Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of ginseng on erectile dysfunction (ED).
Background
Description of the condition
Erectile dysfunction (ED) is defined as the persistent inability to obtain or maintain sufficient penile erection to allow satisfactory sexual intercourse (Khera and Goldstein 2011). ED is one of the most common types of sexual dysfunctions in men (Korenman 1995; Lewis 2010; Shamloul 2013). Over 50% of men aged 40 to 70 years will experience some degree of ED according to the data from the Massachusetts Male Aging Study and it is highly correlated with age (Feldman 1994; Johannes 2000). The worldwide prevalence of the condition is projected to be approximately 322 million men in 2025 (Aytaç 1999; Bacon 2003). The estimated total annual cost of ED to the UK was GBP 53 million in 1997/1998, GBP 74.8 million in 2000, and over GBP 80 million in 2012 (Department of Health 2014; Plumb 1999; Wilson 2002). In the USA, each man with ED spent on average USD 119.26 annually for all ED‐related services or treatment in 2001 (Sun 2005), and annual medical expenditure was about USD 330 million in 2000 (Wessels 2007). The main risk factors are age, smoking, hypertension, coronary artery or peripheral vascular disease, obesity, sedentary life style, hyperlipidemia, trauma or surgery to the pelvis or spine, diabetes mellitus, benign prostatic hypertophy, depression and low urinary tract symptoms. (Pastuszak 2016). The origins of the condition are psychogenic, iatrogenic and organic (Muneer 2014; NIH Consensus Conference 1993; Shamloul 2013); and the causes in about 20% of cases are psychological problems (Khera and Goldstein 2011). Current treatment options for ED include oral medication (sildenafil, tadalafil, vardenafil), alprostadil self‐injection, alprostadil urethral suppository, testosterone replacement, vacuum erection devices, penile implants, penile revascularization, and psychological counselling (Mayo Clinic 2014; Muneer 2014; Shamloul 2013). Treatment with an oral phosphodiesterase inhibitor has improved the treatment of ED of any cause, but 30% to 35% of men do not respond (McMahon 2006; Shamloul 2013). ED has impacts on men who experience it: it can decrease their quality of life and self‐esteem and increase the incidence of depression and interpersonal relationship problems (Rosen 2016).
Description of the intervention
Ginseng has been one of the most popular trade goods for health care and treatment of diseases in Asia, and is currently consumed in 35 countries around the world (Baeg 2013). The production ratio of fresh North American ginseng root is estimated 9.4% of world production in 2007. The distribution rate of root and processed products in North America was 15% and it was worth USD 313 million in 2009 (Baeg 2013). Ginseng has been used for various conditions in East Asian countries for at least two thousand years (Xiang 2008). It belongs to the genus Panax and includes Panax ginseng, Panax quinquefolius and Panax japonicus. Among these varieties, Korean Panax ginseng has been reported to be the most effective in improving brain function, relieving pain and preventing tumours because it contains more types of ginsenoside and other compounds than American and Sanchi ginsengs (Choi 2013). Ginseng is generally classified in three different ways, depending on how it is processed: fresh ginseng (less than four years old); white ginseng (four to six years old and dried after peeling); and red ginseng (harvested when six years old, steamed and dried) (Yun 2001). The therapeutic effects of ginseng are very diverse, and the evidence for its efficacy in treating several conditions such as cardiovascular disease (Buettner 2006), Alzheimer's disease (Lee 2009), common cold (Seida 2011), and hypertension (Hur 2010), has been evaluated. Ginseng has also been used to improve general conditions relevant to quality of life and athletic performance in the healthy population (Bahrke 2009; Coleman 2003).
How the intervention might work
Ginseng is a herb that contains various chemical compounds. Consequently, pharmacological ingredients that are related to the effect of ginseng on ED should be identified to elucidate the underlying mechanism of action (Ernst 2010). In the case of Panax ginseng, ginsenosides (a class of steroid glycosides and triterpene saponins) are reported as the most important active components. To date, about 150 different ginsenosides have been identified (Christensen 2009). The mechanisms underlying the effect of ginseng in treating ED are thought to be related to multiple pathways (Moyad 2012). First, ginseng and ginsenosides promote endothelial nitric oxide (NO) release, which exerts a direct effect on ED through triggering erection mediated by relaxation of the smooth muscles of the corpus cavernosum (Choi 1998; Choi 1999; De Andrade 2007). Second, ginseng has the potential benefit of improving cardiovascular risk factors including hypertension, hyperglycemia and hyperlipidemia, which are regarded to be important risk factors of ED (Buettner 2006). In addition ginseng is a natural sexual enhancer (West 2015), whose effect might be related to central humoral regulation involved in sexual arousal as well as physical energy enhancement through its alleged anti‐fatigue effect (Moyad 2012).
Why it is important to do this review
Compounds containing ginseng are some of the most popular and best‐selling herbal medicines in the world (Ernst 2002). They are used for a broad range of conditions including ED (AUA 2005; Khera and Goldstein 2011). One systematic review presented evidence in support of red ginseng as a treatment for ED (Jang 2008). Another systematic review analysis was recently published that evaluated all of the current RCTs of ginseng in the Korean literature (Choi 2013). This review included an additional two Korean RCTs related to ED compared to the previous review, which had demonstrated positive effects of ginseng on ED. The addition of these studies is likely to reinforce the evidence for the favourable effects of ginseng for ED. Recently, several primary studies have been published. Thus, there is a need for a well‐organised and up‐to‐date systematic review to evaluate the efficacy of ginseng for ED. This review will update and critically appraise the current evidence regarding the use of ginseng to treat ED.
Objectives
To assess the effects of ginseng on erectile dysfunction (ED).
Methods
Criteria for considering studies for this review
Types of studies
Randomised or quasi‐randomised controlled trials. We will impose no restrictions with regard to language or publication status. We will exclude cluster‐randomised studies. We will include cross‐over studies if data are available separately for the study period prior to cross‐over.
Types of participants
Adults with ED, irrespective of type and pathologic basis. Trials that included men with ED and with comorbid conditions such as cardiovascular disorder, spinal cord injury, prostate cancer and diabetes will be eligible (Khera and Goldstein 2011).
We will include trials in which only a subset of participants are eligible as long as data are available separately for the relevant subsets.
Types of interventions
All types of ginseng, regardless of species (e.g. Panax ginseng, Panax quinquefolius and Panax japonicus), processed status (e.g. white ginseng or red ginseng), or dose will be included.
We will include any trials comparing any type of ginseng to placebo, and PDE‐5 inhibitors. Trials in which ginseng forms part of a complex herbal medicine will be excluded. If the control groups are related to other types of herbal medicines and complementary therapies, we will exclude those studies.
We will include ginseng as the only treatment or with other 'conventional' treatments, as long as the same standard treatment is provided to both groups. 'Conventional' treatment interventions include phosphodiesterase inhibitors (e.g. sildenafil, tadalafil or vardenafil), injection (e.g. intracavernosal alprostadil), vacuum devices, or psychosexual counselling (Khera and Goldstein 2011).
Types of outcome measures
Measurement of outcomes assessed in this review will not be used as criteria for exclusion.
Primary outcomes
Participant or partner‐reported self‐assessment of improvement of erection or sexual satisfaction (e.g. total International Index of Erectile Function (IIEF) score, Watts Sexual Function Questionnaire, global efficacy questionnaire) before versus after intervention. We will consider the clinically important difference in the erectile function domain score value (Question 7) of IIEF is larger than 4 (Rosen 2011).
Improvement in intercourse success (number of successful intercourse attempts or percentage of successful sexual intercourse attempts) before versus after intervention.
Adverse events related to ginseng (e.g. headache, sleepiness, gastrointestinal complaints, or pesticide intoxication by pesticide residue).
Secondary outcomes
Quality of life (QOL; using only validated QOL questionnaires) including Sexual Quality of Life–Men (SQOL–M) questionnaires, World Health Organization Quality of Life (WHOQOL–BREF) instrument, or SF–36 QOL questionnaires.
Timing of outcome assessment
We will assess both short‐term (up to six months) and long‐term data (more than six months).
The 'Summary of findings' table will include all primary and secondary outcomes.
Participant‐ or partner‐reported self‐assessment of improvement of erection or sexual satisfaction.
Improvement in intercourse success.
Adverse events.
QOL.
Search methods for identification of studies
A search of the relevant literature will be conducted regardless of the language or publication status. We will update the literature if it is more than six months from the publication date, and incorporate any new studies if identified.
Electronic searches
We will search the following electronic databases.
Cochrane Central Register of Controlled Trials (CENTRAL; latest issue) in the Cochrane Library; (for the search strategy, see Appendix 1).
MEDLINE Proquest (from 1946; see Appendix 2).
Embase Proquest (from 1947; see Appendix 3).
CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; from 1981).
AMED Proquest (Allied and Complementary Medicine Database; from 1985).
Chinese Medical Database (China National Knowledge Infrastructure (CNKI); www.cnki.net/;from 1994).
Wanfang Data Knowledge Service Platform (www.wanfangdata.com/; from 1982).
Chinese Scientific and Technological Journals Database (VIP; www.cqvip.com/; from 1989).
Japan Science and Technology Information Aggregator (J‐STAGE; www.jstage.jst.go.jp; from 1921).
Korean Medicine Information System (Oriental Medicine Advanced Searching Integrated System (OASIS)/Korea Institute of Oriental Medicine; oasis.kiom.re.kr/eng/main.jsp; from 1963).
KoreaMed (Korean Association of Medical Journal Edition; www.koreamed.org/; from 1958).
Korean Medical Database (KMbase; Medical Research Information Center; kmbase.medric.or.kr/; from 1958).
Research Information Service System (RISS; Korea Education & Research Information Service; www.riss.kr/; from 1958).
The Town Society of Science Technology (TSSN; Korea Institute of Science andTechnology Information; society.kisti.re.kr/; from 1963).
Korean Studies Information Service System (KISS; Korean Studies Information; kisseng.kstudy.com/; from 1954).
Korean Traditional Knowledge Portal (KTKP; Korean Intellectual Property Office; www.koreantk.com/ktkp2014/?lang=en; from 1963).
We will search for ongoing studies by accessing the following databases.
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch/).
Chinese Clinical Trial Registry (http://www.chictr.org.cn/enIndex.aspx).
International Standard Randomised Controlled Trial Number Register (ISRCTN; www.controlled‐trials.com/isrctn/).
U.S. National Institutes of Health Clinical Trials Database (www.ClinicalTrials.gov).
Clinical Research Information Service (CRIS) (cris.nih.go.kr/cris/en/search/basic_search.jsp) of the Republic of Korea.
In addition, we will search abstract proceedings of the annual meetings of the American Urological Association from 1996, European Association of Urology from 2004 and International Society of Sexual Medicine from 2004 for relevant records.
Searching other resources
The bibliographic references of all included trials will be reviewed to identify other potentially relevant studies. We will also manually search relevant journals, such as Journal of Ginseng Research (from 1976) (,http://ocean.kisti.re.kr/IS_mvpopo001P.do?method=multEMain&poid=skg&sFree= or http://www.ginsengres.org/). If available, we will also review unpublished conference proceedings (e.g. Proceedings of the Ginseng Society Conference (from 1974) and the Korean Oriental Medical Society Conference (from 1963)) and internal reports relevant to ginseng and erectile dysfunction. We will contact the authors of the included studies and researchers in the field with regard to any potential ongoing and unpublished studies, if necessary. We will also contact the main manufacturers of ginseng products to identify unpublished and relevant trials.
Data collection and analysis
Selection of studies
We will use reference management software to remove duplicates at the beginning of the selection process. Two review authors (Lee HW, Kim T‐H) will independently scan the abstract, title, or both, of remaining records retrieved, to determine which studies should be assessed further. Two review authors (Lee HW, Kim T‐H) will investigate the full text of all potentially relevant records, map records to studies, and classify studies as included studies, excluded studies, studies awaiting classification, or ongoing studies in accordance with the criteria for each provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We will resolve any discrepancies through consensus or recourse to a third review author (Lee MS). If resolution of a disagreement is not possible, we will designate the study as 'awaiting classification' and we will contact study authors for clarification. We will document reasons for exclusion of studies that may have reasonably been expected to be included in the review in a 'Characteristics of excluded studies' table. We will present an adapted PRISMA flow diagram showing the process of study selection (Liberati 2009).
Data extraction and management
Three review authors (Lee HW, Lee MS, Kim T‐H) will independently extract data from the reports of included studies using a data collection form that we will pilot test ahead of time on at least one study. We will resolve any disagreement by discussion or, where necessary, by arbitration by a fourth review author (Alraek T). The following study characteristics will be extracted and will be provided in the 'Characteristics of included studies' table.
Methods: study design, duration of the study, the date when the study was conducted, trial setting, ethical approval.
Participants: inclusion and exclusion criteria, age, country, ethnic group, total number of participants enrolled and numbers of participants randomised to the ginseng and control groups, causes of erectile dysfunction, severity of erectile dysfunction, the number of drop‐out participants.
Interventions: details of ginseng (route, frequency, duration as applicable, type and dose of whole extraction of ginseng, dose of active compound in ginseng or combination treatments), control interventions.
Outcomes: the details of outcome definition, method of outcome measurement, timing of outcome measurement, and any relevant subgroups measured for each outcome.
Others: study funding sources and the details of declarations of interest among the trialists.
We will extract outcomes data relevant to this Cochrane Review as needed for calculation of summary statistics and measures of variance. For dichotomous outcomes, we will attempt to obtain numbers of events and totals for population of a 2 × 2 table, as well as summary statistics with corresponding measures of variance. For continuous outcomes, we will attempt to obtain means and standard deviations or data necessary to calculate this information. We will provide information, including trial identifier, about potentially relevant ongoing studies in the table 'Characteristics of ongoing studies'. We will attempt to contact the corresponding authors of the included trial reports to obtain any key missing data. We will use the PROGRESS framework to assess ginseng for health equity including disadvantaged or low‐ and middle‐income country populations via the extraction of sociodemographic data of participants (O'Neill 2014).
Dealing with duplicate and companion publications
In the event of duplicate publications, companion documents or multiple reports of a primary study, we will maximise yield of information by mapping all publications to unique studies and collating all available data. We will use the most complete data‐set aggregated across all known publications. In case of doubt, we will give priority to the publication reporting the longest follow‐up associated with our primary or secondary outcomes.
Assessment of risk of bias in included studies
According to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions, we will assess risk of bias using the Cochrane's 'Risk of bias' assessment tool (Higgins 2011b). We will evaluate the following domains.
Random sequence generation.
Allocation concealment.
Blinding of participants and personnel.
Blinding of outcome assessment.
Incomplete outcome data.
Selective reporting.
Other sources of bias.
We will judge risk of bias domains as 'low', 'high' or 'unclear' risk of bias, according to the criteria. We will present a 'Risk of bias' summary figure to illustrate these findings.
For performance bias (blinding of participants and personnel) and detection bias (blinding of outcome assessment), we will assess risk of bias on an outcome‐specific basis, and we will group outcomes according to whether measured subjectively or objectively when reporting our findings in the 'Risk of bias' tables. All of our primary and secondary outcomes will be reported by participants or partners and therefore they will be considered as subjective outcomes in both performance and detection bias.
We will assess the domain of incomplete outcome data on an outcome‐specific basis, and we will group outcomes as short‐term or long‐term when reporting our findings in the 'Risk of bias' tables. We will summarise the risk of bias for each study by outcome, as well as across studies and domains for each outcome. Three review authors (Lee HW, Lee MS, Kim T‐H) will assess the risk of bias independently. They will resolve disagreements by discussion or, where necessary, by arbitration by a fourth review author (Alraek T).
Measures of treatment effect
For dichotomous data, we will present treatment effects as risk ratios (RRs) with 95% confidence intervals (CIs). For continuous data, we will express treatment effects as mean differences (MDs) with 95% CIs, unless different studies use different measures to assess the same outcome, in which case we will express data as standardised mean differences (SMDs) with 95% CIs. We will conduct all statistical analyses using Cochrane’s software program Review Manager 5 (RevMan).
Unit of analysis issues
If we identify cross‐over trials for inclusion, we will adopt the first phase of the study data for analysis. Data from multiple time‐point observations will be classified as short‐term (within four weeks) or long‐term (over four weeks) follow‐up. Should we identify trials with more than two intervention groups for inclusion in the review, we will handle these in accordance with guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c).
Dealing with missing data
We will request missing data from the original study investigators, whenever possible. If missing data, which cannot be provided by the original study authors, are detected, we will make the assumption that these outcomes are classified as treatment failures, and only the available data will be analysed. Where possible, we will perform a sensitivity analysis to test this assumption, and we will discuss the potential impact on the findings.
Assessment of heterogeneity
In the event of excessive heterogeneity unexplained by subgroup analyses, we will not report outcome results as the pooled effect estimate in a meta‐analysis but will provide a narrative description of the results of each study. We will use the I² statistic to assess the level of heterogeneity among the included studies. We will adopt a tiered percentage scale for assessment of heterogeneity (e.g. 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; 75% to 100% may represent considerable heterogeneity) as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). If heterogeneity is observed, we will attempt to determine possible reasons for it by performing subgroup analysis (Deeks 2011).
Assessment of reporting biases
We will attempt to obtain study protocols to assess for selective outcome reporting. To detect publication bias, funnel plots will be drawn using Egger's method if more than 10 studies are included in an individual analysis (Egger 1997). We will consider whether asymmetry indicates a possible reporting bias.
Data synthesis
We will conduct meta‐analyses using the random‐effects model and 95% CIs. We will interpret random‐effects meta‐analyses with due consideration of the whole distribution of effects. In addition, we will perform statistical analyses according to the statistical guidelines contained in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). For dichotomous data, we will use the Mantel‐Haenszel method. For continuous data, we will use the inverse‐variance method.
Subgroup analysis and investigation of heterogeneity
We expect the following characteristics to introduce clinical heterogeneity and, if data are available, we will conduct predefined subgroup analysis according to the:
dose of ginseng (≦ 600 mg/day and > 600 mg/day);
cause of ED;
baseline ED severity.
We will use the test for subgroup differences in RevMan to compare subgroup analyses if there are sufficient studies.
Sensitivity analysis
Sensitivity analysis will principally be conducted as follows.
Low risk of bias (exclusion of studies judged high risk or unclear risk of bias).
The option of using missing data (using the 'last observation carried forward' method).
'Summary of findings' table
We will perform a GRADE assessment of the quality of the evidence on an outcome‐specific basis according to the following five GRADE criteria: study limitations (risk of bias), inconsistency, indirectness, imprecision, and publication bias (Guyatt 2008). Two review authors will independently rate the quality of evidence for each outcome as 'high', 'moderate', 'low', or 'very low' using GRADEpro GDT (available from www.guidelinedevelopment.org). We will resolve any discrepancies by consensus or, if needed, by arbitration by a third review author. We will present a summary of the evidence for the main outcomes in a 'Summary of findings' table.
For each comparison, we will present a summary of the evidence for the main outcomes in a 'Summary of findings' table, which provides key information about the best estimate of the magnitude of the effect in relative terms and absolute differences for each relevant comparison of alternative management strategies, numbers of participants and studies addressing each important outcome, and the rating of the overall confidence in effect estimates for each outcome (Guyatt 2011; Schünemann 2011). If meta‐analysis is not possible, we will present results in a narrative 'Summary of findings' table.
Acknowledgements
None.
Appendices
Appendix 1. CENTRAL search strategy
| Search # | Search Terms |
| 1 | MeSH descriptor erectile dysfunction explore all trees |
| 2 | erectile dysfunction |
| 3 | MeSH descriptor erectile failure explore all trees |
| 4 | erection failure |
| 5 | Impotence |
| 6 | MeSH descriptor (impotence, Vasculogenic) explore all trees |
| 7 | MeSH descriptor panax explore all trees |
| 8 | ginseng |
| 9 | panax |
| 10 | 7 OR 8 OR 9 |
| 11 | 1 OR 2 OR 3 OR 4 OR 5 OR 6 |
| 12 | 10 AND 11 |
Appendix 2. MEDLINE (OVID) search strategy
| Search # | Search Terms |
| 1 | “erectile dysfunction”[MeSH] |
| 2 | “erectile dysfunction” |
| 3 | “erectile failure” |
| 4 | “erection failure” |
| 5 | Impotence |
| 6 | “impotence, Vasculogenic”[MeSH] |
| 7 | “panax”[MeSH] |
| 8 | ginseng |
| 9 | panax |
| 10 | 7 OR 8 OR 9 |
| 11 | 1 OR 2 OR 3 OR 4 OR 5 OR 6 |
| 12 | 10 AND 11 |
Appendix 3. Embase search strategy
| Search # | Search Terms |
| 1 | “erectile dysfunction”[MeSH] |
| 2 | erectile dysfunction |
| 3 | "erectile failure" [MeSH] |
| 4 | (erection failure |
| 5 | Impotence |
| 6 | “impotence, Vasculogenic”[MeSH] |
| 7 | panax [MeSH] |
| 8 | ginseng |
| 9 | panax |
| 10 | 7 OR 8 OR 9 |
| 11 | 1 OR 2 OR 3 OR 4 OR 5 OR 6 |
| 12 | 10 AND 11 |
Contributions of authors
The protocol was drafted by Lee HW, Lee MS, Kim T‐H, Alraek T, Zaslawski C, Kim JW, and Moon DG. The search strategy was developed and will be run by Lee MS and Kim T‐H. Copies of studies will be obtained by Lee HW and Kim T‐H. Selection of the studies to include will be done by Lee HW and Kim T‐H; Lee MS will act as an arbiter in the study selection stage. Extraction of data from studies will be conducted by Lee HW, Lee MS and Kim T‐H; Alraek T will act as an arbiter in the data extraction stage. Entering data into RevMan will be conducted by Lee HW and Zaslawski C. Carrying out the analysis will be done by Lee HW, Lee MS, Kim T‐H, Alraek T, Zaslawski C, Kim JW, and Moon DG. Interpretation of the analysis will be done by Lee HW, Lee MS, Kim T‐H, Alraek T, Zaslawski C, Kim JW, and Moon DG. The final review will be drafted by Lee HW, Lee MS, Kim T‐H, Alraek T, Zaslawski C, Kim JW, and Moon DG. The review will be updated by Lee HW, Lee MS, Kim T‐H, Alraek T, Zaslawski C, Kim JW, and Moon DG.
Sources of support
Internal sources
-
Korea Institute of Oriental Medicine, Korea, South.
HW Lee was supported by Korea Institute of Oriental Medicine (K16292) and MS Lee was supported by Korea Institute of Oriental Medicine (K162921)
External sources
None, Other.
Declarations of interest
Alraek T: none known.
Kim JW: none known.
Kim T‐H: none known.
Lee HW: none known.
Lee MS: none known.
Moon DG: none known.
Zaslawski C declares the following relevant activities outside the submitted work: serves as President of the Chinese Medicine Council of New South Wales (Australia) and receives payment from the organization for his role; serves as Member of the Accreditation Committee of the Chinese Medicine Board of Australia and receives payment from the organization for his role; received consultancy support paid to his institution by Korea Institute of Oriental Medicine to fund a research assistant to work on a research project relating to post sequelae of stroke; his institution (University of Technology Sydney, Australia) received payment from Korea Institute of Oriental Medicine for consultancy research not related to this review; and received support from Korea Institute of Oriental Medicine for conference attendance at Korea Institute of Oriental Medicine.
Notes
We have based parts of the Methods section of this protocol on a standard template developed by the Cochrane Metabolic and Endocrine Disorders Group, which has been modified and adapted for use by the Cochrane Urology Group.
New
References
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