The epidemiology of sex steroid hormones and their signaling and metabolic pathways in the etiology of prostate cancer

https://doi.org/10.1016/j.jsbmb.2004.10.002Get rights and content

Abstract

The purpose of this review is to discuss the epidemiologic literature on the association of sex steroid hormones and components of their signaling and metabolic pathways with prostate cancer and to describe data evaluating racial variation in sex steroid hormone pathways as a possible explanation for the notably higher risk of prostate cancer in African-American men compared to white or Asian men. Although sex steroid hormones likely contribute to the growth and progression of prostate cancer, associations between hormones and prostate cancer risk across the range of normal levels have been difficult to reliably demonstrate epidemiologically. Methodologic issues no doubt have made the detection of these associations difficult. Of particular importance are (1) the inadequacy of measuring circulating hormones in middle age as a surrogate for the exposure in the target cells in the prostate at the relevant time in life and (2) the current inability to integrate across components of the sex steroid hormone signaling pathway to fully capture target cell androgenic and estrogenic stimulation. Although the approach of evaluating polymorphisms in genes involved in sex steroid hormone signaling or metabolism as a way to minimize some of the issues in the direct measurement of hormones is logical, the findings among these studies are somewhat difficult to reconcile as well. The problems of the changing case mix due to screening for elevated PSA, small sample sizes increasing the likelihood of false negative and false positive results, the controls and their allele frequencies not being representative of the population at risk, and lack of knowledge of the functional consequence of a polymorphism in relation to other polymorphisms in that gene or without consideration of other genes involved in the same pathway may be contributory. The primary result of the Prostate Cancer Prevention Trial confirms that intraprostatic dihydrotestosterone levels in the normal range indeed do contribute to the growth of prostate adenocarcinoma. However, the secondary result of higher-grade disease in cases in the finasteride arm coupled with clinical studies showing higher grade disease in non-metastatic cases with lower serum androgens, if not a pathological artifact or detection bias in the finasteride arm, possibly suggests a complex relationship between androgens and the growth versus differentiation of a prostate tumor. Finally, racial variation in components of the sex steroid hormone pathway do appear to exist, but whether the extent of the variation is adequately great such that it accounts for some of the substantial differences in prostate cancer incidence among blacks, whites, and Asians is unclear.

Introduction

Sex steroid hormones contribute to the growth and progression of prostate cancer, but whether the range of normal levels is associated with prostate cancer risk has been difficult to reliably demonstrate. This review discusses the epidemiologic literature on the association of circulating concentrations of sex steroid hormones and polymorphisms in components of their signaling and metabolic pathways with prostate cancer and presents possible explanations for the inconsistencies among these studies. Also described are epidemiologic data suggesting that racial variation in sex steroid hormones and their signaling pathways may, in part, account for the 60% higher prostate cancer incidence in African-American men and the 38% lower incidence in Asian-American men compared to white men [1].

Section snippets

Androgens

Androgens are clearly important in the development, maturation, and the maintenance of the prostate, affecting both the proliferation and differentiation status of the luminal epithelium. Castration results in the involution of prostate gland as a result of diffuse atrophy primarily of the luminal epithelial cells, but not the stromal cells [2]. The replacement of androgen results in the proliferation of the epithelial cells, but once normal volume is attained additional androgenic stimulation

The androgen receptor

The actions of testosterone and dihydrotestosterone in androgen-responsive tissues are mediated by the androgen receptor [53]. This receptor is sometimes mutated in prostate cancers with various predicted effects on its functionality [54] and possibly a wider array of activating steroid and non-steroid ligands [54], [55]. The gene encoding this receptor, located on the long arm of the X chromosome, contains a variable length CAG repeat (encodes polyglutamine) in exon 1. In experimental

Sex steroid hormone synthesis and metabolism

Shown in figure is the androgen and estrogen synthetic and metabolic pathway in the testis, prostate, and liver (excluded adrenal sources for simplicity) and the genes that catalyze the steps in the pathway. Many of the genes in this pathway are polymorphic, although with the exception of SRD5A2, encoding 5α-reductase type 2, and CYP17, encoding steroid 17α-hydroxylase/17,20 lyase, variations in these genes have been understudied for their relation with prostate cancer. The recent availability

Racial variation in sex steroid hormones and hormone signaling

Racial variation in prostate cancer incidence and mortality rates in the US is pronounced. African-American men have the highest prostate cancer incidence rate (standardized to 2000 US population age standard, 1992–1999: 275.3 per 100,000 men annually) and mortality rate (75.1 per 100,000 men annually) among any racial or ethnic group in the US. By comparison, the incidence and mortality rates are 1.6 (172.9 per 100,000 men) and 2.3 (32.9 per 100,000 men) times that for whites, respectively.

Conclusions

Epidemiologic evidence that normal variation in circulating concentrations of androgens, estrogens, and sex hormone binding globulin, normal sequence variation in genes that encode the androgen and estrogen receptors, and normal sequence variation in genes that encode enzymes involved in the biosynthesis or the inactivation of androgens and estrogens contribute to the development of prostate cancer is weak to modest at the present. The primary result of the Prostate Cancer Prevention Trial

Acknowledgments

This work was supported by grants from: CA55075 (Harvard), the Maryland Cigarette Restitution Fund at Johns Hopkins, and Howard-Hopkins Partnership Pilot Project Initiative.

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