Hypothesis / aims of study
Both static and dynamic processes play a role in the pathophysiology of bladder outlet obstruction (BOO) associated with benign prostatic hyperplasia (BPH). The static component (cellular proliferation) is hormonally regulated by androgen and estrogen receptor signalling. In contrast, the hormonal regulation of the dynamic smooth muscle tone is poorly understood, yet the dynamic component is a key target of several BPH pharmacotherapies including alpha 1 antagonists and phosphodiesterase (5) inhibitors. In this study, our aim was to investigate the effects of estrogen on human prostatic smooth muscle contractility. We hypothesised that changes in smooth muscle tone are mediated by non-genomic estrogen signalling through the G Protein Estrogen Receptor (GPER).
Study design, materials and methods
Human prostate tissue was collected from the transition zone (TZ) of a cohort of men undergoing radical prostatectomy, and conventional tension recordings were used to assess spontaneous contractility of the tissue following treatment with the GPER specific agonist (G1) and compared to 17β-estradiol (E2). The key parameters assessed were basal tension (mN), adjusted amplitude (N/g) and frequency. Data is expressed as the mean ± SEM.
Non-malignant TZ specimens were obtained from a cohort of men with an average age of 64±3.14 years. Application of 100nM 17β-estradiol (E2) significantly reduced the basal tension (Δ-6.16±2.07%) and adjusted amplitude (Δ-29.57±7.52%) of the spontaneous contractions of the prostate within 10 minutes (p<0.05, n=6). There was a notable interpatient variability in the reduction of parameters in response to 17β-estradiol. Regression analysis determined that age was strongly negatively correlated (R2 = 0.633) with the percentage decrease of the adjusted amplitude of contractions, indicating that older men had a greater reduction in the adjusted amplitude of spontaneous contractions in response to E2.
The rapid, significant decrease in spontaneous contractile parameters by 100nM E2 was replicated in patient matched specimens by the G Protein Estrogen Receptor specific agonist, G1, with no significant difference in efficacy observed between 100nM E2 and 100nM G1 (Paired two way ANOVA with Dunnets post hoc test, n = 5, n.s > 0.05).
Interpretation of results
Spontaneous contractions were significantly (p < 0.05) and rapidly reduced within 10 minutes by G2 and E2, supporting a hormonal, non-genomic effect on smooth muscle tone. The percentage relaxation induced by G1 and E2 was non-significantly different, indicating activation of GPER induces smooth muscle relaxation.
Overall these data show that promotion of non-genomic estrogen action is a potential mechanism for therapeutic targeting of the dynamic component of BPH.