The rationale for inhibiting 5alpha-reductase isoenzymes in the prevention and treatment of prostate cancer

Abstract

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 5alpha-reductase and, thus, a potential therapeutic benefit could be achieved through the inhibition of 5alpha-reductase.

Materials and methods: A literature review was performed using PubMed/MEDLINE and congress abstracts to examine evidence supporting the potential of 5alpha-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 5alpha-reductase isoenzyme with over expression of type 1 of particular importance in prostate cancer development and progression. The 2 5alpha-reductase inhibitors currently clinically available are finasteride, a type 2 5alpha-reductase inhibitor, and dutasteride, a dual 5alpha-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 5alpha-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 5alpha-reductase represents a valid target for prostate cancer risk reduction and treatment strategies. The greater suppression of dihydrotestosterone observed with agents that inhibit each 5alpha-reductase isoenzyme may translate into enhanced outcomes and studies are under way to test this hypothesis.

Fig. 1

Prostate cancer natural history

Fig. 2

AR signaling pathway in healthy prostate. In androgen responsive target cells testosterone (T) is converted to DHT by 5αR enzymes. DHT binds to AR and causes dissociation of heat shock proteins (Hsp), allowing translocation of DHT-AR complex into nucleus, where it binds to AREs. Recruitment of coactivator proteins (Co) enables transcriptional activation of target genes. Modified from Tindall and Dehm.

Fig. 3

Type 1 and 2, 5αR immunostaining in BPH, PIN, primary prostate cancer, recurrent cancer and metastases. Reproduced with permission from Thomas et al.