Comparisons of Steroid Hormonal Factors in Nested Case Control Studies

In a number of studies circulating levels of steroid hormones and other hormonal factors have been evaluated in nested case-control studies derived from ongoing cohort studies. The details of each study are summarized in the following paragraphs.

Nomura et al. [159] compared prostate cancer cases with matched controls from a cohort of Hawaiian Japanese men followed for approximately 14 years. There were no significant differences between cases and controls or associations with risk for circulating testosterone, DHT, estrone, 17^-estradiol, and SHBG measured once at the start of the cohort study. There was a relation between risk and an increasing ratio of testosterone to DHT, which was borderline significant (0.05<p<0.1). The results from this nested case-control study may suggest an inverse relation between (peripheral) 5a-reductase activity and prostate cancer risk.

Barrett-Connor et al. [160] followed a cohort of white upper-middle class Californian men for a period of 14 years. There was no significant relation between risk for prostate cancer and base-line serum concentrations of testosterone, estrone, and SHBG. However, relative risk increased linearly with increasing serum level of androstenedione, a testosterone precursor. Relative risk also increased with increasing serum level of 17^-estradiol, but this was not significant.

Hsing and colleagues [161,162] conducted a population-based nested case-control study in a cohort of mostly European-American men. Blood samples were obtained in 1974, but exact follow-up time was not specified. Men of 70 years and older and younger than 70 were studied separately. There were no significant differences between cases and controls or associations with risk for base-line testosterone, DHT, DHEA, DHEA sulfate, estrone, or 17^-estradiol. The ratio of testosterone to DHT was higher in cases than in controls, regardless of age, and for men younger than 70 years, prostate cancer risk was increased with an increasing testosterone/DHT ratio; these associations were only borderline significant. These findings may suggest an inverse relation between 5a-reductase activity and prostate cancer risk.

Nomura et al. [163] reported on a 20-year follow-up of their cohort study of Hawaiian Japanese men. In this follow-up, no significant differences were found between cases and controls or associations with risk for base-line testosterone, free testosterone, DHT, ratio of testosterone to DHT, androsterone glucuronide, 3a,17^-androstanediol glucuronide, and androstenedione. These findings mostly confirmed those of their earlier report [159].

Gann et al. [164] conducted a prospective nested case-control study using probably largely white cases of prostate cancer and controls from the US Physician's Health Study with a follow-up of approximately six years. There were no significant differences between cases and controls for testosterone, SHBG, DHT, ratio of testosterone to DHT, 3a,17f-androstanediol glucuronide, or 17f-estradiol. Because several highly significant associations were found between plasma levels of the various steroid hormones and SHBG studied, odd ratios were calculated after simultaneous adjustment for all these hormonal factors. This approach yielded a significant positive association with risk for testosterone and the ratio of testosterone to DHT, and inverse associations with risk for SHBG and 17f-estradiol.A positive association with risk for 3a,17f-an-drostanediol glucuronide was borderline significant. There was no association with risk for DHT. These observations contradict earlier mentioned findings suggesting a relation between (peripheral) 5a-reductase activity and prostate cancer risk.

Guess et al. [165] conducted a population-based case-control study from a cohort of European-American men in the Kaiser Permanente Medical Care Program, with a median follow-up of 14 years. There were no significant differences between cases and controls or associations with risk for base-line serum testosterone, free testosterone, DHT, androsterone glucuronide, or 3a,17f-an-drostanediol glucuronide.

Vatten et al. [166] reported results of a population-based nested case-control study from a cohort of Norwegian men with a mean follow-up of 10 years. There were no significant differences between cases and controls or associations with risk for base-line serum testosterone, DHT, ratio of testosterone to DHT, or 3a,17f-androstanediol glucuronide.

Dorgan et al. [167] reported results from population-based nested case-control study from a cohort of Finnish men from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of cigarette smokers with a follow-up of 58 years. There were no significant differences between cases and controls or associations with risk for base-line serum testosterone, free testosterone, SHBG, DHT, DHEA sulfate, 3a,17f-androstanediol glucuronide, androstenedione, estrone, or 17f-estradiol. There was a non-significant trend towards a higher ratio of testosterone to DHT in cases than controls and a non-significant positive association with risk for this ratio. These finding perhaps suggest an inverse relation between 5a-reductase activity and prostate cancer risk.

Heikkila et al. [174] conducted a population-based nested case-control study in a Finnish cohort study where serum was collected and stored from a cohort of 16,481 men which was followed for up to 24 years. Over this period 166 prostate cancer cases were identified and 300 matched controls were obtained from the cohort. There were no differences between cases and control and there was association with prostate cancer risk for serum levels of testosterone, SHBG, and androstenedione. However, there was a borderline significant (p = 0.06) trend for increasing risk with increasing levels of testosterone, but only when cases identified in the first eight years of follow-up were excluded. This finding supports the notion of a relationship between elevated androgen levels and prostate cancer risk.

Kantoff et al. [168] studied the association between prostate cancer risk and the in TA dinucleotide repeat polymorphisms in the human SRD5A2 gene, which encodes for type II 5a-reductase enzyme, in a nested case-control study using the Physician's Health Study cohort. As indicated earlier, the functional significance of these polymorphisms is not known. These investigators observed that the frequency of the three most common genotypes was not associated with risk. Men that were homozygous for long repeats were at lower risk for prostate cancer than men with the predominant shorter repeat length genotype, with a borderline significantly decreased odds ratio. These findings are in sharp contrast with the earlier mentioned observation that long alleles are unique to African Americans who are at very high risk for prostate cancer [150].

Another polymorphism in the SRD5A2 gene was identified by Makridakis et al. [156] as indicated earlier, which is a mis-sense alanine to threonine mutation at codon 49, probably associated with an increase in 5a-reductase activity. Although the frequency of the mutation was low in a nested case-control study using the Hawaii-Los Angeles Multiethnic Cohort Study of Diet and Cancer, it appeared to be responsible for 8-9% of cases in African Americans and Hispanic men [156]. The age-adjusted relative risk of prostate cancer for possessing a mutated allele was 3.28 (significant at the p = 0.05 level) in African American men and 2.50 (not significant) in Hispanics. For advanced prostate cancer, the relative risks for possessing a mutated allele were more significant: 7.22 (95% confidence interval (CI): 2.17-27.91) in African American men and 3.60 (95% CI: 1.09-12.27) in Hispanics. The results of this study support the notion that increased 5a-reductase activity may be related to prostate cancer risk. However, it seems unlikely that the alanine to threonine mutation at codon 49 in the SRD5A2 gene is involved in a substantial proportion of prostate cancer cases.

The relation between prostate cancer risk and the occurrence of the aforementioned valine to leucine mutation at codon 89 in the SRD5A2 gene, a polymorphism that is associated with reduced 5a-reductase activity, was examined by Febbo et al. [175] and Lunn et al. [153]. Febbo et al. [175], who conducted a nested case-control study using the Physician's Health Study cohort, found the valine-leucine and leucine-leucine genotypes in 50% of cases and 51 % of controls and these were not associated with elevated prostate cancer risk as compared with the valine-valine genotype. Lunn et al. [153] confirmed these findings in a case-control study that employed prostate cancer patients from urology clinics in North Carolina. Controls, not matched to cases, were drawn from BPH and impotence patients from the same clinics. Most men were European American and 5-11% were African American. The valine-leucine and leucine-leucine genotypes were found in 56 % of cases and 49 % of controls and were not associated with prostate cancer risk as compared with the valine-valine genotype. These observations are consistent with the results of Febbo et al. [175] who did not find a relation between plasma concentrations of 3a,17^-androstane-diol glucuronide and the three different SRD5A2 gene codon 89 genotypes.

Lunn et al. [153], in the same case-control study, also examined the association between prostate cancer risk and the earlier mentioned single base-pair mutation polymorphism in CYP17 gene [157] which encodes for cytochrome

P450C17a 17a-hydroxylase and 17,20-lyase enzyme activity. The CYP17A2 allele that contains a single base-pair mutation was found in 69% of cases and 57% of controls and it was significantly associated with prostate cancer risk (odds ratio of 1.7). The association was limited to men younger than 65 years with no increased odds ratio for men 65 years or older. Opposite findings of this association between prostate cancer risk and the presence of the CYP17A2 allele were reported from a Swedish case-control study by Wadelius et al. [176]. The frequency of the A1/A2 or A2/A2 genotype was 61% in prostate cancer cases (n= 178) and 71 % in population controls (n= 160). The odds ratio of having the A1/A1 genotype as compared to the A1/A2 or A2/A2 genotype was 1.61 (significant at the 95 % level). This latter finding is consistent with a preliminary report of higher circulating testosterone levels found in men that are homozy-gous for the A1 allele as compared with men with an CYP17A2 allele [176].

In six case-control studies the association was examined between the aforementioned CAG and GGC (or GGN) repeat polymorphisms in the human androgen receptor gene [155, 169-171, 177, 178]. In these studies, CAG repeat lengths of shorter than 22, 20, or less than 20 were non-significantly associated with slightly increased risk for prostate cancer [155, 169-171]. In one study [169], the trend of increased risk with decreasing repeat length was significant, but not in two other studies looking at this [170,171]. In summary, these findings suggest that prostate cancer risk may be slightly increased with shorter CAG repeat alleles and that it may be related with a greater androgen receptor transactivation activity, which is associated with shorter CAG repeat alleles. Three of these studies also addressed GGN or GGC repeats in the androgen receptor gene, the functional significance of which is unknown at present, but contradictory findings were obtained [155, 171, 178]. In all three studies the combined effects of CAG and GGN repeat length were found to be greater than those of either polymorphism separately [155, 171, 178]. However, the functional significance of this combined effect is not clear.

From the studies discussed above it must again be concluded that, with few exceptions, no clear or convincing patterns are apparent about associations between circulating hormone concentrations and prostate cancer risk at the individual level. In most studies an association was found between increased risk and increased ratios of testosterone to DHT, but this was statistically significant in only three of six studies. Although these findings suggest a relation between reduced 5a-reductase activity and prostate cancer risk, no associations were found between risk and the levels of 5a-reduced androgen metabolites that are indicators of 5a-reductase activity. Significant associations were found between prostate cancer risk and elevated levels of testosterone and androstenedione and decreased levels of SHBG and 17b-estradiol,but they each occurred in only a single study [160,164] and were not found in other studies. It is possible that relevant associations may have been missed in most studies, because, except in the study by Gann et al. [164], the individual hormone data were not adjusted for concentrations of other hormones, although there are many inter-correlations between these. Eaton et al. [179] conducted a meta-analysis study using most, but not all, studies included in this overview and some unpublished data not available to us. They found no significant differences for the ratios of mean hormone levels between cases and controls, except for slightly elevated levels of 3a,17^-androstanediol glucuronide. This meta-analysis is in agreement with our analysis, with the only consistent finding being slightly elevated ratios between cases and controls of 3a,17^-androstanediol glucuronide in five of five studies. However, Eaton et al. [179] did not take into account the risk estimates produced by these studies, which seriously limits their conclusions.

The results of three nested case-control studies on prostate cancer risk and polymorphisms in the human type II 5a-reductase enzyme gene (SRD5A2) do not support the hypothesis of an association between risk and increased 5«-re-ductase activity [153,168,175]. There are only contradictory data on a relation between prostate cancer risk and a polymorphism with unknown functional significance in the CYP17 gene encoding for the cytochrome P450C17a ^«-hydroxylase and 17,20-lyase activity which is involved in androgen biosynthesis [153,177].

In five similar studies of polymorphisms in trinucleotide repeats in the androgen receptor gene, a weak association was found between risk and shorter CAG repeat alleles, which may be related with greater androgen receptor trans-activation activity, but this association was significant in only one study [155, 169-171,177]. However, short CAG repeats were also correlated with early onset of prostate cancer [172].An association between risk and polymorphisms in androgen receptor GGC or GGN repeat lengths is not clear because results of three studies of this were inconsistent, and the functional significance of these polymorphisms is not known [155,171,178]. There is possibly an interaction between CAG and GGC/GGN repeat length in relation to prostate cancer risk, but results of the studies examining this were inconsistent [155,171,178].

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