Sexual health is an important issue in quality of life of males and females. In males’ sexual well-being, dissatisfaction in sexual life is significantly caused by erectile dysfunction (ED), which is defined as a consistent or recurrent inability of a man to attain and/or maintain penile erection sufficient for sexual activity [
Reviews as well as multinational surveys for Asian countries showed the prevalence of self-reported moderate ED in aging males (40–70 years) ranging from 17.7% (Taiwan), 22% (Malaysia), 28.3% (China), 32.2% (Korea), and 34% (Japan) [
In Malaysia, one of the most popular herbs,
Traditionally used remedies for enhancing testosterone level in man are (water) extracts of the roots of
Clinical trials to support and substantiate the traditional use of
Literature-based evidence on the alleged ergogenic potency of (water) extracts of
The potential of the therapeutic efficacy as well as safety/tolerability of
This 12-week randomized, double-blind, placebo-controlled and parallel group designed trial in Malay males was conducted in accordance with the Guideline for Good Clinical Practice (ICH-6) and Declaration of Helsinki. The study protocol was evaluated and approved by the Human Research and Ethics Committee for Clinical Studies of Universiti Sains Malaysia (USM) (approval date 24 December, 2008). The intervention was carried out from January 2009 (first patient in) to August 2010 (last patient out) at the Clinical Trial Unit (CTU), Hospital Universiti Sains Malaysia (HUSM), Kubang Kerian, Malaysia.
After signed informed consent, healthy married men between 30 years and 55 years of age or those with stable chronic medical illnesses, for example, controlled diabetes mellitus and/or hypertension on monotherapy or low dose combination therapy were included (accepted comedication in obese and overweight subjects, for example, antidiabetic drug metformin and hypertension, for example, antihypertensive drug amlodipine, atenolol, perindopril). Subjects were excluded with major uncontrolled psychiatric disorders, history of alcohol or drug abuse, history of major hematological, renal or hepatic disorder, stroke or myocardial infarction within the last six months, peptic ulcer or bleeding disorder, elevated blood pressure beyond the range of 90/50 to 170/100 mmHg, clinically relevant baseline laboratory abnormality, and/or use of herbal products or drugs that could contain testosterone or any androgenic activity in the last month before start of trial. These products and alcohol were also not permitted during trial.
Subjects were given the option of withdrawing from the study for any reason at any time or, for example, evidence of intolerance towards
The sample size estimation for this trial was based on data of efficacy studies performed with other traditional herbal medicines since effects of
The subjects adhered to a total of four visit intervals for screening (visit 1, week 1 to week 2), recording of measurements at baseline (visit 2, day 0), at week 6 (visit 3, day
During the intervention, each subject consumed four capsules per day containing either verum or placebo. One verum capsule contains as active ingredients 75 mg of the special freeze-dried water extract of
Primary endpoints were taken as the efficacy parameters of Quality of Life (SF-36) questionnaire and physical fitness tests such as flexibility (sit and reach), muscular strength (hand grip; back and leg), muscular endurance (sit-up and push up), and cardiovascular endurance as well as the safety profiles which were measured at each visit after enrollment.
The SF-36 QOL scale, validated for use in Malaysia [
Each session of the physical fitness tests contained of a battery of different types of tests so that various physiological and muscular parameters could be activated/stimulated, finally leading to an improvement of these fitness activities: flexibility—(type of test: sit and reach), muscular strength (hand grip; back and leg), muscular endurance (sit-up and push up), body composition (Bioelectrical Impedance Analysis), and cardiovascular endurance/cardiorespiratory fitness. All these tests were carried out on the same day for each participant and the duration took approximately two hours for each session of five to eight subjects.
The safety assessments reflected the documented Adverse Events (AE, description, severity, causality to treatment as assessed by the investigators), physical examination, clinical and laboratory measures including blood urea serum electrolytes (BUSE), creatinine, Serum Glutamate-Oxalacetate Transaminase (AST), Serum Glutamate-Pyruvate Transaminase (ALT), alkaline phosphatase (ALP), total protein, albumin, globulin and bilirubin, Prostatic Specific Antigen, glucose, uric acid, lipid profile, full blood count, and the ratio testosterone : epitestosterone.
The secondary endpoints were assessed at baseline and after 6 weeks and 12 weeks of treatment: Sexual Health Questionnaires (SHQ) and International Index of Erectile Function (IIEF-15), hormonal profiles, that is, free testosterone, serum total testosterone, Insulin-like Growth Factor 1 (IGF-1), dehydroepiandrosterone sulfate (DHEA-SO4), sex hormone binding globulin (SHBG), Seminal Fluid Analysis (SFA, using standardized methods for collection [
The SHQ used in this study contains questions divided into two domains “Sexual Libido” and “Sexual Satisfaction”. The IIEF-scale which is useful to evaluate erectile dysfunction of a population consists of 15 questions divided into five domains: “Erectile Function”, “Orgasmic Function”, “Sexual desire”, “Intercourse Satisfaction”, and “Overall Satisfaction”. The scores correspond to clinical interpretations ranging from “severe” to “no dysfunction”. The IIEF-scale is culturally adapted and validated for use in Malaysia [
Blood tests were analyzed at the Gribbles’s clinical laboratories (Petaling Jaya, Selangor, Malaysia). DEXA scan and SFA (single lab technician) were conducted at Hospital Universiti Sains Malaysia (HUSM). Physical fitness tests were conducted by Sport Science Lab personnel at HUSM.
The main aim of the statistical analysis was to explore the safety profiles and to show the effectiveness of the trial drug measured by changes of the parameters in the
Data was explored and descriptive statistical analysis was conducted by variables especially on the safety profiles. Mean (SD, standard deviation) was described for continuous variables of normality distributed data and median (IQR, inter quartile range) for nonnormal distribution, while frequency and percent (%) were described for categorical data. Independent
Further efficacy analysis on selected outcome parameters at significance level
All data were documented in the case report forms (CRF). Data entry was done at Clinical Trial Unit (CTU), School of Medical Sciences, Universiti Sains Malaysia USM. Results from the trial were analysed and stored at School of Medical Sciences, Universiti Sains Malaysia. The statistical analysis was performed using Statistical Package Social Sciences, SPSS (PASW 18.0) under license of USM, Malaysia.
A total of 122 male subjects were screened for eligibility and 109 subjects were randomized to
Number of subjects as in the Intention-to-Treat analysis datasets by primary* and secondary** outcomes. Subjects were omitted for analysis if they have no baseline data and/or without at least one postbaseline evaluation at week-6 or week-12. For SFA, only 36 subjects who turned up at both visit 2 and visit 4 were included for efficacy analysis. For safety profiles, the full dataset included all subjects who took at least one dose of study medication and had at least one postbaseline efficacy evaluation.
Baseline comparisons on demographic and physical examination data on study participants between randomized groups of
Baseline comparisons on demographic and physical examination data on study participants between randomized groups of
Variables |
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Placebo ( |
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Demographic characteristics | |||
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Age (years) | 43.6 (6.52) | 42.8 (6.73) | 0.553 |
Educational level ( |
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Primary | 4 (7.5) | 0 (0.0) | |
Secondary | 43 (81.1) | 49 (89.1) | 0.113‡ |
Tertiary | 6 (11.3) | 6 (10.9) | |
Ethnicity ( |
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Malay | 53 (98.1) | 53 (96.4) | 0.609‡‡ |
Non-Malay | 1 (1.9) | 2 (3.6) | |
Duration of married (mean years, SD) | 16.9 (8.02) | 17.2 (7.27) | 0.842 |
No. of children (median, range) | 4 (0–13) | 4 (0–10) | 0.718** |
Smoking | 18 (33.3) | 24 (43.6) | 0.609‡ |
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Physical examinations | |||
| |||
Systolic blood pressure (mmHg) | 118.1 (12.9) | 118.9 (13.1) | 0.750 |
Diastolic blood pressure (mmHg) | 76.1 (8.9) | 74.2 (8.6) | 0.259 |
Height (meter) | 1.65 (0.05) | 1.67 (0.06) | 0.171 |
Body weight (kg) | 71.9 (10.5) | 71.9 (11.1) | 0.975 |
Waist circumference (cm) | 86.0 (11.5) | 85.3 (13.8) | 0.757 |
*Independent
There is no significant difference between groups with respect to hematological or clinical blood chemistry parameters including Fasting Blood Sugar, liver function, full blood counts, Prostate Specific Antigen (PSA), lipid profile, and hormone profile except for total testosterone, whereby subjects in the placebo group had significantly higher total testosterone values (mean 18.8 (4.6) nmol/L) compared to
For the ITT-analysis, data from 102 subjects (52
From the eight domains in the SF-36 forms, the domain “physical functioning” (9 items on moderate and vigorous activities, climbing, bending and kneeling, walking, and bathing/dressing), “role physical”, and “vitality” showed significant improvements.
In the
Mean values of overall scores (±SEM) of Physical Functioning domain from baseline to week 12 for
On Reported Health Transition
In other SF-36 domains, increasing trends are seen in role physical, vitality, and general health in
Eighteen subjects (12 placebo and 6
Comparison on each physical test outcomes between
For the analysis, 102 subjects (52 EL and 50 placebo) were included where three cases (all on placebo) with missing data on week 12 were treated with LOCF principle.
For all analyzed subjects the scores in the five domains at baseline correspond to clinical interpretation as having “no” or “mild” “erectile dysfunction”.
In the herbal group the overall Erectile Function score increases significantly from baseline to week 12 as compared to placebo (
Analysis of individual questionnaire items under the Erectile Function domain reveals for item Q1 “
In the other IIEF domains no significant changes were observed between both groups.
For the analysis, 102 subjects (52 EL and 50 placebo) were included where three cases (all placebo) with missing data on week 12 were treated with LOCF principle.
At baseline, the analyzed subjects had in both groups score values of approximately 67% to 73% of the maximum score points (total score range min–max: 3 to 15 for sexual libido; total score range min–max: 5 to 22 for sexual satisfaction). No significant difference on Sexual Libido and Sexual Satisfaction mean scores is detected between
However, the overall Sexual Libido score for subjects in the herbal group significantly increased between week 6 and week 12 as compared to placebo (
Regarding the overall Sexual Satisfaction scores, the
DEXA scan was performed in 97 subjects (49 placebo and 48 EL) for ITT analysis (8 LOCF from baseline and 12 LOCF from week 6) and considered as a secondary endpoint.
No significant difference between
Throughout the study no significant changes among the
Analysis was performed in 36 subjects (22 EL and 14 placebo) who have participated in both SFA examinations (at baseline V2 and week 12 V4).
Between group comparisons on all SFA parameters (volume, count, % motility, and normal oval) at baseline and after week 12 showed no significant difference at 5% and 10% level of significance. The changes and differences between groups with regard to time were not significant even after controlling the baseline values, age, smoking status, number of children, and marriage duration as shown by ANCOVA analysis.
Total Seminal Fluid Analysis volume shows a slight increasing trend during intake of the herbal product (baseline to V2: 3.273 mL and V4: 3.454 mL) in contrast to stable values or a declining trend for placebo subjects (V2: 3.714 mL, V4: 3.607 mL). However, subgroup analysis with different baseline values reveals relevant and significant improvement of SFA volume in subjects who took
Mean seminal fluid volumes (mL; ±SEM) for subjects with low baseline (Day 0) values with cutoff 3.5 mL after 12 weeks intake of
Similar results were obtained from a subgroup analysis of SFA motility parameters, when their baseline values were divided between low and high starting points (taking the median value as the cutoff point) (Figure
Mean motility (%) (±SEM) for all subjects (total,
There is also an increasing trend in the SFA sperm Ova-shaped parameters in the herbal group as compared to placebo for (+4.3%,
All safety parameters obtained from clinical, laboratory, and physical examinations reflect no significant difference between
Two Serious Adverse Events (SAEs) occurred in 1 subject at the end of trial (V4) in the herbal group and were not related to treatment (hospitalization: low back pain; liposome). A total of 31 Adverse Events (AEs) were recorded in 26 subjects: 20 AEs in 15 subjects from the placebo group and 11 AEs in 11 subjects during intake of
Incidence of adverse events (AE) observed during the study. The number of AEs recorded for subjects on
Adverse event |
|
Placebo | Causality |
---|---|---|---|
Headache | 0 | 1 | Probable |
URTI with viral fever | 1 | 0 | Unlikely |
URTIS | 3 | 5 | Unlikely |
Generalised body ache | 1 | 0 | Unlikely |
Conjunctivitis | 1 | 2 | Unlikely |
Infected chalazion | 1 | 0 | Unlikely |
Ankle pain | 1 | 1 | Unlikely |
Epigastric pain | 0 | 1 | Unlikely |
Lumbar pain | 0 | 1 | Unlikely |
Archilles tendinitis | 1 | 0 | Unlikely |
MVA with abrasion | 0 | 1 | Unlikely |
Pneumonia | 0 | 1 | Unlikely |
Medial meniscus injury | 0 | 1 | Unlikely |
Foot pain | 0 | 3 | Unlikely |
Herpes zoster | 1 | 0 | Unlikely |
R index finger pain | 1 | 0 | Unlikely |
Muscle sprain | 0 | 1 | Unlikely |
Eye discomfort | 0 | 1 | Unlikely |
Age | 0 | 1 | Unlikely |
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During daily intake of the herbal extract, the quality of life, physical fitness, erectile functioning and sexual health, sexual libido, and sexual satisfaction improved in various domains over time and several items of these questionnaires showed meaningful changes and statistically significant trends compared to placebo. In spite of score values at approximately 70% of the maximum attainable scores at baseline, scattered but remarkable efficacy results were seen in quality of life, physical fitness, and sexual well-being in men treated with
This trial provided important results on males’ erectile functioning and sexual health, substantiating the traditional use of
These data support the attitudes of Malaysian men of preventing or treating erectile dysfunction with traditional herbal medicine including Tongkat Ali (
In the present study, Seminal Fluid Analysis (SFA) showed remarkable but unexpected results in primarily healthy subjects who took
It is so far known that the traditionally used water extracts of the root of
For the first time a placebo-controlled clinical trial with 109 randomized male subjects demonstrated for a freeze-dried water extract of the roots of
The authors would like to thank the phytopharmaceutical company Biotropics Malaysia Berhad, Kuala Lumpur, Malaysia, for financial support of the clinical trial. A. George and Z. M. M. Kamal are employees of this company.