Study characteristics

Methods

Trial design: Randomised, multiple arm trial.

Participants

Participants: 54 randomised

Inclusion criteria: aged 22 to 43 years, with laparoscopically confirmed endometriosis,

14 reguarly menstruating women and 11 post‐menopausal women no on HRT and with no history of post‐menopausal bleeding, endometrial or ovarian carcinoma were comparisons.

Exclusion critieria:

Setting: UK and Spain

Timing:

Interventions

Danazol 600 mg per day for six months (n=20)

versus

Buserelin 400 mcg 8 hourly intranasally for six months (n=15)

versus

Zoladex depot 3.6 mg intramuscularly monthly for six months (n=19)

Outcomes

This trial did not report on any outcomes of interest for this review.

Serum CA 125 levels

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomised" no further details

Allocation concealment (selection bias)

Unclear risk

No details on methods used to conceal allocation to study groups.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No details of blinding of study personnel or participants

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

43/54 participants had 3 and 6 month blood samples.

Selective reporting (reporting bias)

High risk

This paper states that all patients were part of randomised studies assessing the efficacy of Danazol, Buserelin, and Zoladex in the treatement of endometriosis but does not reference these trials.

Study characteristics

Methods

Trial design: Prospective randomised double blind controlled study

Participants

Participants: 213 patients. 124 patients were randomised who reported pain symptoms

Mean age:

Inclusion: aged 18 to 48 years with laparoscopically confirmed pelvic endometriosis and dysmenorrhoea, dyspareunia or pelvic pain.

Exclusion: no surgical procedures were performed during the diagnostic laparoscopy, no patient who had received hormonal treatment during the previous 6 months.

Setting:

Timing:

Interventions

Nafarelin acetate 400mcg bid IN + placebo PO or 6 months (n=45)
versus
Nafarelin acetate 200mcg bid IN + placebo PO for 6 months (n=45)
versus
Danazol 400mg bid PO + placebo IN for 6 months (n=34)

Outcomes

Pain: dysmenorrhoea, dyspareunia, pelvic pain.

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors responded to methods query

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computerised randomisation

Allocation concealment (selection bias)

Low risk

Centralised randomisation, sequentially numbered, sealed opaque envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

All patients received placebo so patients and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All women randomised were analysed with intention to treat for main outcome

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: "Multicentre, randomised, double‐blind, double‐placebo study"

Participants

Participants: 208 women were randomised, 192 were analysed

Mean age: Nafarelin = 29.8 ± 0.6 and LA = 31.7 ± 0.6 (SEM)

Inclusion criteria:

• Laparoscopically diagnosed endometriosis within 18 months prior to study19‐44 years old

• Patients demonstrating clinical symptoms and signs

• Bone mineral density within normal age range

Exclusion criteria:

• Conditions or drug therapies that may interfere with the study

• Pregnant or lactating women

• Danazol use within 6 months prior to study

• GnRHa use within 12 months prior to study

• OCP within 30 days prior to study treatment

• Thyroid disease

Setting: United States of America

Timing:

Interventions

Nafarelin 200mcg BD IN + placebo every 4 weeks IM for 6 months (n=105)

versus

LA Depot 3.75mg every 4 weeks IM + placebo BD IN for 6 months (n=103)

Outcomes

Pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

'Randomisation using permuted blocks of random numbers'

Allocation concealment (selection bias)

Unclear risk

No details were provided of method used to conceal allocation to treatment group.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Placebo nasal spray and injection, "Subjects remained blind regarding the study medication and assignment, and the study coordinator and investigator remained blind as to subject treatment status by having injections prepared and administered by a third party"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Details for attrition:
24 women withdrew due to:ineffectiveness 3 (Naf) and 3 (LA), adverse effects 4 (Naf) and 8 (LA), lost to follow up 5 (LA), administrative reasons 1 (LA)

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: 'Multicentre, open, randomised study'

Participants

Participants: 71 women were randomised, 48 were analysed

Mean age: Goserelin = 29.5 and Danazol = 29.85

Stage: I to IV

Inclusion criteria:

• Laparoscopically diagnosed endometriosis within 2 months prior to study

• 18‐40 years old

• rAFS score of equal or greater to 2

• Normal menstrual cycle (21 ‐ 42 days)

• Normal cervical smear for previous 12 months

Exclusion criteria:

• Pregnant or lactating women

• Other medical illnesses

• Hormone use within 2 months prior to study

• Danazol or GnRHa use within 12 months prior to study

• Hypersensitivity to trial drugs

• Showing signs of virilization

• Taking anticoagulant therapy

• Surgical treatment

Setting: Australia and New Zealand

Timing: Not stated

Interventions

Goserelin acetate 3.6mg every 4 weeks SC for 24 weeks (n=35)
versus

Danazol 200mg TDS PO for 24 weeks (n=36)

Outcomes

Pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration
rAFS score
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted regarding methods and data, awaiting response

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Patients were randomised in a 1 to 1 ratio". No further details of method used to generate the randomisation sequence are provided.

Allocation concealment (selection bias)

Unclear risk

No details were provided of method used to conceal allocation to treatment groups.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Open label trial as blinding of study personnel and participants would not have been possible due to nature of intervention.

No details provided of blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"Analysis was performed on both an 'intention to treat' basis and also on a 'patient treated' basis
details given for attrition:
19 in Danazol and 4 in Goserelin group withdrew due to: Adverse effect 9 (Dan), Unwilling to continue 8 (Dan) and 4 (Gos), Withdrawn by investigator 1 (Dan), Other 1 (Dan)

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Open, multi‐centre, central randomised study

Participants

Participants: 120 eligible women; 71 were randomised; 55 were analysed

Mean age: 31 ± 5.9 years

Stage: I ‐ IV

Inclusion criteria:

• Laparoscopically diagnosed endometriosis

• Symptomatic

• Recurrence of endometriosis after surgery

• Over 18 years old

• No other hormone therapy except insulin

Exclusion criteria:

• Amenorrhoea

• Patient having had hysterectomy

• Pregnant women

• Serious illness e.g. liver disease

Setting: France

Timing:

Interventions

Leuprorelin 3.75mg SC depot every 28 days for 24 weeks (n=33)
versus
Danazol 600‐800mg PO daily for 24 weeks (n=22)

Outcomes

Pain: dysmenorrhoea, dyspareunia, pelvic pain, induration and pelvic tenderness
rAFS score
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Cannot use data unless mean and SD specified; author contacted. Author replied that study was sponsored by a pharmaceutical company who hold the raw data. He is attempting to locate a contact for further information.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Central randomisation"

Allocation concealment (selection bias)

Low risk

"Central randomisation"

Blinding (performance bias and detection bias)
All outcomes

High risk

Open study as blinding would not have been possible due to nature of intervention. No mention of blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Sufficient reporting of attrition:

• Refuse 2nd laparoscopy n=1 (L)

• Lost to follow up n=2 (L) n=9 (D)

• Progression of disease n=2 (D)

• Not meeting protocol n=1 (D)

• Other n=1 (D)

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design:

Participants

Participants:

Mean age:

Inclusion criteria:

Exclusion criteria:

Setting:

Timing:

Interventions

Intervention:

Comparison:

Outcomes

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Study characteristics

Methods

Trial design: "Double‐blind randomised study"

Participants

Participants: 49 eligible women; 49 were randomised and 47 were analysed

Mean age: mean age not stated, median age 30 years (range 21‐46years)

Inclusion criteria:

• Laparoscopically diagnosed endometriosis

• Not to use any hormonal preparations during study

• No hormone treatment in previous 3 months

• No GnRHas for previous 12 months

• No steroid therapy for previous 12 months

Exclusion criteria:

Setting: Europe

Timing: not stated

Interventions

Nafarelin 200mcg daily IN + placebo PO for 6 months (n=12)
versus
Nafarelin 400mcg daily IN + placebo PO for 6 months (n=12)
versus
Nafarelin 200mcg daily IN + norethisterone 1.2mg daily PO for 6 months (n=25)

Outcomes

Pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration
Adverse effects
AFS score

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Need raw data for symptom scores. Authors contacted regarding methods and data. No response to date.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

1:1:2 Naf200:Naf400:Naf200+Norethisterone "randomisation was carried out on a block basis"

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment group.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Participants and study personnel were blinded to treatment through the use of a placebo

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Two participants from the Naf+Norethisterone group withdrew from the trial due to mood swings (1 participant) and pregnancy (1 participant),

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: "Prospective, randomised, placebo‐controlled, double‐blind, parallel study"

Participants

Participants: 49 women eligible; 49 were randomised and 46 were analysed

Age: mean of 31 years (19‐44years)

Stage: most mild to moderate (IV n=1)

Inclusion criteria:

• Menstruating regularly 3 months before study

• Clinical symptoms of endometriosis

• Not taken oral contraceptive or oral steroid therapy for 3 months

• Not taken long acting depot gestagens or GnRHas within past 6 months

• Not pregnant in prior 3 months

• Not breastfeeding

• No history of osteoporosis or coagulation disorders

Exclusion criteria:

• Intraperitoneal adhesions making visual inspection and careful evaluation of the extension of endometriotic lesions difficult or impossible

Setting: Sweden

Timing:

Interventions

Triptorelin 3.75mg IM depot every 4 weeks for 24 weeks (n=24)
versus
Placebo IM every 4 weeks for 24 weeks (n=25)

Outcomes

Pain
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Needs raw score for pain. Authors contacted and awaiting response.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details were provided of method used to generate the randomisation sequence.

Allocation concealment (selection bias)

Unclear risk

No details were provided of method used to conceal treatment group allocation.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Participants and researchers were blinded through the use of identical kits for injections.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Three participants withdrew from the study. Two from the placebo group (1 prior to the first injection due to pregnancy, and one after 4 months due to lack of effect), and one from the Triptorelin group due to hypoestrogenic side effects and depression.

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design:

Participants

Participants:

Mean age:

Inclusion criteria:

Exclusion criteria:

Setting:

Timing:

Interventions

Intervention:

Comparison:

Outcomes

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Study characteristics

Methods

Trial design: "Multi‐centre, double‐blind study"

Participants

Participants: 169 women eligible; 169 were randomised and 147 analysed for efficacy

Mean age:

Inclusion criteria:

• Laparoscopically diagnosed endometriosis

Exclusion criteria:

Setting: USA

Timing:

Interventions

Nafarelin 400mcg daily IN for 6 months (n=111)
versus
Danazol 600mg daily PO for 6 months (n=58)

Outcomes

Symptoms
Change in laparoscopic scores
Adverse effects
Quality of life score

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Need more info on randomisation and participants and raw data for quality of life. Authors contacted, awaiting response.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

2:1 Nafarelin: Danazol

Allocation concealment (selection bias)

Unclear risk

No details

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

"double‐blind"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Sufficient details for attrition:

• Side effects n=6 (N) n=3 (D)

• Elevated liver enzyme n=1 (D)

• Administrative reasons n=12

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Randomised, no further detail.

Participants

Participants: 15 participants with laparoscopically diagnosed endometriosis

Mean age:

Inclusion criteria:

Exclusions criteria:

Setting: Mexico

Timing:

Interventions

Goserelin acetate 3.6 mg every 21 days (n=8) average age 29 years

Nafarelin acetate 200 or 400 mcg 12 hourly for six months (n=7) average age 30.4 years

Outcomes

Serum levels of follicle stimulating hormone, luteinising hormone, estradiol and prolactin.

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Article in Spanish. Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details provided of method used to generate random sequence.

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment group

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No details provided of blinding of participants or personnel.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow up.

Selective reporting (reporting bias)

Unclear risk

Insufficient information to enable a judgement of low risk of bias.

Study characteristics

Methods

Trial design: "Randomised comparative study"

Participants

Participants: 45 women eligible; 45 were randomised and 33 were analysed

Mean age: 33 years (LA)

Stage: I to IV

Inclusion criteria:

• Laparoscopic diagnosis of endometriosis

• Pain symptoms

Exclusion criteria:

Setting: Taiwan

Timing:

Interventions

Leuprorelin acetate 3.75mg SC depot every 28days for 20 weeks (n=30)
versus
Danazol 200mg QID (800mg/day) PO for 20 weeks (n=15)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain
Change in AFS score
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Need raw data for pain. Authors contacted, and additional methodological data provided, no raw data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomisation was in the ratio two LA to one danazol with this study having its randomisation list"

Allocation concealment (selection bias)

Unclear risk

"sequentially numbered, identical containers of identical drugs"

Blinding (performance bias and detection bias)
All outcomes

Low risk

Outcome assessors were blinded to treatment group

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No details were provided on attrition

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: "Randomised, parallel, comparative study"

Participants

Participants: 59 women eligible; 59 were randomised and 41 were analysed for efficacy

Mean age: 34.8 ± 6.6 (N) and 32.4± 7.2 (D)

Inclusion criteria:

• Laparoscopically diagnosed within 3 months prior to study

• Age 18‐48 years

• Barrier contraception

Exclusion criteria:

• Pregnancy

• Breastfeeding

• Menopause or post‐menopausal

• Use of oestrogen, progesterone or contraceptive steroids in previous 3 months

• Impaired hepatic or renal function

• Cardiovascular disease

• AIDS or other sexually transmitted diseases

Setting: Taiwan

Timing:

Interventions

Nafarelin acetate 200mcg BD (400mcg/day) IN for 180 days (n=29)
versus
Danazol 200mg TID (600mg/day) PO for 180 days (n=30)

Outcomes

Total symptom severity score and physician assessed pelvic tenderness
Change in laparoscopic score
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors provided additional data on methods

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation done by a pharmacy

Allocation concealment (selection bias)

Low risk

Sealed, opaque, sequentially numbered, identical envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Investigators, outcome assessors and clinicians were blinded according to author

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"All 59 patients were considered as the intent‐to‐treat population"

• 4 withdrawals due to:

• Three patients (3/4) underwent Herb drug treatment, withdrawals

• All patients (4/4) were anxious with side effects, including significant weight gain, acne vagaries, and severe menopausal syndrome.

• One patient went abroad after randomisation

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Parallel arm, randomised controllled trial

Participants

Participants: 14 women eligible

Age: Group 1 29.3 ±6.1, Group 2 28.9 ±1.7

Inclusion: Women with laparoscopically confirmed endometriosis

Severe dysmenorrhea with or without deep dysparunia and pelvic pain

Exclusion: Prior hormonal treatment

Planning to conceive in the next one to two years

Setting: Thailand

Timing:

Interventions

Buserelin acetate 6.6 mg implants injected subcutaneously in the lateral region of the anterior abdominal wall:

Group 1: every 8 weeks for 3 doses (n=7)

Group 2: every 12 weeks for 2 doses (n=7)

Outcomes

Serum estradiol, bone mineral density

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information provided to enable a judgement of low risk.

Allocation concealment (selection bias)

Unclear risk

Insufficient information provided to enable a judegment of low risk.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No details provided of blinding of participants or personnel.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No losses to follow up.

Selective reporting (reporting bias)

Low risk

All prespecified outcomes are reported on.

Study characteristics

Methods

Trial design: "controlled comparative clinical study"

Participants

Participants: 60 women eligible; 60 were randomised and 55 were analysed

Mean age: 30± 0.5 (T) and 30± 0.8 (D)

Stage: II to IV

Inclusion criteria:

• Laparoscopically diagnosed endometriosis

• No medication affecting pituitary or ovarian function in preceding 6 months

Exclusion criteria:

• Stage I endometriosis

Setting: Germany

Timing:

Interventions

Triptorelin 3.75mg IM depot every 28 days for 24 weeks (n=30)
versus
Danazol 200mg TDS (600mg/day) PO for 24 weeks (n=25)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration
Adverse effects
Change in AFS score

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted and awaiting response regarding methods.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer generated randomisation list

Allocation concealment (selection bias)

Unclear risk

No details

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No details

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Sufficient detail for attrition:

• Refused to fulfil protocol n=3 (D)

• Pregnancy n=2 (D)

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: "Ongoing, Phase III, multi‐centre, double‐blind, double‐dummy study"

Participants

Participants: 24 women were randomised, 23 were analysed
Mean age: 33.9 (N) and 32.6 (D)

Inclusion criteria:

Exclusion criteria:

Setting: Sweden

Timing

Interventions

Nafarelin 400mcg daily IN for 6 months (n=16)
versus
Danazol 600mg daily PO for 6 months (n=8)

Outcomes

Pain, dysmenorrhoea, dyspareunia
Changes in AFS score

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted with regards to methods and raw data. Awaiting response.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No details, "double blind, double dummy"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Sufficient data on attrition:

• Intercurrent lower back pain n=1 (N)

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Parallel arm, randomised controlled trial

Participants

Participants: 30 women randomised (Group 1 ‐ three monthly leuprolide n = 15, Grou p2 ‐ monthly leuprolide n = 15)

27 women analysed (Group 1 ‐ three monthly leuprolide n = 14, Group 2 ‐ monthly leuprolde n = 13)

Mean age: Group 1: 28.6 ± 6.0, Group 2: 31.0 ± 5.2

Inclusion: Premenopausal women (FSH < 30 mIU/ml), aged 18‐38, symptomatic endometriosis at stage I ‐ IV of the revised American Fertility Society (rAFS) classification, diagnosed at laparoscopy.

Exclusion: any major disease

Setting: Univeristy clinics in Milan, Genoa, Rome, Italy.

Timing: timing of recruitment not stated.

Interventions

Intervention: Leuprolide acetate 11.25 mg intramuscularly every 84 days (group 1) for 6 months

Comparison: Leuprolide acetate 3.75 mg every 28 days (group 2) for 6 months.

Outcomes

Pain symptoms according to Biberoglu and Behrman varbal rating scale,

rAFS score, bone mineral density, acceptability of treatment schedule.

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Was previously excluded for pain not being an outcome but ????should be included as pain score is an outcome

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Eligible subjects were randomised according to a computer generated sequence

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment groups.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

"open label trial"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

One woman from group 1 (three monthly) withdrew from study as she did not want to undergo repeated venipunctures and laparoscopy. Two women in group 2 (monthly) stopped treatment due to a desire to conceive.

Selective reporting (reporting bias)

Low risk

All prespecified outcome are reported on.

Study characteristics

Methods

Trial design: Multi‐centre, open, randomised study

Participants

Participants: 355 women eligible and 310 were analysed

Mean age:

Inclusion criteria:

• Age 20‐40 years old

• Laparascopically diagnosed endometriosis within 6 weeks of study entry

Exclusion criteria:

• Danazol treatment in last 6 months

• Oral contraceptives in last 2 months

• Drugs releasing IUD in last 3 months

• Any other investigational drug in 4 weeks

• Conditions for which danazol is contraindicated

Setting: USA

Timing: Not stated

Interventions

Buserelin 400mcg TDS (1200mcg/day) IN for 6 months (n=149)
versus
Buserelin 200mcg daily SC for 6 months (n=60)
versus
Danazol 400‐800mg daily PO for 6 months (n=101)

Outcomes

Intermenstrual pelvic pain, dyspareunia, pelvic tenderness and induration
Changes in rAFS score
Adversse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted regarding methods and raw data for pain.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"assigned to... treatment groups according to a randomisation schedule" 2:1 Buserelin: Danazol. No other details are provided of method used to generate random sequence.

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment groups.

Blinding (performance bias and detection bias)
All outcomes

High risk

Open study

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No details on attrition

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: "Phase III, randomised, double‐blind, multi‐centre study"

Participants

Participants: 63 women eligible; 63 were randomised and 52 were analysed

Mean age: 30 years

Stage: I to IV

Inclusion criteria:

• Laparoscopically diagnosed endometriosis within 3 months of study entry

• Pain secondary to endometriosis

• Over 18 years old

• No previous treatment with leuprolide acetate or other GnRHas

• At least one ovary intact

• Non pregnant

• Non lactating

• No treatment for endometriosis within 3 months of study entry

Exclusion criteria:

Setting: USA

Timing: Not stated.

Interventions

Leuprolide acetate 3.75mg IM depot every 4 weeks for 20 weeks (n=32)
versus
Placebo (diluent) 2ml IM every 4 weeks for 20 weeks (n=31)

Outcomes

Dysmenorrhoea, pelvic pain, dyspareunia, pelvic tenderness, induration

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted for details on allocation concealment and SEMs. Letter returned to sender, author moved with no forwarding address.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Patients were assigned a 3 digit patient number in sequential order from those numbers allocated to each investigator. The patient number encoded the random assignment to a treatment group"

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment group.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Patients and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Sufficient details for attrition:
7 withdrawn as subsequently determined they had failed to meet entry requirements, 4 excluded because they had received less than 3 injections of the study drug.
There were partial exclusions for efficacy data due to non‐compliance with intended study procedures and dosing regimens for 15 patients (7=Leuprolide and 8=placebo).
27 placebo (24 terminated because of worsened symptoms, 1 because of salpingitis, 1 became pregnant and 1 was non‐compliant) and 3 (2 because of intolerable pain and 1 because of an adverse event) leuprolide patients prematurely terminated study.

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: "Open‐label, randomised, prospective study"

Participants

Participants: 36 women eligible, 36 were randomised and 29 were analysed

Mean age: 30.8 ± 0.6 (SE)

Inclusion Criteria: Laparoscopically diagnosed endometriosis, no hormonal treatment 8 months prior to study entry

Exclusion criteria: not stated

Setting: USA

Timing: Not stated.

Interventions

Buserelin 400mcg TDS (1200mcg/day) IN for 6 months (n=10)
versus
Buserelin 200mcg daily SC for 6 months (n=9)
versus
Danazol 200mg QDS (800mg/day) PO for 6 months (n=10)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain
Change in rAFS scores
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted regarding allocation concealment

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details were provided of the method used to generate the randomisation sequence.

2:1 Buserelin: Danazol

"Those who were randomised into Buserelin were given an option of SC injections or IN sprays of the drug"

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal the allocation to treatment groups.

Blinding (performance bias and detection bias)
All outcomes

High risk

"open label"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detail for attrition:
3 in SC Buserelin, 2 in IN Buserelin and 2 in Danazol group. 2 withdrew for family reasons, 3 were non‐compliant, 1 had sever emotional side effects on IN Buserelin and 1 was allergic to Danazol.

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Prospective, parallel, randomised controlled trial.

Participants

Participants: 100 women randomised (50 per group). All women randomised appear to have been analysed,

Mean age: Group 1: 27.3 ± 4.4, Group 2: 28.2 ± 5.2

Inclusion:

Exclusion:

Setting: Belgium

Timing: January 1985 ‐ December 1987

Interventions

Intervention: Intranasal Buserelin spray 300 μg three times a day for 6 months (n = 50).

Comparison: Biodegradable implant containing 6.6 mg Buserelin injected subsutaneously at 0, 6 and 12 weeks (n = 50).

Outcomes

Change in AFS scores between start and end of treatment.

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

States "randomized" with no further information of method used to generate the randomisation sequence.

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment groups.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding of participants and personnel was not possible due to nature of intervention and comparison. Pre and post treatment assessment was carried out by the same observer, however no details are provided as to whether the observer was blinded to treatment group.

Study characteristics

Methods

Trial design: Prospective, open label randomised controlled trial.

Participants

Participants: 20 women were randomised and analysed (10 per treatment group. There was also a control group of 250 'normal' women)

Mean age: GnRA Group: 31.0 ± 1.1. Danazol Group: 30.7 ± 1.5, Control Group: 31.0 ± 1.0

Inclusion: Laparoscopically diagnosed and staged endometriosis.

Exclusion: History and/or symptoms of autoimmune disease, acute or chronic infection, malignancy, or drug abuse,

Setting: Chicago, IL, USA

Timing: Not stated

Interventions

Intervention: GnRA Group (n=10): Four participants received Buserelin intranasally 0.4 mg three times a day, four received Buserelin subcutaneously 0.2 mg daily, and two received Leuprolide intranasally 1.6 mg daily for 6 months.

Danazol Group (n=10): Danazol 200 mg four times a day

Outcomes

Autoantibody production, clinical outcome

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Patient assignment was at random". No further details provided of method used to generate random sequence.

Allocation concealment (selection bias)

Unclear risk

Method used to conceal allocation to treatment groups not provided.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Open label trial. All serum collections were coded and stored at a laboratory until tested simultaneously after all data had been reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow up reported.

Selective reporting (reporting bias)

Low risk

Prespecified outcomes are reported on.

Study characteristics

Methods

Trial design: Randomised controlled study

Participants

Participants: 62 women were randomised and analysed

Mean age: Buserelin = 29.8 ± 3.3 and Danazol 31.3 ± 4.3

Inclusion criteria:

• Laparoscopically diagnosed endometriosis within 3 months prior to study

• No therapeutic intervention

Exclusion criteria:

• Bilateral tube occlusion or partner with severe dyspermia

• Danazol or other sex hormone use within 6 months prior to study

• Systemic or endocrine disease

Setting: Italy

Timing:

Interventions

Buserelin 400mcg TDS IN for 6 months (n=30)
versus
Danazol 200mg TDS PO for 6 months (n=32)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain
rAFS score
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted for information on raw data for pain scores, and methods. No response to date

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No details

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detail for attrition:

• 1 subject from Buserelin group withdrew due to severe pelvic pain

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Multicentre, randomised controlled study

Participants

Participants: 35 women eligible, 35 were randomised, 35 were analysed

Mean age: not stated

Inclusion criteria:

• Laparoscopically diagnosed stage I or II endometriosis

• One or more of dysmenorrhoea, pelvic pain and deep dyspareunia

Exclusion criteria:

Setting: Italy

Timing: not stated.

Interventions

Buserelin acetate 1200 mcg daily IN for 6 months (n=19)
versus
Expectant management (n=16)
Treatment group followed up for 18 months and expectant management group for 12 months

Outcomes

Dysmenorrhoea, pelvic pain and deep dyspareunia
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted regarding methodology and data. Still awaiting response.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details provided of method used to generate randomisation sequence.,

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment groups.

Blinding (performance bias and detection bias)
All outcomes

High risk

Blinding was not possible due to the nature of the intervention (Buserelin acetate versus expectant management (no treatment) )

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All women who were randomised were analysed

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Randomised, prospective open labelled study

Participants

Participants: 44 women with endometriosis (confirmed laparoscopically/histologically), consecutively selected at the pain and endoscopy out‐patient clinic.

Mean age: 28.8 ±4.9 years for LNG‐IUS and 41.4±5.8 years for GnRHa

Inclusion criteria: 18‐40 years of age

chronic pelvic pain.

No use of oral hormone contraceptives for at least 3 months or with depot progestogens or GnRHa for at least 6 months prior to randomisation.

Exclusion: obese patients (BMI >30kg/m²), smokers, diabetics, alcohol or drug users, patients wishing to conceive, those with chronic disease, acute and/or chronic inflammatory and/or infectious processes, family history of thromboembolic events, taking medications known to interfere with inflammation markers for a period of less than 15 days before the study.

Setting: Brazil

Timing: not stated.

Interventions

LNG‐IUS (n=22)

versus

GnRHa (n=22) 3.75mg leuprolide i.m. monthly treatment for 6 months

Outcomes

BMI, SAP, DAP, HR, pain score (VAS), inflammatory markers

Notes

No ITT analysis

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

'Randomised by computer programme'

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment group.

Blinding (performance bias and detection bias)
All outcomes

High risk

Open labelled. Blinding not possible due to nature of invtervention and comparison.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

GnRHa (1 pregnancy before drug administered and 3 moved and lost to follow‐up)

Selective reporting (reporting bias)

Low risk

All a priori outcomes discussed

Study characteristics

Methods

Trial design:

Participants

Participants:

Mean age:

Inclusion criteria:

Exclusion critieria:

Setting:

Timing:

Interventions

Intervention:

Comparison

Outcomes

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

This manscript appears to be a secondary analysis of two trials cited in it ??? to check

Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.

Study characteristics

Methods

Trial design: "Double‐blind, double‐dummy, randomised, parallel study"

Participants

Participants: 49 women were randomised and 45 were analysed

Mean age:

Stage: I to III

Inclusion criteria:

• Laparoscopically diagnosed endometriosis

• Symptomatic

• Regular menstrual cycle 24‐36 days

• Not pregnant

• Negative pap smear

• Barrier contraception

Exclusion criteria:

• Concurrent disease which may interfere with drug

• Surgical therapy within 6 months prior to study entry

• Steroid therapy within 3 months prior to study entry

Setting: Australia / New Zealand

Timing: not stated.

Interventions

Nafarelin 200mcg BDS (400mcg/d) IN + placebo PO for 6 months (n=33)
versus
Danazol 200mg TDS (600mg/d) PO + placebo IN for 6 months (n=16)

Outcomes

Dyspareunia, pelvic pain, pelvic tenderness, induration
Change in rAFS score
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted with regards to allocation concealment. Author replied that the data was difficult to find but would try

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Computer generated list of random numbers"

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment groups.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Placebo pill + placebo nasal spray so patient and investigators blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

3 participants "dropped out" of intranasal nafarelin group, no "drop outs" from Danazol group.

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: "randomised, controlled clinical study"

Participants

Participants: 22 women were randomised, 18 were analysed

Mean age: LNG‐IUS = 29.2 +/‐ 5.5 and Lupron = 32.6 +/‐ 5.3

Inclusion criteria:

• Laparoscopically diagnosed endometriosis made 3 months before enrolment in the study

• Chronic pelvic pain that was cyclic

• VAS of 3 or more

• Regular menstrual cycle (25‐35 days) for 3 months or more before study entry

• Had not used any hormonal therapy for at least 3 months before study entry

• Had not taken long acting progestins or GnRHas within the preceding 9 months

• Not pregnant or breastfeeding during the 3 months preceding study

• No osteoporosis, coagulation disorders or contraindications to LNG‐IUS

Exclusion criteria:

• Use of medication outside study

Setting: Brazil

Timing:

Interventions

LNG‐IUS IU for 6 months (n=11)
versus
Lupron Depot 3.75mg IM every 4 weeks for 6 months (n=11)

Outcomes

Pain as defined by VAS
Change in laparoscopic outcome as defined by ASRM

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Computer generated system"

Allocation concealment (selection bias)

Low risk

"Sealed envelopes"

Blinding (performance bias and detection bias)
All outcomes

High risk

Different route of administration of intervention

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detail given for attrition:

• 4 withdrawals due to refusal of second laparoscopy

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: "parallel, randomised, double‐placebo design"

Participants

Participants: 236 women were randomised, 213 analysed
Age: most 30‐40
Stage: 45% had III and IV
Inclusion criteria:
18‐45 years old. Laparoscopically diagnosed endometriosis within 3 months prior to study enrolment. No hormonal treatment for endometriosis 6 months prior to study.

Exclusion critieria:

Setting: USA, Canada, Sweden

Timing: not stated

Interventions

Nafarelin IN 200mcg BD + placebo PO for 6 months (n=77)
versus
Nafarelin IN 400mcg BD + placebo PO for 6 months (n=79)
versus
Danazol PO 400mg BD + placebo IN for 6 months (n=80)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration
AFS score
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted regarding randomisation and allocation concealment

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details provided of method used to generate random sequence.

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment groups.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Placebo nasal sprays and tablets to blind patients and researchers, "both the patients and the investigators were thus blinded regarding the medication"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detail given for attrition:
9 for reasons not related to the study drugs
7 in 800mcg Nafarelin and 4 in Danazol due to hot flushes
2 in Danazol due to rapid rise in serum enzymes
1 in Danazol because of a lack of efficacy

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Randomised study

Participants

Participants: 194 women were randomised, 167 were analysed

Mean age:

Stage: 41% had stage III or IV

Inclusion criteria:

• Laparoscopically diagnosed endometriosis

Exclusion criteria:

Setting: Europe (not further defined)

Timing: not stated

Interventions

Nafarelin 200mcg BD IN (n=104) for 6 months
versus
Danazol 200mgs TDS PO (n=63) for 6 months

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration
rAFS score

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted with regards to methodology and raw scores for pain. No response to date

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No details

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No details

Selective reporting (reporting bias)

Low risk

A priori outcomes presented

Study characteristics

Methods

Trial design: "double‐blind, prospective, multi centre, randomised clinical trial"

Participants

Participants: 179 women were randomised and analysed

Mean age: 3 monthgroup = 31.0 +/‐ 6.1 and 6 month group = 31.3 +/‐ 5.7 (SEM)

Stage: I to IV

Inclusion criteria:

• 18‐46 years old

• Laparoscopically diagnosed endometriosis within 24 months prior to study enrolment

• 24‐36 day menstrual cycle

• Symptomatic endometriosis

Exclusion criteria:

• Hormone treatment 3 months prior to study

• Significant illness or lab test abnormality

• Prior treatment with Nafarelin

• Pregnant or lactating women

Setting: USA

Timing: not stated.

Interventions

Nafarelin 200mcg BD IN for 3 months + placebo IN for 3 months after (n=91)
versus
Nafarelin 200mcg BD IN for 6 months (n=88)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted and replied

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details provided of method used to generate random sequence.

Allocation concealment (selection bias)

Low risk

'randomisation was done by a pharmacy'

Blinding (performance bias and detection bias)
All outcomes

Low risk

Placebo nasal spray to blind participants; participants, investigators, outcome assessors and clinicians were blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants who were randomised were analysed

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: "Open, prospective, randomised, parallel study", multi centre

Participants

Participants: 80 women were randomised, 68 were analysed

Median age: Buserelin = 28 and Danazol = 30 (? range)

Inclusion criteria:

• Laparoscopically diagnosed endometriosis

• 18 ‐ 40 years old

• Symptomatic disease

• Active menstrual cycle

Exclusion criteria:

• Previous use of danazol or hormone treatment without success

• Use of danazol within 6 months prior to study

• Serious endocrine disease or use of other drugs which may interfere with therapy

Setting: UK

Timing:

Interventions

Buserelin 300mcg TDS IN for 7 months (n=34)
versus
Danazol 600mg OD PO for 7 months (n=34)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration
rAFS score
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Preliminary findings for the first 68 women treated only

Attempted to contact author regarding data. Author not contactable

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"The code was derived from random number tables"

Allocation concealment (selection bias)

Low risk

"A sealed envelope was provided for each patient, and opened only after the patient's name had been entered on it"

Blinding (performance bias and detection bias)
All outcomes

High risk

Open study

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detail for attrition:

• 1 randomised patient failed to start treatment as her symptoms improved

• So far 4 have withdrawn from study due to adverse effects: 3 (Dan) and 1 (Bus)

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Randomised study

Participants

Participants: 13 women were randomised and analysed

Age: 24 ‐ 37

Inclusion criteria:

• Laparoscopially diagnosed endometriosis within 6 weeks of study

• Not received medical treatment in the previous 6 months

Exclusion criteria:

• Surgery alone or hormonal treatment and surgery were indicated

• Concurrent serious endocrine or systemic disease

• History of alcohol or substance abuse

• Use of an oral contraceptive within the past 2 months

• Drug‐releasing intrauterine device within the past 3 month

Setting: Canada

Timing:

Interventions

Buserelin 400mcg TDS IN for 6 ‐ 9 months (n=7)
versus
Buserelin 200mcg OD SC injection for 6 ‐ 9 months (n=6)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration
AFS score
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Author contacted regarding methods and replied

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computerised allocation

Allocation concealment (selection bias)

Low risk

Sealed, opaque, sequentially numbered, identical envelopes

Blinding (performance bias and detection bias)
All outcomes

High risk

Only outcome assessors were blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants who were randomised were analysed

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: randomised controlled trial

Participants

Participants: 30 women randomised,

Mean age: 31 years

Inclusion criteria: laparoscopically diagnosed endometriosis

Exclusion criteria: not stated

Setting: London, UK

Timing: not stated

Interventions

Intervention: Danazol 200 mg orally three times a day (total dose of 600 mg daily) for six months.

Comparison: Goserelin 3.6 mg monthly subcutaneously for six months.

Outcomes

Serum hormone concentrations

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details provided of the method used to generate the random sequence.

Allocation concealment (selection bias)

Unclear risk

No details provided of the method used to conceal allocation to treatment group.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No details of blinding, but unlikely due to nature of intervention and comparison.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No details are provided on attrition. All women randomised appear to have been analysed.

Selective reporting (reporting bias)

Unclear risk

All prespecified outcomes are reported on.

Study characteristics

Methods

Trial design: double blind randomised controlled trial

Participants

Participants: 20 women with endometriosis were randomised, 10 women without endometriosis were controls.

Mean age: women with endometriosis 28.6 ± 5.4 years, women without endometriosis 28.1 ± 5.1 years.

Stage I ‐ 7 participants, Stage II ‐ 4 participants, Stage III ‐ 5 participants, Stage IV ‐ 4 participants.

Inclusion criteria: Laparoscopically diagnosed endometriosis.

Exclusion criteria:

Setting: Greece

Timing: 1993 ‐ 1998

Interventions

Intervention: Danazol 200 mg orally three times a day (total dose of 600 mg daily) for six months (n=10).

Comparison: Leuprolide acetate depot IM 3.75 mg every 28 days for six months (n=10).

Outcomes

Serum soluble CD23 concentrations.

Notes

Intention‐to‐treat analysis:

Sample size calculation: The sample size of 10 per group was chosen arbitrarily

Funding:

Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Computerized random‐number generator" used to generate randomisation sequence.

Allocation concealment (selection bias)

Low risk

Concealment of allocation to treatment group was achieved by the use of "sealed, numbered, opaque envelopes"

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

States this trial is double masked, but no details are provided of who was blinded and how.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants randomised were analysed.

Selective reporting (reporting bias)

Low risk

The prespecificed outcome of serum soluble CD23 concentrations was reported on.

Study characteristics

Methods

Trial design: Randomised, open label, comparative study

Participants

Participants: 61 women were randomised, 56 were analysed

Age: 21‐40

Stage: "varying degrees"

Inclusion criteria:

• Laparoscopically diagnosed endometriosis within 6 weeks prior to study

Exclusion criteria:

• Use of Danazol within past 6 months

• Use of other sex steroid within past 3 months

• Primary surgery indicated

• Serious systemic disease

Setting: UK

Timing: not stated

Interventions

Buserelin 400mcg TDS IN for 6 months (n=41)
versus
Danazol 400‐800mg OD PO for 6 months (n=20)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain
AFS score
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding: Study funded by research grant from Hoechst‐Roussel US

Authors contacted regarding methods, and replied

This manuscript presents provisional data on an incomplete study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

2:1 Buserelin: Danazol, "Recruited patients were randomised by an open‐label method"

Allocation concealment (selection bias)

Low risk

"centralised randomisation process" "sealed opaque sequentially numbered envelopes

Blinding (performance bias and detection bias)
All outcomes

High risk

Open label

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Details given for attrition:

• 4 excluded due to failure to attend follow up

• 1 declined a second look laparoscopy

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: "randomised, double‐blind" study

Participants

Participants: No details of numbers of participants

Inclusion criteria:

• Laparoscopically diagnosed endometriosis

• Experiences significant pain

• No treatment of endometriosis within 3 months prior to study

Exclusion criteria:

Setting: USA

Timing:

Interventions

Lupron depot 3.75mg IM every 4 weeks for 24 weeks
versus
Placebo IM every 4 weeks for 24 weeks

Outcomes

Pain
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Study mentioned in paper referring to two studies

Authors contacted regarding methods and data, awaiting response

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details provided of method used to generate the random sequence.

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment group.

Blinding (performance bias and detection bias)
All outcomes

Low risk

"double‐blind", placebo injection used to blind participant

Incomplete outcome data (attrition bias)
All outcomes

High risk

No details are provided of number of participants.

Selective reporting (reporting bias)

Low risk

Prespecified outcomes discussed

Study characteristics

Methods

Trial design: "prospective, randomised, double‐blind, parallel, placebo‐controlled study"

Participants

Participants: 120 women were randomised, 120 were analysed

Age: 18‐40

Inclusion criteria:

• Laparoscopically diagnosed endometriosis within 24 months prior to study

• Elected to have leuprolide acetate as a treatment option

• Sexually active

• Not pregnant or breastfeeding

• Intact uterus and at least one ovary in good health

• Not received treatment for endometriosis within previous 3 months

• Not received medroxyprogesterone acetate within previous 6 months

• No history of use of a GnRHa

Exclusion criteria:

• coexisting conditions that might interfere with the conduct or analysis of study

• concomitant disease that might cause pain

• contraindication to leuprolide

• Unable to complete questionnaires

• suspected history of alcohol or drug abuse

Setting: USA

Timing: not stated

Interventions

Leuprolide acetate 3.75mg single IM for 4 weeks (n=60)
versus
Placebo for 4 weeks (n=60)

Outcomes

Pain as defined by VAS and ESSS
Quality of Life SF36

Notes

Intention‐to‐treat analysis: All participants recruited are analysed.

Sample size calculation: not stated.

Funding: not stated.

Authors contacted regarding methods and raw data, awaiting response

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"assigned to groups in the order in which they were enrolled according to a computer generated schedule prepared before the start of the study"

Allocation concealment (selection bias)

Unclear risk

No details were provided of method used to conceal allocation to treatment groups.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

States double‐blind. A placebo injection was used to blind participants, but no other details of blinding of trial personnel or outcome assessors is provided. .

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants completed the trial with no attrition.

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Multicentre study

Participants

Participants: 191 women were randomised and analysed

Stage: II to IV

Mean age:

Inclusion criteria:

• Laparoscopically diagnosed endometriosis

• Over 18 years old

• Patients who have received hormonal therapy

• Patients with persistent diagnosed endometriosis post‐operatively

Exclusion criteria:

• Patients receiving conservative surgery

Setting: Japan

Timing:

Interventions

Buserelin 300mcg OD IN for 6 months (n=69)
versus
Buserelin 300mcg BD IN for 6 months (n=59)
versus
Buserelin 300mcg TDS IN for 6 months (n=63)

Outcomes

Intermenstrual abdominal pain, lumbago, dyspareunia, pain on defecation, pelvic tenderness, flexibility of the uterus, nodules in the posterior cul‐de‐sac, endometrial cyst
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted regarding methods and data, awaiting response

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details

Allocation concealment (selection bias)

Unclear risk

"envelope"

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No details

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All women who were randomised were analysed

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Multicentre, parallel, randomised, double‐blind, double‐dummy study

Participants

Participants: 315 women were randomised, 307 were analysed for safety and 263 were analysed for efficacy

Mean age:not stated

Inclusion criteria:

• Laparoscopically diagnosed endometriosis

• 18‐45 years old

• Not pregnant

• Pap smear negative for malignancy

• Normal menstrual cycle 21‐36 days for previous 4 months

• Weight between 45‐110 kg

Exclusion criteria:

• Amenorrhoea

• Concurrent disease which may interfere with endometriosis or contraindicate the use of androgenic therapy

• Surgical treatment at baseline or within 6 months prior to study

• Use of danazol, androgenic hormones, eostrogens, or progestogens within 3 months prior to study

Setting: Multiple sites within Europe

Timing: not stated

Interventions

Nafarelin 200mcg BD IN + placebo PO for 6 months (n=206)
versus
Danazol 200mg TDS PO + placebo IN for 6 months (n=101)
Note: 8 participants who were randomised never took the study medication

Outcomes

Pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration
AFS score
Adverse effects

Notes

Intention‐to‐treat analysis: No

Sample size calculation: not stated

Funding: Supported in part by Syntex Research, Palo Alto, California, US

Authors contacted regarding methods, awaiting response

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"patients were randomised so that 2 were assigned to receive nafarelin for every 1 assigned to receive danazol". No further information was provided on method used to generate random sequence.

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment groups.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Placebo tablets and spray were used to blind participants.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detail for attrition:

• "307 were included in the safety analyses, of whom 263 also qualified for the efficacy analyses (171 nafarelin and 92 danazol recipients)"

• 25 had been treated < 150 days

• 7 were treated > 150 days but refused or otherwise missed the post‐treatment laparoscopy

• 12 violated the study protocol

• 14 discontinued due to adverse events

• 4 for intercurrent illness

• 4 for personal reasons

• 1 due to ineffective treatment

• 2 lost to follow up

Selective reporting (reporting bias)

Low risk

All pre‐specified primary outcomes were reported on.

Study characteristics

Methods

Trial design: Randomised study

Participants

Participants: 21 women were randomised and analysed

Mean age: 33 +/‐ 5 (SD)

Inclusion criteria:

• Laparoscopically diagnosed endometriosis

• Pelvic pain

Exclusion criteria: not stated
Setting: UK

Timing: not stated

Interventions

Leuprolide acetate 3.75 SC monthly for 3 months (n=10)
versus
Danazol 400mg daily PO for 3 months (n=11)

Outcomes

Pain (Biberoglu + Behrman scale)

Notes

Intention‐to‐treat analysis: Yes

Sample size calculation: not stated

Funding: not stated

Authors contacted regarding methods (blinding) and SD data, awaiting response

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was "computer generated".

Allocation concealment (selection bias)

Low risk

"concealed in an envelope only opened at commencement of treatment"

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No details provided of blinding of participants or trial personnel,

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All women who were randomised were analysed

Selective reporting (reporting bias)

Low risk

All prespecified primary outcomes were reported on, however data is presented as

Study characteristics

Methods

Trial design: Randomised, open study

Participants

Participants: 50 women were randomised, 47 were analysed

Age: 20‐40

Inclusion criteria:

• Laparoscopically diagnosed endometriosis

• No treatment for endometriosis within previous 12 months

Exclusion criteria:

Setting: Italy

Timing:

Interventions

Leuprolide acetate 3.75mg IM monthly for 6 months (n=30)
versus
Danazol 600mg OD PO for 6 months (n=20)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted regarding methods and replied

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"randomly allocated"

Allocation concealment (selection bias)

Low risk

Randomisation done by a pharmacy

Blinding (performance bias and detection bias)
All outcomes

High risk

Open study

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Withdrawals after randomisation <10%
"drop out patients without M.D. consultation"

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Randomised controlled trial

Participants

Participants: 83 women were randomised, 71 were analysed

Mean age: LNG‐IUS = 29.4 +/‐ 4.8 and Lupron = 30.5 +/‐ 6.4 (SD)

Stage: I to IV

Inclusion criteria:

• Laparoscopically and histologically confirmed endometriosis within 3 to 24 months prior to study enrolment

• 18‐40 years old

• Complaints of cyclic chronic pelvic pain with or without dysmenorrhoea

• VAS pain score of greater or equal to 3 during the pretreatment cycle

• Regular menstrual cycle of 25‐35 days for at least 3 months prior to study

Exclusion criteria:

• Hormone treatment within 3 months of entering study

• Long acting progestins or GnRHa within 9 months prior to study

• Pregnant or breastfeeding within 3 months prior to study

• Osteoporosis, coagulation disorders or contra‐indications to LNG‐IUS

Setting: Brazil

Timing: February 2002 to May 2004

Interventions

LNG‐IUS (Mirena) 20mcg/day 5 years IU for 6 months (n=40)
versus
Lupron 3.75mg every 28 days IM for 6 months (n=43)

Outcomes

Pain as defined by VAS score
Psychological general well being index

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted regarding data, awaiting response

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was by "computer generated system".

Allocation concealment (selection bias)

Low risk

"sealed envelopes" were used to conceal allocation to treatment groups.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of participants would not have been possible due to nature of the intervention. Outcome assessors were blinded according to author.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"data analysis did not follow intention‐to‐treat principles" but details given for attrition:

• 6 each from both groups withdrew

• 1 pregnant and 5 did not complete pain diary (LNG‐IUS)

• 6 did not complete pain diary (Lupron)

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: "multi‐centre, open, parallel study"

Participants

Participants: 315 women were randomised and analysed
Mean age: Goserelin = 30.4 and Danazol = 29.7
Stage: I to IV

Inclusion criteria:

• laparoscopically confirmed endometriosis

• AFS score of greater or equal to 2

• Symptomatic (total pelvic score of equal or greater than 3) or asymptomatic disease, with or without infertility

Exclusion criteria:

• Stage IV disease

Setting: USA

Timing: not stated

Interventions

Goserelin 3.6mg every 28 days SC for 24 weeks (n=208)
versus
Danazol 400mg BD PO for 24 weeks (n=107)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration
rAFS score
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted regarding methods and data, awaiting response

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised 2:1 Goserelin: Danazol. No other details are provided of method used to generate random sequence.

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment group.

Blinding (performance bias and detection bias)
All outcomes

High risk

Open study

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"All randomised subjects were included in the overall analysis of treatment outcome"

details given for attrition:

• 15 in Goserelin and 18 in Danazol group withdrew

• 6 in Goserelin and 13 in Danazol group withdrew due to adverse events

Selective reporting (reporting bias)

Low risk

All pre specified primary outcomes were reported on

Study characteristics

Methods

Trial design: Randomised, parallel study

Participants

Participants: 194 women were randomised, 170 were analysed

Mean age:

Inclusion criteria:

• Laparoscopically confirmed endometriosis

• 18 ‐ 45 years old

• Body weight of 45 ‐ 110kg

• Menstrual cycle of 24 ‐ 36 days

• Symptomatic

• Not pregnant

• Negative pap smear test

Exclusion criteria:

• Prescence of amenorrhoea

• Interferring concurrent disease

• Surgical treatment at baseline laparoscopy or within 6 months prior to study

• Gonadal hormone or danazol use within 3 months prior to study

• Simultaneous participation in other studies

Setting: The Netherlands

Timing:

Interventions

Nafarelin 200mcg BD IN + placebo PO for 6 months (n=127)
versus
Danazol 200mg BD PO + placebo IN for 6 months (n=67)

Outcomes

Pain defined by symptoms severity score
AFS score
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Authors contacted regarding methods and data. Letter returned with author unknown at Department

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

randomised 2:1 Nafarelin: Danazol. No other details provided of method used to generate random sequence.

Allocation concealment (selection bias)

Unclear risk

no details provided of method used to conceal allocation to treatment group.

Blinding (performance bias and detection bias)
All outcomes

Low risk

double placebo, double blind

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Details for attrition:

• 20 in Nafarelin and 4 in Danazol group withdrew due to:

• adverse effects 7 (Naf) vs 2 (Dan)

• intercurrent illness 1 (Naf) vs 2 (Dan)

• personal reasons 3 (Naf)

• lost to follow up 3 (Naf)

• lack of drug efficacy 1 (Naf)

• other 5 (Naf)

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design:

Participants

Participants: 81 women were randomised in a 2:1 ratio to leuprolide n=54, or danazol n=27

Mean age: mean age not provided, median age was 32 years (range 19‐41).

Inclusion criteria: Laparoscopically confirmed endometriosis

Exclusion criteria: not stated

Setting: Italy

Timing: 1992 to 1999

Interventions

Intervention: Leuprolide acetate 3.75 mg subcutaneously every 28 days, for 6 months.

Comparison: Danazol 200 mg orally three times a day for 6 months.

Outcomes

rAFS scores

Subjective symptom scores using a numerical scale

Adverse events

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"randomly allocated", no further details provided about method used to generate the random sequence.

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment group.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No details provided of blinding, but unlikely due to nature of routes of administration.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

3 women from leuprolide group (n = 54) and 5 from danazol group (n = 27) withdrew due to "adverse findings"

Selective reporting (reporting bias)

Unclear risk

Prespecified outcomes are reported.

Study characteristics

Methods

Trial design: Randomised study

Participants

Participants: 20 women were randomised, 19 analysed

Mean age: 30.4 +/‐ 3.8 (SEM?)

Inclusion criteria:

• Laparoscopically diagnosed disease

• No treatment within 4 months prior to study

Exclusion criteria: not stated

Setting: UK

Timing: not stated

Interventions

Buserelin 200mcg TDS IN for 6 months (n=10)
versus
Buserelin 300mcg TDS IN for 6 months (n=10 with one withdrawal due to adverse effects)

Outcomes

Symptomatic changes
rAFS score
Adverse effects

Notes

Authors contacted but unable to provide further details as trial was almost 20 years old

Intention‐to‐treat analysis: No

Sample size calculation: not stated

Funding: Hoechst UK supplied the Buserelin used in this study. No further details provided.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"randomly allocated". No further details of method used to generate random sequence.

Allocation concealment (selection bias)

Unclear risk

No details provided of method used to conceal allocation to treatment groups.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

"this paper reports an open study" with no further details.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detail for attrition:

• 1 from Buserelin 300mcg TDS group withdrew after 3 months due to adverse effects

Selective reporting (reporting bias)

Unclear risk

No comparisons between groups for symptomatic changes

Study characteristics

Methods

Trial design: Multi‐centre, randomised trial

Participants

82 women were randomised, 74 were analysed

Mean age:

Inclusion criteria:

Exclusion critiera:

Setting: UK

Timing:

Interventions

Nafarelin 200mcg BD IN + placebo PO for 6 months (n=55)
versus
Danazol 200mg TDS PO + placebo IN for 6 months (n=26)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration

Notes

Authors contacted but unable to provide further details as trial was almost 20 years old

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding (performance bias and detection bias)
All outcomes

Low risk

Patients were blinded and received placebo nasal spray or tablets

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Details for attrition given:

• 8 withdrew:

• Nafarelin = 3 due to side effects, 1 left country, 1 poor compliance

• Danazol = 2 due to side effects, 1 poor compliance

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: "open, randomised comparative study" multicentre

Participants

Participants: 307 women were randomised, 286 were analysed

Age: 18‐40

Stage: I to IV

Inclusion criteria:

• laparoscopically confirmed endometriosis within 12 weeks prior to study enrolment

Exclusion criteria:

• No hormonal agents within 8 weeks prior to study

• No GnRHas or Danazol within 24 weeks prior to study

• No anticoagulants

Setting: Europe

Timing: not stated

Interventions

Goserelin acetate 3.6mg every 28 days SC for 24 weeks (n=204)
versus
Danazol 200mg TDS PO for 24 weeks (n=103)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration
rAFS score
Adverse effects

Notes

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomisation was in the ratio two goserelin: one danazol with each centre having its randomisation list", "The randomised trial of Zoladex and Danazol was a multi centre trial with randomisation envelopes provided by the sponsors ICI to each of the centres as plain sealed envelopes and computerised randomisation lists for each centre" (author's reply)

Allocation concealment (selection bias)

Low risk

"plain, sealed envelopes"

Blinding (performance bias and detection bias)
All outcomes

High risk

Open study

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Details given for attrition:

• 81 in Goserelin and 54 in Danazol group withdrew due to lack of effect, adverse effects, pregnancy and administrative reasons

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Placebo, randomised, parallel study

Participants

34 women were randomised and analysed

Mean age: GnRHa = 31.02 ± 2.5 and Placebo = 32.13 ±1.5 (SD)

Inclusion criteria:

• Laparoscopically diagnosed endometriosis

• Symptomatic

• Surgically or pharmacologically treated in 6 months prior

• Regular menstrual cycle in prior 3 months

• Not pregnant

Exclusion criteria:

• Cardiovascular burden

• Hormone dependent neoplasms

• Osteoporosis

• Bilateral oophorecystectomy

• Abnormal liver and renal tests

Setting: Poland

Timing:

Interventions

GnRHa 50mg OD PO for 12 weeks (n=16)
versus
Placebo PO for 12 weeks (n=18)

Outcomes

Dysmenorrhoea, dyspareunia, pain in pelvic minor

Notes

Author provided additional details on methods

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Centralised randomisation process, computerised allocation according to author

Allocation concealment (selection bias)

Low risk

Sealed, opaque, sequentially numbered, identical envelopes and sequentially numbered, identical containers of identical drugs

Blinding (performance bias and detection bias)
All outcomes

Low risk

Participants, investigators, outcome assessors and clinicians were all blinded according to author

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All women who were randomised were analysed

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Prospective, randomised study

Participants

Participants: 15 women were randomised and analysed

Mean age: 32.1 +/‐ 0.9 (SE)

Inclusion criteria:

• Laparoscopically diagnosed endometriosis within 3 months prior to study

• Infertile women

• Regular menstrual cycles

Exclusion criteria: not stated.

Setting: USA

Timing: not stated

Interventions

Leuprolide 400mcg QDS IN for 26 weeks (n=10)
versus
Danazol 200mg QDS PO for 26 weeks (n=5)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain
rAFS score

Notes

Authors contacted regarding methods and data, awaiting response

Intention‐to‐treat analysis:

Sample size calculation:

Funding:

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised 2:1 ratio Leuprolide: Danazol. Method used to generate the random sequence is not provided.

Allocation concealment (selection bias)

Unclear risk

No details are provided of the method used to conceal allocation to treatment groups.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

No details are provided of blinding of participants or trial personnel.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised participants were analysed

Selective reporting (reporting bias)

Low risk

All prespecified primary outcomes were reported on

Study characteristics

Methods

Trial design: "Parallel, randomized, double placebo design"

Participants

18 women randomised and analysed.

Mean age: Nafarelin = 34.1±1.8 and Danazol = 32.6±1.9

Inclusion criteria: Women with laparoscopically confirmed pelvic endometriosis

Exclusion criteria: not stated

Setting:

Timing:

Interventions

Intranasal nafarelin 200 mcg twice daily with placebo tablets (n=12)

vs

Danazol tablets 200 mg three times daily with placebo nasal spray (n=6)

Outcomes

Serum lipids and lipoproteins

AFS endometriosis score

Notes

Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.

Study characteristics

Methods

Trial design: "double‐blind, multi‐centre, randomised trial"

Participants

270 women were randomised and 253 were analysed

Age: Leuprolide = 31.0 and Danazol = 29.8

Inclusion criteria:

• Laparoscopically diagnosed endometriosis within 4 months prior to study

• Over 18 years of age

• No surgical treatment at time of laparoscopy

• Premenopausal

• Not pregnant or lactating

• Never previously taken GnRHa

• Any other treatment completed at least 3 months prior to study

Setting: USA

Timing:

Interventions

Leuprolide 3.75mg monthly IM + placebo OD PO for 24 weeks (n=134)
versus
Danazol 800mg OD PO + placebo monthly IM for 24 weeks (n=136)

Outcomes

Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness
rAFS score
Analgesic use

Notes

Authors contacted regarding methods and data, awaiting response

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details

Allocation concealment (selection bias)

Unclear risk

No details

Blinding (performance bias and detection bias)
All outcomes

Low risk

Placebo injection and tablets to blind participants and investigators

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Details given for attrition:

• 17 patients were excluded due to:

• failure to meet inclusion criteria 2 (Leu) and 1 (Dan)

• non‐compliance 3 (Leu) and 10 (Dan)

• inadvertent dosing with another patient's designated leuprolide 1

Selective reporting (reporting bias)

Low risk

All primary outcomes stated were reported on

Study characteristics

Methods

Trial design: Prospective randomined controlled trial

Participants

40 randomised, 30 analysed

Ages of participants not stated.

Inclusion criteria: Women with mild, moderatate or severe endometriosis, confirmed by laparoscopy

Exclusion criteria: moderate to severe pelvic adhesive disease, bilateral tubal obstruction, positive pregnancy test

Setting: USA

Timing:

Interventions

Leuprolide acetate 0.1 mg SC daily for three months (n=15)

vs

Danazol 400 mg orally daily for three months (n=15)

Outcomes

AFS score

size of ovarian endometrioma

Notes