Blockade of androstenedione-induced stimulation of androgen-sensitive parameters in the rat prostate by combination of Flutamide and 4-MA

Abstract

In order to mimic the human situation in which adrenal steroid precursors are converted to the active androgen dihydrotestosterone (DHT) in prostatic tissue, we have used castrated rats supplemented with the precursor steroid androstenedione ( Δ 4-dione) released from Silastic implants. While it is well known that the action of DHT can be partially neutralized by antiandrogens which compete for binding to the androgen receptor, we have used 17 β- N, N-diethylcarbamoyl-4-methyl-4-aza-5 α-androstan-3-one (4-MA), an inhibitor of 5α-reductase, the enzyme which converts testosterone into DHT, in order to decrease intraprostatic DHT levels and thus facilitate the action of the antiandrogen. Animals were treated for 7 days with Flutamide (FLU, 2 mg) or 4-MA (4 mg) injected subcutaneously, twice daily, alone or in combination. 4-MA administered alone caused a 54% inhibition of Δ 4-dione-stimulated ventral prostate weight while FLU exerted a 74% inhibitory effect and 4-MA + FLU further improved inhibition to 81%. We then measured, by in situ hybridization, the levels of prostatic mRNAs encoding the C1 and C3 components of the prostatic binding protein (PBP) which are highly specific and sensitive markers of androgen action. PBP-C3 mRNA levels fell by 95% following castration while treatment with Δ 4-dione completely reversed the effect of castration. Administration of FLU or 4-MA independently caused 33% and 10% decreases, respectively, of PBP-C3 mRNA levels stimulated by Δ 4-dione while the combination of both compounds further inhibited PBP-C3 mRNA levels to reach a 55% inhibition. Similar effects were observed on PBP-C1 mRNA levels. Moreover, while FLU or 4-MA alone caused 72 and 75% decreases in intraprostatic DHT levels, respectively, the combined treatment caused a 89% decrease in the intraprostatic concentration of the androgen. The present data show that the combination of a pure antiandrogen and a 5α-reductase inhibitor has greater inhibitory effects than either compound used alone on androgen-sensitive parameters in the rat ventral prostate. It is likely that an important part of the beneficial effect of the antiandrogen is due to its blockade of access to the androgen receptor of the high intraprostatic levels of testosterone resulting from the action of the 5α-reductase inhibitor used alone.