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Weight Gain and Erectile Dysnfunction

JAMA. 2004;291(24):2978-2984 (doi:10.1001/jama.291.24.2978)
Katherine Esposito; Francesco Giugliano; Carmen Di Palo; et al.
Obese Men: A Randomized Controlled Trial
Effect of Lifestyle Changes on Erectile Dysfunction in
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Controlled Trial
Men's Health; Men's Sexual Function; Public Health; Obesity; Randomized
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Erectile Dysfunction in Obese Men
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ORIGINAL CONTRIBUTION
Effect of Lifestyle Changes on
Erectile Dysfunction in Obese Men
A Randomized Controlled Trial
Katherine Esposito, MD
Francesco Giugliano, MD
Carmen Di Palo, MD
Giovanni Giugliano, MD
Raffaele Marfella, MD, PhD
Francesco D’Andrea, MD
Massimo D’Armiento, MD
Dario Giugliano, MD, PhD ERECTILE DYSFUNCTION IS AN IMportant
cause of decreased quality
of life in men,1-3 and may
affect an estimated 30 million
men in the United States.3 In the Health
Professionals Follow-up Study, moderate
to severe erectile dysfunction was
reported by 12% of men younger than
59 years; 22% of men aged 60 to 69
years; and 30% of men older than
69 years.4
Moreover, several modifiable lifestyle
factors, including physical activity
and leanness, were associated with
maintenance of 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 have a 30%
higher risk for erectile dysfunction than
those with a normal BMI (25).4 The
prevalence of overweight or obesity in
men reporting symptoms of erectile
dysfunction may be as high as 79%,5 although
vascular risk factors commonly
associated with obesity also may
play an important role.6
Obesity is an independent risk factor
for cardiovascular disease,7 and is
associated with elevated levels of several
proinflammatory cytokines, such
as interleukin 6 (IL-6), interleukin 8
(IL-8), and C-reactive protein (CRP),
Author Affiliations: Center for Obesity Management
(Drs Esposito and Di Palo), Division of Metabolic
Diseases (Drs D. Giugliano and Marfella),
Departments of Urology (Drs F. Giugliano and
D’Armiento), and Plastic and Reconstructive Surgery
(Drs G. Giugliano and D’Andrea), and Center
of Excellence in Cardiology (Drs Esposito, Marfella,
and D. Giugliano), Second University of Naples,
Naples, Italy.
Corresponding Author: Katherine Esposito, MD, Center
for Obesity Management, Department of Geriatrics
and Metabolic Diseases, Policlinico Universitario,
Piazza L. Miraglia, 80138 Naples, Italy (katherine
. This e-mail address is being protected from spambots. You need JavaScript enabled to view it ).
Context Healthy lifestyle factors are associated with maintenance of erectile function
in men.
Objective To determine the effect of weight loss and increased physical activity on
erectile and endothelial functions in obese men.
Design, Setting, and Patients Randomized, single-blind trial of 110 obese men
(body mass index 30) aged 35 to 55 years, without diabetes, hypertension, or hyperlipidemia,
who had erectile dysfunction that was determined by having a score of
21 or less on the International Index of Erectile Function (IIEF). The study was conducted
from October 2000 to October 2003 at a university hospital in Italy.
Interventions The 55 men randomly assigned to the intervention group received detailed
advice about how to achieve a loss of 10% or more in their total body weight by
reducing caloric intake and increasing their level of physical activity. Men in the control
group (n=55) were given general information about healthy food choices and exercise.
Main Outcomes Measures Erectile function score, levels of cholesterol and tryglycerides,
circulating levels of interleukin 6, interleukin 8, and C-reactive protein, and endothelial
function as assessed by vascular responses to L-arginine.
Results After 2 years, body mass index decreased more in the intervention group (from
a mean [SD] of 36.9 [2.5] to 31.2 [2.1]) than in the control group (from 36.4 [2.3] to
35.7 [2.5]) (P.001), as did serum concentrations of interleukin 6 (P=.03), and Creactive
protein (P=.02). The mean (SD) level of physical activity increased more in the
intervention group (from 48 [10] to 195 [36] min/wk; P.001) than in the control group
(from 51 [9] to 84 [28] min/wk; P.001). The mean (SD) IIEF score improved in the
intervention group (from 13.9 [4.0] to 17 [5]; P.001), but remained stable in the control
group (from 13.5 [4.0] to 13.6 [4.1]; P=.89). Seventeen men in the intervention
group and 3 in the control group (P=.001) reported an IIEF score of 22 or higher. In
multivariate analyses, changes in body mass index (P=.02), physical activity (P=.02),
and C-reactive protein (P=.03) were independently associated with changes in IIEF score.
Conclusion Lifestyle changes are associated with improvement in sexual function
in about one third of obese men with erectile dysfunction at baseline.
JAMA. 2004;291:2978-2984 www.jama.com
See also p 3011 and Patient Page.
2978 JAMA, June 23/30, 2004—Vol 291, No. 24 (Reprinted) ©2004 American Medical Association. All rights reserved.
Downloaded from www.jama.com by guest on June 25, 2009
a marker of inflammation.8-11 Markers
of low-grade inflammation are positively
associated with endothelial dysfunction
in human obesity.8,10 Erectile
and endothelial dysfunctions may have
some shared pathways12 through a defect
in nitric oxide activity, which may
be inhibited through age-, disease-, and
behavioral-related pathways. In theory,
intervention in modifiable health behaviors,
especially reducing body
weight and increasing physical activity,
may reduce the risk of both erectile
dysfunction and endothelial dysfunction
in obese men, but this
hypothesis has not been tested.
The aim of this randomized controlled
trial of obese men with erectile
dysfunction was to determine if lifestyle
changes designed to obtain a sustained
and long-term reduction in body
weight (10% of initial weight maintained
for 2 years) and an increase in
physical activity positively affect erectile
and endothelial functions.
METHODS
Obese men with erectile dysfunction,
aged 35 to 55 years, were recruited from
the outpatient department for weight
loss at the Second University of Naples,
Naples, Italy, in October 2000. The trial
ended in October 2003. Erectile function
was assessed by completing questions
1 to 5 on the International Index
of Erectile Function (IIEF), which is a
multidimensional questionnaire.13 The
5 questions asked were (1) How often
were you able to get an erection during
sexual activity?; (2)Whenyou had erections
with sexual stimulation, how often
were your erections hard enough for
penetration?; (3) When you attempted
sexual intercourse, how often were you
able to penetrate (enter) your partner?;
(4) During sexual intercourse, how often
were you able to maintain your erection
after you had penetrated (entered)
your partner?; and (5) During sexual intercourse,
how difficult was it to maintain
your erection to completion of intercourse?
The IIEF score represents the
sum of questions 1 to 5, with a maximum
score of 25; a score of 21 or less
indicates erectile dysfunction.
Weassessed 140menwith IIEF scores
lower than 22 to determine eligibility.
These men had no evidence of participation
in diet reduction programs within
the last 6 months and had completed a
health and medical history questionnaire,
which served as a screening tool.
Exclusion criteria were diabetes mellitus
or impaired glucose tolerance (plasma
glucose levels of 140-200 mg/dL [7.8-
11.1 mmol/L] 2 hours after a 75-g oral
glucose load), impaired renal function,
including macroalbuminuria, pelvic
trauma, prostatic disease, peripheral or
autonomic neuropathy, hypertension
(blood pressure140/90mmHg), cardiovascular
disease, psychiatric problems,
use of drugs or alcohol abuse
(500 g of alcohol per week in the last
year). After the exclusion of 30 ineligible
men, 110 obese, sedentary (1
hour per week of physical activity) men
were enrolled in the trial. The study was
approved by the institutional committee
of ethical practice at the Second University
of Naples. Participants provided
informed written consent for voluntary,
unpaid participation.
Men were randomly assigned to
either the intervention or control group
using a computer-generated random
number sequence (FIGURE 1). Allocation
was concealed in sealed study folders
that were maintained at a central,
secure location until after informed consent
was obtained. The nurses who
scheduled the study visits did not have
access to the randomization list. However,
the staff members involved in the
intervention had to be aware of the
group assignment; thus, the study was
only partially blinded. Laboratory staff
did not know the participants’ group
assignments.
Men in the intervention group were
given detailed advice about how to
achieve a reduction in total body weight
of 10% or more. The program consisted
of instruction regarding reducing
caloric intake, setting goals, and selfmonitoring
(food diaries) through a
series of monthly small group sessions.
Behavioral and psychological
counseling was also offered. The mean
daily caloric intake was 1700 kcal for
the first year and 1900 kcal for the second
year. The recommended composition
of the dietary regimen per 1000
kcal was carbohydrates, 50% to 60%;
proteins, 15% to 20%; total fat, less than
30%; saturated fat, less than 10%;monounsaturated
fat, 10% to 15%; polyunsaturated
fat, 5% to 8%; and fiber, 18
g. Dietary advice was tailored to each
man on the basis of food records collected
on 3 nonconsecutive days and
completed the week before the meeting
with the nutritionist. Thesemenalso
received individual guidance on increasing
their level of physical activity,
mainly walking, but also swimming or
aerobic games (ie, football, baseball,
soccer). Men were in the program for
2 years. They had monthly sessions with
the nutritionist and exercise trainer during
the first year and bimonthly sessions
during the second year. Compliance
with the program was assessed by
attendance at the meetings and completion
of the food diaries.
Men in the control group were given
general oral and written information
about healthy food choices and exercise
at baseline and at subsequent bimonthly
visits, but no specific individualized
program was provided.
Height and weight were recorded
with participants wearing lightweight
clothing and no shoes using a Seca 200
Figure 1. Flow of Patients Through the Trial
30 Ineligible
20 Did Not Meet
Protocol
Eligibility Criteria
10 Unwilling to
Participate
140 Men Assessed for Eligibility
3 Withdrew
and Declined
Follow-up
3 Withdrew
and Declined
Follow-up
55 Assigned
to Control
Group
55 Assigned to
Intervention
Group
55 Included in
Analysis
55 Included in
Analysis
110 Randomized
ERECTILE DYSFUNCTION IN OBESE MEN
©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, June 23/30, 2004—Vol 291, No. 24 2979
Downloaded from www.jama.com by guest on June 25, 2009
scale (Seca, Hamburg, Germany) with
attached stadiometer. Waist-to-hip ratio
(WHR) was calculated as waist circumference
in centimeters divided by
hip circumference in centimeters.
Twenty-four hour nutrient intakes were
calculated with food-composition tables
and patients’ weekly food diaries. All
men were asked to complete a record
of food intake for 3 days to assess dietary
adherence and to record occupational,
household, and leisure-time
physical activity to assess exercise activity.
Foods were measured using standard
measuring cups and spoons and
weight-approximation diagrams. No
participants in either group took any
drug specific for erectile dysfunction at
baseline (exclusion criterion); however,
if during the course of the study
there was a need for such use, this was
discussed and recorded.
Endothelial function was assessed
with the L-arginine test, as previously
described.14 Briefly, an intravenous bolus
of 3 g of L-arginine (10 mL of a 30%
solution of L-arginine monochloride),
the natural precursor of nitric oxide,
was injected intravenously within 60
seconds. Blood pressure and platelet aggregation
response to 1.25 μmol of
adenosine diphosphate were measured
before L-arginine injection and after
10 minutes. L-arginine mimics some
of the effects of nitric oxide, including
vasodilatation and antiplatelet activity;
because the vascular effects of Larginine
are thought to derive from
metabolic conversion to nitric oxide, the
L-arginine test has been used for evaluating
endothelial function.15 In our laboratory,
following the L-arginine bolus
(difference between basal and 10-
minute values) in a matched control
group of nonobese men (n=50), there
was a decrease in platelet aggregation
by 13% and a mean (SD) decrease in
blood pressure by 6.5 (1.5) mm Hg.4
Assays for serum levels of total and
high-density lipoprotein cholesterol, triglycerides,
and glucose were performed
in the hospital’s chemistry laboratory.
Plasma insulin levels were
assayed by radioimmunoassay (Ares, Serono,
Italy). Serum samples for cytokine
and CRP levels were stored at
−80°C prior to being assayed. Serum
concentrations of IL-6 and IL-8 were determined
in duplicate using a highly sensitive,
quantitative sandwich enzyme assay
(Quantikine HS, R&D Systems,
Minneapolis, Minn). High-sensitivity
CRP was assayed by immunonephelometry
on Behring Nephelometer 2 (Dade
Behring, Deerfield, Ill). In our laboratory,
the medians (interquartile ranges)
for these values were 2.1 pg/mL (0.3-
5.2 pg/mL) for IL-6; IL-8, 3.1 pg/mL
(0.8-6.2 pg/mL); and CRP, 0.7 mg/L
(0.2-3.2 mg/L). These values are based
on 50 healthy, nonobese men who were
matched to obese men for age and metabolic
characteristics.
Data are presented as mean (SD) unless
otherwise indicated and were analyzed
using the intention-to-treat principle.
Wecompared baseline data using
a t test for continuous variables and the
Wilcoxon test for IL-6, IL-8, and CRP.
We compared risk factors and nutrient
intake after 2 years using a t test based
on the values at the end of follow-up and
a t test based on differences from baseline.
Results of the analysis omitting patients
lost during follow-up did not differ
from that including the last available
records; data are therefore shown for the
analysis that includes all men as randomized.
Spearman rank correlation coefficients
were used to quantify the relationships
between metabolic variables
and cytokine levels. The effects of intervention
on IIEF score, indices of endothelial
function, and cytokine levels
were tested by means of paired t tests and
a Wilcoxon matched test. The 2 test was
used for comparing proportions of men
in the 2 groups that obtained erectile
function after treatment. Multivariate regression
analysis tested the independent
association and contribution of
changes in BMI, WHR, physical activity,
indices of endothelial function, and
plasma cytokine concentrations with the
dependent variable (changes in IIEF
score), and also included baseline IIEF
score as a covariate. P.05 was consid-
Table 1. Characteristics of the Study Participants*
Characteristic
Intervention Group
(n = 55)
Control Group
(n = 55)
P
Value
Age, y 43.5 (4.8) 43 (5.1) .62
Weight, kg 103 (9.4) 101 (9.7) .55
Body mass index† 36.9 (2.5) 36.4 (2.3) .65
Waist-to-hip ratio 1.02 (0.09) 1.01 (0.09) .75
Erectile dysfunction score‡ 13.9 (4) 13.5 (4) .55
Blood pressure, mm Hg
Systolic 127 (7.5) 128 (7.7) .49
Diastolic 86 (3.7) 85 (4.1) .48
Cholesterol level, mg/dL
Total 213 (32) 210 (29) .45
High-density lipoprotein 39 (10) 40 (9) .76
Triglycerides, mg/dL 169 (56) 174 (51) .23
Glucose, mg/dL 103 (10) 104 (11) .77
Insulin, μU/mL 21 (8) 19 (7) .35
Interleukin, pg/mL§
6 4.5 (1.9-9) 4.4 (2-8.6) .39
8 5.3 (2.3-10) 5.0 (2.2-9.7) .45
C-reactive protein, mg/L§ 3.3 (1.2-8.1) 3.4 (1.2-8.3) .37
Response to L-arginine
Platelet aggregation, % −4 (2.2) −3.6 (2.1) .19
Mean blood pressure, mm Hg −2.5 (1.3) −2.4 (1.4) .27
SI conversion factors: To convert total cholesterol and high-density lipoprotein cholesterol from mg/dL to mmol/L, multiply
by 0.0259; glucose from mg/dL to mmol/L, multiply by 0.0555; insulin from μU/mL to pmol/L, multiply by 7.175;
and triglycerides from mg/dL to mmol/L, multiply by 0.0113.
*Data are presented as mean (SD) unless otherwise indicated.
†Calculated as weight in kilograms divided by the square of height in meters.
‡Based on the International Index of Erectile Function (range, 1-25).
§Data are presented as median (interquartile range).
ERECTILE DYSFUNCTION IN OBESE MEN
2980 JAMA, June 23/30, 2004—Vol 291, No. 24 (Reprinted) ©2004 American Medical Association. All rights reserved.
Downloaded from www.jama.com by guest on June 25, 2009
ered statistically significant. All analysis
were conducted using SPSS statistical
software (version 9.0, SPSS Inc,
Chicago, Ill).
RESULTS
One hundred ten men were randomly
assigned to the intervention (n=55) or
control group (n=55) (Figure 1). Both
groups were comparable and relatively
healthy (TABLE 1). The prevalence of
smokerswassimilar in the2groups:27%
in the intervention group and31%in the
control group (P=.34). All men were
obese, with BMI values ranging from 30
to 49. The mean erectile function score
was also comparable between groups
with values ranging from 7 to 19 in the
intervention group and from 7 to 20 in
the control group. As expected for an
obese male population, serum IL-6, IL-8,
and CRP levels were higher than previously
reported in nonobese men.8,11
Spearman rank correlation coefficients
between IIEF score and metabolic variables
are shown in TABLE 2. Univariate
correlations are provided, but they were
scarcely affected by adjustment for age.
Erectile function score was positively
associated with mean blood pressure
responses to L-arginine and negatively
associated with BMI, WHR, and CRP.
After 2 years of follow-up, there were
3 dropouts in the intervention group
and 3 in the control group, all of which
occurred after 24 weeks of follow-up.
Dropouts from the intervention group
showed a decrease in body weight after
24 weeks of follow-up, suggesting
that they were adhering to the lifestyle
changes. Five men in the control group
and 4 in the intervention group used
pharmacological therapy for erectile
dysfunction (phosphodiesterase type 5
inhibitors) during the course of the
study; however, excluding these men
in the analysis did not affect the results,
and therefore data are pooled for
all participants.
Baseline data showed no important
difference in nutrient intake between the
2 groups (TABLE 3). After 2 years, patients
in the intervention group compared
with the control group consumed
a greater percentage of calories
from complex carbohydrates, protein,
and monounsaturated fat; had a greater
intake of fiber; had a lower ratio of
omega-6 to omega-3 fatty acids; and had
lower intakes of total calories, saturated
fat, and cholesterol (Table 3). The
level of physical activity increased more
in the intervention group (from 48 [10]
to 195 [36] min/wk) than in the control
group (from 51 [9] to 84 [28] min/
wk; P.001).
After 2 years, men in the intervention
group had significant decreases in
body weight, BMI, WHR, blood pressure,
levels of glucose, insulin, total
cholesterol and triglycerides, but a significant
increase in high-density lipoprotein
cholesterol (TABLE 4). There
was no significant change in these parameters
among men in the control
group (Table 4). Serum concentrations
of IL-6 and CRP were significantly
reduced in the intervention
group compared with the control group.
Erectile function score improved in the
intervention group, but remained stable
in the control group (FIGURE 2). Seventeen
men in the intervention group
and 3 in the control group (P=.001) reported
an IIEF score of 22 or higher.
Thus, 31% of men in the intervention
group regained sexual function.
In the intervention group, changes
in IIEF score were related to the reduc-
Table 2. Correlations With Erectile
Dysfunction Score in Obese Men (N = 110)
Characteristic
Correlation
Coefficient
P
Value
Weight −0.45 .01
Body mass index −0.37 .02
Waist-to-hip ratio −0.49 .007
Cholesterol level
Total −0.15 .06
High-density
lipoprotein
0.08 .09
Triglycerides −0.09 .12
Glucose −0.08 .15
Insulin −0.04 .24
Interleukin*
6 −0.10 .06
8 −0.17 .05
C-reactive protein* −0.25 .03
Response to L-arginine
Platelet aggregation 0.14 .06
Mean blood pressure 0.28 .03
*Log-transformed data.
Table 3. Nutrient Indices at Entry to Study and After 2 Years
Nutrient
Intervention Group (n = 55) Control Group (n = 55)
Corrected
Difference
in Mean Change
at 2 Years (95% CI)
P Value
at 2 Years
Mean (SD)
P
Value
Mean (SD)
P
Baseline 2 Years Baseline 2 Years Value
Total energy, kcal/d 2340 (205) 1950 (168) .01 2390 (215) 2340 (174) .07 −340 (−520 to −160) .01
Carbohydrates, %
Regular 57 (2.5) 55 (2.9) .01 57 (2.1) 57 (2.9) .56 −2 (−3.4 to −0.6) .02
Complex 43 (3.7) 50 (2.5) .001 39 (2.4) 40 (2.2) .15 6 (2 to 4) .001
Fiber, g/d 15 (1.5) 25 (1.7) .01 15 (1.6) 16 (1.8) .10 9 (5 to 13) .009
Protein, % 13 (1.9) 16 (1.7) .02 13 (1.8) 14 (1.7) .08 2.0 (0.5 to 3.5) .04
Fat, % 30 (2.6) 29 (2.7) .06 30 (3.3) 29 (2.9) .59 0 (−1 to 1) .90
Saturated 14 (2.5) 9 (1.3) .01 14 (2.4) 14 (2.5) .90 −5 (−9 to −1) .001
Monounsaturated 9 (1.4) 14 (1.7) .01 10 (1.6) 10 (1.4) .95 5 (1.5 to 8.5) .01
Polyunsaturated 7 (1.2) 6 (0.9) .07 6 (1.1) 5 (0.8) .09 0 (−1.5 to 1.5) .88
Ratio of omega-6 to omega-3 fatty acid 12 (2.4) 6 (0.9) .001 13 (2.1) 12 (1.9) .08 −5 (−9 to −1) .001
Cholesterol, mg/d 360 (39) 276 (26) .01 356 (40) 327 (31) .05 −53 (−95 to −11) .02
ERECTILE DYSFUNCTION IN OBESE MEN
©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, June 23/30, 2004—Vol 291, No. 24 2981
Downloaded from www.jama.com by guest on June 25, 2009
tions in BMI (r=−0.35; P=.02) and increases
in the level of physical activity
(r=0.40, P=.02). The relationship between
BMI and IIEF score was continuous
in this population, with no evidence
of a threshold effect. These
associations remained statistically significant
after performing a multivariate
analysis in which IIEF score was the
dependent variable and BMI, WHR,
level of physical activity, indices of endothelial
function, baseline IIEF score,
and serum CRP concentrations were the
independent variables. Body mass index
(25% of the variance; P=.02),
physical activity (26% of the variance;
P=.02), and CRP (18% of the variance;
P=.03) were independent predictors
of IIEF score and explained almost
68% of the variability in score
changes.
COMMENT
In this study, we tested the hypothesis
that lifestyle changes aimed at reducing
body weight and increasing physical
activity would induce amelioration
of erectile and endothelial
functions in obese men. The physiological
rationales underlying this hypothesis
are that healthy lifestyle factors
are associated with maintenance of
good erectile function in men4; obesity
has been positively associated with
endothelial dysfunction and increased
serum concentrations of vascular inflammatory
markers9,10; and both endothelial
and erectile dysfunction may
share some common metabolic and vascular
pathways that may be influenced
by behavioral-related pathways.
16,17
Obese men with erectile dysfunction
had evidence of abnormal endothelial
function, which was indicated
by reduced blood pressure and
platelet aggregation responses to
L-arginine and elevated serum concentrations
of markers of low-grade inflammation,
such as IL-6, IL-8, and
CRP. In the baseline cross-sectional
analysis of all 110 obese men, we observed
significant associations between
IEEF score and proxy indicators
of elevated body fat, the vascular
response to L-arginine, and circulating
IL-8 and CRP levels. The association
we found between IEEF score and
indices of endothelial dysfunction supports
the presence of common vascu-
Figure 2. Individual Changes in Erectile
Function Score of Obese Men
IIEF Score
24
16
20
12
8
4
Baseline
Intervention Group
(n = 55)
Control Group
(n = 55)
2 Years Baseline 2 Years
IIEF indicates International Index of Erectile Function.
Data markers with error bars indicate mean (SD).
Table 4. Clinical and Metabolic Characteristics of the Study Participants after 2 Years*
Characteristic
Intervention Group (n = 55) Control Group (n = 55) Corrected
Difference
in Mean Change
at 2 Years (95% CI)
P Value
2 Years at 2 Years
Mean
Change
P
Value 2 Years
Mean
Change
P
Value
Weight, kg 88 (8.5) −15 .001 99 (9.2) −2 .27 −13 (−18 to −11) .007
Body mass index† 31.2 (2.1) −5.7 .001 35.7 (2.5) −0.7 .19 −5 (−7.5 to −2.5) .001
Waist-to-hip ratio 0.93 (0.08) −0.09 .001 1.00 (0.09) −0.01 .56 −0.08 (−0.12 to −0.06) .01
Erectile dysfunction score‡ 17 (5) 3.01 .001 13.6 (4.1) 0.1 .89 3 (1.2 to 4.8) .008
Blood pressure, mm Hg
Systolic 124 (7.4) −3 .04 127 (7.8) −1 .50 −2 (−3 to −1) .01
Diastolic 82 (3.6) −4 .02 85 (4.5) 0 .98 −4 (−6.5 to −1.5) .009
Cholesterol level, mg/dL
Total 202 (24) −11 .04 212 (31) 2 .72 −13 (−23 to −3) .02
High-density lipoprotein 48 (9) 9 .001 40 (9) 0 .99 9 (5 to 13) .01
Triglycerides, mg/dL 150 (45) −19 .04 170 (47) −4 .67 −15 (−29 to −1) .05
Glucose, mg/dL 95 (8) −8 .02 103 (11) −1 .34 −7 (−12 to −2) .02
Insulin, μU/mL 14 (5) −7 .04 17 (7) −2 .09 −5 (−9 to −1) .04
Interleukin, pg/mL§
6 3.1 (0.9-7) −1.4 .04 4.5 (2.1-8.8) 0.1 .67 −1.5 (−2.9 to 0.3) .03
8 4.1 (1.3-8.9) −1.2 .05 4.7 (1.4-8.4) −0.3 .23 −0.9 (−2.0 to 0.3) .07
C-reactive protein, mg/L§ 1.9 (0.9-7.1) −1.4 .01 3.4 (1.3-8.2) 0 .67 −1.4 (−2.5 to −0.3) .02
Response to L-arginine
Platelet aggregation, % −11 (4.8) −7 .01 −4.3 (3.2) −0.7 .17 −6.3 (−9.3 to −3.3) .02
Mean blood pressure, mm Hg −5.1 (1.9) −2.6 .001 −2.6 (1.5) −0.2 .47 −2.4 (−3.2 to −1.6) .02
SI conversion factors: To convert total cholesterol and high-density lipoprotein cholesterol from mg/dL to mmol/L, multiply by 0.0259; triglycerides from mg/dL to mmol/L, multiply
by 0.0113; glucose from mg/dL to mmol/L, multiply by 0.0555; and insulin from μU/mL to pmol/L, multiply by 7.175.
*Data are presented as mean (SD) unless otherwise indicated.
†Calculated as weight in kilograms divided by the square of height in meters.
‡Based on the International Index of Erectile Function scale.
§Data are presented as median (interquartile range).
ERECTILE DYSFUNCTION IN OBESE MEN
2982 JAMA, June 23/30, 2004—Vol 291, No. 24 (Reprinted) ©2004 American Medical Association. All rights reserved.
Downloaded from www.jama.com by guest on June 25, 2009
lar pathways underlying both conditions
in obese men. A disturbance in
nitric oxide activity linked to reduced
nitric oxide availability could provide
a unifying explanation for this association.
In particular, in isolated corpus
cavernosum strips from patients with
erectile dysfunction both neurogenic
and endothelium-dependent relaxation
is impaired.18 Moreover, erectile
dysfunction in diabetic men correlates
with endothelial dysfunction and
endothelial activation, including circulating
concentrations of P-selectin
and cellular adhesion molecules.19 In
addition to being a powerful indicator
of risk, recent evidence suggests that
CRP may directly participate in lesion
formation through leukocyte activation
and endothelial dysfunction.20-22
This study provides evidence that
weight loss achieved by lifestyle
changes can ameliorate erectile function
in obese men with erectile dysfunction
at baseline. In the Massachusetts
Male Aging Study, Derby et al16
found that men who were overweight
at baseline were at an increased risk
of developing erectile dysfunction
regardless of whether they lost weight
during follow-up. By contrast, men
who initiated physical activity in
midlife had a 70% reduced risk for
erectile dysfunction relative to those
who remained sedentary. In quantitative
terms, this means that sedentary
men may be able to reduce their risk
of erectile dysfunction by adopting
regular physical activity at a level of at
least 200 kcal/d, which corresponds to
walking briskly for 2 miles.23 In our
study, about one third of obese men
with erectile dysfunction regained
their sexual function after 2 years of
adopting healthy behaviors, mainly
regular exercise and reducing weight.
This may be in line with epidemiological
evidence that physical activity was
associated with a 30% lower risk of
erectile dysfunction, while obesity was
associated with a 30% higher risk of
erectile dysfunction.4 Additionally,
men in the intervention group showed
improvement in the number of surrogate
traditional and novel cardiovascular
risk factors, which were better
than those seen in men in the
control group.
Obesity is a state of chronic oxidative
stress and inflammation.24 The increased
oxidative stress associated with
obesity may increase free radical formation,
which could quench and deactivate
nitric oxide, reducing its availability
for target cells. Obese men
participating in weight loss programs
with dietary modifications and increased
physical activity experienced reduced
oxidative stress associated with
improved nitric oxide availability.25 As
impaired nitric oxide activity appears
to play an important role in the pathogenesis
of erectile dysfunction,26 improved
nitric oxide availability associated
with weight loss may be implicated
in the amelioration of erectile function
in our series of obese men. A reduced
CRP level due to sustained lifestyle
changes may have contributed to
amelioration of erectile function after
treatment. Levels of CRP correlate significantly
with reduced nitric oxide
availability22 and increasing severity of
penile vascular disease as measured by
penile Doppler.27 Moreover, consistent
findings support a predictive role
of CRP and IL-6 for cardiovascular
events in different populations,28 while
IL-8 is a potent chemoattractant.29
Our study has several limitations. Psychological
factors or relational situations
may negatively influence erectile
activity,30 so it is entirely possible that
improvement in mental health through
alleviation of anxiety and depression in
the intervention group, as well as improvement
in self-image of the obese patient
after weight loss, may have played
a role in the results. Because the aim of
the study was to assess the role of lifestyle
changes on endothelial and erectile
dysfunction, we did not assess psychological
profiles of the participants.
However, it seems unlikely that psychological
factors also played an important
role in the amelioration of endothelial
function at the end of the study. Our
findings may not be totally generalizable
to primary care populations because
the intervention was intensive and
involved a lot of contact with the study
team. However, this should not detract
from the potential importance of the
findings for public health in the light of
the increasing evidence that sustained
lifestyle modifications have a profound
impact on diseases.
Our data demonstrate that lifestyle
changes, including a reduced calorie
diet and increased exercise, improve
erectile function in obese men and resulted
in about one third of men with
erectile dysfunction regaining sexual
function after treatment. This improvement
was associated with amelioration
of both endothelial function and
markers of systemic vascular inflammation.
Interventions focused on modifiable
health behaviors may represent
a safe strategy to improve erectile function
and reduce cardiovascular risk in
obese patients.
Author Contributions: Dr Esposito had full access to
all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analysis.
Study concept and design: Esposito, Giugliano.
Acquisition of data: Esposito, Giugliano, Di Palo,
Giugliano, Marfella.
Analysis and interpretation of data: Esposito, D’Andrea,
D’Armiento, Giugliano.
Drafting of the manuscript: Esposito, Di Palo, Giugliano.
Critical revision of the manuscript for important intellectual
content: Esposito, Giugliano, Di Palo,
Giugliano, Marfella, D’Andrea, D’Armiento, Giugliano.
Statistical expertise: Marfella, Giugliano.
Obtained funding: Esposito.
Administrative, technical, or material support:
Giugliano, Di Palo, Giugliano, D’Andrea.
Supervision: Esposito, D’Armiento, Giugliano.
Funding/Support: Financial support for the research
presented in this article was provided by the Second
University of Naples, the Center of Excellence in Cardiology,
and the Department of Geriatrics and Metabolic
Diseases, Naples, Italy.
Role of the Sponsor: The funding organization that
sponsored this study was academic and took no part
in the design, conduct, or interpretation of the data.
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