Criteria for considering studies for this review
Types of studies
Published and unpublished randomised controlled trials (RCTs) will be eligible for inclusion. We will exclude non-randomised studies (for example studies with evidence of inadequate sequence generation such as alternate days, patient numbers) as they are associated with a high risk of bias.
Types of participants
Menopausal women: women who are going through the menopausal transition or women who are postmenopausal.
Perimenopause: the period of menopausal transition leading to a natural menopause, which ends 12 months after the final menstrual period. A specific staging can be found in the Stages of Reproductive Aging Workshop (STRAW) + 10 criteria (Harlow 2013).
Postmenopause: after one year with absence of menses and follicle stimulating hormone (FSH) levels > 40 IU/L, also women following surgical menopause (removal of both ovaries) will be included.
Types of interventions
Trials comparing any dose and form of DHEA by any route of administration versus any other active intervention, placebo or no treatment will be eligible for inclusion. Treatment duration should be no less than one week.
Types of outcome measures
General wellbeing or quality of life (as defined by different scoring scales for example the Psychological General Well-Being Index (PGWB), The Medical Outcomes Study 36-item short form survey (SF-36), Life Satisfaction Index-Z (LSI-Z), Satisfaction with Life Scale (SWLS), Health Status Questionnaire (HSQ), Quality of Life scale (QoL), Beck Depression Inventory (BDI), Hamilton Depression Scale (HDRS)).
Any adverse effects
Adverse effects will be described as they have been reported in the studies (for example risk of breast cancer, cardiovascular risk, androgenic side effects).
Menopausal symptoms (e.g. vaginal dryness, hot flushes, night sweats defined by different scoring scales including the Menopause Rating Scale (MRS) (Heinemann 2004), Kupperman Index (KI), Greene Climacteric Scale (GCS)).
Sexual function (defined by different scoring scales e.g. the Female Sexual Function Index (FSFI), Brief Index of Sexual Functioning for Women (BISF-W), Changes in Sexual Functioning Questionnaire (CSFQ), Derogatis Interview for Sexual Functioning (DISF/DISF-SR), Golombok-Rust Inventory of Sexual Satisfaction (GRISS)).
Search methods for identification of studies
We will search for all published and unpublished RCTs investigating the effects of DHEA in menopausal women, without language restriction and in consultation with the Menstrual Disorders and Subfertility Group (MDSG) Trials Search Co-ordinator. We will use ENDNOTE for the bibliographic management of references found in the search output.
(1) We will search the following electronic databases, trial registers and websites from inception to the present:
Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials (Appendix 1), the Cochrane Central Register of Controlled Trials (CENTRAL) (Appendix 2), MEDLINE (Appendix 3) , EMBASE (Appendix 4), PsycINFO (Appendix 5) and CINAHL (Appendix 6). The MEDLINE search will be combined with the Cochrane highly sensitive search strategy for identifying randomised trials which appears in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.0.2, chapter 6, 6.4.11). The EMBASE, PsycINFO and CINAHL searches are combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/methodology/filters.html#random).
(2) Other electronic sources of trials will include (Appendix 7):
• trial registers for ongoing and registered trials
o www.clinicaltrials.gov (a service of the US National Institutes of Health),
o www.who.int/trialsearch/Default.aspx (World Health Organization International Clinical Trials Registry Platform search portal);
• DARE (Database of Abstracts of Reviews of Effects) in The Cochrane Library at http://onlinelibrary.wiley.com/o/cochrane/cochrane_cldare_articles_fs.html (for reference lists from relevant non-Cochrane reviews);
• the Web of Knowledge at http://wokinfo.com/ (another source of trials and conference abstracts);
• OpenGrey at www.opengrey.eu/ for unpublished literature from Europe;
• LILACS database at http://regional.bvsalud.org/php/index.php?lang=en (for trials from the Portuguese and Spanish speaking world);
• PubMed and Google (for recent trials not yet indexed in MEDLINE).
Searching other resources
3. We will handsearch reference lists of articles retrieved by the search and contact experts in the field to obtain additional data. We will also handsearch relevant journals and conference abstracts that are not covered in the MDSG Specialised Register, in liaison with the Trials Search Co-ordinator.
Data collection and analysis
Selection of studies
Only RCTs studying the effectiveness and safety of DHEA administration for menopausal women will be included. Data from crossover trials will be included and analysed using the generic inverserse variance method. The authors will independently scan the titles and abstracts of the articles retrieved by the search. Full texts of potentially eligible studies will be retrieved and examined independently by the authors. The full text articles will be selected according to the inclusion criteria. In the case of doubts or disagreement between the two authors, a third author will be consulted to gain consensus on whether to include the trial or not. The selection process will be documented with a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart.
Data extraction and management
The data obtained will be extracted by two review authors. In the case of a disagreement between the two authors, a third author will be consulted to achieve consensus. Data will be extracted by using a data extraction form designed and pilot tested by the authors. If studies are reported in multiple publications, the data will be extracted from the different publications and will be combined into a single data extraction form so no data will go missing. The following characteristics of included studies will be included in the extraction form: methods, participants, interventions and outcomes.
Assessment of risk of bias in included studies
To assess the risk of bias in the included studies the Cochrane Collaboration's recommended tool is a domain based evaluation. We will use this tool to assess the following domains and divide the assessments into high, unclear or low risk of bias.
Selection bias (random sequence generation, allocation concealment).
Performance bias (blinding of participants and personnel).
Detection bias (blinding of outcome assessment).
Attrition bias (incomplete outcome data).
Reporting bias (selective reporting).
Other bias (other sources of bias).
Disagreements will be resolved by discussion or by a third review author. We will describe all judgements fully and present the conclusions in the risk of bias table, which will be incorporated into the interpretation of review findings by means of sensitivity analyses (see below). We will take care to search for within-trial selective reporting, such as trials failing to report obvious outcomes, or reporting them in insufficient detail to allow inclusion. We will seek published protocols and compare the outcomes between the protocol and the final published study.
Measures of treatment effect
For dichotomous data we will use the numbers of events in the control and intervention groups of each study to calculate the Mantel-Haenszel odds ratios (ORs). For continuous data, if all studies report the same outcomes we will calculate mean differences (MDs) between treatment groups. If similar outcomes are reported on different scales, we will calculate the standardised mean difference (SMD). We will treat ordinal data as continuous data or it may be possible to categorise the findings as dichotomous data. We will calculate 95% confidence intervals (CIs) for all outcomes. Where data for calculation of ORs or MDs are not available we will use the most detailed numeric data available that may facilitate similar analyses of included studies.
Unit of analysis issues
The primary analysis will be per woman randomised. Data that do not allow valid analysis will be briefly summarized in an additional table and will not be included in the meta-analysis. Statistical advice will be sought regarding the analysis of crossover trials to facilitate the appropriate inclusion of crossover data in the meta-analysis.
Dealing with missing data
If relevant data are missing from an included study the original investigators of the trial will be contacted to request the missing data from them. If the original investigator can not be contacted or does not reply, we will determine whether to include or exclude the trial or only include the data that are fully available. If variance data for the primary outcome are missing (for example SD) then these will be imputed from the range where possible.
Assessment of heterogeneity
We will consider whether the clinical and methodological characteristics of the included studies are sufficiently similar for meta-analysis to provide a clinically meaningful summary. Statistical heterogeneity will be assessed by measuring the I² statistic. We will assume that there is substantial heterogeneity when I² is calculated to be greater than 50% (Higgins 2003; Higgins 2011).
Assessment of reporting biases
In view of the difficulty of detecting and correcting for publication bias and other reporting biases, the authors will aim to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert to duplication of data. If there are 10 or more studies in an analysis, we will use a funnel plot to explore the possibility of small study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies).
Where sufficient data are available, data will be combined for the primary outcomes by using a fixed-effect model. The following comparisons will be made:
1. DHEA versus control (placebo or no intervention);
2. oral versus other routes of administration (e.g. intravaginal DHEA, transdermal patches);
3. DHEA versus hormone therapy (estrogen and progesterone in combination and separately, androgen therapy);
4. DHEA versus any other medical treatment (e.g. antidepressants or clonidine);
5. DHEA versus any other non-medical treatment (e.g. non-medical therapies such as acupuncture or complementary therapies).
Subgroup analysis and investigation of heterogeneity
Where sufficient data are available, we will conduct subgroup analyses for the primary outcomes to determine the separate evidence within the following subgroups:
1. BMI (< 18 kg/m2, 18 to 25 kg/m2, > 25 kg/m2);
2. menopausal status (peri- or postmenopausal);
3. duration of the intervention (≤ 6 weeks, > 6 to 26 weeks, > 26 weeks);
4. younger female (< 40 years, after bilateral oophorectomy or premature ovarian insufficiency);
5. hyposexual desire disorder or low libido;
5. inflammatory disease (e.g. systemic lupus erythematosus (SLE), Sjögren);
6. breast cancer.
If we detect substantial heterogeneity we will explore possible explanations in sensitivity analyses. We will take any statistical heterogeneity into account when interpreting the results, especially if there is any variation in the direction of effect.
We will conduct sensitivity analyses ;for the primary outcomes to determine whether the conclusions are robust to arbitrary decisions made regarding the eligibility and analysis. These analyses will include consideration of whether the review conclusions would have differed if:
1. eligibility was restricted to studies without high risk of bias;
2. a random-effects model had been adopted;
3. alternative imputation strategies had been implemented;
4. the summary effect measure was relative risk rather than odds ratio.
Overall quality of the body of evidence: summary of findings table
We will prepare a summary of findings table using GRADEPRO or Guideline Development Tool software. This table will evaluate the overall quality of the body of evidence for the primary review outcomes (general wellbeing or quality of life and adverse effects) using the GRADE criteria (study limitations (that is risk of bias), consistency of effect, imprecision, indirectness and publication bias). Judgements about the quality of evidence (high, moderate or low) will be justified, documented and incorporated into the reporting of results for each outcome.