Antiplatelet (aspirin) therapy as a new option in the treatment of vasculogenic erectile dysfunction: a prospective randomized double-blind placebo-controlled study

Abstract

Purpose:
To investigate the efficiency of antiplatelet (aspirin) therapy in vasculogenic erectile dysfunction (VED) patients with a high mean platelet volume.

Methods:
A total of 184 patients diagnosed with VED between the ages of 18 and 76 were randomly divided into two groups and treated for 6 weeks [group 1: 120 patients (mean age 48.3), aspirin 100 mg/day; group 2: 64 patients (mean age 47.7), placebo 100 mg/day]. The changes from baseline to end point in erectile function scores on the International Index of Erectile Function (IIEF-EF) and the number of patients who answered "yes" to questions 2 and 3 of the sexual encounter profile (SEP) were compared statistically.

Results:
The mean baseline IIEF-EF scores in groups 1 and 2 were 14.1 ± 4.9 and 14.3 ± 5.2, respectively (p = 0.7966), the number of patients who answered "yes" to SEP-2 was 62 (51.6%) in group 1 and 32 (50%) in group 2 (p = 0.8366), and the number of patients who answered "yes" to SEP-3 was 38 (31.6%) in group 1 and 20 (31.2%) in group 2 (p = 0.9557). In the aspirin group, the changes from baseline to end point in the IIEF-EF, SEP-2, and SEP-3 scores were 7.2, 36.6, and 46.6%, respectively. In the placebo group, these changes were 2.0, 9.4, and 12.5%, respectively. When compared with the placebo group, aspirin-treated subjects showed a significant improvement in all three efficacy measures (p < 0.0001).

Conclusions:
100 mg of aspirin administered once a day significantly improved EF in men with VED.

Full text

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International Urology and Nephrology
https://doi.org/10.1007/s11255-018-1786-0
UROLOGY - ORIGINAL PAPER
Antiplatelet (aspirin) therapy asanew option inthetreatment
ofvasculogenic erectile dysfunction: aprospective randomized
double‑blind placebo‑controlled study
ZekiBayraktar1 · SelamiAlbayrak1
Received: 6 November 2017 / Accepted: 4 January 2018
© Springer Science+Business Media B.V., part of Springer Nature 2018
Abstract
Purpose To investigate the efficiency of antiplatelet (aspirin) therapy in vasculogenic erectile dysfunction (VED) patients
with a high mean platelet volume.
Methods A total of 184 patients diagnosed with VED between the ages of 18 and 76 were randomly divided into two groups
and treated for 6weeks [group 1: 120 patients (mean age 48.3), aspirin 100mg/day; group 2: 64 patients (mean age 47.7),
placebo 100mg/day]. The changes from baseline to end point in erectile function scores on the International Index of Erec-
tile Function (IIEF-EF) and the number of patients who answered “yes” to questions 2 and 3 of the sexual encounter profile
(SEP) were compared statistically.
Results The mean baseline IIEF-EF scores in groups 1 and 2 were 14.1±4.9 and 14.3±5.2, respectively (p=0.7966), the
number of patients who answered “yes” to SEP-2 was 62 (51.6%) in group 1 and 32 (50%) in group 2 (p=0.8366), and the
number of patients who answered “yes” to SEP-3 was 38 (31.6%) in group 1 and 20 (31.2%) in group 2 (p=0.9557). In the
aspirin group, the changes from baseline to end point in the IIEF-EF, SEP-2, and SEP-3 scores were 7.2, 36.6, and 46.6%,
respectively. In the placebo group, these changes were 2.0, 9.4, and 12.5%, respectively. When compared with the placebo
group, aspirin-treated subjects showed a significant improvement in all three efficacy measures (p<0.0001).
Conclusions 100mg of aspirin administered once a day significantly improved EF in men with VED.
Keywords Aspirin· Antiplatelet· Antithrombocytic· Erectile dysfunction· Treatment
Abbreviations
ASA Acetylsalicylic acid
CAD Coronary artery disease
cAMP Cyclic adenylate monophosphate
cGMP Cyclic guanylate monophosphate
COX Prostaglandin H synthase
DUS Doppler ultrasonography
IIEF International Index of Erectile Function
MPV Mean platelet volume
NO Nitric oxide
PSV Peak systolic velocity
PAD Peripheric artery disease
PG Prostaglandin
SEP Sexual encounter profile
TxA2 Thromboxane
VED Vasculogenic erectile dysfunction
Introduction
Erectile dysfunction (ED) is the inability to attain and/or
maintain sufficient penile erection for satisfactory sexual
intercourse [21]. ED has been classified as psychogenic,
organic, or mixed because it is a multifactorial disease with a
pathophysiology affected by causes that are vascular (periph-
eral and coronary artery disease, etc.), neurogenic (multiple
sclerosis, Parkinson’s disease, Alzheimer’s disease, etc.),
hormonal (hypothyroidism, hypogonadism, hyperprolactine-
mia, etc.), iatrogenic (cystectomy, prostatectomy, etc.), ana-
tomic (trauma, etc.), and psychogenic [4, 8].
* Zeki Bayraktar
zbayraktar@medipol.edu.tr
Selami Albayrak
salbayrak@medipol.edu.tr
1 Department ofUrology, School ofMedicine, Istanbul
Medipol University, Çamlık Mah. Piri Reis Cad. Papatya
Sitesi No: 48, 34890Pendik, Istanbul, Turkey

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Recent data show that more than 90% of ED cases in over
40years old have an organic cause and that vascular diseases
are the most common etiology. Although ED is a natural
consequence of aging, its severity is directly related to vas-
cular risk factors such as high blood pressure, atheroscle-
rosis, coronary artery disease, smoking, dyslipidemia, and
diabetes mellitus, all of which are associated with endothe-
lial dysfunction [8].
Since the penis can be considered a barometer of the
body’s endothelial function, it is reasonable to identify vas-
cular risk factors as direct causes of and contributors to ED.
Therefore, ED may also be the first clinical presentation of
any of these comorbidities, as vascular endothelium plays
a pivotal role in regulating vascular homeostasis of the cor-
pora cavernosa [8].
Some studies have reported that platelets play a pivotal
role in the pathogenesis of atherosclerosis and peripheric
artery disease (PAD). There is evidence of an association
between mean platelet volume (MPV) and cardiovascu-
lar disease, PAD, and stroke. Platelet aggregation plays
an important role in the pathogenesis of acute myocardial
infarction. MPV, an indicator of platelet activation, has been
reported to be higher in patients with coronary artery disease
(CAD) than in healthy individuals and may be an independ-
ent risk factor for myocardial infarction. Large platelet size
is an independent predictor of increased risk for CAD and
PAD [9, 18].
The antiplatelet effect of acetylsalicylic acid (ASA) has
been known for many years, and it is widely used to treat
cardiovascular diseases [11, 25]. Furuno etal. [14] reported
that all doses of ASA suppressed platelet activity and at
higher doses, endothelial-mediated arterial dilatation wors-
ened. Aspirin decreases vascular smooth muscle cell pro-
liferation and proinflammatory mediators and improves
endothelium-dependent vasorelaxation mediated by nitric
oxide (NO) [11, 14, 28]. Aspirin impairs platelet activation,
implying that a prostanoid (PG) is involved in the activation
process. However, the effect of aspirin on platelet PGs is
an exceptional example of the general aspirin–PG relation-
ship. The antiplatelet effects of aspirin endure for the entire
life of the platelet [18]. Aspirin exhibits its antiaggregant
(antithrombocytic) effect by reducing thromboxane A2
(TxA2) synthesis, which is a strong aggregant and vasocon-
strictor agent. It also reduces TxA2 synthesis by irrevers-
ibly inhibiting prostaglandin (PG) H synthase-1 (COX-1)
and prostaglandin H synthase-2 (COX-2) enzyme activities.
PGH2 is the precursor of thromboxane A2. Ultimately, the
antithrombotic effect results from the synthesis of prosta-
glandin and thromboxane A2 being inhibited by aspirin [11].
Mean platelet volume (MPV) is an indicator of platelet
size. It is easily measured by automated blood counters, it
is routinely available at a relatively low cost, and it indi-
rectly reflects platelet activity [19]. Large platelets are
metabolically and enzymatically more active than small
platelets and produce more thromboxane, known as the
most potent vasoconstrictor agent. Increased platelet activity
plays an important role in atherosclerosis formation through
mechanisms such as thrombocyte gathering, thromboxane
synthesis, and expression of adhesion molecules [1, 9, 12].
Some recent studies have reported a relationship between
high MPV values and VED [2, 5, 10, 15, 19, 22, 27]. How-
ever, to date, no studies have investigated the efficacy of
antiplatelet therapy on VED. We hypothesize that aspirin
improves erectile function (EF) in patients with ED. The aim
of the present study was to assess the efficacy of aspirin in
VED patients with high MPV values.
Methods
The study protocol was approved by the institutional eth-
ics committee of the School of Medicine, Istanbul Medipol
University, Turkey (01/06/2015-66291034-32). The study of
192 men too place from August 2015 to September 2017.
Patients were randomized into two treatment groups at a 2:1
ratio according to the order of application. Group 1, with 126
patients, was given aspirin (100mg/day) (Aspirin® 100mg)
for 6weeks [11]. Group 2, with 66 patients, was given a
placebo (100mg/day). Placebo tablets were produced from
starch and contained same ingredients as the aspirin tablets
except acetylsalicylic acid.
Four patients in group 1 and two patients in group 2 were
excluded because of a lack of follow-up. Two patients in
group 1 were excluded because of protocol violations. A
total of 184 patients who completed the study were subjected
to detailed medical histories, physical examinations, erec-
tile function evaluations, laboratory evaluations, and penile
color Doppler ultrasonographies (pDUS). All patients were
reevaluated for drug side effects after 1week. However, IIEF
questionnaire were not conducted at this time. ED level was
evaluated with the sum of IIEF-EF scores (questions 1–5
and 15). Patients were grouped according to their scores as
mild (17–25), moderate (11–16), and severe ED (1–10) [23].
Patients were questioned twice: during the initial visit and
6weeks after treatment. Patients were asked sexual encoun-
ter profile (SEP) question 2 (Were you able to insert your
penis into partner’s vagina?) and SEP question 3 (Did your
erection last long enough for you to have successful inter-
course?). The study’s co-primary efficacy measures were
changes from baseline to end point in the IIEF-ED domain
score and percentage of “yes” responses to SEP questions
2 and 3. All evaluations and analyses were performed by
urologists and were double blind (both patients and urolo-
gists were blind to the study).
Penile color Doppler evaluation was conducted
following La Vignera et al. [18]. Patients were

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classified according to the peak systolic velocity (PSV).
PSV≥ 35 cm/s values were accepted as normal (no
arterial insufficiency). PSV values of<25, 25–29, and
30–34cm/s were categorized as severe, moderate, and
mild arterial insufficiency, respectively. Patients with
PSV values<35cm/s were diagnosed with VED and
were included in the study. Patients with≥35cm/s PSV
were excluded from the study, even if their IIEF-EF scores
were<26.
Total blood count including hemoglobin (Hgb), white
blood cell (WBC), red blood cell (RBC), platelet (PLT),
and mean platelet volume (MPV) were measured in the
patient and control groups. All parameters were meas-
ured by using commercially available assay kits (Sysmex
Europe GmbH, Norderstedt, Germany) with an autoana-
lyzer (Sysmex XT 200i, Hamburg, Germany). Normal val-
ues for MPV according to these assay kits were 7.8–11fL.
Blood samples were drawn from the antecubital vein and
analyzed immediately (without freezing) after overnight
fasting. Blood samples were collected in tubes contain-
ing dipotassium ethylenediaminetetraacetic acid. All of
the measurements were performed immediately after
venipuncture to prevent invitro platelet activation (within
1h of sampling).
The study’s inclusion and exclusion criteria are in
Table1. Statistical analyses were performed using MedCalc
statistical software (Version 16.4.3, MedCalc Software bvba,
Ostend, Belgium). The descriptive statistics (mean±SD and
percentages), Student’s t tests, and Wilcoxon signed-rank
tests were used to compare parametric and nonparametric
values, respectively; p values<0.05 were considered to be
statistically significant.
The 184 subjects were randomized into two treatment
groups at a 2:1 ratio (aspirin:placebo), which was calculated
to provide at least 95% treatment effect (p<0.0001) [4.1
(95% CI 3.7–6.2) for IIEF-EF, 29% (95% CI 14.9–42.9%) for
SEP-2, and 34.6% (95% CI 19.1–48.8%) for SEP-3].
Results
The mean age in groups 1 and 2 was 48.3± 12.5 and
47.7±11.8years, respectively (p=0.7523). MPV values
were 11.57±0.17 in the aspirin group and 11.54±0.16 in
the placebo group (p=0.4130). In the aspirin group, the
Table 1 The inclusion and exclusion criteria of the study
sBP systolic blood pressure, dBP diastolic blood pressure, IIEF International Index of Erectile Function, MPV mean platelet volume, PSV peak
systolic velocity in penile color Doppler
Inclusion criteria Men with vascular ED:
>18years old
IIEF-EF score<26
PSV<35cm/s
MPV>11
Exclusion criteria Patients with neurogenic or endocrinological ED:
History of pelvic trauma or surgery
History of pelvic radiation
Untreated endocrine disease (such as hypopituitarism, hypothyroidism, or hypogonadism)
Recent history of stroke, spinal cord injury, or other significant central nervous system injuries
Vascular risk factors for ED:
Diabetes, smoking, or hypertension (sBP>170 or dBP>100)
Active infectious disease
Malignancy (current treatment with cancer chemotherapy or antiandrogens)
Renal or hepatic failure
Clinically significant penile deformity
Psychiatric diseases
Unstable angina within prior 6months
Myocardial infarction
Coronary artery disease (coronary artery bypass graft surgery or percutaneous coronary intervention within prior 90days)
Evidence of congestive heart failure within prior 6months
New significant conduction defect within prior 90days
Contraindication for aspirin (i.e., allergic reactions, stomach or intestinal ulcer, bleeding of the stomach or intestines,
hematological diseases such as thrombotic thrombocytopenic purpura, hemophilia and Von Willebrand’s disease, or the
habit of drinking too much alcohol)

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mean baseline IIEF-EF score—the number of the patients
who answered “yes” to SEP-2 and SEP-3—was 14.1±4.9,
62 (51.6%) and 38 (31.6%), respectively. In the placebo
group, the mean baseline IIEF-EF score—the number of
the patients who answered “yes” to SEP-2 and SEP-3—was
34 (60.7%) and 20 (35.7%), respectively. There was no sig-
nificant difference between the two groups in terms of the
age, MPV, baseline IIEF-EF scores, or SEP-2 and SEP-3
ratios (Table2).
After treatment, mean scores for IIEF-EF, SEP-2, and
SEP-3 in the aspirin group were 21.3±4.1, 106 (88.3%),
and 94 (78.3%), respectively. In the placebo group, the
scores were 16.3±4.4, 38 (59.3%), and 28 (43.7%), respec-
tively. The changes in the aspirin group from baseline to end
point in the three measures were 7.2 (difference between
means), 36.6, and 46.6%, respectively. The same changes
in the placebo group were 2.0 (difference between means),
9.4, and 12.5%. The change in IIEF-EF score was signifi-
cantly higher in the aspirin group than in the placebo group
(p<0.0001). The change in “yes” responses to SEP-2 was
significantly greater in the aspirin group (36.6%) than in
the placebo group (9.4%) (p=0.0001). The change in
“yes” responses to SEP-3 was significantly greater in the
aspirin group (46.6%) than in the placebo group (12.5%)
(p<0.0001). At the end of the study, 52 patients (43.3%)
in the aspirin group and 18 patients (28.1%) in the placebo
group had an IIEF-EF domain score>25. The difference is
statistically significant (p=0.0436). While the increases in
IIEF, SEP-2, and SEP-3 measures were statistically signifi-
cant in the aspirin group, there was no significant difference
in the placebo group. The aspirin group showed a significant
improvement in all three efficacy measures (p<0.0001).
For mild, moderate, and severe ED subgroups who took
aspirin, the mean increases in IIEF-EF scores were 7.9,
10.1, and 3.6, respectively, but were lower in the placebo
group: 3.3, 2.0, and 0.6 (p<0.0001). IIEF-EF increases
in the aspirin group for the mild and moderate ED sub-
groups were greater than minimal clinically important dif-
ferences (MCID) as reported by Rosen etal. [24]. In the
aspirin group, the changes in SEP-2 and SEP-3 were statis-
tically significant in the mild and moderate ED subgroups
(p<0.0001), but not significant in the severe ED subgroup
(Table3).
None of the patients in the study reported worse sexual
results after treatment. There were minimal gastric com-
plaints such as dyspepsia and abdominal burning in five
patients (4.1%) in the aspirin group (p=0.1015). No drug-
related severe adverse effects were observed.
Discussion
These findings suggest that aspirin may be a new treatment
option in patients with VED, especially those with high
MPV values. Rosen etal. [24] reported that minimal clini-
cally important differences (MCID) on the IIEF-EF scale
were 2, 5, and 7 for mild, moderate, and severe ED, respec-
tively. This study’s mean was higher, 7.2. This difference
means there was a clinically significant increase in IIEF-EF
for ED patients who took aspirin.
Penile erection is controlled by complex neural and
vascular interactions that cause cavernosal smooth muscle
relaxation [16, 29]. ASA is a cardioprotective agent that
inhibits platelet activity, a decrease in vascular smooth
Table 2 Baseline characteristics
of the patients in both groups
ED erectile dysfunction, EF erectile function, IIEF International Index of Erectile Function, n number of
subjects per category, N number of subjects in each treatment group, MPV mean platelet volume, SD stand-
ard deviation
Aspirin (N=120) Placebo (N=64) p values
Age±SD (years) 48.3±12.5 47.7±11.8 0.7523
<40 22 (18.3%) 12 (18.7%) 0.9470
40–49 42 (35%) 20 (31.2%) 0.6044
50–59 40 (33.3%) 22 (34.3%) 0.8915
≥60 16 (13.3%) 10 (15.6%) 0.6703
ED duration [n (%)]
≥3months and<6months 14 (11.6%) 8 (12.5%) 0.8579
≥6months to<12months 60 (50%) 34 (53.1%) 0.6895
≥12months 46 (38.3%) 22 (34.3%) 0.5933
MPV 11.57±0.17 11.54±0.16 0.2462
ED severity [n (%)]
Mild (17–25) 56 (46.6%) 30 (46.8%) 0.9794
Moderate (11–16) 40 (33.3%) 22 (34.3%) 0.8915
Severe (1–10) 24 (20%) 12 (18.7%) 0.8327

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Table 3 Changes in IIEF-ED scores and SEP-2 and SEP-3 ratios with treatment in all groups
All ED patients (N=184) Aspirin (N=120) Placebo (N=64) p values
Age (years±SD) 48.3±12.5 47.7±11.8 0.7523
IIEF-EF score; baseline 14.1±4.9 14.3±5.2 0.7966
Post-treatment 21.3±4.1 16.3±4,4 <0.0001
Change in IIEF-EF +7.2±4.4 +2.0±4.6 <0.0001
p<0.0001 p=0.0204
“Yes” responses, SEP-2, n (%); baseline 62 (51.6%) 32 (50%) 0.8366
Post-treatment 106 (88.3%) 38 (59.3%) <0.0001
Change in SEP-2 44 (36.6%) 6 (9.4%) 0.0001
p<0.0001 p=0.2925
“Yes” responses, SEP-3, n (%); baseline 38 (31.6%) 20 (31.2%) 0.9557
Post-treatment 94 (78.3%) 28 (43.7%) <0.0001
Change in SEP-3 56 (46.6%) 8 (12.5%) <0.0001
p<0.0001 p=0.1456
Mild ED patients (n=86) n=56 n=30 p values
Age, years±SD 41.6±9.3 40.9±8.7 0.7346
IIEF-EF score; baseline 19.2±4.3 19.6±4.7 0.6916
Post-treatment 27.1±4.4 22.9±4.8 0.0001
Change in IIEF-EF 7.9±4.3 3.3±4.6 <0.0001
p<0.0001 p=0.0093
“Yes” responses, SEP-2, n (%); baseline 34 (60.7%) 15 (50%) 0.3423
Post-treatment 54 (96.4%) 17 (56.6%) <0.0001
Change in SEP-2 20 (35.7%) 2 (6.6%) 0.0034
p<0.0001 p=0.6114
“Yes” responses, SEP-3, n (%); baseline 20 (35.7%) 12 (40%) 0.6959
Post-treatment 50 (89.2%) 16 (53.3%) 0.0002
Change in SEP-3 30 (53.5%) 4 (13.3%) 0.0003
p<0.0001 p=0.3059
Moderate ED patients (n=62) n=40 n=22 p values
Age, years±SD 46.2±10.4 45.7±11.3 0.8612
IIEF-EF score; baseline score 14.6±4.4 14.6±4.5 1.000
Post-treatment 24.7±4.5 16.6±4.6 <0.0001
Change in IIEF score 10.1±4.2 2.0±4.5 <0.0001
p<0.0001 p=0.1523
“Yes” responses, SEP-2, n (%); baseline 19 (47.5%) 12 (54.5%) 0.6009
Post-treatment 39 (97.5%) 15 (68.1%) 0.0011
Change in SEP-2 20 (50%) 3 (13.6%) 0.0049
p<0.0001 p=0.3599
“Yes” responses, SEP-3, n (%); baseline 14 (35%) 6 (27.2%) 0.5328
Post-treatment 37 (92.5%) 9 (40.9) <0.0001
Change in SEP-3 23 (57.5%) 3 (13.6%) 0.0009
p<0.0001 p=0.3432
Severe ED patients (n=42) n=24 n=12 p values
Age, years±SD 57.1±8.9 56.5±9.3 0.8521
IIEF-EF score; baseline score 8.7±2.4 8.9±2.3 0.8126
Post-treatment 12.3±2.7 9.5±2.4 0.0046
Change in IIEF score 3.6±2.1 0.6±2.0 0.0002
p<0.0001 p=0.5382
“Yes” responses, SEP-2, n (%); baseline 9 (37.5%) 5 (41.6%) 0.8145

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muscle cell proliferation, and a reduction in proinflamma-
tory mediators [14, 28].
Some experimental studies have also reported benefi-
cial effects of aspirin on erectile function. In diabetic rats,
aspirin has been found to normalize the diminished mean
intracavernosal pressure/mean arterial blood pressure ratio
required to recuperate erectile function [16]. Argiolas etal.
[3] reported that aspirin had beneficial effects on erectile
function at the peripheral but not central level. In exvivo
studies, aspirin has been shown to improve arterial blood
flow and to prevent hypercoagulation in the penis of the
Chacma baboon during erection [6].
In vitro studies show that aspirin can protect and restore
ED. This has been indicated by an improved relaxation
response to acetylcholine, improvements in electrical field
stimulation, and the presence of sodium nitroprusside in cor-
pus cavernosum strips [16]. These vasoactive responses are
mediated through the local generation of nitric oxide, acety-
lation of endothelial nitric oxide synthetase, and increased
levels of neuronal nitric oxide synthase in penile vessels, and
all are independent of the levels of cyclooxygenase I or II
and the intracellular or extracellular calcium level. Interest-
ingly, the concentration of aspirin that increases endothelial
nitric oxide generation is compatible with the therapeutic
range in humans. Therefore, aspirin is expected to improve
vascular and neurogenic ED in therapeutic doses. This ben-
efit is reflected by ED improvement in patients with bipolar
disorder being treated with lithium, which can impair the
NO-mediated relaxation of cavernosal tissue [13].
This benefit of aspirin has also been shown clinically. In a
randomized double-blind placebo-controlled trial of 32 male
patients with “stable” bipolar disorder, significant advan-
tages of aspirin over placebos were observed in reducing
overall sexual dysfunction and improving erectile function
[26]. Aspirin (240mg/day) significantly improved the over-
all and intercourse satisfaction when compared to placebo
treatment (63.9 vs. 14.4%) in 6weeks after treatment with-
out causing changes in the blood lithium level or disease
severity. Aspirin improved all sexuality-related outcomes,
scores in all domains, the severity category of erectile dys-
function, and the proportion of patients who had experienced
MCID in the erectile function domain. However, the larg-
est effect of aspirin was observed in the erectile function
domain, which is probably the main target of lithium. The
authors of this study interpreted these findings as evidence
for the safety and efficacy of aspirin in the treatment of sev-
eral domains of lithium-induced sexual dysfunction in male
patients with bipolar affective disorder [26].
There is also indirect evidence for the beneficial effects
of aspirin on erectile function from a study that assessed the
effectiveness of a progressive treatment program for ED in
patients with cardiovascular diseases. In this study of 453
ED patients with vascular risk factors who received anti-ED
treatment, 48 patients (10.7%) achieved spontaneous erec-
tion 2years later, of whom 46 (95.8%) were taking aspi-
rin. No association was found between aspirin and adverse
effects, with no differences were noted between patients tak-
ing or not taking aspirin [17].
Furthermore, Tauseef etal. [28] suggested that ASA
with antioxidant activity ameliorated endothelium-depend-
ent vasorelaxation because of the raised bioavailability of
NO. Bornman etal. [6, 7] reported that platelets might play
a significant role in hypercoagulability and fibrin deposi-
tion during erection and could be an important factor in the
pathogenesis of aging impotence, and more importantly,
aspirin might delay penile atherosclerosis. Hafez etal. [16]
also suggested that ASA might be used in the prophylactic
treatment of diabetic ED to preserve the erection capacity
of patients.
Interestingly, despite the experimental studies report-
ing positive effects of aspirin on penile erection, and more
importantly, despite studies reporting the increased platelet
activation in VED patients [2, 5, 10, 15, 19, 22, 27], to date,
there has been no study on the effect of aspirin on VED. The
antiplatelet effect of aspirin has been known for many years,
and MPV, a potential marker of platelet reactivity, is used
routinely in inpatient and outpatient settings at a relatively
low cost [9, 19]. This is the first study to investigate the
efficacy of aspirin in VED.
Minhas etal. [20] investigated the interaction of endothe-
lium-derived NO and PGs in regulating the corporal smooth
muscle tone in rabbit corpus cavernosum, and they reported
Table 3 (continued)
Severe ED patients (n=42) n=24 n=12 p values
Post-treatment 13 (54.1%) 6 (50%) 0.8148
Change in SEP-2 4 (16.6%) 1 (8.3%) 0.5026
p=0.2534 p=0.4672
“Yes” responses, SEP-3, n (%); baseline 4 (16.6%) 2 (16.6%) 1.000
Post-treatment 7 (29.1%) 3 (25%) 0.7984
Change in SEP-3 3 (12.5%) 1 (8.3%) 0.7092
p=0.3075 p=0.6860

International Urology and Nephrology
1 3
that there was a tonic release of NO which did not appear
to be inhibited by a vasoconstrictor prostanoid. Endothelium-
dependent relaxation to acetylcholine results in the dual pro-
duction of NO and a cyclooxygenase-derived endothelium
contracting factor, which acts in opposition to NO; this factor
is unlikely to act on PGH2/TXA2 receptors.
Nitric oxide is synthesized by neuronal (nNOS) and
endothelial NO synthase (eNOS) and plays an important role
in the cavernosal smooth muscle relaxation with the NO/cyclic
guanosine monophosphate (cGMP) cascade [3]. Hafez etal.
[16] detected a significantly increased expression in nNOS lev-
els in ASA-treated diabetic rats. According to them, increased
nNOS expression might be an important factor in improving
ED in ASA-treated diabetic rat penises. They also reported
that the intracavernosal pressure (ICP)/mean arterial blood
pressure (MAP) ratio in the ASA-treated diabetic group was
significantly higher than that of diabetic rats in invivo stud-
ies. Most importantly, this normalized effect shows the protec-
tive effect of ASA in diabetes. They said that based on these
findings, ASA might be a novel therapeutic option in diabetic
ED and might even be used for the prophylactic treatment of
diabetic ED to preserve the erection capacity of patients [16].
PGs, which seem to play a role in regulating penile erec-
tion, also interact with NO in several ways. Importantly, the
release of a COX-dependent contracting factor by the corpus
cavernosa, as shown by Minhas etal., can explain why aspi-
rin improves erectile dysfunction [20, 26].
This is the first clinical study investigating the effect of
aspirin in VED. Although there are some experimental stud-
ies investigating the relationship between aspirin and penile
erection, there has been no clinical study on patients with
VED. The present study demonstrates that aspirin may be
an effective and safe therapeutic option for the treatment of
VED, especially in patients with elevated MPV. The sample
size in this study provided at least 95% power in detecting
clinically significant treatment differences (change from
baseline score between subjects, treated with aspirin 100mg
vs. placebo) in IIEF-EF, SEP-2, and SEP-3. But this study
has some limitations. For example, subjects were relatively
young and a highly select patient population. Many potential
ED patients, including elderly men with comorbidities such
as diabetes and hypertension, were not included in the study
due to rather strict exclusion criteria. As a result, the number
of subjects was limited and the patient population was selec-
tive. For this reason, similar studies should be performed
with larger and more diverse patient groups.
Conclusions
Aspirin is an effective and safe therapeutic option for
patients with VED, especially for patients with a high
MPV. Low-dose aspirin may be used in patients with ED
for treatment purposes or for delaying penile atheroscle-
rosis. However, there is a need for more extensive studies
on this subject.
Compliance with ethical standards
Conflict of interest Both authors declare that they have no conflict of
interest.
Ethical standards All procedures performed in studies involving
human participants were in accordance with the ethical standards of
the institutional and/or national research committee and with the Dec-
laration of Helsinki (1964) and its later amendments or comparable
ethical standards.
Human and animal rights statement This article does not contain any
studies with animals performed by any of the authors.
Informed consent Informed consent was obtained from all individual
participants included in the study.
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