Metabolic syndrome (MetS) is a composite and worldwide epidemic disorder with relevant socioeconomic impact, due to its association with increased associated morbidity. Recent epidemiological trials suggest a possible association between MetS and prostatic diseases, including benign prostatic hyperplasia (BPH), benign prostatic enlargement, and related lower urinary tract symptoms (LUTS). Several pathways are involved in the association between MetS and LUTS/BPH. Metabolic factors are determinant for the enlargement of the prostatic gland and the consequent modification of the volume and shape of the prostate. Metabolic parameters must be investigated during the diagnostic work up of men with LUTS due to BPH.
KeywordsMetabolic syndrome, Lower urinary tract symptoms, Benign prostatic enlargement, Benign prostatic hyperplasia
Lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) are highly prevalent in the adult male [ ]. Traditionally, male LUTS were thought to be merely caused to benign prostatic enlargement (BPE). However, a simplistic causal relationship linking prostatic overgrowth, bladder outlet obstruction and LUTS, has been challenged, based on the lack of a strict correlation between BPE and LUTS [ ].
Emerging data indicate nowadays that a spectrum of age-related disorders, such as type 2 diabetes (T2DM), cardiovascular (CV) disease, hypogonadism, or a combination of these conditions such as metabolic syndrome (MetS), have a heretofore unrecognized, negative impact on LUTS. Several MetS components have been closely associated with BPH and LUTS, suggesting that MetS has very heterogeneous clinical ramifications [ ].
Although the exact nature of the association between MetS and LUTS/BPH are still not completely understood [ ], finding that men with metabolic alterations show a faster-developing BPH or are more frequently candidate to BPH surgery [ ] support the hypothesis that metabolic and pathological alterations characterizing MetS can also predispose to the development and progression of BPH/LUTS. Chronic inflammation has been proposed as a possible mechanism at the crossroad between these two entities. Hence, visceral adipose tissue secretes various bioactive substances that can induce inflammatory response and have proinflammatory effects: the progressive development of inflammation in men with MetS can explain the emerging link between MetS, BPE, and LUTS [ ].
MetS can broadly be considered a systemic inflammatory state and a chronic inflammation-driven tissue remodeling and overgrowth is recognized to play a causative role in BPH/LUTS [ ].
Metabolic Syndrome: Definition and Prevalence
MetS is a complex disorder with a high socioeconomic cost and it is considered worldwide epidemic. According to the 2003–12 National Health and Nutrition Examination Survey (NHANES) data, more than 50 million people are affected by MetS in US, involving approximately 33% of the US adult population, with significantly higher prevalence in women compared with men (35.6% vs. 30.3%) [ ]. The increasing of MetS prevalence was seen with increasing age. Prevalence of the MetS was 18.3% among those aged 20–39 years and increased to 46.7% among those aged 60 years or older.
In the last decades, several definitions of MetS have been proposed and updated a number of times ( Fig. 5.1 ). However, MetS always describes the combination of metabolic and cardiological abnormalities, including central obesity, hypertension, dyslipidemia, insulin resistance with compensatory hyperinsulinemia, and glucose intolerance.
Currently, the most commonly used definitions are focused on abdominal obesity measured by waist circumference: the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP-III) and the International Diabetes Federation (IDF). Otherwise, the European Group for the Study of Insulin Resistance (EGIR) and the World Health Organisation (WHO) definitions principally focus on insulin resistance [ ].
MetS and BPH: Preclinical Evidences and Pathophysiology
In 1998 for the first time Hammarsten et al. revealed an association between MetS features and BPH. Men with fast-growing BPH had a higher prevalence of NIDDM and treated hypertension. These patients were also taller and more obese as measured by body weight, BMI, waist measurement, hip measurement, and WHR. Moreover, they had elevated fasting plasma insulin levels and lower HDL cholesterol level than men with slow-growing BPH. The annual BPH growth rate correlated positively with diastolic blood pressure, BMI, and four other expressions of obesity and fasting plasma insulin level, and negatively with the HDL cholesterol level. In conclusion, the data suggested that NIDDM, hypertension, tallness, obesity, high insulin, and low-HDL cholesterol levels constitute a risk factor for the development of BPH.
Furthermore, a growing body of evidence has documented a strong and independent association between BPH/LUTS and obesity/MetS [ ].
Relationship between MetS and LUTS has been investigated also in animal models including a mouse model of type 2 diabetes mellitus/obesity (diabesity). In particular these mice with a neuron-specific conditional Shp2 deletion developed obesity and diabetes and the associated pathophysiological complications that resemble those encountered in humans, including hyperglycemia, hyperinsulinemia, hyperleptinemia, insulin and leptin resistance, vasculitis, diabetic nephropathy, urinary bladder infections, prostatitis, gastric paresis, and impaired spermatogenesis. In males was evident florid bacterial infection of the urinary bladder, prostate, seminal vesicles, and adipose tissue surrounding the vas deferens demonstrating an association of prostate inflammation to bladder dysfunction [ ]. Since these evidences, hyperglycemia, insulin resistance, hypogonadism, and low-grade chronic inflammation have been proposed as crosslink between MetS and LUTS/BPH [ ].
Although the association among the aforementioned conditions and MetS is generally accepted, all the pathways involved in the pathogenetic mechanism are still not completely clarified. In particular, chronic inflammation has been proposed to play a causative role in BPH/LUTS, rather than merely occurring in response to prostate and bladder tissue remodeling. An autoimmune dysregulation and an immune response toward a Th1/Th17 cytokine profile might lead to the development of chronic immune-mediated tissue destruction and fibromyomatosus remodeling, as observed in the initial phase of BPH development.
Moreover, hypogonadism resulted in an important determinant in developing LUTS/BPH in MetS subject. Recent data suggested that low testosterone in males might be considered an additional MetS component [ , , ]. Although testosterone supplementation in MetS significantly improves metabolic parameters like fasting glucose, glucose tolerance, waist circumference, triglycerides, and HDL cholesterol [ ], warnings for the potential prostatic side effects strongly limit a widespread clinical use. These concerns are based on the concept that androgens are essential for prostate growth, which potentially can worsen LUTS. However, some prospective [ ] and cross-sectional studies [ , ] have demonstrated an inverse association between serum testosterone levels and LUTS or BPH. Consistent with these observations, testosterone replacement therapy has been proposed to treat LUTS in hypogonadal men with both BPH [ , ] and MetS [ ].
To better understand the link between MetS and LUTS/BPH, an animal model of MetS-like syndrome was obtained by feeding rabbits with a high fat diet (HFD) for 12 weeks [ ]. HFD rabbits recapitulate most of the components of MetS described in humans, including altered glucose tolerance, dyslipidemia, increased abdominal adiposity, and hypertension. Compared to standard rabbits, HFD rabbits showed hypogonadotropic hypogonadism, erectile dysfunction, and LUT abnormalities, consisting of a prostatitis-like syndrome and bladder alterations and also developed decreased seminal vesicles and testis weight. In these models chronic treatment with testosterone for 12 weeks restored plasma testosterone levels, prevented HFD-induced seminal vesicles hypotrophy, and completely normalized fasting glucose levels, glucose tolerance, and VAT accumulation.
Immunohistochemical analysis demonstrated an important development of HFD-induced prostate fibrosis, hypoxia, and inflammation. Interestingly in this study testosterone supplementation normalizes all the aforementioned HFD-induced prostatic alterations, including inflammation, hypoxia, and fibrosis, thus suggesting that hypogonadism-related inflammation could be a potential mechanism in linking MetS and LUTS/BPH.
An antiinflammatory effect of testosterone in castration-induced prostate inflammation was previously reported [ ]. Androgens therefore act as endogenous inhibitors of immune responses, even in the prostate, as already reported for other autoimmune processes [ , ]. Although these data showing that testosterone supplementation reduces the expression of proinflammatory cytokines are consistent with previous studies [ ], the detailed mechanisms of testosterone-mediated immunomodulation are still unknown.
Moreover, obesity itself induces adipose cell enlargement and chemokine release, leading to macrophage infiltration of adipose tissue [ , ]. Rising evidences suggest the ability of IL-8 to stimulate prostatic growth, and a significant and stepwise correlation between various MetS components and seminal IL-8 (sIL-8) has been proposed as a surrogate marker of prostate inflammation [ ]. IL-8 is a proinflammatory chemokine secreted by several cell types that contributes to inflammation by acting in concert with IL-1β and IL-6. Of all kinds of cytokines and chemokines, sIL-8 seems to be the most reliable and predictive surrogate marker of prostatitis. Higher IL-8 levels have been reported in the expressed prostatic secretions of subjects with BPH, bacterial prostatitis, and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). IL-8 has been shown to be actively involved in BPH-associated chronic inflammation and mediates epithelial and stromal cell proliferation. In clinical BPH-prostate tissue studies, epithelial and stromal cells were analyzed to secrete IL-8 actively in response to various stimuli, including the proinflammatory cytokines interferon (IFN) γ and IL-17, which are produced by prostate-infiltrating Th1 and Th17 cells, respectively.
As underlined by Penna et al. [ ], human stromal prostatic cells actively contribute to the organ-specific inflammatory process by acting as targets of bacterial or viral toll-like receptors agonists and as antigen-presenting cells capable of activating antigen-specific CD4 + T cells. In BPH, toll-like receptor activation leads to the production of proinflammatory cytokines (IL-6) and chemokines (IL-8 and CXCL10) capable of recruiting CXCR1 and CXCR2-positive leukocytes and CD15 + neutrophils.
Moreover, another important component of MetS, insulin resistance caused by obesity results in a proinflammatory state. Tissue inflammation results in tissue fibrosis, which is supposed to represent an inflammation-initiated, aberrant wound-healing process characterized by myofibroblast accumulation, collagen deposition, extracellular matrix (ECM) remodeling, and increased tissue stiffness. A few studies have investigated possible associations between MetS-induced inflammation and overactive bladder or urinary incontinence (UI). Some investigators have studied the role of urinary cytokines in patients with OAB [ , ] ( Fig. 5.2 ).
MetS and LUTS/BPE: The Role of Inflammation
Several recent epidemiological and histopathological studies suggest that MetS plays a significant role in BPH/LUTS development and progression. However, most of these studies did not find a univocal causal relationship between these two clinical entities.
Even if visceral obesity and insulin resistance can be considered the focal pathophysiological alterations characterizing MetS, several other factors, such as sex-steroid imbalance and a proinflammatory state, could also be involved in its pathogenesis and clinical manifestation. Indeed, chronic low-grade inflammation has been recognized as a crucial pathogenic mechanism underlying the pathophysiology of MetS [ ]. Similarly, several recent studies have clearly indicated that prostate chronic inflammation is not only a common finding in BPH [ , ] but has also plays a primary role in triggering prostatic cells overgrowth [ ]. In particular, MetS could induce or maintain an inflammatory state within the prostate that could even be exacerbated by a relative hyperestrogenism [ ] or by androgen deficiency [ ]. Hence, a chronic inflammatory insult could be considered the most probable candidate link between MetS and BPE/LUTS ( Fig. 5.3 ).
The diagnosis of BPH is based on histological findings of proliferating stromal and epithelial cells within the prostatic transition zone. Even if the precise etiology of BPE is still unclear, a number of epidemiological evidence have led to the hypothesis that an inflammatory process represents the key driver for both the development and the progression of BPH [ , , , ].
Several clinical studies evaluated the role of prostatic inflammation on BPE development and progression. Indeed, intraprostatic inflammation within BPH tissue detected in baseline prostate biopsy samples predicted not only BPH progression, but also an increased risk of acute urinary retention or BPH-related surgery in a subgroup of 1197 men with BPH in the placebo arm of the Medical Therapies of Prostate Symptoms study [ ]. Likewise, the degree of histological chronic inflammation was weakly but significantly associated with the severity of LUTS in a subgroup analysis of the Reduction by Dutasteride of Prostate Cancer Events trial [ ]. Accordingly, in a population of obstructed men requiring a surgical procedure, only the presence of a severe inflammatory pattern, leading to the disruption of the normal glandular arrangement, was determinant for the worsening of LUTS [ ]. Moreover, data from a multicenter study in men surgically treated for BPH showed that specimens of patients with MetS presented a more severe intraprostatic inflammation in histopathological assessment in comparison with patients with BPH without MetS [ ], in addition to an increased prostate volume [ ]. Thus, it has been recently postulated that MetS promotes a direct inflammatory effects within the prostate [ ]. In a study enrolling young male partners of infertile couples [ ], IL-8 levels in seminal plasma (a well-defined surrogate marker of prostate inflammation) [ ] and a number of ultrasonographic features of prostatitis showed a stepwise positive association with the number of MetS components. Moreover, central obesity and dyslipidemia were significantly associated with markers of prostate inflammation. These findings indicate that metabolic derangements have detrimental effects already early in human life, even in asymptomatic or paucisymptomatic individuals.
Prostate Size and Shape: The Influence of MetS
Since 1998, different studies have associated single MetS parameters to BPH, but only few studies based on the concept of the MetS construct have been published. This correlation was found both in western and eastern population studies.
More recently in a prospective study on over 370 consecutive patients [ ] undergone surgery for BPH, the number of MetS parameters and MetS itself was associated with higher calculated prostate volume. In this trial the authors evaluated a possible correlation between different MetS features to specific prostate diameters: AP diameter was mainly correlated with HDL cholesterol, CC diameter with triglycerides, and LL diameter with systolic blood pressure. However, at the binary regression, only low-HDL cholesterol was the main determinant for the enlargement of all diameters and consequently of the whole PV.
In a recent metaanalysis [ ], 8 studies were included for a total of 5403 patients, of which 1426 (26.4%) had MetS defined according to current classification and prostate volume difference between patients with MetS versus patients without MetS was evaluated: the combination of results of trials showed that patients with MetS have significantly higher total prostate volume versus those without MetS (+ 1.8 mL, P < 0.001) ( Fig. 5.4 ). Differences in prostate volume between patients with or without MetS were confirmed even when only studies based on NCEP-ATPIII criteria were considered (+ 1.73 mL, P < 0.002); in particular, transitional prostate volume was 3.67 mL higher in MetS patients. Metaregression analysis showed that waist circumference and, again, low-HDL cholesterol level was the strongest factor related to increasing prostate volume.
The role of dyslipidemia is not surprising since lipids (oxidized low-density lipoprotein, LDL) increase in vitro the secretion of growth (VEGF, b-FGF) and proinflammatory factors (interleukin 6 [IL-6], IL-8, and IL-7) by human stromal BPH cells in culture; Nandeesha et al. [ ] reported that HDL cholesterol was lower and total and LDL cholesterol higher in patients with symptomatic BPH than in controls. However, other studies did not confirm the association between dyslipidemia and BPE [ ]. In the Rancho Bernardo cohort study, Parsons et al. [ ] found a fourfold increased risk of BPH among diabetic men with LDL cholesterol in the highest tertile, but not in the overall cohort. This observation suggests that dyslipidemia itself is not strong enough to induce prostate enlargement, but the concomitant presence of other metabolic derangements, such as diabetes or those concurring with the MetS construct, favors the process.
Advanced age was a further determinant in transitional and total prostate volume enlargement: indeed in elderly men with a larger prostate, the occurrence of MetS could represent a major contributing factor in BPE progression as evident in some longitudinal studies like Baltimore Longitudinal Study of Aging. In a study on over 600 men, age (OR, 2.45) and waist circumference (OR, 1.45) were significantly correlated with prostate volume [ ].
MetS and in particular dyslipidemia and central obesity are specifically associated with a greater overall (and transitional) increase of prostate volume; this aspect together with the derangements caused by inflammatory functional alterations seems to be crucial in MetS and LUTS/BPH association.
The Correlation Between MetS and LUTS
The evidence on the association between MetS and LUTS mainly derived from epidemiological studies in populations from US and Asian with conflicting results. The Boston Area Community Health (BACH) survey [ ] used the Adult Treatment Panel III Report criteria created by the National Education Program (NCEP-ATPIII) to define MetS and the American Urologic Association symptom index (AUA-SI) to quantify LUTS. The authors reported a trend of increasing prevalence of MetS with increasing AUA-SI scores. In particular, the prevalence of MetS was increased by 40% in men with mild to severe symptoms (AUA-SI 2-35 vs. AUA-SI 0-1). Moreover, increased prevalence of MetS was observed even with mild symptoms, primarily for incomplete emptying, intermittency, and nocturia. Interestingly, a statistically significant association was observed only between MetS and voiding symptom score of 5 or greater, but not storage symptom score of 4 or greater. Similarly, the NHANES III found that those men who fulfilled MetS criteria had a significantly increased risk of LUTS compared with controls [ ]. Conversely, a negative correlation between MetS and LUTS has been described in some Eastern Asia studies [ ].
MetS was not directly associated with LUTS [ ] in a study from Japan: in particular, MetS was significantly inversely correlated with storage symptoms in middle-aged men (aged 50–64 years). Moreover, a South Korean study [ ] including 33,841 men aged ≥ 30 years showed a negative association between MetS and LUTS. Similarly, lower total and voiding IPSS scores were found in Taiwanese men with MetS compared with controls [ ].
A 2015 systematic review and metaanalysis of studies with a US Preventive Services Task Force level of evidence II-2 found no significant relationship between total IPSS or its storage or voiding subscores and MetS [ ]. This finding was confirmed in another 2015 metaanalysis, specifically designed to evaluate MetS and LUTS relationships. The researchers did not find a significant difference regarding total IPSS or its voiding or storage subscores between men with and without MetS. In addition, the presence of MetS was not significantly associated with the risk of having moderate-severe LUTS (OR 1.13) [ ]. By contrast, some of the components of MetS, such as hypertriglyceridemia, elevated fasting glucose and/or T2DM (CI 1.15–2.73), were significantly associated with increased risk of LUTS.
Further studies specifically designed to evaluate the association between MetS and LUTS have been recently published describing the positive correlation between MetS and LUTS. A population-based European study demonstrated a strong positive association between MetS (defined by NCEP-ATPIII criteria) and LUTS severity. The presence of MetS was correlated not only with total IPSS score, but also with voiding and storage subscores, as well as each single question of the IPSS questionnaire [ ]. Moreover, higher IPSS scores were also positively associated with each component of MetS, and an increased risk of LUTS treatment was associated with severity of MetS. Indeed, the presence of two components was associated with a 51% increased risk of being treated for LUTS, rising to nearly 250% when all five components were present. In particular, men with a waist circumference ≥ 102 cm were 39% (OR 1.39) and 40% (OR 1.40) more likely to report a voiding IPSS subscore ≥ 5 and a storage IPSS subscore ≥ 4, respectively ( Fig. 5.5 ). Accordingly, MetS (defined by NCEP-ATPIII criteria) was the only independent parameter associated with a risk of IPSS storage subscores ≥ 4 upon multivariate analysis in a single-center Italian cohort study in 431 men with BPE-related LUTS [ ].
A comparable correlation between the number of MetS components and the severity of urinary symptoms has been also reported in a prospective cross-sectional study on male aged 50-59 years who had participated in a health examination at the hospital [ ]: the authors demonstrated that the number of men with LUTS (IPSS > 7), enlarged prostate volume (total prostate volume ≥ 30 mL), and/or reduced urinary flow rate ( Q max < 15 mL/s) significantly increased with the increasing number of metabolic abnormalities.
The conflicting results on the relationship between MetS and LUTS could be explained by the heterogeneity of the studied populations. If most of the US or European population-based studies demonstrate a positive association between MetS and LUTS, Asian studies often show opposite results. These findings indicate that ethnicity could represent a central issue for the association of MetS and LUTS. Moreover, these differences could be related with the multiple separate definitions of MetS and its components related to different ethnicities too. Furthermore, most of the studies evaluated LUTS using the IPSS. However, the IPSS measures the subjective perception of LUTS, which can be associated with other variables, such as race or ethnic background, age, overall health, and socioeconomic status, as well as quality of life (QoL). By contrast, the strong evidence that MetS is associated with increased prostate size, most of the transition zone, supports a role for metabolic derangements in the development and progression of BPE.
Moreover nowadays it is clear that the correlation between MetS and its components to cardiovascular events and, recently, a metaanalysis has revealed the association between major adverse cardiac events and LUTS in the male population [ ], suggesting an holistic approach in considering the cardiovascular, metabolic, urinary, and prostatic morbidities of aging men.