Androgen Metabolic Pathways Research Articles

Synthesis of testosterone and 5 alpha-reduced androgens during initiation of spermatogenesis in the rat.

Numerous investigators demonstrated increased 5 alpha-reductase activity in testes of developing rats. The rapid in vitro metabolism of progesterone to 5 alpha-reduced androgens occurs at certain stages of testicular development. This was considered evidence for the conclusion that testosterone is primarily an intermediate rather than the final product in testes of immature rats. However, a discrepancy is noted when developmental patterns of circulating or intratesticular levels of androgens are compared with the patterns of accumulation of metabolites of progesterone in vitro. In blood and testicular tissue of 17-20 day old rats a testosterone peak has been reported, while in the in vitro studies such peak was not observed. In this study radiolabelled pregnenolone was utilized in vitro as a substrate, and a pattern of androgen formation similar to that observed in the in vivo studies was noted. A peak of androgen formation (testosterone and 5 alpha-androstanediol) was observed used prior to completion of the meiotic prophase. However, when testosterone was utilized as the substrate, no correlation between 5 alpha-reduction and completion of the meiotic prophase was detected. This suggests that the rise in testosterone may be associated with completion of the meiotic prophase. Investigation of the androgen metabolic pathways revealed the following age-related patterns: no change in 17 beta-hydroxysteroid dehydrogenase, activation of 5 alpha-reductase at 12 days of age, and activation of 3 alpha-hydroxysteroid dehydrogenase between 14 and 18 days of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen metabolism and biotransformation in nontumoral and malignant human liver tissues and cells

There is indirect multiple evidence that hints at a potential role of sex steroids in development and progression of human hepatocellular carcinoma (HCC). In the present study, we have investigated androgen metabolism in a panel of human liver cancer cell lines (HA22T, Huh7, HepG2) and in normal, cirrhotic and malignant human liver tissues aiming to dissect the potential impact of individual enzyme activities and their products in normal and diseased human liver, both in vivo and in vitro. Using our intact cell analysis we were able to assess rates and pathways of androgen metabolism in living conditions. Overall, incubation of cultured cells or tissue minces with either testosterone (T) or androstenedione (Ad) used as precursor resulted in a large extent of 17βoxidation of T to Ad (cells: 28–77%; tissues: 35–50%). In malignant liver cell lines, both HA22T and Huh7 cells showed consistent amounts of the 5α-reductase enzyme products (18% and 15%, respectively), while 5β-reductase activity was more pronounced in Huh7 cells (18%) than in HA22T cells (1.8%). Interestingly, a significant extent of estrogen formation could be observed in Huh7 cells (5.4–11.5%), while no aromatase activity could be detected in HA22T cells. In HepG2 cells, along with a relatively high proportion of Ad, estrogens represented the most prominent (50–55%) end product of androgen metabolism, regardless of the precursor used. In liver tissues, equivalent results could be obtained, with a consistent proportion of 17βoxidation of T to Ad (35–50%) being observed in the majority of samples. However, while normal liver tissue samples exhibited a minor proportion of bioactive androgens (3.4%) with no aromatase products, HCC tissues showed a significant extent of aromatase activity (nearly 20%) with estrogen representing the most prominent metabolic product after 24 h incubation with either T or Ad. HCV and alcoholic cirrhotic tissues displayed different patterns of androgen metabolism. The former produced limited amounts of bioactive androgens (5.3%) and considerable levels of the intermediate aromatase product 19OH-Ad (up to 28%), the latter exhibited a prevalence of androgen degradation through the 5β-reductase pathway (9.8%) and a significant extent of aromatase activity (16% as a whole). In conclusion, three major metabolic states could be depicted, depending on prevalent pathways of androgen metabolism and steroid receptor status: estrogenic, androgenic, and mixed. This model supports the idea that local estrogen biosynthesis may be implicated in human HCC and provides a basis for the exploitation of aromatase inhibitors and/or ER antagonists or selective estrogen receptor modulators (SERMs) as a new therapeutic strategy in HCC patients.

Pathways of adipose tissue androgen metabolism in women: depot differences and modulation by adipogenesis

The objective was to examine pathways of androgen metabolism in abdominal adipose tissue in women. Abdominal subcutaneous (SC) and omental (OM) adipose tissue samples were surgically obtained in women. Total RNA was isolated from whole adipose tissue samples and from primary preadipocyte cultures before and after induction of differentiation. Expression levels of several steroid-converting enzyme transcripts were examined by real-time RT-PCR. Androgen conversion rates were also measured. We found higher expression levels in SC compared with OM adipose tissue for type 1 3beta-hydroxysteroid dehydrogenase (3beta-HSD-1; P < 0.05), for aldo-keto reductase 1C3 (AKR1C3; P < 0.0001), for AKR1C2 (P < 0.0001), and for the androgen receptor (P < 0.0001). 17beta-HSD-2 mRNA levels were lower in SC adipose tissue (P < 0.05). Induction of adipocyte differentiation led to significantly increased expression levels in SC cultures for AKR1C3 (4.7-fold, P < 0.01), 11-cis-retinol dehydrogenase (6.9-fold, P < 0.02), AKR1C2 (5.6-fold, P < 0.004), P-450 aromatase (5.7-fold, P < 0.02), steroid sulfatase (3.1-fold, P < 0.02), estrogen receptor-beta (11.8-fold, P < 0.01), and the androgen receptor (4.0-fold, P < 0.0005). Generally similar but nonsignificant trends were obtained in OM cultures. DHT inactivation rates increased with differentiation, this effect being mediated by dexamethasone alone, through a glucocorticoid receptor-dependent mechanism. In conclusion, higher mRNA levels of enzymes synthesizing and inactivating androgens are found in differentiated adipocytes, consistent with higher androgen-processing rates in these cells. Glucocorticoid-induced androgen inactivation may locally modulate the exposure of adipose cells to active androgens.

Inherited variation in the androgen pathway is associated with the efficacy of androgen-deprivation therapy in men with prostate cancer: Ross RW, Oh WK, Xie W, Pomerantz M, Nakabayashi M, Sartor O, Taplin ME, Regan MM, Kantoff PW, Freedman M, Dana-Farber Cancer Institute, Boston, MA

Androgen-deprivation therapy (ADT) is the most common and effective systemic therapy for advanced prostate cancer. We hypothesized that germline genetic variation in the androgen axis would improve the efficacy of ADT. A cohort of 529 men with advanced prostate cancer treated with ADT was genotyped for 129 DNA polymorphisms distributed across 20 genes involved in androgen metabolism. Three polymorphisms in separate genes (CYP19A1, HSD3B1, and HSD17B4) were significantly (P < 0.01) associated with time to progression (TTP) during ADT, remaining so in multivariate analyses and after correcting for the number of hypotheses tested. Individuals carrying more than one of the polymorphisms associated with improved TTP demonstrated a better response to therapy than individuals carrying zero or one (P < 0.0001). This report is the first to examine the influence of inherited variation in the androgen metabolic pathway on the efficacy of ADT, establishing the importance of pharmacogenomics on individual's response to this therapy. At least two potential clinical benefits may be realized from this study. The first is prognostic; genotyping patients at these loci may yield important information that could improve efficacy prediction. The second is therapeutic; these results shed light on the pathways that govern response to ADT. Drugs could be developed (or may already exist) to inhibit or augment these targets to improve ADT efficacy.

The interaction of CYP3A5 polymorphisms along the androgen metabolism pathway in prostate cancer

Prostate cancer is a leading solid tumor among men in the Western world. Androgens play an important role in the carcinogenesis and treatment of prostate cancer. CYP3A5 is a cytochrome P450 superfamily member which also has activity in testosterone metabolism. In this study, we looked for two-gene interactions associated with clinical characteristics of prostate cancer in the Finnish population. We used multifactor-dimensionality reduction for the identification of the two-gene interactions in androgen metabolism pathway genes together with clinical characteristics of prostate cancer among 754 genotyped prostate cancer patients. The CYP3A5*3/*3 and SRD5A2 A49T GG genotype interaction was associated with the clinical tumor stage T2-T4 (T-stage, TNM classification) with odds ratio (OR) 2.14, 95% confidence interval (CI) 1.35-3.40. Patients with CYP3A5*3/*3 and KLK3 I179T CC/TC genotypes had increased OR 2.30, 95% CI 1.16-4.58 for metastatic disease. Further, two-gene interaction CYP3A5*3/*3 and KLK3 -252A > G AA was associated with Gleason scores >or=7 with OR 1.52, 95% CI 1.11-2.09. Prostate cancer patients with CYP3A5*3/*3 and KLK -252A > G GG/AG genotypes had decreased OR of 0.70 with 95% CI 0.50-0.98 for high prostate-specific antigen levels at diagnosis. For prostate cancer patients aged below 65 years, the OR for interaction of CYP3A5*1/*3 or *1/*1 and AKR1C3 Q5H CC genotypes was 1.84 with 95% CI 1.03-3.28. For prostate cancer, the best two-gene interaction included genotypes SRD5A2 V89L GG and AKR1C3 Q5H CC with OR 1.30, 95% CI 1.01-1.66. It remains to be clarified whether these polymorphism associations identified here are also present in other populations.

Inherited Variation in the Androgen Pathway Is Associated With the Efficacy of Androgen-Deprivation Therapy in Men With Prostate Cancer

Androgen-deprivation therapy (ADT) is the most common and effective systemic therapy for advanced prostate cancer. We hypothesized that germline genetic variation in the androgen axis would improve the efficacy of ADT. A cohort of 529 men with advanced prostate cancer treated with ADT was genotyped for 129 DNA polymorphisms distributed across 20 genes involved in androgen metabolism. Three polymorphisms in separate genes (CYP19A1, HSD3B1, and HSD17B4) were significantly (P < .01) associated with time to progression (TTP) during ADT, remaining so in multivariate analyses and after correcting for the number of hypotheses tested. Individuals carrying more than one of the polymorphisms associated with improved TTP demonstrated a better response to therapy than individuals carrying zero or one (P < .0001). This report is the first to examine the influence of inherited variation in the androgen metabolic pathway on the efficacy of ADT, establishing the importance of pharmacogenomics on individual's response to this therapy. At least two potential clinical benefits may be realized from this study. The first is prognostic -genotyping patients at these loci may yield important information that could improve efficacy prediction. The second is therapeutic -these results shed light on the pathways that govern response to ADT. Drugs could be developed (or may already exist) to inhibit or augment these targets to improve ADT efficacy.

Cyp11b1 Is Induced in the Murine Gonad by Luteinizing Hormone/Human Chorionic Gonadotropin and Involved in the Production of 11-Ketotestosterone, a Major Fish Androgen: Conservation and Evolution of the Androgen Metabolic Pathway

We have shown previously that Cyp11b1, an 11beta-hydroxylase responsible for glucocorticoid biosynthesis in the adrenal gland, was induced by cAMP in androgen-producing Leydig-like cells derived from mesenchymal stem cells. We found that Cyp11b1 was induced in male Leydig cells, or female theca cells, when human chorionic gonadotropin was administered in immature mice. Expression of Cyp11b1 in rodent gonads caused the production of 11-ketotestosterone (11-KT), a major fish androgen, which induces male differentiation or spermatogenesis in fish. As in teleosts, plasma concentrations of 11-KT were elevated in human chorionic gonadotropin-treated mice. In contrast to teleosts, however, plasma concentrations of 11-KT were similar in both sexes, despite levels of testosterone, a precursor substrate, being about 20 times higher in male mice. Because expression of 11beta-hydroxysteroid dehydrogenase type 2, was much higher in the mouse ovary than in the testis, conversion of testosterone into 11-KT may occur more efficiently in the ovary. In a luciferase reporter system that was responsive to and activated by androgens, 11-KT efficiently activated mammalian androgen receptor-mediated transactivation. Our results suggest that the androgen metabolic pathway is conserved between teleosts and mammals, despite sexual dominance and reproductive functions of 11-KT being altered during evolution.

Novel 5α‐steroid reductase (SRD5A3, type‐3) is overexpressed in hormone‐refractory prostate cancer

Prostate cancer often relapses during androgen-depletion therapy, even under conditions in which a drastic reduction of circulating androgens is observed. There is some evidence that androgens remain present in the tissues of hormone-refractory prostate cancers (HRPC), and enzymes involved in the androgen and steroid metabolic pathway are likely to be active in HRPC cells. We previously carried out a genome-wide gene expression profile analysis of clinical HRPC cells by means of cDNA microarrays in combination with microdissection of cancer cells and found dozens of transactivated genes. Among them, we here report the identification of a novel gene, SRD5A2L, encoding a putative 5 alpha-steroid reductase that produces the most potent androgen, 5 alpha-dihydrotestosterone (DHT), from testosterone. Liquid chromatography-tandem mass spectrometry analysis following an in vitro 5 alpha-steroid reductase reaction validated its ability to produce DHT from testosterone, similar to type 1 5 alpha-steroid reductase. Because two types of 5 alpha-steroid reductase were previously reported, we termed this novel 5 alpha-steroid reductase 'type 3 5 alpha-steroid reductase' (SRD5A3). Reverse transcription-polymerase chain reaction and northern blot analyses confirmed its overexpression in HRPC cells, and indicated no or little expression in normal adult organs. Knockdown of SRD5A3 expression by small interfering RNA in prostate cancer cells resulted in a significant decrease in DHT production and a drastic reduction in cell viability. These findings indicate that a novel type 3 5 alpha-steroid reductase, SRD5A3, is associated with DHT production and maintenance of androgen-androgen receptor-pathway activation in HRPC cells, and that this enzymatic activity should be a promising molecular target for prostate cancer therapy.

Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines

Androgens play an important role in controlling the growth of the normal prostate gland and in the pathogenesis of benign prostate hyperplasia, and prostate cancer. Although testosterone is the main androgen secreted from the testes, dihydrotestosterone (DHT), a more potent androgen converted from testosterone by 5alpha-reductase isozymes, type I and II, is the major androgen in the prostate cells. The aim of this study is to investigate the cellular and molecular effects of dutasteride, a potent inhibitor of 5alpha-reductase type I and type II, in androgen-responsive (LNCaP) and androgen-unresponsive (DU145) human prostate cancer(PCa) cell lines. The expression pattern of 190 genes, selected on the basis of their proved or potential role in prostate cancerogenesis related to androgen signalling, were analysed using a low density home-made oligoarray (AndroChip 2). Our results show that dutasteride reduces cell viability and cell proliferation in both cell lines tested. AndroChip 2 gene signature identified in LNCaP a total of 11 genes differentially expressed (FC >or= +/-1.5). Eight of these genes, were overexpressed and three were underexpressed. Overexpressed genes included genes encoding for proteins involved in biosynthesis and metabolism of androgen (HSD17B1;HSD17B3;CYP11B2), androgen receptor and androgen receptor co-regulators (AR;CCND1), and signal transduction(ERBB2; V-CAM; SOS1) whereas, underexpressed genes (KLK3; KLK2; DHCR24) were androgen-regulated genes (ARGs). No differentially expressed genes were scored in DU145. Microarray data were confirmed by quantitative real-time PCR assay (QRT-PCR). These data offer a selective genomic signature for dutasteride treatment in prostate epithelial cells and provide important insights in prostate cancer pathophysiology.

Evaluation of Genetic Variations in the Androgen and Estrogen Metabolic Pathways as Risk Factors for Sporadic and Familial Prostate Cancer

Previous studies suggest that enzymes involved in the androgen metabolic pathway are susceptibility factors for prostate cancer. Estrogen metabolites functioning as genotoxins have also been proposed as risk factors. In this study, we systematically tested the hypothesis that common genetic variations for those enzymes involved in the androgen and estrogen metabolic pathways increase risk for sporadic and familial prostate cancer. From these two pathways, 46 polymorphisms (34 single nucleotide polymorphisms, 10 short tandem repeat polymorphisms, and 2 null alleles) in 25 genes were tested for possible associations. Those genes tested included PRL, LHB, CYP11A1, HSD3B1, HSD3B2, HSD17B2, CYP17, SRD5A2, AKR1C3, UGT2B15, AR, SHBG, and KLK3 from the androgen pathway and CYP19, HSD17B1, CYP1A1, CYP1A2, CYP1B1, COMT, GSTP1, GSTT1, GSTM1, NQO1, ESR1, and ESR2 from the estrogen pathway. A case-control study design was used with two sets of cases: familial cases with a strong prostate cancer family history (n = 438 from 178 families) and sporadic cases with a negative prostate cancer family history (n = 499). The controls (n = 493) were derived from a population-based collection. Our results provide suggestive findings for an association with either familial or sporadic prostate cancer with polymorphisms in four genes: AKR1C3, HSD17B1, NQO1, and GSTT1. Additional suggestive findings for an association with clinical variables (disease stage, grade, and/or node status) were observed for single nucleotide polymorphisms in eight genes: HSD3B2, SRD5A2, SHBG, ESR1, CYP1A1, CYP1B1, GSTT1, and NQO1. However, none of the findings were statistically significant after appropriate corrections for multiple comparisons. Given that the point estimates for the odds ratio for each of these polymorphisms are <2.0, much larger sample sizes will be required for confirmation.

Metabolic Profiles of Androgens in Malignant Human Liver Cell Lines

In this study we have investigated androgen (testosterone and androstenedione) metabolism in malignant HepG2, Huh-7, and HA22T human liver cell lines. Following 72-h incubation with testosterone or androstenedione, estrogen formation through aromatase activity was consistently higher in HepG2 cells (being nearly 100%) and moderate in Huh7 cells (34%), while it was undetectable in HA22T cells. The produced estrogens are completely conjugated by estrogen sulpho-transferase (EST) in HepG2 cells, while nearly 25% remains in the free form in Huh-7 cells. The HA22T and Huh-7 cells show a markedly different balance of 5alpha- versus 5beta-reduced androgens (65.7% vs. 2.5% and 2.6% vs. 22.2%, respectively), while no detectable 5alpha/5beta-reduced androgen is formed in HepG2 cells. These divergent metabolic profiles, coupling aromatase to EST, and to 5alpha/5beta-reductase, hint at a differential regulation of androgen metabolic pathways that may ultimately lead to a distinct impact of biologically active metabolites on growth and function of human liver cancer cells.

MP-08.26: Genetic polymorphisms of genes involved in androgen metabolism and synthesis pathway and prostate cancer risk among Chinese population

MP-08.26: Genetic polymorphisms of genes involved in androgen metabolism and synthesis pathway and prostate cancer risk among Chinese population

Profiling Genetic Variation along the Androgen Biosynthesis and Metabolism Pathways Implicates Several Single Nucleotide Polymorphisms and Their Combinations as Prostate Cancer Risk Factors

Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T(1)-T(2)) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 -34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3 -252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology.

Association of the polymorphisms of genes involved in androgen metabolism and signaling pathways with familial prostate cancer risk in a Japanese population

Background: Androgen plays a central role in the normal and malignant development of prostate glands. Genetic polymorphisms of genes involved in androgen metabolism and signaling might be associated with the risk of prostate cancer. Methods: One hundred and two patients with prostate cancer with a family history and 117 healthy age- and residence-matched male controls were enrolled. Genotypes of the CAG repeat length of androgen receptor (AR), CYP17, 5α-reductase type II (SRD5A2), UDG-glucuronosyltransferase (UGT) 2B15, PSA promoter genes were analyzed. Results: For single polymorphisms, the presence of Y alleles showed a significantly lower risk of prostate cancer in comparison with the D/D genotype in UGT2B15 (odds ratio [OR] = 0.41, 95% confidence interval [CI] = 1.40–4.28, p = 0.0015), and the presence of A2 alleles showed a weak tendency to decrease prostate cancer risk in comparison with the A1/A1 genotype in CYP17 (OR = 0.69, 95% CI = 0.39–1.23, p = 0.21). The stratification of cases according to clinical stage and pathological grade showed that the A2/A2 genotype was significantly associated with localized stage cancer in comparison with metastatic stage cancer (OR = 5.18, 95% CI = 1.49–17.95, p = 0.007). The combination of UGT2B15 and CYP17 genotypes could identify higher risk subjects even in subjects with low-risk UGT2B15 genotypes, i.e., Y/Y + D/Y genotypes (OR = 1.97, 95% CI = 0.92–4.22, p = 0.079). Conclusion: Genetic polymorphisms of the genes involved in androgen metabolism and signaling were significantly associated with familial prostate cancer risk. Single nucleotide polymorphisms of low-penetrance genes could be targets to understand genetic susceptibility to familial prostate cancer.

A comparative study on androgen metabolism in three invertebrate species

A comparative approach was taken in this study to evaluate androgen (androstenedione and testosterone) metabolism in three invertebrate species: the gastropod Marisa cornuarietis, the amphipod Hyalella azteca, and the echinoderm Paracentrotus lividus. The existence of 17β/3β-hydroxysteroid dehydrogenase (HSD) and 5α-reductase catalyzed reactions was demonstrated in all three species. Androstenedione was primarily converted to 5α-androstanedione in M. cornuarietis, while it was primarily metabolized to testosterone in P. lividus and H. azteca. In addition, and consistent with vertebrate findings, tissue specific pathways and sexual dimorphism in androgen metabolism were observed. Namely, testosterone was metabolized to dihydrotestosterone in P. lividus gonads (via 5α-reductase), and metabolized to 4-androstene-3β,17β-diol in the digestive tube (via 3β-hydroxysteroid dehydrogenase). Furthermore, the synthesis of 17β-reduced metabolites of androstenedione (testosterone and dihydrotestosterone) was 3- to 4-fold higher in males of M. cornuarietis than in females. Organotin compounds, which have been shown to interfere with some aspects of androgen metabolism, had no major effect on testosterone metabolism in any of the three species. Fenarimol enhanced 5α-reductase-mediated catalysis in gonads of P. lividus. Overall, results demonstrate the ubiquity of some androgen biotransformation processes in invertebrates and reveals interphyla differences in androgen metabolic pathways, and different sensitivity of these pathways to some xenobiotics.

265: Genetic Polymorphisms of Genes Involved in Androgen Metabolism and Synthesis Pathway and Prostate Cancer Risk among Chinese Population

265: Genetic Polymorphisms of Genes Involved in Androgen Metabolism and Synthesis Pathway and Prostate Cancer Risk among Chinese Population

Changing demography of prostate cancer in Asia

There has been a recent trend in Asia towards increasing incidence of prostate cancer, with some low-risk regions, such as Japan and Singapore, reporting a more rapid increase than high-risk countries. In this study, age-specific and age-standardised (world) incidence rates and mortality rates for prostate cancer in Asian countries for 1978–1997 were retrieved and compared. The results confirm that the incidence of prostate cancer has risen by 5–118% in the indexed Asian countries. Incidence at centres in Japan rose as much as 102% (Miyagi 6.3–12.7 per 100,000 person-years) whilst the incidence in Singaporean Chinese increased 118% from 6.6 to 14.4 per 100,000 person-years. The lowest incidence rate recorded was in Shanghai, China and the highest rates were in Rizal Province in the Philippines, although still much lower than those in the United States of America (USA) and many European countries. Whilst the absolute value of the increase is not comparable to North American and European populations, the incidence ratio in many Asian centres is similar to that of the high-risk countries. The mortality data for prostate cancer showed a similar rising trend. The increases in age-adjusted mortality rates per 100,000 person-years, adjusted to the world standard, ranged from 50% in Thailand to 260% in Korea. The difference may be partly due to genetic polymorphism in the androgen receptor and androgen metabolism pathway enzymes as well as to dietary or environmental factors. In particular, phytochemicals, such as isoflavonoids and tea polyphenols, which are common in Asian diets showed promising anti-mitotic activity in animal and clinical studies. In conclusion, with gradual Westernisation, many Asian countries may be losing their cultural protective factors and acquiring high-risk ones. A better understanding of how these factors interact to cause prostate cancer through further studies with a multi-ethnic perspective will facilitate appropriate public health strategies to minimise high-risk factors and maintain protective factors and keep prostate cancer at bay.

Prevention of Hormone-Related Cancers: Prostate Cancer

Androgens are known to play an important role in normal prostate development, benign prostatic hyperplasia, established prostate cancer, and in prostate carcinogenesis. However, despite convincing experimental and clinical evidence, the epidemiologic data correlating sex steroid levels with disease risk is inconsistent. More recent work has focused on studies of polymorphisms in germ-line DNA in an effort to develop polygenic models of prostate cancer susceptibility and prognosis. Such models have the potential to aid in the selection of men for specific chemopreventive interventions and to help determine which men with localized prostate cancer are most likely to benefit from aggressive therapy. In this review, we will provide a brief summary of androgen metabolic pathways followed by an assessment of the epidemiology literature addressing the relationship between androgens and prostate cancer. Finally, we will address the two major questions that have arisen in response to the recently published results from the Prostate Cancer Prevention Trial: Who are the best candidates for finasteride chemoprevention, and what are the clinical implications of the high prevalence of prostate cancer that was detected in men with prostate-specific antigen levels in the so-called "normal" range?

Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways.

Ethnicity, when it is used to mean shared genetic inheritance within a group, has become one of the most important factors in determining prostate carcinoma risk. Genetic polymorphisms were hypothesized to be the probable explanation for differences in risk among ethnic groups. The authors evaluated the association between polymorphisms in genes involved in the androgen biosynthesis and metabolism pathway and the risk of prostate carcinoma. Two hundred twenty-six patients with the pathologic diagnosis of sporadic prostate tumor and 156 healthy matched (age, ethnic group) male controls from a large epidemiologic cohort were genotyped for previously described polymorphisms in the androgen receptor (AR), 5alpha-reductase type II (SRD5A2), p450c17 (CYP17), and aromatase (CYP19) genes. The different polymorphisms in prostate carcinoma patients also were analyzed according to age of onset, preoperative prostate-specific antigen level, tumor stage, and tumor grade. The distribution of the tetranucleotide simple tandem repeat polymorphism (STRP) in intron 4 of CYP19 was significantly different in control and cancer patients (P = 0.012). The 171 allele and the 187 allele were associated with prostate carcinoma risk (P = 0.05 and P = 0.045, respectively). Conversely, no association was observed between prostate carcinoma risk and the other polymorphisms studied as follow: the CAG repeat in exon 1 of AR, the (TA)n dinucleotide repeat polymorphism in the 3' untranslated region, and the A49T or V89L substitutions in SDR5A2, the single base pair (bp) (a T to C transition) polymorphism that creates an additional Sp1-type (CCACC box) promoter site in CYP17. In prostate carcinoma patients, CAG repeats of AR, and TA repeats of SDR5A2 are associated with age of onset (P = 0.05 and P < 0.001, respectively). The association between the 171-bp allele of CYP19 and prostate carcinoma risk suggests that aromatase could be used as a new indicator for prostate carcinoma prevention in men of White French ethnogeographic origin. Conversely, it is possible that an individual carries both a high- and a low-risk marker (e.g., CYP17 A2 allele and V89L in SRD5A2) resulting in no overall difference in risk observed across the population. For these reasons, the development of a polygenic model, incorporating multiple loci from the individual genes may maximize the chance of identifying individuals with high-risk genotypes.

Altered balance between the 5 alpha-reductase and aromatase pathways of androgen metabolism during controlled ovarian hyperstimulation with human menopausal gonadotropins.

To evaluate androgen production and metabolism during controlled ovarian hyperstimulation. Five women, aged 33-42, were studied. All participants were undergoing controlled ovarian hyperstimulation with gonadotropin-releasing hormone agonist and human menopausal gonadotropins. Serum estradiol, estrone, androstenedione, testosterone, 3 alpha-androstanediol glucuronide, and sex hormone-binding globulin levels were measured at 6 time points during the cycle. The levels of all steroids increased significantly from baseline during controlled ovarian hyperstimulation. Mean total testosterone levels increased from 0.29 +/- 0.05 ng/mL to 0.58 +/- 0.07 ng/mL after gonadotropin stimulation. Sex hormone-binding gonadotropin levels increased from 50 +/- 16 nM to 73 +/- 12 nM after gonadotropin stimulation. Estrone/androstenedione and estradiol/testosterone ratios, reflecting the aromatase pathway, increased whereas 3 alpha-androstanediol glucuronide/androstenedione and 3 alpha-androstanediol glucuronide/testosterone ratios, reflecting 5 alpha-reductase activity, decreased. Controlled ovarian hyperstimulation with human menopausal gonadotropins results in increased serum testosterone and androstenedione levels. Whereas there is an enhancement in androgen metabolism by aromatase, 5 alpha-reductase activity with regard to androgen metabolism is diminished.