**3. Mechanism of BPH Related to BOO**

BPH causes obstruction by inducing functional and morphological changes in the prostate. Functionally, an increase in prostatic smooth muscle tone has been confirmed, which is influenced sympathetically [21]. Moreover, the presence of metabolic syndrome is associated with increased sympathetic nervous system activity and LUTS [22,23]. In such cases, alpha(α)-adrenergic antagonists can improve BPH-induced male LUTS [24]. Morphologically, BPH is characterized by unregulated proliferation of connective tissues, smooth muscles, and glandular epithelium [25]. Tissue proliferation leads to increased prostate volume (PV), subsequently compressing the prostatic urethra. McNeal found that BPH patients had an increase in BPH nodules in the periurethral zone and size of glandular nodules [26]. Further, either epithelium or fibro-muscular stroma proliferation could be found in the resected BPH tissues [27,28].

#### **4. Mechanism of BPH-Imbalance of Internal Hormones**

Abundant evidence showed that development of BPH requires testicular androgen [29]. Conversion of dihydrotestosterone (DHT), a metabolite of testosterone, in the prostate is considered as a major factor involved in the BPH pathogenesis. Elevated serum DHT level is associated with larger PV and higher prevalence of BPH [30]. Prostatic DHT and androgen receptor (AR) levels increase with age [31], whereas testosterone level declines with age. Increase in estrogen to testosterone ratio has been recognized as an important factor inducing the development of prostatic inflammation and cytokines [32]. In such cases, administration of 5α-reductase type II inhibitor resulted in increased plasma testosterone levels and further reduced the prostatic inflammation, suggesting the protective effect of testosterone against inflammation compared to that of DHT [33,34]. Imbalance in testosterone and estrogen levels also contributes to decreased activity of some suppressor cells, which maintain tolerance to prostatic antigen and prevent autoimmunity [35,36]. Moreover, the insulin-like growth factor (IGF) signaling pathway has been implicated in BPH development [37]. An IGF receptor antagonist, metformin, has an anti-proliferative effect, which attenuated testosterone-induced BPH in rats by decreasing the expression of estrogen receptor alpha [38]. Furthermore, neurotransmitter serotonin (5-HT) could possibly play a role in the pathogenesis of BPH. 5-HT can downregulate ARs and prevent prostate branching [39]. However, 5-HT depletion contributes to BPH development through modulation of ARs [39]. In summary, imbalance of internal hormones results in the development of BPH and prostatic inflammation.

### **5. Mechanism of BPH-Chronic Inflammation**

A previous clinical study showed that men with prostatitis-like symptoms have significantly higher urinary symptom score [18]. Young-onset prostatitis was positively associated with LUTS [40]. Chronic inflammation along with BPH can coexist in human pathologic specimens [41]. Correlations were found between histopathology of chronic inflammation and severity of LUTS in a subgroup of patients from the randomized REDUCE (reduction in the use of corticosteroids in exacerbated COPD) trial [42]. Moreover, nonsteroidal anti-inflammatory drugs were inversely associated with the onset of LUTS [43]. These clinical results suggested the involvement of prostatic inflammation in the pathogenesis of BPH with LUTS.

The most important cytokine involved in the development of BPH is interleukin (IL)-8, which can directly promote epithelial and stromal proliferation [44]. Plasma IL-8 could serve as a reliable surrogate marker of prostatic inflammatory conditions, including chronic prostatitis and BPH [45]. Moreover, IL-8 can induce stromal cells for the emergence of a reactive myofibroblast phenotype [46]. Human BPH cells, including epithelial and stromal cells, act as antigen-presenting cells (APCs), which can secrete IL-8 and associated cytokines [47]. These cytokines promote prostatic immune cells upregulation for more specific cytokines, which in turn recruit more lymphomononuclear cells. These recruited lymphomononuclear cells express cognate receptors, CXCR1 and CXCR2, which induce proliferation of prostatic cells through autocrine/paracrine effect and generation of fibroblast grow factors [48]. Therefore, the cross-talk between the BPH and immune cells creates a positive feedback loop that can amplify inflammation, and the intraprostatic chronic inflammatory processes are induced and sustained.
