Age and Obesity Promote Methylation and Suppression of 5α-Reductase 2: Implications for Personalized Therapy of Benign Prostatic Hyperplasia

Purpose: In men with symptomatic benign prostatic hyperplasia 5 alpha-reductase inhibitors are a main modality of treatment. More than 30% of men do not respond to the therapeutic effects of 5 alpha-reductase inhibitors. We have found that a third of adult prostate samples do not express 5 alpha-reductase type 2 secondary to epigenetic modifications. We evaluated whether 5 alpha-reductase type 2 expression in benign prostatic hyperplasia specimens from symptomatic men was linked to methylation of the 5 alpha-reductase type 2 gene promoter. We also identified associations with age, obesity, cardiac risk factors and prostate specific antigen. Materials and Methods: Prostate samples from men undergoing transurethral prostate resection were used. We determined 5 alpha-reductase type 2 protein expression and gene promoter methylation status by common assays. Clinical variables included age, body mass index, hypertension, hyperlipidemia, diabetes, prostate specific antigen and prostate volume. Univariate and multivariate statistical analyses were performed followed by stepwise logistic regression modeling. Results: Body mass index and age significantly correlated with methylation of the 5 alpha-reductase type 2 gene promoter (p < 0.05) whereas prostate volume, prostate specific antigen or benign prostatic hyperplasia medication did not correlate. Methylation highly correlated with 5 alpha-reductase protein expression (p < 0.0001). In a predictive model increasing age and body mass index significantly predicted methylation status and protein expression (p < 0.01). Conclusions: Increasing age and body mass index correlate with increased 5 alpha-reductase type 2 gene promoter methylation and decreased protein expression in men with symptomatic benign prostatic hyperplasia. These results highlight the interplay among age, obesity and gene regulation. Our findings suggest an individualized epigenetic signature for symptomatic benign prostatic hyperplasia, which may be important to choose appropriate personalized treatment options.