Regarding prostate-specific antigen: let's not shoot the messenger.

It is well known that androgens drive prostate cancer and the inhibition of 5a-reductase results in an inhibition of the conversion of testosterone to dihydrotestosterone, the active androgen in the prostate. Recently, two large prospective randomized trials have tested the 5a-reductase inhibitors, finasteride and dutasteride compared to placebo for the chemoprevention of prostate cancer in middle aged and elderly men. Both trials demonstrated that 5a-reductase inhibitor therapy significantly decreased subsequent low-grade (Gleason score4 6) prostate cancers, however, high-grade (Gleason score 8–10) prostate cancers were significantly increased by nearly 2-fold. Stated otherwise, therapy with a 5a-reductase inhibitor to prevent prostate cancer resulted in one additional high-grade cancer as a trade-off to avoid four low-grade cancers. Although these findings have been vigorously debated, there has been no definitive explanation why they should be discounted, and they have come under intense scrutiny by the US Food and Drug Administration. Additionally, these findings should not be surprising since it was previously shown that the treatment of men with finasteride who have high-grade prostatic intraepithelial neoplasia (PIN), a common precursor lesion of prostate cancer, results in a significant increase in prostate cancer by 1 year. 5a-reductase inhibitors significantly reduce the synthesis of prostate-specific antigen (PSA), a protein made by the epithelial cells of the prostate. We propose that the actual reduction in prostate tissue PSA concentration over time might result in the promotion of high-grade prostate cancer. Furthermore, we feel this needs serious attention by the medical community given the widespread use of these drugs to treat both benign prostatic hyperplasia (BPH) and male pattern baldness. Histologic prostate cancer is exceedingly common in the USA; autopsy data reveal that latent prostate cancer is present in 30% of men in their 30s, 50% of men in their 50 s and more than 75% of men in their 80s. In contrast, the lifetime risk of invasive prostate cancer in the USA is 16%. Therefore, most prostate cancers in the population are indolent and of no threat to health or life. But, how might chemoprevention with 5a-reductase inhibitors promote histologic indolent prostate cancers to become high-grade invasive cancers?