Erectile Function in Subjects With the Metabolic Syndrome

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1 1 von :33 To Print: Click your browser's PRINT button. NOTE: To view the article with Web enhancements, go to: Mediterranean Diet Improves Erectile Function in Subjects With the Metabolic Syndrome K Esposito; M Ciotola; F Giugliano; M De Sio; G Giugliano; M D'armiento; D Giugliano Int J Impot Res. 2006;18(4): Nature Publishing Group Posted 07/19/2006 Abstract and Introduction Abstract Men with the metabolic syndrome demonstrate an increased prevalence of erectile dysfunction (ED). In the present study, we tested the effect of a Mediterranean-style diet on ED in men with the metabolic syndrome. Men were identified in our database of subjects participating in controlled trials evaluating the effect of lifestyle changes and were included if they had a diagnosis of ED associated with a diagnosis of metabolic syndrome, complete follow-up in the study trial, and intervention focused mainly on dietary changes. Sixty-five men with the metabolic syndrome met the inclusion/exclusion criteria; 35 out of them were assigned to the Mediterranean-style diet and 30 to the control diet. After 2 years, men on the Mediterranean diet consumed more fruits, vegetables, nuts, whole grain, and olive oil as compared with men on the control diet. Endothelial function score and inflammatory markers (C-reactive protein) improved in the intervention group, but remained stable in the control group. There were 13 men in the intervention group and two in the control group (P=0.015) that reported an IIEF score of 22 or higher. Mediterranean-style diet rich in whole grain, fruits, vegetables, legumes, walnut, and olive oil might be effective per se in reducing the prevalence of ED in men with the metabolic syndrome. Introduction The metabolic syndrome consists of a constellation of factors that raise the risk of cardiovascular disease and type 2 diabetes. Recent estimates indicate that the metabolic syndrome is highly prevalent in the US, with an estimated 24% of the adult population affected. [1] Its clinical identification is based on measures of abdominal obesity, atherogenic dyslipidemia, raised blood pressure, and glucose intolerance. [2] The etiology of this syndrome is largely unknown, but presumably represents a complex interaction between genetic, metabolic, and environmental factors, including diet. [3,4] Several recent studies also suggest that a proinflammatory state and endothelial dysfunction also associate with the metabolic syndrome. [5,6,7,8,9,10] We have recently shown that subjects with the metabolic syndrome had increased prevalence of erectile dysfunction (ED) (26.7 vs 13%, P=0.03); moreover, there was an increase in ED prevalence (International Index of Erectile Function, IIEF <21) as the number of components of the metabolic syndrome increased, suggesting that the cumulative burden of cardiovascular risk may be central to the pathogenesis of ED. [11] Mediterranean-style diet rich in whole grain, fruits, vegetables, legumes, walnut, and olive oil might be effective in reducing both the prevalence of the metabolic syndrome and the cardiovascular risk associated with. [12] One of the mechanisms responsible for the cardioprotective effect of such diet may be through reduction of the low-grade inflammatory state associated with the metabolic syndrome.

2 2 von :33 In the present study, we analyzed the effect of Mediterranean diet on ED in subjects with the metabolic syndrome. Subjects and Methods Men were identified in our database of subjects participating in randomized controlled trials evaluating the effect of lifestyle changes. [12,13] To be included in the present analysis, men must have the following: a diagnosis of ED; a diagnosis of metabolic syndrome; complete follow-up in the study trial; intervention focused mainly on dietary changes. Metabolic syndrome was diagnosed as recommended by the Adult Treatment Panel III: [2] (1) abdominal adiposity as defined by a waist circumference of >102 cm in men and >88 cm in women; (2) low serum HDL-cholesterol (<40 or <50 mg/dl in men and women, respectively); (3) hypertriglyceridemia as defined by an elevated triglyceride of 150 mg/dl; (4) elevated blood pressure as defined by a blood pressure of at least 130/85 mmhg; and (5) abnormal glucose homeostasis as defined by a fasting plasma glucose concentration of 110 mg/dl. Erectile function was assessed by completing the IIEF-5 which consists of Items 5, 15, 4, 2, and 7 from the full-scale IIEF-15. [14] A score of 21 or less indicates the presence of ED. The abbreviated score was used for its simplicity and immediacy. Subjects were excluded if they had clinical or instrumental signs or symptoms of cardiovascular disease, psychiatric problems, a history of alcohol abuse (at least 500 g alcohol/week in the last year), or if they smoked or took any medication. Sixty-five men with the metabolic syndrome met the inclusion/exclusion criteria to be enrolled in the study; 35 out of them were assigned to the intervention diet and 30 to the control diet. Subjects in the intervention diet were given detailed advice about the usefulness of the experimental diet. The program involved education on reducing, if needed, dietary calories, personal goal-setting, and self-monitoring (food diaries) through a series of monthly small-group sessions. Behavioral and psychological counseling was also offered. The dietary advice was tailored to each subject on the basis of 3-day food records. The recommended composition of the dietary regimen was the following: carbohydrates 50-60%, proteins 15-20%, total fat <30%, saturated fat <10%, and <300 mg of cholesterol consumed per day. Moreover, subjects were advised to consume at least g of fruits, g of vegetables, and g of nuts per day; in addition, they were also encouraged to consume 400 g of whole grains daily (legumes, rice, maize, and wheat) and to increase the consumption of olive oil. Subjects were also advised to increase consumption of fish and to reduce intake of red or processed meat. Patients were in the program for 24 months and had monthly sessions with the nutritionist for the first year, and bimonthly sessions for the second year. Compliance with the program was assessed by attendance at the meetings and completion of the diet diaries. Subjects in the control diet were given general oral and written information about healthy food choices at baseline and at subsequent visits, but no specific individualized program was offered to them. Subjects for both groups also received guidance on increasing their level of physical activity, mainly walking for a minimum of 30 min per day, but also swimming or aerobic ball games. Height and weight were recorded with participants wearing lightweight clothing and no shoes using a Seca 200 scale with attached stadiometer (Seca, Hamburg, Germany). Nutrient intakes (24 h) were calculated with food-composition tables and patients' weekly diet diaries. All subjects were asked to complete for 3 days a record a food intake, and to record occupational, household, and leisure time physical activity, to assess dietary adherence and exercise activity. Foods were measured using standard measuring cups and spoons and weight-approximation diagrams. Endothelial Function Endothelial function was assessed with the L-arginine test, as previously described. [15,16] Briefly, after connecting men to a device for automatic measurements of blood pressure and heart rate (Finapres, Omheda 2300, Englewood, CA, USA), an intravenous bolus of 3 g L-arginine (10 ml of a 30% solution of L-arginine monochloride), the natural precursor of nitric oxide, was injected intravenously within 60 s. Blood pressure and platelet aggregation response to 1.25 µm adenosin diphosphate (ADP) were measured before and 10 min after L-arginine injection. We developed a score in which both responses were summed up: for blood pressure, 1 point was attributed to a response of mean blood pressure <2 mmhg, 2 points for a response between 2 and 3 mmhg, 3 points for a response between 3 and 4 mmhg, 4 points for a response between 4 and 5 mmhg, and 5 points for a response >5 mmhg; for platelet aggregation, 1 point for a response <2.5%, 2 points for a response between 2.5 and 5%, 3 points between 5 and 7.5%, 4 points between 7.5 and 10%, and 5 points for a response >10%. In our laboratory, the mean blood pressure and platelet aggregation decreases following the L-arginine bolus (difference between basal and 10 min values) in a matched control group of healthy men and women (n=50/50) were -6.5±1.5 mmhg and -13±3%, respectively, which correspond to the maximal score of 10. Laboratory Analysis

3 3 von :33 Assays for serum total and high-density lipoprotein cholesterol, triglyceride, and glucose levels were performed in the hospital's chemistry laboratory. Plasma insulin levels were assayed by radioimmunoassay (Ares, Serono). Serum samples for CRP levels were stored at -80 C until assay. High-sensitivity CRP was assayed by immunonephelometry on Behring Nephelometer 2 (Dade Behring, Marburg, Germany). Statistical Analysis Data are presented as mean±s.d. unless stated otherwise. We compared baseline data using a t-test for continuous variables and Wilcoxon test for CRP. We compared risk factors and nutrient intakes after 2 years using a test based on the values at the end of follow-up and a t-test based on differences from baseline. The effects of intervention on IIEF score, indices of endothelial function, and CRP levels were tested by means of paired t-tests and a Wilcoxon matched test. The χ 2 -test was used for comparing proportions of men in the two groups that obtained normal erectile function after treatment. Multivariate regression analysis tested the independent association and contribution of changes in nutrient intake, BMI, waist, physical activity, indices of endothelial function, and plasma CRP concentrations with the dependent variable (changes in IIEF score), also including baseline IIEF score as covariate. P<0.05 was considered significant. All analysis were conducted using SPSS version 9.0 (SPSS Inc., Chicago, IL, USA). Results The clinical and metabolic characteristics of participants are shown in Table 1. Both groups were comparable, including the mean erectile function score, with values ranging from 9 to 20 in the intervention group and from 8 to 20 in the control group. There was no need for any medication for chronic diseases, such as hypertension, diabetes or dyslipidemia in the course of the study in both groups. Baseline data showed no important difference in the nutrient intake between the two groups ( Table 2 ). After 2 years, men on the Mediterranean diet consumed a greater percentage of calories from polyunsaturated and monounsaturated fat; had a greater intake of omega-3 fatty acids; and lower saturated fat than had controls. Total fruit, vegetable, nuts, and whole grain intakes and olive oil consumption were also significantly higher in the intervention group. The level of physical activity increased in both groups (intervention group: 38 min/week; control group: 35 min/week) without any difference between them. After 2 years, men on the intervention diet had a significant decrease in glucose, insulin, LDL-cholesterol, triglycerides, and blood pressure, and a significant increase of HDL-cholesterol ( Table 3 ). Fourteen men in the intervention group had impaired fasting glucose (between 110 and 125 mg/dl) at baseline and six had frank diabetes (fasting glucose >126 mg/dl); the corresponding number after diet were eight and three, respectively (P<0.05). There was no significant change in any of these parameters in the control group, nor in the prevalence of IGF or diabetes (10 men with IFG and four men with diabetes). Serum concentrations of CRP were significantly reduced in those on the Mediterranean diet compared with controls. Endothelial function score also improved in the intervention group. Erectile function score also improved in the intervention group ( Table 4 ). There were 13 men in the intervention group and two in the control group (P=0.015) that reported an IIEF score of 22 or higher. Thus, about one third of men of the intervention group regained a normal sexual function. Only two men in the control group reported an IIEF score below 1 s.d. of baseline, indicating worsening of ED. In the intervention group, changes in IIEF score were related to increased intake of fruits, vegetables, nuts, and legumes (P<0.01) and the ratio of polyunsaturated to saturated lipids (P<0.02). These associations remained significant after performing a multivariate analysis in which IIEF score was the dependent variable and BMI, waist, level of physical activity, endothelial function score, baseline IIEF score, and serum CRP concentrations were the independent variables. Nutrient intake (34% of the variance, P=0.01), endothelial function score (14% of the variance, P=0.045), and CRP (16% of the variance, P=0.03) were independent predictors of IIEF score and explained near 64% of the variability in its changes. Discussion In this study, we tested the hypothesis that a Mediterranean-style diet would induce amelioration of erectile function in men with the metabolic syndrome. The physiological rationales underlying this hypothesis are that: (a) healthy lifestyle factors are associated with maintenance of good erectile function in men; [17] (b) the metabolic syndrome associate with ED, endothelial dysfunction, and increased serum concentrations of vascular inflammatory markers; [11,18] and (c) dietary factors may be important in the development of ED. [19] Our results show that consumption of a Mediterranean-style diet in men with the metabolic syndrome and ED at

4 4 von :33 baseline produced significant improvement of erectile and endothelial functions, together with a significant reduction of systemic vascular inflammation, as indicated by the reduced levels of CRP. As a whole, these findings suggest that a Mediterranean-style diet is a strategy for amelioration of vascular functions, including erectile function. ED is an important cause of decreased quality of life in men. [20,21,22] Thirty million men in the US may have ED. [22] In the Health Professionals Follow-up Study, moderate to big problems of erectile function were present in 12, 22, and 30% of male younger than 59 years of age, years of age, and older than 69 years of age, respectively. [23] Moreover, several modifiable lifestyle factors, including physical activity and leanness, were associated with maintenance of good erectile function. For instance, men with a body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) higher than 28.7 are likely to carry a 30% higher risk for ED than those with a normal BMI (25 or lower). The mechanism by which a Mediterranean-style diet can improve ED in men with the metabolic syndrome is unclear. Macronutrient intake produces oxidative stress that leads to a proinflammatory state, [24] which has been suggested to be an important factor for impairment of endothelial function, [18] which in turn shares some common metabolic and vascular pathway with ED. [25] This intriguing evidence is also supported by the ability of antioxidant vitamins [26,27] or food antioxidants [28] to improve the transient endothelial dysfunction seen in healthy subjects after consumption of a single high-fat meal. Moreover, modulation of the fiber content of the meal may influence the cytokine milieu: increasing the fiber content (from 4.5 to 16.8 g) of a high-carbohydrate meal was associated with significant reduction of circulating interleukin-18 levels in both healthy subjects and in type 2 diabetic patients. [29] As dietary fiber may have anti-inflammatory roles, [30] it may be that the fiber content of the Mediterranean diet, eventually magnified by some other components with antioxidant capability, may influence the transient oxidative stress that occurs after macronutrient ingestion. Our data support this interpretation, as consumption of fruits, vegetables and legumes, which are rich in dietary fiber and antioxidants, remained significant determinants of IIEF changes in multivariate analysis. One limitation of this study is whether individual components of the diet can account for the changes observed, or whether the changes in metabolic risk factors are a result of the sum of all the dietary changes. Although multiple dietary interventions, as in the present study, render difficult the assessment of the effect of each one separately, the clinical utility of a whole-diet approach in the prevention of cardiovascular disease has been emphasized. [31] Moreover, we have found that a dietary pattern which was high in fruit, vegetables, nuts, whole grains, and fish but low in red and processed meat and refined grains was more represented in subjects without ED as compared with men with ED. This dietary pattern is quite similar to the traditional Mediterranean diet, [32] further supporting the role of dietary factors in improving vascular health and hence also ED. We could not quantify attrition rate of the Mediterranean diet over time as we selected only subjects who completed the follow-up of 2 years. However, the amount of drop-outs with a Mediterranean-style diet is thought to be less than that for other popular diets. [33] Lastly, we have not included a real control group without any specific dietary intervention; on the other hand, the presence of control subjects left on their usual diet might have lead to even more benefits when compared with the Mediterranean-diet group. To the best of our knowledge, these results represent the first demonstration that a Mediterranean-style diet rich in whole grain, fruits, vegetables, legumes, walnut, and olive oil might be effective per se in reducing the prevalence of ED in men with the metabolic syndrome. Lifestyle changes should include dietary patterns similar to the Mediterranean-style diet in order to obtain the best results even in the presence of modest weight loss. CLICK HERE for subscription information about this journal. Table 1. Characteristics of the Study Participants a Characteristic Mediterranean diet (n=35) Control diet (n=30) P-value Age (years) 44.3 ± ± 5.9 NS Body mass index (kg/m 2 ) 27.9 ± ± 3.8 NS Waist circumference (cm) 99 ± ± 10 NS

5 5 von :33 Plasma glucose (mg/dl) 110 ± ± 10 NS Serum insulin (µu/ml) 17 ± 6 16 ± 7 NS HOMA 3.7 ± ± 0.7 NS Serum lipids (mg/dl) Total cholesterol 215 ± ± 32 NS HDL-cholesterol 39 ± 6 40 ± 6 NS LDL-cholesterol 140 ± ± 21 NS Triglycerides 158 ± ± 64 NS Blood pressure (mmhg) Systolic 135 ± ± 8 NS Diastolic 85 ± 5 86 ± 7 NS IIEF score 14.4 ± ± 3.7 NS Endothelial function score 6.9 ± ± 1.1 NS CRP (mg/l) b 2.4 (0.76/5.1) 2.2 (0.5/5.7) NS a Data are presented as mean ± s.d. except where otherwise indicated. b Median (interquartile range). NS-Not Significant. Table 2. Nutrient Indices at Entry to Study and After 2 Years Nutrient Mediterranean diet (n=35) Total energy (kcal/day) 2450 ± ± 345 Control diet (n=30) Baseline 2 years Baseline 2 years 2410 ± ± 401 P value at 2 years Carbohydrates (%) 54 ± 5 55 ± 5 55 ± 5 56 ± 5 NS Protein (%) 15 ± 2 15 ± 2 15 ± 2 15 ± Fat (%) 31 ± 4 30 ± 4 30 ± 3 30 ± 4 NS Saturated 13 ± ± ± ± 2.6 <0.001 MUFA 10 ± ± ± ± 1.2 <0.001 PUFA 8 ± ± ± ± Omega-3 fatty acids (g/day) 0.6 ± ± ± ± 0.2 <0.001 Olive oil (g/day) 15 ± ± ± ± 2.9 <0.001 Fruits, vegetables, nuts, and legumes (g/day) NS 206 ± ± ± ± 35 <0.001 P value at 2 years indicates difference between the two interventions (Med-diet vs control diet). NS-Not Significant. Table 3. Changes in Assessed Variables After 2 Years

6 6 von :33 Variable Mediterranean diet (n=35) Mean change Control diet (n=30) Mean change P-value Body mass index (kg/m 2 ) -0.3 ± ± 0.2 NS Waist circumference (cm) -1 ± ± 0.5 NS Plasma glucose (mg/dl) -5 ± 3-1 ± 1 <0.05 Serum insulin (µu/ml) -2 ± ± 0.2 <0.05 Serum lipids (mg/dl) Total cholesterol -5 ± 4-2 ± 2 NS HDL-cholesterol +3 ± 1 0 ± 0.5 <0.05 LDL-cholesterol -10 ± 4 1 ± 2 <0.02 Triglycerides -16 ± 8-2 ± 2 <0.05 Blood pressure, mmhg Systolic -4 ± 1 0 ± <0.05 Diastolic -2 ± 1-1 ± 1 NS Endothelial function score +1.6 ± ± 0.1 <0.01 CRP (mg/l) -0.9 ± ± 0.1 <0.01 NS-Not Significant. Table 4. Changes in IIEF Score Between the Two Groups Mediterranean diet Control diet P-value Basal 14.4 ± ± 3.7 NS 2 years 18.1 ± ± 3.5 <0.01 Difference in mean change 3 ( ) a =0.01 a 95% confidence intervals. NS-Not Significant. References Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey. JAMA 2002; 287: 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: Groop L. Genetics of the metabolic syndrome. Br J Nutr 2000; 83(Suppl 1): S39â S48. Lidfeldt J, Nyberg P, Nerbrand C, Samsioe G, Schersten B, Agardh CD. Socio-demographic and psychological factors are associated with features of the metabolic syndrome: the Women's Health in the Lund Area (WHILA) study. Diabetes Obes Metab 2003; 5: Han TS, Sattar N, Williams K, Gonzalez-Villalpando C, Lean ME, Haffner SM. Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City

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8 8 von : mellitus. Am J Clin Nutr 2003; 78: King ED. Dietary fiber, inflammation, and cardiovascular disease. Mol Nutr Food Res 2005; 49: Hu FB, Willett WC. Optimal diets for prevention of cardiovascular disease. JAMA 2002; 288: Willett WC, Sacks F, Trichopoulou A, Drescher G, Ferro-Luzzi A, Helsing E et al. Mediterranean diet pyramid: a cultural model for healthy eating. Am J Clin Nutr 1995; 61 (Suppl 6): S1402-S1406. Parikh P, McDaniel MC, Ashen MD, Miller JI, Sorrentino M, Chan V et al. Diets and cardiovascular disease. An evidence-based assessment. Am J Coll Cardiol 2005; 45: Reprint Address Correspondence: Dr K Esposito, Division of Metabolic Diseases, University of Naples SUN, Piazza Miraglia, Naples 80138, Italy. katherine.esposito@unina2.it K Esposito, 1 M Ciotola, 1 F Giugliano, 2 M De Sio, 2 G Giugliano, 3 M D'armiento 2 and D Giugliano 1 1 Division of Metabolic Diseases, University of Naples SUN, Naples, Italy 2 Division of Urology, University of Naples SUN, Naples, Italy 3 Plastic and Reconstructive Surgery, University of Rome 'La Sapienza', Rome, Italy