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Metabolic syndrome and risk for ED: a meta-analysis

Abstract

There are many recent observational studies on metabolic syndrome (MS) and the risk for ED, and it is still inconclusive whether MS increases the risk for ED. This meta-analysis aims to detect a relationship between MS and ED. We identified eligible studies by searching PubMed, Embase and the Cochrane Library for articles published before August 2013. Adjusted relative risks (RR) with 95% confidence interval (CI) were calculated using random-effects or fixed-effects models. A total of 10 studies involving 4092 participants were included in the meta-analysis. MS was associated with an increased incidence of ED (RR=1.60, 95% CI=1.27–2.02, P<0.001), with significant evidence of heterogeneity among these studies (P for heterogeneity <0.001, I2=92.9%). The subgroup and sensitivity analyses confirmed the stability of the results and no publication bias was detected. The present meta-analysis suggests that MS is significantly associated with the risk for ED. Large-scale and well-designed prospective studies are required to further investigate the association between MS and risk for ED.

Introduction

ED is common and increases as men age,1 and it is being increasingly recognized as a public health problem. In the United States, ED currently affects approximately 18 million men.2 A number of risk factors are associated with ED, including advanced age, obesity, hypertension, dyslipidemia, cigarette smoking, diabetes and cardiovascular disease (CVD).3, 4

Metabolic syndrome (MS) is a constellation of metabolic abnormalities including obesity, hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol and hyperglycemia. The experts of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP)-III created an operational definition of MS in 2001.5 MS was defined by the presence of three of the following: abdominal circumference >102 cm, hypertriglyceridemia >150 mg dl−1, high-density lipoprotein cholesterol <40 mg dl−1, blood pressure >130/85 mm Hg or glycemia >110 mg dl−1. MS is associated with a twofold increase of 5- to 10-year risk for CVD.6The relationship between MS and CVD has been established, as well as the relationship between CVD and ED.7However, few studies have investigated the association between MS and ED.8 In addition, evidence is limited because the majority of these studies are case–control studies or cross-sectional studies. Over the past few years, some cohort studies conducted in different countries and populations demonstrating the association between MS and ED have been published, but whether MS is an independent risk factor or merely a silent marker of ED remains unclear. With accumulating evidence worldwide, we performed a meta-analysis of studies that evaluated the association between MS and ED.

Materials and methods

Search strategy

PubMed, Embase and the Cochrane Library were searched to identify relevant studies eligible for the meta-analysis before 1 August 2013. The following search terms were used: ‘metabolic syndrome’, ‘erectile dysfunction’ ‘sexual dysfunction’ and ‘impotence’, and the reference lists of selected articles were also manually examined to find relevant studies not discovered in the databases. If more than one article were published using the same data or the same author, only the article with the largest sample size was included. This search strategy was performed iteratively until no new relevant article was found. The language was limited to English.

Inclusion criteria and data extraction

An initial screening of titles or abstracts was performed first to identify possibly relevant studies, and then the full texts of studies identified on the basis of titles and abstracts were examined. The studies included in the meta-analysis must have met all the inclusion criteria: (1) the study should have evaluated the association between MS and ED; (2) should have used a case–control or cohort design; and (3) should provide sufficient data for calculating the association between MS and ED.

The following information was extracted independently by two investigators (LHL and ZT), and any disagreements were resolved through discussion to reach a consensus: (1) name of the first author, (2) year of publication, (3) country of origin, (4) age of the study population, (5) number of participants, (6) MS criteria; and (7) definition or measurement.

Statistical analysis

The association of MS and ED was estimated by calculating pooled RR and 95% CI. The significance of pooled RR was determined using the Z test (P<0.05 was considered statistically significant). Homogeneity was tested by the Q statistic (significance level at P<0.10) and the I2 statistic (significance level at I2 >50%). The combined risk estimates were computed using either fixed-effects models or random-effects models in the presence of heterogeneity.9, 10 We conducted subgroup analyses to explore heterogeneity across studies, and the difference between subgroups was tested by meta-regression analysis. Potential publication bias was assessed by visual inspection of Begg’s funnel plots in which the log RRs were plotted against their SEs. We also performed Begg’s and Egger’s tests to evaluate the presence of publication bias.11, 12 All analyses were performed using STATA 12.0 (Stata Corporation, College Station, TX, USA).

Results

We initially identified 794 results relevant to the search terms from these selected databases. Of them, the majority were excluded after the first screening based on abstracts or titles, because they were not relevant or they were reviews. A total of 38 potentially eligible studies were identified by a literature search. After examining the full texts of these papers, we excluded 28 studies because association of interest was not evaluated, they were duplicate papers of the same studies, requested data were not reported or the articles were in Russian. Finally, we identified 10 studies13, 14, 15, 16, 17, 18, 19, 20, 21, 22 that met the inclusion criteria; the search process has been detailed in Figure 1.

Figure 1
figure1

Flow chart of studies for inclusion in meta-analysis.

Study characteristics

The main characteristics of the 10 observational studies are presented in Table 1. These studies were published between 2005 and 2012. Five studies were conducted in Europe, four in Asia and one in Brazil, and sample sizes ranged from 60 to 1952 (total 4092). The ascertainment of ED was based on the international index of erectile function (IIEF-5) Questionnaire, and MS was defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) criteria in eight studies, by the International Diabetes Federation consensus in one study and by The Bureau of Health Promotion in Taiwan in one study. Table 2 summarizes the methodological quality of the studies.

Table 1 Characteristics of the included studies
Table 2 The methodological quality of the included studies

Meta-analysis results

Figure 2 shows the results from the random-effects model combining the RRs for ED. Men with MS when compared with the reference group experienced a significantly increased risk of developing ED (RR=1.60, 95% CI=1.27–2.02, P<0.001). Substantial heterogeneity was observed (I2=92.9%, P for heterogeneity <0.001).

Figure 2
figure2

Meta-analysis of the association between MS and risk for ED.

As significant heterogeneity was found among these studies, subgroup analysis was performed by ethnicity and study design. No significant increased risk was observed in the subgroup analysis (Table 3).

Table 3 Results of subgroup analysis between MS and ED

Sensitivity analyses were conducted to explore the potential sources of heterogeneity in the association between MS and ED. Exclusion of a study16 that had the largest samples, which served as the reference group, yielded similar results (RR=1.70, 95% CI=1.31–2.23, P<0.001), with substantial evidence of heterogeneity (P<0.001, I2=91.4%). Exclusion of two studies16, 18 showed a somewhat greater risk (RR=1.90, 95% CI=1.54–2.34, P<0.001); yet, heterogeneity was still present (P<0.001, I2=83.4%). Further exclusion of any single study did not materially alter the overall combined RR, suggesting that no single study exhibited excessive influence on the results of this meta-analysis.

Publication bias

There was no statistical evidence of publication bias on the basis of Begg’s test (P=0.47) and Egger’s test (P=0.11). Funnel plots demonstrated no visual evidence of publication bias (Figure 3).

Figure 3
figure3

Begg’s funnel plot for publication bias evaluating the association between MS and ED.

Discussion

To the best of our knowledge, the present study represents the first meta-analysis quantitatively for the association between MS and risk for ED. Our study included two prospective cohort studies, four case–control studies and four cross-sectional studies involving 4092 participants. From our analysis, we identified and evaluated 10 studies from the published literature comparing the risk for ED between subjects with MS and those without. The analysis demonstrates that subjects with MS have significantly increased risk for ED.

The underlying mechanisms involved in the association between MS and ED have evoked huge interest in clinicians, scientists and the public. MS may lead to ED through multiple mechanisms. Hypogonadism, which may be caused by MS, can lead to secondary ED through altered testosterone:estrogen levels.23 Severe hypogonadism in men usually results in loss of libido and potency, which can be restored by androgen administration. Testosterone can affect the ability to achieve erections by stimulating the expression of nitric oxide synthase, thereby increasing the availability of nitric oxide in cavernosal tissue.24 Another mechanism is atherosclerosis, which has been a significant etiological factor in ED.25 Atherosclerotic disease stemming from the same disease processes underlying MS may also lead to ED by affecting the vascular tissues of the penis.26, 27 MS can also lead to endothelial dysfunction, which has been implicated in vascular disorders. The endothelium is a vital source of nitric oxide, the main vasodilatory neurotransmitter for erection. Endothelial dysfunction therefore leads to a decrease in vascular nitric oxide levels, with resulting impaired vasodilation; the increase in free radical concentration also leads to atherosclerotic damage.28 Vascular damage resulting in the occlusion of cavernous arteries by atherosclerosis, impairment of endothelial-dependent or -independent smooth muscle relaxation, or a combination of these pathomechanisms may explain the association between MS and ED.

There are several limitations that need to be taken into account when considering its results in our analysis. One potential limitation of the present meta-analysis was the various methods of assessment for MS used among studies. Definitions for MS are heterogeneous, as multiple sets of diagnostic criteria were initially created to identify insulin-resistant patients or to predict clinical events.29 Nowadays, however, the NCEP ATPIII criterion is the one most commonly used as it incorporates key concepts of MS, relies on frequently used laboratory studies and is less restrictive than the other classifications.28 However, the results did not significantly change after the exclusion of three studies that did not use the NCEP ATPIII criterion.16, 17

A second limitation is the substantial heterogeneity among studies for the association between MS and risk for ED. Nevertheless, we were able to detect the major source of heterogeneity through the subgroup and sensitivity analyses. Independent variables including ethnicity, study design and MS criteria were used to examine the source of heterogeneity. However, these variables could not explain the source of heterogeneity, suggesting that other unknown confounding variables might be the source of residual heterogeneity.

Finally, there are four cross-sectional studies in the included studies that limit the quality of our meta-analysis. In the future, large and well-designed prospective studies are necessary to further confirm the association between MS and risk for ED.

In conclusion, our meta-analysis supports the hypothesis that MS significantly increases the risk for ED. The findings of our study have great public health significance. The onset of MS and the associated risk for ED may be delayed through lifestyle modifications that counteract obesity and MS, such as healthy diet and increased physical activity.30 It is important to recommend lifestyle intervention for the early prevention and control of MS.

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Acknowledgements

We thank Professor An-Yang Wei for his excellent technical support. This study was supported by the National Natural Science Foundation of China (81170566) and Natural Science Foundation of Guangdong Province (S2012010009091).

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Correspondence to S H He or A Y Wei.

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Liu, L., Zhang, T., Zhang, Y. et al. Metabolic syndrome and risk for ED: a meta-analysis. Int J Impot Res 26, 196–200 (2014). https://doi.org/10.1038/ijir.2014.3

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Keywords

  • erectile dysfunction
  • meta-analysis
  • metabolic syndrome

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