ORIGINAL RESEARCH & REVIEWS

ERECTILE FUNCTION

Daily Oral L-Arginine Plus Tadalafil in Diabetic Patients with Erectile

Dysfunction: A Double-Blinded, Randomized, Controlled Clinical Trial
Moustafa El Taieb, MD,1 Eisa Hegazy, MD,2 and Ahmed Ibrahim, MD3

ABSTRACT

Introduction: Erectile dysfunction is a common condition among diabetic men. Many treatments are now
available with variable responses.
Aim: This study aimed to evaluate the effect of daily oral L-arginine plus tadalafil in diabetic patients with mild to
moderate erectile dysfunction.
Methods: A double-blinded, randomized, controlled clinical trial was conducted with 108 diabetic male pa-
tients. Each patient was assessed by medical and sexual histories, International Index of Erectile Function 5-item
questionnaires, pharmaco-penile duplex ultrasonography, and serum testosterone level.
Main Outcome Measure: Improvement in International Index of Erectile Function 5-item, serum testosterone
level and pharmaco-penile duplex ultrasonography.
Results: Erectile functions were significantly improved in all patients after treatment as compared with baseline
and placebo (P < .001). Patients who received both drugs showed significant improvement compared to those
treated with single drugs, as assessed by International Index of Erectile Function scores and total testosterone
(P < .001). Pharmaco-penile ultrasound duplex results showed non-significant differences among patients
treated with both drugs and those with each drug alone.
Conclusion: Daily use of L-arginine with tadalafil significantly increased the International Index of Erectile
Function scores and total testosterone levels as compared to each drug alone in diabetic patients with erectile
dysfunction. No differences were found based on pharmaco-penile duplex findings. El Taieb M, Hegazy E,
Ibrahim A. Daily Oral L-Arginine Plus Tadalafil in Diabetic Patients with Erectile Dysfunction: A Double-
Blinded, Randomized, Controlled Clinical Trial. J Sex Med 2019; 19:1390e1397.
Copyright
2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Erectile dysfunction; Diabetes mellitus; tadalafil; L-arginine

INTRODUCTION
Erectile dysfunction (ED) is a major complaint of diabetic
patients.1 The prevalence of ED is increasing and is associated
with age, metabolic syndrome, and vasculogenic disorders.2e4
Prevalence may reach 75% in diabetic patients depending on
the duration, severity, and degree of hyperglycemia.5 The path-
ogenesis of ED in diabetes mellitus (DM) is multifactorial and
includes both psychological and organic factors. Vasculogenic
Received February 7, 2019. Accepted June 13, 2019.
1
Department of Dermatology, Venereology and Andrology, Faculty of Med-
icine, Aswan University, Sahary City, Aswan, Egypt;
2
Department of Dermatology, Venereology and Andrology, Faculty of
Medicine, South Valley University, Qena, Egypt;
3
Department of Community Medicine, Faculty of Medicine, Asuit University,
Asyut, Egypt
Copyright ª 2019, International Society for Sexual Medicine. Published by
Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jsxm.2019.06.009
causes are the most common organic factor in DM, but other
factors such as hypogonadism, autonomic neuropathy, age,
drugs, and chronic diseases are known to play a role.6
Nitric oxide (NO) is the main vasoactive neurotransmitter of
penile erection controlling smooth muscle relaxation. Impair-
ment of NO metabolism in DM leads to ED.7,8 A diagnosis of
ED depends on the clinical history, International Index of
Erectile Function 5-item questionnaire (IIEF-5), and pharmaco-
penile duplex ultrasonography (PPUD). Recently, it has been
suggested that platelet indices can predict ED in diabetic
patients.9
Phosphodiesterase type 5 inhibitors (PDE5Is) are considered
the first-line treatment for ED. They act by preventing degra-
dation of cyclic guanosine monophosphate.10 Daily administra-
tion of PDE5Is was initiated as an alternative treatment option
that provides an experience closer to a natural sexual life.
Tadalafil is a potent, reversible, and selective inhibitor of PDE5;
however, it differs from the other PDE5 inhibitors in that its

1390 J Sex Med 2019;16:1390e1397

L-Arginine Plus Tadalafil in Diabetic Patients with Erectile Dysfunction
long elimination half-life can reach up 18 hours, in contrast to
the 4- to 5-hour half-lives of sildenafil and vardenafil.11,12
L-Arginine is an amino acid found in numerous foods that has
the potential to improve endothelial function, so it may be suitable
to also improve erectile function. L-Arginine is the precursor of
NO, a neurotransmitter necessary for relaxation of the penile
muscles. It has been observed that L-arginine in combination with
yohimbine improves erectile functions in patients with ED.13,14
The aim of this work was to evaluate the effect of daily L-argi-
nine oral supplementation plus tadalafil in diabetic patients with
mild to moderate vasculogenic ED as diagnosed by PPUD.
Patients
This double-blinded, randomized, controlled clinical trial
included 108 patients with type 2 DM, as confirmed at our
diabetes unit, and mild to moderate ED with IIEF-5 scores be-
tween 12 and 16. Patients were recruited from the andrology
clinic at the Dermatology, Venerology and Andrology Depart-
ment, Faculty of Medicine, Aswan University, from October
2017 to October 2018. Of the 456 patients with ED who were
examined during this period, we recruited 108 patients who met
the inclusion criteria, completed the IIEF-5 questionnaire, and
underwent PPUD and testosterone measurement.
Sample size calculations were carried out using G*Power 3
software (Heinrich-Heine-Universität; Düsseldorf, Germany).15
A calculated minimum sample of 108 participants divided into
4 groups (27 L-arginine, 27 tadalafil, 27 both, and 27 placebo)
was needed to detect an effect size of 0.2 in the mean IIEF-5
scores with an error probability of .05 and 95% power on a 2-
tailed test. The distribution of patients among the 4 groups
was based on randomized coded cards. Randomization was car-
ried out using tables of random numbers that were arranged in
consecutive order. The allocation of patients and follow-up were
performed by assistants (Figure 1).
Group A was given L-arginine 5 g oral tablets daily for 8
weeks, group B was given tadalafil 10 mg oral tablets daily for 8
Figure 1. Flow diagram of sample size calculation and patient allocation.
J Sex Med 2019;16:1390e1397
1391
weeks, group C was given L-arginine 5 g and tadalafil 10 mg oral
tablets daily for 8 weeks, and group D was given placebo (equal
amounts of methyl cellulose tablets) daily for 8 weeks. Both
patients and physicians were blinded with regard to the treat-
ment modality. Each participant received 2 tablets of the same
color, shape, and size. For groups A and B, one tablet was the
drug and the other was placebo; for group C, both tablets were
drugs; and for group D (control), both tablets were placebo.
Patients with a history of pelvic trauma, major pelvic surgical
intervention, hypogonadism, hyperprolactinemia, hypertension,
chronic prostatitis, chronic liver disease, smoking, or chronic
intake of central nervous system or antiandrogen drugs and pa-
tients with Peyronie’s disease or any fibrotic anomalies in the
penis were excluded from this study.
METHODS
Each patient was assessed by detailed medical and sexual his-
tories, and they completed the IIEF-5, which includes items on
erection confidence, desire, orgasmic function, maintenance
frequency, and intercourse satisfaction. Four items were scored
from 0 to 5, and 1 item was scored from 1 to 5.16 Medical ex-
aminations included general and local examinations and hemo-
globin A1c (HBA1c) serum levels to detect the glycemic control
of patients over the previous 3 months according to the Diabetes
Control and Complications Trial.17 PPUD was performed at
baseline and after treatment after intracavernous injection of 10
mg prostaglandin E1 without audiovisual sexual stimulation to
evaluate the grade of erection and to determine the diameter of
cavernous arteries before and after erection, peak systolic flow
velocity (PSV), end diastolic velocity (EDV), and resistance index
(RI). Blood samples were taken from each subject to detect
serum total testosterone (nmol/L) levels before and 48 hours after
treatments between 8:00 and 10:00 AM using the Architect Plus
i1000SR (Abbot Diagnostics; Lake Forest, IL). Completion of
the IIEF-5 questionnaire, PPUD, and blood tests occurred at
baseline directly before the first treatment and 48 hours after the
1392 El Taieb et al

Table 1. Comparison of baseline characteristics among the study groups

L-Arginine 5 g (n ¼ 27) Tadalafil 10 mg (n ¼ 27) Both (n ¼ 27) Placebo (n ¼ 27) P value

Age (y) 43.19 ± 4.8 43.04 ± 5.9 45.33 ± 4.3 43.11 ± 4.6 .256*
P value† P1 ¼ .912 P3 ¼ .091 P5 ¼ .101 P6 ¼ .956
P2 ¼ .113 P4 ¼ .956 — —
Occupation, n (%) .427‡
Unskilled 23 (85.2) 18 (66.7) 19 (70.4) 19 (70.4)
Skilled 4 (14.8) 9 (33.3) 8 (29.6) 8 (29.6)
Disease duration (y) 4.41 ± 0.4 5.00 ± 0.5 4.37 ± 0.3 8.76 ± 1.7 .091
P value† P1 ¼ .764 P3 ¼ .750 P5 ¼ .030 P6 ¼ .032
P2 ¼ .985 P4 ¼ .063 — —
HbA1c (mmol/mol) 8.05 ± 1.1 7.84 ± 1.0 7.74 ± 1.2 7.95 ± 1.3 .818
P value† P1 ¼ .542 P3 ¼ .767 P5 ¼ .537 P6 ¼ .772
P2 ¼ .365 P4 ¼ .748 — —
P1 ¼ L-arginine vs tadalafil; P2 ¼ L-arginine vs both; P3 ¼ tadalafil vs both; P4 ¼ tadalafil vs placebo; P5 ¼ both vs placebo; P6 ¼ L-arginine vs placebo.
*Analysis of variance test was used to compare the mean differences among groups.
†
Post hoc test with Bonferroni corrections was used for pairwise comparisons.
‡
Chi-square test was used to compare the proportion difference between groups.

last treatment dose for each patient. This was to ensure washout
of the last treatment dose of tadalafil to better evaluate
improvement of vascular function and testosterone levels.
Statistical Analysis
Data were verified, coded by the researcher, and analyzed
using SPSS Statistics 21 (IBM; Armonk, NY). Descriptive sta-
tistics included calculation of the means, standard deviations, and
percentages. Tests of significance included chi-square tests to
compare differences in the distribution of frequencies among
different groups. For continuous variables, analysis of variance
was used to test mean differences in data that followed normal
distributions, and paired-sample t-tests were used for dichoto-
mous repeated measure analysis. Post hoc tests with Bonferroni
corrections were used for pairwise comparisons. A P value
.05
was considered significant.
Ethical Considerations
Approval for this study was obtained from the Ethics Com-
mittee of the Faculty of Medicine at Aswan University prior to
study execution. The trial was registered on the ClinicalTrials.gov
website (https://clinicaltrials.gov/NCT03834610). In addition,
all participants received a written consent form. The informed
consent was clear, indicated the purpose of the study, and
explained the participant’s freedom to participate or withdraw at
any time without any obligation. Furthermore, participant confi-
dentiality and anonymity were ensured by assigning each partici-
pant a code number for the purpose of analysis only. The study was
not based on any incentives or rewards for the participants.
RESULTS
This double-blinded, randomized, controlled clinical trial
was performed on 108 diabetic patients with ED. The
sociodemographic characteristics of the groups studied are re-
ported in Table 1. There were no statistically significant differ-
ences regarding age, disease duration, or HbA1c levels among
study groups at baseline (P > .05). IIEF-5 scores before treat-
ment among the L-arginine, tadalafil, L-arginine plus tadalafil,
and placebo groups showed no significant differences (Table 2).
IIEF-5 scores were significantly increased in all treated groups
after treatment compared with the baseline data (P < .001), but
patients who received the placebo showed no significant increase
(P ¼ .081) (Table 2).
Comparing the different lines of treatment, patients treated
with L-arginine, tadalafil, or both drugs showed significant
increases in their IIEF-5 scores compared to those treated with
placebo only (P < .001). Patients treated with tadalafil showed
significant increases in their IIEF-5 scores compared to those
treated with L-arginine (P < .001), and those treated with
both drugs showed a more significant increase compared to
those treated with L-arginine or tadalafil alone (P < .001)
(Table 2).
Total testosterone levels showed no significant differences
among the study groups at baseline (P > .05). After treatment,
testosterone levels were increased in patients treated with
L-arginine, tadalafil, or both drugs (P < .001), but patients who
received the placebo did not show a significant increase after
treatment (P > .05). Compared with the placebo group, the
other groups showed significant differences in testosterone levels
after treatment (P < .001 for all groups). Tadalafil-treated pa-
tients had significantly higher testosterone levels than patients
treated with L-arginine (P < .001). Also, treatment with both
drugs was associated with a more significant increase in testos-
terone than treatment with L-arginine or tadalafil alone
(P < .011) (Table 3).
PPUD indicated that PSV at baseline showed no significant
differences among the study groups. After treatment, PSV was

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L-Arginine Plus Tadalafil in Diabetic Patients with Erectile Dysfunction 1393

Table 2. Comparison of IIEF-5 scores before and after treatment among the study groups
L-Arginine Tadalafil
5 g (n ¼ 27) 10 mg (n ¼ 27) Both (n ¼ 27) Placebo (n ¼ 27) P value*

IIEF-5 before 12.22 ± 1.5 12.44 ± 1.4 13.67 ± 2.2 11.33 ± 1.4 .243
P value† P1 ¼ .808 P3 ¼ .126 P5 ¼ .053 P6 ¼ .081
P2 ¼ .077 P4 ¼ .063 — —
IIEF-5 after 18.33 ± 1.8 20.07 ± 1.4 23.52 ± 1.3 13.28 ± 1.9 <.001
P value† P1 < .001 P3 < .001 P5 < .001 P6 < .001
P2 < .001 P4 < .001 — —
P value‡ <.001 <.001 <.001 .081
IIEF-5 change (%) 52.21 ± 4.3 62.89 ± 3.7 82.88 ± 7.1 25.77 ± 4.9 <.001
P value† P1 ¼ .146 P3 ¼ .007 P5 < .001 P6 ¼ .026
P2 < .001 P4 < .001 — —
IIEF-5 ¼ International Index of Erectile Function, 5-item version; P1 ¼ L-arginine vs tadalafil; P2 ¼ L-arginine vs both; P3 ¼ tadalafil vs both; P4 ¼ tadalafil vs
placebo; P5 ¼ both vs placebo; P6 ¼ L-arginine vs placebo.
*Analysis of variance test was used to compare the mean differences among groups.
†
Post hoc test with Bonferroni corrections was used for pairwise comparisons.
‡
Paired t-test was used to examine the repeated measure difference between groups.

significantly improved in all study groups (P < .001) for both
the right and left sides, except for the group that received the
placebo (P < .05). Likewise, there were no significant differences
in PSV among patients treated with L-arginine, tadalafil, or both
drugs after treatment, but all of the treated groups showed
significantly higher PSV than the placebo group (P < .001)
(Table 4).
EDV at baseline showed no significant differences among the
study groups. Similarly, after treatment EDV showed no sig-
nificant changes among all of the study groups on both sides
(Table 5). Moreover, RI values showed no significant differences
among the study groups at baseline. They were significantly
increased after treatment in all groups except for the placebo
group. All of the treated groups showed significantly higher RI
values after treatment compared to the placebo group, but there
was no difference between patients treated with L-arginine and
those treated with tadalafil (Table 6).
DISCUSSION
Therapeutic strategies for the treatment of ED include oral,
parenteral, or invasive approaches. Oral medications are consid-
ered the first choice for treatment of ED.18 Tadalafil was
approved for clinical practice after the approval of sildenafil and
vardenafil. Tadalafil reaches peak plasma concentrations within 2
hours after administration. It has a rapid onset, reported to be
within 15 minutes of administration, and it has a long elimi-
nation half-life of 18 hours. The bioavailability of the drug may
persist for up to 36 hours.19,20 L-Arginine is a precursor and
source of NO, a neurotransmitter necessary for relaxation of

Table 3. Comparison of testosterone levels before and after treatment among the study groups
L-Arginine Tadalafil Placebo
5 g (n ¼ 27) 10 mg (n ¼ 27) Both (n ¼ 27) (n ¼ 27) P value*

Serum testosterone before (nmol/L) 10.78 ± 2.9 11.22 ± 3.4 9.56 ± 1.9 10.89 ± 2.7 .143
P value† P1 ¼ .559 P3 ¼ .571 P5 ¼ .082 P6 ¼ .884
P2 ¼ .110 P4 ¼ .661 — —
Serum testosterone after (nmol/L) 16.19 ± 2.8 20.19 ± 3.6 22.48 ± 3.6 11.04 ± 2.7 <.001
P value† P1 < .001 P3 ¼ .011 P5 < .001 P6 < .001
P2 < .001 P4 < .001 — —
P value‡ <.001 <.001 <.001 .154
Serum testosterone change (%) 59.61 ± 9.3 93.27 ± 11.3 144.4 ± 12 1.52 ± 0.7 <.001
P value† P1 ¼ .015 P3 < .001 P5 < .001 P6 < .001
P2 < .001 P4 < .001 — —
P1 ¼ L-arginine vs tadalafil; P2 ¼ L-arginine vs both; P3 ¼ tadalafil vs both; P4 ¼ tadalafil vs placebo; P5 ¼ both vs placebo; P6 ¼ L-arginine vs placebo.
*Analysis of variance test was used to compare the mean differences among groups.
†
Post hoc test with Bonferroni corrections was used for pairwise comparisons.
‡
Paired t-test was used to examine the repeated measure difference between groups.

J Sex Med 2019;16:1390e1397

1394 El Taieb et al

Table 4. Comparison of peak systolic flow velocity before and after treatment among the study groups
L-Arginine 5 g (n ¼ 27) Tadalafil 10 mg (n ¼ 27) Both (n ¼ 27) Placebo (n ¼ 27) P value*

Right side before (cm/s) 21.81 ± 1.1 21.09 ± 1.7 21.97 ± 1.2 21.09 ± 1.6 .952
P value† P1 ¼ .711 P3 ¼ .650 P5 ¼ .656 P6 ¼ .716
P2 ¼ .943 P4 ¼ .997 — —
Right side after (cm/s) 32.65 ± 3.8 33.09 ± 6.1 34.13 ± 4.6 20.33 ± 3.7 <.001
P value† P1 ¼ .769 P3 ¼ .479 P5 < .001 P6 < .001
P2 ¼ .317 P4 < .001 — —
P value‡ <.001 <.001 <.001 .579
Left side before (cm/s) 22.99 ± 1.9 21.23 ± 1.6 24.26 ± 1.1 18.82 ± 1.4 .023
P value† P1 ¼ .335 P3 ¼ .098 P5 ¼ .004 P6 ¼ .025
P2 ¼ .484 P4 ¼ .198 — —
Left side after (cm/s) 33.17 ± 4.5 33.08 ± 4.9 35.52 ± 3.8 19.42 ± 3.9 <.001
P value† P1 ¼ .949 P3 ¼ .081 P5 < .001 P6 < .001
P2 ¼ .093 P4 < .001 — —
P value‡ <.001 <.001 <.001 .622
P1 ¼ L-arginine vs tadalafil; P2 ¼ L-arginine vs both; P3 ¼ tadalafil vs both; P4 ¼ tadalafil vs placebo; P5 ¼ both vs placebo; P6 ¼ L-arginine vs placebo.
*Analysis of variance test was used to compare the mean differences among groups.
†
Post hoc test with Bonferroni corrections was used for pairwise comparisons.
‡
Paired t-test was used to examine the repeated measure difference between groups.

penis muscles.21 Investigations into the use of L-arginine as a
first-line ED treatment have been inconclusive.22,23
The current study showed that a daily oral administration of
10 mg tadalafil for 8 weeks in male patients with DM and
suffering from mild to moderate erectile dysfunction improved
IIEF-5 scores and total testosterone levels. This finding is in
agreement with the study by Wrishkoet et al,24 who reported
that 5 mg tadalafil daily vs placebo showed a significantly suc-
cessful intercourse rate (55%) on initial attempt compared with a
rate of 29% in the placebo group. Also, this finding is in
accordance with the study by McMahon,25 who reported that
patients receiving tadalafil showed significantly greater improve-
ment in IIEF-5 scores compared to the placebo group. Porst
et al26 analyzed data obtained from 1,913 patients from 6 ran-
domized, double-blind, placebo-controlled clinical studies. They
found that daily tadalafil significantly improved IIEF-5 scores.
Patients who received a daily dose of 5 mg showed greater
response than those who received 2.5 mg daily. Giuliano et al27
compared the efficacy of 5 mg tadalafil daily vs 0.4 mg tamsulin
with regard to ejaculatory and erectile function, as well as sexual
satisfaction, in patients with lower urinary tract symptoms sug-
gestive of benign prostatic hyperplasia and erectile dysfunction.

Table 5. Comparison of end diastolic velocity before and after treatment among the study groups
L-Arginine 5 g (n ¼ 27) Tadalafil 10 mg (n ¼ 27) Both (n ¼ 27) Placebo (n ¼ 27) P value*

Right side before (cm/s) 3.88 ± 0.6 4.30 ± 0.7 4.10 ± 0.4 4.61 ± 0.6 .843
P value† P1 ¼ .611 P3 ¼ .815 P5 ¼ .574 P6 ¼ .383
P2 ¼ .784 P4 ¼ .711 — —
Right side after (cm/s) 3.85 ± 0.5 3.70 ± 0.6 3.65 ± 0.5 3.72 ± 0.6 .638
P value† P1 ¼ .844 P3 ¼ .262 P5 ¼ .277 P6 ¼ .846
P2 ¼ .355 P4 ¼ .981 — —
P value‡ .949 .438 .283 .245
Left side before (cm/s) 3.82 ± 0.6 4.56 ± 0.6 3.28 ± 0.4 4.28 ± 0.5 .394
P value† P1 ¼ .349 P3 ¼ .108 P5 ¼ .212 P6 ¼ .560
P2 ¼ .499 P4 ¼ .729 — —
Left side after (cm/s) 3.83 ± 0.5 3.66 ± 0.5 3.21 ± 0.5 3.96 ± 0.6 .904
P value† P1 ¼ .825 P3 ¼ .468 P5 ¼ .745 P6 ¼ .816
P2 ¼ .614 P4 ¼ .693 — —
P value‡ .972 .249 .872 .686
P1 ¼ L-arginine vs tadalafil; P2 ¼ L-arginine vs both; P3 ¼ tadalafil vs both; P4 ¼ tadalafil vs placebo; P5 ¼ both vs placebo; P6 ¼ L-arginine vs placebo.
*Analysis of variance test was used to compare the mean differences among groups.
†
Post hoc test with Bonferroni corrections was used for pairwise comparisons.
‡
Paired t-test was used to examine the repeated measure difference between groups.

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L-Arginine Plus Tadalafil in Diabetic Patients with Erectile Dysfunction 1395

Table 6. Comparison of the resistance index before and after treatment among the study groups
L-Arginine 5 g (n ¼ 27) Tadalafil 10 mg (n ¼ 27) Both (n ¼ 27) Placebo (n ¼ 27) P value*

Right side before 0.81 ± 0.04 0.73 ± 0.06 0.80 ± 0.02 0.74 ± 0.04 .407
P value† P1 ¼ .178 P3 ¼ .212 P5 ¼ .302 P6 ¼ .257
P2 ¼ .918 P4 ¼ .838 — —
Right side after 0.88 ± 0.02 0.89 ± 0.02 0.86 ± 0.02 0.78 ± 0.04 .008
P value† P1 ¼ .930 P3 ¼ .553 P5 ¼ .014 P6 ¼ .003
P2 ¼ .614 P4 ¼ .003 — —
P value‡ .028 .018 .010 .393
Left side before 0.83 ± 0.03 0.76 ± 0.03 0.86 ± 0.02 0.74 ± 0.03 .157
P value† P1 ¼ .070 P3 ¼ .521 P5 ¼ .102 P6 ¼ .212
P2 ¼ .587 P4 ¼ .639 — —
Left side after 0.91 ± 0.01 0.89 ± 0.02 0.88 ± 0.01 0.76 ± 0.04 <.001
P value† P1 ¼ .461 P3 ¼ .855 P5 < .001 P6 < .001
P2 ¼ .385 P4 < .001 — —
P value‡ .014 .001 .041 .588
P1 ¼ L-arginine vs tadalafil; P2 ¼ L-arginine vs both; P3 ¼ tadalafil vs both; P4 ¼ tadalafil vs placebo; P5 ¼ both vs placebo; P6 ¼ L-arginine vs placebo.
*Analysis of variance test was used to compare the mean differences among groups.
†
Post hoc test with Bonferroni corrections was used for pairwise comparisons.
‡
Paired t-test was used to examine the repeated measure difference between groups.

They found that tadalafil significantly improved all sexual
functions, but tamsulin decreased ejaculatory and orgasmic fre-
quency and overall satisfaction and had no significant effect on
ED. Variation in the percentage of improvement between the
current work and previous studies may be due to higher daily
doses in the present study or differences in the patient sample
and patient variables, such as age, obesity, and comorbidities.
Furthermore, this study found that daily oral L-arginine therapy
for 8 weeks by diabetic male patients with mild to moderate ED
significantly increased IIEF-5 scores and total testosterone levels.
This finding is in agreement with previous reports that oral daily
administration of L-arginine in men with ED improved all sexual
functions, including erectile functions and desire, and was also
associated with increased testosterone levels.22,28
To the best of our knowledge, the present study is the first to
evaluate the effect of combined tadalafil and L-arginine on dia-
betic patients with ED. In our study, we found that daily oral L-
arginine supplementation plus tadalafil in men with DM
suffering from mild to moderate ED significantly increased their
IIEF-5 scores and total testosterone levels as compared to L-
arginine or tadalafil alone. Lebert et al21 reported that oral on-
demand use of L-arginine combined with yohimbine 1 to 2
hours before intended sexual intercourse was an effective therapy
with regard to improving erectile function parameters in patients
with mild to moderate ED. Also, it has been found that
combining Pycnogenol (Horphag Research Ltd.; Geneva,
Switzerland) with L-arginine for 8 weeks as a dietary supplement
in patients with mild to moderate ED was effective in improving
total IIEF-5 scores and salivary testosterone.29
The mechanism of ED improvement after L-arginine supple-
mentation may be due to the increased confidence in sexual
activities, which would have a significant impact on improving
the patient’s quality of life. Such positive feedback enhances the
secretion of testosterone from Leydig cells in the testes.13,28 On
the other hand, L-arginine can enhance the synthesis and release
of NO and enhance blood flow to the testes, which can improve
the synthesis and secretion of testosterone.30
The present study showed that both tadalafil and L-arginine
treatments were associated with increased testosterone levels
compared to baseline and placebo. Combined treatment was
associated with significantly increased testosterone levels
compared to each drug alone. This finding was consistent with
Ozcan et al,31 who found that 5 mg tadalafil daily significantly
improved ED due to increased total testosterone levels. The
higher percentage of increase in testosterone levels in the present
study may be due to the higher daily dose of tadalafil compared
to previous works. Carosa et al32 reported an increase in total
testosterone levels in patients treated with PDE5i. Animal studies
showed that PDE5 is expressed in rat Leydig and peritubular
cells,33 and supplementation of sildenafil in rats has been found
to stimulate the expression of steroidogenic protein kinase G1
and acute regulatory protein, thus leading to increased serum
testosterone levels.34
PPDU can provide detailed information about penile vascular
anatomy and hemodynamics, so it was our first-line approach to
evaluating penile arterial and venoocclusive function.35 It can be
performed with either oral or intracavernosal vasoactive agents
before imaging.36 The present study found significantly higher
values of PSV and RI after treatment in all treated groups as
compared with baseline and with placebo. Combined treatment
was not associated with significant changes in PPUD findings
compared to each drug alone. These findings are in agreement
with those of La Vignera et al,37 who found significant
improvement in PSV and RI after tadalafil therapy. They found

J Sex Med 2019;16:1390e1397

1396
that chronic tadalafil administration at a dose of 5 mg daily for
90 days reduced endothelial apoptosis and increased NO levels.
This effect disappeared within 6 months after the administra-
tion of tadalafil was discontinued. It was found that a combi-
nation of L-arginine and yohimbine was associated with
hemodynamic changes in ED patients as evaluated by Doppler
study.38
Limitations
In the present study, patients completed the IIEF-5 ques-
tionnaire based on sexual function under treatment. The IIEF-5
addresses sexual function within the previous 1-month period,
which does not ensure a washout period.
CONCLUSION
The present study concluded that combined daily oral
L-arginine and tadalafil treatment in diabetic patients with ED
is more effective than each drug alone with regard to
improvement in IIEF-5 scores and increase in total testos-
terone levels. Combination therapy was associated with sig-
nificant improvement in PPUD parameters compared to
baseline and placebo, but the improvement was insignificant
compared to each drug alone. Thus, the enhanced effect of
combined treatment may be partially due to increased
testosterone levels.
Corresponding Author: Moustafa El Taieb, MD, Department
of Dermatology, Venereology and Andrology, Faculty of Medi-
cine, Aswan University, Sahary City, Aswan, Egypt. Tel:
þ20972430767; Fax: þ20972430767; E-mail: moustafa.
eltaib@aswu.edu.eg
Conflicts of Interest: The authors report no conflicts of interest.
Funding: None.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
El Taieb and Hegazy
(b) Acquisition of Data
El Taieb and Hegazy
(c) Analysis and Interpretation of Data
Ibrahim, El Taieb and Hegazy
Category 2
(a) Drafting the Article
El Taieb, Ibrahim and Hegazy
(b) Revising It for Intellectual Content
El Taieb, Ibrahim and Hegazy
Category 3
(a) Final Approval of the Completed Article
El Taieb and Ibrahim
El Taieb et al
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