http://informahealthcare.com/tam ISSN: 1368-5538 (print), 1473-0790 (electronic) Aging Male, 2014; 17(2): 76–80 ! 2014 Informa UK Ltd. DOI: 10.3109/13685538.2014.895318
ORIGINAL ARTICLE
The impact of metabolic syndrome on serum total testosterone level in patients with erectile dysfunction Yilmaz Aslan1, Ozer Guzel1, Melih Balci1, Altug Tuncel1, Muslum Yildiz1, and Ali Atan2 Department of Urology, Ankara Numune Research and Training Hospital, Ministry of Health, Ankara, Turkey and 2Department of Urology, School of Medicine, Gazi University, Ankara, Turkey
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1
Abstract
Keywords
Objectives: To determine the association between metabolic syndrome (MetS) and serum testosterone levels (TT) in patients with erectile dysfunction (ED). Methods: This study included 280 ED patients above 40-years-of-age. Participants were divided into two groups according to 2005 criteria of International Diabetes Federation. The severity of ED was determined according to the International Index of Erectile Function-EF (IIEF-EF score; 0–10 severe ED, 11–25 mild to moderate ED). The severity of ED, serum TT levels and other MetS components were compared between the groups. Results: The mean age of the patients was 55.7 ± 8.2 years. One hundred eighteen patients (%42.1) had MetS. Sixty-eight patients with MetS (57.6%) and 71 patients without MetS (43.8%) had severe ED (p ¼ 0.031). A total of 46 (16.4%) patients had hypogonadism. Hypogonadism was seen more prevalent in patients with MetS (22.9% vs. 11.7%, p ¼ 0.013). Logistic regression analyses for ED risk factors demonstrated that abnormal FBG increased the relative risk of severe ED up to 10.7-fold (p50.001) but not presence of hypogonadism (p ¼ 0.706). Conclusion: Metabolic syndrome was seen in almost half of the patients with ED. ED was more severe among MetS patients. Hypogonadism alone is a not risk factor for severe ED.
Erectile dysfunction, hypogonadism, male, metabolic syndrome, testosterone
Introduction Erectile dysfunction (ED) is the inability of men to achieve or maintain a sufficient penile erection to permit satisfactory sexual intercourse [1]. ED is known as a common disorder among men, it worsens the quality of life, and it is seen more frequently in older ages. Its prevalence was reported as 5–10% and 40–60% in 40–years-old and 70 years-old men, respectively [2]. Common risk factors of ED are aging, comorbid conditions, certain medications, obesity, alcohvol and tobacco use [3,4]. Nowadays the Metabolic Syndrome (MetS) is approved important risk factor for ED. Syndrome X, Insulin-Resistance Syndrome or the MetS is a concurrence of some cardiovascular risk factors such as insulin resistance (type 2 diabetes mellitus (T2DM) and/or glucose intolerance), abdominal obesity, dyslipidemia and hypertension (HT) [5–7]. The relationships between these two disorders are mainly associated with common risk factors. Many previous studies focused on the association of ED and MetS [8,9]. MetS patients have increased risk for hypogonadism [10,11]. Correspondence: Yilmaz Aslan, M.D, Ministry of Health, Ankara Numune Research and Training. Hospital, Third Department of Urology, 06120, Sihhiye, Ankara, Turkey. Tel : +90 505 486 22 99. Fax: +90 312 310 34 60. E-mail: [email protected]
History Received 25 November 2013 Revised 3 February 2014 Accepted 13 February 2014 Published online 27 February 2014
In current literature, the prevalance of MetS and relationship between testosterone levels has been less commonly investigated in patients with ED [12,13]. In this study, we investigated the prevalance of MetS and a possible association between MetS and serum testosterone levels in patients with ED.
Methods Two-hundred eighty patients with ED between 40 to 80 years were included in this study. The age, waist circumference (WC), body mass index (BMI), waist-hip ratio (WHR), smoking habits, the presence of T2DM and HT were recorded. WC was measured at the level of the umbilicus while the patient breathed normally and the WHR was defined as the ratio of waist girth to the circumference of the hips. BMI was computed as the ratio of weight to the square of height (kg/m2). The 8-hour plasma levels of the fasting blood glucose (FBG), high-density lipoprotein (HDL), triglyceride (TG), total cholesterol, serum total testosterone (TT) level were measured. Men with serum TT5300 ng/dl were considered hypogonadal. [11] Patients with liver or kidney function failure, trauma and/or surgery in pelvis, urinary malignancy, peripheral or autonomous neuropathy, and cardiovascular disease, drug use for ED (PDE5i, testosterone replacement), use of 5-alpha
Metabolic Syndrome
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DOI: 10.3109/13685538.2014.895318
reductase inhibitors, psychiatric disorders or alcohol abuse were excluded from the study.
Table 1. Principal characteristics of the study population.
Patient assessment
Age WC (cm) FBG (mg/dL) BMI (kg/m2) WHR (cm) HDL (mg/dL) TG (mg/dL) Systolic BP (mmHg) Diastolic BP (mmHg) IIEF-EF score TT (ng/mL)
The International Index of Erectile Function (IIEF) questionnaire’s erectile function (EF) domain was used to assess ED [14]. Patients with IIEF-EF score between 0–10 were grouped as severe ED and patients with IIEF-EF score between 11–25 were grouped as mild to moderate ED. To diagnose MetS, the 2005 International Diabetes Federation (IDF) consensus definition was applied [15]. The IDF is as follows: WC of 94 cm or more, plus any 2 of the following characteristics; TG level 150 mg/dl (1.7 mmol/l) or more), any specific treatment for lipid abnormality. HDL level less than 40 mg/dl (1.0 mmol/l), any specific treatment for lipid abnormality. Increased BP (systolic BP 130 mmHg or greater, diastolic BP 85 mmHg or greater) or treatment for previously diagnosed HT. FBG of 100 mg/dl (5.6 mmol/l) or more or previously diagnosed T2DM. Patients were divided into two groups according to presence of MetS, as follows: group 1 included patients with MetS and group 2 included patients without MetS. Statistical analysis Statistical Package for Social Sciences for Windows (SPSS, Chicago, IL) version 13.0 software was used for statistical evaluation of the results. The severity of ED, serum testosterone level and other MetS components were compared between the groups. Independent sample t test, Mann– Whitney test, Chi-Square test and logistic regression analysis were used. A p value less than 0.05 was considered significant.
Results The mean age of the patients was 55.7 ± 8.2 (54.7 and 56.4 years, in groups 1 and 2, respectively, p ¼ 0.099). The mean WC, BMI and WHR were 96.7 ± 10.7 cm, 28.5 ± 4.3 kg/m2 and 0.97 ± 0.07, respectively. The mean serum FBG, HDL, TG levels, TT and IIEF-EF scores of the whole group were as follows: 145.1 ± 84.1 mg/dL, 42.4 ± 14.0 mg/dL, 181.6 ± 113.4 mg/dL, 5.1 ± 3.4 ng/mL and 11.0 ± 7.9. The patient characteristics of individual groups and the differences are presented in Table 1. According to patients history, 163 patients (61.3%) were smokers. T2DM was observed in 137 patients (48.9%) of whom 67.1% had used oral anti-diabetics, 19.7% with insu¨lin and 9.8% with diet and lifestyle changes for the treatment of T2DM. Ninety-eight (35.1%) patients had HT of whom 57.2% had used antihypertensive medication, while 42.8% did not use any drugs. MetS was found 78 (56.9%) patients of T2DM. Of the 78 patients, 54 (69.2%) patients had severe ED. Similarly, MetS was found 65 (66.3%) patients with HT. Of the 65 patients, 41 (63.1%) patients had severe ED. Abnormal FBG, blood
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Group 1
Group 2
p Value
54.7 ± 7.9 105.0 ± 7.3 161.5 ± 75.0 30.6 ± 4.4 1.00 ± 0.06 40.1 ± 11.1 218.6 ± 125.1 126.4 ± 23.2 84.7 ± 12.7 9.4 ± 7.4 4.4 ± 1.4
56.4 ± 8.3 90.9 ± 8.8 133.5 ± 88.5 27 ± 3.7 0.95 ± 0.07 44.1 ± 15.6 154.2 ± 95.5 116.9 ± 19.5 77.5 ± 10.3 12.2 ± 8.0 5.3 ± 1.9
0.099* 50.001r 50.001r 50.001* 50.001r 50.001r 50.001r 50.001r 50.001r 50.002r 50.001r
Independent sample t test*, Mann–Whitney testr Variables are given as means ± Standard Deviation. Abbreviation: WC ¼ Waist circumference; FBG ¼ Fasting blood glucose; BMI ¼ Body Mass Index; WHR ¼ Waist-Hip ratio; HDL ¼ High-density lipoprotein; TG ¼ Triglyceride; BP ¼ Blood Pressure; IIEF-EF, erectile function domain of the International Index of Erectile Function. TT¼ Total testosterone (2.4–9.5 ng/mL).
pressure (BP), serum HDL, and serum TG ratio were found 87.3%, 55.6%, 55.1% and 70.3% in group 1 and 43.5%, 20.4%, 30.6% and 36.9% in group 2, respectively (p50.001 for all). One-hundred eighteen patients (42.1%) had MetS and 46 (16.4%) patients had hypogonadism. Sixty-eight (57.6%) patients with MetS and 71 (43.8%) patients without MetS had severe ED (p ¼ 0.031). MetS was seen in almost half of the patients with ED. Serum TT levels was found significantly lower in group 1 compared to group 2 (4.4 ± 1.4 ng/mL versus 5.3 ± 1.9 respectively, p50.001). Hypogonadism was seen more prevalent in patients with MetS (22.9% versus 11.7%, p ¼ 0.013). In a further analysis, the patients were divided into 4 groups according to the presence or absence of MetS and hypogonadism. Group1 (n ¼ 27); the patients with MetS and hypogonadism, Group 2 (n ¼ 91); the patients with MetS but without hypogonadism, Group 3 (n ¼ 19); the patients without MetS but with hypogonadism, Group 4 (n ¼ 143); the patients without MetS and hypogonadism. Serum TT levels and IIEF-EF scores were found different among the groups (pTT50.001, pIIEF-EF ¼ 0.024). Post hoc analyses revealed that serum TT levels were found similar in Group 1 and Group 3 (pGroup1-3 ¼ 0.783), and lower than the other groups. IIEF-EF scores were found similar in Groups 4 and 3 (pGroup3-4 ¼ 0.356). And the scores in Group 4 were higher than those in Groups 1 and 2 (PGroup1-4 ¼ 0.043, PGroup2-4¼0.006) (Figure 1). Logistic regression analyses for ED risk factors demonstrated that the presence of abnormal FBG increased the relative risk of severe ED up to 10.7-fold (95% confidence interval 5.1-22.5, p50.001). We did not find significant association between the presence of hypogonadism and risk of severe ED (O.R.¼1.2, 95% confidence interval 0.5–2.7, p ¼ 0.706). (Table 2).
Discussion The MetS is a disease with increased awareness, and it is one of the most important public health concerns of the last decade. MetS definitions were proposed by different study
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14 12 10
Aging Male, 2014; 17(2): 76–80
IIEF-EF TT (ng/ml)
12.4 10.8 9.4
9.3
8 5.5
6
4.8
4 2.5
2.5
2 0 MetS (+) and MetS (+) and MetS (-) and MetS (-) and Hypogonadism (+) Hypogonadism (-) Hypogonadism (+) Hypogonadism (-) Abreviations: IIEF-EF: Erectile function domain of the International Index of Erectile Function. MetS: Metabolic Syndrome,, TT: Serum Total Testosterone
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Figure 1. Relationship among IIEF-EF, serum TT levels and presence of MetS and/or Hypogonadism. Table 2. Logistic regression analysis of metabolic risk factors for erectile dysfunction.
Age Smoking Abnormal WC Abnormal FBG Abnormal HDL Abnormal TG Abnormal BP Presence of Hypogonadism
Beta Coefficient
p Value
O.R.
95% CI (Min-Max)
0.068 0.365 0.318 2.371 0.182 0.161 0.311 0.160
0.003 0.249 0.330 50.001 0.574 0.614 0.371 0.706
1.1 1.4 0.7 10.7 0.8 1.2 1.4 1.2
1.0–1.1 0.8–2.7 0.4–1.4 5.1–22.5 0.4–1.6 0.6–2.2 0.7–2.7 0.5–2.7
Variables entered as categorical variables, except for age. Abbreviation: O.R.: Odds ratio CI: confidence interval; WC: waist circumference; FBG; fasting blood glucose; HDL: high-density Lipoprotein; TG: triglyceride; BP: blood pressure
groups (including, World Health Organization in 1998, European Group for Study of Insulin Resistance in 1999, National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) in 2001, and American Association of Clinical Endocrinologists in 2003). The latest description was made by IDF in 2005. The common components in these definitions are central obesity, insulin resistance, abnormal lipid profile and HT [5]. Pathogenesis of ED is strongly associated with endothelial dysfunction and vascular impairment, and MetS is a well-known risk factor for these disorders [16]. Endothelial dysfunction is also related with diabetes, obesity, and dyslipidemia [17]. Various authors suggested that there may be a possible relation between insulin resistance and endothelial dysfunction, which has been implicated in MetS, ED and diabetes [18]. In Cologne Male Study, the analysis of risk factors revealed that the risk for ED increased 3.7-fold in males aged 40–49 years, 5.1-fold in males aged 50–59 years and 11-fold in males aged 60–69, compared to males aged 30–39 years. Same study found an increase of ED incidence 1.5-fold by the presence of HT and 3.9-fold by the presence of diabetes mellitus [19]. In our study severe ED risk analysis of the age subgroup was not done. Severe ED risk statistically
significant increase with aging but this result may not be clinically important (O.R.¼1.1). According to recent United States data, approximately 20–30% of middle-aged men are affected by MetS [20], and its prevalence was reported by Heidler et al. as 33.8% in males aged 30–69 years. Mainly three studies have investigated the prevalance of MetS in our country. They reported the prevalance of MetS range between 33%–48.1% [6,8,9]. Esposito et al. reported an increase in the prevalance of ED from 13% to 26.7% with the addition of MetS in their age- and BMI-matched control study [21]. Bal et al. reported that the prevalance of ED increases from 61.9% without MetS to 79% with MetS [8]. Heidler et al. reported in their cross-sectional study that 64.9% to 74.8% in men with 50 years or older, 63.8% to 68.4% in men with younger than 50 years old had ED with and without MetS, respectively [7]. Another study by Demir et al. reported the prevalance of ED as 74% in patients with MetS and 50% in patients without MetS [6]. And, Gunduz et al. reported that prevalance of ED increases from 51.2% without MetS to 100% with MetS [10]. All of these studies determined a strong association between MetS and ED [6–9,21]. Studies conducted in patients with ED, Yeh HC et al. investigated 103 men with ED in age groups of 30–80 (mean age 57.5 years) by utilizing two different MetS definitions. MetS was diagnosed in 37% and 32% of the patients using NCEP ATP III and IDF criteria, respectively [12]. In the same study severe ED was found as 31% using NCEP ATP III criteria and 41.4% using IDF criteria. Of the 103 patients 29 patients (28.2%) had severe ED. Bansal et al. evaluated 154 men who had organic ED or mixed organic-psychological ED. They reported that 43% of men with ED had MetS compared to 24% in a matched patient population. Prevalance of severe ED was reported as 70% in the same study [22]. Bal et al. reported that severe ED was 24.8% in MetS patients [8]. As consistent with previous studies we found that IIEF-EF scores was lower in MetS patients (12.2 versus 9.4) and MetS prevalance was found 42.1% in ED patients. Severe ED was found in 57.6% patients with MetS and 43.1% patients without MetS. Previous reports have different rate of MetS prevalance and severe ED. We believe that using different scoring systems for IIEF and diagnostic criteria for MetS may yield this. Also, patient selection criteria, ethnic background, setting and mean age of study population are also effect the results. ED and MetS are frequent in an aging male population, and aging is also a risk factor for ED. Patients with MetS also have increased risk for developing T2DM and also hypogonadism [23–25]. Low levels of testosterone in men are related with insulin resistance or hyperinsulinemia, T2DM, visceral obesity, dyslipidemia and MetS [10]. Clinical features of both aging and hypogonadism are similar, and includes decreased muscle mass, muscle strength, physical performance, bone mineral density, impaired cognitive function and depression, increased fat mass, loss of libido, and ED [24]. According to cross-sectional epidemiological studies, plasma testosterone levels is associated with insulin sensitivity, and low testosterone levels yield to an increased risk of T2DM in men [25]. Onset of ED occurs sooner in patients with diabetes. Among males aged 40 to 70 life-time risk of
Metabolic Syndrome
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DOI: 10.3109/13685538.2014.895318
developing ED increased from 52% without DM to 75% with DM [26]. Our previous study we found that presence of T2DM was significantly associated with severe ED, and the relative risk was as high as 7.1 [13]. In present study T2DM was observed in about half of patients and 56.9% of whom presented MetS. Of these patients, 69.2% patients had severe ED. Futhermore we found that the presence of abnormal FBG increased the relative risk of severe ED up to 10.7-fold. Testosterone and its metabolites are associated with physical, sexual and emotional health [27]. Though the role of testosterone in improving libido is well known, but its role in erection remains unclear [28]. Serum T levels decreases by age, many age-related clinical features such as ED are closely associated with androgen deficiency [24,29]. Hypogonadism is another factor that contributes to vascular pathology, including ED, and it is an independent determinant of endothelial dysfunction [30]. In the present study, 16.4% of the patients had hypogonadism and hypogonadism was more prevalent in patients with MetS. We found that in the absence of both MetS and hypogonadism, serum TT levels and IIEF-EF scores were found to be higher than the other conditions. IIEF-EF scores were found similar among MetS patients in groups 1 and 2 and were also similiar among patients without MetS in groups 3 and 4. TT levels were found similar in groups 3 and 4 but IIEF-EF scores were found similar. In the logistic regression analysis of erectile dysfunction risk factors showed that the presence of hypogonadism was not solely risk factor for severe ED. Yeh HC et al. reported that BMI was significantly higher and serum testosterone was lower in ED patients with MetS than ED patients without MetS. Additionally they found that ED was significantly more severe in patients with MetS defined by NCEP ATP III criteria but no significant difference with the IDF definition [12]. In the present study, we used IDF definition to diagnosis of MetS and we observed that serum TT levels was found significantly lower in MetS patients (4.4 versus 5.3). The study by Yeh HC et al. had two main differences from our study: the number of subjects was limited (n ¼ 103) and they used both IDF and NCEP ATP III definition. Additionally the cutoff WC was 94 cm or larger in the IDF 2005 whereas 102 cm NCEP ATP III definition for diagnosis of MetS. Therefore, we can observe more severe and advanced forms of MetS which can impact on ED and also testosterone level with using NCEP ATP III criteria [12]. We believe that this difference was caused by different of ethnic groups and number of subject. The weakness of our study was the limited number of patients in each group which was a result of the difficulty in finding patients that fulfilled the criteria for these groups. We believe that a study with a higher number of ED patients with MetS and hypogonadism (group 1 in our study), without MetS and but hypogonadism (group 3 in our study) could yield a stronger association. As a result, MetS may play a key role in the pathogenesis in both ED and hypogonadism. In present study MetS was seen in almost half of the patients with ED. ED was more severe among MetS patients. Lower testosterone levels may be a risk factor for severity of ED in MetS patients. Yet, it is not well-known whether MetS is the cause of hypogonadism or not. In the light of our results hypogonadism alone is a not
79
risk factor for severe ED. In any way, in order to reduce the prevalence of these disorders increased awareness is needed and correction of multiple metabolic abnormalities is required to improve these conditions particularly the adoption of a healthy lifestyle is strongly recommended.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA 1993;270:83–90. 2. Behre HM, Tammela TL, Arver S, et al. A randomized, doubleblind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up. Aging Male 2012;15:198–207. 3. Nusbaum MR. Erectile dysfunction: prevalence, etiology, and major risk factors. J Am Osteopath Assoc 2002;102:S1–6. 4. Corona G, Monami M, Rastrelli G, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med 2011;8: 272–83. 5. Grundy SM, Cleeman JI, Daniels SR, et al. American Heart Association; National Heart, Lung, and Blood Institute. American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735–52. 6. Demir T, Demir O, Kefi A, et al. Prevalence of erectile dysfunction in patients with metabolic syndrome. Int J Urol 2006;13:385–8. 7. Heidler S, Temml C, Broessner C, et al. Is the metabolic syndrome an independent risk factor for erectile dysfunction? J Urol 2007; 177:651–4. 8. Bal K, Oder M, Sahin AS, et al. Prevalence of metabolic syndrome and its association with erectile dysfunction among urologic patients: metabolic backgrounds of erectile dysfunction. Urology 2007;69:356–60. 9. Gu¨ndu¨z MI, Gu¨mu¨s BH, Sekuri C. Relationship between metabolic syndrome and erectile dysfunction. Asian J Androl 2004;6:355–8. 10. Laaksonen DE, Niskanen L, Punnonen K, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol 2000;149:601–8. 11. Makhsida N, Shah J, Yan G, et al. Hypogonadism and metabolic syndrome: implications for testosterone therapy. J Urol 2005;74: 27–834. 12. Yeh HC, Wang CJ, Lee YC, et al. Association among metabolic syndrome, testosterone level and severity of erectile dysfunction. Kaohsiung J Med Sci 2008;24:240–7. 13. Aslan Y, Sezgin T, Tuncel A, et al. Is type 2 diabetes mellitus a cause of severe erectile dysfunction in patients with metabolic syndrome? Urology 2009;74:561–4. 14. 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;49:822–30. 15. International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. Available from: http:// www.idf.org. http://www.idf.org/webdata/docs/MetSyndrome_ FINAL.pdf [last accessed 2006]. 16. Melman A, Gingell JC. The epidemiology and pathophysiology of erectile dysfunction. J Urol 1999;161:5–11. 17. McVeigh GE, Cohn JN. Endothelial dysfunction and the metabolic syndrome. Curr Diab Rep 2003;3:87–92. 18. Traish AM, Guay A, Feeley R, Saad F. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. J Androl 2009;30:10–22. 19. Braun M, Wassmer G, Klotz T, et al. Epidemiology of erectile dysfunction: results of the ‘Cologne Male Survey’. Int J Impot Res 2000;12:305–11.
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20. Meigs JB, Wilson PW, Nathan DM, et al. Prevalence and characteristics of the metabolic syndrome in the San Antonio heart and Framingham offspring studies. Diabetes 2003;52:2160–7. 21. Esposito K, Giugliano F, Martedı` E, et al. High proportions of erectile dysfunction in men with the metabolic syndrome. Diabetes Care 2002;28:1201–3. 22. 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;2:96–103. 23. Traish AM, Miner MM, Morgentaler A, Zitzmann M. Testosterone deficiency. Am J Med 2011;124:578–87. 24. Yassin AA, Saad F. Testosterone and erectile dysfunction. J Androl 2008;29:593–604. 25. Selvin E, Feinleib M, Zhang L, et al. Androgens and diabetes in men: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care 2007;30:234–8.
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26. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151:54–61. 27. Mikhail N. AACE Hypogonadism Guidelines. Endocr Pract 2002; 8:439–56. 28. Wang C, Cunningham G, Dobs A, , et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab 2004;89:2085–98. 29. Harman SM, Metter EJ, Tobin JD, et al. Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86:724–31. 30. Akishita M, Hashimoto M, Ohike Y, et al. Low T level is an independent determinant of endothelial dysfunction in men. Hypertens Res 2007;30:1029–34.
ORIGINAL ARTICLE
The impact of metabolic syndrome on serum total testosterone level in patients with erectile dysfunction Yilmaz Aslan1, Ozer Guzel1, Melih Balci1, Altug Tuncel1, Muslum Yildiz1, and Ali Atan2 Department of Urology, Ankara Numune Research and Training Hospital, Ministry of Health, Ankara, Turkey and 2Department of Urology, School of Medicine, Gazi University, Ankara, Turkey
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1
Abstract
Keywords
Objectives: To determine the association between metabolic syndrome (MetS) and serum testosterone levels (TT) in patients with erectile dysfunction (ED). Methods: This study included 280 ED patients above 40-years-of-age. Participants were divided into two groups according to 2005 criteria of International Diabetes Federation. The severity of ED was determined according to the International Index of Erectile Function-EF (IIEF-EF score; 0–10 severe ED, 11–25 mild to moderate ED). The severity of ED, serum TT levels and other MetS components were compared between the groups. Results: The mean age of the patients was 55.7 ± 8.2 years. One hundred eighteen patients (%42.1) had MetS. Sixty-eight patients with MetS (57.6%) and 71 patients without MetS (43.8%) had severe ED (p ¼ 0.031). A total of 46 (16.4%) patients had hypogonadism. Hypogonadism was seen more prevalent in patients with MetS (22.9% vs. 11.7%, p ¼ 0.013). Logistic regression analyses for ED risk factors demonstrated that abnormal FBG increased the relative risk of severe ED up to 10.7-fold (p50.001) but not presence of hypogonadism (p ¼ 0.706). Conclusion: Metabolic syndrome was seen in almost half of the patients with ED. ED was more severe among MetS patients. Hypogonadism alone is a not risk factor for severe ED.
Erectile dysfunction, hypogonadism, male, metabolic syndrome, testosterone
Introduction Erectile dysfunction (ED) is the inability of men to achieve or maintain a sufficient penile erection to permit satisfactory sexual intercourse [1]. ED is known as a common disorder among men, it worsens the quality of life, and it is seen more frequently in older ages. Its prevalence was reported as 5–10% and 40–60% in 40–years-old and 70 years-old men, respectively [2]. Common risk factors of ED are aging, comorbid conditions, certain medications, obesity, alcohvol and tobacco use [3,4]. Nowadays the Metabolic Syndrome (MetS) is approved important risk factor for ED. Syndrome X, Insulin-Resistance Syndrome or the MetS is a concurrence of some cardiovascular risk factors such as insulin resistance (type 2 diabetes mellitus (T2DM) and/or glucose intolerance), abdominal obesity, dyslipidemia and hypertension (HT) [5–7]. The relationships between these two disorders are mainly associated with common risk factors. Many previous studies focused on the association of ED and MetS [8,9]. MetS patients have increased risk for hypogonadism [10,11]. Correspondence: Yilmaz Aslan, M.D, Ministry of Health, Ankara Numune Research and Training. Hospital, Third Department of Urology, 06120, Sihhiye, Ankara, Turkey. Tel : +90 505 486 22 99. Fax: +90 312 310 34 60. E-mail: [email protected]
History Received 25 November 2013 Revised 3 February 2014 Accepted 13 February 2014 Published online 27 February 2014
In current literature, the prevalance of MetS and relationship between testosterone levels has been less commonly investigated in patients with ED [12,13]. In this study, we investigated the prevalance of MetS and a possible association between MetS and serum testosterone levels in patients with ED.
Methods Two-hundred eighty patients with ED between 40 to 80 years were included in this study. The age, waist circumference (WC), body mass index (BMI), waist-hip ratio (WHR), smoking habits, the presence of T2DM and HT were recorded. WC was measured at the level of the umbilicus while the patient breathed normally and the WHR was defined as the ratio of waist girth to the circumference of the hips. BMI was computed as the ratio of weight to the square of height (kg/m2). The 8-hour plasma levels of the fasting blood glucose (FBG), high-density lipoprotein (HDL), triglyceride (TG), total cholesterol, serum total testosterone (TT) level were measured. Men with serum TT5300 ng/dl were considered hypogonadal. [11] Patients with liver or kidney function failure, trauma and/or surgery in pelvis, urinary malignancy, peripheral or autonomous neuropathy, and cardiovascular disease, drug use for ED (PDE5i, testosterone replacement), use of 5-alpha
Metabolic Syndrome
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DOI: 10.3109/13685538.2014.895318
reductase inhibitors, psychiatric disorders or alcohol abuse were excluded from the study.
Table 1. Principal characteristics of the study population.
Patient assessment
Age WC (cm) FBG (mg/dL) BMI (kg/m2) WHR (cm) HDL (mg/dL) TG (mg/dL) Systolic BP (mmHg) Diastolic BP (mmHg) IIEF-EF score TT (ng/mL)
The International Index of Erectile Function (IIEF) questionnaire’s erectile function (EF) domain was used to assess ED [14]. Patients with IIEF-EF score between 0–10 were grouped as severe ED and patients with IIEF-EF score between 11–25 were grouped as mild to moderate ED. To diagnose MetS, the 2005 International Diabetes Federation (IDF) consensus definition was applied [15]. The IDF is as follows: WC of 94 cm or more, plus any 2 of the following characteristics; TG level 150 mg/dl (1.7 mmol/l) or more), any specific treatment for lipid abnormality. HDL level less than 40 mg/dl (1.0 mmol/l), any specific treatment for lipid abnormality. Increased BP (systolic BP 130 mmHg or greater, diastolic BP 85 mmHg or greater) or treatment for previously diagnosed HT. FBG of 100 mg/dl (5.6 mmol/l) or more or previously diagnosed T2DM. Patients were divided into two groups according to presence of MetS, as follows: group 1 included patients with MetS and group 2 included patients without MetS. Statistical analysis Statistical Package for Social Sciences for Windows (SPSS, Chicago, IL) version 13.0 software was used for statistical evaluation of the results. The severity of ED, serum testosterone level and other MetS components were compared between the groups. Independent sample t test, Mann– Whitney test, Chi-Square test and logistic regression analysis were used. A p value less than 0.05 was considered significant.
Results The mean age of the patients was 55.7 ± 8.2 (54.7 and 56.4 years, in groups 1 and 2, respectively, p ¼ 0.099). The mean WC, BMI and WHR were 96.7 ± 10.7 cm, 28.5 ± 4.3 kg/m2 and 0.97 ± 0.07, respectively. The mean serum FBG, HDL, TG levels, TT and IIEF-EF scores of the whole group were as follows: 145.1 ± 84.1 mg/dL, 42.4 ± 14.0 mg/dL, 181.6 ± 113.4 mg/dL, 5.1 ± 3.4 ng/mL and 11.0 ± 7.9. The patient characteristics of individual groups and the differences are presented in Table 1. According to patients history, 163 patients (61.3%) were smokers. T2DM was observed in 137 patients (48.9%) of whom 67.1% had used oral anti-diabetics, 19.7% with insu¨lin and 9.8% with diet and lifestyle changes for the treatment of T2DM. Ninety-eight (35.1%) patients had HT of whom 57.2% had used antihypertensive medication, while 42.8% did not use any drugs. MetS was found 78 (56.9%) patients of T2DM. Of the 78 patients, 54 (69.2%) patients had severe ED. Similarly, MetS was found 65 (66.3%) patients with HT. Of the 65 patients, 41 (63.1%) patients had severe ED. Abnormal FBG, blood
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Group 1
Group 2
p Value
54.7 ± 7.9 105.0 ± 7.3 161.5 ± 75.0 30.6 ± 4.4 1.00 ± 0.06 40.1 ± 11.1 218.6 ± 125.1 126.4 ± 23.2 84.7 ± 12.7 9.4 ± 7.4 4.4 ± 1.4
56.4 ± 8.3 90.9 ± 8.8 133.5 ± 88.5 27 ± 3.7 0.95 ± 0.07 44.1 ± 15.6 154.2 ± 95.5 116.9 ± 19.5 77.5 ± 10.3 12.2 ± 8.0 5.3 ± 1.9
0.099* 50.001r 50.001r 50.001* 50.001r 50.001r 50.001r 50.001r 50.001r 50.002r 50.001r
Independent sample t test*, Mann–Whitney testr Variables are given as means ± Standard Deviation. Abbreviation: WC ¼ Waist circumference; FBG ¼ Fasting blood glucose; BMI ¼ Body Mass Index; WHR ¼ Waist-Hip ratio; HDL ¼ High-density lipoprotein; TG ¼ Triglyceride; BP ¼ Blood Pressure; IIEF-EF, erectile function domain of the International Index of Erectile Function. TT¼ Total testosterone (2.4–9.5 ng/mL).
pressure (BP), serum HDL, and serum TG ratio were found 87.3%, 55.6%, 55.1% and 70.3% in group 1 and 43.5%, 20.4%, 30.6% and 36.9% in group 2, respectively (p50.001 for all). One-hundred eighteen patients (42.1%) had MetS and 46 (16.4%) patients had hypogonadism. Sixty-eight (57.6%) patients with MetS and 71 (43.8%) patients without MetS had severe ED (p ¼ 0.031). MetS was seen in almost half of the patients with ED. Serum TT levels was found significantly lower in group 1 compared to group 2 (4.4 ± 1.4 ng/mL versus 5.3 ± 1.9 respectively, p50.001). Hypogonadism was seen more prevalent in patients with MetS (22.9% versus 11.7%, p ¼ 0.013). In a further analysis, the patients were divided into 4 groups according to the presence or absence of MetS and hypogonadism. Group1 (n ¼ 27); the patients with MetS and hypogonadism, Group 2 (n ¼ 91); the patients with MetS but without hypogonadism, Group 3 (n ¼ 19); the patients without MetS but with hypogonadism, Group 4 (n ¼ 143); the patients without MetS and hypogonadism. Serum TT levels and IIEF-EF scores were found different among the groups (pTT50.001, pIIEF-EF ¼ 0.024). Post hoc analyses revealed that serum TT levels were found similar in Group 1 and Group 3 (pGroup1-3 ¼ 0.783), and lower than the other groups. IIEF-EF scores were found similar in Groups 4 and 3 (pGroup3-4 ¼ 0.356). And the scores in Group 4 were higher than those in Groups 1 and 2 (PGroup1-4 ¼ 0.043, PGroup2-4¼0.006) (Figure 1). Logistic regression analyses for ED risk factors demonstrated that the presence of abnormal FBG increased the relative risk of severe ED up to 10.7-fold (95% confidence interval 5.1-22.5, p50.001). We did not find significant association between the presence of hypogonadism and risk of severe ED (O.R.¼1.2, 95% confidence interval 0.5–2.7, p ¼ 0.706). (Table 2).
Discussion The MetS is a disease with increased awareness, and it is one of the most important public health concerns of the last decade. MetS definitions were proposed by different study
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14 12 10
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IIEF-EF TT (ng/ml)
12.4 10.8 9.4
9.3
8 5.5
6
4.8
4 2.5
2.5
2 0 MetS (+) and MetS (+) and MetS (-) and MetS (-) and Hypogonadism (+) Hypogonadism (-) Hypogonadism (+) Hypogonadism (-) Abreviations: IIEF-EF: Erectile function domain of the International Index of Erectile Function. MetS: Metabolic Syndrome,, TT: Serum Total Testosterone
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Figure 1. Relationship among IIEF-EF, serum TT levels and presence of MetS and/or Hypogonadism. Table 2. Logistic regression analysis of metabolic risk factors for erectile dysfunction.
Age Smoking Abnormal WC Abnormal FBG Abnormal HDL Abnormal TG Abnormal BP Presence of Hypogonadism
Beta Coefficient
p Value
O.R.
95% CI (Min-Max)
0.068 0.365 0.318 2.371 0.182 0.161 0.311 0.160
0.003 0.249 0.330 50.001 0.574 0.614 0.371 0.706
1.1 1.4 0.7 10.7 0.8 1.2 1.4 1.2
1.0–1.1 0.8–2.7 0.4–1.4 5.1–22.5 0.4–1.6 0.6–2.2 0.7–2.7 0.5–2.7
Variables entered as categorical variables, except for age. Abbreviation: O.R.: Odds ratio CI: confidence interval; WC: waist circumference; FBG; fasting blood glucose; HDL: high-density Lipoprotein; TG: triglyceride; BP: blood pressure
groups (including, World Health Organization in 1998, European Group for Study of Insulin Resistance in 1999, National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) in 2001, and American Association of Clinical Endocrinologists in 2003). The latest description was made by IDF in 2005. The common components in these definitions are central obesity, insulin resistance, abnormal lipid profile and HT [5]. Pathogenesis of ED is strongly associated with endothelial dysfunction and vascular impairment, and MetS is a well-known risk factor for these disorders [16]. Endothelial dysfunction is also related with diabetes, obesity, and dyslipidemia [17]. Various authors suggested that there may be a possible relation between insulin resistance and endothelial dysfunction, which has been implicated in MetS, ED and diabetes [18]. In Cologne Male Study, the analysis of risk factors revealed that the risk for ED increased 3.7-fold in males aged 40–49 years, 5.1-fold in males aged 50–59 years and 11-fold in males aged 60–69, compared to males aged 30–39 years. Same study found an increase of ED incidence 1.5-fold by the presence of HT and 3.9-fold by the presence of diabetes mellitus [19]. In our study severe ED risk analysis of the age subgroup was not done. Severe ED risk statistically
significant increase with aging but this result may not be clinically important (O.R.¼1.1). According to recent United States data, approximately 20–30% of middle-aged men are affected by MetS [20], and its prevalence was reported by Heidler et al. as 33.8% in males aged 30–69 years. Mainly three studies have investigated the prevalance of MetS in our country. They reported the prevalance of MetS range between 33%–48.1% [6,8,9]. Esposito et al. reported an increase in the prevalance of ED from 13% to 26.7% with the addition of MetS in their age- and BMI-matched control study [21]. Bal et al. reported that the prevalance of ED increases from 61.9% without MetS to 79% with MetS [8]. Heidler et al. reported in their cross-sectional study that 64.9% to 74.8% in men with 50 years or older, 63.8% to 68.4% in men with younger than 50 years old had ED with and without MetS, respectively [7]. Another study by Demir et al. reported the prevalance of ED as 74% in patients with MetS and 50% in patients without MetS [6]. And, Gunduz et al. reported that prevalance of ED increases from 51.2% without MetS to 100% with MetS [10]. All of these studies determined a strong association between MetS and ED [6–9,21]. Studies conducted in patients with ED, Yeh HC et al. investigated 103 men with ED in age groups of 30–80 (mean age 57.5 years) by utilizing two different MetS definitions. MetS was diagnosed in 37% and 32% of the patients using NCEP ATP III and IDF criteria, respectively [12]. In the same study severe ED was found as 31% using NCEP ATP III criteria and 41.4% using IDF criteria. Of the 103 patients 29 patients (28.2%) had severe ED. Bansal et al. evaluated 154 men who had organic ED or mixed organic-psychological ED. They reported that 43% of men with ED had MetS compared to 24% in a matched patient population. Prevalance of severe ED was reported as 70% in the same study [22]. Bal et al. reported that severe ED was 24.8% in MetS patients [8]. As consistent with previous studies we found that IIEF-EF scores was lower in MetS patients (12.2 versus 9.4) and MetS prevalance was found 42.1% in ED patients. Severe ED was found in 57.6% patients with MetS and 43.1% patients without MetS. Previous reports have different rate of MetS prevalance and severe ED. We believe that using different scoring systems for IIEF and diagnostic criteria for MetS may yield this. Also, patient selection criteria, ethnic background, setting and mean age of study population are also effect the results. ED and MetS are frequent in an aging male population, and aging is also a risk factor for ED. Patients with MetS also have increased risk for developing T2DM and also hypogonadism [23–25]. Low levels of testosterone in men are related with insulin resistance or hyperinsulinemia, T2DM, visceral obesity, dyslipidemia and MetS [10]. Clinical features of both aging and hypogonadism are similar, and includes decreased muscle mass, muscle strength, physical performance, bone mineral density, impaired cognitive function and depression, increased fat mass, loss of libido, and ED [24]. According to cross-sectional epidemiological studies, plasma testosterone levels is associated with insulin sensitivity, and low testosterone levels yield to an increased risk of T2DM in men [25]. Onset of ED occurs sooner in patients with diabetes. Among males aged 40 to 70 life-time risk of
Metabolic Syndrome
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DOI: 10.3109/13685538.2014.895318
developing ED increased from 52% without DM to 75% with DM [26]. Our previous study we found that presence of T2DM was significantly associated with severe ED, and the relative risk was as high as 7.1 [13]. In present study T2DM was observed in about half of patients and 56.9% of whom presented MetS. Of these patients, 69.2% patients had severe ED. Futhermore we found that the presence of abnormal FBG increased the relative risk of severe ED up to 10.7-fold. Testosterone and its metabolites are associated with physical, sexual and emotional health [27]. Though the role of testosterone in improving libido is well known, but its role in erection remains unclear [28]. Serum T levels decreases by age, many age-related clinical features such as ED are closely associated with androgen deficiency [24,29]. Hypogonadism is another factor that contributes to vascular pathology, including ED, and it is an independent determinant of endothelial dysfunction [30]. In the present study, 16.4% of the patients had hypogonadism and hypogonadism was more prevalent in patients with MetS. We found that in the absence of both MetS and hypogonadism, serum TT levels and IIEF-EF scores were found to be higher than the other conditions. IIEF-EF scores were found similar among MetS patients in groups 1 and 2 and were also similiar among patients without MetS in groups 3 and 4. TT levels were found similar in groups 3 and 4 but IIEF-EF scores were found similar. In the logistic regression analysis of erectile dysfunction risk factors showed that the presence of hypogonadism was not solely risk factor for severe ED. Yeh HC et al. reported that BMI was significantly higher and serum testosterone was lower in ED patients with MetS than ED patients without MetS. Additionally they found that ED was significantly more severe in patients with MetS defined by NCEP ATP III criteria but no significant difference with the IDF definition [12]. In the present study, we used IDF definition to diagnosis of MetS and we observed that serum TT levels was found significantly lower in MetS patients (4.4 versus 5.3). The study by Yeh HC et al. had two main differences from our study: the number of subjects was limited (n ¼ 103) and they used both IDF and NCEP ATP III definition. Additionally the cutoff WC was 94 cm or larger in the IDF 2005 whereas 102 cm NCEP ATP III definition for diagnosis of MetS. Therefore, we can observe more severe and advanced forms of MetS which can impact on ED and also testosterone level with using NCEP ATP III criteria [12]. We believe that this difference was caused by different of ethnic groups and number of subject. The weakness of our study was the limited number of patients in each group which was a result of the difficulty in finding patients that fulfilled the criteria for these groups. We believe that a study with a higher number of ED patients with MetS and hypogonadism (group 1 in our study), without MetS and but hypogonadism (group 3 in our study) could yield a stronger association. As a result, MetS may play a key role in the pathogenesis in both ED and hypogonadism. In present study MetS was seen in almost half of the patients with ED. ED was more severe among MetS patients. Lower testosterone levels may be a risk factor for severity of ED in MetS patients. Yet, it is not well-known whether MetS is the cause of hypogonadism or not. In the light of our results hypogonadism alone is a not
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risk factor for severe ED. In any way, in order to reduce the prevalence of these disorders increased awareness is needed and correction of multiple metabolic abnormalities is required to improve these conditions particularly the adoption of a healthy lifestyle is strongly recommended.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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