Endocrine Abstracts

Benign prostatic hyperplasia and prostate cancer are androgen-dependent diseases. Dihydrotestosterone (DHT) is a 5α-reduced metabolite of testosterone (T), which is the causative factor for the progression of these diseases. The 5α-reductase enzyme (5α-R) converts T to DHT, which is responsible for increasing cell proliferation, and hence inhibition of this enzyme could lead to potential treatments for these afflictions. This study aimed to determine the biological activity of three series of pregnenolone derivatives as inhibitors of 5α-R. Also, these molecules evaluated as antiandrogens on androgen-dependent glands. The biological activity of these derivatives was determined by the concentration of each one needed to suppress the activity of both 5α-R types 1 and 2 isozymes by 50% (IC₅₀). The effect of these derivatives on the weight of the prostate, seminal vesicles, and diameter of the flank organs of castrated hamsters previously dosed with 1 mg/Kg T was also established. In vitro experiments showed that derivatives 1f, 2b, and 3d were very effective inhibitors of the activity of 5α-R2, showing IC₅₀ values of 21.8, 20, and 15 nM, respectively. However, derivatives 2b and 3b showed a lower inhibition effect on 5α-R1. The data also indicated that derivatives 2b, 1f, 3b, and 3d were very active in reducing prostate weight in the hamster model of benign prostatic hyperplasia as well as seminal vesicle weight and the diameter size of the pigmented spot of flank organs. Therefore, pregnenolone derivatives studied suppressed type 2 5α-reductase activity, and because of this, the weight and dimension of androgen-dependent organs decreased.