GnRH agonists for uterine fibroids

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the effectiveness and safety of gonadotropin‐releasing hormone (GnRH) agonists for treatment of premenopausal women with uterine fibroids.

Background

Description of the condition

Uterine fibroids are the most common gynaecological tumours affecting premenopausal women. They are benign and are made up of monoclonal smooth muscle cells of the myometrium. They may also be known as myomas or leiomyomata. The prevalence of fibroids is dependent on the demographics of the population studied. A trial enrolling women aged 35 to 49 who were screened by self‐report, review of medical records, and sonography found that by age 35, the incidence of fibroids in African American women was 60% (increasing to over 80% by age 50), and in Caucasian women, 40% at age 35 and almost 70% at age 50 (Baird 2003).

Although most women with fibroids are asymptomatic, fibroids are a major source of gynaecological morbidity and have a substantial impact on women’s health and quality of life (Schwartz 2000). Typical symptoms that arise from fibroids include heavy or prolonged menstrual bleeding, pelvic pain/pressure, and reproductive effects, such as subfertility and adverse pregnancy outcomes.

Treatment of women with fibroids incurs a major financial burden for the healthcare system. In the United States, the total annual cost of surgical and medical treatments provided, number of work hours lost, and complications attributed to fibroids has been estimated at between USD 5.8 and 34.3 billion (Cardozo 2012). Options currently available for management of fibroids include medical therapy, minimally invasive procedures (e.g. uterine artery embolisation), and surgery (e.g. myomectomy, hysterectomy). Despite the range of treatment options, surgery (open, laparoscopic, or robotic) remains the mainstay of therapy, and fibroids were the primary indication for almost 200,000 hysterectomies performed in the United States in 2010 (Wright 2013). Hysterectomy is the second most frequently performed surgical procedure in the United States, and this procedure contributes substantially to surgical morbidity and increasing healthcare costs, suggesting that further evaluation of more conservative therapies is indicated (Wallach 2004).

Description of the intervention

Gonadotropin‐releasing hormone (GnRH) agonists are synthetic peptides that are structurally analogous to the natural GnRH hormone released from the arcuate nucleus of the hypothalamus. GnRH agonists act by binding to GnRH receptors and initially increasing the release of gonadotropins; this is followed by desensitisation, which leads to downregulation to a hypogonadotropic, hypogonadal state ‐ one that simulates menopause (Kessel 1988). Currently, GnRH agonists are used primarily as preoperative therapy, and a Cochrane systematic review has demonstrated how their use can improve both preoperative and postoperative haemoglobin levels, reduce operative time, and shorten the duration of hospital stay (Lethaby 2001). These outcomes are achieved by the action of GnRH agonists in decreasing menstrual bleeding and reducing fibroid volume (and therefore uterine volume) by approximately 50% (Minaguchi 2000). GnRH agonists are also used in assisted reproduction, as well as to treat women with endometriosis, hirsutism, abnormal uterine bleeding, and premenstrual syndrome.

Other medical interventions, such as combined oral contraceptives as examined by Moroni in 2015, progestins or progestin‐releasing intrauterine systems as reported by Sangkomkamhang, danazol as described by Ke, and selective progesterone receptor modulators as reported by Murji, may be used, but use of GnRH agonists is currently reported to be one of the most effective medical therapies for reducing fibroid size and controlling symptoms associated with fibroids (Ke 2009; Moroni 2014; Moroni 2015; Murji 2017; Sangkomkamhang 2013). The challenge of GnRH agonist therapy involves adverse effects, such as exacerbation of symptoms caused by the initial oestrogen flare, development of vasomotor symptoms resulting from hypo‐oestrogenism, and decreased bone mineral density (Bartels 2016).

How the intervention might work

The exact aetiology of fibroids is unknown, but evidence suggests that oestrogens and progestogens play a pivotal role in their growth. It is well established that fibroid growth occurs only in premenopausal women, and this growth is diminished in hypo‐oestrogenic states such as menopause or receipt of GnRH agonist therapy (Adamson 1992). It is believed that women with fibroids do not have abnormally increased levels of circulating oestrogen or progesterone, but that tissue receptor expression for these hormones may play a role in fibroid development (Okolo 2008). Evidence indicates that increased oestrogen receptor gene expression in fibroids when compared to the unaffected myometrium leads to an enhanced response by fibroid cells when under oestrogen stimulation (Brandon 1995).

This importance of oestrogen in fibroid pathogenesis highlights the use of GnRH agonists as an effective medical treatment. GnRH agonists work by 'switching off' the ovaries, meaning that they reduce the production of oestrogen and progesterone (as the ovaries do not receive gonadotropin stimulation), resulting in low gonadotropin levels. This effect is achieved by the initial 'flare' response, followed by downregulation of receptor concentrations, which de‐sensitises the pituitary to continued stimulation. GnRH receptors are also expressed by fibroids, and through these, GnRH agonists have a direct effect on the tissue in reducing proliferation, further contributing to regression of the disease and improvement in clinical symptoms (Khan 2010). Further action of GnRH agonists occurs through the post‐receptor mechanism and results in secretion of biologically inactive gonadotropins (Magon 2011). One mechanism by which GnRH agonists are thought to produce a marked reduction in fibroid volume consists of decreased expression of nuclear factor of activated T cells 5 (NFAT5) (which is a hyperosmolarity gene) ‐ an action that has the effect of causing water to flow out of fibroid cells (McCarthy‐Keith 2011).

GnRH agonists can be used to treat fibroids in various clinical scenarios. Currently, their administration is recommended for a maximum duration of six months, frequently only in the preoperative setting before surgical management (Lethaby 2002). For example, a longer duration of treatment would be especially beneficial in perimenopausal women, to provide symptom relief and potentially avoid surgical intervention until menopause, when GnRH agonist therapy could be ceased as fibroids would spontaneously decrease in size (Imai 2003). Another clinical indication involves subfertility, as the reduction in fibroid volume achieved by GnRH agonist therapy (an effect that is still present up to three to four months after discontinuation of use) may be beneficial before medically assisted reproduction (Ezzati 2009).

Why it is important to do this review

With increasing need for fertility‐sparing and less‐invasive therapeutic options for management of fibroids, it is important to address the benefits and risk of medical therapies, and despite the high prevalence of uterine fibroids, few high‐quality studies have examined these. As mentioned, GnRH agonists are reported to be one of the most effective medical treatments, achieving a substantial reduction in uterine size and improvement in symptoms. However, the benefits of treatment are associated with substantial adverse effects secondary to hypo‐oestrogenism and reversal in improvement after cessation of use. Therefore, a systematic evaluation of GnRH agonists for treatment of women with uterine fibroids is required to clarity the benefits and harms of this therapy, especially as newer GnRH agonists are developed with a better tolerability profile, opening new avenues for clinical application.

Objectives

To evaluate the effectiveness and safety of gonadotropin‐releasing hormone (GnRH) agonists for treatment of premenopausal women with uterine fibroids.

Methods

Criteria for considering studies for this review

Types of studies

We will include data from all published and unpublished randomised controlled trials (RCTs). For cross‐over studies, we will include in the meta‐analysis only data from the first phase of the trial.

Types of participants

Premenopausal women with symptomatic fibroids. The presence of fibroids must be confirmed surgically (by laparoscopy, laparotomy, or hysteroscopy) or via at least one of the following imaging modalities: ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI).

Types of interventions

Treatment with any GnRH agonist for at least four months versus:

• placebo;

• no treatment;

• another medical therapy (another GnRH agonist, a different dose of GnRH agonist, GnRH agonist plus add‐back therapy, or another class of medication);

• surgery (myomectomy or hysterectomy); or

• uterine artery embolisation.

Commercially available GnRH agonists include, but are not limited to, goserelin, leuprolide acetate, nafarelin, buserelin, and triptorelin.

Types of outcome measures

Primary outcomes

• Change in fibroid‐related symptoms in women presenting with symptoms at inclusion

  • Abnormal uterine bleeding measured subjectively (e.g. with pictorial blood loss assessment (preferred measure), via bleeding/pad charts or diaries (improved/not improved), objectively (e.g. using haemoglobin, haematocrit, or ferritin levels)

  • Pain and pelvic pressure measured subjectively (e.g. visual analogue scale, Likert scale)

• Adverse effects including GnRH agonist‐related effects (both short and long term) including, but not limited to, effects of hypo‐oestrogenism, hot flushes, sleep disturbance, vaginal dryness, impaired mood and/or cognition

• Quality of life assessed with standardised and validated measures. Examples of scales that measure health‐related quality of life, including for women with uterine fibroids, may include but are not limited to the Uterine Fibroid Symptom Quality of Life Scale (preferred scale), EuroQoL, and Short Form‐36 (Brooks 1996; Spies 2002; Ware 1992)

Secondary outcomes

• Change in fibroid or uterine size, or both, as measured by ultrasonography, CT, or MRI, for fibroids that resolve completely during the treatment period; recurrence rate over time will be assessed

• Impact on fertility when reported by live birth rate or by ongoing pregnancy, clinical pregnancy, or miscarriage (in studies of women seeking fertility)

Search methods for identification of studies

We will search for all published and unpublished RCTs on GnRH agonists used for treatment of fibroids, without language or date restriction, and in consultation with the Cochrane Gynaecology and Fertility Group (CGF) Information Specialist.

Electronic searches

We will search the following electronic databases for relevant trials.

• The Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, PROCITE platform (from inception onwards) (Appendix 1).

• The Cochrane Central Register of Controlled Trials, via the Cochrane Register of Studies Online (CRSO Web platform) (from inception onwards) (Appendix 2).

• MEDLINE Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations Ovid (from 1946 onwards) (Appendix 3).

• Embase Ovid (from 1980 onwards) (Appendix 4).

• PsycINFO Ovid (from 1806 onwards) (Appendix 5).

• Cumulative Index to Nursing and Allied Health Literature (CINAHL) Ebsco (from 1962 onwards) (Appendix 6).

We will combine the MEDLINE search with the Cochrane highly sensitive search strategy for identifying randomised trials that appears in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0, Chapter 6, 6.4.11). We will combine searches of Embase, PsycINFO, and CINAHL with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (http://www.sign.ac.uk/methodology/filters.html#random).

We will search other electronic sources of trials from inception onwards, including the following.

• Trial registers for ongoing and registered trials.

  • http://www.clinicaltrials.gov (service of the US National Institutes of Health).

  • http://www.who.int/trialsearch/Default.aspx (World Health Organization International Trials Registry Platform search portal).

• Latin American and Caribbean Health Science Information (LILACS) and other Spanish/Portuguese language databases (databases from 1982 ongoing) found in the Virtual Health Library Regional Portal (VHL) (http://bvsalud.org/portal/?lang=en).

• PubMed and Google Scholar (for recent trials not yet indexed in major databases).

Searching other resources

We will handsearch reference lists of relevant trials and systematic reviews retrieved by the search and will contact experts in the field to obtain additional data. We will also handsearch relevant journals and conference abstracts that are not covered in the CGF Register, in liaison with the Information Specialist.

Data collection and analysis

Selection of studies

After an initial screen of titles and abstracts retrieved by the search (conducted by RH), we will retrieve the full texts of all potentially eligible studies. Two review authors (RH and PBC) will independently examine these full‐text articles for compliance with the inclusion criteria and will select eligible studies. We will correspond with study investigators as required to clarify study eligibility and will resolve disagreements by discussion. If any reports require translation, we will describe the process used for data collection. We will document the selection process by preparing a PRISMA flow chart.

Data extraction and management

Two review authors (RH and PBC) will independently extract data from eligible studies using a data extraction form designed and pilot‐tested by the review authors. We will resolve disagreements by discussion. Data extracted will include study characteristics and outcome data (see data extraction table for details; Appendix 7). When studies yield multiple publications, review authors will collate multiple reports of the same under a single study ID with multiple references.

We will correspond with study investigators to request further data on methods and/or results, as required.

Assessment of risk of bias in included studies

Two review authors (RH and PBC) will independently assess the included studies for risk of bias using the Cochrane 'Risk of bias assessment tool' to determine selection (random sequence generation and allocation concealment); performance (blinding of participants and personnel); detection (blinding of outcome assessors); attrition (incomplete outcome data); reporting (selective reporting); and other bias (Higgins 2011). We will assign judgements as recommended in the Cochrane Handbook for Systematic Reviews of Interventions, Section 8.5 (Higgins 2011). We will resolve disagreements by discussion. We will fully describe all judgements and will present conclusions in the 'Risk of bias' table (we will incorporate these into our interpretation of Review findings by performing sensitivity analyses (see below)) (Appendix 8).

With respect to within‐trial selective reporting, when identified studies fail to report the primary outcome of live birth but do report interim outcomes such as clinical pregnancy, we will assess whether interim values are similar to those reported in studies that also report live birth.

Measures of treatment effect

For dichotomous data (e.g. live birth rates), we will use numbers of events in control and intervention groups of each study to calculate Mantel‐Haenszel odds ratios (ORs). For continuous data (size of fibroid), if all studies report exactly the same outcomes, we will calculate the mean difference (MD) between treatment groups. If similar outcomes are reported on different scales (e.g. change in weight), we will calculate the standardised mean difference (SMD). We will reverse the direction of effect of individual studies, if required, to ensure consistency across trials. We will treat ordinal data (e.g. quality of life scores) as continuous data. We will present 95% confidence intervals (CIs) for all outcomes. When data needed to calculate ORs or MDs are not available, we will utilise the most detailed numerical data available that may facilitate similar analyses of included studies (e.g. test statistics, P values). We will assess whether estimates calculated by review authors for individual studies are compatible in each case with estimates reported by study publications.

Unit of analysis issues

We will perform the primary analysis per woman randomised. For cross‐over trials, we will include only data from the first phase.

Dealing with missing data

We will analyse data on an intention‐to‐treat basis as far as possible (e.g. by including all randomised participants in the analysis, within the groups to which they were randomised). We will attempt to obtain missing data from the original trialists. When these cannot be obtained, we will undertake imputation of individual values for live birth only and will assume that live birth did not occur in participants without a reported outcome. For other outcomes, we will analyse only available data. We will subject any imputation undertaken to sensitivity analysis (see below).

If studies report sufficient detail for calculation of mean differences but provide no information on associated standard deviations (SDs), we will assume that the outcome has a standard deviation equal to the highest SD obtained from other studies within the same analysis.

Assessment of heterogeneity

We will consider whether clinical and methodological characteristics of included studies are sufficiently similar for meta‐analysis to provide a clinically meaningful summary. We will assess statistical heterogeneity using the measure of I². We will consider an I² measurement greater than 50% to indicate substantial heterogeneity (Higgins 2011).

Assessment of reporting biases

If we include 10 or more studies in the meta‐analysis, we will investigate reporting bias (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually.

Data synthesis

If studies are sufficiently similar, we will combine data using a fixed‐effect model for the following comparisons.

• GnRH agonist versus placebo or no treatment, stratified by comparator.

• GnRH agonist versus another medical treatment (another GnRH agonist or another dose of GnRH agonist or class of medication), stratified by comparator.

• GnRH agonist versus surgery (myomectomy or hysterectomy), stratified by comparator.

• GnRH agonist versus uterine artery embolisation.

Subgroup analysis and investigation of heterogeneity

If we detect substantial heterogeneity (I² > 50%), we will perform subgroup analyses to examine possible differences between studies that might account for this, such as dose, duration of treatment, mode of administration, body mass index, etc.

Sensitivity analysis

We will conduct sensitivity analyses for the primary outcomes to determine whether conclusions are robust to arbitrary decisions made regarding eligibility and analysis. These analyses will consider whether review conclusions would have differed if:

• eligibility had been restricted to studies without high risk of bias (i.e. studies that are at low risk of selection bias, and not at high risk of bias in any domain);

• a random‐effects model had been adopted; or

• the summary effect measure had been 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 and Cochrane methods (GRADEproGDT 2015; Higgins 2011). This table will evaluate the overall quality of the body of evidence for main review outcomes (i.e. change in fibroid‐related symptoms (abnormal uterine bleeding, pain, pelvic pressure), GnRH agonist‐related effects, quality of life) for the main review comparison (i.e. GnRH agonist vs placebo). We will prepare additional 'Summary of findings' tables for main review outcomes for other important comparisons (i.e. GnRH agonist vs no treatment, GnRH agonist vs other medical intervention, GnRH agonist vs surgery, and GnRH agonist vs uterine artery embolisation). We will assess the quality of evidence using GRADE criteria: risk of bias, consistency of effect, imprecision, indirectness, and publication bias. Two review authors will work independently to assign judgements about evidence quality (high, moderate, low, or very low) and will resolve disagreements by discussion. We will justify judgements and will document and incorporate them into reporting of results for each outcome.

We plan to extract study data, format our comparisons in data tables, and prepare a 'Summary of findings' table before writing the Results and Conclusions sections of our Review.

Appendices

Appendix 1. Cochrane Gynaecology and Fertility Group (CGF) specialised register search strategy

From inception onwards

Procite platform

Keywords CONTAINS "myoma" or "myomas" or "myomata" or "myomatous uterus" or "uterine fibroid embolization" or "uterine fibroids" or "Uterine Fibroid Symptom and Health‐related Quality of Life questionnaire" or "uterine leiomyomas" or "uterine myoma" or "uterine myomas" or "fibroid" or "fibroids"or "fibroids Symptoms" or "fibroids symptoms‐scores" or "Leiomyoma" or "leiomyomata" or "Leiomyoma‐size"

AND

Keywords CONTAINS "Gonadorelin" or "Gonadotrophin releasing agonist" or "Gonadotrophin releasing hormones" or "gonadotropin releasing hormone agonist" or "Goserelin" or "goserelin acetate" or "goserelin pretreatment" or "Gosereline "or "buserelin" or "busereline" or "leuprolide or "leuprolin" or "leuprorelin" or "nafarelin" or "triptorelin" or "Lupron" or "Zoladex" or "deslorelin" or "GnRH agonist" or "GnRH a" or "GnRH agonists" or "GnRHa" or "GnRH analog" or "GnRH analogue" or "GnRH analogues" or "Luteinising hormone releasing hormone" or "luteinizing hormone supplementation" or "Lutenising hormone releasing hormone" or "menotropin" or "menotrophin" or "human menopausal gonadotrophin" or "human menopausal gonadotrophins" or "human menopausal gonadotropins" or Title CONTAINS "Gonadorelin" or "Gonadotrophin releasing agonist" or "Gonadotrophin releasing hormones" or "gonadotropin releasing hormone agonist"

Appendix 2. CENTRAL Register of Studies Online (CRSO) search strategy

From inception onwards

CRSO web platform

MESH DESCRIPTOR Leiomyoma EXPLODE ALL TREES

MESH DESCRIPTOR Myoma EXPLODE ALL TREES

myoma*:TI,AB,KY

fibroid*:TI,AB,KY

leiomyoma*:TI,AB,KY

(fibromyoma* or hysteromyoma*):TI,AB,KY

fibroma*:TI,AB,KY

myomectom*:TI,AB,KY

#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8

MESH DESCRIPTOR Gonadotropin‐Releasing Hormone EXPLODE ALL TREES

(gonadotropin‐releasing hormone*):TI,AB,KY

(buserelin or goserelin or leuprolide or nafarelin or triptorelin):TI,AB,KY

(Lupron or Suprefact or Suprecor):TI,AB,KY

(histrelin or Supprelin):TI,AB,KY

(Zoladex or deslorelin):TI,AB,KY

Synarel:TI,AB,KY

GnRHa:TI,AB,KY

(GnRH a):TI,AB,KY

(GnRH agonist*):TI,AB,KY

(GnRH analog*):TI,AB,KY

#10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20

#9 AND #21

Appendix 3. MEDLINE search strategy

From 1946 onwards

Ovid platform

1 exp Leiomyoma/ 2 myoma$.tw. 3 fibroid$.tw. 4 leiomyoma$.tw. 5 (fibromyoma$ or hysteromyoma$).tw. 6 fibroma$.tw. 7 myomectom$.tw. 8 or/1‐7 9 exp gonadotropin‐releasing hormone/ or exp buserelin/ or exp goserelin/ or exp leuprolide/ or exp nafarelin/ or exp triptorelin pamoate/ 10 gonadotropin‐releasing hormone$.tw. 11 (buserelin or goserelin or leuprolide or nafarelin or triptorelin).tw. 12 (Lupron or Suprefact or Suprecor).tw. 13 (histrelin or Supprelin).tw. 14 (Zoladex or deslorelin).tw. 15 (Suprelorin or Ovuplant).tw. 16 Synarel.tw. 17 GnRHa.tw. 18 GnRH‐a.tw. 19 GnRH agonist$.tw. 20 GnRH analog$.tw. 21 or/9‐20 22 randomized controlled trial.pt. 23 controlled clinical trial.pt. 24 randomized.ab. 25 randomised.ab. 26 placebo.tw. 27 clinical trials as topic.sh. 28 randomly.ab. 29 trial.ti. 30 (crossover or cross‐over or cross over).tw. 31 or/22‐30 32 exp animals/ not humans.sh. 33 31 not 32 34 8 and 21 and 33

Appendix 4. Embase search strategy

From 1980 onwards

Ovid platform

1 exp UTERUS MYOMA/ 2 myoma$.tw. 3 fibroid$.tw. 4 leiomyoma$.tw. 5 fibromyoma$.tw. 6 exp leiomyoma/ 7 or/1‐6 8 exp gonadorelin/ or exp gonadorelin agonist/ 9 exp buserelin acetate/ or exp buserelin/ 10 exp goserelin/ 11 exp leuprorelin/ 12 exp nafarelin acetate/ or exp nafarelin/ 13 exp triptorelin/ 14 gonadotrop?in‐releasing hormone$.tw. 15 (buserelin or goserelin or leuprolide or nafarelin or triptorelin).tw. 16 (Lupron or Suprefact or Suprecor).tw. 17 (histrelin or Supprelin).tw. 18 (Zoladex or deslorelin).tw. 19 (Suprelorin or Ovuplant).tw. 20 Synarel.tw. 21 GnRHa.tw. 22 GnRH‐a.tw. 23 GnRH agonist$.tw. 24 GnRH analog$.tw. 25 or/8‐24 26 7 and 25 27 Clinical Trial/ 28 Randomized Controlled Trial/ 29 exp randomization/ 30 Single Blind Procedure/ 31 Double Blind Procedure/ 32 Crossover Procedure/ 33 Placebo/ 34 Randomi?ed controlled trial$.tw. 35 Rct.tw. 36 random allocation.tw. 37 randomly.tw. 38 randomly allocated.tw. 39 allocated randomly.tw. 40 (allocated adj2 random).tw. 41 Single blind$.tw. 42 Double blind$.tw. 43 ((treble or triple) adj blind$).tw. 44 placebo$.tw. 45 prospective study/ 46 or/27‐45 47 case study/ 48 case report.tw. 49 abstract report/ or letter/ 50 or/47‐49 51 46 not 50 52 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) 53 51 not 52 54 26 and 53

Appendix 5. PsycINFO search strategy

From 1806 onwards

Ovid platform

1 Leiomyoma$.tw. 2 myoma$.tw. 3 fibroid$.tw. 4 (fibromyoma$ or hysteromyoma$).tw. 5 fibroma$.tw. 6 myomectom$.tw. 7 or/1‐6 8 exp Gonadotropic Hormones/ 9 gonadotropin‐releasing hormone$.tw. 10 (buserelin or Suprefact).tw. 11 (goserelin or Zoladex).tw. 12 (leuprolide or lupron).tw. 13 (nafarelin or Synarel).tw. 14 (histrelin or Supprelin).tw. 15 (deslorelin or Suprelorin or Ovuplant).tw. 16 triptorelin$.tw. 17 gonadotropin‐releasing hormone agonist$.tw. 18 gonadotrophin releasing hormone agonist$.tw. 19 GnRH agonist$.tw. 20 GnRH a.tw. 21 GnRHa.tw. 22 or/8‐21 23 7 and 22

Appendix 6. CINAHL search strategy

From 1961 onwards

Ebsco platform

#	Query
S30	S17 AND S29
S29	S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28
S28	TX allocat* random*
S27	(MH "Quantitative Studies")
S26	(MH "Placebos")
S25	TX placebo*
S24	TX random* allocat*
S23	(MH "Random Assignment")
S22	TX randomi* control* trial*
S21	TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) )
S20	TX clinic* n1 trial*
S19	PT Clinical trial
S18	(MH "Clinical Trials+")
S17	S8 AND S16
S16	S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15
S15	TX (gonadotropin releasing hormone agonist*)
S14	TX GnRH a
S13	TX buserelin or TX leuprolin or TX leuprorelin or TX nafarelin or TX triptorelin or TX Lupron or TX Zoladex or TX deslorelin
S12	TX (GnRH agonist*)
S11	TX Gonadorelin OR TX Leuprolide
S10	TX Goserelin
S9	(MM "Gonadorelin") OR (MM "Leuprolide") OR (MM "Goserelin")
S8	S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7
S7	TX myoma*
S6	TX fibromyoma*
S5	TX hysteromyoma*
S4	TX fibroid*
S3	TX leiomyoma*
S2	(MM "Myoma+")
S1	(MM "Leiomyoma")

Appendix 7. Data extraction form

Two review authors (RH and PBC) will prepare the data extraction form as per the Cochrane Handbook for Systematic Reviews of Interventions and will extract data in duplicate.

Appendix 8. Risk of bias tool

Random sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as introducing:

• low risk of bias (any truly random process, e.g. random number table; computer random number generator);

• high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number); or

• unclear risk of bias.

Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions before assignment and will assess whether intervention allocation could have been foreseen in advance of, or during, recruitment, or changed after assignment.

We will assess these methods as introducing:

• low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

• high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

• unclear risk of bias.

Blinding of participants and personnel (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as introducing:

• low, high, or unclear risk of bias for participants; and

• low, high, or unclear risk of bias for personnel.

Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcome assessment as introducing:

• low, high, or unclear risk of bias.

Incomplete outcome data (checking for possible attrition bias due to quantity, nature, and handling of incomplete outcome data)

We will describe for each included study, and for each outcome or class of outcomes, completeness of data including attrition and exclusions from analysis. We will state whether attrition and exclusions were reported and numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion when reported, and whether missing data were balanced across groups or were related to outcomes. When sufficient information is reported, or can be supplied by trial authors, we will re‐include missing data in the analyses that we undertake.

We will assess methods as introducing:

• low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

• high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation); or

• unclear risk of bias.

Selective reporting (checking for reporting bias)

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as introducing:

• low risk of bias (when it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);

• high risk of bias (when not all of the study’s prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest were reported incompletely and so cannot be used; study failed to include results of a key outcome that would be expected to have been reported); or

• unclear risk of bias.

Other bias (checking for bias due to problems not covered by the types of bias listed above)

We will describe for each included study any important concerns that we have about other possible sources of bias.

We will assess whether each study was free of other problems that could put it at risk of bias, including:

• low risk of other bias;

• high risk of other bias; or

• unclear whether risk of other bias is present.

Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to the types of bias presented above, we will assess the likely magnitude and direction of bias and whether we consider it likely to impact study findings. We will explore the impact of the level of bias by undertaking sensitivity analyses.

Contributions of authors

RH prepared the protocol with assistance provided by CF and PBC.

Sources of support

Internal sources

• None, Other.

External sources

• None, Other.

Declarations of interest

None known.

New