Background: The etiology of benign prostatic hyperplasia (BPH) is complex, both age and androgen are thought to be important. However, the failure of androgen blockade treatments suggests other paracrine/autocrine factors involved in BPH. Oxytocin was found to have a paracrine/autocrine role in prostate in recent years. The influence of BPH on prostatic oxytocin receptor (OTR) expression has never been studied.Material and methods: A testosterone-estradiol induced rat model of BPH was employed and human hyperplastic prostate specimens were harvested. Expressions of OTR, α 1 -adrenoreceptor subtypes and nitric oxide synthase isoforms were determined via real-time RT-PCR. OTR was further analyzed with Western-Blotting and histological examination. Subsequently, rat epithelial cells, human stromal cells and epithelial cells were cultured in vitro and treated with gradient concentrations of OT from 1 to 5 days. Cell proliferation was tested by Cell Counting Kit-8 and Flow Cytometry.Results: The rat BPH model was validated with significant increased prostate weight.H-E stain revealed a different histopathology between human and rat BPH. Masson's trichrome staining demonstrated that smooth muscle (SM) cells, epithelium cells and collagen fibers were simultaneously augmented in this rat BPH model and human BPH samples. OTR mainly localized in epithelium in rat prostate whereas it mainly localized in stroma in human prostate. OTR gene was upregulated 3.3-fold in rat BPH and 3.0fold in human BPH, along with increased expression of 2.0-fold α 1a ARs and 3.0-fold eNOS for rat BPH and 5.0-fold α 1a ARs for human BPH. The expression of OTR protein was upregulated 1.4-fold in rat BPH and 3.9-fold in human BPH, respectively. Increased concentrations of exogenous OT can accelerate proliferation of rat epithelial cells and human stromal cells but has no impact on human epithelial cells in vitro. Flow Cytometry showed oxytocin could significantly increase G 2 /M period cell number.Conclusions: Our novel data demonstrates a significant and previously undocumented upregulation of OTR in both rat and human BPH. Moreover, exogenous OT accelerates proliferation of rat prostate epithelial cells and human prostate stromal cells. It is suggested OTR is involved in the development of BPH and OT regulatory system could be a potential new target for the BPH treatment.
Both erectile dysfunction (ED) and lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) are common in the aging male. Numerous clinical trials have demonstrated the efficacy and safety of phosphodiesterase type 5 inhibitors (PDE5-Is) for treating LUTS/BPH with/without ED. However, the influence of BPH on prostatic PDE5 expression has never been studied. A testosterone-induced rat model of BPH was developed and human hyperplastic prostate specimens were harvested during cystoprostatectomy. PDE5, nNOS, eNOS and α 1 -adrenoreceptor subtypes (α 1a ARs, α 1b ARs and α 1d ARs) were determined with real-time RT-PCR for rat tissues whilst PDE5 and α 1 -adrenoreceptor subtypes were determined in human samples. PDE5 was further analyzed with Western-blot and histological examination. Serum testosterone was measured with ELISA. The rat BPH model was validated as having a significantly enlarged prostate. PDE5 localized mainly in fibromuscular stroma in prostate. Our data showed a significant and previously undocumented upregulation of PDE5 in both rat and human BPH, along with increased expression of nNOS and α 1d ARs for rat tissues and α 1a ARs for human BPH. The upregulation of PDE5 in the hyperplastic prostate could explain the mechanism and contribute to the high effectiveness of PDE5-Is for treating LUTS/BPH. Fibromuscular stroma could be the main target for PDE5-Is within prostate.Lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) are common in aging male. The prevalence of BPH is approximately 40% for men in their fifties and reaches to 90% for men in their eighties or above 1 and the incidence of LUTS is around 25% for men in their 50 s or older 2 . This disorder is typically characterized by enlargement of the prostate gland, constriction of the urethra, and the emergence of LUTS. Besides prostatectomy, present pharmaceutical treatments for LUTS/BPH are aimed at relieving symptoms and slowing the progression of the disease. Current oral medical treatment options are 1) α -adrenoceptor antagonists (α -blockers, ABs) which reduce urethral resistance by attenuating the tension of smooth muscle (SM) fibers located in the prostate 2) 5α -reductase inhibitors (5ARIs) which are involved in the hormonal control of prostate growth 3) muscarinic receptor antagonists (MRAs) and 4) a "new emerging treatment" phosphodiesterase type 5 inhibitors (PDE5-Is) 3,4 . Several clinical studies have demonstrated the efficacy and safety of PDE5-Is in treating LUTS/BPH. We recently performed a systematic review and network meta-analysis including 64 RCTs with 28196 participants comparing the effectiveness of different oral drug therapies for LUTS/BPH 5 . This data showed that among all the drug treatments, PDE5-Is combined with ABs ranked highest in efficacy for decreasing the international prostate symptom score (IPSS) including total score, storage subscore and voiding subscore. PDE5-Is used alone also showed promising efficacy, with the exception of not improving maximum flow rate (Q max ). However...
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