (R ¼ 0.42, Po0.01) and mortality rates (R ¼ 0.53, Po0.001) for white men and for incidence (R ¼ 0.40, Po0.05) for black men, but the strength of the correlation depended on the season of UVB irradiance. The annual prostate cancer incidence and mortality rates for white men correlated most strongly with UVB exposure levels in the fall and winter, and incidence rates for black men correlated with UVB exposure levels in the summer. 118 Yet another study examined the association of VDR genotypes (variants at the CDX-2, Fok1 and Taq1 sites), haplotypes and genotype combinations with prostate cancer risk by studying 368 prostate cancer and 243 benign BPH patients. It found that CDX-2, Fok1 and Taq1 genotype and haplotype frequencies were not significantly different in cancer and BPH patients. It also studied the associations of variants with risk in men stratified into low (below median) and high (above median) cumulative exposure/year groups. In men with UVB exposure above the median (1100 h per year), CDX- 2 GA and AA (OR ¼ 2.11 and 2.02, respectively) and Fok1 ff (OR ¼ 2.91) were associated with increased prostate cancer risk. No associations were observed for Taq1 genotypes. These data indicated that VDR variants influence prostate cancer risk and that this association is dependent on the extent of UVB exposure. 119 Given the extensiveness of the available literature on the beneficial effect of sunlight exposure on prostate cancer risk, Moon et al. 120 conducted a review study and concluded that exposure to UVB lowers the risk of prostate cancer. Their findings suggest that, first, host factors, such as skin pigmentation, that affect UVBinduced synthesis of vitamin D and, second, polymorphism in genes that mediate the effectiveness of vitamin D action affect the risk for a variety of diseases including prostate cancer. Similarly, Bodiwala et al. 121 conducted a study to confirm this hypothesis in 212 prostate adenocarcinoma and 135 BPH patients. Their aim was to determine whether earlier findings showing a protective effect for UVB exposure could be reproduced. They confirmed that higher levels of cumulative exposure, adult sunbathing, childhood sunburning and regular holidays in hot climates were each independently and significantly associated with a reduced risk of prostate cancer. Another study was conducted to determine whether VDR (Taql and Fokl variants), tyrosinase (TYR, codon 192 variant) and melanocortin-1 receptor (MC1R, Arg151Cys, Arg160Trp, Val92Met, Asp294His and Asp84Glu variants) genotypes were associated with prostate cancer risk. UVB exposure was determined using a questionnaire. Stratification of cases and controls by quartiles of exposure showed that the protective effect of TYR A1A2 (P ¼ 0.006, OR ¼ 0.075) and A2A2 (P ¼ 0.003, OR ¼ 0.055) was particularly strong in subjects who had received the greatest exposure. They showed that allelism in genes linked with skin pigment synthesis is associated with prostate cancer risk possibly because it mediates the protective effects of UVB. Hence, they concluded that susceptibility to prostate cancer is associated with an interaction between host predisposition and sun exposure. 122 Discussion Carcinoma of the prostate continues to be a major health problem in the. Newly diagnosed prostate

9 cancers are being detected at an early stage in men presenting with no symptoms with abnormal prostatespecific antigen level. As more and more men are being diagnosed with prostate cancer worldwide, knowledge about the etiology and prevention of this disease is important. Despite its high morbidity, the etiology of prostate cancer remains largely unknown. Advancing age, race and a family history of prostate cancer are the only established risk factors. Many putative risk factors, including androgens, diet, physical activity, sexual factors, inflammation and obesity, have been implicated, but their roles in prostate cancer etiology remain unclear. It is estimated that as much as 42% of the risk of prostate cancer may be accounted for by genetic influences. The pathogenesis of prostate cancer likely involves interplay between environmental and genetic factors. To unravel these complex relationships, large well-designed interdisciplinary epidemiological studies are needed. Results of these studies may lead to better detection, treatment and, ultimately, the prevention of prostate cancer. The increasing interest in the role of vitamin D in prostate carcinogenesis and fluctuating results of epidemiological studies warranted the review of all available literature to come to a fruitful conclusion. This review shows that UVB exposure may play a role in the risk of prostate cancer. Ten studies were reviewed and most appeared to show a protective role for sunlight/uvb exposure. The inverse association between sunlight exposure and prostate cancer risk has led researchers to explore whether or not vitamin D may explain this association. In this review, dietary intake of vitamin D did not appear to be protective for prostate cancer risk in the nine studies reviewed. However, the findings by Ahn 99 of a 40% risk reduction with 4600 IU of supplemental vitamin D intake compared with men not using supplements may suggest that dietary intake of vitamin D needs to be higher than the current dietary reference intake to be protective. The current dietary reference intakes are set based on the assumption that some of our need for vitamin D can be met with sun/uvb exposure. As individuals are spending less time in the sun and/or wearing sunscreen, there is current speculation that the dietary reference intakes may need to be increased. If this happens, intake from a combination of food and supplements may have to exceed 600 IU. Finally, we also reviewed seven studies evaluating serum levels of 25(OH)D and prostate cancer risk. These studies yielded conflicting results, with four studies showing no correlation with serum levels and prostate cancer risk. One study showed increased risk with both low and high serum levels. 106 One study by Ahonen et al. 78 found that low serum levels were associated with increased risk of prostate cancer. Future studies in this area should address timing of the drawing of serum levels and development of disease, as well as considering serial measurements of vitamin D over time. For example, the study by Nomura et al. 103 relied on a one-time blood draw and correlated that draw with the development of disease after a 23-year surveillance period. It is likely that there were fluctuations in serum levels over that time period. Attempts to review this literature were conducted before this one. The first one was conducted in The paper gave in-depth information about the in vitro and in vivo studies but did not describe the epidemiological studies in detail. 40 A second review conducted recently concluded that the evidence to date does not strongly support an association between plasma vitamin D status in adulthood and prostate cancer risk. However, the authors cautioned that the absence of a link between vitamin D and prostate cancer risk, even if ultimately confirmed, should not be misinterpreted as evidence against other well-documented health benefits of vitamin D. The review did not describe all available epidemiological studies in the literature on the association between vitamin D and prostate cancer risk. 123 To further confirm the potential protective effects of calcium and vitamin D on prostate cancer, well-designed cohort studies and clinical trials are warranted. A few clinical trials have been conducted to study this hypothesis. In a secondary analysis of a clinical trial designed to investigate calcium supplementation as a chemopreventive strategy against colorectal cancer, Baron et al. 124 assessed vitamin D status and incident prostate cancer. They randomized 672 men to receive either 3 g of calcium carbonate or a placebo over a 4-year period. Men randomized to the treatment arm experienced a slightly reduced risk of prostate cancer. Baseline serum concentrations of 25(OH)D were not associated with the risk of disease. In spite of the inconsistent epidemiological results, in vitro studies continue to show the role of vitamin D as an antiproliferative and antimetastatic agent. Demonstration of VDR on prostate tissue has only added a positive note to the hypothesis, favoring the inverse association between vitamin D and prostate cancer risk. To address this issue, observational studies with very large sample sizes or clinical trials with appropriate study designs are required. We conclude that even though the results of epidemiological studies are conflicting, we should not ignore the fact that vitamin D deficiency is found to be associated with prostate cancer risk either as primarily as UVB exposure, or as a dietary factor, or as an endogenous entity. A thorough research on this subject in the form of large prospective observational studies and interventional clinical trials in the near future will provide us with a better understanding of the role of vitamin D in preventing prostate cancer. Acknowledgements This study was funded by Cancer Treatment Centers of America s. References 1 Bono AV. The global state of prostate cancer: epidemiology and screening in the second millennium. BJU Int 2004; 94 (Suppl 3): Brawley OW, Barnes S. The epidemiology of prostate cancer in the. Semin Oncol Nurs 2001; 17: Chodak G. Prostate cancer: epidemiology, screening, and biomarkers. Rev Urol 2006; 8 (Suppl 2): S3 S8. 4 Damber JE. Prostate cancer: epidemiology and risk factors. Curr Opin Urol 1998; 8: Gronberg H. Prostate cancer epidemiology. Lancet 2003; 361: