1
The Relationship Between Metabolic Syndrome, Its Components, and Erectile Dysfunction: A Systematic Review and a Meta-Analysis of Observational Studies Huseyin Besiroglu, MD,* Alper Otunctemur, MD,* and Emin Ozbek, MD† *Department of Urology, Okmeydani Training and Research Hospital, Istanbul, Turkey; †Department of Urology, Katip Celebi University Atatürk Training and Research Hospital, Izmir, Turkey DOI: 10.1111/jsm.12885
ABSTRACT
Introduction. The studies examining the association between metabolic syndrome (MetS), its components, and erectile dysfunction (ED) should be reevaluated to arrive at comprehensive results in this field. Aim. Our aim was to gather individual studies in order to achieve a more reliable conclusion regarding the relationship between MetS, its components, and ED. Methods. Three investigators searched the Pubmed-Medline and Embase databases using the key words “metabolic syndrome” and “erectile dysfunction.” The individual studies were evaluated for selection of suitable studies. Main Outcome Measures. Eight studies that met all inclusion criteria were chosen, and a pooled analysis of odds ratio (ORs) between MetS and ED was calculated. The components of MetS to ED were also estimated. Results. Eight observational studies with a total of 12,067 participants were examined. The overall analysis revealed a 2.6-fold increase in patients with MetS having ED (2.67[1.79–3.96]; P < 0.0001). All individual components of MetS except high-density lipoprotein level were also found to correlate with an increased prevalence of ED. Of those, fasting blood sugar was detected highest rate for ED with OR of 2.07 ([1.49–2.87]; P < 0.0001). Conclusions. Metabolic syndrome is associated with a high risk rate of ED, and patients with MetS should be informed about this association and encouraged to make lifestyle modifications to improve their general health and to limit cardiovascular risk as well as ED prevalence. However, manuscripts included in meta-analysis were observational studies that prohibits ascertainment of temporal associations and necessitates further prospective studies. Besiroglu H, Otunctemur A, and Ozbek E. The relationship between metabolic syndrome, its components, and erectile dysfunction: A systematic review and a meta-analysis of observational studies. J Sex Med **;**:**–**. Key Words. Erectile Dysfunction; Meta-Analysis; Metabolic Syndrome; Observational Studies
Introduction
M
etabolic syndrome, also known as syndrome X and insulin resistance syndrome, is the term that consists of a cluster of disease statesabdominal obesity, atherogenic dyslipidemia, raised blood pressure, insulin resistance ± glucose intolerance, proinflammatory state, and prothrombotic state [1]. It is responsible for a three-fold increase in the risk of atherosclerotic cardiovascular diseases (CVDs) and also increases © 2015 International Society for Sexual Medicine
mortality from CVD, as well as all-causes, in the general population [2]. Various organizations have used different combinations of criteria for defining metabolic syndrome (International Diabetes Federation, World Health Organization, European Group for the Study of Insulin Resistance, U.S. National Cholesterol Education Program (NCEP), and American Heart Association). Waist circumference (WC) > 102 cm, triglycerides ≥ 150 mg/dL, high-density lipoprotein (HDL) cholesterol < 40 mg/dL, blood pressure ≥ J Sex Med **;**:**–**
2 130/85 mm Hg, and fasting glucose ≥ 110 mg/dL are MetS criteria according to NCEP-Adult Treatment Panel III (ATP III) [1]. The majority of the definitions are based on the individual having three or more of the aforementioned five factors. Erectile dysfunction (ED) is the consistent inability to attain and maintain an erection of the penis sufficient to permit satisfactory sexual intercourse [3]. It is a growing problem worldwide, and 30 million men are estimated to have this condition in the United States [4]. Patients with coronary artery disease have an increased incidence of ED symptoms [5,6]. The etiology of ED is multifactorial including neural, vascular, and hormonal components. A competent vascular system that provides blood supply is absolutely necessary for adequate erection. Thus, any alteration of the vascular system may lead to erectile dysfunction. Coronary artery diseases and ED share similar risk factors such as hypertension, diabetes mellitus, smoking, and hypercholesterolemia, and many of these factors are part of MetS. This has led some to propose that ED might be a good indicator for occult coronary artery disease [7]. MetS may cause ED through multiple mechanisms. All components of MetS are frequently found in the obese population. Abdominal obesity promotes insulin resistance that is associated with hyperinsulinemia and hyperglycemia. It may also lead to an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerosis [8]. MetS can also result in endothelial dysfunction, which has been implicated in vascular disorders leading to ED, and in a study conducted by Thompson et al. [9], a strong association has been indicated between elevated biomarkers of inflammation and endothelial dysfunction with increased odds of prediabetes, diabetes, and the MetS among adults in Inner Mongolia, China. Endothelial dysfunction leads to a decrease in vascular nitric oxide levels, with resulting impaired vasodilation; the increase in free radical concentration also leads to atherosclerotic damage [10]. In light of these common pathways, MetS could be a strong risk factor for ED as well as ED might be a harbinger of cardiovascular diseases. Many studies examining the prevalence of ED in patients with MetS have been conducted to date. Our aim was to gather appropriate individual studies in order to have a more robust and reliable conclusion on this issue. J Sex Med **;**:**–**
Besiroglu et al. Materials and Methods
Study Selection The PubMed-Medline and Embase databases were independently searched by three investigators to retrieve relevant studies published before February 2014. The search was restricted to English-language articles and studies of human participants. The search terms comprised of the following keywords: metabolic syndrome, erectile dysfunction. Studies were included in our metaanalysis if they met the following criteria: (i) the study design was observational; (ii) the outcome of interest was the prevalence of erectile dysfunction in patients with MetS; (iii) odds ratios (OR), and corresponding 95% confidence intervals (CIs) (or data to calculate them) were reported. Data Extraction and Quality Assessment Information extracted from an extensive review of each publication included publication data (first author’s last name, time period of the publication, and country of the population studied), type of study design, cohort size, definitions of metabolic syndrome, MetS components, definition of ED, ORs with their corresponding CIs, and all the covariates (if any) being used in the multivariate analyses and modeling. Two reviewers (H.B and A.O.) independently conducted the literature search, study selection, and data extraction, and any conflicts were resolved by the third investigator (E.O.). The quality of the studies was assessed by meta-analysis of observational studies in epidemiology guideline [11]. Statistical Analysis
Meta-analysis was performed using the fixed effects or the random effects method, depending on the absence or presence of significant heterogeneity [12]. Statistical heterogeneity among trials was assessed by using Cochran’s Q and I2 statistic, and P value < 0.05 or I2 value > 50% was considered to be heterogeneous [13]. The fixed effects method was used to combine the results when statistically significant heterogeneity was absent. When heterogeneity was confirmed, the random effects method was used. Sensitivity analysis was conducted by omitting one study at a time, generating the pooled estimates and comparing with the original estimates. Publication bias was evaluated by creating a funnel plot via each study’s effect size. The Begg and Mazumdar rank correlation test was used to evaluate publication bias [14,15].
3
The absence of OR of MetS and ED 2 article excluded Not robust statistical analysis of OR (CI) 8 articles included in meta-analysis.
Figure 1 Flow meta-analysis
diagram
of
studies
included
in
the
268 393 639 3921 54.1 ± 8.8 40–70 40–83 40–88 2005 2005 2009 2001–2002
238 3306 105 3197 >40 >20 >40 17–88
Turkey Turkey Taiwan Canada
Taiwan USA Finland China
Local aboriginal community in eastern Taiwan NHANES Hämeenlinna Metabolic Syndromresearch program The Fangchenggang Area Male Health and Examination Survey Turkish men Turkish men Free health screening 40 years or over Canadian men
2010–2011 2001–2004 2010 2009
Cohort size (n) Time period Population Country
Cross-sectional Cross-sectional Cross-sectional Cross-sectional
1 article excluded
Tevfik Demir (2006) [20] Bal et al. (2007) [21] Lee et al. (2010) [22] Grover et al. (2006) [23]
Language other than English (40)
Cross-sectional Cross-sectional Cross-sectional Cross-sectional
Nonhuman studies (31) Full text articles reviewed for more detailed evaluation (n=11)
Chao et al. (2012) [16] Weinberg et al. (2013) [17] Pohjantähti et al. (2011) [18] Chen et al. (2012) [19]
Outcomes not relevant (n=120)
Study design
Reviews (n=108)
Authors (publication year)
299 articles excluded;
Relevant studies of the relationship between metabolic syndrome and erectile dysfunction
Potentially relevant publications identified from literature (n=310)
Table 1
Literature Search and Study Characteristics We initially identified 310 studies, either in full publications or abstract forms, using the methodology and the search terms described above. After title and abstract review; 299 articles were removed. Of these, 108 were reviews, 31 were not human studies, 40 had language other than English, and 120 had outcomes not relevant to the subject. Eleven publications were considered to be relevant to our study subject. Of these, three were excluded due to deficiencies for further inclusion criteria. Finally, eight studies were included in our meta-analysis. The details of the literature search are depicted in Figure 1. The eight selected studies [16–23] contained 12,067 participants (ranging from 105 to 3,921). They were published between 2006 and 2013. The detailed characteristics of included studies are presented in Table 1. Four studies used the NCEPATP III, one study used modified Asians NCEPATP III criteria, one study used NCEP-ATP III criteria modified for Asian Americans, one study used the American Heart Association/National Heart, Lung, and Blood Institute criteria, and one
Age, year (range or mean ± SD)
Results
MetS = metabolic syndrome; SD = standard deviation; HDL = high-density lipoprotein; OR = odds ratio; RR = risk ratio; CI = confidence interval; NCEP-ATP-III = National Cholesterol Education Program Adult Treatment Panel III; NHANES III = Third National Health Center Nutrition Examination Survey; AHA/NHLBI = American Heart Association/National Heart, Lung, and Blood Institute
95% CI
1.7–5.0 1.1–5.7 1.44–3.69 1.24–1.69 2.9 2.5 2.30 1.45 OR OR OR OR
12.02 2.55 4.62 1.34
Adjusted RRs
OR OR OR OR
The results were considered statistically significant for P < 0.05. All statistical comparisons were two sided, and P value < 0.05 was considered statistically significant. All analyses were performed using Comprehensive Meta-analysis Version.2 (Biostat, Englewood, NJ, USA).
6.33–22.83 1.85–3.5 2.005–10.623 1.04–1.72
Erectile Dysfunction and Metabolic Syndrome
J Sex Med **;**:**–**
4 Table 2
Besiroglu et al. The definitions of Mets, its components, and erectile dysfunction of the studies included in meta-analysis Erectile dysfunction definition
MetS definition
MetS components criteria Fasting plasma glucose ≥110 mg/dL Serum TG ≥ 150 mg/dL Serum HDL-C < 40 mg/dL Blood pressure ≥130/85 mm Hg Waist circumference >90 cm Fasting plasma glucose > 100 mg/dL Serum TG > 150 mg/dL Serum HDL-C < 40 mg/dL Blood pressure >130/85 mm Hg Waist circumference >102 cm Fasting plasma glucose ≥ 110 mg/dL Serum TG ≥ 150 mg/dL Serum HDL-C < 40 mg/dL Blood pressure >130/85 mm Hg Waist circumference >102 cm Fasting plasma glucose ≥5.6 mmol/L Serum TG ≥ 150 mg/dL Serum HDL-C < 1.03 mmol/L Blood pressure ≥130/85 mm Hg Waist circumference >90 cm Fasting plasma glucose ≥ 110 mg/dL Serum TG ≥ 150mg/dl Serum HDL-C < 40mgdl Blood pressure ≥130/85 mm Hg Waist circumference >102 cm Fasting plasma glucose ≥ 110 mg/dL Serum TG > 150 mg/dL Serum HDL-C < 40 mg/dL Blood pressure ≥130/85 mm Hg Waist circumference >10 cm Fasting plasma glucose ≥ 100 mg/dL Serum TG > 150 mg/dL Serum HDL-C < 40 mg/dL Blood pressure >130/85 mm Hg Waist circumference >90 cm Fasting plasma glucose ≥ 111 mg/dL Serum TG ≥ 150 mg/dL Serum HDL-C < 40 mg/dL Blood pressure ≥130/85 mm Hg Body mass index (BMI) ≥ 28
Chao et al.
IIEF-5
NCEP-ATP III modified for Asians
Weinberg et al.
Single question self-report
AHA/NHLBI
Pohjantähti et al.
IIEF-15
NCEP-ATP III
Kai Chen et al.
IIEF-5
NCEP-ATP III for Asian Americans
Tevfik Demir
IIEF-15
NCEP-ATP III
Bal et al.
IIEF-15
NCEP-ATP III
Lee et al.
IIEF-5
Modified criteria developed by the Bureau of Health Promotion in Taiwan
Grover et al.
IIEF-15
NCEP-ATP III
P value to determine statistical significance P < 0.05
P < 0.05
P < 0.05
P < 0.05
P < 0.05
P < 0.05
P < 0.05
P < 0.05
MetS = metabolic syndrome; IIEF = International Index of Erectile Function; NCEP-ATP-III = National Cholesterol Education Program Adult Treatment Panel III; AHA/NHLBI = American Heart Association/National Heart, Lung, and Blood Institute; TG = trigliseride; HDL = high-density lipoprotein
study used modified criteria developed by the Bureau of Health Promotion in Taiwan. The seven studies used International Index of Erectile Function assessments to confirm the diagnosis of ED, whereas Weinberg et al. used a single question self-report that was validated by O’Donnell et al. [24]. The detailed information regarding MetS, its components, and ED definition criteria were demonstrated in Table 2.
Overall Analysis of Pooled Data The relationship between MetS and ED was examined in eight studies [16–23]. All studies reported a positive association between ED and MetS (OR ranged from 1.34 to 12.02). The pooled analysis of OR of eight individual studies J Sex Med **;**:**–**
revealed that patients with MetS had a higher overall adjusted risk of ED (2.671[1.797–3.969], Q = 60.329; p value for heterogeneity = P < 0.0001; I2 = 88.397%; Figure 2]). Because there was heterogeneity among the studies, a random effect model was used.
MetS Components and ED Fasting Blood Sugar and ED The evaluation of the relationship between fasting blood sugar and ED was reported in eight studies [16–23] and seven of them reported a significantly higher rate of ED (OR ranged from 1.26 to 8.94) in patients with elevated fasting blood sugar. Only one study [19] reached no statistically significant association (OR 1.7 [0.98–2.95] P = 0.059). Pooled
5
Erectile Dysfunction and Metabolic Syndrome Model Study name
Statistics for each study
Odds ratio and 95% CI
Weight (Fixed)
Odds Lower Upper ratio limit limit Z-Value p-Value Chao et al. Weinberg et al. Pohjantähti et al. Kai Chen et al. Tevfik Demir Bal et al. Yung-Chin Lee et al. Grover et al. Fixed Rando
12,020 2,550 4,620 1,340 2,900 2,500 2,300 1,450 1,775 2,671
6,329 22,827 7,599 1,849 3,517 5,704 2,007 10,634 3,598 1,042 1,723 2,280 1,691 4,973 3,869 1,098 5,691 2,183 1,437 3,682 3,470 1,242 1,693 4,704 1,588 1,985 10,093 1,797 3,969 4,860
Relative Relative Relative Relative weight weight weight weight
0,000 0,000 0,000 0,023 0,000 0,029 0,001 0,000 0,000 0,000
3,02 12,01 1,79 19,63 4,27 1,84 5,61 51,84
0,01
0,1
1
Favours A
10
11,21 14,3 7 9,32 14,92 12,27 9,43 12,97 15,50
100
Favours B
Meta Analysis Figure 2 Odds ratios and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between metabolic syndrome and erectile dysfunction in all subjects. Q = 60.329; P value for heterogeneity = P < 0.0001; I2 = 88.397%
analysis of these eight studies showed that the rate of ED was significantly higher in patients with enhanced fasting blood sugar and there was heterogeneity among the studies (OR 2.07[1.49–2.87], P < 0.001; P value for heterogeneity = p < 0.0001; Q = 46.118; I2 = 84.822%; Figure 3).
three studies [19,21,22] did not. The pooled analysis of all these studies revealed that patients with hypertension had a higher overall adjusted risk of ED, and there was heterogeneity among the studies (OR 1.53[1.09–2.159; P = 0.01 Q = 23.530; P value for heterogeneity = P < 0.0001; I2 = 78.750%; Figure 4]).
Hypertension and ED Six studies [16,18–22] reported regarding the relationship between hypertension and ED. Although three of them [16,18,20] reported positive association between ED and hypertension, the other
WC and ED The evaluation of the relationship between WC and ED was reported in five [16,19–22] studies, and while three of them [16,20,21] found positive association, two studies [17,20] reached no signifi-
Model
Study name
Statistics for each study
Odds ratio and 95% CI
Weight (Fixed)
Odds Lower Upper ratio limit limit Z-Value p-Value Chao et al Weinberg et al Pohjantähti et al Chen et al Tevfik Demir Bal et al Lee et al Grover et al Fixed Random
8,940 2,680 4,430 1,310 1,700 1,900 1,600 1,260 1,442 2,075
4,710 1,479 1,665 1,109 0,980 1,047 1,090 1,084 1,304 1,498
16,969 4,856 11,787 1,548 2,950 3,447 2,349 1,465 1,595 2,874
6,699 3,250 2,981 3,170 1,887 2,112 2,398 3,005 7,143 4,392
Relative Relative Relative Relative weight weight weight weight
0,000 0,001 0,003 0,002 0,059 0,035 0,016 0,003 0,000 0,000
2,46 2,86 1,05 36,21 3,32 2,84 6,84 44,42
0,01
0,1 Favours A
1
10
10,55 11,18 6,83 17,02 11,80 11,17 14,28 17,16
100
Favours B
Meta Analysis Figure 3 Odds ratios and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between fasting blood sugar and erectile dysfunction in all subjects. Q = 46.118; P value for heterogeneity = P < 0.0001; I2 = 84.822%
J Sex Med **;**:**–**
6
Besiroglu et al.
Figure 4 Odds ratios and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between HT and erectile dysfunction in all subjects. Q = 23.530; P value for heterogeneity = P < 0.0001; I2 = 78.750%
cant association. Pooled analysis of these five studies revealed that the rate of ED was significantly higher in patients with higher WC levels (OR 1.71 [1.13–2.60]; P = 0.011; P value for heterogeneity P = 0.003; I2 = 74.957%; Q = 15.972, Figure 5).
Dyslipidemia and ED Six studies [16,18–22] reported about the association between trigliseride (TG) level and ED. Only two of them [16,20] reached significant association. The overall analysis of pooled data revealed that positive correlation is available between TG level and ED (OR 1.26 [1.12–1.43]; P < 0.001 P value for heterogeneity P = 0.162; I2 = 36.623%, Q = 7.889; Figure 6). Because there was no heterogeneity among the studies, a fixed effect model was used.
Six studies [16,18–22] reported about the association between HDL level and ED and only one study reached significant association [16]. Pooled analysis of these six studies showed that no association was found between HDL level and ED (OR 1.27[0.77–2.09] P = 0.33; P value for heterogeneity P < 0.0001; I2 = 86.696%, Q = 37.582; Figure 7).
Publication Bias and Sensitivity Analysis Omitting any one of the eight studies regarding MetS and ED did not produce a significant difference on the original pooled ORs. The sensitivity analysis details are depicted in Table 3. To test publication bias, we performed a Funnel plot test, and the shape of it did not reveal any evidence of funnel plot asymmetry. Additionally, the Begg and Mazumdar rank correlation test revealed that no
Figure 5 Odds ratios and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between WC and erectile dysfunction in all subjects. Q = 15.972; P value for heterogeneity P = 0.003; I2 = 74.957%
J Sex Med **;**:**–**
7
Erectile Dysfunction and Metabolic Syndrome
Figure 6 Odds ratios and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between TG and erectile dysfunction in all subjects. Q = 7.889; P value for heterogeneity P = 0.162; I2 = 36.623%
publication bias was available (P = 0.13), but we may conclude that although the result does not show publication bias, this statistical analysis should be interpreted carefully as it is close to the cutoff value of 0.05.
Discussion
We have conducted this meta-analysis so as to provide more powerful documentation for urologic research in this area with a comprehensive
Figure 7 Odds ratios and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between HDL and erectile dysfunction in all subjects. Q = 37.582; P value for heterogeneity P < 0.0001; I2 = 86.696%
Table 3 Sensitivity analysis. Studies were removed from the meta-analysis respectively and OR values and confidence intervals (CI) were calculated after removal Excluded
Random OR
95% CI
Fixed OR
95% CI
P value
Chao et al. Weinberg et al. Pohjantähti et al. Kai Chen et al. Tevfik Demir Bal et al. Lee et al. Grover et al.
2.099 2.719 2.518 3.058 2.647 2.696 2.750 3.033
1.570–2.805 1.721–4.294 1.674–3.789 1.874–4.987 1.721–4.071 1.765–4.120 1.763–4.288 1.841–4.995
1.671 1.688 1.743 1.900 1.735 1.762 1.747 2.205
1.492–1.871 1.499–1.902 1.557–1.951 1.677–2.151 1.548–1.945 1.575–1.972 1.557–1.959 1.877–2.590
The Relationship Between Metabolic Syndrome, Its Components, and Erectile Dysfunction: A Systematic Review and a Meta-Analysis of Observational Studies Huseyin Besiroglu, MD,* Alper Otunctemur, MD,* and Emin Ozbek, MD† *Department of Urology, Okmeydani Training and Research Hospital, Istanbul, Turkey; †Department of Urology, Katip Celebi University Atatürk Training and Research Hospital, Izmir, Turkey DOI: 10.1111/jsm.12885
ABSTRACT
Introduction. The studies examining the association between metabolic syndrome (MetS), its components, and erectile dysfunction (ED) should be reevaluated to arrive at comprehensive results in this field. Aim. Our aim was to gather individual studies in order to achieve a more reliable conclusion regarding the relationship between MetS, its components, and ED. Methods. Three investigators searched the Pubmed-Medline and Embase databases using the key words “metabolic syndrome” and “erectile dysfunction.” The individual studies were evaluated for selection of suitable studies. Main Outcome Measures. Eight studies that met all inclusion criteria were chosen, and a pooled analysis of odds ratio (ORs) between MetS and ED was calculated. The components of MetS to ED were also estimated. Results. Eight observational studies with a total of 12,067 participants were examined. The overall analysis revealed a 2.6-fold increase in patients with MetS having ED (2.67[1.79–3.96]; P < 0.0001). All individual components of MetS except high-density lipoprotein level were also found to correlate with an increased prevalence of ED. Of those, fasting blood sugar was detected highest rate for ED with OR of 2.07 ([1.49–2.87]; P < 0.0001). Conclusions. Metabolic syndrome is associated with a high risk rate of ED, and patients with MetS should be informed about this association and encouraged to make lifestyle modifications to improve their general health and to limit cardiovascular risk as well as ED prevalence. However, manuscripts included in meta-analysis were observational studies that prohibits ascertainment of temporal associations and necessitates further prospective studies. Besiroglu H, Otunctemur A, and Ozbek E. The relationship between metabolic syndrome, its components, and erectile dysfunction: A systematic review and a meta-analysis of observational studies. J Sex Med **;**:**–**. Key Words. Erectile Dysfunction; Meta-Analysis; Metabolic Syndrome; Observational Studies
Introduction
M
etabolic syndrome, also known as syndrome X and insulin resistance syndrome, is the term that consists of a cluster of disease statesabdominal obesity, atherogenic dyslipidemia, raised blood pressure, insulin resistance ± glucose intolerance, proinflammatory state, and prothrombotic state [1]. It is responsible for a three-fold increase in the risk of atherosclerotic cardiovascular diseases (CVDs) and also increases © 2015 International Society for Sexual Medicine
mortality from CVD, as well as all-causes, in the general population [2]. Various organizations have used different combinations of criteria for defining metabolic syndrome (International Diabetes Federation, World Health Organization, European Group for the Study of Insulin Resistance, U.S. National Cholesterol Education Program (NCEP), and American Heart Association). Waist circumference (WC) > 102 cm, triglycerides ≥ 150 mg/dL, high-density lipoprotein (HDL) cholesterol < 40 mg/dL, blood pressure ≥ J Sex Med **;**:**–**
2 130/85 mm Hg, and fasting glucose ≥ 110 mg/dL are MetS criteria according to NCEP-Adult Treatment Panel III (ATP III) [1]. The majority of the definitions are based on the individual having three or more of the aforementioned five factors. Erectile dysfunction (ED) is the consistent inability to attain and maintain an erection of the penis sufficient to permit satisfactory sexual intercourse [3]. It is a growing problem worldwide, and 30 million men are estimated to have this condition in the United States [4]. Patients with coronary artery disease have an increased incidence of ED symptoms [5,6]. The etiology of ED is multifactorial including neural, vascular, and hormonal components. A competent vascular system that provides blood supply is absolutely necessary for adequate erection. Thus, any alteration of the vascular system may lead to erectile dysfunction. Coronary artery diseases and ED share similar risk factors such as hypertension, diabetes mellitus, smoking, and hypercholesterolemia, and many of these factors are part of MetS. This has led some to propose that ED might be a good indicator for occult coronary artery disease [7]. MetS may cause ED through multiple mechanisms. All components of MetS are frequently found in the obese population. Abdominal obesity promotes insulin resistance that is associated with hyperinsulinemia and hyperglycemia. It may also lead to an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerosis [8]. MetS can also result in endothelial dysfunction, which has been implicated in vascular disorders leading to ED, and in a study conducted by Thompson et al. [9], a strong association has been indicated between elevated biomarkers of inflammation and endothelial dysfunction with increased odds of prediabetes, diabetes, and the MetS among adults in Inner Mongolia, China. Endothelial dysfunction leads to a decrease in vascular nitric oxide levels, with resulting impaired vasodilation; the increase in free radical concentration also leads to atherosclerotic damage [10]. In light of these common pathways, MetS could be a strong risk factor for ED as well as ED might be a harbinger of cardiovascular diseases. Many studies examining the prevalence of ED in patients with MetS have been conducted to date. Our aim was to gather appropriate individual studies in order to have a more robust and reliable conclusion on this issue. J Sex Med **;**:**–**
Besiroglu et al. Materials and Methods
Study Selection The PubMed-Medline and Embase databases were independently searched by three investigators to retrieve relevant studies published before February 2014. The search was restricted to English-language articles and studies of human participants. The search terms comprised of the following keywords: metabolic syndrome, erectile dysfunction. Studies were included in our metaanalysis if they met the following criteria: (i) the study design was observational; (ii) the outcome of interest was the prevalence of erectile dysfunction in patients with MetS; (iii) odds ratios (OR), and corresponding 95% confidence intervals (CIs) (or data to calculate them) were reported. Data Extraction and Quality Assessment Information extracted from an extensive review of each publication included publication data (first author’s last name, time period of the publication, and country of the population studied), type of study design, cohort size, definitions of metabolic syndrome, MetS components, definition of ED, ORs with their corresponding CIs, and all the covariates (if any) being used in the multivariate analyses and modeling. Two reviewers (H.B and A.O.) independently conducted the literature search, study selection, and data extraction, and any conflicts were resolved by the third investigator (E.O.). The quality of the studies was assessed by meta-analysis of observational studies in epidemiology guideline [11]. Statistical Analysis
Meta-analysis was performed using the fixed effects or the random effects method, depending on the absence or presence of significant heterogeneity [12]. Statistical heterogeneity among trials was assessed by using Cochran’s Q and I2 statistic, and P value < 0.05 or I2 value > 50% was considered to be heterogeneous [13]. The fixed effects method was used to combine the results when statistically significant heterogeneity was absent. When heterogeneity was confirmed, the random effects method was used. Sensitivity analysis was conducted by omitting one study at a time, generating the pooled estimates and comparing with the original estimates. Publication bias was evaluated by creating a funnel plot via each study’s effect size. The Begg and Mazumdar rank correlation test was used to evaluate publication bias [14,15].
3
The absence of OR of MetS and ED 2 article excluded Not robust statistical analysis of OR (CI) 8 articles included in meta-analysis.
Figure 1 Flow meta-analysis
diagram
of
studies
included
in
the
268 393 639 3921 54.1 ± 8.8 40–70 40–83 40–88 2005 2005 2009 2001–2002
238 3306 105 3197 >40 >20 >40 17–88
Turkey Turkey Taiwan Canada
Taiwan USA Finland China
Local aboriginal community in eastern Taiwan NHANES Hämeenlinna Metabolic Syndromresearch program The Fangchenggang Area Male Health and Examination Survey Turkish men Turkish men Free health screening 40 years or over Canadian men
2010–2011 2001–2004 2010 2009
Cohort size (n) Time period Population Country
Cross-sectional Cross-sectional Cross-sectional Cross-sectional
1 article excluded
Tevfik Demir (2006) [20] Bal et al. (2007) [21] Lee et al. (2010) [22] Grover et al. (2006) [23]
Language other than English (40)
Cross-sectional Cross-sectional Cross-sectional Cross-sectional
Nonhuman studies (31) Full text articles reviewed for more detailed evaluation (n=11)
Chao et al. (2012) [16] Weinberg et al. (2013) [17] Pohjantähti et al. (2011) [18] Chen et al. (2012) [19]
Outcomes not relevant (n=120)
Study design
Reviews (n=108)
Authors (publication year)
299 articles excluded;
Relevant studies of the relationship between metabolic syndrome and erectile dysfunction
Potentially relevant publications identified from literature (n=310)
Table 1
Literature Search and Study Characteristics We initially identified 310 studies, either in full publications or abstract forms, using the methodology and the search terms described above. After title and abstract review; 299 articles were removed. Of these, 108 were reviews, 31 were not human studies, 40 had language other than English, and 120 had outcomes not relevant to the subject. Eleven publications were considered to be relevant to our study subject. Of these, three were excluded due to deficiencies for further inclusion criteria. Finally, eight studies were included in our meta-analysis. The details of the literature search are depicted in Figure 1. The eight selected studies [16–23] contained 12,067 participants (ranging from 105 to 3,921). They were published between 2006 and 2013. The detailed characteristics of included studies are presented in Table 1. Four studies used the NCEPATP III, one study used modified Asians NCEPATP III criteria, one study used NCEP-ATP III criteria modified for Asian Americans, one study used the American Heart Association/National Heart, Lung, and Blood Institute criteria, and one
Age, year (range or mean ± SD)
Results
MetS = metabolic syndrome; SD = standard deviation; HDL = high-density lipoprotein; OR = odds ratio; RR = risk ratio; CI = confidence interval; NCEP-ATP-III = National Cholesterol Education Program Adult Treatment Panel III; NHANES III = Third National Health Center Nutrition Examination Survey; AHA/NHLBI = American Heart Association/National Heart, Lung, and Blood Institute
95% CI
1.7–5.0 1.1–5.7 1.44–3.69 1.24–1.69 2.9 2.5 2.30 1.45 OR OR OR OR
12.02 2.55 4.62 1.34
Adjusted RRs
OR OR OR OR
The results were considered statistically significant for P < 0.05. All statistical comparisons were two sided, and P value < 0.05 was considered statistically significant. All analyses were performed using Comprehensive Meta-analysis Version.2 (Biostat, Englewood, NJ, USA).
6.33–22.83 1.85–3.5 2.005–10.623 1.04–1.72
Erectile Dysfunction and Metabolic Syndrome
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4 Table 2
Besiroglu et al. The definitions of Mets, its components, and erectile dysfunction of the studies included in meta-analysis Erectile dysfunction definition
MetS definition
MetS components criteria Fasting plasma glucose ≥110 mg/dL Serum TG ≥ 150 mg/dL Serum HDL-C < 40 mg/dL Blood pressure ≥130/85 mm Hg Waist circumference >90 cm Fasting plasma glucose > 100 mg/dL Serum TG > 150 mg/dL Serum HDL-C < 40 mg/dL Blood pressure >130/85 mm Hg Waist circumference >102 cm Fasting plasma glucose ≥ 110 mg/dL Serum TG ≥ 150 mg/dL Serum HDL-C < 40 mg/dL Blood pressure >130/85 mm Hg Waist circumference >102 cm Fasting plasma glucose ≥5.6 mmol/L Serum TG ≥ 150 mg/dL Serum HDL-C < 1.03 mmol/L Blood pressure ≥130/85 mm Hg Waist circumference >90 cm Fasting plasma glucose ≥ 110 mg/dL Serum TG ≥ 150mg/dl Serum HDL-C < 40mgdl Blood pressure ≥130/85 mm Hg Waist circumference >102 cm Fasting plasma glucose ≥ 110 mg/dL Serum TG > 150 mg/dL Serum HDL-C < 40 mg/dL Blood pressure ≥130/85 mm Hg Waist circumference >10 cm Fasting plasma glucose ≥ 100 mg/dL Serum TG > 150 mg/dL Serum HDL-C < 40 mg/dL Blood pressure >130/85 mm Hg Waist circumference >90 cm Fasting plasma glucose ≥ 111 mg/dL Serum TG ≥ 150 mg/dL Serum HDL-C < 40 mg/dL Blood pressure ≥130/85 mm Hg Body mass index (BMI) ≥ 28
Chao et al.
IIEF-5
NCEP-ATP III modified for Asians
Weinberg et al.
Single question self-report
AHA/NHLBI
Pohjantähti et al.
IIEF-15
NCEP-ATP III
Kai Chen et al.
IIEF-5
NCEP-ATP III for Asian Americans
Tevfik Demir
IIEF-15
NCEP-ATP III
Bal et al.
IIEF-15
NCEP-ATP III
Lee et al.
IIEF-5
Modified criteria developed by the Bureau of Health Promotion in Taiwan
Grover et al.
IIEF-15
NCEP-ATP III
P value to determine statistical significance P < 0.05
P < 0.05
P < 0.05
P < 0.05
P < 0.05
P < 0.05
P < 0.05
P < 0.05
MetS = metabolic syndrome; IIEF = International Index of Erectile Function; NCEP-ATP-III = National Cholesterol Education Program Adult Treatment Panel III; AHA/NHLBI = American Heart Association/National Heart, Lung, and Blood Institute; TG = trigliseride; HDL = high-density lipoprotein
study used modified criteria developed by the Bureau of Health Promotion in Taiwan. The seven studies used International Index of Erectile Function assessments to confirm the diagnosis of ED, whereas Weinberg et al. used a single question self-report that was validated by O’Donnell et al. [24]. The detailed information regarding MetS, its components, and ED definition criteria were demonstrated in Table 2.
Overall Analysis of Pooled Data The relationship between MetS and ED was examined in eight studies [16–23]. All studies reported a positive association between ED and MetS (OR ranged from 1.34 to 12.02). The pooled analysis of OR of eight individual studies J Sex Med **;**:**–**
revealed that patients with MetS had a higher overall adjusted risk of ED (2.671[1.797–3.969], Q = 60.329; p value for heterogeneity = P < 0.0001; I2 = 88.397%; Figure 2]). Because there was heterogeneity among the studies, a random effect model was used.
MetS Components and ED Fasting Blood Sugar and ED The evaluation of the relationship between fasting blood sugar and ED was reported in eight studies [16–23] and seven of them reported a significantly higher rate of ED (OR ranged from 1.26 to 8.94) in patients with elevated fasting blood sugar. Only one study [19] reached no statistically significant association (OR 1.7 [0.98–2.95] P = 0.059). Pooled
5
Erectile Dysfunction and Metabolic Syndrome Model Study name
Statistics for each study
Odds ratio and 95% CI
Weight (Fixed)
Odds Lower Upper ratio limit limit Z-Value p-Value Chao et al. Weinberg et al. Pohjantähti et al. Kai Chen et al. Tevfik Demir Bal et al. Yung-Chin Lee et al. Grover et al. Fixed Rando
12,020 2,550 4,620 1,340 2,900 2,500 2,300 1,450 1,775 2,671
6,329 22,827 7,599 1,849 3,517 5,704 2,007 10,634 3,598 1,042 1,723 2,280 1,691 4,973 3,869 1,098 5,691 2,183 1,437 3,682 3,470 1,242 1,693 4,704 1,588 1,985 10,093 1,797 3,969 4,860
Relative Relative Relative Relative weight weight weight weight
0,000 0,000 0,000 0,023 0,000 0,029 0,001 0,000 0,000 0,000
3,02 12,01 1,79 19,63 4,27 1,84 5,61 51,84
0,01
0,1
1
Favours A
10
11,21 14,3 7 9,32 14,92 12,27 9,43 12,97 15,50
100
Favours B
Meta Analysis Figure 2 Odds ratios and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between metabolic syndrome and erectile dysfunction in all subjects. Q = 60.329; P value for heterogeneity = P < 0.0001; I2 = 88.397%
analysis of these eight studies showed that the rate of ED was significantly higher in patients with enhanced fasting blood sugar and there was heterogeneity among the studies (OR 2.07[1.49–2.87], P < 0.001; P value for heterogeneity = p < 0.0001; Q = 46.118; I2 = 84.822%; Figure 3).
three studies [19,21,22] did not. The pooled analysis of all these studies revealed that patients with hypertension had a higher overall adjusted risk of ED, and there was heterogeneity among the studies (OR 1.53[1.09–2.159; P = 0.01 Q = 23.530; P value for heterogeneity = P < 0.0001; I2 = 78.750%; Figure 4]).
Hypertension and ED Six studies [16,18–22] reported regarding the relationship between hypertension and ED. Although three of them [16,18,20] reported positive association between ED and hypertension, the other
WC and ED The evaluation of the relationship between WC and ED was reported in five [16,19–22] studies, and while three of them [16,20,21] found positive association, two studies [17,20] reached no signifi-
Model
Study name
Statistics for each study
Odds ratio and 95% CI
Weight (Fixed)
Odds Lower Upper ratio limit limit Z-Value p-Value Chao et al Weinberg et al Pohjantähti et al Chen et al Tevfik Demir Bal et al Lee et al Grover et al Fixed Random
8,940 2,680 4,430 1,310 1,700 1,900 1,600 1,260 1,442 2,075
4,710 1,479 1,665 1,109 0,980 1,047 1,090 1,084 1,304 1,498
16,969 4,856 11,787 1,548 2,950 3,447 2,349 1,465 1,595 2,874
6,699 3,250 2,981 3,170 1,887 2,112 2,398 3,005 7,143 4,392
Relative Relative Relative Relative weight weight weight weight
0,000 0,001 0,003 0,002 0,059 0,035 0,016 0,003 0,000 0,000
2,46 2,86 1,05 36,21 3,32 2,84 6,84 44,42
0,01
0,1 Favours A
1
10
10,55 11,18 6,83 17,02 11,80 11,17 14,28 17,16
100
Favours B
Meta Analysis Figure 3 Odds ratios and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between fasting blood sugar and erectile dysfunction in all subjects. Q = 46.118; P value for heterogeneity = P < 0.0001; I2 = 84.822%
J Sex Med **;**:**–**
6
Besiroglu et al.
Figure 4 Odds ratios and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between HT and erectile dysfunction in all subjects. Q = 23.530; P value for heterogeneity = P < 0.0001; I2 = 78.750%
cant association. Pooled analysis of these five studies revealed that the rate of ED was significantly higher in patients with higher WC levels (OR 1.71 [1.13–2.60]; P = 0.011; P value for heterogeneity P = 0.003; I2 = 74.957%; Q = 15.972, Figure 5).
Dyslipidemia and ED Six studies [16,18–22] reported about the association between trigliseride (TG) level and ED. Only two of them [16,20] reached significant association. The overall analysis of pooled data revealed that positive correlation is available between TG level and ED (OR 1.26 [1.12–1.43]; P < 0.001 P value for heterogeneity P = 0.162; I2 = 36.623%, Q = 7.889; Figure 6). Because there was no heterogeneity among the studies, a fixed effect model was used.
Six studies [16,18–22] reported about the association between HDL level and ED and only one study reached significant association [16]. Pooled analysis of these six studies showed that no association was found between HDL level and ED (OR 1.27[0.77–2.09] P = 0.33; P value for heterogeneity P < 0.0001; I2 = 86.696%, Q = 37.582; Figure 7).
Publication Bias and Sensitivity Analysis Omitting any one of the eight studies regarding MetS and ED did not produce a significant difference on the original pooled ORs. The sensitivity analysis details are depicted in Table 3. To test publication bias, we performed a Funnel plot test, and the shape of it did not reveal any evidence of funnel plot asymmetry. Additionally, the Begg and Mazumdar rank correlation test revealed that no
Figure 5 Odds ratios and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between WC and erectile dysfunction in all subjects. Q = 15.972; P value for heterogeneity P = 0.003; I2 = 74.957%
J Sex Med **;**:**–**
7
Erectile Dysfunction and Metabolic Syndrome
Figure 6 Odds ratios and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between TG and erectile dysfunction in all subjects. Q = 7.889; P value for heterogeneity P = 0.162; I2 = 36.623%
publication bias was available (P = 0.13), but we may conclude that although the result does not show publication bias, this statistical analysis should be interpreted carefully as it is close to the cutoff value of 0.05.
Discussion
We have conducted this meta-analysis so as to provide more powerful documentation for urologic research in this area with a comprehensive
Figure 7 Odds ratios and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between HDL and erectile dysfunction in all subjects. Q = 37.582; P value for heterogeneity P < 0.0001; I2 = 86.696%
Table 3 Sensitivity analysis. Studies were removed from the meta-analysis respectively and OR values and confidence intervals (CI) were calculated after removal Excluded
Random OR
95% CI
Fixed OR
95% CI
P value
Chao et al. Weinberg et al. Pohjantähti et al. Kai Chen et al. Tevfik Demir Bal et al. Lee et al. Grover et al.
2.099 2.719 2.518 3.058 2.647 2.696 2.750 3.033
1.570–2.805 1.721–4.294 1.674–3.789 1.874–4.987 1.721–4.071 1.765–4.120 1.763–4.288 1.841–4.995
1.671 1.688 1.743 1.900 1.735 1.762 1.747 2.205
1.492–1.871 1.499–1.902 1.557–1.951 1.677–2.151 1.548–1.945 1.575–1.972 1.557–1.959 1.877–2.590
