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 C-reactive
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.
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), 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.
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) When you 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.
We assessed 140 men with 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 pressure >140/90 mm Hg), 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 self-monitoring
(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. These men also 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 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 L-arginine
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. We compared 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 χ2 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 considered
statistically significant. All analysis were conducted using SPSS statistical
software (version 9.0, SPSS Inc, Chicago, Ill).
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 smokers was similar in the 2 groups:
27% in the intervention group and 31% 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
reductions 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.
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 vascular 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.
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