Targeting oxytocin for the treatment of bladder outlet obstruction due to benign prostatic hyperplasia

Lee S1, Hammar J2, Van Gramberg J1, Papargiris M1, Seidensticker M3, Risbridger G P1, Whittaker M4, Ellem S1, Middendorff R3, Exintaris B4

Research Type

Basic Science / Translational

Abstract Category

Male Lower Urinary Tract Symptoms (LUTS) / Voiding Dysfunction

Abstract 630
Basic Science: Novel Bladder Insights
Scientific Podium Short Oral Session 31
Friday 31st August 2018
14:07 - 14:15
Hall D
Benign Prostatic Hyperplasia (BPH) Basic Science Pharmacology Physiology Male
1. Monash University, 2. University of Gothenburg, 3. Justus Liebig University, 4. Monash Institute of Pharmaceutical Sciences
Presenter
B

Betty Exintaris

Links

Abstract

Hypothesis / aims of study
The pathogenesis of Benign Prostatic Hyperplasia (BPH) is associated with both the non-malignant growth of the prostate (static component), and / or increased prostatic smooth muscle tone (dynamic component) which can lead to irritative and obstructive lower urinary tract symptoms, as a result of bladder outlet obstruction.  While not life threatening, BPH significantly affects the quality of life of patients.  A recent study has shown that the levels of circulating oxytocin are significantly upregulated in men with BPH, and exogenous oxytocin significantly increased the proliferation of prostatic fibroblasts [1].

Our hypothesis is that oxytocin modulates the contractile activity of the prostate gland in BPH, thereby contributing to the dynamic component of this condition.  

The aims of this study were to investigate whether i) oxytocin regulates the smooth muscle tone of the human prostate gland and ii) the effect of an oxytocin antagonist on human prostate contractility.
Study design, materials and methods
Samples of non-malignant human prostate were collected from the transition (TZ) and peripheral zone (PZ) of men undergoing radical prostatectomy for mild to moderate prostate cancer. Immunohistochemistry was used to confirm the presence and localization of the oxytocin receptor. Tension recordings were obtained using organ bath techniques; increasing concentrations of oxytocin (0.1nM to 10µM) or atosiban (1nM to 300nM) were exposed to the samples.  The amplitude (N/g) and frequency of spontaneous contractions +/- drug treatment were quantified.  A paired Student’s t-test or ANOVA was used to test for statistical significance (P < 0.05).
Results
Using Immunohistochemistry, the oxytocin receptor was found to be widely expressed in both the epithelial and stromal compartment of TZ and PZ specimens of human prostate (n =10). Application of exogenous oxytocin to TZ specimens significantly upregulated the frequency of spontaneous contractions at 10µM by 70 ± 21% when normalized to baseline frequency (p < 0.05, n = 8). The half-maximal increase in frequency (EC50) occurring at 300nM. A similar effect was observed in patient matched PZ specimens (n=4).  The oxytocin receptor antagonist, atosiban produced a concentration dependent decrease (1nM-300nM) in the amplitude and frequency of the spontaneous contractile events (n=10).
Interpretation of results
We can confirm that oxytocin receptors are widely expressed in the TZ and PZ of the human prostate gland.  In addition, oxytocin induces contractility of the TZ and PZ of the human prostate gland.   Moreover, spontaneous contractile activity in both the TZ and PZ of the human prostate gland are significantly reduced by the oxytocin receptor antagonist, atosiban.   Oxytocin may be a valid, novel target for the treatment of bladder outlet obstruction due to enhanced prostatic contractility as a result of BPH.
Concluding message
Given that patients with BPH have elevated levels of oxytocin and that oxytocin has previously been shown to induce proliferation of prostate fibroblasts, is widely expressed in both the prostate stroma and epithelium, and is able to induce muscle contractility, targeting of the oxytocin receptor and associated downstream signalling mechanisms may be an attractive prospect in designing new and novel pharmacotherapies for treating the irritative and obstructive  lower urinary tract symptoms associated with BPH.
References
  1. Xu, H., et al., Oxytocin: its role in benign prostatic hyperplasia via the ERK pathway. Clin Sci (Lond), 2017. 131(7): p. 595-607.
Disclosures
<span class="text-strong">Funding</span> No financial disclosures <span class="text-strong">Clinical Trial</span> No <span class="text-strong">Subjects</span> Human <span class="text-strong">Ethics Committee</span> Cabrini Human Research Ethics Committee (13-14-04-08), Epworth HealthCare Human Ethics Committee (53611) and Monash University Human Research Ethics Committee (2004/145). <span class="text-strong">Helsinki</span> Yes <span class="text-strong">Informed Consent</span> Yes