Background: Benign prostatic hyperplasia and prostate cancer are androgen-dependent
diseases, and dihydrotestosterone (DHT), a 5α-reduced metabolite of testosterone (T), has been implicated
as a causative factor in 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.
Objective: This study focused on evaluating the biological activity of three series of pregnenolone
derivatives as inhibitors of 5α-R and as antiandrogens on androgen-dependent glands.
Methods: To determine the biological activity of these compounds, we evaluated the effect of each
one on suppressing the activity of both types of isozymes of 5α-R (1 and 2) by 50% (IC50). Using animal
studies, we assessed 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.
Results: 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. 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.
Discussion: Pharmacological experiments showed that pregnenolone derivatives possess an antiandrogenic
effect because of the inhibition of DHT production in androgen-dependent glands.
Conclusion: The pregnenolone derivatives studied suppressed type 2 5α-reductase activity and because
of this, the weight and dimension of androgen-dependent organs were decreased.