The association between metabolic syndrome and the risk of prostate cancer, high-grade prostate cancer, advanced prostate cancer, prostate cancer-specific mortality and biochemical recurrence

Background Although a previous meta-analysis reported no association between metabolic syndrome (MetS) and prostate cancer risk, a number of studies suggest that MetS may be associated with the aggressiveness and progression of prostate cancer. However, these results have been inconsistent. This systematic review and meta-analysis investigated the nature of this association. Methods We systematically searched MEDLINE, EMBASE and bibliographies of retrieved studies up to January 2013 using the keywords “metabolic syndrome” and “prostate cancer”. We assessed relative risks (RRs) of the prostate cancer, several parameters of prostate cancer aggressiveness and progression associated with MetS using 95% confidence intervals (95% CIs). Results The literature search produced 547 hits from which 19 papers were extracted for the meta-analysis. In cancer-free population with and without MetS, the combined adjusted RR (95% CI) of prostate cancer risk and prostate cancer-specific mortality in longitudinal cohort studies is 0.96 (0.85 ~ 1.09) and 1.12 (1.02 ~ 1.23) respectively. In the prostate cancer patients with and without MetS, the combined unadjusted OR (95% CI) of high grade Gleason prostate cancer is 1.44 (1.20 ~ 1.72), the OR of advanced prostate cancer is 1.37 (1.12 ~ 1.68) and the OR of biochemical recurrence is 2.06 (1.43 ~ 2.96). Conclusions The overall analyses revealed no association between MetS and prostate cancer risk, although men with MetS appear more likely to have high-grade prostate cancer and more advanced disease, were at greater risk of progression after radical prostatectomy and were more likely to suffer prostate cancer-specific death. Further primary studies with adjustment for appropriate confounders and larger, prospective, multicenter investigations are required.


Background
In men, prostate cancer (PCa) is the most frequently diagnosed malignancy in industrialized countries [1] and it is the second most commonly diagnosed cancer and the sixth leading cause of cancer death worldwide [2]. There is a clear need for a better understanding of the risk factors related to PCa development and progression. Age, race and family history are the only established prostate cancer risk factors and these factors are all nonmodifiable. Recently, modifiable lifestyle factors such as physical activity and diet have been investigated. Because a higher incidence of PCa was associated with a higher prevalence of "western" lifestyle, it has been suggested that these lifestyle factors play a significant role in the pathogenesis of PCa [3].
Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that includes hypertension, diabetes mellitus, obesity, hypertriglyceridemia, and low highdensity lipoprotein cholesterol, with insulin resistance as the underlying hallmark feature [4]. The prevalence of MetS has been increasing worldwide and has become a major public health problem in many western countries. For example, 35%-41% of adults in the USA are reported to exhibit MetS [5]. Recently, increasing evidences suggests that MetS may be involved in the development and progression of certain types of cancer as an independent etiologic factor including breast cancer [6], endometrial cancer [7], colorectal cancer [8], pancreatic cancer [9] and prostate cancer [10]. MetS was firstly observed as a composite factor associated with prostate cancer risk in 2004 [11], and more studies have since reported the association between MetS and prostate cancer. However, the studies investigating the association between MetS and prostate cancer risk have reported inconsistent findings [12][13][14][15][16][17][18][19][20][21].
It is crucial to review and evaluate the magnitude to which MetS affects the development and progression of PCa, as proper management of this modifiable lifestyle factor may help improve PCa outcomes.
A recently performed meta-analysis study summarized the association between MetS and the incidence of some common cancer types, including prostate cancer. The results, based on 14 databases, revealed that MetS was not associated with prostate cancer risk [22]. However, a new investigation on MetS and prostate cancer risk was published recently [19], and much increasing evidence in the latest investigations suggests that MetS may be associated with the aggressiveness and progression of PCa; prostate cancer patients with MetS may suffer more aggressive disease and adverse clinical outcomes [19,[23][24][25][26][27]. However, inverse results [28] or no significant associations [14,20,29,30] have been reported in other studies. Therefore, to thoroughly investigate the nature of this association, we focused on longitudinal cohort studies and conducted a new meta-analysis to confirm the association between MetS and prostate cancer risk by searching the latest literature. Subsequently, we performed another meta-analysis to quantitatively summarize several parameters of PCa aggressiveness and progression, including Gleason score, clinical stage, biochemical recurrence and prostate cancer-specific mortality associated with MetS.

Search strategy
We systematically searched MEDLINE, EMBASE through January 2013 for human studies on the association between MetS and PCa with the following medical subject heading terms and/or text words: "metabolic syndrome", "insulin resistance syndrome", or "syndrome X", combined with "prostate cancer", "prostatic cancer", "prostate neoplasm", or "prostatic neoplasm". We also manually searched relevant journals, bibliographies, and reviews for additional articles. The search had no language restriction.

Inclusion criteria
The eligibility of each study was assessed independently by two investigators (YX and HX). We included only cohort studies of MetS and prostate cancer risk or prostate cancer-specific mortality and clinical studies of MetS and Gleason score or clinical stage at diagnosis or biochemical recurrence after treatment. We included studies that reported standardized forms of relative risk, risk ratio, hazard ratio or odds ratio with estimates of confidence intervals (CIs) or with sufficient data to estimate CIs. We used relative risks (RRs) to represent various effect estimates in a cohort study in this meta-analysis.

Exclusion criteria
We excluded reviews, editorials, meta-analysis and animal studies. Among the 23 studies that underwent full-text reviews, we excluded a study on MetS and prostate cancer risk of re-biopsy [31], a study that did not use a standard definition of MetS [32,33] and one case-control study on MetS and prostate cancer risk [21]. For studies previously published on the same database [34,35], we included only the most recent findings [19,20]. All of the studies on which we focused reported RRs with 95% CIs or sufficient data to estimate them.

Data extraction
The data extracted included publication data (the first author's last name, year of publication, and country of the population studied), study design, population resources, number of cases, risk estimates with their corresponding CIs, and variables controlled for by matching or in the most adjusted model. Abstractions of the data elements were conducted separately by two authors; discordant results were resolved by consensus.

Statistical analysis
Firstly, we updated the data and attempted to analyze the association of MetS with the prostate cancer risk in longitudinal cohort studies only. Subsequently, we assessed the association between MetS and prostate cancer-specific mortaligy in cohort studies and between MetS and high grade Gleason PCa and/or advanced PCa or biochemical recurrence in clinical studies. We pooled all of the RRs for MetS and assessed the heterogeneity between the studies by Q and I 2 statistics, which are distributed as x 2 statistics [36]. A value of P < 0.10 was used to indicate lack of homogeneity (heterogeneity) among effects. We used a fixed-effects model if I 2 value significance was <0.1; otherwise, we used a random-effect model. Sensitivity analysis was conducted by omitting one study at a time, generating the pooled estimates and comparing with the original estimates. Funnel plots and both Begg's and Egger's tests were used to evaluate publication bias. All analyses were performed using STATA version 9.0 statistical software (Stata, College Station, Texas, USA). All statistical comparisons were 2-sided, and a p-value < 0.05 was considered statistically significant).

Main findings Prostate cancer risk
Result from a meta-analysis based on nine longitudinal cohort studies revealed that there was no association between MetS and prostate cancer risk (RR = 0.96, 95% CI 0.85-1.09 n = 9 studies) ( Figure 2).

Prostate cancer aggressiveness
High grade Gleason score The definition of high grade Gleason score is ≥ 7 or > 7. A trend for a 36% increased risk of a high Gleason score in patients with MetS (OR = 1.36, 95% CI 0.90-2.06 n = 7 studies) was identified based on a meta-analysis of seven total relative databases ( Figure 3).
Advanced clinical stage Advanced clinical stage was defined as a clinical stage ≥ T3. Four databases were included in the analysis of the association of MetS with advanced clinical stage. The analysis revealed that MetS was significantly associated with a 37% increased risk of advanced clinical stage (OR = 1.37, 95% CI: 1.12~1.68; n = 4 studies) ( Figure 4).

Prostate cancer progression
Biochemical recurrence Only two databases [23,27] focused on the association of MetS which biochemical recurrence. The Individual study results and the overall summary results are presented in Figure 5. The result indicates that MetS was significantly associated with 2-folds of increased risk of biochemical recurrence (OR = 2.06, 95% CI: 1.43-2.96, n = 2 studies).

Sensitivity analysis
We conducted sensitivity analysis by omitting one study at a time, generating the pooled estimates and comparing the pooled estimates with the original estimates. Omitting any one of nine studies concerning MetS and prostate cancer risk or omitting any one of four studies concerning MetS and advanced clinical stage produced no dramatic influence on the original pooled RRs. Omitting Jeon 2012 database [28] in the 7 studies concerning MetS and Gleason score produced a significant OR = 1.44 (95% CI: 1.20~1.72), whereas none of the remaining severn studies exhibited a significant influence on the original estimates. For biochemical recurrence and prostate cancerspecific mortality, there were too few studies to do a sensitivity analysis.

Publication bias
Visual inspection of the Begg funnel plot for both PCR and Gleason score did not reveal the asymmetry typically associated with publication bias (Figure 7). Evidence of   association could be detected between Mets and prostate cancer.
We believe the result is reliable for two reasons. Firstly, only longitudinal cohort studies were included in this analysis, imparting strong evidence for our conclusions. In addition, the association between MetS and prostate cancer may be affected by several factors, including heterogeneity among the individual studies. The heterogeneity may arise from differences in age, race, the definition of MetS [22], and geographic factors [26]. Further, MetS is a syndrome composed of at least 3 components, and the individual component may exert antagonistic functions on one another Thus the syndrome may represent an integrated outcome that combines neutralizing positive and negative functions. For example, a meta-analysis revealed that diabetes mellitus was significantly negatively associated with prostate cancer risk in population-based studies (RR = 0.72, 95% CI: 0.64-0.81) and cohort studies conducted in the USA (RR = 0.79, 95% CI: 0.73, 0.86) [38]. Furthermore, several genome-wide association  studies suggest that diabetes mellitus and prostate cancer share certain genetic factors, including the HNF1β and JAZF1 genes, and a previous study suggested that JAZF1 might represent a potential target against diabetes and obesity [39]. Although hypertension was found to be positively associated with prostate cancer risk [33,[40][41][42], Obesity is negatively with localized prostate cancer (0.94, 95% CI, 0.91-0.97) and positively associated with advanced prostate cancer risk (1.07, 95% CI 1.01-1.13) [43].

Risk of advanced prostate cancer
However, after analyses of several parameters of PCa aggressiveness and progression, we found MetS to be significantly associated with an increased risk of prostate cancer with a high-Gleason score or advanced clinical stage, with biochemical recurrence after primary treatment and with prostate cancer-specific mortality. Risk of prostate cancer-specific mortality and prostate cancer is the most prevalent solid organ tumor, accounts for 29% of all cancer cases and the second most common cause of death by cancer among men in the USA [44]. Therefore we believe that there is a compelling need to investigate this association between MetS and prostate cancer although the association is not strong. Nevertheless, the reliability of these results is limited. First, Gleason score and clinical stage data were extracted from cross-sectional studies not longitudinal cohort studies. Second, there exists a small difference among studies on the definition of high-grade Gleason PCa, some authors defined a high Gleason score ≥ 7 whereas others defined a high score as >7. Third, the pathological stage data in some studies were from biopsy not radical prostatectomy specimens. Last but not least, to date there remains limited studies focusing on this association, although many of the available studies are well designed case-control or longitudinal cohort studies.
In addition to the limitations listed above, another limitation for the analyses of the association between MetS and prostate cancer risk or prostate cancer parameters is that we did not perform a meta-regression to attempt to explain the heterogeneity of the study because of the varying adjustments in the individual studies. The result of a recent meta-analysis on 9 crosssectional studies of metabolic syndrome in adult cancer survivors increases the weight of this suspicion, as it revealed that no significant association was found for nonhematologic malignancies, including testicular tumor, prostate cancer, sarcoma, and epithelial ovarian [45]. Therefore, there is an urgent future need to confirm this association and to find potential mechanisms to explain  Figure 7 Funnel plot with pseudo 95% confidence limits.
how metabolic factors affect the development or progression of PCa.

Conclusions
Based on the current findings, MetS is not associated with prostate cancer risk, but preliminary evidences demonstrates that men with MetS more frequently suffer high-grade prostate cancer, more advanced disease and are at greater risk of progression after radical prostatectomy and prostate cancer-specific death. Together, these findings indicate that MetS may be associated with the progression of prostate cancer and adverse clinical outcomes. Further studies with adjustment for appropriate confounders and larger, prospective, multicenter investigations are required in the future.

Competing interests
No potential conflicts of interest were disclosed.

Authors' contributions
This study was designed and supervised by XJ. Literature search, selection and data extraction was by YX and HX, and data analyses were performed by YX, HX, ZC, SJ, QX, YZ and GL. Data interpretation and manuscript writing received contributions from all authors. All authors read and approved the final manuscript.