Mizoguchi Shinsuke, Mori Kenichi, Wang Zhou, Liu Teresa, Funahashi Yasuhito, Sato Fuminori, DeFranco Donald B, Yoshimura Naoki, Mimata Hiromitsu
Department of Urology, Oita University Graduate School of Medicine, Yufu, Japan.
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Prostate. 2017 May;77(7):803-811. doi: 10.1002/pros.23320. Epub 2017 Feb 9.
There is increasing evidence showing that chronic non-bacterial prostatic inflammation is involved in the pathogenesis of benign prostatic hyperplasia (BPH) and male lower urinary tract symptoms (LUTS). It has also been reported that estrogen receptor β (ERβ) could have an immunoprotective role in prostatic tissue. Therefore, we investigated the effect of ERβ-activation on not only prostatic inflammation, but also bladder overactive conditions in a rat model with nonbacterial prostatic inflammation.
Male Sprague-Dawley rats (8 weeks, n = 15) were divided into three groups: sham-saline group (n = 5), formalin-vehicle group (n = 5), and formalin-treatment group (n = 5). The sham-saline group had sham operation and 50 μl normal saline injected into each ventral lobe of the prostate. The formalin-vehicle group had 50 μl 5% formalin injection into bilateral ventral lobes of the prostate. The formalin-treatment group was treated with 3α-Adiol (a selective ERβ agonist precursor) at a dose of 3 mg/kg daily from 2 days before induction of prostatic inflammation, whereas formalin-vehicle rats received vehicle (olive oil). In each group, conscious cystometry was performed on day 28 after intraprostatic formalin injection or sham treatment. After cystometry, the bladder and prostate were harvested for evaluation of mRNA expression and histological analysis.
In cystometric investigation, the mean number of non-voiding contractions was significantly greater and voiding intervals were significantly shorter in formalin-vehicle rats than those in sham-saline rats (P < 0.05). In RT-qPCR analysis, mRNA expression of NGF, P2X2, and TRPA1 receptors was significantly increased in the bladder mucosa, and mRNA expression of TNF-α, iNOS and COX2 in the ventral lobes of prostate was significantly increased in formalin-vehicle rats compared with sham-saline rats (P < 0.05). In addition, relative mRNA expression ratio of ERβ to ERα (ERβ/ERα) in the ventral lobes of prostate was significantly decreased in formalin-vehicle rats compared with sham-saline rats (P < 0.05). These changes were ameliorated by 3α-Adiol administration in formalin-treatment rats.
These results indicate that ERβ activation by 3α-Adiol administration, which normalized the ERβ/ERα expression ratio in the prostate, can improve not only prostatic inflammation, but also bladder overactivity. Therefore, ERβ agonists might be useful for treating irritative bladder symptoms in patients with symptomatic BPH associated with prostatic inflammation. Prostate 77:803-811, 2017. © 2017 Wiley Periodicals, Inc.
越来越多的证据表明，慢性非细菌性前列腺炎参与了良性前列腺增生（BPH）和男性下尿路症状（LUTS）的发病机制。也有报道称，雌激素受体β（ERβ）可能在前列腺组织中具有免疫保护作用。因此，我们在非细菌性前列腺炎大鼠模型中研究了ERβ激活对前列腺炎症以及膀胱过度活动状态的影响。
将雄性Sprague-Dawley大鼠（8周龄，n = 15）分为三组：假手术-生理盐水组（n = 5）、福尔马林-溶剂组（n = 5）和福尔马林-治疗组（n = 5）。假手术-生理盐水组进行假手术，并向前列腺每个腹叶注射50μl生理盐水。福尔马林-溶剂组向前列腺双侧腹叶注射50μl 5%福尔马林。福尔马林-治疗组在前列腺炎症诱导前2天开始每天以3mg/kg的剂量给予3α-雄烷二醇（一种选择性ERβ激动剂前体），而福尔马林-溶剂组大鼠给予溶剂（橄榄油）。每组在前列腺内注射福尔马林或进行假手术后第28天进行清醒膀胱测压。膀胱测压后，摘取膀胱和前列腺进行mRNA表达评估和组织学分析。
在膀胱测压研究中，福尔马林-溶剂组大鼠的非排尿收缩平均次数显著多于假手术-生理盐水组大鼠，排尿间隔显著短于假手术-生理盐水组大鼠（P < 0.05）。在RT-qPCR分析中，与假手术-生理盐水组大鼠相比，福尔马林-溶剂组大鼠膀胱黏膜中NGF、P2X2和TRPA1受体的mRNA表达显著增加，前列腺腹叶中TNF-α、iNOS和COX2的mRNA表达显著增加（P < 0.05）。此外，与假手术-生理盐水组大鼠相比，福尔马林-溶剂组大鼠前列腺腹叶中ERβ与ERα的相对mRNA表达比值（ERβ/ERα）显著降低（P < 0.05）。在福尔马林-治疗组大鼠中，给予3α-雄烷二醇可改善这些变化。
这些结果表明，给予3α-雄烷二醇激活ERβ，使前列腺中ERβ/ERα表达比值正常化，不仅可以改善前列腺炎症，还可以改善膀胱过度活动。因此，ERβ激动剂可能有助于治疗伴有前列腺炎症的有症状BPH患者的膀胱刺激性症状。《前列腺》77:803 - 811，2017年。© 2017威利期刊公司。
