Connections between lower urinary tract symptoms related to benign prostatic enlargement and metabolic syndrome with its components: a systematic review and meta-analysis

Abstract

A significant amount of epidemiological evidences have underlined an emerging link between metabolic syndrome (MetS) and lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement a (BPE). We aimed to assess the connections between LUTS and MetS with its components. Meta-analysis were conducted to determine the mean differences (MD) and confidence intervals of IPSS total score, IPSS-voiding, IPSS-storage and prostate volume (PV) in patients with or without MetS. Ln(odds-ratio) were calculated to estimate the risk of having moderate-to-severe LUTS (IPSS ≥ 8). Nineteen studies were identified as eligible for this systematic review, with a total of 18,476 participants, including 5554 (30.06%) with and 12 922 (69.94%) without MetS. Pooled analysis did not demonstrate significant MD of IPSS, IPSS-voiding and IPSS-storage in men with or without MetS but PV was significantly different (MD = 2.18; p = 0.03). Presence of MetS was not significantly associated with moderate-to-severe LUTS (odds ratio = 1.13; p = 0.53) and only altered serum triglycerides and diabetes were associated with this risk. The association between MetS and LUTS/BPE remain unclear and further observational studies in a population with metabolic disorders should be conducted in order to address it's potential role in determining LUTS/BPE.

• Age
• benign prostatic enlargement
• insulin resistance
• LUTS
• metabolic syndrome
• non-alcholic fatty liver disease
• prostate
• testosterone

Introduction

Metabolic syndrome (MetS) is a widespread epidemic disease that included a cluster metabolic alteration with a high socio-economic impact, due to its association with increased morbidity and mortality.

A significant amount of epidemiological evidences have underlined an emerging link between MetS, benign prostatic enlargement (BPE) secondary to benign prostatic hyperplasia (BPH) and related lower urinary tract symptoms (LUTS) [1–4].

Among these features, central obesity, lipidic disorder and hyperinsulinemia represent the trigger causes of MetS and related pathological conditions. These alterations include increase in the activity of the sympathetic nervous system and muscle tone of the prostate, resulting in more severe LUTS independently from prostate enlargement [5–7]. Among MetS features, reduced HDL and increased triglyceride levels were significantly related to higher prostatic inflammation by secreting IL-8 in response not only to oxidized LDL, but also to insulin [8], indicating that different MetS features could synergistically boost inflammation and tissue-remodeling in BPH/LUTS [5,9,10]. In a recent meta-analysis, authors found that MetS-induced differences in prostate volumes were greater in patients with metabolic disorders. Hence, obese, dyslipidaemic and aged patients were more at risk of having MetS as a determinant of their increased prostate size [1].

However, besides previous pathological pathways, the presence of BPE and the observation of MetS should be not directly attributable to the presence of more severe LUTS [11]. In fact, discordant results have rising the hypothesis of ethnic disparities about the connection between MetS and LUTS/BPE [12,13].

The aim of this systematic review and meta-analysis was to assess the connections between LUTS/BPE and MetS with its components.

Methods

Systematic literature search

This analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines [14]. We performed a systematic literature search of PubMed, EMBASE, Cochrane, and Academic One File databases using Medical Subject Headings (MeSH) indexes, keyword searches, and publication types until December 2014. The search was limited to English-Language articles. The search terms included “prostate“, “benign prostatic hyperplasia“, “benign prostatic enlargement“, “metabolic syndrome“, “prostate volume“, “insulin resistance“, “obesity, “hypertension“, “triglycerides“, “cholesterol”, “lower urinary tract symptoms”. We also searched reference lists of relevant articles. We tried to contact all corresponding authors when data were found to be missing.

We defined MetS according to the USA National Cholesterol Education Program – Adult Treatment Panel III (NCEP-ATPIII), which requires at least three of the following five components: central obesity (waist circumference of >94 cm), elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), elevated blood pressure (≥130/85 mmHg), elevated fasting glucose (≥6.1 mmol/L or 110 mg/dL) and reduced HDL cholesterol (<1.03 mmol/L or 40 mg/dL). Previous diagnoses of hypertension and type-2 diabetes mellitus were included as evidence of raised blood pressure or fasting glucose. We also included studies based on the revised MetS criteria proposed by the International Federation of Diabetes and the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI criteria). The latter essentially differs in its reduced threshold of hyperglycemia of 6.0 mmol/L (or 100 mg/dL) and in considering possible ethnic differences in the waist circumference (WC) threshold (≥90 cm for South-Asians and ≥94 cm for Caucasian) [1].

Eligible studies included published journal articles that provided quantitative data on LUTS assessed by the validated International Prostate Symptom Score (IPSS) and prostate volume (PV).

Study selection

Citation lists of retrieved articles were screened manually to ensure sensitivity of the search strategy. References of the included papers were hand searched to identify other potential relevant studies. Studies were reviewed by two independent reviewers (G.I.R. and D.U.); differences in opinion were discussed in consultation with the last author (G.M.).

Data were extracted independently by two reviewers. Discrepancies for inclusion between the investigators were resolved by discussion or further consultation with a third author.

The quality of these eligible citations was assessed using Newcastle – Ottawa quality assessment scale quality scoring system [15]; two authors scored independently.

We constructed evidence tables detailing study characteristics, outcome measures, MetS definition and study quality. We compared and contrasted studies reporting the connection between MetS and LUTS, summarizing patient characteristics and evidenced results.

Statistical analysis

For the meta-analysis, the pooled mean differences (MDs) for continuous variables and the ln(OR) were used for data pooling.

Meta-analysis was conducted to determine the MD and confidence intervals (CIs) of IPSS total score, IPSS-voiding, IPSS-storage and prostate volume in patients with or without MetS. Ln(OR) were calculated to estimate the risk of having moderate-to-severe LUTS (IPSS ≥ 8) in patients with MetS and to determine the role of each MetS components on this risk among selected studies.

SE[ln(OR)] was calculated through a first-order Taylor series conversion, where SE[ln(OR)] = (1/OR)*SE[OR]. Begg's and Egger's methods were used to assess publication bias. Funnel plots were drawn. Statistical heterogeneity was assessed using the Cochran's Q and I² statistics. Specifically, statistical heterogeneity was tested using the chi-square test. I² ≤ 50%, the variation of the studies was considered to be homogenous, the fixed effect model was adopted. If I² > 50%, there was significant heterogeneity between studies, the random effects model was used. All p values are 2-tailed, α ≤ 0.05 was considered statistically significant (p ≤ 0.05).The analyzes was performed using RevMan software v.5.1 (Cochrane Collaboration, Oxford, UK) and using SPSS v. 19 software (SPSS Inc, IBM Corp, Somers, NY).

Results

In total, 151 studies were identified from the online databases and relevant references. After evaluating the title and abstract of each study, 75 studies were excluded as they did not meet the inclusion criteria. Subsequently, we carefully read the full texts of the remaining 76 studies and thus 19 studies (Table 1) were identified as eligible for this systematic review, with a total of 18 476 participants, including 5554 (30.06%) with and 12 922 (69.94%) without MetS (Figure 1). The quality assessment score was ≥50% in more than half studies (12/19).

Figure 1. Flow Diagram of included studies.

Table 1. Studies on the association between MetS components, and LUTS.

Year	Authors	Country	Number of samples	BPH definition	Mets components definition	MetS features and BPH findings	NOS quality Score
2014	Zhang et al.	China: cross-sectional	394	LUTS (IPSS); PSA; TRUS; PV	FPG (≥110 mg/dl)	PV was correlated with FINS (r = 0.421, p = 0.001), but no FPG (r = 0.091, p = 0.364) or HbA1c levels (r = 0.153, p = 0.127)	5
2014	Russo et al.	Italy: cross-sectional	544	LUTS (IPSS); PSA; TRUS; PV	IDF	IR was an independent predictor of severe LUTS (IPSS≥20) (OR = 2.0, 9,5% CI 1.20-3-34)	5
2014	Vanella et al.	Italy: experimental	132	LUTS (IPSS); PSA; TRUS; PV	IDF	No differences of IPSS, IPSS-voiding, IPSS-storage and PV in men with and without MetS.	5
2014	De Nunzio et al.	Italy: observational	431	LUTS (IPSS); PSA; PV	NCEP ATP III	On multivariate analysis, the presence of MetS was associated with an increased risk of an IPSS storage subscore ≥4 (OR: 1.782; p = 0.03)	5
2014	Kim et al.	Korea: retrospective	4076	LUTS (IPSS); PSA; PV	NCEP ATP III	In the larger PV group ( ≥ 28 mL), the age-adjusted OR for having moderate-to-severe LUTS was significantly lower in subjects with MetS (OR: 0.666; p < 0.01) and in subjects with MS having 4 or 5 risk factors (OR: 0.612; p < 0.05).	4
2013	Gacci et al.	Italy: cross-sectional	271	Prostatectomy for moderate/severe LUTS due to BPH	AHA/NHLBI criteria or previous diagnosis of type 2 diabetes	Inflammatory score (p = 0.049), lower uroflowmetric parameters (p = 0.0008) IPSS (p = 0.064)	5
2013	Park et al.	Korea: retrospective study	1224	PV, LUTS (IPSS)	NCEP ATP III	IPSS, TPV>30 mL, and PVR>50 mL significantly increased with an increasing of number of MetS components (p < 0.001)	4
2012	Byun et al.	Korea: retrospective study	420	PV, LUTS (IPSS)	NCEP ATPIII AHA/NHLBI	PSA and PV was correlated with MetS and with number of MetS components (p < 0.001)	4
2012	Yang et al.	Taiwan: prospective study	708	LUTS (IPSS) PSA, DRE, PV	NCEP ATP III	MetS group have lower IPSS score (p = 0.05). The negative association between voiding score, severity of LUTS, and MetS became higher as the number of MetS increased (p < 0.01).	4
2012	Gao et al.	China: cross-sectional	3103	LUTS (IPSS); PSA; PV	NCEP ATP III	The presence of MetS was not associated with the severity of LUTS (OR: 0.97), but its subcategories of moderate or severe storage symptoms were inversely related to MetS (OR: 0.64).	5
2011	Ohgaki et al.	Japan: observational	900	LUTS (IPSS); PSA; PV	NCEP ATP III; IDF; JASSO	In the younger and older men, LUTS was observed equally in those with and without the MetS	4
2011	Yim et al.	Korea: retrospective study	848	TRUS, PSA, DRE	NCEP ATP III	PV is not significantly larger in the MS group (18.4 versus 17.8 cc; p = 0.225), but in pt. with elevated FPG and WC is (p = 0.001).	4
2011	Jeong et al.	Korea: retrospective study	1357	LUTS (IPSS) PSA, DRE, TRUS	NCEP on Detection, Evaluation, And Treatment of High Blood Cholesterol in Adults guidelines	PV and BPE is higher MetS pt. (p < 0.001). No differences in IPSS or voiding or storage subscore were noted. Diabetes and obesity are risk factors for BPE (p < 0.001)	4
2010	Lee et al.	Taiwan: cross-sectional	639	LUTS (IPSS), PSA, PV	NCEP on Detection, Evaluation, And Treatment of High Blood Cholesterol in Adults guidelines	Subjects with ED had significantly higher prevalence of MetS (p < 0.01, OR = 2.30, 95% CI: 1.44–3.69)	4
2009	Wang et al.	Taiwan: case-control convenience sample from diabetes clinic and health fair Age <45	226	LUTS (IPSS); FR/PVR	DM defined by American Diabetes Association criteria	IPSS (6.1 versus 4.1, p = 0,0001), storage symptoms (2.7 versus 2.0, p = 0.02), voiding symptoms (3.5 versus 2.1 p < 0.001)	5
2009	Kupelian et al.	USA: observational	1899	LUTS (IPSS); PV; PSA	NCEP ATP III	Increased odds of the MetS were observed in men with mild to severe LUTS (OR: 1.68). A statistically significant association was observed between the MetS and a voiding symptom score of 5 or greater (OR: 1.73) but not for a storage symptom score of 4 or greater (OR: 0.94). These associations were observed primarily in younger men (younger than 60 years) and were null in older men (60 years old or older).	5
2008	Park et al.	Korea: retrospective study (KLoSHA)	348	LUTS (IPSS), PV, PSA	NCEP ATP III	No significant differences in IPSS score (p > 0.05)	4
2007	Ozden et al.	Turkey: prospective study	78	PSA, TP, TZ	NCEP ATP III	Higher, BMI, FPG, serum triglyceride, PSA levels, lower serum HDL-C, compared with Pt. without MetS (p < 0.05). TP growth rate and TZ growth rate higher in Pt. MetS (0.64 ml/yr and 0.93 ml/yr, p < 0.05)	5
2005	Rohrmann et al.	USA: cross-sectional study	878	LUTS (IPSS)	NCEP ATP III	Diabetes, hypertension and HbA1c are positively associated with LUTS. No statistically significant associations between FPG and LUTS	5

PSA =  prostate-specific antigen, PV = prostate volume, FPG =  fasting plasma glucose, WC =  waist circumference, LUTS = lower urinary tract symptoms, IPSS = International Prostate Symptom Score, FINS = fasting insulin, HbA1c = glycosylated hemoglobin, FR/PVR = flow rate/post-void residual, HOMA-IR = Homeostasic model of assessment index, TP =  total prostate, TZ =  transitional zone, DRE = digital rectal examination, NCEP ATP III = National Cholesterol Education Program Expert Panel Adult Treatment Panel III, AHA/NHLBI 0 American Heart Association and the National Heart, Lung, and Blood Institute.

International prostate symptom score

International Prostate Symptom Score (IPSS) outcomes in patients with MetS were reported in 14 studies [5,6,8,16–27]. There was statistically significant heterogeneity in these studies (x² = 40.43, I² = 68%; p = 0.0001) (Figure 2A).

Figure 2. International Prostate Symptom Score (IPSS) (A), Voiding IPSS (B), Storage IPSS (C) and prostate volume (D) in patients with and without metabolic syndrome (MetS). CI=confidence interval; SD=standard deviation.

Mean differences of IPSS were not statistical different in men with or without MetS (MD = 0.10; [95% CI −0.51 to 0.71]; p =  0.75).

As concerning IPSS sub scores, pooled analysis demonstrated no statistical differences of IPSS-voiding (MD = 0.12 [95% CI −0.35 to 0.58]; p = 0.62) and IPSS-storage (MD = −0.03 [95% CI –0.35 to 0.29]; p = 0.86) in men with or without MetS (Figure 2B–C).

Prostate volume

Prostate volume was reported in 12 studies for the pooled meta-analysis [6,8,16–18,20–22,25,26,28,29]. There was statistically significant heterogeneity in these studies (x² = 67.15, I² = 84%, p < 0.0001). Patients with MetS exhibited greater prostate volume in patients with MetS with significant statistical differences (MD = 2.18; [95% CI 0.73 to 3.64], p = 0.03) (Figure 2D).

Risk of moderate-to-severe LUTS

A total of six studies examined the association between MetS and the risk of having moderate-to-severe LUTS (IPSS ≥ 8) [16,22,25,30–32]. There was statistically significant heterogeneity in these studies (x² = 33.97, I² = 85%, p < 0.000001). In patients with MetS the pooled ORs [95% CI] of having moderate-to-severe LUTS was 1.13 [0.78–1.63]. The test of overall effect was not statistical significant (Z = 0.63, p = 0.53) (Figure 3A).

Figure 3. Risk of having moderate-to-severe lower urinary tract symptoms (IPSS ≥ 8) expressed as odds ratio (OR [95% CI]) in patients with metabolic syndrome (A), in patients with waist circumference ≥90 cm (or ≥ 90 cm for Asians) (B), with HDL < 40 mg/dl (C), with triglycerides ≥ 150 mg/dl (D), in patients with elevated fasting glucose (≥6.1 mmol/L or 110 mg/dL) (E).CI = confidence interval; Homa-index = homeostatic model assessment index.

MetS components and risk of moderate-to-severe LUTS

A total of 7 studies investigated the role of MetS components on the risk of having moderate-to-severe LUTS [5,21,24,30,31,33].

The impact of waist circumference (WC) was showed in three studies [5,30,31]. There was not a statistically significant heterogeneity in these studies (x² = 4.42, I² = 55%, p = 0.11). In patients with WC ≥90 cm for Asian or ≥94 for Caucasian the pooled ORs [95% CI] of having moderate-to-severe LUTS was 1.13 [0.93–1.38]. The test of overall effect was not statistical significant (Z = 1.22, p = 0.22) (Figure 3B).

The role of HDL was obtained in three studies [30,31,33]. There was not a statistically significant heterogeneity in these studies (x² = 1.15, I² = 0%, p = 0.56). In patients with HDL <40 mg/dl the pooled ORs [95% CI] of having moderate-to-severe LUTS was 1.22 [0.91–1.64]. The test of overall effect was not statistical significant (Z = 1.32, p = 0.19) (Figure 3C).

The connection between triglycerides and LUTS severity has been demonstrated in four studies [21,30,31,33]. The heterogeneity among these studies was not statistical significant (x² = 4.57, I² = 34%, p = 0.21). In patients with triglycerides ≥150 mg/dl the pooled ORs [95% CI] of having moderate-to-severe LUTS was 1.31 [1.01–1.71] with statistical significant (Z = 2.01, p = 0.04) (Figure 3D).

The role of diabetes on LUTS severity has been reported in four studies [21,24,30,31].

There was a statistically significant heterogeneity in these studies (x² = 12.52, I² = 76%, p = 0.02). The test of overall effect was not statistical significant (Z = 2.59, p = 0.01) (Figure 3E). In patients with elevated fasting glucose (≥6.1 mmol/L or 110 mg/dL) or previous diagnosis of diabetes, the pooled ORs [95% CI] of having moderate-to-severe LUTS was 1.77 [1.15–2.73]. The test of overall effect was statistical significant (Z = 2.59, p = 0.01) (Figure 3E). The presence of hypertension has been not investigated due to the lack of considerable data.

The relationship between MetS components and IPSS differences were not confirmed in a linear, age, prostate volume and PSA-adjusted, multivariate model, weighing each study for the number of patients enrolled (all p value > 0.1).

Discussion

Connections between lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement (BPE) and metabolic syndrome (MetS) have been diffusely reported in literature. The underling pathological pathways are mainly attributable to hyperinsulinemia, increased sympathetic nervous system activity and smooth muscle tone of the prostate [27,34].

To this regard, Byun et al. founded that patients with more than one MetS component were significantly more likely to have a larger prostate volume and higher serum PSA level [28].

In a recent meta-analysis on the associations between MetS and BPE, authors found that MetS-induced differences in prostate volumes were almost equally weighted as a factor of age, waist circumference or serum HDL concentration. Hence, obese, dyslipidaemic and aged patients were more at risk of having MetS as a determinant of their increased prostate size. Furthermore, increased-central adiposity, as reflected by waistline, was another MetS-related factor that significantly contributes to variation in prostate enlargement [1].

However, besides previous pathological pathways, the presence of BPE and the observation of MetS should be not directly attributable to the presence of more severe LUTS.

To this regards, literature data have recently underlined some controversies about the connection between LUTS/BPE and MetS. As concerning this, studies from Asian cohorts have evidenced an absent or even negative association between MetS and symptoms severity [17–19,21,30]. Anyway, these studies were conducted in healthy middle-aged men. However, in an age-matched autopsy series, the prevalence and severity of histologic BPH were similar in Caucasian respect Southeast Asian men, despite very different diet and lifestyle [35]. These findings are in contrast with previous observations contradicting the supposition of different geographical impact and MetS at least regarding BPE.

In fact, we would point-out that when analyzing the impact of metabolic disorders on prostatic diseases, it should be considered whom population is affected by. Men above their 60s and with contextual comorbidities seem the most appropriate.

In fact, these discordances may justify results of the current meta-analysis and the lack of statistical significance concerning the mean differences of IPSS, IPSS-storage and IPSS-voiding in patients with and without MetS. Moreover, although only six studies assessed the association between MetS and the risk of having moderate-to-severe LUTS (IPSS ≥ 8), the pooled OR of 1.13 was not statistical significant (p = 0.53).

As concerning prostate volume analysis, herein we have reported significant greater prostate volume in men affected by MetS after the pooled analysis (MD = 2.18; p = 0.03), similarly to recent literature data [1].

The significant increase of prostate volume induced by MetS could be explained by several factors.

In this context, it has been also postulated that MetS could influence LUTS/BPE at an intraprostatic level. Gacci et al. recently reported that MetS was associated not only with an increased prostate volume, but also with a severe intraprostatic inflammation. These observations strengthened the hypothesis that MetS, and hyperinsulinemia-related increase, could boosts a chronic inflammation-driven prostate overgrowth. As concerning MetS components, reduced HDL, and increased triglyceride levels are significantly related to higher prostatic inflammation by secreting interleukin-8 in response not only to oxidized low-density lipoprotein, but also indicating that different MetS features could synergistically boost inflammation and tissue remodeling in LUTS/BPO [8,36].

As concerning central obesity, several studies reported that larger WC (>102 cm) and an increase in BMI were positively correlated with increased LUTS/BPE. In a prospective study on men with no obesity related morbidities as diabetes, impaired fasting glucose, hypertension, or dyslipidaemia, BMI waist circumference were positively correlated with prostate volume [37]. These data have recently been confirmed in the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial [38].

However, results of the present of meta-analysis showed that among MetS components, alteration of waist circumference and serum HDL were not associated with increased OR of having moderate-to-severe LUTS. By contrast, altered serum triglycerides and diabetes were associated with this risk.

These observations could be explained by the increase of insulin-like growth factors (IGFs) and insulin induced by diabetes and the increase of adipokines secondary to hypertriglyceridemia that lead to prostate disarrangement [5,23,39].

The sex hormone milieu may further contribute to the association between MetS and BPE and nowadays, late onset hypogonadism (LOH) is recognized as another MetS-associated condition [40–43].

The hypothesis on the pathogenic mechanism that links metabolic syndrome hypogonadism with LUTS suggests that testosterone may act on the structures of the lower urinary tract because of the presence of androgen receptors on urethral and bladder epithelial cell [44–48]. Also, testosterone and its metabolites have been shown to be able to maintain the reflex activity of the pelvic autonomic nervous system [49].

To this regard, testosterone replacement therapy (TRT) in men with hypogonadism can revert hypogonadal features related to metabolic syndrome but also LUTS (especially voiding disturbance) of patients with LOH. Studies suggest that in addition to improvement in sexual functions, testosterone therapy may also improve LUTS/bladder functions by increasing bladder capacity and compliance and decreasing detrusor pressure at maximal flow in men with LOH.

The theoretical basis to explain the improvement of metabolic syndrome features has been addressed to the improving of obesity parameters (body weight, waist circumference and BMI) and lowering of total cholesterol, LDL cholesterol, triglycerides, fasting blood glucose, HbA1c, and blood pressure. These findings result in a sustained improvement in erectile function and muscle and joint pain, which contributed to an improvement in long-term health-related quality of life [46].

Based on this context, The International Society for the Study of the Aging Male (ISSAM) Hypogonadism panel have recently published Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men [50]. Although recommendations can never replace clinical expertise, it is now strengthened that TRT is able to revert LOH symptoms. Improvement in hypogonadal signs and symptoms occur for different organ systems (body composition, cognitive function, LUTS/BPE, cardiovascular disease, sexual function) that can be translated into an increase of quality of life of men.

However, taking into account all previous considerations, connections between MetS components and more severe LUTS could be also attributable to bladder dysfunction and not to BPE.

In fact, there are also evidences that storage symptoms may be susceptible to different risk factors of MetS, secondary to the possible role of the autonomic nervous system. The activation of the parasympathetic nervous system can cause detrusor muscle contraction and may therefore contribute to detrusor over-activity, which is characteristic of the prevalence of storage symptoms [51].

De Nunzio et al. observed that MetS is associated with an increased risk of storage symptoms in patients with BPE. This subjects presented a higher IPSS storage subscore (p ≤ 0.002). Patients with an IPSS storage subscore ≥4 presented a higher BMI and a higher waist circumference when compared with the less symptomatic patients. Instead MetS was not associated with an increased risk of IPSS and IPSS voiding subscore ≥5 [16], supporting the hypothesis of a contribution of MetS on storage symptoms.

Before concluding some limitations should be addressed. The inclusion of studies with significant heterogeneity and lack of geographical distinction in the analysis could represent potentially bias.

However, some strengths of this study includes the addressing for the first time of the impact of MetS and its components on LUTS/BPE severity and also the inclusion of studies that only reported cohorts with clear MetS definitions.

The association between MetS and LUTS/BPE remain unclear and further observational studies in a population with metabolic disorders should be conducted in order to address their potentially role in determining LUTS/BPE.

Conclusion

Patients affected by MetS and LUTS/BPE are rising and emerging links have been postulated. However, current literature is limited to severe heterogeneity and ethnic disparities and results of the current meta-analysis demonstrated that MetS was not determinant in worsen LUTS/BPE. Moreover, among underling pathways, diabetes and hyper triglyceridemia may represent significant MetS components able to more severe LUTS/BPE. Clinical connections between MetS and LUTS/BPE should be further investigated in order to set new preventive strategies and counteract the development of LUTS/BPE in men at risk.

Declaration of interest

Each author declares no conflict of interest.