Combined blockade of testicular and locally made androgens in prostate cancer: A highly significant medical progress based upon intracrinology

Recently two drugs, namely the antiandrogen MDV-3100 and the inhibitor of 17α-hydroxylase abiraterone have been accepted by the FDA for the treatment of castration-resistant prostate cancer (CRPC) with or without previous chemotherapy, with a prolongation of overall survival of 2.2-4.8 months. While medical (GnRH agonist) or surgical castration reduces the serum levels of testosterone by about 97%, an important concentration of testosterone and dihydrotestosterone remains in the prostate and activates the androgen receptor (AR), thus offering an explanation for the positive data obtained in CRPC. In fact, explanation of the response observed with MDV-3100 or enzalutamide in CRPC is essentially a blockade of the action or formation of intraprostatic androgens. In addition to the inhibition of the action or formation of androgens made locally by the mechanisms of intracrinology, increased AR levels and AR mutations can be involved, especially in very advanced disease. Future developments look at more efficient inhibitors of the action or formation of intraprostatic androgens and starting treatment earlier when blockade of androgens can exert long-term control and even cure prostate cancer treated at a stage before the appearance of metastases. This article is part of a Special Issue entitled 'Essential role of DHEA'.