512 hibitor therapy. These findings corroborate what has been reported by McVary et al and imply that autonomic hyper- activity may be an important determinant of LUTS in men with BPH [39,40]. Several other investigators confirmed the relationship between increased autonomic activity and BPH/LUTS [42,43]. 　Hyperinsulinemia is also associated with an increase in the level of free insulin-like growth hormone 1 (IGF-1) [44]. Several studies reported that the increase in the level of IGF-1 predisposes patients to a higher risk of BPH [45-47]. Consequently, hyperinsulinemia may also indirectly in- crease the risk of BPH by increasing the level of IGF-1. 2. Impaired nitric oxide and nitric oxide synthase activity MetS has been associated with elevated levels of C-reactive protein (CRP) as well as other inflammatory markers [48-50]. This may reduce nitric oxide (NO) synthesis in en- dothelial cells [51]. Similarly, other components of MetS, namely, hyperglycemia and dyslipidemia, are associated with increased free radical production [52]. The latter may inhibit NO synthesis via activation of the protein kinase C pathway that may ultimately lead to decreased NO syn- thase (NOS) activation [52]. 　The diminished prostatic NO/NOS activity may lead to increased smooth muscle proliferation, prostatic enlarge- ment, and subsequent LUTS [37]. Takeda et al examined tissue preparations of human and canine prostates and ob- served that NO plays an important role in mediating smooth muscle relaxation within the gland [53]. Conse- quently, the impairment of NO activity may contribute to voiding dysfunction in LUTS patients by impairing muscu- lar relaxation. 　Bloch et al performed a histochemical and ultra- structural examination of the prostate tissue with the in- tent of determining the location of endothelial and neuro- nal NOS in human prostate [54]. Their study resulted in several important findings. First, they observed that NO plays an important role in the autonomic innervation of all compartments of prostatic tissue. Second, they found that in obstructive BPH, the nitrergic innervation is reduced compared with that in normal prostate tissue. They con- cluded that the increased muscular tone in patients with BPH may be attributed to strengthened α-adrenergic stim- ulations as well as to decreased nitrergic innervation. 　Apart from smooth muscle relaxation, NO has crucial functions in maintaining vascular health. It defends against the initiation of atherosclerosis by inhibiting adhe- sion of platelets and leukocytes to the vascular wall. It de- creases the proliferation of vascular smooth muscles [52]. Bloch et al [54] suggested that NO has an important role in the regional circulation of the prostate gland; thus, im- paired NO/NOS activity may lead to endothelial dysfunc- tion and atherosclerosis. Numerous animal studies have linked atherosclerosis and chronic ischemia to bladder and prostatic changes [37]. Rabbits with induced pelvic athero- sclerosis developed bladder fibrosis, smooth muscle atro- phy, and decreased bladder compliance [55] as well as Korean J Urol 2011;52:507-516 Abdollah et al chronic prostatic ischemia with resultant stromal and cap- sular fibrosis, glandular cystic atrophy, impaired smooth muscle relaxation, and increased prostatic weight [56,57]. 3. The Rho kinase system The Rho kinase system plays an important role in the main- tenance of tonic contraction or high basal tone and may con- tribute to prostate contractility [58]. Specifically, the Rho kinase system causes smooth muscle contraction by mod- ifying the calcium sensitivity of the contractile machinery [37,59]. This appears to be mediated by the inhibition of my- osin-light chain phosphatase, which promotes myosin- light chain phosphorylation and contraction through ac- tin-myosin interaction [37,60,61]. NO counteracts this by favoring the active form of myosin–light chain phosphatase [61]. In contrast, α-adrenergic activity stimulates the Rho kinase pathway [37]. Similarly, the higher levels of inter- leukin (IL)-8 and the vasoconstrictor endothelin-1, which are usually observed in men with MetS, may lead to an in- creased Rho kinase system activity [37,50,52,58,59,62-64]. All of these MetS components (ie, impaired NO activity, au- tonomic hyperactivity, elevated IL-8 level, and elevated endothelin-1 level) may favor the activity of the Rho kinase system and may in turn result in a higher prostate con- tractility and LUTS. 4. Proinflammatory status Metabolic syndrome is associated with proinflammatory status. This is demonstrated by elevated levels of CRP, IL-1β, IL-6, and tumor necrosis factor α (TNF-α) in men with MetS [48-50,62]. Obesity induces adipose cell enlarge- ment and chemokine release, leading to macrophage in- filtration of adipose tissue [65]. Macrophage infiltration further perpetuates the proinflammatory state and may account for the adipose secretion of adipokines such as IL-1β, IL-6, IL-8, CRP, and TNF-α [65-68]. Macrophage and T-lymphocyte infiltrates are commonly found in pros- tate tissue removed during open prostatectomy and tran- surethral resection of the prostate [69]. Similarly, several proinflammatory cytokines are upregulated in BPH, sug- gesting an immunologic etiology for the inflammation [69]. Cytokines IL-6 and IL-8, for example, are elevated in MetS and may contribute to inflammation in BPH/LUTS, as both can be secreted by stromal cells with cytokine stimulation and both result in proliferation of prostatic tissues [70]. In patients with BPH, seminal IL-8 levels were positively cor- related with LUTS via the IPSS [71]. 5. Abnormalities of sex hormones Sex hormonal changes may further contribute to the link- age of BPH/LUTS and MetS. Men with MetS as well as those with LUTS/BPH may have lower androgen and high- er estrogen levels. Rohrmann et al analyzed 260 indivi- duals from NHANES III and reported that elevated estro- gen levels and molar estradiol/testosterone ratios as well as lower androstanediol glucuronide (a metabolite of dihy- droxytestosterone [DHT]) levels were associated with