Androgen and prostate cancer: is the hypothesis dead?

Data from animal, clinical, and prevention studies support the role of androgen in prostate cancer growth, proliferation, and progression. However, results serum-based epidemiologic studies in humans have been inconclusive. Part of the inconsistency in these findings stems from differences in study population, assay accuracy, intraperson variation, and limited sample size. Recently, data from a large pooled analysis of 18 prospective studies (3,886 cases and 6,438 healthy controls) showed no association between serum androgen and prostate cancer risk. It is not surprising that the pooled analysis did not find a positive link between circulating levels of total testosterone and prostate cancer risk because, individually, few of the 18 studies included in the pooled analysis reported a substantial positive association. The null result, however, does not pronounce a death sentence for the androgen hypothesis; rather, it underscores the importance of a better understanding of androgen action within the prostate, including the relationship between tissue and serum levels of androgen. In this commentary, we explain why circulating levels of testosterone may not reflect androgen action in the prostate and why tissue levels of androgen, in particular dihydrotestosterone, and the androgen receptor and its coregulators are critical to androgen action in the prostate and should be incorporated in future studies. It is timely to integrate system thinking into our research and use an interdisciplinary approach that involves different disciplines, including epidemiology, endocrinology, pathology, and molecular biology, to help dissect the complex interplay between sex steroids and genetic and lifestyle factors in prostate cancer etiology.