Vitamin E and ginseng combined supplement for treatment of male erectile dysfunction: A double-blind, placebo-controlled, randomized, clinical trial

Journal Pre-proof Vitamin E and ginseng combined supplement for treatment of male erectile dysfunction: a double-blind, placebo-controlled, randomized, clinical trial Borna Tadayon Najafabadi, Morteza Jafarinia, Kiandokht Ghamari, Kamyar Shokraee, Farhad Tadayyon, Shahin Akhondzadeh

PII:

S2212-9588(19)30597-X

DOI:

https://doi.org/10.1016/j.aimed.2019.12.001

Reference:

AIMED 220

To appear in:

Advances in Integrative Medicine

Received Date:

20 August 2019

Revised Date:

2 November 2019

Accepted Date:

13 December 2019

Please cite this article as: Tadayon Najafabadi B, Jafarinia M, Ghamari K, Shokraee K, Tadayyon F, Akhondzadeh S, Vitamin E and ginseng combined supplement for treatment of male erectile dysfunction: a double-blind, placebo-controlled, randomized, clinical trial, Advances in Integrative Medicine (2019), doi: https://doi.org/10.1016/j.aimed.2019.12.001

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Vitamin E and ginseng combined supplement for treatment of male erectile dysfunction: a double-blind, placebo-controlled, randomized, clinical trial Short Title: Vitamin E and ginseng for treatment of ED Category: Neuropsychopharmacology Borna Tadayon Najafabadi1 MD., Morteza Jafarinia MD., Kiandokht Ghamari1 MD., kamyar

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Shokraee1 MD., Farhad Tadayyon MD., Shahin Akhondzadeh1 Ph.D.

Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences,

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The first three authors contributed equally to this work.

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Tehran, Iran

Corresponding author: Prof. ShahinAkhondzadeh, Psychiatric Research Center, Roozbeh

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Psychiatric Hospital, Tehran University of Medical Sciences, South Kargar Street, Tehran, Iran

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13337. Tel: 98-21-55412222, Fax: +98-21-55419113, Email: [email protected]

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Abstract Background: Erectile dysfunction (ED) is among the most common

sexual dysfunctions

affecting the male population over 40 years old. The first line of treatment for this condition is phosphodiesterase 5 inhibitors. Although these drugs are very effective, some patients are reluctant to use them due to their side effects or patient unresponsiveness. We hypothesized that a supplement of vitamin E and ginseng, due to anti-oxidative

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properties, can ameliorate erectile dysfunction.

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Objective: This study aimed to evaluate the effect of vitamin E and ginseng supplement to enhance erectile function among patients with erectile dysfunction .

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Methods: In a six-week, double-blind, parallel-group, placebo-controlled trial, patients

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between 18 to 60 years of age, with erectile dysfunction based on the international index of erectile function (IIEF) questionnaire, were equally randomized to receive daily

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supplement of vitamin E and ginseng (100 IU vitamin E, 67 mg Korean ginseng, and 40mg Siberian ginseng) or placebo. Participants were evaluated for erectile dysfunction

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with the IIEF scale and adverse event on the second, fourth, and sixth week. Analysis of variance was used to compare groups in terms of erectile function. Results: Fifty-two participants were randomly allocated to the groups and all finished the trial. Participants in our groups did not differ significantly in their baseline variables.

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After six weeks, the analysis revealed a significant improvement of erectile function in the supplement group over the placebo group (p-value=0.033). Other domains of sexual function did not show significant difference between the groups. Adverse events profile of the supplement group was clinically acceptable and similar to the placebo group.

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Conclusion: Our results revealed that the vitamin E and ginseng combined supplement can improve erectile function after six weeks while maintaining a safe and acceptable adverse event profile. Further trials with longer follow-up time and bigger population is still suggested.

Keywords: Antioxidants; Erectile dysfunction; Ginseng; Randomized clinical trial; Sexual

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dysfunction; Vitamin E

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1. Introduction:

Erectile dysfunction is defined as the persistent inability to acquire or sustain a penile erection sufficient enough for satisfactory vaginal intercourse [1]. It is among the most common male sexual dysfunctions which include different disorders such as erectile dysfunction, decreased libido, and ejaculatory disorders [2]. Erectile dysfunction primarily

the

link

erectile

dysfunction

has

with

hypertension,

diabetes

mellitus,

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shown

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involves men over 40 and its prevalence positively correlates with age. Studies have also

hyperlipidemia, metabolic syndrome, depression, and lower urinary tract symptoms [3].

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Consequently, since the risk factors for this condition and cardiovascular diseases are

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disease among high-risk individuals [4].

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similar, it is believed that erectile dysfunction can be an indicator of cardiovascular

Endothelial function and nitric oxide (NO) play a central role in physiology of erectile

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dysfunction. NO, derived from the endothelium and parasympathetic nerve terminals, causes cavernosal smooth muscle relaxation and subtunical small vein occlusion, which subsequently allow penile erection. The intracellular mechanism, through which NO exerts its effect, is the transformation of guanosine triphosphate (GTP) to cyclic guanosine

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monophosphate (cGMP) by guanylyl cyclase[5].

Pharmacotherapy of erectile dysfunction has greatly improved since the introduction of Phosphodiesterase type 5 (PDE-5) inhibitor drugs, which include sildenafil, tadalafil, and vardenafil. Other treatment modalities include penile injections, vacuum instruments, and

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penile prosthesis. PDE-5 is an enzyme that facilitates hydrolysis of cGMP which eventually causes

detumescence

[3, 6].

However,

although

PDE-5

inhibitors

have

revolutionized the treatment of erectile dysfunction, still some patients are either unresponsive to these drugs or cannot take them because of concomitant conditions such a nitrate use or retinitis pigmentosa [7]. Studies have demonstrated that the efficacy of PDE-5 inhibitors are 65 to 70% in short term and yet around 30% of the patients do

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not achieve erections needed for successful intercourse [8-10]. In addition, side effects

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such as headache and flushing for sildenafil, and muscle pain for tadalafil may cause

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discontinuation of treatment[11].

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Considering the existing limitations, the search for new oral agents to treat erectile dysfunction seems necessary to give the patients,

unresponsive to PDE-5 inhibitors,

materials in

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another chance before proceeding to more invasive treatments. Two traditionally used treatment of this condition are vitamin E and ginseng [12, 13]. Vitamin E is

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believed to benefit erectile dysfunction sufferers via its free radical scavenger properties [14]. Ginseng, in addition, has been more widely used to ameliorate different aspects of sexual

dysfunction,

especially

in

Chinese

medicine [12].

However,

although

data

suggesting ginseng benefits for erectile dysfunction is available, robust evidence of its

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efficacy to reduce erectile dysfunction is still needed [15, 16]. Therefore, we hypothesized that a combination supplement of vitamin E and ginseng can ameliorate erectile dysfunction among patients. The reason, why a combined supplement was chosen, was to be able to utilize two different agents with similar anti-oxidative properties. This could , in turn, let us minimize doses used to decrease the chances of any adverse events or

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interactions. Our study, consequently, aims to evaluate the effects of the mentioned

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supplement on erectile dysfunction.

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2. Materials and Methods

2.1. Study setting and design Participants

were

enrolled in

a

six-week,

double-blind,

multi-center,

parallel-group,

randomized, placebo-controlled clinical trial between December 2017 to March 2019 from the psychosomatic outpatient clinic of the Imam hospital complex (affiliated with Tehran

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University of Medical Sciences, Tehran, Iran). This clinic is a secondary care clinic

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located in a hospital complex offering a wide range of health care services with a patient catchment area of all the city of Tehran. Prior to participant registration, the

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study protocol was approved by Tehran University of Medical Sciences’ institutional

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review board (IRB no:1396.3850) and it also was registered at the Iranian registry of clinical trials (IRCT no: IRCT20090117001556N101). This trial was conducted according

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2.2. Participants

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to the Helsinki declaration and its subsequent revisions.

Married men aged 18 to 60 years old, who came to the study recruiting center, were asked about any concomitant sexual dysfunction regardless of their chief complaint. All of the patients visited in the clinic underwent this screening. Afterwards, those with a

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positive answer were asked to fill out the International Index of Erectile Function (IIEF) questionnaire. This questionnaire is a 15-item questionnaire designed to evaluate five different domains of sexual function (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction) independently[17, 18]. We used the validated Farsi translation of this questionnaire [19]. Participants who scored 25 or less

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(pertaining to the threshold of mild erectile dysfunction) on the erectile dysfunction domain were then evaluated for the exclusion criteria consisting of: (1) presence of any treatable

conditions

causing

erectile

dysfunction

like

testosterone

insufficiency,

hyperprolactinemia, or drug induced erectile dysfunction, (2) history of pelvic or penile surgeries or radiation due to the possibility of iatrogenic nerve or vascular injuries, (3) use of any erection-enhancing medication during the past four weeks, (4) use of any

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anticoagulation therapy (to avoid risk of bleeding due to the interaction with ginseng), (5)

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presence of any psychiatric disorder. This set of exclusion criteria was set to avoid the recruitment of patients in whom any new pharmacotherapy was inappropriate (exclusion

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criteria 1 and 2), safety of ginseng was not established (exclusion criterion 4), co-treatment

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might obscure the putative causation (exclusion criterion 3), and validity of outcome measurement tool was not established (exclusion criterion 5). Each participant was

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individually informed about the trial design and their rights such as anytime withdrawal at will with no effect on their relationship with their health care provider. Participants

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who were suitable and willing entered the trial and their demographic data was collected.

2.3. Intervention

Participants were first randomized to two groups. One of the groups received vitamin E and

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ginseng supplement tablets (100 IU vitamin E, 67 mg Korean ginseng, and 40mg Siberian ginseng; X-Ade, Golden life, Australia) once daily for a 6-week course. The other group received the placebo tablets, which was similar to the supplement in color, texture, taste, and smell, in the same manner. All of the participants were suggested to take their daily dose with a glass of water, after their lunch. The placebo tablets used in this trial

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were starch based. The tablets were given to the patient all at once in the first day of treatment. Participants were also asked not to take any new medication or psychotropic treatment during the trial. Further, no additional counseling or education was provided. The participant’s compliance to treatment was assessed by counting the number of tablets remaining at the 4th week of treatment.

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2.4. Outcomes

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The primary outcome of interest in our study was the change in the erectile function domain score on the scale of the IIEF questionnaire. IIEF is a self-administered 5

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domain questionnaire designed to evaluate various aspects of male sexual function during

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the past month [17]. In this study, we used a Farsi translation of this questionnaire which has already been examined and shown to be valid and reliable[19]. Erectile function

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domain of this questionnaire consisted of 6 questions and its score range was from 1 to 30. Scores ranging from 1 to 5 on this scale usually means no sexual intercourse or no

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attempts and also higher scores represent a better function.

In this scale, scores of 10,

16, 21, and 25 demarcate thresholds for severe, moderate, mild to moderate, and mild erectile dysfunction respectively [20]. Participants were asked to fill the IIEF questionnaire prior to trial commencement in person and after 2, 4, and 6 weeks into

treatment over

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the phone. All the outcome assessors were trained simultaneously by an expert urologist (F.T.) and an expert psychiatrist (M.J.) who were very familiar with the questionnaire. Participants were also instructed to fill out a prepared 25-item adverse event form at the 2-week intervals and were also encouraged to report any other adverse effects.

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Furthermore, other domains of the IIEF questionnaire score change alongside adverse events developed during the study were considered as our secondary outcome of interest.

2.5. Randomization and blinding A computer-generated random queue (blocks of 4, 1:1 ratio), of letters A and B, was used. The letters were consecutively put in numbered, opaque, sealed envelopes. This part of was

done by a party not

engaged

elsewhere in the study.

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the randomization

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Consequently, the envelopes were consecutively assigned to participants based on their order of recruitment. The assignment of the letters to treatment groups was also only

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revealed to the project coordinator.

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In terms of blinding, none of the participants were informed of neither the letter nor the group they were assigned to. Similarly, outcome assessors were blind to the assignments.

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Placebo and active agent tablets were completely similar in terms of shape, size, color, texture, taste, and smell, which made them indistinguishable for the patients and the

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assessors.

2.6. Sample size and statistical analysis

The term minimal clinically important difference (MCID), for the erectile dysfunction

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domain of the IIEF, refer to the minimum amount of difference in the score that is clinically significant. This number for mild erectile dysfunction is considered to be 2.8 [21]. Considering a standard deviation (SD) of 4 and an MCID of 2.8, alongside a type I error of 0.05 and a power of 80%, we calculated a sample size of 21 per group. But,

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we added 25% to compensate for the dropout rate and a final sample size of 26 in each group was achieved [21]. The statistical analysis was performed using the IBMSPSS Statistic 19.0.0 (IBM Corporation). The categorical and continuous variables were reported as frequency (percentage) and Mean  SD, respectively. For baseline variables comparison, independent sample t-test for

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continuous variables (mean difference(MD) and standard error (SE) of mean difference are reported) and Pearson chi-square (or Fisher’s exact test when suitable) for categorical

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variables were used. In addition, to compare the changes in each IIEF domain, either between treatment groups or within each treatment group, we performed repeated

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measures analysis of variances (ANOVA) to reveal the time  treatment interaction.

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Wherever sphericity of the data could not be assumed (by Mauchly’s test of sphericity), the Greenhouse-Geisser correction was used. Further, since age is the major predictor of

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erectile dysfunction, we performed an additional repeated measure analysis of covariances (ANCOVA) with the age variable as the covariate to adjust for its effects. A p-value ≤

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0.05 was considered significant throughout the analysis.

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3. Results

3.1. Participants One-hundred-one patients were screened for the eligibility criteria, while fifty-two patients who met the criteria were randomly allocated to either supplement or to the placebo groups (26 in each group). Interestingly, all of the participants finished the trial and no

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drop-out was observed. The study flow diagram is demonstrated in figure 1. Our participant

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population consisted of males with a mean age of 41.18  6.59 years ranging from 32 to 57 year-old, none of whom suffered diabetes mellitus. They also had a mean erectile

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function score of 18.63  5.81. Table 1 demonstrates detailed comparison of baseline

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variables for each treatment group and shows that no significant difference was observed

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3.2. Outcomes

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between them.

3.2.1. Primary outcome As

Table 1 demonstrates, the baseline IIEF erectile function domain score did not

significantly differ between the two groups (MD[SE of mean difference]=0.62[1.68], p-

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value=0.716). Table 2 also details the comparison of various IIEF domain score changes between and within

groups. As indicated in the table, the score change during the

course of our trial was significantly greater for the vitamin E and ginseng supplement group versus the placebo group. This was while our analysis revealed that only the score changes among our active agent group was significant. Furthermore, our ANCOVA

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analysis, aiming to adjust for the effects of age and achieving more precise effect size, yielded significant timetreatment group interaction (Greenhouse-Geisser F(62.1, 2.0)=5.08, p-value=0.008). After 6 weeks, participants who received the supplement experienced a mean score reduction of MDSE=4.540.77 (p-value<0.001) on the erectile function domain which is higher than MCID. However, as

Figure 2 depicts, the greatest score

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increase for supplement group was achieved at the second week (MDSE of the mean

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difference=5.540.85).

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3.2.2. Secondary outcome

Similarly, repeated measures ANOVA was used to compare other domains of the IIEF

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scale and its summary is presented in the table 2. None of the domains, other than erectile function, displayed a significant time  treatment interaction difference between

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the groups. Nevertheless, the same interaction within the supplement group participants was significant for all the four remaining domains, while among the placebo group, only

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sexual desire was meaningfully heightened.

In terms of adverse effects, neither group reported any clinically important adverse effect or any that causes treatment cessation. Table 3 entails adverse event profile of the groups

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separately. The frequency of seven observed adverse effects did not vary between groups significantly.

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4. Discussion

Our results demonstrated that the vitamin E and ginseng supplement ameliorated erectile dysfunction among participants superior to the placebo although other sexual function improvements were not significantly improved. Since our participants in the groups had similar baseline properties, this observed enhancement can be solely attributed to the

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supplement used. Furthermore, as the change in the IIEF erectile function score was

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greater than the MCID, it is fair to conclude that the difference from the baseline status is important from a clinical point of view. Considering that the vitamin E and ginseng

the possibility that our sample size could not detect the

superiority of the supplement over

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only improved sexual desire,

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supplement could enhance other sexual functions compared to baseline, while placebo

placebo remains. In addition, another equally

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important issue, the adverse effects, showed no meaningful difference between the groups

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and had a clinically acceptable profile.

To the best of our knowledge, this is the first study to use a vitamin E and ginseng supplement

for

erectile

dysfunction.

However,

some

studies

have

addressed

the

beneficiary effects of vitamin E and ginseng individually. A systematic review and meta-

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analysis by Jang et al., found seven RCTs, with various methodological quality, that evaluated the use of red ginseng in the treatment of erectile dysfunction [16]. Threehundred-sixty-three men whose age ranged from 24 to 70 years were included in those seven trials and were treated for 4 to 12 weeks. The dose of the red ginseng used was from 600 mg to 1000 mg each day. All RCTs reported positive outcomes for ginseng. Meta-

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analysis of six of the RCTs revealed the efficacy of red ginseng for amelioration of erectile dysfunction (n=349, relative risk=2.40; 95% confidence interval of 1.65, 3.51, and p < 0.0001)[16].

On the other hand, there are very few studies which directly assess the impact of vitamin E on erectile dysfunction in human. Kondoh et al., however, evaluated the

initial PDE5 inhibitors. This study reported 8

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9 patients who did not respond to

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additional benefits of adding vitamin E (300 mg per day) for at least one month among

participants experienced favorable subjective changes in their erectile function [22].

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Similarly, De Yonge et al. compared effects of vitamin E and sildenafil administered both

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separately and combined in diabetic rats. This study concluded that in their animal model, vitamin E enhanced the therapeutic effects of the PDE5 inhibitor [23]. Another

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study, which assessed relation of age-related erectile dysfunction and vitamin E in rats, reported an improved erectile function in

aged rats receiving vitamin E [24]. Taking

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everything into consideration, although the evidence for either vitamin E or ginseng in treatment of erectile dysfunction is not strong, data suggests these two agents can ameliorate erectile dysfunction. This is , in fact, in line with our study findings and

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hypothesis.

To better understand how vitamin E and ginseng might benefit erectile dysfunction, it is noteworthy to mention a possible mechanism of action. One of the cellular determinants for erectile dysfunction is the cavernosal blood oxidative stress. Oxidative stress occurs when an excessive amount of reactive oxygen species (ROS) is introduced to the cells

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[25].

These

reactive

species

include

superoxide

(O2),

hydrogen

peroxide(H2O2),

hypochlorous acid (HOCL), and peroxynitrite (OONO) which are the most prominent free radicals implicated in vascular diseases. As mentioned earlier, NO plays a central role in a normal erection. Superoxide radicals react with the available NO in the cavernosal blood to form peroxynitrate which in turn inactivates superoxide dismutase,

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which is the enzyme in charge of superoxide removal. This reduced depletion of superoxide consequently causes more NO molecules to react with it. Moreover,

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peroxynitrate has opposite relaxing effect on the smooth muscle compared to NO that finally causes ineffective cavernosal relaxation and erectile dysfunction. These free

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radicals also cause endothelial cell damage and impair NO production. Further, direct

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vasoconstrictive effects of superoxide, by immobilization of calcium, should also be considered [26]. However, it cannot be left unsaid that this is one hypothesis that tries to

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explain the relation between oxidative stress and erectile dysfunction.

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Vitamin E and ginseng are well known for their anti-oxidative properties. This vitamin is the most abundant, lipophilic, radical-scavenger, anti-oxidant in the human bod which scavenges free radicals mainly by hydrogen atom transfer. Interestingly, it has been reported that vitamin E is mostly capable of scavenging peroxyl radicals [27]. Ginseng,

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similarly, possesses antioxidant features in a variety of tissues and conditions [28-33]. Its primary active constituents are different ginsenosides and their portions vary across different types and preparations of ginseng [34, 35]. These activities are believed to be due to the down regulation of ROS-stimulated mitogen-activated protein kinase (MAPK) and Akt pathways [36]. Thus, considering these facts, a probable mechanism through

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which

vitamin E and ginseng supplement might improve

erectile function is through

attenuation of oxidative stress.

The vitamin E and ginseng supplement demonstrated an acceptable adverse event profile similar to

placebo. This profile plays an important role in our discussion since some of

the erectile dysfunction patients are reluctant to use PDE5 inhibitors because of their

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adverse effects [11]. In this case, supplements such as the one used in this study might

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introduce those patients to a more easily achieved erection. Furthermore, as discussed in the introduction , those patients who are not responsive to

PDE5 inhibitors might want

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to give these natural supplements a chance before proceeding to more invasive options.

Our study had limitations such as a small number of participants and absence of separate

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groups for vitamin E and ginseng in addition to the combined supplement. Unfortunately, Since erectile dysfunction is a condition with many known and unknown contributing

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factors, randomization in a small sample size might not similarly distribute all the confounding factors among groups, although by chance. This, in turn, can threaten the veracity of results interpretation. Our participants were recruited from those who seek medical help in a secondary care setting, thus, the results, in terms of generalizability,

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might be susceptible to bias since our sampling frame might not, in the best way, represent non health care seekers and general population suffering erectile dysfunction. Moreover, we only followed the participants for six weeks and more long-term data can definitely enhance our knowledge on this issue. Therefore, further research using larger sample sizes inclusive of more groups and longer course is suggested.

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5. Conclusion

Our study demonstrated that the combined vitamin E and ginseng supplement could enhance

erection of erectile dysfunction sufferers while maintaining a safe and

acceptable adverse event profile. Therefore, we suggest that this supplement can be used

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for those unresponsive to PDE5 inhibitors or those who encounter side effects as an

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option before more invasive treatments. The results of our study, however, should be interpreted with caution due to the limitations. Regarding other areas of sexual function, improvement with the supplement, the difference with

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although participants experienced

Ethical statement

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placebo was not significant.

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The Study protocol was approved by the institutional review board (IRB) of Tehran University of Medical Science (IR.TUMS.REC. 1396.3850) and conducted consistent with Declaration of Helsinki and subsequent revisions. The trial was registered at the Iranian registry of clinical trials (www.irct.ir; registration number: IRCT20090117001556N101) prior to the study. Participant

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rights were fully explained and informed consent was obtained individually. Author contributions: SA, principal investigator and data Management from December 2017 March 2019; BT, KG and KS, data collection and data analysis from December 2017 -March 2019; MJ and FT writing the manuscript and data analysis from December 2017 -March 2019.

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Disclosure of interests None of the authors contributing to this article have any conflict of interest to report. Acknowledgements This study was thesis of Dr. Borna Tadayon for MD at Tehran University of Medical Sciences. It was supported by a grant from Tehran University of Medical Sciences (Grant Number: 38141).

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We Thank to Darman Yab Company for providing the medications that we used in this trial.

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[27] E. Niki, Role of vitamin E as a lipid-soluble peroxyl radical scavenger: in vitro and in vivo evidence, Free Radic. Biol. Med. 66 (2014) 3-12. [28] H.G. Kim, S.S. Jang, J.S. Lee, H.S. Kim, C.G. Son, Panax ginseng Meyer prevents radiation-induced liver injury via modulation of oxidative stress and apoptosis, Journal of ginseng research 41(2) (2017) 159-168. [29] W. Wang, H. Shen, J.J. Xie, J. Ling, H. Lu, Neuroprotective effect of ginseng against spinal

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Ki, Korean Red Ginseng attenuates ethanol-induced steatosis and oxidative stress via AMPK/Sirt1 activation, Journal of ginseng research 39(2) (2015) 105-15. [34] A. Ying, Q.T. Yu, L. Guo, W.S. Zhang, J.F. Liu, Y. Li, H. Song, P. Li, L.W. Qi, Y.Z. Ge, E.H. Liu, Q. Liu, Structural-Activity Relationship of Ginsenosides from Steamed Ginseng in the Treatment of Erectile Dysfunction, Am. J. Chin. Med. 46(1) (2018) 137-155.

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[35] K.S. Cho, C.W. Park, C.K. Kim, H.Y. Jeon, W.G. Kim, S.J. Lee, Y.M. Kim, J.Y. Lee, Y.D. Choi, Effects of Korean ginseng berry extract (GB0710) on penile erection: evidence from in vitro and in vivo studies, Asian journal of andrology 15(4) (2013) 503-7. [36] Y.-M. Lee, H. Yoon, H.-M. Park, B.C. Song, K.-J. Yeum, Implications of red Panax ginseng in oxidative stress associated chronic diseases, Journal of ginseng research 41(2) (2017)

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113-119.

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Figure Legends:

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Figure 1: Flow chart of the trial

Figure 2: International index of erectile function (IIEF) scale erectile function domain mean score changes during the trial (error bars represent standard error of the mean)

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26

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Table 1: Baseline variable comparison between treatment groups Treatment group Vitamin E and Ginseng ( n=26 ) 42.12 11.08

8.17 8.29

Count

4 7 15

8.12

2.32

6.12

2.37

SD

40.23 10.12

4.26 6.85

15.4% 26.9% 57.7%

Count

%

p-value 0.302 0.651

2 10 14

0.540

7.7% 38.5% 53.8%

6.58 2.87 1.58

0.716 0.896 0.776

7.69

2.46

0.527

5.85

2.01

0.661

18.08 6.65 4.58

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5.50 3.46 1.32

Mean

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18.69 6.77 4.69

%

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SD

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Age Marriage duration Education Pre high-school High-school Post high-school IIEF Erectile function domain Orgasmic function Sexual desire Intercourse satisfaction Overall satisfaction

Mean

Placebo ( n=26 )

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SD standard deviation, n number, IIEF International Index of Erectile Function

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Table 2: Analysis of variances (ANOVA) repeated measures of different IIEF domains score changes statistics summary for timetreatment interaction between or within treatment groups GreenhouseMean IIEF domain df F p-value Geisser correction square Erectile function Between groups Yes 1.88 50.07 3.63 0.033 Supplement Yes 2.09 248.96 29.31 <0.001 Placebo Yes 1.58 54.71 2.54 0.103 Orgasmic function Between groups Yes 1.97 1.83 0.46 0.630 Supplement Yes 1.60 13.42 4.59 0.022 Placebo Yes 1.72 12.17 1.90 0.167 Sexual desire Between groups Yes 2.54 1.47 1.21 0.306 Supplement Yes 2.11 22.30 16.95 <0.001 Placebo Yes 1.77 17.63 9.23 0.001 Intercourse satisfaction Between groups Yes 1.94 1.22 0.35 0.703 Supplement Yes 1.87 24.70 12.33 <0.001 Placebo Yes 1.88 16.91 3.19 0.053 Overall satisfaction Between groups Yes 2.06 3.36 1.40 0.252 Supplement Yes 1.72 11.31 5.00 0.015 Placebo Yes 1.47 1.41 0.34 0.645 IIEF International Index of Erectile Function, df degree of freedom

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Table3: Adverse events reported in the study groups

Treatment group Supplement (n = 26) Count %

Placebo (n = 26) Count

%

p-value*

1

3.85

2

7.69

1.000

Dry mouth

2

7.69

3

11.54

1.000

Nausea

2

7.69

2

7.69

1.000

Vomiting

3

11.54

2

7.69

1.000

Itching

1

3.85

1

3.85

Constipation

2

7.69

0

0.00

Dizziness

2

7.69

2

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Headache

1.000

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0.490 1.000

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7.69

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n number *p-values calculated with Fisher’s exact test

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