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Research Article

Erectile Dysfunction as an Early Marker of

Microangiopathic Complications in Type 2 Diabetes
Mellitus
Caretta N1*, de Rocco Ponce M1, de Kreutzenberg
Abstract
SV2, Guarneri G2, Garolla A1, Avogaro A2 and
Foresta C1 Erectile dysfunction (ED), a very frequent finding among type 2 diabetes
1
Department of Medicine, Section of Endocrinology and patients (T2DM), is associated with cardiovascular disease. To investigate
Centre for Human Reproduction Pathology, University of the prevalence of ED among our T2DM population and its association with
Padova, Italy microangiopathic complications (diabetic retinopathy (DR) and microalbuminuria
2
Section of Diabetes and Metabolic Diseases, Department [mAlb]), we performed a retrospective cross-sectional study involving 121 patients
of Medicine, University of Padova, Padua, Italy attending the Diabetology Unit of Padua Hospital. All subjects were studied with
*Corresponding author: Caretta N, Department accurate anamnesis, IIEF-5 questionnaire, microalbuminuria determined in spot
of Medicine, Section of Endocrinology and Centre for urine sample, fundus examination and carotid artery echo-color-doppler. ED
Human Reproduction Pathology, University of Padova, prevalence was 64.8% while DR and mAlb prevalence was 25.6% and 23.1%
Via Giustiniani, Padua, Italy respectively. In ED group vs. non-ED, DR prevalence was 32.9% vs. 11.9%
(p=0.012) and mAlb prevalence was 26.6% vs. 16.7% (p=0.218). ED group had
Received: January 27, 2017; Accepted: February 20, a worse glycemic control (HbA1c 7.6 1.6 vs. 7.0 1.0 %, p=0.010) and a
2017; Published: February 22, 2017 longer T2DM duration (10.3 9.2 vs. 6.0 5.7 years, p=0.002). Furthermore,
ED was associated with a higher carotid intima-media thickness (IMT 0.9 0.2
vs. 0.8 0.2 mm, p=0.049). ED was the first vascular complication in 57% of
patients, occurring some years before DR and mAlb. Association with DR and
mAlb is independent of common cardiovascular risk factors. In conclusion, ED
onset in diabetic subjects is a very important finding that can be considered
an early microangiopathic marker in T2DM subjects, suggesting the evaluation
for the presence of other microangiopathic complications and a more intense
control of cardiovascular risk factors.
Keywords: Erectile Dysfunction; Diabetes; Diabetic Retinopathy;
Microalbuminuria; Cardiovascular Disease; Nitric Oxide

Abbreviations neuropathy (DN) and diabetic nephropathy. Around 30% of diabetic

patients suffer from DR, ranging from mild to severe. Male sex, higher
ED: Erectile Dysfunction; T2DM: Type 2 Diabetes Mellitus; glycated haemoglobin levels, longer duration of diabetes mellitus,
DR: Diabetic Retinopathy; Malb: Microalbuminuria; DN: Diabetic higher blood pressure values and use of insulin are all associated
Neuropathy; IIEF-5: International Index Of Erectile Function with the development of retinopathy [4,5]. Diabetic nephropathy in
5; MI: Myocardial Infarction; CVD: Cardiovascular Disease; T2DM occurs in 20-40% of patients and microalbuminuria (mAlb)
CHD: Coronary Heart Disease; Hba1c: Glycated Hemoglobin; is a marker of early nephropathy [6,7]. DR and mAlb are both
LH: Luteinizing Hormone; FSH: Follicle-Stimulating Hormone; associated with an increased incidence of cardiovascular disease
E2: Estradiol; PSA: Prostatic-Specific Antigen; Egfr: Estimated (CVD) and mortality [4,7]. Erectile dysfunction (ED), defined as the
Glomerular Filtration Rate; LDL: Low-Density Lipoprotein; HDL: persistent inability to achieve or maintain penile erection sufficient
High-Density Lipoprotein; IMT: Intima-Media Thickness; BMI: for satisfactory sexual performance [8], may be the first sign of
Body Mass Index; NO: Nitric Oxide CVD. Montorsi et al. have shown that ED can precede coronary
Introduction and peripheral artery disease of some years [9] and a relationship
between ED and silent myocardial ischemia has been demonstrated
Type 2 diabetes mellitus (T2DM) is not merely a disorder in apparently uncomplicated T2DM patients [10]. ED has a much
of carbohydrate metabolism, but a cause of vascular diseases higher prevalence among diabetic vs. non-diabetic subjects [11]. A
affecting nearly all arterial vessels which are classically divided large Italian case study observed a prevalence of 35.8% [12], while
in microangiopathic and microangiopathic. The link between others between 35 and 90% [13]. The ADVANCE study (Action in
diabetes and macroangiopathic disease was suggested many years diabetes and Vascular Disease: Preterax and Diamicron Modified-
ago, observing a higher risk of myocardial infarction (MI) and Release Controlled Evaluation) showed that in diabetic patients the
cardiovascular death in several diabetic populations. In Italy, diabetic presence of ED at the enrolment was associated with a high risk for
patients have a cardiovascular mortality excess of about 30-40% vs. non all cardiovascular events, coronary heart disease (CHD) and cerebral-
diabetic individuals [1-3]. Microangiopathic disease is characterized vascular disease [14]. To our knowledge, no data is still available
by three major manifestations: diabetic retinopathy (DR), diabetic about onset precocity of ED among microangiopathic complications,

Austin Andrology - Volume 2 Issue 1 - 2017 Citation: Caretta N, de Rocco Ponce M, de Kreutzenberg SV, Guarneri G, Garolla A, Avogaro A, et al. Erectile
Submit your Manuscript | www.austinpublishinggroup.com Dysfunction as an Early Marker of Microangiopathic Complications in Type 2 Diabetes Mellitus. Austin Andrology.
Caretta et al. All rights are reserved 2017; 2(1): 1012.
Caretta N Austin Publishing Group

color-doppler. Patients have been considered smokers, if active

smokers or former smokers, we assumed a cut-off for hypertension
of a systolic blood pressure >140mmHg and/or a diastolic blood
pressure >90mmHg, hypercholesterolemia was defined as LDL-
cholesterol >100mg/dl or non-HDL cholesterol >130mg/dl, the
estimated glomerular filtration rate was calculated using the CKD-
EPI equation.
Data are expressed as mean standard deviation for continuous
variables or as N with percentage for categorical variables. For
comparison, a two-sample t-test was performed to identify the
Figure 1A: DR Prevalence in DE group vs. Non DE group.
differences of continuous variables between the ED and non-ED
groups, whereas the Pearson X2 test was performed for categorical
variables between the ED and non-ED groups. Multiple analysis of
covariance (MANCOVA) was applied to correct for DM duration and
HbA1c the differences found between the ED and non-ED groups.
The level of significance was considered as P <0.05. Statistical analysis
was performed using SPSS statistics software for Windows version 23.
Results and Discussion
In our T2DM population we found a high prevalence of ED that
reached 64.8% (79 patients). DR prevalence was 25.6% in the whole
cohort, being significantly higher in the ED group than in non-ED
Figure 1B: mAIb prevalence in DE group vs. Non DE group.
group (32.9 vs. 11.9%, p=0.012) (Figure 1A). mAlb prevalence was
23.1%, and similarly to RD, higher in patients with ED than in non-
therefore we investigated the prevalence of ED among our T2DM
ED subjects (26.6 vs. 16.7%, p=0.218) (Figure 1B). The ED group had
population, its association with micro-vascular complications (DR
a worse glycemic control, as demonstrated by higher fasting plasma
and mAlb) and their occurrence timing.
glucose, and HbA1c levels, and presented a longer T2DM duration
Materials and Methods (Table 1). On the other hand, other studied parameters, as age,
smoke, overweight/obesity (i.e. BMI >25Kg/m2), waist circumference,
This is a retrospective cross-sectional study, involving 121 patients
arterial hypertension, serum lipid profile, eGFR, and hormones did
attended at the Diabetology Unit of Padua Hospital, who followed not differ between ED and non-ED group (Table 1). As regards
a normal screening schedule for the complications of T2DM. All ongoing therapy, data did not show any difference between ED and
patients were T2DM patients and had an age between 40 and 78 years non-ED group.
with a mean age of 58.2 8.5 years, mean T2DM duration of 8.8 years,
BMI 29.0 4.7 Kg/m2 and glycated haemoglobin (HbA1c) 7.5 1.4% Moreover ED was associated with morphological alterations
(Table 1). All the subjects underwent an accurate medical history in the carotid artery and specifically with a higher intima-media
collection including ongoing therapy, International Index of Erectile thickness (IMT 0.9 0.2 vs. 0.8 0.2 mm), this finding remained
Function (IIEF-5) questionnaire, physical examination (weight, statistically significant after adjustment for T2DM duration and
height, BMI, waist circumference and blood pressure), biochemical metabolic control (p=0.049).
blood tests (fasting plasma glucose, glycated haemoglobin, total Finally, we were able to establish the onset timing of each
cholesterol, high-density lipoprotein cholesterol, triglycerides, and microangiopathic complication. ED occurred first in a large majority
creatininemia), hormone levels (LH, total testosterone, estradiol of patients (57% of the patients), DR was the first microangiopathic
(E2) and PSA). Blood collection and pressure measurements were complication in 16%, and mAlb in 15% of the subjects. When ED
performed in fasting condition, between 08.00 and 10.00 a.m., occurs first, it anticipates on average the onset of mAlb and the
avoiding cigarette smoking for a minimum of 12h. Blood samples diagnosis of DR by 30 months. Statistical analysis showed that,
were collected in SST II, LHPST II, and EDTA tubes and analysed when ED occurs first, this is independent of risk factors such as
concurrent to blood draw. We excluded patients with post-surgical hypertension (p=0.457), hypercholesterolemia (p=0.572), smoke
ED, neoplastic patients, with end-stage renal or liver insufficiency and (p=0.403), overweight/obesity (i.e. BMI >25Kg/m2, p=0.374) or poor
transplanted patients. glycemic control (i.e. HbA1c >7.5%, p=0.930).
The presence of ED and age of its onset was assessed with In our diabetic cohort we found a statistically significant
anamnesis together with IIEF-5 questionnaire for ED. Urinary association between ED and DR, we also observed a higher
albumin excretion rate was determined in three or more samples prevalence of pathological albuminuria in the ED group vs. non-DE
of spot urine within six months, and considered pathological when group, although this trend did not reach the statistical significance,
>30mg/gcreatininuria (mAlb), DR was screened and staged through probably as a consequence of the physiological wide variability of
fundus examination. Furthermore, in the context of the general urinary albumin excretion [15] or because of the numerosity cohort
T2DM complication screening, patients underwent a carotid US considered. These findings are consistent with previous data that

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Table 1: Diabetes can affect erection at different levels, essentially through

All subjects (n Non-DE
DE (n) P hormones derangement, neuronal impairment, local factors and,
121) (n)
above all, vasculopathy [13]. As regards vasculopathy, we already
Age (years) 58.2 8.5 56.5 6.7 59.2 9.2 0.072
know that diabetes mellitus associates with vascular diseases classically
T2DM duration (years) 8.8 8.6 6.0 5.7 10.3 9.5 0.002 divided in macroangiopathic and microangiopathic. Among
Fasting plasma glucose
157 52
142.4 165.2
0.007 microangiopathic complications we recognize diabetic nephropathy,
(mg/dl) 33.7 58.1
revealed by its early marker microalbuminuria, and diabetic
HbA1c (%) 7.5 1.4 7.0 1.0 7.6 1.6 0.010
retinopathy. In our population we found an association between ED
BMI (Kg/m2) 29.0 4.7 28.0 3.4 29.5 5.3 0.091 and DR and also a higher prevalence of mAlb among ED patients.
Overweight/obesity (%) 81 78.5 83.6 0.765 A possible explanation for this clustering of microangiopathic
Waist circumference (cm) 101.8 10.7 99.4 8.5
103.1
0.052
complications could be a generalized endothelial dysfunction
11.6 which is a hallmark of both mAlb [22] and DR [16]. Endothelial
Systolic blood pressure 132.0 136.1
(mmHg)
134.7 18.9
18.1 19.4
0.258 dysfunction is characterized by a reduced vasodilatation in response
Diastolic blood pressure
80.1 10.4 79.6 11.3 80.3 9.9 0.735 to stimuli, procoagulation, inflammation and arterial stiffness [23].
(mmHg)
Many factors in diabetes promote endothelial dysfunction, which
Hypertension (%) 51.2 45.2 54.4 0.348
has been already well documented both in diabetic [24] and in
Smokers (%) 62.6 59.4 64.8 0.648 non-diabetic obese subjects [25]. ED is a well established marker of
Total cholesterol (mg/dl) 178.7 38.1
172.1 182.3
0.162 diffuse endotheliopathy, a condition common to diabetes, and the
31.5 41.0
physiopathological pathway for the development of its complications,
HDL-cholesterol (mg/dl) 45.7 12.1 46.4 10.2 45.4 13.1 0.687
microalbuminuria [26] and diabetic retinopathy [27].
non-HDL cholesterol 125.7 136.9
133.0 37.5 0.120
(mg/dl) 30.6 40.3 Conversely, the higher prevalence of DR and mAlb in the DE
130.8 159.3
Triglycerides (mg/dl) 149.4 108.9
68.6 124.5
0.172 group we observed in our population is not attributable to differences
105.0 in common cardiovascular risk factors like smoke, higher BMI,
LDL-cholesterol (mg/dl) 103.1 31.9 99.6 26.2 0.360
33.2 waist circumference, hypertension, dislipidemia, renal function, and
Creatininemia (mmol/l) 80.8 20.1 78.3 15.3 82.2 22.2 0.311 hormones. On the other hand, we find a correlation between ED and
eGFR (CKD, ml/min) 120.3 23.5 93.2 13.9 88.4 17.7 0.129 a longer DM duration and a worse metabolic control confirming the
LH (UI/l) 6.2 3.6 5.9 4.0 6.3 3.4 0.582
importance of hyperglycaemia in the pathogenesis of DE as already
demonstrated in other studies [28].
Testosterone (nmol/l) 13.3 6.5 12.0 6.4 13.9 6.5 0.220

Estradiol (pmol/l) 86.1 40.3 67.0 29.9 92.0 42.3 0.102 Given this association between microangiopathic complications
and ED, we also investigated which one occurred first in our
PSA (ng/ml) 1.33 1.43 1.4 1.3 1.3 1.6 0.780
cohort, in order to identify the more precocious microangiopathic
Carotid IMT (mm) 0.87 0.34 0.8 0.2 0.9 0.2 0.049 manifestation. Our results show that ED occurs some years before
T2DM: Type 2 Diabetes Mellitus; IMT: Intima-Media Thickness; PSA: Prostatic the other microangiopathic complications in most cases. ED may
Specific Antigen; BMI: Body Mass Index; Hba1c: Glycated Haemoglobin; Egfr:
thus be considered a very early marker of microangiopathic disease
Estimated Glomerular Filtration Rate.
suggesting a more intensive control of cardiovascular risk factors
showed an association between diabetic retinopathy and erectile and further evaluation for the presence of other microangiopathic
dysfunction in type 2 diabetics [16,17] and a relationship between ED complications.
end albuminuria in T2DM men [18] and recognizing albuminuria as
an independent risk factor of erectile dysfunction in T2DM patients The validity of ED as an early marker of initial vascular disease
[19]. Furthermore, ED is usually the first chronic complications of is confirmed by its significant association with a higher IMT value in
DM to appear, and it may anticipate by years the diagnosis of the the carotid arteries, as already demonstrated in previous studies in
other microangiopathic complications. non-diabetic subjects [29].

Erectile dysfunction is defined as the persistent inability to Conclusion

achieve or maintain penile erection sufficient for satisfactory sexual ED is a very frequent finding among T2DM patients, and
performance [8]. Erection is a complex mechanism in which there is associates with other microangiopathic complications, such as
an increase in blood flow to the corpora cavernosa, which occludes DR and early diabetic nephropathy (i.e. microalbuminuria), this
venous blood efflux and thereby raises intracavernous pressure to association is independent of other classical risk factors, like
ensure a firm erection. This hemodynamic phenomenon results from hypertension, hypercholesterolemia or overweight/obesity. Among
the interplay of neurological, endocrinological, tissutal, psychological, microangiopathic complication, in more than one half of our patients,
relational and vascular factors. In particular, endothelial-derived ED occurred some years before the others. ED onset in diabetic
nitric oxide (NO) is probably the most important mediator of patients is hence a very important finding concerning cardiovascular
vasodilatation, and endothelial dysfunction, affecting NO release, is risk because it can anticipate DR and mAlb. ED can therefore be
crucial to vasodilatation impairment in ED [20]. Actually, ED is in considered an early microangiopathic marker in T2DM subjects,
70% of cases vasculogenic [21] in part as a consequence of endothelial suggesting the evaluation for the presence of other microangiopathic
dysfunction. complications and a more intense control of cardiovascular risk
Among diabetic patients there is a high prevalence of ED [12]. factors.

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Austin Andrology - Volume 2 Issue 1 - 2017 Citation: Caretta N, de Rocco Ponce M, de Kreutzenberg SV, Guarneri G, Garolla A, Avogaro A, et al. Erectile
Submit your Manuscript | www.austinpublishinggroup.com Dysfunction as an Early Marker of Microangiopathic Complications in Type 2 Diabetes Mellitus. Austin Andrology.
Caretta et al. All rights are reserved 2017; 2(1): 1012.

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