SEX STEROIDS METABOLISM IN BENIGN AND MALIGNANT PROSTATE TISSUE: AN EX-VIVO MODEL TO CHARACTERIZE THE ROLE OF ENZYMATIC PROFILE IN BIOLOGICAL BEHAVIOUR

Background: In vitro studies revealed that androgens and estrogens play a crucial role in prostate homeostasis. However, human studies failed to correlate circulating sex hormones with prostate disease. We investigated whether local hormone metabolism accounts for this discrepancy. Materials and Methods: Using an ex-vivo model of intact tissue cultures, we characterized the enzymatic profile of biopsy specimens from patients with benign prostatic hyperplasia (BPH) and cancer (PC), focusing on 17β- hydroxysteroid dehydrogenase (17βHSD) and aromatase activities. Results: 13 BPH and 11 PC specimens were analysed. Tissue fragments were incubated with 3H-testosterone or 3Handrostenedione in serum-free medium. Conversion was evaluated by TLC separation and beta-scanning of organic extracted supernatants. We identified 3 different patterns for H3-androstenedione: 1) no conversion; 2) androstenedione to testosterone; and 3) androstenedione to estradiol. Interestingly, 64% of BPHs showed pattern 1 whereas 71% of PCs showed pattern 3. In PCs, androstenedione was metabolized at a rate of 5.99-7.5 fmol/h and estradiol accounted for 35% of total radioactivity. Enzymatic conversion correlated with histology and PSA, but not serum hormones. PCs with highest Gleason scores (9: 4+5) expressed pattern 2. Expression of 17βHSD isoenzymes-3/5 was associated with malignancy. No testosterone conversion occurred in 77% of BPHs (no 17βHSD/aromatase), whereas 10% of radioactivity was found in conjugated metabolites (BPH). Conclusion: We found that 17βHSD and aromatase activity in prostate tissue cultures correlate with biological behaviour. Our study suggests that it is possible to estimate individual risk by characterizing individual enzymatic phenotype directly from biopsies. Increased production or clearance of potentially genotoxic metabolites could favour proliferation and transformation. These data also have implications on novel pharmacological targets.