The Journal of Steroid Biochemistry and Molecular Biology
The epidemiology of sex steroid hormones and their signaling and metabolic pathways in the etiology of prostate cancer
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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