The Rationale for Inhibiting 5α-Reductase Isoenzymes in the Prevention and Treatment of Prostate Cancer

Purpose

Androgens are essential for prostatic growth and development but they also have a significant role in prostate disease pathogenesis. Dihydrotestosterone, the primary prostatic androgen, is transformed from testosterone by types 1 and 2 5α-reductase and, thus, a potential therapeutic benefit could be achieved through the inhibition of 5α-reductase.

Materials and Methods

A literature review was performed using PubMed®/MEDLINE® and congress abstracts to examine evidence supporting the potential of 5α-reductase inhibitors in the primary prevention of prostate cancer and in limiting the progression of diagnosed disease.

Results

Prostate disease development is associated with increased expression of each 5α-reductase isoenzyme with over expression of type 1 of particular importance in prostate cancer development and progression. The 2 5α-reductase inhibitors currently clinically available are finasteride, a type 2 5α-reductase inhibitor, and dutasteride, a dual 5α-reductase inhibitor. Dual inhibition by dutasteride has been shown to translate into a greater degree and consistency of dihydrotestosterone suppression compared with finasteride. The Prostate Cancer Prevention Trial showed that finasteride significantly decreased the 7-year risk of prostate cancer in men with prostate specific antigen 3.0 ng/ml or less, while the ongoing Reduction by Dutasteride of Prostate Cancer Events study is assessing whether dutasteride decreases the risk of biopsy detectable prostate cancer in men with prostate specific antigen 2.5 to 10 ng/ml and a previous negative biopsy. Small-scale studies have demonstrated potential effects of 5α-reductase inhibition in prostate cancer treatment that warrant further investigation, while dutasteride use in men undergoing expectant treatment is also being examined.

Conclusions

The inhibition of 5α-reductase represents a valid target for prostate cancer risk reduction and treatment strategies. The greater suppression of dihydrotestosterone observed with agents that inhibit each 5α-reductase isoenzyme may translate into enhanced outcomes and studies are under way to test this hypothesis.

Key Words: prostate, prostatic neoplasms, cholestenone 5 alpha-reductase, androgens, dihydrotestosterone

Abbreviations and Acronyms: 5αR, 5α-reductase, ADI, androgen depletion independent, AR, androgen receptor, ARE, androgen response element, BPH, benign prostatic hyperplasia, DHT, dihydrotestosterone, PCPT, Prostate Cancer Prevention Trial, PIN, prostatic intraepithelial neoplasia, PSA, prostate specific antigen, REDUCE, Reduction by Dutasteride of Prostate Cancer Events, TA, transit amplifying