Synthetic progestins stimulate prostatic binding protein messenger RNAs in the rat ventral prostate

Abstract

In order to assess the intrinsic androgenic activity of the synthetic progestins currently used as antiandrogens for the treatment of prostate cancer and other androgen-sensitive diseases, cyproterone acetate (CPA), medroxyprogesterone acetate (MPA) and megestrol acetate (MEG) were administered for 4 days to adult rats castrated 4 days previously. The effects of these compounds were measured on highly specific and sensitive markers of androgen action in the rat ventral prostate, namely the levels of messenger RNAs encoding the C1 (PBP-C1) and C3 (PBP-C3) components of rat prostatic binding protein (PBP). Steady-state mRNA levels were measured by dot-blot hybridization as well as by in situ hybridization. Treatment with CPA or MEG, at the twice daily dose of 10 mg, caused respective 2- and 4.5-fold increases in the steady-state levels of mRNA encoding PBP-C1. MPA, at the dose of 0.45 mg, twice daily, was approximately 40 times as potent as MEG, leading to an 8-fold increase in PBP-C1 mRNA levels. While the pure nonsteroidal antiandrogen flutamide (10 mg, twice daily) did not cause accumulation of PBP mRNAs when administered to castrated rats, it completely reversed the stimulatory effects of the synthetic progestins CPA, MPA and MEG. The results obtained by in situ hybridization were similar to those obtained by dot-blot analysis. Moreover, the synthetic progestins caused similar androgenic effects on PBP-C3 mRNA levels. The present data indicate that all three synthetic progestins currently used for the treatment of prostate cancer possess significant intrinsic androgenic activity as evidenced by their stimulatory effects on the accumulation of mRNAs sensitive to androgen action. Consequently, as indicated by this sensitive and androgen-specific in vivo rat model, such compounds are not recommended for the treatment of conditions requiring an optimal blockade of androgens, especially prostate cancer.