Low sun exposure and elevated serum prostate specific antigen in African American and Caucasian men.
Prostate cancer is the most commonly diagnosed cancer in the United States (Boring, Squires, Tong, & Montgomery, 1994), and it is the second leading cancer-related cause of death among men (Carter & Coffey, 1988). Its distribution is far from uniform, however. The strongest determinant is age, with 80% of diagnosed cases being in men older than 65 (Boring, et al. 1994). Mortality rates vary greatly between countries. For example, rates in Japan are one fifteenth those in America, although rates among Japanese immigrants quadruple after migration to the United States (Haenszel & Kurihara, 1968). Within the U.S., mortality rates in African Americans are twice those of white men, and these differences are not attributable to differences in socioeconomic class (Ernster, et al., 1977). Finally, mortality rates vary geographically, with rates between countries varying 10-fold (Zaridze, Boyle, & Smans, 1984). However, autopsy studies have found that the prevalence of latent prostate cancer does not vary greatly between countries (Yatani, et al., 1982), suggesting that the variation in mortality may be caused by factors affecting tumor growth (Dhom, et al. 1983).
Much of this variation fits with the hypothesis that vitamin D deficiency increases the risk of prostate cancer (Schwartz & Hulka, 1990). Vitamin D is synthesized in the skin after exposure to UV radiation (Holick, 1989), so the sun is the major source of vitamin D (Holick, 1990). Ecological studies at both the state (Schwartz & Hulka, 1990) and national (Hanchette & Schwartz, 1992) have found an inverse association between UV exposure and prostate cancer mortality. The elderly tend to be exposed to less UV light (Lund & Sorenson, 1979) and have reduced ability to synthesize Vitamin D (Baker, Peacock, & Nordin, 1980). Studies have also shown a high prevalence of vitamin D deficiency among older men worldwide (Weisman, Schen, Eisenberg, Edelstein, & Harrell, 1981; McKenna, Freany, Meade, & Muldowney, 1985). High melanin content reduces formation of pre-vitamin D (Clemens, Adams, Henderson, & Holick, 1982; Matsuoka, Wortsman, Haddad, Kolm, & Hollis, 1991), leading to decreased levels of vitamin D in people with increased skin pigmentation (Matsuoka, et al. (1991); M'Buyamba-Kabangu, et al. 1987; Bell, et al. 1985; Reid, Cullen, Schooler, Livingston, & Evans, 1990). This is in accordance with the high rate of prostate cancer observed in African-Americans, although one study found that the differences in vitamin D level were due to socioeconomic class (Meier, et al., 1991). African-Americans have also been found to have equivalent levels of 1,25 dihydroxy vitamin D (1,25- OH-D) (Reid, et al. 1990; Meier, et al., 1991), which is the more biologically active form.
There is also biochemical evidence for vitamin D playing a role in prostate cancer. Vitamin D receptors have been found in prostate cells and many prostate cancer cell lines (Miller, et al., 1992; Skowronski, Peehl, & Feldman, 1993), and genetic variation in the receptor gene has recently been correlated with increased risk of prostate cancer (Ingles, et al., 1997). Overall, there were no significant associations with vitamin D receptor polymorphisms with prostate cancer risk in 372 prostate cancer cases and 591 controls. However, among a subset of men with plasma 25-hydroxyvitamin D below the median, there was a 57% reduction in risk for men with the BB versus the bb genotype (Ma, et al., 1998). In contrast, a cohort of over twenty thousand United States residents had no association between prostate cancer and prediagnostic levels of serum vitamin D metabolites (Braun, Helzlsouer, Hollis, & Comstock, 1995). Ethnic differences, especially in African Americans, have been documented in the commonly used BsmI as a marker for the vitamin D receptor 3' untranslated region genotype. (Ingles et al, 1997).
Vitamin D inhibits the growth of many types of cancer cells in vitro and in vivo (Miller, et al., (1992); Skowronski, et al. (1993); Peehl, et al., (1994); Bahnson et al. (1993); Corder, et al. (1993); Getzengerg et al. (1997), and 1,25 OH vitamin D has been shown in vitro to inhibit normal and cancerous prostate cell growth while promoting cell differentiation (Skowronski, et al., 1993; Peehl, et al., 1994).
The epidemiologic evidence is as yet inconclusive. One study found an association between low levels of 1,25 OH vitamin D and risk of prostate cancer (Braun, et al. (1995). This risk was most significant for men older than fifty-seven, and did not explain increased incidence among African-Americans. Two other studies have failed to reproduce this finding (Gann, et al., 1996; Mettlin, et al. 1997), although neither was able to rule out the possibility of a smaller effect. A recent prospective study found that men with increased calcium intake (which lowers 1,25-OH-D levels) were at greater risk for prostate cancer. In contrast, decreased fructose consumption (which raises 1,25-OH-D levels by transiently lowering phosphorous levels) was associated with decreased risk (Giovannucci, et al., 1998).
Prostate cancer screening consists of the prostate specific antigen (PSA) and the digital rectal examination. The PSA is a blood test that screens for a glyco-protein that is detected only in the epithelial cells of the prostate gland. PSA levels greater than 4ng./ml. suggest prostatic pathology (Catalona, 1996). About 80% of men with PSA levels greater than four will be found to have cancer of the prostate (Cahill, 1995). A recent study found that PSA velocity decreased in men taking 1,25-OH-D (Gross, Stamey, Hancock, & Feldman, 1998). Research on the environmental associations with elevated prostate specific antigen could provide critical early data on the etiology of prostate cancer.
This study is a cross-sectional analysis of baseline data from a community-based cohort of men participating in the South Carolina Prostate Cancer Project (SCPCP), a study funded to test the effect of different educational interventions on participation in prostate cancer screening (Weinrich, Weinrich, Boyd, & Mettlin, 1998). In the original SCPCP cohort, there were 1151 African American men and Caucasian men aged 50-70 years. Among these men, 881 obtained a free prostate cancer examination, including a prostate specific antigen (PSA) assay. Subjects for the present analyses were 685 men (of the 811 men with PSA assays) who completed follow-up telephone interviews that included a self-report of sun exposure. Figure 1 shows details of the recruitment process.
In the initial stage, purposive sampling was used to recruit at-risk men from 11 counties at 216 community sites in central South Carolina. Community sites where men were recruited were distributed as follows: 57.5 % from work sites, 28.7% from churches, and 13.8% from other sources, including barber shops, meal sites, car dealerships, National Association for Advancement of Colored People (NAACP) sites, and housing projects (Weinrich, Boyd, Greene, Mossa, & Weinrich, 1998). The sample included African American men aged 40-49 years that were excluded from the current analyses in order to avoid possible confounding of race effects by age. Other inclusion criteria were no history of prostate cancer; not undergoing diagnostic studies to test for Prostate Cancer; and informed consent.
The men were recruited when they attended community sites where an educational program on prostate cancer was given. Refusal rates are not available for the men who chose to not come to the educational program on the day of the presentation. Almost all program attendees then completed the background questionnaire. There were only 53 refusals for the 216 sites where the programs were presented (an average of 0.2 refusals per site). The reasons given for refusing to complete the questionnaire were: already had exam (4), see a doctor normally (9), and no time (5); thirty-five men gave no reason. Eleven men indicating ethnicity other than African American or Caucasian were excluded from the analyses, resulting in 1,151 men in the initial interview.
In the second stage, men went to see a physician of their own choice for free Prostate Cancer screening, which included a digital rectal examination (DRE) and a serum prostate-specific antigen (PSA) assay. Out of the cohort of 1,151 men ages 50 to 70 years old, 811 (70.5%) obtained PSA assays.
The third stage of recruitment entailed contacting the 811 men about 15 months after their date of PSA screening, in order to assess sun exposure. One hundred twenty-six men from the 811 men were excluded from analyses for the following reasons: unable to contact (71), refused (11), no telephone (32), deceased (2), and contacted, but unable to answer sun exposure question (10). Data were analyzed for the remaining 685 men.
Established protocols that were followed for the first two stages of recruitment: initial and the second stage which involved prostate cancer screening have been published previously (Weinrich, Weinrich, Boyd, & Mettlin, in press). For the third stage of recruitment, all men were called by telephone 15 months after they received the Prostate Cancer screening and asked a series of questions which included the sun exposure question.
The analyses combined data from the initial questionnaire, the serum PSA level, and the sun exposure telephone interview. Seventy five percent of the prostate specific antigen (PSA) results were obtained from SmithKline Beecham Clinical Laboratories, 14% were obtained from Lab Corp, and the rest of the results (11%) from other laboratories.
The question to measure sun exposure was developed by the investigators. The sun exposure question was pilot tested with 40 men and minor changes in the wording made to enhance comprehension. The final question was, "How many days/week do you get outside in the sunlight for at least half an hour?". The four response options were: (1) None, (2) 1-2 times/ week, (3) 3-5 times/week, (4) Over 5 times/week. To avoid small cell sizes, the four possible responses were dichotomized: infrequent sun exposure (0 to 2 times/ week) or frequent sun exposure (3 or more times/week).
A simple logistic regression model was used to calculate the crude odds ratio (OR) for the association of sun exposure categories of PSA (normal/abnormal based on ? 4 ng/ml or > 4 ng/ml). The crude OR in this simple model was compared to the adjusted OR in a model to which one potential confounder (race, age, education, marital status, income, living arrangements, previous screening history, urinary symptoms, or pain in the lower back and groin) had been added. A change in the adjusted OR often percent or more compared to the crude OR was interpreted as evidence of data-based confounding by the added variable (Rothman, & Greenland, 1998).
Race was considered a potential effect modifier for the low sun exposure-abnormal PSA association. A model containing sun exposure, race, and their interaction was therefore examined using the likelihood ratio test (LRT). Although the interaction between sun exposure and race was not statistically significant (p=0.53), melanin-mediated racial differences in the effects of sun exposure upon PSA levels are plausible. Consequently, separate multiple logistic regression models for Caucasians and African Americans were used to investigate further the association between low sun exposure and abnormal PSA levels.
Description of the cohort. African American men represented 47.6% of the sample (Table 1). The three levels of education were roughly equally represented, each with about one third of the sample. Low income men were represented with 19.7% of the men having incomes below $9,600 per year. Most of the men were married (85.1%), and most of the men lived with someone (88.6%).
Most of the men (78.1%) reported a history of previous prostate cancer screening (usually digital rectal examination) at the initial interview. Only 34.2% of the men had ever had a PSA assay and fewer than half of those had obtained a PSA test within the last year. About one-fourth of the sample described urinary symptoms (28.5%) and/or pain in the lower back or groin (29.1%) (Table 1).
Sun exposure and Prostate Specific Antigen (PSA). Of the 685 subjects, 586 (85.6%) reported frequent exposure to the sun (half an hour or more, three or more times per week). The distribution of study variables by sun exposure
status is shown in Table 1. There was an inverse association between sun exposure and abnormal PSA. Only 6.1% of men with frequent sun exposure had an abnormal PSA, versus 10.1% of men with infrequent sun exposure; The corresponding (crude) odds ratio was 0.58. Younger, more educated, and higher income men obtained sun exposure less frequently (p<0.05). Race, age, marital status, living arrangements, previous screening history; urinary symptoms, and pain did not differ significantly with respect to sun exposure.
Potential confounders with PSA. Race, age, education, marital status, and living arrangements as well as previous screening history, urinary symptoms, and pain were considered as potential confounders (Table 2). When considered as potential confounders, only age, education, and income changed the resulting crude OR by ten percent or more, and were therefore included as confounders in the multiple logistic regressions. The other variables were dropped from consideration.
Logistic regression for sun exposure. Results for the multiple logistic regression model, including all subjects and adjusted for age, education, and income, is shown in Table 3. Frequent sun exposure was associated with a 50% lower odds ratio (OR) for an abnormal serum PSA level after adjustment for age, education, and income (OR=0.45; 95% Confidence Interval (CI)=0.21-0.97). Because of the hypothesis that high melanin levels decrease formation of pre-vitamin D(16),(17), separate models of sun exposure and abnormal PSA for African American and Caucasian men were constructed and are also presented in Table 4. Among African American men, frequent sun exposure was associated with a 40% lower odds ratio for an abnormal PSA when adjusted for age, education, and income (from OR=1.00 to OR=0.59; 95% CI=0.20-1.69). The inverse association was even stronger among Caucasian men (OR=0.32; 95% CI=0.10-1.01).
There was no statistically significant difference between African Americans and Caucasian men in the association of sun exposure with PSA level (p=0.8). However, the direction was still consistent with the hypothesis that sun exposure may have a stronger protective effect in Caucasian men than in African American men due to biological differences in sun exposure from different skin pigmentation.
Prostate Cancer. Abnormal PSA was used as the outcome variable because of its biological relevance and because there were too few prostate cancer cases (n=22) to use prostate cancer as an outcome. Three (0.4%) prostate cancer cases were exposed to sun infrequently as defined as 0-2 times per week. In contrast, 19 (2.8%) prostate cancer cases were exposed to sun frequently (3 or more times per week). When the analysis was restricted to men without prostate cancer, the reduction of the odds of abnormal PSA with frequent sun exposure was stronger (adjusted OR=0.28; 95% CI=0.12-0.70, p=0.006).
This cross-sectional study suggests an association between sun exposure and serum prostate specific antigen levels that may vary by race in a community-based cohort of 685 men. Frequent sun exposure was associated with a 50% lower odds ratio for abnormal serum PSA level after adjustment for age, education, and income. Among African American men, frequent sun exposure was associated with a 40% lower odds ratio for abnormal PSA when adjusted for age, education, and income. The association was even stronger, 60%, among Caucasian men. There are no previously published literature that uses PSA as an outcome to which to compare the results. This data supports the hypothesis of increased sun exposure and decreased risk for prostate cancer with the limitation that elevated PSA is not equivalent to prostate cancer. The stronger odds ratio for Caucasian men (60%) verus African American men (40%) supports the increased risk hypothesis due to decreased levels of vitamin D in people with increased skin pigmentation.
Results can be generalized only to populations similar to this southern community-based 6sample. An important limitation of the study is that only one question measured sun exposure. In addition, the outcome variable, elevated PSA, can be an indicator of benign prostatic hyperplasia or prostatitis as well as prostate cancer.
Further studies in African American men and Caucasian men are indicated with more exact measures of ultraviolet exposure, skin color or melanin content, serum Vitamin D levels, and measurement of vitamin D receptor genotype. Future research should be undertaken in a larger sample, in order to confirm the association between limited sun exposure and higher serum PSA levels, and to examine the manner in which the strength of that association may depend on skin pigmentation. More precise measures of sun exposure are needed, as well as better measures of skin pigmentation than the simple dichotomization into Caucasians and African Americans considered here. This research needs to be conducted as it may answer some of the questions associated with increased prostate cancer mortality in African American men.
It is premature to recommend preventive health education of increased sun exposure. However, health educators should begin considering the potential dilemmas associated with conflicting sun preventive measures for prostate cancer and skin cancer. IF additional studies document an association between increased sun exposure and decreased prostate cancer, research would be needed to weigh the risk of increased skin cancer against the decreased risk of prostate cancer. Changing a preventive health care message from decreased sun exposure (for skin cancer) to increased sun exposure (for prostate cancer) should not be undertaken lightly. The impact of changing health care messages from one message to another message needs to be researched. When health messages are changed, there is the potential for a negative impact and/or a public response of "It will change anyway; why should I concern myself?"
Table 1. Distribution of Study Variables by Sun Exposure (N=685) Frequent Infrequent Sun Sun Variable Exposure * Exposure * Total N (%) N (%) N (%) PSA Normal 550 93.9 89 89.9 639 93.3 Abnormal 36 6.1 10 10.1 46 6.7 Demographics Race African-American 286 48.8 40 40.4 326 47.6 Caucasian 300 51.2 59 59.6 359 52.4 Age(+) 50-59 Years 380 64.8 76 76.8 456 66.6 60-70 Years 206 35.2 23 23.2 229 33.4 Education (+) Less than HS 200 34.1 21 21.2 221 32.3 High School 197 33.6 29 29.3 226 33.0 College 189 32.3 49 49.5 238 34.7 Marital Status Married 495 84.5 88 88.9 583 85.1 Not Married 91 15.5 11 11.1 102 14.9 Income (+) $600 123 21.0 12 12.1 135 19.7 $9601-$25,020 220 37.5 28 28.3 248 36.2 >25020 243 41.5 59 59.6 302 44.1 Living Arrangements Alone 67 11.4 7 7.1 74 10.8 With Someone 516 88.1 91 91.9 607 88.6 Missing 3 0.5 1 1.0 4 0.6 Screening History Yes screen-past year 78 13.3 14 14.1 92 13.4 Yes screen-year ago 374 63.8 69 69.7 443 64.7 No screen 134 22.9 16 16.2 150 21.9 PSA Screen History Yes screen-past year 91 15.5 15 15.2 106 15.5 Yes screen-year ago 110 18.8 18 18.2 128 18.7 No screen 385 65.7 66 66.7 451 65.8 DRE Screen History Yes screen-past year 157 26.8 32 32.3 189 27.6 Yes screen-year ago 285 48.6 50 50.5 335 48.9 No screen 144 24.6 17 17.2 161 23.5 Urinary Symptoms 169 28.8 26 26.3 195 28.5 Pain in groin, back, upper legs, testicles 174 29.7 25 25.3 199 29.1 * Frequent sun exposure =>3 times/week; infrequent sun exposure =<2 times/week Table 2. The Effects of Potential Confounders on the Association Between Frequent Sun Exposure and Abnormal Serum PSA Levels (N=685). Adjusted Odds Ratio for effect of Frequent Adjustment Variable Sun Exposure 95% CI None 0.58 (crude OR) 0.28-1.22 Race 0.55 0.26-1.16 Age 0.50 * 0.24-1.07 Education 0.52 * 0.25-1.11 Marital Status 0.58 0.28-1.20 Income 0.49 * 0.23-1.05 Living Arrangements" 0.56 0.27-1.17 Previous Screening History 0.58 0.28-1.22 Urinary Symptoms 0.58 0.28-1.20 Pain 0.58 0.28-1.21 * Data-based confounder of the Sun Exposure-Abnormal PSA relationship: adjusted OR differs by more than 10% from crude OR. "N=681 for this variable. Table 3. Multivariate-Adjusted Associations of Abnormal Serum PSA and Sun Exposure and Other Selected Exposures (Confounding Variables). Variable Odds Ratio 95% CI Sun Exposure 0.45 * 0.21-0.97 Age 50-59 years 1.00 60-70 years 2.32 * 1.24-4.34 Education Less than High School 1.08 0.44-2.64 High School 1.19 0.52-2.72 Some College and above 1.00 Income $9600 2.02 0.94-4.32 $9600-$25020 1.00 >$25020 0.77 0.34-1.74 * p<0.05 Table 4. Separate Multivariate-Adjusted Associations of Abnormal Serum PSA and Sun Exposure and Other Selected Exposures (Confounding Variables) in African-American and Caucasian Men Aged 50-70 Years. African-American Caucasian Odds Odds Variable Ratio 95% CI Ratio 95% CI Sun Exposure 0.59 0.20-1.69 0.32 0.10-1.01 Age 50-59 years 1.00 1.00 60-70 years 1.68 0.74-3.83 4.52 * 1.56-13.05 Education Less than High School 1.36 0.41-4.42 0.74 0.17-3.22 High School 1.30 0.39-4.34 1.16 0.37-3.69 Some College and above 1.00 1.00 Income $9600 2.49 0.95-6.53 0.93 0.17-4.94 $9600-$25020 1.00 1.00 >$25020 1.30 0.38-4.47 0.57 0.19-1.72 * p<0.05
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Sally Weinrich, Ph.D., R.N., is with the School of Nursing at the University of Louisville. Gary Ellison, M.P.H., is with the National Cancer Institute. Martin Weinrich, Ph.D., is with the School of Medicine at the University of Louisville. Kevin S. Ross is with the University of North Carolina at Chapel Hill and Carol Reis-Starr, Ph.D., is in the Divison of Geriatric Medicine & Gerontology at Emory University. Address all correspondence to Dr. Weinrich at: School of Nursing; University of Louisville; Louisville, Kentucky, 40292; Phone: 502.852.8782; FAX: 502.852.8783; e-mail: email@example.com.
This research was supported by the National Cancer Institute, R01 CA60561-01. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.