Steroid Hormonal Factors in Populations with Different Risk for Prostate Cancer

A number of studies have compared circulating levels of steroid hormones and other hormonal factors in very high risk African Americans with those in high risk European Americans, lower risk Asian Americans, and very low risk Asians living in Asia or African black men. The details of these studies are summarized in the following paragraphs.

Ahluwalia et al. [139] studied African Americans and black Nigerian men that were matched controls in a case control study of prostate cancer. Plasma levels of testosterone and estrone were significantly higher in the Americans than in the Nigerian men, whereas levels of DHT and 17^-estradiol were not different. Similar differences were found for the prostate cancer cases. Hill et al. [62-64] compared the hormonal status of small groups of middle-aged African American, European American, and black (rural) South African men consuming their customary diets. In a separate study, African American, European American, and black South African boys and young African American and black South African men were compared [140]. In the older men, plasma levels of the testosterone precursor dehydroepiandrosterone (DHEA) were lower in the two groups of black men than in the white men, and estrone levels were higher. Plasma levels of the testosterone precursor androstenedione and 17ff-estradiol were higher in the African men than in the two American groups, but there were no differences among these groups in testosterone levels. In the study with the boys and young men, similar findings were obtained for testosterone and DHEA. However, androstenedione levels were lower (and not higher) in the African than in the American subjects, and 17f-estradiol was lower in young black boys than in white boys but higher in older black boys and young black men than in white boys and men. These interesting data suggest a complex interaction between ethnic background and environmental differences that change during sexual maturation. In these studies by Hill and co-workers among South African black men, the young men were different from the older men for androstenedione and DHEA. This observation suggests that it may be important for the interpretation of hormonal profiles to separately consider younger and older men.

Ross et al. [133] compared healthy young African-American men and young US Caucasian males. Total circulating testosterone and free testosterone were ~20% higher in the black men than in the white group. Serum estrone concentrations were also higher (by 16%) in the blacks than in the whites. There were no differences between the groups in circulating 17f-estradiol and SHBG. The 19-21% difference in circulating testosterone may be sufficiently large to explain the twofold difference in prostate cancer risk between white and black men in the US. This study suggests an association between prostate cancer risk and high concentrations of circulating androgens and, perhaps, estrogens. Henderson et al. [141] compared hormone levels in pregnant African-American and white women in their first trimester. Serum testosterone levels were 47% higher in black women than in white women, and 17f-estradiol levels were 37 % higher. No differences were observed in SHBG and human chorionic gonadotrophin. These findings may suggest that US black males are exposed to higher androgen concentrations than white men even before birth.

The US black and white men from the study by Ross et al. [133] were compared with Japanese men of the same age [134]. The serum testosterone levels of Japanese men were intermediate between those of the US whites and blacks, but their SHBG levels were lower. This suggests a higher free testosterone in the Japanese than in the US men, but free testosterone was not measured. The two US groups had higher circulating levels of the conjugated androgen metabolites androsterone glucuronide and 3a,17f-androstanediol glucuronide than the Japanese men. This suggests that in comparison with the high risk US groups, the low risk Japanese population has a lower rate of testosterone metabolism, most likely a lower activity of the enzyme 5a-reductase that converts testosterone to DHT and the testosterone precursor androstenedione to andro-sterone. However, the higher levels of androsterone glucuronide in US men could also indicate a higher testosterone production rate than in Japanese men. Lookingbill et al. [142] reported similar observations, comparing young healthy US Caucasians and Chinese males in Hong Kong. The Caucasian men had 67%

higher serum levels of androsterone glucuronide and 76% higher levels of 3a,17b-androstanediol glucuronide than the Chinese men. Circulating levels of testosterone, free testosterone, or DHT were not different, but Caucasian men had higher serum levels of the androgen precursors DHEA sulfate and an-drostenedione. These data are also suggestive of a higher 5a-reductase activity in high risk Caucasians than in low risk Chinese men, and they suggest an increased production of androgen precursors in the Caucasians.

In contrast to the observations of Ross et al. [133,134] and Lookingbill et al. [142], De Jong and co-workers [143] found 71% higher circulating total testosterone levels in 50-79 year-old Caucasian Dutch men (high risk) than in Japanese men (low risk). DHT levels were not different, but the ratio of DHT to testosterone was slightly lower in Dutch than Japanese men, perhaps indicating lower 5a-reductase activity, but no androgen metabolites were measured. Serum levels of 17^-estradiol were higher in the Dutch than the Japanese men. SHBG levels were not different, but the ratio of testosterone to SHBG concentrations was higher in Dutch than Japanese men, suggesting higher amounts of free testosterone in Dutch men, but this was not measured. Ellis and Nyberg [144] compared serum testosterone levels in non-Hispanic white US Army Vietnam veterans with those in African American, Hispanic, Asian/Pacific Islander, and Native American veterans. The serum testosterone levels in the African American men were significantly higher than those in the non-Hispanic white men, but the differences among the other groups were not significant. The serum testosterone difference between black and white men was larger in men 31-35 years of age (6.6%) than for men 35-40 (3.7%) or 40-50 of age (0.5%).

Wu et al. [145] compared circulating hormone levels in a population-based study of healthy African-American, Caucasian, Chinese-American, and Japanese-American men 35-89 years of age, 8.2% of whom were 60 years old or younger. Serum levels of total testosterone were 9-11% (significant) higher in Asian-Americans than in Caucasians, and they were intermediate and not different from the two other groups in African-Americans. The serum levels of bioavailable testosterone (not bound to SHBG) and free testosterone (not bound to either SHBG or albumin) was 11-12% (significant) higher in Chinese-Americans than Caucasian men. SHBG levels were not different among the groups. In comparison with Caucasian men, DHT levels were 7% higher (significant) in African-Americans and Japanese-Americans, but similar in Chinese-Americans. The ratio of DHT to testosterone was 10% lower (significant) in Chinese-Americans than in Caucasians, but not significantly different in African- and Japanese-Americans than Caucasians. These data do not support the notion of a relation between increased 5a-reductase activity or testosterone production and prostate cancer risk, but no direct indicators of 5a-re-ductase activity such as androsterone glucuronide and 3a,17^-androstanediol glucuronide were measured.

Santner et al. [146] conducted the only study of direct measurement of androgen production and metabolism by 5a-reductase in populations with different risk for prostate cancer. A radioisotope method using intravenous injection of tritiated testosterone was used to measure the conversion of testosterone to

DHT in young healthy US Caucasians, Chinese-Americans, and Chinese men living in Beijing, China. No differences in the conversion of testosterone to DHT were found among these three groups. Circulating testosterone and SHBG levels were lower in the Beijing Chinese than in the two US groups, and the differences with the US Chinese subjects were significant, but there were no differences in free testosterone. There was an insignificant trend towards lower metabolic conversion rates of testosterone comparing US Caucasians with the Chinese groups and US Chinese with Beijing Chinese. Testosterone production rates were lower in Beijing Chinese than in the two US groups, and the difference with American-Chinese was significant. The ratios of urinary 5b- to 5a-reduced steroids, which is an indicator of overall 5a-reductase activity, were not different in US Caucasian male students compared to Chinese students living in Hong Kong. Urinary excretion of androsterone, etiocholanolone, and total ketosteroids was lower in the Chinese than in the US students. Together, these data indicate that 5a-reductase activity is not different in Asian and Caucasian men and is not affected by the environment in which Asian men live, but they suggest that the living environment influences testosterone production in Asian men.

The SRD5A2 gene, which encodes for human type II 5a-reductase enzyme and is expressed in the prostate [147, 148], contains polymorphic TA dinu-cleotide repeats in its transcribed 3' untranslated region [149]. Reichardt et al. [150] demonstrated that alleles containing longer TA dinucleotide repeats are unique to African Americans, which may be related to their extremely high risk for prostate cancer. However, the functional significance of these polymorphisms is not yet known.

Makridakis et al. [151] identified another polymorphism in the SRD5A2 gene, the presence of a valine to leucine mutation at codon 89. In a homozygous state, this mutation confers lower 5a-reductase activity as measured in Asian men with this genotype compared to heterozygous men and men without the mutation [151]. The frequency of the 89 leucine-leucine genotype (lower 5a-reductase activity) was 3-4% in African American and white men, 15% in Latinos, and 22 % in Asian Americans. The higher frequency of the 89 leucine-leucine genotype in Latino American men and particularly Asian Americans may be related to their low risk for prostate cancer. These findings were confirmed by Lunn et al. [153].

Makridakis et al. [156] also identified yet another polymorphism in the SRD5A2 gene, a mis-sense alanine to threonine mutation at codon 49, associated with a substantial increase in activity of the enzyme. The frequency of the mutation was very low, 1.0 and 2.3%, in healthy high risk African Americans and lower risk Hispanic men, respectively, and it seems unlikely that this mutation is responsible for the large ethnic/racial variations in prostate cancer risk.

The CYP17 gene, which encodes for the cytochrome P450C17a enzyme that has both 17a-hydroxylase and 17,20-lyase activity in the biosynthesis of andro-gens in the adrenal and testis, is polymorphic with two common alleles, the wild type CYP17A1 allele and the CYP17A2 allele containing a single base-pair mutation [157]. This mutation creates an additional Sp1 site in the promoter region, which suggests increased expression potential [157], The functional significance of this polymorphism in men is not known, but pre- and post-

menopausal women with the A2 allele had higher circulating estradiol and progesterone levels than women homozygous for the A1 allele, and circulating levels of DHEA and androstenedione, but not testosterone, were increased in post-menopausal women. Lunn et al. [153] reported frequencies of the A1/A1 and A1/A2 genotype of between 40 and 44% and frequencies of the A2/A2 genotype between 16 and 17% in both African American and European American men, resulting in an A2 allele frequency of 0.36-0.38. In Asians (Taiwanese), however, the frequency of the A1/A1 genotype was 24%, that of the A1/A2 genotype 49%, and that of the A2/A2 genotype 27%, resulting in an A2 allele frequency of 0.52. The frequency differences between the Asians and the American groups were statistically significant, and are possibly related with the low prostate cancer risk in Asian men.

The human HSD3B2 gene, which is located on chromosome 1p13 and encodes for type II 3^-hydroxysteroid dehydrogenase (an enzyme that catabolizes DHT and is expressed in the adrenals and testes), contains several complex di-nucleotide polymorphisms [152].Devgan et al. [154] reported that the frequency of HSD3B2 alleles differs among ethnic groups. African American men are unique in one minor allele, and the most common allele is more frequent in European Americans than in either African Americans or Asian men. The second most common allele is more frequent in African Americans than in either Asians and European men. However, the functional significance of these HSD3B2 gene polymorphisms is unknown.

The human androgen receptor gene, located on the X chromosome, contains polymorphisms which are CAG and GGC (or GGN) microsatellite repeats of different length in exon 1 encoding for the N-terminus of the protein associated with transactivation activity [138]. The CAG repeat length is involved in determining transactivation activity of the androgen receptor; 40 or more repeats are associated with human androgen insensitivity syndromes and reduction of repeat length results in increased transactivation activity in vitro [136-138]. However, the functional significance of the GGC repeat length is not clear. Irvine et al. [155] reported that most African American men have CAG repeat lengths of less than 22, whereas fewer European and Asian Americans have such shorter alleles. Very short alleles of less than 17 repeats were almost exclusively found in African Americans. The most common GGC allele occurred in most Asian American men, fewer European Americans, and only one in five African Americans. The frequency of short GGC repeats of less than 16 was highest in African Americans, lower in Asian Americans, and lowest in European Americans. GGC repeats longer than 16 were rare in the Asian American men, but more frequent in African Americans and European Americans. Thus, shorter CAG repeat alleles, which may be associated with greater androgen receptor transactivation, were the most frequent in the highest risk population (African Americans) and lowest in the lowest risk group (Asian Americans), and the frequency was intermediate in intermediate risk European American men. The high frequency of short GGC repeats in African Americans is perhaps also related with their extremely high risk for prostate cancer.

In conclusion, the above summary indicates few clear or convincing patterns about associations between circulating hormone concentrations and prostate cancer risk at the population level. Two studies examined the levels of 5a-re-duced androgen metabolites (androsterone glucuronide and 3a,17^-an-drostanediol glucuronide), which are considered indicators of 5a-reductase activity [158].In both studies the levels of these metabolites were lower in low risk Asian populations than in high risk European Americans [134,142]. These observations suggest lower 5a-reductase activity in the Asians and, therefore, reduced formation of DHT and androgenic stimulation of the prostate. This notion is supported by the higher frequency in Asian men than European Americans or African Americans of a 5a-reductase (SRD5A2) gene polymorphism that appears to be associated with lower 5a-reductase activity [135,151]. However, when overall conversion of testosterone into DHT was directly measured, no differences were found between Asian and European American men [146]. Furthermore, levels of 5a-reduced androgen metabolites were not higher in very high risk African Americans than in intermediate risk European Americans, and circulating levels of DHT and the ratio of DHT to testosterone were similar in ethnic populations that differ in prostate cancer risk [142,143, 145]. Although circulating levels of testosterone and free testosterone were slightly higher in African Americans than in European Americans in all studies addressing this issue, this was statistically significant in only one study. In addition, lower as well as higher testosterone concentrations have been reported to occur in lower risk Asian or African men as compared with higher risk European or African Americans, but testosterone levels were lower in Japanese and Chinese men living in Asia than in any ethnic group living in the US. In conclusion, there is at present no substantive evidence in favor of the hypothesis that elevated 5a-reductase activity is causally related to prostate cancer risk at the population level, and only limited evidence for the hypothesis that elevated (free) testosterone levels are associated with prostate cancer risk.

The only two other patterns appearing from the above summarized studies are that levels of estrogens are higher and those of DHEA lower in black Africans and African Americans than in men of European descent (there are virtually no data on Asians in this regard) [62-64,133,139,140,143]. Higher estrogen levels were only found in black men younger than 50 years. Although the biological significance of these findings is not clear, they may be related to the high susceptibility of black men to prostate cancer when they live in an US environment. Whether this is associated with dietary or other life-style factors or exposures to environmental pollutants is not clear. There are, to the knowledge of the author, no epidemiologic studies that explored a possible role of environmental chemicals with hormonal activity in the etiology of prostate cancer. It is noteworthy that the above summarized endocrine differences between very high risk African Americans and high risk European American were not consistent in younger and older men, and they were not similar to the differences observed between the high risk US populations and the low risk African black men [62-64,139]. These inconsistencies may suggest that the factors and endocrine mechanisms involved in determining the difference in risk between African black men and African-Americans are different from those that determine the difference in risk between African Americans and European Americans [13].

Finally, androgen receptor transactivation activity may be an important factor. A CAG repeat length polymorphism in the androgen receptor gene was found to be associated with prostate cancer risk in two studies, and short CAG repeat alleles are probably associated with greater androgen receptor activity. Short CAG repeat alleles were most frequent in African Americans (at very high risk for prostate cancer), least frequent in Asian Americans (at low risk), and intermediate in European Americans (at intermediate risk).

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