Risk of DHT Formation

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Men castrated at a young age and patients with male hypogonadism seldom experience prostate cancer. Ethnic differences in the incidence of clinical prostate cancer are evident, although differences in the incidence of latent cancer among the races are small. Therefore, the activity of 5a-reductase in the formation of DHT may be an etiological and/or progressive factor in clinical cancer.42

The levels of total and free testosterone in African-Americans were 19% and 21% higher than those in whites (both p = 0.02), respectively.43 Three reports, in which testosterone, DHT, estradiol, and sex hormone-binding globulin were measured in prospective cohort studies, were reviewed by meta-analysis.44 Men whose total testosterone level was in the highest quartile were 2.34-fold more likely to develop prostate cancer than men in the lowest quartile. Levels of DHT and estradiol did not differ significantly, but low sex hormone-binding globulin was revealed as a risk factor. Thus, levels of circulating bioavailable testosterone may be associated with prostate cancer. On the contrary, the serum testosterone level in Japanese youths was not different from that of Caucasian and African-American youths in the USA, but the latter two groups had increased serum levels of 3a,17p-androstanediol glucuronide and andros-terone glucuronide, suggesting high DHT formation.45 Racial differences in the activity of SRD5A2 continue as men age.46 A high serum testosterone level correlates with high grade cancer47 and increased risk of relapse.48 Conversely, patients with high grade cancer had correlated low level of serum testosterone,49'50 however, the initial step in the development of prostate cancer may be proceeded more by increased levels of androgen. The activity of 5a-reductase in the prostate increased by various androgens via feed-forward control.51-53 Therefore, an increased level of testosterone, even a small increase, serves as a substrate and raises the activity of 5a-reductase, which consequently elevates the DHT level.

The gene encoding SRD5A2 contains five exons and is located on chromosome 2p23. No specific mutations or polymorphisms of 5a-reductase have been detected in the families of patients with hereditary prostate can-cer.54 Therefore, polymorphisms of SRD5A2 in a comparison between ethnic groups or in a case-control study have widely been examined. The number of dinucleotide repeats (TA)n in the 3' untranslated region of the 5a-reductase gene was discussed in relation to the risk of prostate cancer,55 because longer alleles may cause a modest reduction in the activity of the enzyme. Initially, differences in the number of repeats were found among the races, but no evidence revealed any correlation between the differences and the risk.56 The (TA)n repeats were not correlated with the level of androstane-3a,17p-diol glucuronide.57 On the contrary, in the Chinese population, which has the lowest incidence of prostate cancer, men who are heterozygous for the (TA)0/(TA)n allele had a modest risk reduction compared with men who are homozygous for the (TA)0 allele and have higher serum DHT levels.58 Men who are homozygous for the (TA)9 or (TA)18 alleles and men who are of the (TA)9/(TA)18 genotype have a modestly reduced risk.59 The number of (TA)n repeats was related with age at the onset of prostate cancer.60 Of 208 patients with localized prostate cancer, 30 were (TA)n heterozygotes in peripheral lymphocytes, and this genotype was then compared with that of tumor DNA. Fifty-seven percent of the tumors showed loss of heterozygosity (LOH) or microsatellite instability in this marker. Tumors showing these somatic mutations tend to be of a high grade and stage.61 Together with these reports, (TA)n repeat length may partly be viewed as an etiologic/progressive factor.62

Screening among healthy, racially/ethnically diverse male populations detected 10 missense substitutions and three double mutations that are all naturally found in human males.63 Of the ten single amino acid substitutions, V89L (substitution of leucine for valine at codon 89) is on almost 33% of the chromosomes, followed by A49T (substitution of threonine for alanine at codon 49) on 2.0%. Other mutations are rare, at less than 2%. The Vmax of A49T is 5-fold higher than that of the wild type, and the Vmax of V89L shows 50% reduced activity.

In men with the LL genotype of V89L, the serum levels of testosterone and free testosterone were reduced by 12% and 16% respectively, and that of 5a-androstane-3a,17p-diol glucuronide was reduced by 10%.64 The frequency of the VV genotype was the highest in African-Americans at 58.9%, lower in Caucasians at 57.1%, and the lowest in Asians at 29.4 %.65 The VV genotype is associated with a higher serum level of 5a-androstane-3a,17p-diol glucuronide than the VL and LL genotype, thus a correlation with the higher incidence of prostate cancer in African-Americans was suggested. Men with the V allele are at a 2-fold greater risk for prostate cancer development and an additional 2-fold increase in the risk of progression when compared to men with the LL genotype.66 Similarly, men with the VV or VL genotypes had an increased risk for prostate cancer compared with those with the LL genotype.67 On the contrary, no correlation between the V89L genotype and prostate cancer was reported,58-60'68 or conversely, the L allele may be of a risk but not significantly.69-72 Finally, meta-analysis from nine studies concluded no association between SRD5A2 genotype and prostate cancer risk.62

An association between A49T polymorphism and prostate cancer was reported in African-Americans and Hispanic men.73 The missense mutation in healthy men of both populations is rare, but men with AT/TT genotypes have increased risk of clinically significant cancer at 7.2-fold in African-Americans and 3.6-fold in Hispanic men. The polymorphism was correlated with extracapsular extension in Caucasians.74 On the contrary, no association was found between this polymorphism and tumor stage, grade, or family history.75 Men with one or two copies of the variant T allele had a 24% lower androstanediol glucuronide level than men homozygous for the wild type allele.57 Meta-analysis, however, revealed a modest effect of T allele on cancer.62 The T allele was not detected in the Japanese population, indicating racial differences in the polymorphism. R227Q (substitution of glutamine for arginine at codon 227) significantly reduces enzyme activity, but men with RQ phenotype are rare, and this polymorphism was not associated with prostate cancer.58

From these reports, it seems to be difficult to determine the risk for prostate cancer attributable to polymorphisms of SRD5A2. In each case-control study, selection of the control group could not completely exclude men with tiny foci of cancer or benign hyperplastic prostate, which is an androgen-dependent disease. The Japanese population is considered to be ethnically homogeneous, and the incidence of prostate cancer was formerly low. However, the incidence is increasing at the fastest rate of all male malignancies, therefore, the different incidences among countries can not be explained by racial differences only. Finally, reports of genetic association are influenced by study size and time of publication, thus results have been variable.76

The diet of Japanese men has changed to include foods with high fat and protein compositions since World War II. A diet of 25% reduced fat and the same total calories caused a 10% decrease in serum testosterone of healthy volunteers.77 Isoflavonoids (genistein and daidzein) derived from soybean and green tea gallates (epigallocatechin-3-gallate and epicatechin-3-gallate) are favorite foods for Oriental men, and are also 5a-reductase inhibitors.78'79 7-Linolenic acid,80 eicosapentaenoic acid,81 and free fatty acids82 are also inhibitors. Ingested foods may influence androgen metabolism, and consequently the incidence of prostate cancer.

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