Risk Factors for Prostate Cancer Development
Prostate cancer incidence escalates dramatically with increasing age. Although it is a very unusual disease in men younger than 50 years, rates increase exponentially thereafter. The registration rate by age cohort in England and Wales increased from eight per thousand population in men aged 50 to 56 years to 68 per thousand in men aged 60 to 64 years; 260 per thousand in men aged 70 to 74 years, and peaked at 406 per thousand in men aged 75 to 79 years. In this same population, the death rate per thousand in 1992 in cohorts of men aged 50 to 54 years, 60 to 64 years, and 70 to 74 years was 4, 37, and 166, respectively. At all ages, incidence of prostate cancer in blacks exceeds those of whites.
Approximately 15% of men with a diagnosis of prostate cancer will be found to have a first-degree male relative (e.g., brother, father) with prostate cancer, compared with approximately 8% of the U.S. population. Approximately 9% of all prostate cancers may result from heritable susceptibility genes. Several authors have completed segregation analyses, and though a single, rare autosomal gene has been suggested to cause cancer in some of these families, the burden of evidence suggests that the inheritance is considerably more complex.[5-7]
The development of the prostate is dependent upon the secretion of dihydrotestosterone (DHT) by the fetal testis. Testosterone causes normal virilization of the Wolffian duct structures and internal genitalia and is acted upon by the enzyme 5-alpha-reductase (5AR) to form DHT. DHT has a 4-fold to 50-fold greater affinity for the androgen receptor than testosterone, and it is DHT that leads to normal prostatic development. Children born with abnormal 5AR (due to a change in a single base pair in exon 5 of the normal type II 5AR gene), are born with ambiguous genitalia (variously described as hypospadias with a blind-ending vagina to a small phallus) but masculinize at puberty because of the surge of testosterone production at that time. Clinical, imaging, and histologic studies of kindreds born with 5AR deficiency have demonstrated a small, pancake-appearing prostate with an undetectable prostate-specific antigen (PSA) level and no evidence of prostatic epithelium. Long-term follow-up demonstrates that neither benign prostatic hyperplasia (BPH) nor prostate cancer develop.
Other evidence suggesting that the degree of cumulative exposure of the prostate to androgens is related to an increased risk of prostate cancer includes the following:
- Neither BPH nor prostate cancer have been reported in men castrated prior to puberty.
- Androgen deprivation in almost all forms leads to involution of the prostate, a fall in PSA levels, apoptosis of prostate cancer and epithelial cells, and a clinical response in prostate cancer patients.[10,11]
- The results of two large-scale chemoprevention trials using 5AR inhibitors (finasteride and dutasteride) demonstrate that intraprostatic androgens modulate prostate cancer risk. In both studies, reductions in overall prostate cancer risk were identified although with increased risk of high-grade disease.[12,13]
Ecological studies have found a correlation between serum levels of testosterone, especially DHT, and overall risk of prostate cancer among African American, white, and Japanese males.[14-16] However, evidence from prospective studies of the association between serum concentrations of sex hormones, including androgens and estrogens, does not support a direct link. A collaborative analysis of 18 prospective studies, pooling prediagnostic measures on 3,886 men with incident prostate cancer and 6,438 control subjects, found no association between the risk of prostate cancer and serum concentrations of testosterone, calculated-free testosterone, dihydrotestosterone sulfate, androstenedione, androstanediol glucuronide, estradiol, or calculated-free estradiol. A caution for interpreting the data is the unknown degree of correlation between serum levels and prostate tissue level. Androstanediol glucuronide may most closely reflect intraprostatic androgen activity, and this measure was not associated with the risk of prostate cancer. This lack of association affirms that risk stratification cannot be made on serum hormone concentrations.
The risk of developing and dying from prostate cancer is dramatically higher among blacks, is of intermediate levels among whites, and is lowest among native Japanese.[18,19] Conflicting data have been published regarding the etiology of these outcomes, but some evidence is available that access to health care may play a role in disease outcomes.
An interesting observation is that although the incidence of latent (occult, histologically evident) prostate cancer is similar throughout the world, clinical prostate cancer varies from country to country by as much as 20-fold. Previous ecologic studies have demonstrated a direct relationship between a country’s prostate cancer-specific mortality rate and average total calories from fat consumed by the country’s population.[22,23] Studies of immigrants from Japan have demonstrated that native Japanese have the lowest risk of clinical prostate cancer, first generation Japanese-Americans have an intermediate risk, and subsequent generations have a risk comparable to the U.S. population.[24,25] Animal models of explanted human prostate cancer have demonstrated decreased tumor growth rates in animals who are fed a low-fat diet.[26,27] Evidence from many case-control studies has found an association between dietary fat and prostate cancer risk,[28-30] though studies have not uniformly reached this conclusion.[31-33] In a review of published studies of the relationship between dietary fat and prostate cancer risk, among descriptive studies, approximately half found an increased risk with increased dietary fat and half found no association. Among case-control studies, about half of the studies found an increased risk with increasing dietary fat, animal fat, and saturated and monounsaturated fat intake while approximately half found no association. Only in studies of polyunsaturated fat intake were three studies reported of a significant negative association between prostate cancer and fat intake. Fat of animal origin seems to be associated with the highest risk.[20,35] In a series of 384 patients with prostate cancer, the risk of cancer progression to an advanced stage was greater in men with a high fat intake. The announcement in 1996 that cancer mortality rates had fallen in the United States prompted the suggestion that this may be caused by decreases in dietary fat intake during the same time period.[37,38]
Two studies were conducted within the Prostate Cancer Prevention Trial in which prospective nutritional information was collected and all subjects were recommended to undergo biopsy. Findings included that, among 9,559 subjects there was no association between any supplement or nutrient (including fat) and risk of prostate cancer overall but the risk of high-grade cancer was associated with high intake of polyunsaturated fats. In a subset of 1,658 cases and 1,803 controls, specific fatty acids were examined and docosahexaenoic acid was associated with risk of high-grade disease while trans-fatty acids (TFA) 18:1 and TFA 18:2 were inversely associated with risk of high-grade disease. These large scale studies suggest a complex relationship between nutrients such as fat and risk of prostate cancer.[39,40]
The explanation for this possible association between prostate cancer and dietary fat is unknown. Several hypotheses have been advanced, including:
- Dietary fat may increase serum androgen levels, thereby increasing prostate cancer risk. This hypothesis is supported by observations from South Africa and the United States that changes in dietary fat intake change urinary and serum levels of androgens.[41,42]
- Certain types of fatty acids or their metabolites may initiate or promote prostate carcinoma development. The evidence for this hypothesis is conflicting, but one study suggests that linoleic acid (omega-6 polyunsaturated fatty acid) may stimulate prostate cancer cells, while omega-3 fatty acids inhibit cell growth.
- An observation made in an animal model is that male offspring of pregnant rats who are fed a high-fat diet will develop prostate cancer at a higher rate than animals who are fed a low-fat diet. This observation may explain some of the variations in prostate cancer incidence and mortality among ethnic groups; an observation has been made that first trimester androgen levels in pregnant blacks are higher than those in whites.
Dairy and Calcium Intake
In a meta-analysis of ten cohort studies (eight from the United States and two from Europe), it was concluded that men with the highest intake of dairy products (relative risk [RR] = 1.11; 95% confidence interval [CI], 1.00–1.22; P = .04) and calcium (RR = 1.39; 95% CI, 1.09–1.77; P = .18) were more likely to develop prostate cancer than men with the lowest intake. The pooled RRs of advanced prostate cancer were 1.33 (95% CI, 1.00–1.78; P = .055) for the highest versus lowest intake categories of dairy products and 1.46 (95% CI, 0.65–3.25; P > .2) for the highest versus lowest intake categories of calcium. High intake of dairy products and calcium may be associated with an increased risk of prostate cancer although the increase may be small.
Regular multivitamin use has not been associated with the risk of early or localized prostate cancer. However, in this large (295,344 men) study, there was a statistically significantly increased risk of advanced and fatal prostate cancer among men with excessive use of multivitamins.
The Aspirin/Folate Polyp Prevention Study, a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas, was conducted between July 6, 1994, and December 31, 2006. In a secondary analysis, the authors addressed the effect of folic acid supplementation on the risk of prostate cancer. Participants were followed for up to 10.8 (median = 7.0, interquartile range = 6.0–7.8) years and asked periodically to report all illnesses and hospitalizations. Supplementation with 1 mg of folic acid was associated with an increased risk of prostate cancer. However, dietary and plasma levels among nonmultivitamin users were inversely associated with risk. These findings highlight the potentially complex role of folate in prostate carcinogenesis.[48,49]
Cadmium exposure is occupationally associated with nickel-cadmium batteries and cadmium recovery plant smelters and is associated with cigarette smoke. The earliest studies of this agent documented an apparent association, but better-designed studies have failed to note an association.[51,52]
Dioxin (2,3,7,8 tetrachlorodibenzo-p-dioxin or TCDD) is a contaminant of an herbicide used in Vietnam. This agent is similar to many components of herbicides used in farming. A review of the linkage between dioxin and prostate cancer risk by the National Academy of Sciences Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides, found only two articles on prostate cancer with sufficient numbers of cases and follow-up to allow analysis.[53,54] The analysis of all available data suggests that the association between dioxin exposure and prostate cancer is not conclusive.
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