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From the Departments of * Endocrinology and
Urology, Hospital Italiano de Buenos Aires,
Argentina.
| Correspondence to: Dr Pablo Knoblovits, Endocrinology Division, Hospital Italiano de Buenos Aires, Gascón 450, C1181ACH Argentina (e-mail: pablo.knoblovits{at}hospitalitaliano.org.ar). |
| Received for publication February 19, 2009; accepted for publication October 8, 2009. |
Erectile dysfunction (ED) is associated with metabolic and endocrine
diseases including obesity, metabolic syndrome (MS), and type 2 diabetes
mellitus (DM2). Insulin resistance (IR), present in patients with obesity, MS,
and DM2, causes disturbances in the signaling pathways required for nitric
oxide production, with subsequent endothelial dysfunction. In addition, IR
appears to alter testosterone production. We evaluated in eugonadal patients
with ED: 1) the presence of obesity and IR, 2) testosterone levels and their
association with obesity and IR, and 3) the degree of ED according to the
presence of IR. In a prospective study, 78 eugonadal patients with ED (group
P) were recruited and compared with 17 men without ED as a control group
(group C). Erectile function was evaluated according to the International
Index of Erectile Function 5 (IIEF-5). IR was measured by homeostasis model
assessment (HOMA). IR was defined as HOMA of 3 or greater. Patients with ED
had significantly higher body mass index (BMI), waist circumference (WC), HOMA
values, and prevalence of IR when compared with group C. Total (TT) and
bioavailable testosterone (BT) levels were lower in group P compared with
group C. There was a significant negative correlation between HOMA and IIEF-5,
HOMA and TT, WC and IIEF-5, WC and TT, and WC and BT. Group P patients with IR
had higher WCs and lower IIEF-5 scores when compared with patients in group P
without IR. In conclusion, patients with ED showed a higher BMI, WC, and HOMA
and lower levels of TT and BT. There is a negative correlation between
erectile function and IR and abdominal obesity. The TT levels are lower in
patients with increased BMI, WC, and IR. However, a negative correlation was
shown only between BT (biologically active fraction) and abdominal
obesity.
Key words: Male sexual function, waist circumference, obesity
Erection is a neuromyovascular phenomenon, in which the nitric oxide (NO) released by nerve endings and endothelial cells plays a key role. NO is produced from L-arginine through an enzymatic step in which NO synthetase is involved. Once produced, NO stimulates guanylate cyclase present in the smooth muscle. This enzyme induces the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP phosphorylation induces the release of cytoplasmic calcium, allowing smooth muscle relaxation in the corpus cavernosum, with consequent blood repletion (penis tumescence) (Barouch et al, 2002; Trussell and Legro, 2007).
Insulin-resistance (IR), present in most patients with obesity, MS, and DM2, is a metabolic alteration that produces endothelial dysfunction determined by lower synthesis and release of NO, combined with higher NO consumption in tissues exposed to high concentrations of reactive oxygen species (Cersosimo and De Fronzo, 2006). The reduction in NO levels affects the different arteries of the body, impairing its vasodilator mechanism (McFarlane et al, 2001). It is conceivable that the endothelial dysfunction caused by IR is also present in the corpus cavernosa of patients with ED, affecting the erectile mechanisms. A higher prevalence of IR in the ED population was observed in noncontrolled studies (Bansal et al, 2005).
A normal testosterone concentration is associated with adequate insulin sensitivity (Holmäng et al, 1992; Mårin, 1995; Boyanov et al, 2003). Many studies have demonstrated an association between hypogonadism and MS (Makhsida et al, 2005; Muller et al, 2005; Kupelian et al, 2006) and between hypogonadism and IR (Pitteloud et al, 2005; Kapoor et al, 2006). In addition, lower testosterone levels predispose to ED (Buvat and Bou Jaoudé, 2006; Mikhail, 2006; Saad et al, 2007).
In this study, we aimed to evaluate 1) the presence of obesity and IR, 2) the levels of testosterone and its relationship with obesity and IR, and 3) the degree of ED according to the presence of IR in a eugonadal group of patients with ED and in a group of men with normal erectile function (control group) in an andrology clinical setting.
Materials and Methods
Population
We studied 78 men (group P) of 40 to 70 years, in a stable relationship
during the last 6 months, who consulted for ED at the andrology division in
our hospital. Patients were excluded if they had pharmacologic (onset of ED
within 6 months of the beginning of treatment with any drugs described as
associated with ED) or anatomic (Peyronie disease) ED, hyperprolactinemia,
hypogonadism (defined as bioavailable testosterone [BT] <0.8 ng/mL in 2
samples on different days), alcohol abuse, history of prostate or pelvic
surgery, severe chronic illness, and/or use of drugs that may interfere with
laboratory results (eg, antiandrogens, corticosteroids, metformin, and
antilipemic drugs among others). Patients with a previous diagnosis of type 1
or type 2 DM were excluded because of the known association of these
conditions with ED and of DM2 with IR and obesity.
As a control group, we included 17 men with normal erectile function (group C) who consulted the same hospital division for benign prostate diseases. Groups were matched by ages.
Our intended sample, according to our power calculation, was 50 patients and 50 controls. However, because of the high prevalence of IR, we achieved statistical significance with a smaller control group.
Anthropometric Parameters
Weight (kg) and height (m) were measured in lightweight clothing without
shoes by standard procedures. Body mass index (BMI) was calculated according
to the formula, weight (kg)/height2 (m2), and was
considered normal when less than 25 kg/m2, overweight between 25
and 29.9 kg/m2, and obese when 30 or more kg/m2. Waist
circumference (WC; cm) was measured with a measuring tape around the navel,
with the subject standing and breathing normally.
International Index of Erectile Function 5
International Index of Erectile Function 5 (IIEF-5) is a validated
questionnaire to evaluate the ED degree; the questionnaire consists of 5
questions with 5 possible answers each, with a score from 1 to 5. Based on a
possible total score of 25, a score less than 21 indicates some degree of ED.
The lower the score, the more severe the degree of ED; using the 21 cut-off
value, the test has a 98% sensitivity and 88% specificity for diagnosing ED
(Rosen et al, 1999).
Laboratory Tests
A venipuncture was performed between 8:00 and 10:00 AM, and
fasting blood samples were obtained. Platelet-free serum was obtained by
centrifugation and immediately stored at –20°C.
Total testosterone (TT) was measured using a competitive radioimmunoassay (RIA) double antibody (Diagnostic System Laboratories Inc, Webster, Texas). The lower limit of detection was 0.05 ng/mL, and the laboratory reference range was 2.8 to 8.8 ng/mL for men; the intra-assay coefficient of variation was 7.5%, and the interassay coefficient of variation was 8.1%.
BT was calculated using TT and sex hormone–binding globulin (SHBG) values by the method of Vermeulen et al (1999), with a reference range of 0.8 to 6.0 ng/mL.
Prolactin was measured by a chemiluminescence immunoassay on the Architect analyzer (Abbott Laboratories Argentina S.A., Buenos Aires, Argentina). The lower limit of detection was 0.6 ng/mL, the interassay coefficient of variation was 4%, and the reference range was 5 to 20 ng/mL.
Insulin was measured using an in-house competitive RIA (modified version of Herbert et al, 1965) employing a polyclonal anti-insulin antibody from guinea pig. The tracer was porcine insulin labeled with 125I, the lower limit of detection was 2.5 µIU/mL, the intra-assay coefficient of variation was 5.1%, and the interassay coefficient was 10.4%.
Glucose was measured by enzymatic O2 consumption. A 2-hour oral glucose tolerance test (OGTT) with a glucose load of 75 g was performed in all patients, regardless of their fasting basal glucose results, according to World Health Organization criteria (World Health Organization, 1985). Serum glucose levels after a 120-minute glucose load were considered normal at less than 140 mg/dL, impaired between 140 and less than 200 mg/dL, and consistent with DM2 at 200 mg/dL and above.
A homeostasis model assessment (HOMA) index was calculated according to the formula, (serum glucose [mg/dL] x insulin [µIU/mL])/405 (Matthews et al, 1985). IR was defined as a HOMA of 3 or greater. A HOMA index provides a good correlation with the insulin sensitivity index assessed by the gold standard test, the euglycemic clamp.
Statistical Analysis
Data was analyzed using Instat statistical software (version 3.01; GraphPad
Software, La Jolla, California). Differences in the characteristics of
patients with ED and in the control group were compared with a 2-sample
t test for continuous variables; categoric variables were compared
using 
2. Pearson's correlation coefficients were used to
assess the relationship between serum concentrations of testosterone (TT and
BT) and measures of adiposity (BMI and WC), and between IR (HOMA) and IIEF-5.
Data are presented as means ± SD. All P values are 2 sided,
and P < .05 indicates statistical significance.
Patients and participants in the control group signed an informed consent, and the trial protocol was approved by the Ethics Committee of the Hospital Italiano.
Results
From the 78 patients with ED (group P), 2 were excluded because of diagnosis of normogonadotrophic hypogonadism and 2 others were excluded because of DM2 diagnosed by OGTT; no cases of hyperprolactinemia were detected. The mean duration of ED was 3.8 ± 3.6 years. In group C, no cases of hypogonadism, hyperprolactinemia, or DM2 were found.
The mean age was similar in both groups (60 ± 9.3 years vs 55.8 ± 8.2 years for groups P and C, respectively; P = .09). Patients in group P presented higher WC and greater BMI than men in group C. In addition, a lower percentage of patients with normal BMI and a higher prevalence of obesity were found in group P (Table 1).
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When laboratory parameters were compared, significantly higher insulin levels (21.9 ± 11.1 µIU/mL vs 16.8 ± 11.0 µIU/mL; P = .04) and HOMA (5.0 ± 2.9 vs 3.5 ± 2.5; P = .03) were observed in group P. IR was more prevalent in group P (75.67%) compared with group C (47.05%) (P = .04). There were no differences in basal and 120-minute serum glucose levels between group P and group C. TT and BT levels were lower in group P compared with group C (TT, 4.2 ± 1.2 ng/mL vs 5.5 ± 1.9 ng/mL [P = .02]; BT, 1.7 ± 0.6 ng/mL vs 2.1 ± 1.6 ng/mL [P = .02]) (Table 2).
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A positive correlation was observed between HOMA and BMI (r = .32, P = .002), as well as between HOMA and WC (r = .30, P = .005). A negative correlation was observed between HOMA and IIEF-5 (r = –.21, P = .004) (Figure 1), HOMA and TT (r = –.25, P = .01) (Figure 2), BMI and TT (r = –.28, P = .008) (Figure 3), BMI and IIEF-5 (r = –.22, P = .04) (Figure 4), WC and IIEF-5 (r = –.23, P = .03) (Figure 5), WC and TT (r = –.41, P < .0001) (Figure 6), and WC and BT (r = –.30, P = .006) (Figure 7). There was no significant correlation between HOMA and BT (r = –.05, P = .64), BMI and BT (r = –.12, P = .26), TT and IIEF-5 (r = .17, P = .11), or BT and IIEF-5 (r = .09, P = .41).
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3) presented higher WC (106.9
± 10.3 cm vs 101.8 ± 10.7 cm; P = .04), higher serum
glucose levels (91.9 ± 12.3 mg/dL vs 83.6 ± 14.8 mg/dL;
P = .02), and lower IIEF-5 score (13.7 ± 4.4 vs 16.2 ±
3.2; P = .02) compared with group P patients without IR (HOMA <3).
There were no significant differences in mean age, TT level, BT level, and BMI
between patients in group P with and without IR
(Table 3).
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Discussion
Our findings demonstrate a higher degree of IR in 40- to 70-year-old men with ED, in comparison with men of the same age with normal erectile function.
Under physiologic conditions, insulin has hemodynamic action; after crossing the endothelial barrier, insulin promotes relaxation of the precapillary sphincter, which induces vasodilation. As a result of this action, a greater number of microvessels are recruited, the capillary network expands, and peripheral microvascular perfusion increases (Cersosimo and De Fronzo, 2006). The vasodilating action of insulin is exerted through NO synthesis in endothelial cells because insulin directly stimulates the expression and activation of NO synthetase.
IR is the pathophysiologic base of the metabolic and cardiovascular disturbances collectively known as MS. Hypertriglyceridemia and the increase of small and dense low-density lipoprotein cholesterol particles contribute to vascular damage and trigger an inflammatory response, resulting in monocyte adhesion to the endothelial cells. The increased flow of free glucose and fatty acids to the vascular smooth muscle cells and to the surrounding inflammatory cells stimulates an excessive formation of reactive oxygen and nitrogen species. Subsequently, the increase in free radicals in the mitochondria impairs NO production. In addition, IR determines a lower synthesis and release of NO owing to lower activity and expression of NO synthetase, which is combined with an accelerated consumption of NO during neutralization of oxidative stress (McFarlane et al, 2001; Cersosimo and De Fronzo, 2006).
Therefore, when IR and disorders associated with glucose and lipid metabolism develop, a decrease in NO levels is observed, leading to an alteration in the vasodilation mechanisms mediated by the endothelium. This disruption in the normal endothelial vascular function, particularly in arterioles and capillaries, worsens the metabolic functions of insulin, producing a negative feedback mechanism.
It is likely that similar endothelial dysfunction is also present in the cavernous bodies, impairing the erectile mechanisms (Sullivan et al, 1999; Jeremy et al, 2000; Jones et al, 2003). The small diameter (1–2 mm) and the relatively high content of smooth endothelial and muscular cells by unit of tissue volume compared with other organs determine a higher cavernous artery susceptibility to damage induced by oxidative stress (Kim et al, 2007).
Bansal et al (2005) evaluated the prevalence of IR, measured by the quantitative insulin sensitivity check index, in 154 men with ED. They reported a 79.2% incidence of IR in patients with ED but without comparing them with a control group.
We also previously reported a greater prevalence of MS in patients with ED, compared with a control group (Costanzo et al, 2008). In the present study, we observed a higher BMI and obesity prevalence in patients with ED in comparison with subjects with normal erectile function. WC was significantly higher in patients with ED in comparison with the control group.
MS prevalence in patients with ED has been also evaluated in other studies, and a high prevalence of abdominal obesity has been found in these patients (Bansal et al, 2005; Bal et al, 2007; Corona et al, 2007; Traish et al, 2009). A prospective study carried out in Rancho Bernardo, California, after 25 years of follow-up, demonstrated that higher BMI was associated with a significant increase in ED risk (Fung et al, 2004).
As expected, a positive association between BMI and WC was observed with the HOMA index. Our findings demonstrated a negative correlation between erectile function score and HOMA index, and between WC and BMI. Thus, the higher the degree of IR and obesity, the worse the erectile function would be. It has been reported that weight loss in obese patients with ED improves sexual function and is associated with a lower concentration of endothelial dysfunction markers (Esposito et al, 2004). Kim et al (2007) demonstrated that the use of metformin therapy recovers the expression of NO synthetase in the penis of obese rats. Currently, there is no evidence available regarding the action of insulin-sensitizing agents on ED in men. Thus, IR secondary to visceral obesity could result in ED through endothelial-mediated dysfunction of the corpus cavernosum, impairing vasodilation owing to a reduced availability of NO.
Despite excluding patients with hypogonadism, our results showed lower TT and BT levels in the group of patients with ED, compared with the control group with normal erectile function. We also found a negative correlation between TT levels and HOMA index, and between BMI and WC, whereas BT was negatively correlated only with WC. These findings suggest that the lower TT levels observed in this group of patients are likely associated with a greater prevalence of obesity. Vermeulen et al (1999) found that BMI is an independent factor in determining testosterone levels. The same authors also described a negative correlation between free testosterone levels and the percentage of body fat, abdominal fat, and insulin levels. The findings of lower TT levels in patients with ED and a negative correlation between TT levels and BMI, and between WC and HOMA, can be associated with an impaired hepatic synthesis of SHBG, as is usually seen in the presence of hyperinsulinemia (secondary to IR) and obesity (Couillard et al, 2000; Abate et al, 2002; Tsai et al, 2004).
Nevertheless, the negative correlation of BT with WC and the lower BT levels found in patients with ED in relation to the control group seem to confirm the importance of visceral obesity in TT and BT levels and suggest an endocrine action of the visceral fat tissue over the regulation of gonadal function.
Testosterone influences sexual activity by different mechanisms, which include the production of NO through NO synthetase stimulation. Because the patients evaluated in our study were eugonadal, it is unlikely that lower levels of testosterone, within limits of normal range, would favor a worse erectile function.
One limitation of our study is that results may not be applicable to the general population because patients and controls were recruited from an andrology clinic.
In conclusion, the present study shows a greater prevalence of obesity and higher degree of IR in patients with ED. A worse erectile function (lower score on IIEF-5) in patients with IR and a negative correlation between erectile function score and HOMA index were also observed. These findings suggest a potential role of MS in the pathophysiology of ED, as a result of endothelial dysfunction associated with impaired insulin action. Therefore, ED might be considered as a marker of vascular and metabolic damage, which could potentially evolve to overt cardiovascular disease and DM2.
Acknowledgments
We are grateful to Claudio Benadiva, MD, from the Center for Advanced Reproductive Services, University of Connecticut Health Center, for his valuable suggestions and comments on this work.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
