ORIGINAL ARTICLE Vascular risk factors and erectile dysfunction in a cohort of healthy men

Transcription

1 (2006) 18, & 2006 Nature Publishing Group All rights reserved /06 $ ORIGINAL ARTICLE in a cohort of healthy men A Ponholzer 1, C Temml 2, M Rauchenwald 1 and S Madersbacher 1 1 Department of Urology and Andrology, Danubehospital, SMZO, Vienna, Austria and 2 Department of Preventive Health, City of Vienna, Vienna, Austria To determine the impact of vascular risk factors in the genesis of erectile dysfunction (ED) in a cohort of healthy men. Participants of a health-screening project were carefully selected as men without known vascular disease. Erectile dysfunction was quantified via the IIEF5-questionnaire. All men underwent a detailed health examination including determination of blood pressure, blood lipid profile and fasting serum glucose. In total 1519 men ( years) were analysed. Age (Po0.01), elevated levels of total cholesterol (P ¼ 0.04) and low-density lipoproteins (LDL) (P ¼ 0.02) were associated with moderately to severly impaired erectile function (IIEF5: o12). Men with total cholesterol 4240 mg/dl had a 2.7 ( )-fold increased risk for moderate to severe ED, the respective figure for LDL 4160 mg/dl was 2.6 ( ). In this well characterized, healthy population, elevated serum lipids are the most important risk factors for the development of ED. (2006) 18, doi: /sj.ijir ; published online 16 March 2006 Keywords: impotence; hyperlipidemia; endothelial dysfunction; vascular impairment; blood pressure; diabetes Introduction Erectile dysfunction (ED) is defined as the inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse. 1 It may result from psychological, neurological, hormonal or vascular impairment and has been estimated to affect approximately 150 million men worldwide. 2,3 Current thinking favours changes in the penile arterial system as a key factor in the genesis of ED. 4 This is underlined by the fact that ED shares common risk factors with atherosclerosis in general such as nicotine abuse, hypertension, diabetes mellitus (DM) and hyperlipidemia. 5 8 Endothelial dysfunction and vascular obstruction due to atherosclerosis caused by these well-established risk factors seem to be a final pathway leading to the clinical manifestation of ED. 9 However, published information on the interaction between erectile function and these major Correspondence: Dr A Ponholzer, Departments of Urology and Andrology, Danubehospital, SMZO, Langobardenstrasse 122, Vienna 1220, Austria. anton.ponholzer@wienkav.at Received 4 January 2006; revised 14 February 2006; accepted 15 February 2006; published online 16 March 2006 vascular risk factors has been limited. Main reasons, therefore, are different definitions of ED, different classifications of DM, hypertension and hyperlipidemia and because of confounding effects such as concomitant medication and different duration of the underlying disease. For a better understanding of the role of vascular risk factors on ED, we set up a cross-sectional study in middle-aged men without a history of DM, hypertension, hyperlipidemia, coronary heart disease, peripheral arterial disease or stroke and without any medication. The aim of our study was to gain further insight into the impact of elevated blood pressure (BP), blood lipid- and glucose metabolism, nicotine abuse and parameters of obesity (body mass index, BMI; waist hip ratio, WHR) in the genesis of ED. For diagnosis and classification of ED, the International Index of Erectile Function 5 (IIEF5) was used. Methods Study cohort Over a 6-month-period in the year 2001, consecutively all men aged years participating in a voluntary health examination in the area of Vienna were assessed regarding erectile function via IIEF5

2 490 and entered the database. The Department of Preventive Health of the City of Vienna regularly performs these examinations at seven locations where citizens can undergo health evaluation free of charge once a year. In addition, employees of large companies are invited to participate. For the final analysis, all participants with a known history of myocardial infarction, coronary heart or peripheral arterial disease, stroke, DM, hypertension, hyperlipidemia or any medication were excluded. Presence/absence of these major vascular risk factors and vascular diseases was checked and controlled by a general practitioner (GP) at the investigation site. The GP was blinded regarding IIEF5 score. On site lab results and BP determination did not enter primary exclusion criteria. Institutional review board approval was obtained and all study participants gave informed consent. Health investigation During the health examination, the following parameters are routinely assessed: (1) detailed medical history; (2) assessment of all concurrent medical drugs and therapies; (3) physical examination with assessment of age, weight, height, heart rate, BP, ECG and spirometry; (4) sociodemographic parameters including marital status, cigarette smoking, alcohol consumption, exercise habits, dietary habits, (5) urinalysis with a dipstick test; (6) blood laboratory study of a total of 14 parameters including kidney and liver function tests, red and white cell counts, low- and high-density lipoprotein counts (LDL, HDL), total cholesterol, triglycerides and fasting serum glucose. Parameters Total cholesterol, triglyerides and HDL were quantified using Hitachi 717 by Roche (BM) with serum of fasting patients between 0800 and Lowdensity lipoprotein was calculated according to the Friedwald s-formula. Cutoff values for elevated lipid metabolism were defined as 240 mg/dl for total cholesterol, 160 mg/dl for LDL and 200 mg/dl for triglycerides. 10 For systolic and diastolic BP determination, three measurements were obtained for each individual, (1) by the study nurse before medical examination, (2) by the GP during medical examination and (3) by the study nurse after medical examination each time after the patient had been sitting for 5 min. Mean values of these three measurements were used for all analyses. Cutoff values for elevated BP were defined as 140 mm Hg for systolic BP and 90 mm Hg for diastolic BP. 11 Diabetes mellitus was diagnosed when fasting blood glucose was 4125 mg/dl. 12 Nicotine abuse was defined as regularly smoking during the previous 12 months, any medication was documented when used at investigation time. Body mass index was defined as weight in kg/height in meters 2. Waist hip ratio was determined for each patient at the investigation site. Each parameter was diagnosed and confirmed by the GP who performed the health examination. Assessment of erectile dysfunction For ED assessment the IIEF5, the abridged, 5-item version of the IIEF as described by Rosen and Cappelleri in was used. Erectile dysfunction and different forms of ED-severity were defined according to the IIEF-5 score and the classification system of Rosen and Cappelleri. 13 No ED: IIEF5 score 22 25; mild to moderate ED: IIEF5 score 12 21; moderate to severe ED: IIEF5 score: Statistical analysis All statistical analyses were conducted using Statistical Package for Social Sciences, version (SPSS Inc., Chicago, IL, USA) and Primer of Biostatistics, Version 5.0 (McGraw-Hill, 2002). ANOVA-analysis and multiple linear regression analysis were used to identify significant differences in mean values of the parameters across IIEF5 score groups and associated risk of these parameters with IIEF5 scores, respectively. w 2 -analysis was used for categorical variables according to the defined cutoff values in regard to ED status. All hypotheses testing was two-sided with Pp0.05 considered to be significant. Results Principal cohort characteristics In total, 1519 men with a mean age of 42.9 years (7standard deviation (s.d.): 7.9 years) entered the analysis. Age distribution was n ¼ 595 (39.2%) for years, n ¼ 568 (37.4%) for years and n ¼ 356 (23.4%) for years. For mean values (7s.d. and range) of the major study parameters and percentage of nicotine abuse, see Table 1. Erectile dysfunction Mean IIEF5 score was 20.4 (73.2) with an ED-status of severe ED in n ¼ 36 (2.4%; IIEF5 score 5 11), mild to moderate ED in n ¼ 862 (56.7%; IIEF ) and no ED in n ¼ 621 (40.9%; IIEF ). Vascular risk factors Mean values (7s.d.) of vascular risk and obesity parameters are shown in Table 1. In the total population, the proportion of elevated levels was 25.6% for systolic BP (4140 mm Hg), 18.5% for diastolic BP (490 mm Hg), 14.7% for triglycerides

3 Table 1 Principal patient characteristics of total population 491 (n ¼ 1519) Min Max s.d. Mean Age (years) IIEF5 score Body mass index Waist hip ratio RR systolic (mm Hg) RR diastolic (mm Hg) Triglycerides (mg/dl) Cholesterol (mg/dl) HDL (mg/dl) LDL (mg/dl) Fasting serum glucose (mg/dl) n (%) Nicotine abuse Yes 400 (26.3) No 824 (54.3) Ex 295 (19.4) Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; RR, relative risk; s.d., standard deviation. Table 2 Mean values according to IIEF5 score (mean) IIEF5 score P-value Age (years) o0.01 Body mass index Waist hip ratio RR systolic (mm Hg) RR diastolic (mm Hg) Triglycerides (mg/dl) Cholesterol (mg/dl) HDL (mg/dl) LDL (mg/dl) Fasting serum glucose (mg/dl) Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; RR, relative risk. Values in bold are significant. (4200 mg/dl), 27.5% for total cholesterol (4240 mg/ dl), 35.9% for HDL (o50 mg/dl), 22.7% for LDL (4160 mg/dl) and 0.8% for fasting serum glucose (4125 mg/dl). Mean values of risk factors according to IIEF5 score are listed in Table 2, percentages of elevated levels of risk factors according to IIEF5 score are listed in Table 3. Men with moderate to severe ED (IIEF5 score 5 11) had an 8.3% higher total cholesterol (P ¼ 0.04) and an 11.8% higher LDL-serum level (P ¼ 0.02) compared to men with none or moderate ED (IIEF5 score 12 25) (Table 2). The relative risk for having moderate to severe ED was 2.7 ( ) with total cholesterol levels X240 mg/dl and 2.6 ( ) with LDL levels X160 mg/dl. According to multiple linear regression analysis, this risk increase was significant (P ¼ 0.04, 0.02) (Table 3). Discussion Erectile dysfunction is a highly prevalent disorder with vascular risk factors (i.e. hypertension, DM, hyperlipidemia and nicotine abuse) playing a central role in its genesis. 2,6 9 But even if the relationship between these factors and ED is well established today, our insight into their specific role in the pathogenesis of ED is hampered due to different definitions of risk factors, underlying medications and the duration of lipid-, glucose- and BP dysregulation in current literature. Therefore, we tested for the first time the impact of BP, fasting blood glucose and elevated blood lipids together with nicotine abuse on the prevalence of ED in men without a history of vascular risk and without concurrent medication. In our analysis of 1519 men with a mean age of 43 years, besides age (Po0.01), total cholesterol (P ¼ 0.04) and LDL (P ¼ 0.02) turned out to be significantly elevated in men with moderate to severe ED (IIEF5 score 5 11), thus increasing the prevalence of moderate to severe ED with a relative risk of 2.6 (total cholesterol) and 2.7 (LDL). There was no hint for an influence of the investigated parameters on mild to moderate ED (IIEF5 score 12 21) compared to men with normal erectile function. In contrast, neither BP, nor fasting serum glucose, nicotine abuse, BMI or WHR showed to have an independent correlation to erectile function. Regarding hypertension and nicotine abuse, these results are in contrast to current literature. 1,2 We interprete the lacking correlation as a consequence of the low mean age of our population. Vascular

4 492 Table 3 Percentages of pathological parameters according to IIEF5 score (%) IIEF5 score P-value RR Body mass index o X Waist hip ratio o X RR systolic (mm Hg) o X RR diastolyc (mm Hg) o X Triglycerides (mg/dl) o X Cholesterol (mg/dl) o ( ) X HDL (mg/dl) p LDL (mg/dl) o ( ) X Fasting serum glucose (mg/dl) o X Smoking Yes No RR ¼ relative risk for IIEF5 score 5 11 versus (795% CI); P-value according to multiple regression analysis. Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; RR, relative risk. Values in bold are significant. damage in terms of endothelial dysfunction is known to be triggered primarly by dsyregulation of lipid metabolism. A significant effect caused by nicotine abuse or hypertension could probably be seen in an older cohort with already established atherosclerosis. In fact, the impact of lipid metabolism on ED is well known. As the first one, Juenemann et al. 14 reported, in 1990, a marked increase of LDL and a decrease of HDL fractions in patients with vasculogenic impotence as compared to those with nonvasculogenic erectile dysfunction. In 1994, the Massachusetts Male Aging Study Group reported that the probability of complete impotence was 0% in the older men with HDL values more than 90 mg/dl, whereas the probability increased to 7.2 and 16.1%, respectively when the HDL values dropped to 60 or 30 mg/dl. 8 Just recently, Nikoobakth et al. 15 also reported on results compareable to ours, revealing LDL and total cholesterol as significant risk factors for ED with a relative risk between 1.74 and Furthermore, several animal studies were able to demonstrate a significant effect of hyperlipidemia on erectile function. 16,17 As a consequence, just recently Saltzman et al. 18 reported on a significant improvement of ED in men with hyperlipidemia as the only risk factor for ED when treated with statins. We interprete the impact of lipid metabolism dysregulation on ED as a consequence of its key role in endothelial dsyfunction as the first step in the development of atherosclerosis. 19 Endothelial dysfunction is associated with high oxidative stress, mainly triggered by increased levels of LDL. 20 It has been suggested that the impairment of endotheliumdependent relaxation in hypercholesterolemia and atherosclerosis might be due to impaired ability to synthesize or release NO, which is an endotheliumderived factor. 21 According to results deriving from an animal model, reduced NO-synthase may be a central link causing an impaired endothelium-dependent relaxation of cavernous smooth muscle in hypercholesterolemia. 22 The authors of this study conclude, that hypercholesterolemia may cause impairment of endothelium-dependent relaxation and that oxidized LDL is the major causative cholesterol of the impaired relaxation response. 22 Conclusion In contrast to BP, glucose metabolism and nicotine abuse, increased levels of LDL and total cholesterol turned out to be significantly involved in the early genesis of ED. These findings support the theory of endothelial dysfunction as a key process in vasculogenic forms of impotence. References 1 NIH Consensus Development Panel on Impotence. NIH Consensus Conference: impotence. JAMA 1993; 270: Lue TF. Erectile dysfunction. N Engl J Med 2000; 342: Ataya IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999; 84: Boyle P. Epidemiology of erectile dysfunction. In: Carson C, Kirby R, Goldstein I (eds). Textbook of Erectile Dysfunction. Oxford: Isis Medical Media, 1999, pp Walczak MK, Lokhandwala N, Hodge MB, Guay AT. Prevalence of cardiovascular risk factors in erectile dysfunction. J Gend Specif Med 2002; 5: Seftel AD, Sun P, Swindle R. The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in men with erectile dysfunction. J Urol 2004; 171:

5 7 Ponholzer A, Temml C, Mock K, Marszalek M, Obermayr R, Madersbacher S. Prevalence and risk factors for erectile dysfunction in men using a validated questionnaire. Eur Urol 2005; 47: Feldman HA, Goldstein I, Hatzichristou DG. Impotence and its medical and psychological correlates: results from the Massachusetts Male Aging Study. J Urol 1994; 151: Melman A, Gingell JC. The epidemiology and pathophysiology of erectile dysfunction. J Urol 1999; 161: Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999; 341: Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JI et al. The seventh report of the joint national committee on prevention, detection, evaluation and treatment of high blood pressure. JAMA 2003; 289: The expert committee on the diagnosis and classification of diabetes mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26: S5 S Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: Juenemann KP, Muth S, Rohr G, Siegsmund M, Alken P. Does lipid metabolism influence the pathogenesis of vascular impotence? Int J Impotence Res 1990; 2(Suppl 2): Nikoobakht M, Nasseh H, Pourkasmaee M. The relationship between lipid profile and erectile dysfunction. Int J Impot Res 2005; 17: Ahn TY, Gomez-Coronado D, Martinez V, Cuevas P, Goldstein I, Saenz de Tejada I. Enhanced contractility of rabbit corpus cavernosum smooth muscle by oxidized low density lipoproteins. Int J Impotence Res 1999; 11: Seo KK, Yun HY, Kim H, Kim SC. Involvement of endothelial nitric oxide synthase in the impaired endothelium-dependent relaxation of cavernous smooth muscle in hypercholesterolemic rabbit. J Androl 1999; 20: Saltzman EA, Guay AT, Jacobson J. Improvement in erectile function in men with organic erectile dysfunction by correction of elevated cholesterol levels: a clinical observation. J Urol 2004; 172: Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation 2004; 109: III Brevetti G, Martone VD, de Cristofaro T. High levels of adhesion molecules are associated with impaired endothelium-dependent vasodilation in patients with peripheral arterial disease. Thromb Maemost 2001; 85: Sreeharan N, Jayakody RL, Senaratne MPJ, Thomson ABR, Kappagoda CT. Endothelium-dependent relaxation and experimental atherosclerosis in the rabbit aorta. Can J Physiol Pharmacol 1986; 64: Kim SC. Hyperlipidemia and erectile dysfunction. Asian J Androl 2000; 2: