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Pre-operative endometrial thinning agents before endometrial destruction for heavy menstrual bleeding

  1. Yu Hwee Tan1,*,
  2. Anne Lethaby2

Editorial Group: Cochrane Menstrual Disorders and Subfertility Group

Published Online: 15 NOV 2013

Assessed as up-to-date: 11 APR 2013

DOI: 10.1002/14651858.CD010241.pub2


How to Cite

Tan YH, Lethaby A. Pre-operative endometrial thinning agents before endometrial destruction for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD010241. DOI: 10.1002/14651858.CD010241.pub2.

Author Information

  1. 1

    ADHB, Obstetrics and Gynaecology, Auckland, New Zealand

  2. 2

    University of Auckland, Obstetrics and Gynaecology, Auckland, New Zealand

*Yu Hwee Tan, Obstetrics and Gynaecology, ADHB, Auckland, New Zealand. hwee_85@yahoo.co.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 15 NOV 2013

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Characteristics of included studies [ordered by study ID]
Alborzi 2002

MethodsA single-centre, open, randomised study

Randomisation method not reported

No dropouts after randomisation

Power calculation not reported

Source of funding not reported


Participants90 women

Inclusion criteria: chief complaint of menorrhagia; reproductive age; no response to medication or to D & C
Exclusion criteria: active pelvic inflammatory disease, malignant or premalignant endometrial pathology; extensive uterine cavities; distorted large fibroid; future desire to maintain fertility

Resectoscope used for surgery


Interventions1. Preoperative thinning of the endometrium by danazol 600 mg/d for four to six weeks or GnRHa (Decapeptyl) one ampoule/mo for two months

2. No preoperative thinning of the endometrium

Timing of surgery not reported


Outcomes1. Duration of operation

2. Menstrual blood loss at 12 months (amenorrhoea and failed treatment)


NotesThe number of participants randomly assigned not specifically stated—only the number of endometrial ablations performed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation method not described. Stated that the trial was randomised only in the abstract

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskThe two groups were given different preoperative treatment

Blinding of outcome assessment (detection bias)
All outcomes
High riskThe two groups were given different preoperative treatment

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts reported

Selective reporting (reporting bias)High riskData on side effects were collected but are not reported in the publication

Other biasUnclear riskNo table describes the characteristics of the randomly assigned groups, so it is not possible to assess whether the groups were similar at baseline

Bhatia 2008

MethodsA single-centre randomised controlled trial

Randomly assigned in 1:1 ratio

Computer-generated randomisation schedule

Intention-to-treat analysis

Power calculation for sample size performed—sample size of 100 women (i.e. 50 women per arm) to provide the study 80% power to detect 20% fall in the 'no bleed' rate from standard treatment

Serono UK Ltd (manufacturer of Cetrorelix) stated as providing unconditional grant to pay for trial nurse


Participants106 premenopausal women
Inclusion criteria: selected transcervical resection of endometrium after failed medical management of dysfunctional uterine bleeding; normal smear history; o concurrent gynaecological problems; no desire for additional children; if submucous fibroids less than 5 cm; if on hormonal therapy or Mirena, had to discontinue treatment three months before surgery

Exclusion criteria: uterine size equivalent 12 weeks or more of pregnancy; previous transcervical resection of endometrium (TCRE); those with menopausal symptoms and significant medical problems or severe allergic reactions


Interventions1. Cetrorelix 3 mg subcutaneous injection at four to seven days before TCRE and placebo injection at three to four weeks before TCRE

2. Leuprorelin acetate 3.75 mg subcutaneous injection at three to four weeks before TCRE and placebo injection at four to seven days before TCRE


OutcomesPrimary:

1. Amenorrhoea rate at six months after surgery

2. Endometrial thickness as measured on TVS on day of surgery

Secondary:

1. Intraoperative and histological assessment of the endometrium

2. Drug adverse effect profile

3. Biochemical evidence of suppression

4. Duration of operation

5. Operative view

6. Blood loss

7. Fluid deficit

8. Complication rate

9. Overall participant satisfaction in menstrual flow at six months after surgery


NotesThree withdrawals in cetrorelix group for medical reasons

Three withdrawals in leuprorelin group—2 for medical reasons, 1 for personal reasons


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation list was prepared with use of a computer-generated, 1:1 block randomisation schedule from North Staffordshire University. The list was kept by the trial nurse and was forwarded to the local ethics committee 

Allocation concealment (selection bias)Low riskThe injection was prepared by the trial nurse in a separate treatment room from the room where an investigator was seeing the participant. Once prepared, the injection was placed behind a curtain, and the participant was then brought into the treatment room. The woman was advised to lie down in semi-prone position on a couch while facing the wall, and the injection was administered in the gluteal region by the trial nurse

Blinding of participants and personnel (performance bias)
All outcomes
Low riskInjections given were blinded to participants, investigators and surgeons. Apart from helping with blood samples, the trial nurse was not involved in the measurement of any outcomes or analysis

Blinding of outcome assessment (detection bias)
All outcomes
Low riskApart from helping with blood samples, the trial nurse was not involved in the measurement of any outcomes or analysis
The randomisation list was forwarded to the main investigator (KB) only after completion of follow-up process 

Incomplete outcome data (attrition bias)
All outcomes
Low riskOf 110 consecutive eligible women, four declined to participate because they were not keen to have an extra injection. A total of 106 consecutive women undergoing TCRE were randomly assigned to receive either leuprorelin or cetrorelix before their operation. Six dropouts were reported, three in each group: Operation was cancelled in five women who had received both injections, because of newly detected medical problems (three raised blood pressure, one hyperglycaemia and one acute illness), and one participant from the leuprorelin group decided not go ahead with the operation for personal reasons a few days after her first injection. The minimum required total of 100 women underwent surgery, with 50 in each group and none lost to follow-up. All 100 women were analysed

Selective reporting (reporting bias)Low riskAll prespecified outcomes were reported

Other biasUnclear riskBaseline characteristics of both groups were similar. However, uterine cavity mean length was > 10% longer in cetrorelix group

Donnez 1997

MethodsA multi-centre double-blind randomised trial (37 centres in 12 countries)

(AZTEC—Adjunctive Zoladex for Thinning the Endometrium Comparison Study)

Randomly assigned in a 1:1 ratio

Computer-generated randomisation scheme produced for each centre

Intention-to-treat and per-protocol analyses of data performed.

Power calculation not reported.

Pharmaceutical company stated as source of funding


Participants358 women

Inclusion criteria: over 30 years old, dysfunctional uterine bleeding (diagnosed clinically), recognisable menstrual cycles, uterine volume less than seven-week gestation, cavity length less than 10 cm, negative cervical smear in previous 12 months, negative endometrial biopsy, no pelvic inflammatory disease in previous two months

Exclusion criteria: pregnancy or breast feeding, previous endometrial resection, any hormonal agent used in previous two months, submucous fibroids, use of intrauterine device in previous three months

Resectoscope used for surgery


Interventions1. GnRH analogue—two goserelin implants (3.6 mg) four weeks apart preoperatively (180 women)

2. Placebo—two placebo implants four weeks apart preoperatively (178 women)

In both groups, treatment was timed to allow surgery six weeks after the first injection and on day 7 of the menstrual cycle


Outcomes1. Endometrial thickness at surgery (ultrasound and histological measurement)

2. Endometrial atrophy (on histology) at surgery

3. Duration of operation

4. Difficulty of operation (subjective assessment by surgeon as routine, easier or more difficult than usual)

5. Intraoperative distension medium absorption

6. Menstrual symptoms at 24 weeks postoperatively (using diary card to record blood loss and pain)

7. Participant satisfaction at 24 weeks postoperatively (assessed by participant questionnaire)

8. Side effects during treatment


NotesOne participant withdrew before treatment, five withdrew during treatment, six withdrew at or after surgery; six withdrawals (three in each group) were caused by adverse events (three considered treatment-related—one perforated uterus, a case of headache and nervousness in another participant)

Authors stated that outcomes were analysed on an intention-to-treat basis, but withdrawals were minimal after randomisation for some outcomes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation scheme

Allocation concealment (selection bias)Low riskSequential allocation with central control

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind—presumably participants and surgeons

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAs above

Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimal exclusions and lost to follow-up—unlikely to affect assessment of outcomes

Selective reporting (reporting bias)Unclear riskNo prior published protocol identified

Other biasUnclear riskSome baseline imbalances between groups

English 1998

MethodsA single-centre double-blind randomised trial

Method of randomisation not reported

Allocation concealment by opaque sealed envelopes

Minimal dropouts after randomisation: 3/39 for one outcome, 5/39 for another outcome

Power calculation not reported

Source of funding not reported


Participants39 women

Inclusion criteria: diagnosis of dysfunctional uterine bleeding following hysteroscopy

Exclusion criteria: not reported

Resectoscope used for surgery


Interventions1. GnRH analogue (Decapeptyl SR) 3.75 mg intramuscular injection (six and two weeks before surgery)

2. Danazol 200 mg capsules orally twice daily (six weeks before surgery until two weeks postsurgery)

3. Placebo capsules orally twice daily (six weeks before surgery until two weeks after surgery)

Follow-up for seven menstrual cycles


OutcomesPrimary:

Duration of surgery with TCRE

Secondary:

Pictorial blood assessment chart (PBAC) score; uterine fluid absorption; adverse events


NotesReasons for withdrawals not specified, but minimal loss to follow-up. Authors contacted to clarify data but information not available, and measures of variation for some outcomes were imputed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Low riskOpaque sealed envelopes

Blinding of participants and personnel (performance bias)
All outcomes
Low riskSurgeon blind to interventions for endometrial thinning. Participants blind to treatment with danazol or placebo (not with GnRHa, as this was given by injection)

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAs above

Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons not given for withdrawals, but minimal loss to follow-up

Selective reporting (reporting bias)Unclear riskFull information not provided on some of the prespecified outcomes

Other biasUnclear riskNo table provided to assess whether baseline variables in randomly assigned groups were similarly distributed. Source of funding not reported

Fraser 1996

MethodsA two-centre (Sydney, Melbourne) open randomised study

Randomly assigned in a 1:1 ratio with use of a computer-generated randomisation scheme

Power calculation for sample size performed—300 women per group required to show a difference in menstrual blood loss with a 95% confidence interval and a power of 90%. Authors rationalised that 25 women per group would be sufficient, based on previous studies

No intention-to-treat analysis

Pharmaceutical company stated as source of funding


Participants60 women

Inclusion criteria: younger than 50 years of age, 21- to 42-day menstrual cycle, menorrhagia (diagnosed clinically), not responding to conventional medical treatment

Exclusion criteria: submucous fibroids, adenomyosis, hormonal agent used within two months, danazol or goserelin used within six months

Rollerball ablation used for surgery


Interventions1. GnRH analogue—two goserelin implants (3.6 mg) four weeks apart, the first on day 2 of the menstrual cycle (30 women)

2. Danazol 200 mg orally twice daily for two months (30 women)


Outcomes1. Endometrial thickness at surgery (subjective visual assessment by surgeon)

2. Uterine cavity length (before therapy and three months postoperatively)

3. Duration of operation

4. Difficulty of operation (subjective assessment by surgeon as simple, intermediate, difficult)

5. Distension medium absorption

6. Intraoperative blood loss (from haemoglobin in irrigation fluid using a modified alkaline-haematin method)

7. Menstrual blood loss at one, two, three and six months after surgery (using alkaline-haematin method)

8. Dysmenorrhoea for six months after surgery (by participant questionnaire)

9. Side effects during treatment


NotesThree women withdrew from goserelin group and one woman from danazol group for reasons unrelated to the study medication. These women were excluded from data analysis

Dysmenorrhoea was graded using an ordinal scale as none, mild, moderate and severe


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random number table

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study with participants undergoing different treatment protocols

Blinding of outcome assessment (detection bias)
All outcomes
High riskAs above

Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimal dropouts and reasons given—unlikely to affect assessment of estimates

Selective reporting (reporting bias)Unclear riskNo prior published protocol identified

Other biasUnclear riskInsufficient data provided about baseline factors. Drugs for study provided by drug manufacturer

Garry 1996

MethodsA single-centre open randomised trial

Method of randomisation not described

Power calculation for sample size performed—at least 60 women per group required to detect a difference of 1.2 mm between goserelin and danazol at 90%

No intention-to-treat analysis

Pharmaceutical company stated as source of funding


Participants160 women

Inclusion criteria: premenopausal, over 20 years old, dysfunctional uterine bleeding requiring hysterectomy

Exclusion criteria: pregnancy, breast feeding, hormonal agents in the previous month, danazol or GnRH analogues in the previous six months

Nd:YAG laser used for surgery


Interventions1. GnRH analogue—two goserelin implants (3.6 mg) at eight and four weeks before surgery (38 women)

2. Danazol 200 mg four times a day for eight weeks (33 women)

3. GnRH analogue—one goserelin implant (3.6 mg) at four weeks before surgery (38 women)

4. Danazol 200 mg four times per day for four weeks (36 women)


Outcomes1. Endometrial thickness before and after pretreatment (by ultrasound, histology and subjective measurement by surgeon)

2. Uterine cavity length (before and after therapy)

3. Duration of operation

4. Distension medium absorption

5. Menstrual loss (assessment by clinician at six months)

6. Participant satisfaction (assessment by clinician at six months)

7. Side effects during treatment


NotesSix women withdrew after randomisation. 15 women did not complete the study

Postoperative menstrual loss assessed on ordinal scale as amenorrhoea, hypomenorrhoea, normal flow or no improvement


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation method not described

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study in which participants received different treatment protocols

Blinding of outcome assessment (detection bias)
All outcomes
High riskAs above

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo reasons given for dropouts and not balanced across randomly assigned groups

Selective reporting (reporting bias)Unclear riskNo prior published protocol identified

Other biasUnclear riskFunding by pharmaceutical company

Jack 2005

MethodsSingle-centre open randomised trial

Computer-generated balanced random number blocks in 1:1 ratio used

Power calculation for sample size: at least 90 participants per group required to have 80% power to detect a 20% difference in satisfaction and a 10% difference in acceptability

Modified intention-to-treat analysis for most outcomes (no inclusion of 13 dropouts after randomisation because women did not fit inclusion criteria of the trial)

Funding by the Scottish Executive Health Department


Participants210 women (13 of these excluded/dropped out after randomisation)

Inclusion criteria: complaint of excessive menstrual; agreeable to microwave endometrial ablation under local anaesthesia; normal endometrial pathology; family completed; uterine size ≤ 12 weeks

Exclusion criteria: not reported

Surgery by microwave

Location: Aberdeen, UK


Interventions1. Either Danazol 200 mg twice a day for four to five weeks or GnRHa (Goserelin) 3.6 mg subcutaneous injection five weeks before surgery

2. No preoperative treatment—surgery in the postmenstrual phase of the cycle


OutcomesPrimary:

1. Acceptability of treatment (at two weeks)

2. Satisfaction rate (at 12 months)

3. Participant satisfaction rate (at five years)

Secondary:

1. Duration of operation

2. Endometrial thickness

3. SF-12 QOL scores

4. Menstrual blood loss at 12 months and five years

5. Side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated balanced random number blocks

Allocation concealment (selection bias)Low riskSealed opaque sequentially numbered randomisation envelopes at a separate site—telephoned through to a distant site

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants had different preoperative protocols

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned whether outcome assessment was blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons carefully specified for exclusions before treatment and dropouts after treatment—unlikely to affect assessments of estimates

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

Other biasLow riskGroups balanced at baseline and no evidence of other potential bias

Kriplani 2001

MethodsA single-centre randomised trial

Participants were reported as blinded, but lack of a placebo control group may have unmasked the participants

Method of randomisation by computer0generated randomisation table

Power calculation for sample size not reported by power calculations reported after data analysis

Intention-to-treat analysis not reported, but no dropouts were reported

Source of funding not reported


Participants50 women

Inclusion criteria: history of heavy menstrual bleeding confirmed by pictorial chart assessment, but details not given; no further desire for childbearing; uterus < 12 weeks gravid size; negative cervical cytology; benign endometrial histology

Exclusion criteria: bleeding disorder

Surgery by resectoscope

Location: New Delhi, India

Source: not described


Interventions1. DMPA (depot medroxy progesterone acetate—150 mg six weeks before surgery + another dose after surgery)

2. No preoperative or postoperative treatment—immediate surgery in the postmenstrual phase


Outcomes1. Duration of surgery (minutes)

2. Fluid deficit (mL)

3. Postoperative amenorrhoea (up to four years of follow-up)

4. Requirement for further surgery (up to four years)

5. Endometrial thickness (mm)


NotesNo reported dropouts, but number of eligible women not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation table

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated as single-blind but not clear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAs above

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts reported

Selective reporting (reporting bias)Unclear riskNo prior published protocol identified

Other biasUnclear riskNot clear whether groups were balanced at baseline

Kriplani 2002

MethodsSingle-centre open randomised trial

Computer-generated randomisation method

No power calculation for sample size reported

Reasons for withdrawals not given, but minimal at one year and not likely to affect estimates. Estimates at six years only for a subgroup of all randomly assigned participants

Intention-to-treat analysis not reported

Source of funding not reported


Participants132 women

Inclusion criteria: excessive menstrual blood loss (defined) confirmed by PBAC (value not given); no bleeding disorders; negative cervical cytology and benign endometrial histology; uterus ≤ 12 weeks in size; no further desire for childbearing

Exclusion criteria: not reported

Resectoscope used for surgery


Interventions1. Danazol 400 to 600 mg/d for four to six weeks before surgery

2. No preoperative treatment—surgery in the postmenstrual phase

Duration: six years (subgroup of participants only)


Outcomes1. Endometrial thickness (mm)

2. Fluid deficit (mL)

3. Duration of operation

4. Requirement for repeat surgery

5. Menstrual blood loss at one and six years

6. Dysmenorrhoea


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants had different pretreatment protocols

Blinding of outcome assessment (detection bias)
All outcomes
High riskAs above

Incomplete outcome data (attrition bias)
All outcomes
Low riskFor immediate postoperative outcomes, minimal loss to follow-up; for assessment of menstrual symptoms and additional surgery at six years, approximately half of each randomly assigned group lost to follow-up, so these assessments were biased

Selective reporting (reporting bias)Unclear riskNo published protocol identified and no adverse events reported

Other biasLow riskGroups balanced at baseline and no evidence of other potential bias

Lissak 1999

MethodsA single-centre open randomised trial

Randomly assigned using a random number table

Pilot study—no power calculation for sample size and intention-to-treat analysis not reported

No source of funding stated


Participants30 women

Inclusion criteria: 30 to 55 years of age

Menorrhagia confirmed using pictorial chart

Failed therapy with oral contraceptive agents

Exclusion criteria: Active or chronic pelvic inflammatory disease, undiagnosed vaginal bleeding, previous caesarean section

Thermal balloon used for ablation


Interventions1, GnRH analogue—decapeptyl depot 3.75 mg one month before surgery

2. No pretreatment


Outcomes1. Uterine cavity length

2. Duration of operation

3. Menstrual loss at six months

4. Mean duration of menstrual flow (days) at six months

5. Participant satisfaction


NotesDuration of operation not included in this review, as with balloon ablation, this is independent of any pretreatment

Unequal numbers in randomly assigned groups—13 in one group and 17 in the other


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants underwent different treatment protocols

Blinding of outcome assessment (detection bias)
All outcomes
High riskAs above

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts reported

Selective reporting (reporting bias)Unclear riskNo prior published protocol

Other biasUnclear riskUnequal numbers in randomly assigned groups

Rai 2000

MethodsSingle-centre open randomised trial

Randomly assigned using sealed opaque envelopes

No power calculation for sample size reported. No withdrawals, so analysis by intention to treat

No source of funding stated


Participants100 women

Inclusion criteria: not stated

Exclusion criteria: not stated

Resectoscope used for surgery


Interventions1. GnRH analogue—naferelin nasal spray twice daily for eight weeks (25 women)

2. Danazol—200 mg three times per day for eight weeks (25 women)

3. Progestogen—medroxyprogesterone acetate 10 mg three times daily for eight weeks (25 women)

4. No preoperative therapy—surgery immediately after menstruation ceased (25 women)


Outcomes1. Endometrial thickness (objective assessment by pathologist)

2. Endometrial histology after therapy

3. Menstrual loss at 12 months (assessment by patient)

4. Participant satisfaction at 12 months


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not reported

Allocation concealment (selection bias)Low riskNumbered sealed opaque envelopes

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskParticipants not blinded, but surgery performed by one blinded surgeon and endometrial outcomes assessed by blinded histopathologist

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAs above

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawals after randomisation

Selective reporting (reporting bias)Unclear riskNo prior published protocol

Other biasUnclear riskNot clear whether groups were balanced at baseline, as no table of values reported

Romer 1996

MethodsA single-centre open randomised trial

Method of randomisation not described

No power calculation for sample size reported, and intention-to-treat analysis not reported

No source of funding stated


Participants40 women

Inclusion criteria: clinically diagnosed menorrhagia

Exclusion criteria: cavity length over 10 cm, submucous fibroids, malignant pathology on biopsy

Rollerball ablation used for surgery


Interventions1. GnRH analogue—decapeptyl depot four weeks preoperatively (10 women)

2. Danazol—200 mg three times per day for four weeks (10 women)

3. Progestogen—orgametril (lyestrenol) 10 mg per day for four weeks (10 women)

4. No preoperative therapy—surgery on day 5 to 9 of cycle (10 women)


Outcomes1. Endometrial thickness (subjective assessment by surgeon)

2. Endometrial histology after therapy

3. Menstrual loss at six months (assessment by clinician)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation method not described

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants underwent different treatment protocols

Blinding of outcome assessment (detection bias)
All outcomes
High riskParticipants underwent different treatment protocols

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts reported

Selective reporting (reporting bias)Unclear riskNo prior published protocol identified

Other biasUnclear riskNot clear whether groups balanced at baseline

Shawki 2002

MethodsA multi-centre (n = 3) open randomised parallel-group trial

Method of randomisation not described

No power calculation for sample size and no reported dropouts, so analysis by intention to treat

No source of funding reported


Participants131 women

Inclusion criteria: abnormal uterine bleeding refractory to medical management at a level to justify hysterectomy; no longer desiring to have children; uterine size < 12 weeks; participant refusal of continued medication attempts

Exclusion criteria: neoplasia

Endometrial destruction by resectoscope or by rollerball, according to surgeon preference


Interventions1. GnRHa 3.6 mg sc for one month (23 women)

2. GnRHa 3.6 mg sc for three months (26 women)

3. Danazol 400 to 600 mg per day for three months (26 women)

4. Medroxyprogesterone acetate (MPA) before surgery (27 women)

5. Dilatation & curettage immediately before the procedure (39 women)


Outcomes1. Menstrual blood loss at 12 months

2. Duration of operation

3. Side effects

Duration: one year


NotesNumbers unbalanced between randomly assigned groups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants had different pretreatment protocols

Blinding of outcome assessment (detection bias)
All outcomes
High riskParticipants had different pretreatment protocols

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo details of attrition

Selective reporting (reporting bias)Unclear riskNo prior published protocol identified

Other biasUnclear riskNo indication whether groups balanced at baseline. Numbers in randomly assigned groups very different

Sorensen 1997

MethodsA single-centre open randomised trial

Randomised by computer into three groups

No power calculation for sample size reported

No intention-to-treat analysis

Pharmaceutical company stated as source of funding


Participants60 women

Inclusion criteria: clinically diagnosed menorrhagia

Exclusion criteria: premalignant or malignant endometrial histology on biopsy, fibroids larger than 5 cm in diameter

Resectoscope used for surgery


Interventions1. GnRH analogue—one goserelin implant (3.6 mg) four to six weeks before surgery

2. GnRH analogue—two goserelin implants (3.6 mg) one four to six weeks before surgery and one on the day of surgery

3. No preoperative therapy—timing of surgery within cycle not reported


Outcomes1. Weight of endometrial strips removed

2. Duration of operation

3. Distension medium absorption

4. Menstrual loss at six and 12 months (as assessed by participant questionnaire, measurement of the number of sanitary towels used and number of days of menstrual loss)

5. Dysmenorrhoea at 12 months (as assessed by participant questionnaire)

6. Patient satisfaction (as assessed by patient questionnaire)


NotesStandard deviation for distension medium absorption estimated from mean and range


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer randomisation

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study in which participants received different treatment protocols

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study in which participants received different treatment protocols

Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimal dropouts and balanced between randomly assigned groups—unlikely to affect assessment of estimates

Selective reporting (reporting bias)Unclear riskNo prior published protocol identified

Other biasUnclear riskFunding by pharmaceutical company

Sowter 1997

MethodsA single-centre open randomised trial

Method of randomisation not described

No power calculation for sample size reported

Analysis not by intention to treat

No source of funding stated


Participants77 women

Inclusion criteria: clinically diagnosed menorrhagia, younger than age 50

Exclusion criteria: not described

Resectoscope used for surgery


Interventions1. GnRH analogue—two goserelin implants (3.6 mg) eight and four weeks preoperatively (35 women)

2. No preoperative therapy—surgery performed in early proliferative phase of menstrual cycle (40 women)


Outcomes1. Menstrual loss at 12 to 24 months (as assessed by participant questionnaire)

2. Dysmenorrhoea at 12 to 24 months (as assessed by participant questionnaire)

3. Participant satisfaction at 12 to 24 months (as assessed by participant questionnaire)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation method not described

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study in which participants received different treatment protocols

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study in which participants received different treatment protocols

Incomplete outcome data (attrition bias)
All outcomes
High riskWomen not analysed in their randomly assigned groups, and assessment of estimates could be biased

Selective reporting (reporting bias)Unclear riskNo prior published protocol identified

Other biasUnclear riskBaseline characteristics compared according to treatment received, not according to randomisation schedule

Sutton 1994

MethodsA single-centre open randomised trial

Randomly assigned in a 1:1 ratio

Randomisation method not described

No power calculation for sample size reported

No intention-to-treat analysis

No source of funding stated


Participants120 women

Inclusion criteria: premenopausal, 25 to 50 years of age with clinically diagnosed menorrhagia; uterus less than 12 weeks of gestation in size, cavity length less than 12 cm

Exclusion criteria: endometrial hyperplasia present on biopsy; hormonal agents used in previous two months, or danazol or goserelin used in previous six months

Resectoscope used for surgery


Interventions1. GnRH analogue—two goserelin implants at eight and four weeks before surgery (55 women)

2. Danazol—200 mg orally four times per day for eight weeks before surgery (55 women)


Outcomes1. Endometrial thickness (by ultrasound, histology and subjective visual assessment by surgeon)

2. Duration of operation

3. Difficulty of operation (assessment by surgeon)

4. Menstrual loss at 12 weeks (as assessed by clinician)

5. Participant satisfaction at 12 weeks (as assessed by clinician)


Notes10 women withdrew from study before taking medication

Seven danazol participants withdrew from study because of side effects


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation method not described

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study with participants undergoing different treatment protocols

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study in which participants received different treatment protocols

Incomplete outcome data (attrition bias)
All outcomes
High riskWithdrawals unbalanced between groups and related to effects of treatment received

Selective reporting (reporting bias)Unclear riskNo prior published protocol identified

Other biasUnclear riskNot clear whether groups balanced at baseline

Taskin 1996

MethodsA single-centre (Turkey) double-blind randomised trial

Randomly assigned in a 1:1 ratio using a table of random numbers—concealment of allocation not described

No power calculation for sample size reported

Intention-to-treat analysis not reported

No source of funding described


Participants13 women

Inclusion criteria: dysfunctional uterine bleeding that did not respond to medical therapy; consent to undergo hysteroscopy

Exclusion criteria: abnormal smear; suspected uterine malignancy; submucosal fibroids or masses distorting uterine lining; adnexal pathology; "large" (not defined) uterine volume

All women underwent routine cervical smear; endometrial sampling; transvaginal and transabdominal ultrasound examinations

Rollerball used for surgery


Interventions1. GnRH analogue—depot goserelin (3.75 mg) on day 21 of cycle, with a second dose given four weeks later (seven women)

2. Placebo—two saline injections four weeks apart (six women)

Surgery was performed 10 to 14 days after the last injection under general anaesthesia


OutcomesPrimary:

Degree of fluid absorption (mL)

Other:

Operating time (minutes)


NotesNo reported dropouts


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind with placebo control

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind with placebo control

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo reported dropouts

Selective reporting (reporting bias)Unclear riskNo prior published protocol identified

Other biasLow riskGroups appear balanced at baseline; no source of funding reported

Taskin 1998

MethodsA single-centre parallel-group randomised controlled trial

Randomisation on 1:1 ratio using a table of random numbers—concealment of allocation not reported

No power calculation for sample size reported

Intention-to-treat analysis not reported

No source of funding described


Participants17 women

Inclusion criteria: diagnosis of dysfunctional uterine bleeding that did not respond to conservative treatment

Exclusion criteria: abnormal cervical smear; suspected uterine malignancy; submucosal fibroids or masses distorting the endometrial lining; adnexal pathology

All women had preoperative cervical smears, endometrial sampling and transvaginal and transabdominal ultrasound examinations

Surgery by rollerball


Interventions1. GnRH analogue (not specified) 3.75 mg on day 21 of the menstrual cycle and four weeks later, with surgery scheduled 10 to 14 days after the second dose

2. Placebo (saline injections) under same regimen approximately two months before surgery


OutcomesPrimary:

Amount of irrigant and irrigant deficit

Secondary:

Operation time


NotesAuthors contacted for clarification of data, but information not available


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Low riskInvestigators stated as blinded to allocation; not explicitly stated whether participants were blinded, although placebo treatment makes this likely. Outcomes unlikely to be affected by participants' knowledge of treatment

Blinding of outcome assessment (detection bias)
All outcomes
Low riskInvestigators stated as blinded to allocation; not explicitly stated whether participants were blinded, although placebo treatment makes this likely. Outcomes unlikely to be affected by participants' knowledge of treatment

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo reported dropouts after randomisation

Selective reporting (reporting bias)Unclear riskResults of all outcomes measured not clearly reported

Other biasLow riskGroups appeared similar at baseline. Funding source not reported

Vercellini 1996

MethodsMulti-centre randomised trial (three centres in Italy)

Centralised randomisation in a 1:1 ratio by telephone using computer-generated randomisation scheme

Power calculation for sample size—80% power to detect a difference in fluid absorption of 300 mL; at level of 5% 30 women required per group

No intention-to-treat analysis

Pharmaceutical company stated as source of funding


Participants71 women

Inclusion criteria: aged 40 or older with menorrhagia diagnosed clinically and with pictorial blood loss assessment chart, uterus less than eight weeks of gestation in size

Exclusion criteria: pregnant, breast feeding, recently used hormonal agents or inhibitors of menstruation, fibroids larger than 3 cm in diameter


Interventions1. GnRH analogue—goserelin implant (3.6 mg) eight and four weeks before surgery (35 women)

2. No preoperative therapy—surgery in early proliferative phase of menstrual cycle (36 women)


Outcomes1. Endometrial thickness (subjective visual assessment by surgeon)

2. Duration of operation

3. Distension medium absorption

4. Time to return to work or to resume domestic activities


NotesEight women withdrew from the study before surgery for reasons unrelated to their therapy. Two additional women withdrew after surgery


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation list

Allocation concealment (selection bias)Low riskCentralised allocation by telephone

Blinding of participants and personnel (performance bias)
All outcomes
High riskWomen had different treatment protocols

Blinding of outcome assessment (detection bias)
All outcomes
High riskWomen had different treatment protocols

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskWithdrawals unbalanced between groups

Selective reporting (reporting bias)Unclear riskNo prior protocol identified

Other biasLow riskNo other potential source of bias identified

Vilos 2010

MethodsA single-centre parallel-group randomised controlled trial

Randomisation method not described

No power calculation for sample size reported

No intention-to-treat analysis

Source of funding not reported


Participants105 women

Inclusion criteria: participant’s Higham menstrual score > 150 one to two months before surgery

Exclusion criteria: Genital tract malignancy; unresolved endometrial hyperplasia; anatomic or pathologic uterine anomalies; history of previous classical caesarean section or transmural myomectomy; intrauterine pregnancy; acute genital and/or urinary tract infection; women wishing to preserve their fertility; women expecting amenorrhoea as an outcome; IUCD in place; failed previous endometrial ablation


Interventions1. GnRH analogue—goserelin (3.6 mg sc) four weeks before surgery

2. Suction curettage immediately before surgery

Surgery by ThermaChoice II balloon endometrial ablation


Outcomes1. Reduction in Higham score

2. Combined amenorrhoea/hypomenorrhoea

3. Eumenorrhoea

4. Success of treatment (normal bleeding or less)

5. Dysmenorrhoea

6. Premenstrual syndrome symptoms

7. Participant satisfaction rates

8. Further surgery (any or hysterectomy)

9. Adverse events

10. Health-related quality of life

All outcomes assessed at 12 months


NotesFive women withdrew after randomization but before treatment

Two women withdrawn at time of surgery as unable to be treated with balloon endometrial ablation for reasons not associated with treatment


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod of randomization not explained

Allocation concealment (selection bias)Low riskConcealment was achieved by placing the randomization code into an opaque envelope, and treatment allocation was revealed after entry criteria had been met and informed consent obtained

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo mention of blinding of participants or personnel; however, would be difficult to blind between suction curettage and goserelin as different treatment protocols

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo mention of blinding of outcome assessors to interventions and allocations, but would be difficult to blind given different treatment protocols

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition rate > 10%, but no mention in article about number of participants required to gain adequate power

Selective reporting (reporting bias)High riskA lot of outcomes looked, at but not all reported or reported adequately

Other biasUnclear riskBaseline characteristics of both groups similar, except for uterine balloon volume (50% larger in suction curettage group)

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Alford 1996This comparative study was excluded because randomisation was not used. Drug regimens were changed sequentially as authors "gained more experience of their effectiveness". The effects of leuprolide acetate (a GnRH analogue) (24 participants), danazol (six participants), tamoxifen (four participants) and medroxyprogesterone acetate (Depo-Provera) (six participants) were compared. Endometrial atrophy at surgery and postoperative menstrual symptoms were evaluated. Leuprolide acetate and danazol appeared to be superior to tamoxifen and medroxyprogesterone acetate, but the duration of follow-up time was also shorter in these first two groups

Cicenelli 2007This randomised study was excluded because the participant group consisted of women with endometrial polyps who were undergoing hysteroscopic surgery. It does not meet the inclusion criteria for participants

Cooper 1996This randomised trial used cervical resistance to dilatation as its only treatment outcome measure within a larger randomised trial comparing hysterectomy with hysteroscopic treatments for menorrhagia. The effects of goserelin (60 participants) in women allocated to endometrial resection or laser ablation were compared with no treatment (20 participants) in women allocated to hysterectomy. Goserelin increased cervical resistance. This study also evaluated in a double-blind randomised manner the effect of misoprostol in reducing GnRH-induced cervical resistance to dilatation (64 women randomly assigned to misoprostol or placebo). Misoprostol had no beneficial effect. The study was excluded because no other intraoperative or postoperative outcomes were assessed, and the study treatment groups did not meet inclusion criteria

Cooper 2001This was a prospective double-arm controlled observational study assessing endometrial pretreatment with GnRHa versus immediate ablation with the 3D bipolar NovaSure system. No indication suggested that the groups had been allocated randomly

Florio 2010This study was excluded, as it looked at hysteroscopic surgery in women with endometrial polyps rather than at endometrial ablation techniques. It does not meet the inclusion criteria for participants

Florio 2012This study was excluded, as it looked at hysteroscopic surgery rather than endometrial ablation techniques

Gabbanini 2009This study was excluded, as it looked at hysteroscopic surgery in women with intrauterine pathology (polyps, submucous myoma, septate uterus) rather than endometrial ablation techniques. It does not meet the inclusion criteria for participants

Mavrelos 2010This randomised study was excluded because it looked at the use of preoperative GnRH analogues before hysteroscopic treatment of women with submucous fibroids. It does not meet the inclusion criteria for participants

Muzii 2010This randomised study was excluded because it looked at the efficacy of GnRH analogue treatment before hysteroscopic resection of submucous myomas in participants with abnormal uterine bleeding. It does not meet the inclusion criteria for participants

Perino 1993A prospective comparative study of 193 participants undergoing hysteroscopic surgery for uterine septa, submucous fibroids and abnormal uterine bleeding. Within this study were 56 women who were undergoing endometrial resection for abnormal uterine bleeding with benign pathology. 36 of these women received two injections of leuprolide acetate depot (3.75 mg) at 28-day intervals. Operating time, intraoperative blood loss, volume of distension medium used and number of subsequent treatment failures at 12 months after surgery were evaluated. The study was excluded because no randomisation technique was used to determine treatment allocation

Rich 1995A randomised study of 48 women comparing danazol, norethisterone, cyproterone acetate and medroxyprogesterone acetate taken for four weeks before endometrial ablation. The study was excluded, as it did not meet inclusion criteria for outcome measures

Serden 1992A comparison of preoperative GnRH analogue (leuprolide acetate) (56 women), danazol (26 women), progestogens (medroxyprogesterone acetate or norethindrone acetate) (nine women) and no therapy (46 women). GnRH analogues appeared to result in the highest amenorrhoea rate, but this group also had the shortest duration of follow-up. This study was excluded because although participants were randomly allocated to different treatments, the numbers in each group and the duration of follow-up were very different, suggesting that true randomisation was not used

Triolo 2006This randomised study was excluded because the participant group consisted of women with endo-uterine pathologies (polyps, submucous myoma, septate uterus) who were undergoing hysteroscopic surgery. It does not meet the inclusion criteria for participants

Trivedi 1999A comparison of pretreatment with danazol (28 women), goserelin (four women), prior suction curettage (three women), progestogens (four women) and no endometrial preparation (625 women) and their effects on postoperative symptoms and participant satisfaction. This study was not randomised

Vercellini 1994A comparison of goserelin depot (3.6 mg) (33 participants) and surgery in proliferative phase of the cycle (22 participants). The study compared duration of operation, distention medium absorption, difficulty of surgery, duration of postoperative bleeding, time to return to work and time to resume normal domestic activities. Goserelin appeared to reduce operating time and distension medium absorption. The duration of postoperative bleeding and the time to return to work were unaffected. The study was excluded because participant choice rather than randomisation was used to determine treatment allocation

Zapico 2005This study was excluded because it was not randomised, and it does not meet the inclusion criteria for study design

 
Characteristics of studies awaiting assessment [ordered by study ID]
Gannon 1994

MethodsAbstract not available

Participants

Interventions

Outcomes

Notes

Mayonda 1994

MethodsOpen randomised parallel-group study

Participants48 women. Inclusion criteria: menorrhagia, endometrial ablation planned as treatment

Interventions(1) Danazol; (2) cyproterone acetate; (3) norethisterone; (4) medroxyprogesterone acetate for four weeks before ablation

Outcomes(1) Endometrial thickness by ultrasonography; (2) side effects

NotesAbstract presented at the Victor Bonney Society Meeting in 1994

McDonald 1994

MethodsParallel-group open-label randomised controlled trial

Participants42 women. No inclusion or exclusion criteria reported in abstract

Interventions(1) goserelin implant (3.6 mg) one month before surgery; (2) no preoperative treatment

Surgery with intramenstrual resection

OutcomesEase of surgery, fluid loss, amenorrhoea rates, further surgery

NotesNo reply received from author

Nagele 1995

MethodsParallel-group placebo-controlled randomised trial

Participants49 women

No inclusion criteria reported

Exclusion criteria: irregular menses, uterus > 12 weeks in size, submucous fibroids > 5 cm; recent gynaecological treatment, serious illness

Interventions(1) Danazol 200 mg three times daily for six weeks before surgery; (2) placebo

OutcomesAdverse events, menstrual loss and other unspecified outcomes

NotesAbstract presented at 27th British Congress of Obstetrics and Gynaecology

Watermeyer 2005

MethodsOpen randomised parallel-group study

Participants40 women

Inclusion criteria: validated dysfunctional uterine bleeding

Interventions(1) GnRHa agonist; (2) timed treatment after end of a period

OutcomesMenstrual loss; amenorrhoea rates; participant satisfaction

NotesAuthor could not be reached by email. Abstract presented at the Royal College of Obstetricians and Gynaecologists 6th International Scientific Meeting, September 2005

 
Comparison 1. GnRH analogues versus placebo or no treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Intraoperative complications—uterine perforation5592Risk Ratio (M-H, Fixed, 95% CI)1.47 [0.35, 6.06]

 2 Postoperative amenorrhoea at 12 months or less7605Risk Ratio (M-H, Fixed, 95% CI)1.58 [1.24, 2.01]

    2.1 one month of therapy
389Risk Ratio (M-H, Fixed, 95% CI)1.80 [0.95, 3.40]

    2.2 two months of therapy
4516Risk Ratio (M-H, Fixed, 95% CI)1.54 [1.19, 2.01]

 3 Postoperative amenorrhoea at 24 months or longer2357Risk Ratio (M-H, Fixed, 95% CI)1.62 [1.04, 2.52]

    3.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.79, 11.44]

    3.2 two months of therapy
1337Risk Ratio (M-H, Fixed, 95% CI)1.50 [0.94, 2.41]

 4 Requiring further surgery within 12 months of follow-up4488Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.53, 1.86]

    4.1 one month of therapy
269Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.21, 1.97]

    4.2 two months of therapy
2419Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.55, 2.61]

 5 Requiring further surgery ≥ 24 months of follow-up2319Risk Ratio (M-H, Fixed, 95% CI)1.51 [0.97, 2.35]

    5.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 two months of therapy
1299Risk Ratio (M-H, Fixed, 95% CI)1.51 [0.97, 2.35]

 6 Endometrial thickness (ultrasound, mm)120Mean Difference (IV, Fixed, 95% CI)-2.70 [-3.49, -1.91]

    6.1 one month of therapy
120Mean Difference (IV, Fixed, 95% CI)-2.70 [-3.49, -1.91]

 7 Endometrial thickness (descriptive data)Other dataNo numeric data

    7.1 two months of therapy
Other dataNo numeric data

 8 Atrophic endometrial glands4483Risk Ratio (M-H, Fixed, 95% CI)6.02 [4.11, 8.81]

    8.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)15.0 [0.97, 231.84]

    8.2 two months of therapy
3463Risk Ratio (M-H, Fixed, 95% CI)5.84 [3.97, 8.58]

 9 Optimal endometrial thinning (operator assessment)120Risk Ratio (M-H, Fixed, 95% CI)6.0 [0.87, 41.21]

    9.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)6.0 [0.87, 41.21]

 10 Side effects2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 hot flushes
1346Risk Ratio (M-H, Fixed, 95% CI)3.16 [2.24, 4.45]

    10.2 sweating
1346Risk Ratio (M-H, Fixed, 95% CI)3.08 [1.50, 6.32]

    10.3 headaches
1346Risk Ratio (M-H, Fixed, 95% CI)1.46 [1.02, 2.08]

    10.4 withdrawal from treatment due to side effects
2372Risk Ratio (M-H, Fixed, 95% CI)3.20 [0.35, 29.75]

 11 Duration of operation (minutes)6502Mean Difference (IV, Fixed, 95% CI)-3.62 [-4.76, -2.49]

    11.1 one month of therapy
139Mean Difference (IV, Fixed, 95% CI)-13.60 [-19.44, -7.76]

    11.2 two months of therapy
5463Mean Difference (IV, Fixed, 95% CI)-3.23 [-4.39, -2.07]

 12 Where operative difficulty encountered2415Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.22, 0.46]

   12.1 one month of therapy
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    12.2 two months of therapy
2415Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.22, 0.46]

 13 Distension medium absorption during surgery4137Mean Difference (IV, Fixed, 95% CI)-154.53 [-211.41, -97.65]

    13.1 one month of therapy
139Mean Difference (IV, Fixed, 95% CI)-149.0 [-291.32, -6.68]

    13.2 two months of therapy
398Mean Difference (IV, Fixed, 95% CI)-155.59 [-217.64, -93.53]

 14 Distension medium absorption during surgery (descriptive data)Other dataNo numeric data

    14.1 two months of therapy
Other dataNo numeric data

 15 Women with moderate/heavy postoperative blood loss4480Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.59, 0.92]

    15.1 one month of therapy
259Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.22, 1.51]

    15.2 two months of therapy
2421Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.60, 0.94]

 16 Postoperative dysmenorrhoea2133Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.40, 0.87]

    16.1 one month of therapy
158Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.25, 1.07]

    16.2 two months of therapy
175Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.41, 0.98]

 17 Satisfaction with outcome6599Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.93, 1.05]

    17.1 one month of therapy
268Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.71, 1.16]

    17.2 two months of therapy
4531Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.94, 1.06]

 
Analysis 1.7 Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 7 Endometrial thickness (descriptive data).
Endometrial thickness (descriptive data)

StudyGnRHaControlMann-Whitney U test

two months of therapy

Donnez 1997n=176

Median thickness: 1.61 mm

No range reported
n=173

Median thickness: 3.53 mm

No range reported
Estimated ratio: 0.46, 95% CI 0.41, 0.52; p=0.0001

Rai 2000n=25

Median: 1.5 mm

Range: 1 - 4
n=25

Median:2 mm

Range: 0.5 - 4
p=0.02

 
Analysis 1.14 Comparison 1 GnRH analogues versus placebo or no treatment, Outcome 14 Distension medium absorption during surgery (descriptive data).
Distension medium absorption during surgery (descriptive data)

StudyGnRHaPlacebo or no treatmentTest results

two months of therapy

Donnez 1997n=177

Median fluid absorption: 150mL

No range reported
n=175

Median fluid absorption: 225mL

No range reported
Adjustments made for effect of centre.

GnRHa treated patients absorbed on average a median of 40mL less fluid than placebo treated patients, p=0.0325

 
Comparison 2. GnRH analogues versus danazol

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 2 Postoperative amenorrhoea at 12 months or less5340Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.90, 1.52]

    2.1 one month of therapy
291Risk Ratio (M-H, Fixed, 95% CI)1.60 [0.83, 3.11]

    2.2 two months of therapy
3174Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.78, 1.47]

    2.3 three months of therapy
141Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.49, 2.74]

    2.4 three months of therapy with danazol and one month with GnRHa
134Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.42, 2.74]

 3 Postoperative amenorrhoea at 24 months1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.49, 2.05]

 4 Requesting further surgery during follow-up120Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.02, 7.32]

    4.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.02, 7.32]

 5 Endometrial thickness (ultrasound)120Mean Difference (IV, Fixed, 95% CI)0.20 [-0.46, 0.86]

    5.1 one month of therapy
120Mean Difference (IV, Fixed, 95% CI)0.20 [-0.46, 0.86]

 6 Endometrial thickness (descriptive data)Other dataNo numeric data

    6.1 one month of therapy
Other dataNo numeric data

    6.2 two months of therapy
Other dataNo numeric data

 7 Atrophic endometrial glands4318Risk Ratio (M-H, Fixed, 95% CI)1.28 [1.03, 1.58]

    7.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.53, 1.46]

    7.2 two months of therapy
3298Risk Ratio (M-H, Fixed, 95% CI)1.33 [1.06, 1.67]

 8 Satisfactory thinning (hysteroscopy)2165Risk Ratio (M-H, Fixed, 95% CI)1.09 [1.00, 1.19]

    8.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.75, 1.34]

    8.2 two months of therapy
1145Risk Ratio (M-H, Fixed, 95% CI)1.10 [1.00, 1.21]

 9 Optimal endometrial thinning (operator assessment)120Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.49, 2.05]

    9.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.49, 2.05]

 10 Complete atrophy (hysteroscopy)2142Risk Ratio (M-H, Fixed, 95% CI)1.84 [1.23, 2.75]

    10.1 two months of therapy
2142Risk Ratio (M-H, Fixed, 95% CI)1.84 [1.23, 2.75]

 11 Side effects3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    11.1 hot flushes
2168Risk Ratio (M-H, Fixed, 95% CI)1.99 [1.50, 2.64]

    11.2 vaginal dryness
2168Risk Ratio (M-H, Fixed, 95% CI)2.16 [1.30, 3.59]

    11.3 depression
2168Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.89, 1.97]

    11.4 voice changes
2168Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.37, 1.65]

    11.5 hirsutism
2168Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.29, 2.08]

    11.6 decrease in libido
2168Risk Ratio (M-H, Fixed, 95% CI)2.15 [1.08, 4.28]

    11.7 headaches
1110Risk Ratio (M-H, Fixed, 95% CI)1.89 [1.23, 2.91]

    11.8 withdrawal from treatment due to side effects
3285Risk Ratio (M-H, Fixed, 95% CI)0.08 [0.01, 0.59]

 12 Weight gain158Mean Difference (IV, Fixed, 95% CI)-2.3 [-3.70, -0.90]

 13 Duration of operation (minutes)4325Mean Difference (IV, Fixed, 95% CI)-5.02 [-6.25, -3.78]

    13.1 one month of therapy with GnRHa and danazol
174Mean Difference (IV, Fixed, 95% CI)-6.40 [-9.16, -3.64]

    13.2 two months of therapy with GnRHa and danazol
3150Mean Difference (IV, Fixed, 95% CI)-3.78 [-5.92, -1.64]

    13.3 three months of therapy with GnRHa and danazol
152Mean Difference (IV, Fixed, 95% CI)-6.0 [-8.24, -3.76]

    13.4 three months of danazol and one month of GnRHa
149Mean Difference (IV, Fixed, 95% CI)-4.0 [-7.08, -0.92]

 14 Where operative difficulty encountered156Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.31, 1.51]

    14.1 two months of therapy
156Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.31, 1.51]

 15 Distension medium absorption during surgery3223Mean Difference (IV, Fixed, 95% CI)-22.38 [-87.07, 42.32]

    15.1 one month of therapy
174Mean Difference (IV, Fixed, 95% CI)-504.0 [-776.80, -231.20]

    15.2 two months of therapy
3149Mean Difference (IV, Fixed, 95% CI)6.32 [-60.27, 72.92]

 16 Postoperative blood loss—objective156Mean Difference (IV, Fixed, 95% CI)-6.4 [-9.19, -3.61]

    16.1 two months of therapy
156Mean Difference (IV, Fixed, 95% CI)-6.4 [-9.19, -3.61]

 17 Satisfaction with outcome3286Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.83, 1.01]

    17.1 one month of therapy
171Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.90, 1.13]

    17.2 two months of therapy
3215Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.78, 1.01]

 
Analysis 2.6 Comparison 2 GnRH analogues versus danazol, Outcome 6 Endometrial thickness (descriptive data).
Endometrial thickness (descriptive data)

StudyGnRHaDanazolTest results

one month of therapy

Garry 1996n=39

Median: 1.0

Range: 0.5-2.0
n=37

Median: 1.0

Range: 0.5-3.0
Results not reported

two months of therapy

Garry 1996n=38

Median: 0.5 mm

Range: 0.5-1.5
n=32

Median: 0.5

Range 0.4-1.5
Results not reported

Rai 2000n=25

Median 1.5 mm

Range: 1-4
n=25

Median 1.5 mm

Range 1 - 3.5 mm
P value not reported

Not significantly different

Sutton 1994n=55

Median: 1.5 mm

No other data reported
n=55

Median: 2.0 mm

No other data reported
Difference between the 2 treatments: 0.9 mm [-1.5, -0.3]

Wilcoxon Rank sum test: p=0.0015

 
Comparison 3. GnRH analogues versus progestogens

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 2 Postoperative amenorrhoea at 12 months or less3146Risk Ratio (M-H, Fixed, 95% CI)1.58 [0.96, 2.61]

    2.1 one month of therapy
257Risk Ratio (M-H, Fixed, 95% CI)1.84 [0.85, 3.98]

    2.2 two months of therapy
150Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.57, 2.91]

    2.3 three months of therapy
139Risk Ratio (M-H, Fixed, 95% CI)1.67 [0.55, 5.03]

 3 Postoperative amenorrhoea at 24 months120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.79, 11.44]

    3.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.79, 11.44]

 4 Requiring further surgery at two years of follow-up120Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.02, 7.32]

    4.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.02, 7.32]

 5 Endometrial thickness (ultrasound)120Mean Difference (IV, Fixed, 95% CI)-2.80 [-3.59, -2.01]

    5.1 one month of therapy
120Mean Difference (IV, Fixed, 95% CI)-2.80 [-3.59, -2.01]

 6 Endometrial thickness (descriptive data)Other dataNo numeric data

    6.1 two months of therapy
Other dataNo numeric data

 7 Endometrial atrophy (histology)270Risk Ratio (M-H, Fixed, 95% CI)2.25 [1.13, 4.49]

    7.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)3.5 [0.95, 12.90]

    7.2 two months of therapy
150Risk Ratio (M-H, Fixed, 95% CI)1.83 [0.80, 4.19]

 8 Optimal endometrial thinning (operator assessment)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.79, 11.44]

   8.2 two months of therapy
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Duration of operation (minutes)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    9.1 one month of therapy
150Mean Difference (IV, Fixed, 95% CI)-15.0 [-19.44, -10.56]

    9.2 three months of therapy
153Mean Difference (IV, Fixed, 95% CI)-17.0 [-20.90, -13.10]

 10 Satisfaction with outcome150Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.65, 0.99]

   10.1 one month of therapy
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    10.2 two months of therapy
150Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.65, 0.99]

 
Analysis 3.6 Comparison 3 GnRH analogues versus progestogens, Outcome 6 Endometrial thickness (descriptive data).
Endometrial thickness (descriptive data)

StudyGnRHaProgestogensMann-Whitney U test

two months of therapy

Rai 2000n=25

Median: 1.5 mm

Range: 1 - 4
n=25

Median: 2 mm

Range: 0.5 - 3
No p value reported

Not significantly different

 
Comparison 4. GnRH analogue versus GnRH antagonist

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Intraoperative complications1300Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.25, 3.92]

    1.1 uterine perforation
1100Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 71.92]

    1.2 traumatic dilatation of cervix
1100Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.99]

    1.3 fluid deficit > 1500 mL
1100Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.15, 6.82]

 2 Postoperative amenorrhoea at 12 months or less1100Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.79, 1.14]

    2.1 six months after surgery
1100Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.79, 1.14]

 3 Postoperative amenorrhoea and/or hypomenorrhoea at 12 months or less1100Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.83, 1.06]

    3.1 six months after surgery
1100Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.83, 1.06]

 4 Requiring further surgery within 12 months of follow-up1100Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.31, 5.65]

    4.1 at six months of follow-up
1100Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.31, 5.65]

 5 Endometrial thickness (ultrasound)1171Mean Difference (IV, Fixed, 95% CI)0.53 [0.29, 0.77]

    5.1 hyperplasia included
188Mean Difference (IV, Fixed, 95% CI)0.54 [0.17, 0.91]

    5.2 hyperplasia excluded
183Mean Difference (IV, Fixed, 95% CI)0.53 [0.22, 0.84]

 6 Side effects1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 hot flushes
1100Risk Ratio (M-H, Fixed, 95% CI)0.4 [0.17, 0.95]

    6.2 skin irritation
1100Risk Ratio (M-H, Fixed, 95% CI)2.67 [0.75, 9.47]

    6.3 nonspecific adverse effects
1100Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.15, 6.82]

 7 Duration of operation (minutes)1100Mean Difference (IV, Fixed, 95% CI)2.26 [-1.11, 5.63]

 8 Good operative view1100Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.04]

 9 Distension medium absorption during surgeryOther dataNo numeric data

 10 Postoperative dysmenorrhoea1100Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.48, 2.09]

 11 Satisfaction with outcome1100Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.81, 1.07]

    11.1 at six months of follow-up
1100Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.81, 1.07]

 
Analysis 4.9 Comparison 4 GnRH analogue versus GnRH antagonist, Outcome 9 Distension medium absorption during surgery.
Distension medium absorption during surgery

StudyGnRH antagonistGnRH analogueMann-Whitney U test

Bhatia 2008n=50

Median: 300 mL

Range 0 to 2000
n=50

Median: 250 mL

Range 0 to 2000
Mann-Whitney test

P = 0.641

 
Comparison 5. GnRH analogue versus dilatation & curettage

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 2 Normal bleeding or less at 12 months192Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.91, 1.16]

    2.1 at 12 months of follow-up
192Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.91, 1.16]

 3 Postoperative amenorrhoea at 12 months or less192Risk Ratio (M-H, Fixed, 95% CI)20.13 [1.21, 333.63]

    3.1 at 12 months of follow-up
192Risk Ratio (M-H, Fixed, 95% CI)20.13 [1.21, 333.63]

 4 Requiring further surgery within 12 months of follow-up1100Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.18, 3.18]

    4.1 at one year of follow-up
1100Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.18, 3.18]

 6 Side effects—presence of PMS symptoms193Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.67, 1.58]

    6.1 at one year of follow-up
193Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.67, 1.58]

 7 Postoperative dysmenorrhoea192Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.66, 1.52]

    7.1 at one year of follow-up
192Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.66, 1.52]

 8 Satisfaction with outcome192Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.83, 1.05]

    8.1 at 12 months of follow-up
192Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.83, 1.05]

 
Comparison 6. Danazol versus no pretreatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 2 Postoperative amenorrhoea at 12 months or less2179Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.80, 1.39]

    2.1 one month of therapy
1129Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.68, 1.34]

    2.2 two months of therapy
150Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.82, 2.08]

 3 Postoperative amenorrhoea at two years or more281Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.79, 2.04]

    3.1 one month of therapy
281Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.79, 2.04]

 4 Requiring further surgery at two years or more2152Risk Ratio (M-H, Fixed, 95% CI)1.37 [0.28, 6.69]

    4.1 one month of therapy
2152Risk Ratio (M-H, Fixed, 95% CI)1.37 [0.28, 6.69]

 5 Endometrial thickness (ultrasound)2Mean Difference (IV, Random, 95% CI)Totals not selected

    5.1 one month of therapy
2Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 6 Endometrial thickness (descriptive data)Other dataNo numeric data

    6.1 two months of therapy
Other dataNo numeric data

 7 Atrophic endometrial glands270Risk Ratio (M-H, Fixed, 95% CI)3.15 [1.46, 6.80]

    7.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)17.0 [1.11, 259.87]

    7.2 two months of therapy
150Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.89, 4.49]

 8 Optimal endometrial thinning (operator assessment)120Risk Ratio (M-H, Fixed, 95% CI)6.0 [0.87, 41.21]

    8.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)6.0 [0.87, 41.21]

 10 Duration of operation (minutes)2157Mean Difference (IV, Fixed, 95% CI)-6.84 [-7.97, -5.72]

    10.1 one month of therapy
1132Mean Difference (IV, Fixed, 95% CI)-7.90 [-9.13, -6.67]

    10.2 two months of therapy
125Mean Difference (IV, Fixed, 95% CI)-1.30 [-4.12, 1.52]

 11 Distension medium absorption during surgery (mL)2156Mean Difference (IV, Fixed, 95% CI)-109.45 [-193.25, -25.65]

    11.1 one month of therapy
1132Mean Difference (IV, Fixed, 95% CI)-119.90 [-209.00, -28.80]

    11.2 two months of therapy
124Mean Difference (IV, Fixed, 95% CI)-52.0 [-265.65, 161.65]

 12 Satisfaction with outcome150Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.93, 1.08]

    12.1 two months of therapy
150Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.93, 1.08]

 
Analysis 6.6 Comparison 6 Danazol versus no pretreatment, Outcome 6 Endometrial thickness (descriptive data).
Endometrial thickness (descriptive data)

StudyDanazolControlMann-Whitney U test

two months of therapy

Rai 2000n=25

Median: 1.5 mm

Range: 1 - 3.5
n=25

Median: 2 mm

Range: 0.5 - 4
p=0.02

 
Comparison 7. Progestogens versus no pretreatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 2 Postoperative amenorrhoea at 12 months or less150Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.26, 1.12]

    2.1 two months of therapy
150Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.26, 1.12]

 3 Postoperative amenorrhoea at two to four years270Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.36, 1.54]

    3.1 one month of therapy
270Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.36, 1.54]

 4 Requiring further surgery at two to four years270Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.50, 17.95]

    4.1 one month of therapy
270Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.50, 17.95]

 5 Endometrial thickness (ultrasound)120Mean Difference (IV, Fixed, 95% CI)0.10 [-0.78, 0.98]

    5.1 one month of therapy
120Mean Difference (IV, Fixed, 95% CI)0.10 [-0.78, 0.98]

 6 Endometrial thickness (descriptive data)Other dataNo numeric data

    6.1 two months of therapy
Other dataNo numeric data

 7 Atrophic endometrial glands270Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.53, 3.25]

    7.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.27, 92.62]

    7.2 two months of therapy
150Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.37, 2.68]

 8 Optimal endometrial thinning (operator)120Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.21, 18.69]

    8.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.21, 18.69]

 11 Satisfaction with outcome150Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.93, 1.08]

    11.1 two months of therapy
150Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.93, 1.08]

 
Analysis 7.6 Comparison 7 Progestogens versus no pretreatment, Outcome 6 Endometrial thickness (descriptive data).
Endometrial thickness (descriptive data)

StudyProgestogensNo treatmentMann-Whitney U test

two months of therapy

Rai 2000n=25

Median: 2 mm

Range: 0.5 - 3
n=25

Median: 2 mm

Range: 0.5 - 4
No p value reported

Not significantly different

 
Comparison 8. Danazol versus progestogens

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 2 Postoperative amenorrhoea at 12 months or less2103Risk Ratio (M-H, Fixed, 95% CI)1.89 [1.12, 3.18]

    2.1 two months of therapy
150Risk Ratio (M-H, Fixed, 95% CI)2.43 [1.23, 4.81]

    2.2 three months of therapy
153Risk Ratio (M-H, Fixed, 95% CI)1.34 [0.58, 3.06]

 3 Postoperative amenorrhoea at two years120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.79, 11.44]

    3.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.79, 11.44]

 4 Requiring further surgery at two years of follow-up120Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 13.87]

    4.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 13.87]

 5 Endometrial thickness (ultrasound)120Mean Difference (IV, Fixed, 95% CI)-3.00 [-3.76, -2.24]

    5.1 one month of therapy
120Mean Difference (IV, Fixed, 95% CI)-3.00 [-3.76, -2.24]

 6 Endometrial thickness (descriptive data)Other dataNo numeric data

    6.1 two months of therapy
Other dataNo numeric data

 7 Atrophic endometrial glands270Risk Ratio (M-H, Fixed, 95% CI)2.5 [1.27, 4.92]

    7.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)4.0 [1.11, 14.35]

    7.2 two months of therapy
150Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.89, 4.49]

 8 Optimal endometrial thinning (operator)120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.79, 11.44]

    8.1 one month of therapy
120Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.79, 11.44]

 10 Duration of operation (minutes)153Mean Difference (IV, Fixed, 95% CI)-11.0 [-14.59, -7.41]

    10.1 three months of therapy
153Mean Difference (IV, Fixed, 95% CI)-11.0 [-14.59, -7.41]

 11 Satisfaction with outcome150Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.93, 1.08]

    11.1 two months of therapy
150Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.93, 1.08]

 
Analysis 8.6 Comparison 8 Danazol versus progestogens, Outcome 6 Endometrial thickness (descriptive data).
Endometrial thickness (descriptive data)

StudyDanazolProgestogensMann-Whitney U test

two months of therapy

Rai 2000n=25

Median: 1.5 mm

Range: 1 - 3.5
n=25

Median: 2 mm

Range: 0.5 - 3
No p value reported

Not significantly different

 
Comparison 9. GnRHa or danazol versus no pretreatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 2 Postoperative amenorrhoea at 12 months or less2280Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.89, 1.43]

 3 Amenorrhoea at five years1154Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.91, 1.20]

 4 Improvement (light bleeding/amenorrhoea) at five years1154Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.98, 1.05]

 5 Requiring further surgery at one year1197Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.06, 15.29]

 6 Requiring further surgery at five years1197Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.32, 1.65]

 7 Endometrial thickness (mm)1197Mean Difference (IV, Fixed, 95% CI)-1.9 [-2.54, -1.26]

 8 Side effects1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 hot flushes
1197Risk Ratio (M-H, Fixed, 95% CI)2.95 [2.02, 4.31]

    8.2 nausea
1197Risk Ratio (M-H, Fixed, 95% CI)2.06 [1.22, 3.48]

    8.3 rashes/itch
1197Risk Ratio (M-H, Fixed, 95% CI)3.88 [1.34, 11.19]

    8.4 weight gain
1197Risk Ratio (M-H, Fixed, 95% CI)2.36 [1.42, 3.94]

 9 Duration of operation (minutes)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    9.1 TCRE + rollerball
190Mean Difference (IV, Fixed, 95% CI)-15.0 [-16.87, -13.13]

    9.2 microwave
1197Mean Difference (IV, Fixed, 95% CI)0.40 [-0.89, 1.69]

 10 Postoperative menorrhagia2280Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.22, 2.93]

 11 Satisfaction with outcome at 12 months of follow-up1188Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.87, 1.05]

 12 Satisfaction with outcome at five years1154Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.83, 1.06]

 
Summary of findings for the main comparison. GnRH analogues compared with placebo or no treatment for heavy menstrual bleeding

GnRH analogues compared with placebo or no treatment for heavy menstrual bleeding

Patient or population: women with heavy menstrual bleeding
Settings:
Intervention: GnRH analogues
Comparison: placebo or no treatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Placebo or no treatmentGnRH analogues

Postoperative amenorrhoea at 12 months or lessStudy populationRR 1.58
(1.24 to 2.01)
605
(seven studies)
⊕⊝⊝⊝
very low1,2,3

246 per 1000389 per 1000
(305 to 494)

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Few studies were blinded, and only one study had good quality.
2Moderate heterogeneity.
3Mostly small studies.
 
Summary of findings 2. GnRH analogues compared with danazol for heavy menstrual bleeding

GnRH analogues compared with danazol for heavy menstrual bleeding

Patient or population: women with heavy menstrual bleeding
Settings:
Intervention: GnRH analogues
Comparison: danazol

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

DanazolGnRH analogues

Postoperative amenorrhoea at 12 months or less348 per 1000408 per 1000
(314 to 530)
RR 1.17
(0.9 to 1.52)
340
(five studies)
⊕⊝⊝⊝
very low1,2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1No trials were blinded, and only one had adequate allocation concealment.
2Substantial heterogeneity.
 
Summary of findings 3. GnRH analogues compared with progestogens for heavy menstrual bleeding

GnRH analogues compared with progestogens for heavy menstrual bleeding

Patient or population: women with heavy menstrual bleeding
Settings:
Intervention: GnRH analogues
Comparison: progestogens

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ProgestogensGnRH analogues

Postoperative amenorrhoea at 12 months or less258 per 1000408 per 1000
(248 to 674)
RR 1.58
(0.96 to 2.61)
146
(three studies)
⊕⊝⊝⊝
very low1,2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1One trial had adequate allocation concealment, and none reported blinding.
2Wide confidence intervals with limited number of participants.
 
Summary of findings 4. GnRH analogue compared with GnRH antagonist for heavy menstrual bleeding

GnRH analogue compared with GnRH antagonist for heavy menstrual bleeding

Patient or population: women with heavy menstrual bleeding
Settings:
Intervention: GnRH analogue
Comparison: GnRH antagonist

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

GnRH antagonistGnRH analogue

Postoperative amenorrhoea at 12 months or less840 per 1000798 per 1000
(664 to 958)
RR 0.95
(0.79 to 1.14)
100
(one study)
⊕⊕⊕⊝
moderate1

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1One trial with small population.
 
Summary of findings 5. GnRH analogue compared with dilatation & curettage for heavy menstrual bleeding

GnRH analogue compared with dilatation & curettage for heavy menstrual bleeding

Patient or population: women with heavy menstrual bleeding
Settings:
Intervention: GnRH analogue
Comparison: dilatation & curettage

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Dilatation & curettageGnRH analogue

Postoperative amenorrhoea at 12 months or less0 per 10000 per 1000
(0 to 0)
RR 20.12
(1.21 to 333.63)
92
(one study)
Very low quality1

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1No blinding of participants; selective reporting and small sample size in only one study.
 
Summary of findings 6. Danazol compared with no pretreatment for heavy menstrual bleeding

Danazol compared with no pretreatment for heavy menstrual bleeding

Patient or population: women with heavy menstrual bleeding
Settings:
Intervention: danazol
Comparison: no pretreatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

No pretreatmentDanazol

Postoperative amenorrhoea at 12 months or less517 per 1000543 per 1000
(414 to 719)
RR 1.05
(0.8 to 1.39)
179
(two studies)
⊕⊕⊝⊝
low1,2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1One trial had adequate description of randomisation, the other had adequate allocation concealment, but neither reported blinding.
2Limited number of participants.
 
Summary of findings 7. Progestogens compared with no pretreatment for heavy menstrual bleeding

Progestogens compared with no pretreatment for heavy menstrual bleeding

Patient or population: women with heavy menstrual bleeding
Settings:
Intervention: progestogens
Comparison: no pretreatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

No pretreatmentProgestogens

Postoperative amenorrhoea at 12 months or less520 per 1000281 per 1000
(135 to 582)
RR 0.54
(0.26 to 1.12)
50
(one study)
⊕⊕⊝⊝
low1,2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Adequate allocation concealment but not clear if blinded.
2One trial with few participants.
 
Summary of findings 8. Danazol compared with progestogens for heavy menstrual bleeding

Danazol compared with progestogens for heavy menstrual bleeding

Patient or population: women with heavy menstrual bleeding
Settings:
Intervention: danazol
Comparison: progestogens

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ProgestogensDanazol

Postoperative amenorrhoea at 12 months or less269 per 1000509 per 1000
(302 to 856)
RR 1.89
(1.12 to 3.18)
103
(two studies)
⊕⊕⊝⊝
low1,2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Only one of two trials had adequate allocation concealment, and neither trial reported blinding.
2Both trials had limited numbers of participants.
 
Summary of findings 9. GnRHa or danazol compared with no pretreatment for heavy menstrual bleeding

GnRHa or danazol compared with no pretreatment for heavy menstrual bleeding

Patient or population: women with heavy menstrual bleeding
Settings:
Intervention: GnRHa or danazol
Comparison: no pretreatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

No pretreatmentGnRHa or danazol

Postoperative amenorrhoea at 12 months or less428 per 1000483 per 1000
(381 to 611)
RR 1.13
(0.89 to 1.43)
280
(two studies)
⊕⊕⊝⊝
low1,2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1One of two trials had adequate allocation concealment, but neither trial reported blinding.
2Only two trials with limited numbers of participants.