ASSOCIATION AMONG METABOLIC SYNDROME, TESTOSTERONE LEVEL AND SEVERITY OF ERECTILE DYSFUNCTION

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1 ASSOCIATION AMONG METABOLIC SYNDROME, TESTOSTERONE LEVEL AND SEVERITY OF ERECTILE DYSFUNCTION Hsin-Chih Yeh, 1 Chii-Jye Wang, 1,2 Yung-Chin Lee, 1 Hsi-Lin Hsiao, 1 Wen-Jeng Wu, 1,2 Yii-Her Chou, 1,2 and Chun-Hsiung Huang 1,2 1 Department of Urology, Kaohsiung Medical University Hospital, and 2 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. The purpose of this study was to determine the influence of metabolic syndrome (MS) and serum testosterone in patients with erectile dysfunction (ED) and their possible association. A total of 103 men with ED were enrolled. The International Index of Erectile Function (IIEF) questionnaire was used to assess erectile condition. MS was defined according to the criteria formulated by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and the International Diabetes Federation (IDF). The mean age of the study population was 57.5 ± 10.7 years, with an average IIEF of 14.7 ± 6.7. The age and prevalence of MS using the NCEP ATP III criteria, but not the IDF criteria, were significantly different between mild and moderate/severe ED patients (p = and 0.009, respectively). The percentage of hypertension (78.6% vs. 36.2%; p < 0.001) and raised fasting glucose levels (46.4% vs. 19.1%; p = 0.004) were significantly higher in the moderate/severe ED group, and both differences remained significant in multivariate analysis (p = and 0.042, respectively). In addition, serum testosterone levels were significantly lower in ED patients with MS (p = 0.002). In summary, the presence of MS is associated with more severe ED. Among the components of MS, elevated blood pressure and fasting blood glucose were independent risk factors. NCEP ATP III criteria seem to correlate better with the degree of ED than the IDF definition. Our results also indicate that MS is associated with a lower testosterone level in patients with ED. Key Words: erectile dysfunction, metabolic syndrome, testosterone (Kaohsiung J Med Sci 2008;24:240 7) Erectile dysfunction (ED) is the consistent inability to achieve or maintain an erection that is sufficient for satisfactory sexual intercourse. This disorder can be detected clinically using the International Index of Erectile Function (IIEF) questionnaire, which has been 240 Received: Sep 11, 2007 Accepted: Oct 19, 2007 Address correspondence and reprint requests to: Dr Chii-Jye Wang, Department of Urology, Kaohsiung Medical University Hospital, 100 Shih-Chuan 1 st Road, Kaohsiung 807, Taiwan. urology@kmu.edu.tw extensively used and verified in over 60 different languages. Nowadays, ED is increasingly recognized as a public health problem, estimated to affect approximately 150 million men worldwide [1,2]. Metabolic syndrome (MS) is a cluster of vascular risk factors that are independently associated with type II diabetes and cardiovascular diseases [3 5]. The constituents of MS include central obesity, dyslipidemia, hypertension and glucose intolerance. The syndrome is remarkably common, affecting about 24% of American adults who are years of age [6]. The prevalence is expected to rise further as populations Kaohsiung J Med Sci May 2008 Vol 24 No Elsevier. All rights reserved.

2 Metabolic syndrome, testosterone level and ED severity lead sedentary lifestyles and become more obese. The existence of MS can possibly aggravate the degree of ED by compromising penile vascular function [7,8]. Testosterone plays a role in the maintenance of male erectile function. Low testosterone levels are an endocrine factor that may contribute to ED [9]. The concept that MS is associated with male hypogonadism has recently emerged [10,11]. Consequently, the correlation among MS, serum testosterone levels and ED severity is receiving increased attention. Although studies are appearing for Caucasian men, there are limited data for Asian males. The aim of the present study was to determine the effect of MS and serum testosterone in patients with ED and the relationships among them in a Taiwanese population. MATERIALS AND METHODS From November 2005 to July 2006, 103 men with ED who attended Kaohsiung Medical University Hospital and Kaohsiung Municipal Hsiao-Kang Hospital were enrolled. The Institutional Review Board of our hospital approved the study. All of the men gave informed consent to participate and had demographic data collected, complete medical, surgical and psychosexual histories taken, and underwent detailed physical examination and laboratory tests. Patients were interviewed for ED using the IIEF questionnaire. The erectile function domain consists of questions 1 to 5 and question 15 for assessing the global erectile function [12]. Scoring of the IIEF allowed classification of each patient as having no (26 30), mild (17 25), moderate (11 16) or severe (0 10) ED. Blood samples were drawn between 8:00 and 11:00 AM for biochemical and hormone analysis. Body weight (kg) and height (cm) were measured and the body mass index (BMI) was calculated and recorded. Waist circumference was measured at the level of the umbilicus while the patient breathed normally. MS was defined using the consensus report of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) [13]. According to NCEP ATP III, MS is the presence of at least three of the following: abdominal obesity (waist circumference > 102 cm), hypertension (blood pressure 130/85 mmhg), hyperglycemia (fasting blood glucose 110 mg/dl), hypertriglyceridemia ( 150 mg/dl), and reduced highdensity lipoprotein (HDL) cholesterol (< 40 mg/dl). Another definition of MS, using the International Diabetes Federation (IDF) criteria [14], was also assessed in this study. Patients were defined as having MS by central obesity (waist circumference 90 cm in Chinese men) plus two of any of the following: blood pressure 130/85 mmhg, fasting plasma glucose 100 mg/dl, serum triglyceride 150 mg/dl, and HDL cholesterol < 40 mg/dl. A smoker was defined as a person who smoked 10 cigarettes/day and had done so for more than 6 months and a drinker was defined as someone who consumed alcohol every week and had done so for 6 consecutive months. Patients with penile anatomic abnormalities such as Peyronie s disease, congenital curvature or hypospadias, neuropathic changes of the penis resulting from radical pelvic surgery or spinal cord injury, primary hypoactive sexual desire, major psychiatric illness or drug abuse were excluded. Results were expressed as mean ± standard deviation and range. The values of clinical variables were compared using χ 2 test, independent Student s t test, and Pearson s correlation. Multiple logistic regression analysis was used to determine the independent factors influencing the severity of ED. A two-tailed p value < 0.05 was considered to be statistically significant. RESULTS The mean age of the study population was 57.5 ± 10.7 years (range, years), with an average IIEF of 14.7 ± 6.7 (range, 1 25). Mean total testosterone level was ± ng/dl (range, ng/dl). The degree of ED was categorized as mild (n = 47), moderate (n = 27) and severe (n = 29) according to the IIEF erectile function domain scores (Table 1). MS was diagnosed in 37% and 32% of the participants using NCEP ATP III and IDF criteria, respectively. χ 2 analysis revealed significant differences in the percentage of MS between groups stratified by ED severity when utilizing NCEP ATP III criteria (p = 0.019) compared to the IDF definition (p = 0.089). Parameters between the mild and moderate/ severe ED groups were analyzed (Table 2). Patients with moderate to severe ED were significantly older than those with mild ED (59.6 ± 11.0 years vs ± 9.7 years; p = 0.031), and they also showed a higher prevalence of MS according to NCEP ATP III criteria (48.2% vs. 23.4%; p = 0.009). Total testosterone Kaohsiung J Med Sci May 2008 Vol 24 No 5 241

3 H.C. Yeh, C.J. Wang, Y.C. Lee, et al Table 1. Association between metabolic syndrome (MS) and severity of erectile dysfunction (ED)* Severity of ED Mild (n = 47) Moderate (n = 27) Severe (n = 29) Total (n = 103) MS (NCEP ATP III) Yes 11 (23.4) 15 (55.6) 12 (41.4) 38 (36.9) No 36 (76.6) 12 (44.4) 17 (58.6) 65 (63.1) MS (IDF) Yes 11 (23.4) 13 (48.1) 9 (31.0) 33 (32.0) No 36 (76.6) 14 (51.9) 20 (69.0) 70 (68.0) *Data presented as n (%); p < NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III; IDF = International Diabetes Federation. p Table 2. Univariate analysis of the association between qualitative/quantitative variables and the severity of erectile dysfunction (ED)* Mild ED (n = 47) Moderate/severe ED (n = 56) p Smoking Yes 16 (34.0) 17 (30.4) No 31 (66.0) 39 (69.6) Drinking Yes 10 (21.3) 16 (28.6) No 37 (78.7) 56 (71.4) MS (NCEP ATP III) Yes 11 (23.4) 27 (48.2) No 36 (76.6) 29 (51.8) MS (IDF) Yes 11 (23.4) 22 (39.3) No 36 (76.6) 34 (60.7) Age (yr) 55.0 ± ± Testosterone (ng/dl) ± ± BMI (kg/m 2 ) 24.9 ± ± IPSS 6.5 ± ± PSA (ng/ml) 1.6 ± ± *Data presented as n (%) or mean ± standard deviation; p < MS = metabolic syndrome; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III; IDF = International Diabetes Federation; BMI = body mass index; IPSS = International Prostate Symptom Score; PSA = prostate specific antigen. level was lower in the moderate/severe ED group compared to the mild ED group (p = 0.059). There were no statistically significant differences between the two groups with regard to MS as defined by IDF criteria, BMI, International Prostate Symptom Scores, prostate specific antigen, cigarette smoking, and alcohol consumption. The components of the NCEP ATP III criteria were further studied (Table 3). In moderate/severe ED patients, 44 (78.6%) had raised blood pressure and 26 (46.4%) had raised fasting glucose. In contrast, in the 242 mild ED group, only 17 (36.2%) had raised blood pressure and nine (19.1%) had raised fasting blood glucose. Both hypertension and hyperglycemia were significantly different between the two groups (p < and p = 0.004, respectively). By means of logistic regression analysis, the two components were identified as independent risk factors for more severe ED (p = and 0.042, respectively). Adjusted odds ratios (OR) were 5.5 (95% confidence interval [CI], ) for elevated blood pressure and 2.9 (95% CI, ) for elevated fasting glucose. Kaohsiung J Med Sci May 2008 Vol 24 No 5

4 Metabolic syndrome, testosterone level and ED severity Table 3. Relationship between each component of the metabolic syndrome (as defined by National Cholesterol Education Program Adult Treatment Panel III criteria) and severity of erectile dysfunction (ED)* Mild ED (n = 47) Moderate/severe ED (n = 56) p Raised blood pressure < Yes 17 (36.2) 44 (78.6) No 30 (63.8) 12 (21.4) Raised fasting glucose Yes 9 (19.1) 26 (46.4) No 38 (80.9) 30 (53.6) Raised waist circumference Yes 2 (4.3) 2 (3.6) No 45 (95.7) 54 (96.4) Reduced HDL cholesterol Yes 34 (72.3) 43 (76.7) No 13 (27.7) 13 (23.3) Raised triglyceride Yes 13 (27.7) 21 (37.5) No 34 (72.3) 35 (62.5) *Data presented as n (%); p < HDL = high-density lipoprotein. Patients divided into two groups according to the presence of MS were also analyzed (Table 4). ED was significantly more severe in patients with MS defined by NCEP ATP III criteria (IIEF = 12.7 ± 5.7 vs ± 7.0; p = 0.022). There was still no significant difference with the IDF definition. In ED patients with MS, BMI was significantly higher and serum testosterone was significantly lower compared to ED patients without MS (p = and 0.002, respectively). The association was the same when using the IDF definition. Finally, total testosterone levels were significantly inversely correlated with BMI (r = 0.354, p = ) and waist circumference (r = 0.226, p = 0.022), but the correlation with age was insignificant (p = 0.493). DISCUSSION MS is traditionally used to identify individuals who have increased metabolic and atherosclerotic risk. Men with MS have a two- to fourfold increased risk of cardiovascular disease [4,5]. Using NCEP ATP III criteria, we found that MS is a rather common condition in patients with ED, with an incidence of 37%, similar to the results of Bansal et al [15]. The incidence of MS in patients with moderate-to-severe ED was even higher, at nearly half of the studied population (48.2%). The result consolidates the idea that a routine survey for MS in patients with ED can be feasible and effective in detecting cardiovascular risk markers. Several studies have demonstrated the strong association between ED and MS [7,15 17]. Seftel et al concluded that ED shared common risk factors with cardiovascular diseases [16]. Esposito et al reported that men with MS had an increased prevalence of ED [7]. Demir et al stated that MS has to be accepted as a new risk factor for ED [17]. In our patients with ED, those with MS were characterized by worse erectile function (IIEF = 12.7 ± 5.7 in patients with MS vs ± 7.0 in patients without MS; p = 0.022). Namely, there is a significant association between severity of ED and MS. MS is a constellation of cardiovascular risk factors that are related to endothelial dysfunction [8,18]. Penile erection essentially relies on the release of nitric oxide (NO) by endothelial cells [19]. Accordingly, the association between ED and MS is supposed to result from endothelial dysfunction [7,8,19,20]. Of note, both endothelial and ED were responsive to a weight loss and exercise program [21]. Correction of multiple metabolic abnormalities, particularly with lifestyle changes, is required to improve both conditions [21,22]. Increased awareness is needed, especially when many of the components of MS are not considered to be diseases by the general population. In 2005, the IDF formulated a substantial revision of earlier MS criteria [14]. The characteristics of the Kaohsiung J Med Sci May 2008 Vol 24 No 5 243

5 H.C. Yeh, C.J. Wang, Y.C. Lee, et al Table 4. Univariate analysis of the association between qualitative/quantitative variables and metabolic syndrome (MS) in patients with erectile dysfunction* Patients with MS (n = 38) Patients without MS (n = 65) p Smoking Yes 9 (23.7) 24 (36.9) No 29 (76.3) 41 (63.1) Drinking Yes 12 (31.6) 14 (21.5) No 26 (68.4) 51 (78.5) Age (yr) 59.5 ± ± Testosterone (ng/dl) ± ± BMI (kg/m 2 ) 25.9 ± ± IPSS 6.3 ± ± PSA (ng/ml) 1.4 ± ± IIEF 12.7 ± ± *Data presented as n (%) or mean ± standard deviation; defined by National Cholesterol Education Program Adult Treatment Panel III; p < BMI = body mass index; IPSS = International Prostate Symptom Score; PSA = prostate specific antigen; IIEF = International Index of Erectile Function. IDF definition are indispensability of central obesity, ethnicity-specific values of waist circumference, and lowering diagnostic cutoff values for fasting plasma glucose. However, in our study, the IDF criteria failed to reveal a significant association between MS and severity of ED (p=0.085). NCEP ATP III criteria seemed to be a more sensitive indicator of MS and a better predictor of ED severity than the IDF definition. The essential, not optional, composition of visceral obesity in the IDF guidelines may miss some patients who are relatively lean. We further investigated the relationship between the components of MS and ED severity, and found that hypertension and glucose intolerance are the key elements that exacerbated the degree of ED. The ageadjusted OR of elevated blood pressure and fasting blood glucose were 5.5 and 2.9 for a more severe ED, respectively. Observational studies have described the association between both conditions and ED [23 28]. In a large database of 272,325 patients with ED, 42% had hypertension and 20% had diabetes [16]. In a survey of 7,689 men, Giuliano et al reported that 67%, 71%, and 77% of patients with hypertension alone, diabetes alone, and both diseases, respectively, had ED [28]. They concluded that patients with hypertension and/or diabetes have a high prevalence of bothersome, untreated ED. 244 ED is not an unusual complication in patients with diabetes, which is attributed to autonomic neuropathy and peripheral vascular disease [27]. Hyperglycemia activates various molecular pathways, such as decreased endothelial NO synthase (enos) expression, reduced bioavailability of enos cofactor tetrahydrobiopterin, impaired enos phosphorylation, activated oxidative stress, and heightened vasoconstriction, resulting in endothelial injury [29]. An increased incidence of ED in hypertensive men has also been well established in previous studies [23,24,28]. Both endothelial and non-endothelium-dependent impairment of vasodilatation contributes to ED in hypertensive patients [30]. A hypertensive state and poor blood glucose control may lead to more severe ED through affecting the penile vascular bed. A reduction in total testosterone level is a consequence of male aging, and is estimated to occur at a rate of 1% reduction annually after the third decade of life [31]. However, the magnitude of the decrease does not vary significantly with age. This was also found in our study. Recently, it has been recognized that a low testosterone level is associated with obesity and MS [10,11,32,33]. Tsai et al reported that low testosterone is a predictor of increased visceral fat [32]. In a review of world literature from 1988 to 2004, Makhsida et al found that MS is strongly associated Kaohsiung J Med Sci May 2008 Vol 24 No 5

6 Metabolic syndrome, testosterone level and ED severity with hypogonadism in men [11]. They suggested that hypogonadism is likely to be a fundamental component of MS. Kaplan et al indicated that the combination of obesity and MS has a major exacerbating impact on the age-related decrease in testosterone levels [33]. Our results showed that total testosterone level is significantly lower in patients with MS and is inversely correlated with BMI and waist circumference (whether ATP III or IDF criteria), supporting their relation in ED patients. It is not well understood whether hypotestosteronemia causes MS or vice versa. Testosterone inhibits the differentiation of preadipocytes into mature adipocytes via androgen receptors, which are more abundant in visceral adipocytes [34]. Furthermore, testosterone can improve insulin sensitivity via a reduction in circulating non-esterified fatty acids by inhibiting lipoprotein lipase activity [35]. Therefore, a low testosterone level may lead to central obesity, insulin resistance and MS. On the contrary, adipose tissue produces more leptin and aromatase, resulting in reduced testosterone production and increased estradiol conversion [11]. The hyperinsulinemia of MS may lead to androgen decline by inhibiting sex hormone-binding globulin [36]. This explains why obese or metabolically abnormal men have lower testosterone levels [33,37]. In any case, there is increasing evidence of the beneficial role that androgen replacement therapy plays in decreasing the risk of MS and associated cardiovascular morbidities [38]. In conclusion, the presence of MS is associated with more severe ED. Among the elements of MS, those that are independently associated with ED severity are hypertension and raised fasting blood glucose. Recognizing ED that is complicated by MS can help physicians to identify individuals who are candidates for lifestyle modification and appropriate treatment of underlying cardiovascular risk factors. NCEP ATP III criteria appear to correlate better with the degree of ED than IDF criteria. Nevertheless, both definitions of MS are inversely correlated with serum testosterone levels, and future studies are needed to explain the underlying mechanism. REFERENCES 1. Lue TF. Erectile dysfunction. N Engl J Med 2000;342: Meuleman EJ. Prevalence of erectile dysfunction: need for treatment? Int J Impot Res 2002;14:S Lorenzo C, Okoloise M, Williams K, et al. The metabolic syndrome as predictor of type 2 diabetes: the San Antonio heart study. Diabetes Care 2003;26: Wilson PW, Kannel WB, Silbershatz H, et al. Clustering of metabolic factors and coronary heart disease. Arch Intern Med 1999;159: Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288: Meigs JB. Epidemiology of the metabolic syndrome, Am J Manag Care 2002;8:S Esposito K, Giugliano F, Martedi E, et al. High proportions of erectile dysfunction in men with the metabolic syndrome. Diabetes Care 2005;28: Solomon H, Man JW, Jackson G. Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. Heart 2003;89: Foresta C, Caretta N, Rossato M, et al. Role of androgens in erectile function. J Urol 2004;171: Laaksonen DE, Niskanen L, Punnonen K, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol 2003;149: Makhsida N, Shah J, Yan G, et al. Hypogonadism and metabolic syndrome: implications for testosterone therapy. J Urol 2005;174: Rosen RC, Riley A, Wagner G, et al. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49: Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285: Alberti KG, Zimmet P, Shaw J, et al. The metabolic syndrome a new worldwide definition. Lancet 2005;366: Bansal TC, Guay AT, Jacobson J, et al. Incidence of metabolic syndrome and insulin resistance in a population with organic erectile dysfunction. J Sex Med 2005; 2: Seftel AD, Sun P, Swindle R. The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in men with erectile dysfunction. J Urol 2004;171: Demir T, Demir O, Kefi A, et al. Prevalence of erectile dysfunction in patients with metabolic syndrome. Int J Urol 2006;13: Brunner H, Cockcroft JR, Deanfield J, et al. Endothelial function and dysfunction. Part II: association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens 2005;23: Maas R, Schwedhelm E, Albsmeier J, et al. The pathophysiology of erectile dysfunction related to endothelial Kaohsiung J Med Sci May 2008 Vol 24 No 5 245

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